WO2018214886A1 - 一种氘代azd9291的晶型、制备方法及用途 - Google Patents

一种氘代azd9291的晶型、制备方法及用途 Download PDF

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WO2018214886A1
WO2018214886A1 PCT/CN2018/087902 CN2018087902W WO2018214886A1 WO 2018214886 A1 WO2018214886 A1 WO 2018214886A1 CN 2018087902 W CN2018087902 W CN 2018087902W WO 2018214886 A1 WO2018214886 A1 WO 2018214886A1
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crystal form
formula
azd9291
deuterated
deuterated azd9291
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PCT/CN2018/087902
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French (fr)
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吴豫生
耿阳
梁阿朋
牛成山
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浙江同源康医药股份有限公司
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Priority to JP2020515809A priority Critical patent/JP6971390B2/ja
Priority to US16/615,771 priority patent/US10882845B2/en
Priority to ES18804966T priority patent/ES2956943T3/es
Priority to EP18804966.2A priority patent/EP3647312B1/en
Publication of WO2018214886A1 publication Critical patent/WO2018214886A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • 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

Definitions

  • the invention relates to a crystal form of deuterated AZD9291, and a preparation method and use of the crystal form belong to the technical field of medicine.
  • the Epidermal Growth Factor Receptor is a transmembrane protein tyrosine kinase of the erbB receptor family.
  • a growth factor ligand eg, epidermal growth factor (EGF)
  • the receptor can homodimerize with an additional EGFR molecule, or with another family member (eg, erbB2 (HER2), erbB3 (HER3), Or erbB4 (HER4)) heterodimerization occurs.
  • HER2 erbB2
  • HER3 erbB3
  • HER4 erbB4
  • Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of key tyrosine residues in the intracellular domain and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival.
  • Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many
  • erbB represented as legitimate targets for anticancer drug development, as many drugs targeting EGFR or erbB2 is now widely used in clinical applications, including Gefitinib (IRESSA TM), erlotinib (TARCEVA TM) and lapatinib (TYKERB TM) and the like. Both erbB receptor signaling and its oncogenesis are provided in New England Journal of Medicine (2008) (No. 358, 1160-1174) and Biochemical and Biophysical Research Communications (2004) (No. 319, 1-11). A detailed discussion of participation in the process.
  • Lung cancer is the world's highest incidence of cancer. It ranks first among all cancers in China, and it is also the cancer with the highest morbidity and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, of which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors.
  • the existing first-generation EGFR inhibitors such as erlotinib and gefitinib have good curative effect on such patients, which can reduce tumors in more than 60% of patients and significantly prolong the progression-free survival of patients. .
  • the vast majority of patients will acquire resistance within 6-12 months. This resistance pattern is a further mutation of EGFR, which reduces its sensitivity to first-generation EGFR inhibitors.
  • T790M The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139).
  • T L-threonine
  • M L-methionine
  • the mutated EGF tyrosine kinase R no longer binds to gefitinib or erlotinib.
  • the first generation of EGFR inhibitors will no longer work, resulting in such patients currently in a state of no drug availability.
  • the first generation of EGFR inhibitors, such as gefitinib and erlotinib, in the T790M mutant cell line H1975 were greater than 3 [mu]M and were essentially inactive.
  • WO2013014448 discloses pyrimidine derivatives which are useful as EGFR inhibitors and their use for the treatment of cancer, wherein G is selected from 4,5,6,7-tetrahydropyrazole [1,5-a]pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo[1,5-a]pyridine-3- Base, R 2 is methyl or methoxy, and the structure is as follows:
  • deuterated AZD9291 compounds have been reported by CN104140418B and CN105237515A, but no reports on the crystalline form of the pharmaceutically acceptable salt of deuterated AZD9291 have been reported.
  • the crystal form is the solid state of the drug.
  • the study of the drug crystal form is the study of the basic state of the drug. Only by having a full and comprehensive understanding of the crystal form of the chemical drug, it is possible to find a drug crystal that is more suitable for treating the disease.
  • Type solid material The crystalline form of the drug can affect the physical and chemical properties of the drug, and directly affect the clinical basis of the drug to play a role in the treatment of disease.
  • the compound of Formula III when the compound of Formula III is metabolized in the body to remove the methyl group on the indole nitrogen, the compound of the formula IV (AZ5104) is formed, and the blood-brain barrier cannot be transmitted, so that the tumor metastasized to the brain is lost. effect. If the methyl group on the indole nitrogen of the compound of formula III is deuterated, the metabolic stability of the methyl group is increased, and the blood concentration and brain concentration in the body are better improved, thereby Achieve better results. Therefore, it is important to study the stable crystal form of the deuterated AZD9291.
  • the present invention is primarily directed to providing a crystalline form of deuterated AZD9291 and providing methods for its preparation and pharmaceutical use.
  • the crystal form of the deuterated AZD9291 provided by the present invention has a structural formula as shown in formula (I) or formula (II).
  • the X-ray powder diffraction obtained by Cu-K ⁇ ray measurement of the crystal form is at 2 ⁇ angle (the unit of 2 ⁇ angle is °): 7.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.4 ⁇ 0.2, 10.3 ⁇ 0.2, 15.1 ⁇ 0.2, 16.3 ⁇ 0.2, 18.7 ⁇ 0.2, 22.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.0 ⁇ 0.2 have diffraction peaks.
  • the crystal form of deuterated AZD9291 provided by the invention has the structural formula as shown in formula (I) or formula (II), and the X-ray powder obtained by Cu-K ⁇ ray measurement is diffracted at an angle of 2 ⁇ (unit is °). 7.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.4 ⁇ 0.2, 10.3 ⁇ 0.2, 15.1 ⁇ 0.2, 16.3 ⁇ 0.2, 17.0 ⁇ 0.2, 17.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.7 ⁇ 0.2, 19.4 ⁇ 0.2, 19.7 ⁇ 0.2, There are diffraction peaks at 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.6 ⁇ 0.2, 22.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 24.8 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.0 ⁇ 0.2.
  • the crystal form of the deuterated AZD9291 provided by the present invention has a structural formula as shown in the formula (I) or the formula (II), and the X-ray powder obtained by Cu-K ⁇ ray measurement is diffracted at a 2 ⁇ angle (unit of 2 ⁇ angle) For °): 7.1 ⁇ 0.2, 8.5 ⁇ 0.2, 9.4 ⁇ 0.2, 10.3 ⁇ 0.2, 12.6 ⁇ 0.2, 14.4 ⁇ 0.2, 15.1 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 17.0 ⁇ 0.2, 17.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.2 ⁇ 0.2, 18.7 ⁇ 0.2, 19.4 ⁇ 0.2, 19.7 ⁇ 0.2, 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.6 ⁇ 0.2, 22.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 24.8 ⁇ 0.2 25.6 ⁇ 0.2, 26.0 ⁇ 0.2, 26.9 ⁇ 0.2, 27.7 ⁇ 0.2, 28.2 ⁇ 0.2, 29.5 ⁇ 0.2, 30.7 ⁇
  • the crystal form of deuterated AZD9291 provided by the present invention has a structural formula as shown in formula (I) or formula (II), and the X-ray powder diffraction pattern obtained by Cu-K ⁇ ray measurement of the crystal form is substantially as shown in Fig. 1 .
  • the invention also provides the use of a crystalline form of deuterated AZD9291 in the manufacture of a medicament for the treatment of cancer.
  • the cancer is non-small cell lung cancer.
  • the preparation method of the crystalline form of deuterated AZD9291 provided by the invention comprises the following steps:
  • the solvent system is methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, water, 1,4-dioxane, t-butyl acetate, acetone/water mixture, Either ethanol/t-butyl acetate mixture or 1,4-dioxane/water mixture.
  • the solvent system is an acetonitrile or acetone/water mixture.
  • the invention has the beneficial effects that the crystal form of the deuterated AZD9291 mesylate salt provided by the invention has stable physical and chemical properties and stable deuteration rate, and ensures the deuteration rate of the deuterated methyl group on the niobium nitrogen, so that It has good metabolic stability in vivo, which makes it have good bioavailability in organisms.
  • oral bioavailability is 30.9%
  • rats are PO (oral) pharmacokinetic experiments
  • the body has a good blood concentration and brain concentration distribution, the highest blood concentration can reach 117ng / mL, AUC can reach 1268h ⁇ ng / mL, which can achieve better results.
  • the single impurities are all below 0.1%, which is in line with the development of API and CMC.
  • Figure 3 is a DSC-TGA spectrum of the deuterated AZD9291 mesylate salt form provided by the present invention.
  • Figure 4 is a liquid chromatogram of the deuterated AZD9291 mesylate salt form provided by the present invention.
  • the synthetic route is as follows:
  • Method 1 Compound D-AZD9291 (5.02 g, 1 mmol) was added to acetonitrile (40 mL), then the solution was warmed to 70 ° C, and methanesulfonic acid (0.96 g, 1 mmol) in acetonitrile (10 mL) was added dropwise. After the addition, the mixture was stirred at 70 ° C for 2 hours, filtered hot, and the filtrate was allowed to stand at room temperature for 10 hours, then filtered, and the solid was collected, washed with acetonitrile, and then dried in a vacuum oven. Dry at 40 ° C to obtain a crystal form.
  • the X-ray powder diffraction analysis of the prepared crystal form of the compound of the formula (I) or the formula (II) is carried out, and the obtained X-ray powder diffraction pattern is shown in Fig. 1.
  • the X-ray powder diffraction peak data is shown in Table 1.
  • the X-ray powder diffraction patterns of the crystalline forms obtained in Process 1 and Method 2 of the present invention are identical.
  • the 2 ⁇ angle value of the X-ray powder diffraction peak has an error range of ⁇ 0.2°. It should be understood that the 2 ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines and between samples, and the range of values may differ by ⁇ 0.2 units, so the recited values are not to be construed as absolute values.
  • a peak having a peak intensity higher than 20% can be selected as the characteristic peak of the crystal form of the present invention.
  • the crystalline form of the compound of the formula (I) or formula (II) obtained has a melting point of 239 to 240 ° C (melting point test). DSC (differential scanning calorimetry) showed a melting point between 249 ° C and 254 ° C.
  • the above experimental results show that the physicochemical properties of the crystal form are stable and the deuteration rate can be kept unchanged.
  • the deuterated AZD9291 crystal form is very suitable for the application of drugs such as preparations.
  • the deuterated AZD9291 mesylate salt form of the present invention is used for oral bioavailability test of rats, and its oral bioavailability can reach 30.9%.
  • the high bioavailability of oral administration proves that this crystal form is suitable for the development of oral preparations.
  • the crystal form of the compound of the formula (I) or the formula (II) obtained by the method 1 or the method 2 of the present invention is not changed in moisture absorption or the like after being left at room temperature for 1 month.
  • HPLC HPLC chart is shown in Fig. 4
  • HPLC detection data is shown in Table 3. Its purity is as high as 99.83%, and the content of each single impurity is below 0.1%, which is very suitable for the subsequent development of drug substances and preparations as well as subsequent pharmacokinetic experiments and zoological experiments.
  • the deuterated AZD9291 mesylate salt form prepared by the present invention was placed in a laboratory at room temperature, and the stability at room temperature was examined. The purity was measured by HPLC, and the results are shown in Table 4.
  • the crystal form prepared by the present invention has good stability at room temperature, and the purity is consistent with HPLC detection.
  • the present invention provides a deuterated AZD9291 crystalline form which acts as an epidermal growth factor receptor EGFR inhibitor, particularly an EGFR mutant inhibitor.
  • the present invention provides a deuterated AZD9291 crystal form which can be used for the preparation of a medicament for modulating EGFR tyrosine kinase activity or treating EGFR-related diseases, which inhibits activation or resistance mutations of one or more EGFR, such as L858R activating mutant, Exon19 deletion EGFR activating mutants, T790M resistant mutants, especially for cancer treatment, such as non-small cell lung cancer.

Abstract

本发明属于医药技术领域，具体公开了一种氘代AZD9291的晶型，以及该晶型的制备方法和用途。所述氘代AZD9291的晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、15.1±0.2、16.3±0.2、18.7±0.2、22.0±0.2、25.6±0.2、26.0±0.2处具有衍射峰。本发明还公开了所述的氘代AZD9291的晶型在制备用于治疗癌症的药物中的用途。本发明提供的氘代AZD9291的晶型理化性质稳定，代谢稳定性好，其在体内的血药浓度和脑部的浓度显著提高，可达到更好的疗效。

Description

一种氘代AZD9291的晶型、制备方法及用途 技术领域
本发明涉及一种氘代AZD9291的晶型，该晶型物的制备方法及用途，属于医药技术领域。
背景技术
表皮生长因子受体EGFR(Epidermal Growth Factor Receptor)是erbB受体家族的跨膜蛋白酪氨酸激酶的一种。当与生长因子配体(例如表皮生长因子(EGF))结合时，受体可以与附加的EGFR分子发生同源二聚，或者与另一家族成员(例如erbB2(HER2)、erbB3(HER3)、或者erbB4(HER4))发生异源二聚。erbB受体的同源二聚和/或异源二聚导致胞内域中关键酪氨酸残基的磷酸化，并且导致对参与细胞增殖和生存的许多细胞内信号传导通路的刺激。erbB家族信号传导的失调促进增殖、侵入、转移、血管生成和肿瘤细胞生存，并且已在许多的人类癌症中(包括肺癌、头颈部癌和乳腺癌等)得到描述。
因此，以erbB家族为代表的作为抗癌药物开发的合理靶点，如靶向EGFR或erbB2的许多药物现在已经在临床上广泛的应用，包括吉非替尼(IRESSA TM)、厄洛替尼(TARCEVA TM)和拉帕替尼(TYKERB TM)等。New England Journal of Medicine(2008)(第358期，1160-1174)和Biochemical and Biophysical Research Communications(2004)(第319期，1-11)中都提供了对erbB受体信号传导及其在肿瘤发生中的参与的详细论述。
肺癌是全球发病率最高的癌症，在中国肺癌发病率位居所有癌症中第一位，也是中国发病率和死亡率最高的癌症。在中国的肺癌病人中，大约30％的病人具有EGFR突变，其中L858R和外显子19缺失突变占大约90％以上，这类病人对EGFR抑制剂更为敏感。现有已上 市第一代EGFR抑制剂如厄洛替尼、吉非替尼等对这类病人有较好的疗效，能够使其中60％以上的病人肿瘤缩小，明显延长病人的无进展生存期。但绝大多数病人在6-12个月会获得耐药，这种耐药模式是EGFR的进一步突变，这就降低了其对第一代EGFR抑制剂的敏感性。这些突变中最常见的是所谓的“gatekeeper”突变T790M(Science,2004,Vol.304,1497-1500；New England Journal of Medicine 2004,350,2129-2139)。由原来在该位点的L-苏氨酸(T)为L-甲硫氨酸(M)所替代，变异后的EGF酪氨酸激酶R不再与吉非替尼、厄洛替尼结合，从而使第一代EGFR抑制剂将不再起效，导致这类病人目前处于无药可用的状态。临床发现对第一代EGFR抑制剂产生耐药的病人中有50％检测都有EGFR T790M突变。在T790M突变细胞系H1975中第一代EGFR抑制剂，如吉非替尼和厄洛替尼，均大于3μM，基本没有活性。
为了提高对耐药EGFR T790M等突变的抑制活性，WO2013014448公开了可作为EGFR抑制剂的嘧啶衍生物及其治疗癌症的用途，其中，G选自4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基、1H-吲哚-3-基、1-甲基-1H-吲哚-3-基或吡唑并[1,5-a]吡啶-3-基，R 2为甲基或甲氧基，结构如下：
Figure PCTCN2018087902-appb-000001
在该专利公开文献中，如式Ⅲ所示的化合物(AZD9291)已于2015年11月13日获美国FDA加速批准(商品名：Tagrisso，AZD9291)上市，用于治疗表皮生长因子受体EGFR T790M突变阳性的晚期非小细胞肺癌患者。
Figure PCTCN2018087902-appb-000002
目前，CN104140418B和CN105237515A等均报道了一些氘代AZD9291化合物，但是还没有见到关于氘代AZD9291的可药用盐的晶型专利的报道。晶型是药物存在的固体物质状态，药物晶型研究就是对药物基础状态的研究，只有对化学药物晶型状态有了比较充分和全面的认识，才有可能寻找更合适于治疗疾病的药物晶型固体物质。药物晶型可以影响药物的理化性质，直接影响药物临床发挥治疗疾病作用的基础。同时，由于一些药物本身的溶解性等问题，将其做成可以药用接受的盐，能够大大改善其溶解性，提高药物的吸收利用。本公司一直从事肺癌药物的研究，很早就已经开始了EGFR靶点的药物研究，取得了一系列的研究成果，如专利CN102659692、US08916572、CN107382879、WO2017219500和WO2018050052等等。在我们的研究过程中发现，式Ⅲ所示化合物可以通过血脑屏障进入大脑，并且文献Clin.Cancer Res.2016,22(20),5130-5140中也报道了此结果。但是，当式Ⅲ所示的化合物在体内代谢脱掉吲哚氮上的甲基后生成的式Ⅳ所示的化合物(AZ5104)，就不能透过血脑屏障，因此对脑部转移的肿瘤失去作用。如果将式Ⅲ所示的化合物吲哚氮上的甲基进行氘代，这样就增加了此甲基的代谢稳定性，其在体内的血药浓度和脑部的浓度得到更好的提高，从而达到更好的疗效。因此，研究氘代AZD9291的稳定晶型具有重要意义。
Figure PCTCN2018087902-appb-000003
发明内容
本发明主要是提供一种氘代AZD9291的晶型，并提供了其制备方法和药物用途。
本发明提供的一种氘代AZD9291的晶型，结构式如式(Ⅰ)或式(Ⅱ)所示，
Figure PCTCN2018087902-appb-000004
该晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度(2θ角度的单位为°)为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、15.1±0.2、16.3±0.2、18.7±0.2、22.0±0.2、25.6±0.2、26.0±0.2处具有衍射峰。
本发明提供的一种氘代AZD9291的晶型，结构式如式(Ⅰ)或式(Ⅱ)所示，该晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度(单位为°)为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、15.1±0.2、16.3±0.2、17.0±0.2、17.3±0.2、17.7±0.2、18.7±0.2、19.4±0.2、19.7±0.2、20.2±0.2、20.7±0.2、21.6±0.2、22.0±0.2、22.8±0.2、23.5±0.2、24.2±0.2、24.8±0.2、25.6±0.2、26.0±0.2处具有衍射峰。
本发明提供的一种氘代AZD9291的晶型，结构式如式(Ⅰ)或式(Ⅱ)所示，该晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度(2θ角度的单位为°)为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、12.6±0.2、14.4±0.2、15.1±0.2、15.6±0.2、16.3±0.2、17.0±0.2、17.3±0.2、17.7±0.2、18.2±0.2、18.7±0.2、19.4±0.2、19.7±0.2、20.2±0.2、20.7±0.2、21.6±0.2、22.0±0.2、22.8±0.2、23.5±0.2、24.2±0.2、24.8±0.2、25.6±0.2、26.0±0.2、26.9±0.2、27.7±0.2、28.2±0.2、29.5±0.2、30.7±0.2、31.7±0.2、32.5±0.2、33.1±0.2、33.8±0.2、34.6±0.2、34.9±0.2、35.6±0.2、37.9±0.2、38.7±0.2处具有衍射峰。
本发明提供的一种氘代AZD9291的晶型，结构式如式(Ⅰ)或 式(Ⅱ)所示，该晶型使用Cu-Kα射线测量得到的X射线粉末衍射图案基本如图1所示。
本发明还提供了氘代AZD9291的晶型在制备用于治疗癌症的药物中的用途。
优选地，所述癌症是非小细胞肺癌。
本发明提供的氘代AZD9291的晶型的制备方法，包括下述步骤：
1)将氘代AZD9291化合物加入到溶剂体系中，升温到40～80℃，然后再向所述溶剂体系中加入甲磺酸，甲磺酸的摩尔数是氘代AZD9291化合物的1～1.5倍，保持40～80℃，反应1～5小时，然后热过滤；
2)将热过滤后的滤液在室温下自然冷却，析出晶体；
3)过滤，收集晶体物，然后所述晶体物经洗涤、干燥，得到氘代AZD9291甲磺酸盐的晶型物。
作为一种具体的实施方式，所述的溶剂体系为甲醇、乙醇、异丙醇、丙酮、乙腈、四氢呋喃、水、1,4-二氧六环、乙酸叔丁酯、丙酮/水混合液、乙醇/乙酸叔丁酯混合液、1,4-二氧六环/水混合液中的任一种。
作为一种优化的实施方式，所述的溶剂体系为乙腈或丙酮/水混合液。
作为一种优化的实施方式，所述丙酮/水混合液中丙酮与水的体积比为：丙酮/水＝10:1～15:1。
本发明的有益效果是：本发明提供的氘代AZD9291甲磺酸盐的晶型物，物理化学性质稳定，氘代率稳定，保证了吲哚氮上氘代甲基的氘代率，使其在体内的代谢稳定性好，使其在生物体内有很好的生物利用度，如在大鼠实验中，口服生物利用度为30.9％，同时大鼠PO(口服)药代动力学实验时，体内的有很好的血药浓度和脑部的浓度分布，最高血药浓度能达到117ng/mL，AUC可以达到1268h·ng/mL，从而能达到了更好的疗效。并且，单杂均在0.1％以下，非常符合API和CMC的开发。
附图说明
图1是本发明提供的氘代AZD9291甲磺酸盐晶型的X射线粉末衍射图谱；
图2是本发明提供的氘代AZD9291甲磺酸盐晶型经过6个月的稳定性加速实验后的X射线粉末衍射图谱；
图3是本发明提供的氘代AZD9291甲磺酸盐晶型的DSC-TGA图谱；
图4是本发明提供的氘代AZD9291甲磺酸盐晶型的液相图谱。
具体实施方式
下面对本发明的技术方案进行详细说明。
式(Ⅰ)或式(Ⅱ)所示化合物晶型的制备
Figure PCTCN2018087902-appb-000005
1)合成氘代AZD9291(D-AZD9291)
合成路线如下：
Figure PCTCN2018087902-appb-000006
将50毫克中间体B，130毫克中间体A与35毫克一水对甲苯磺酸溶解在5毫升2-戊醇中，然后升温至50摄氏度，氮气保护下搅拌过夜，TLC显示原料基本消失，反应液旋干，然后加入20毫升二氯甲烷和20毫升饱和碳酸钠水溶液，分层后，再用20毫升二氯甲烷洗涤水层两次，合并有机层，干燥、旋干，过柱分离得到50毫克D-AZD9291产品。D-AZD9291的核磁分析数据如下： 1H-NMR(400MHz,d 6-DMSO)δ10.22(s,1H),9.16(s,1H),8.68(s,1H),8.33(d,J＝5.2Hz,1H),8.24(d,J＝8.0Hz,1H),7.90(s,1H),7.53(d,J＝8.2Hz,1H),7.26-7.22(m,2H),7.17-7.13(m,1H),7.04(s,1H),6.46-6.40(m,1H),6.30-6.25(m,1H),5.79-5.76(m,1H),3.86(s,3H),2.90-2.37(m,2H),2.72(s,3H),2.30-2.27(m,2H),2.20(s,6H)；m/z(ES+)(M+H) +＝503.3。
2)制备式(Ⅰ)或式(Ⅱ)所示化合物晶型
Figure PCTCN2018087902-appb-000007
方法1：将化合物D-AZD9291(5.02g,1mmol)加入到乙腈(40mL)中，然后将此溶液升温到70℃，将甲磺酸(0.96g,1mmol)的乙腈溶液(10mL)滴加到上述溶液中，加完后，将此混合液在70℃搅拌2个小时，热过滤，将滤液室温下静置析晶10个小时，然后过滤，收集固体，用乙腈洗涤，然后在真空干燥箱中40℃干燥，获得晶型物。 1H-NMR(400MHz,d 6-DMSO)δ9.54(s,1H),9.22(s,1H),8.78(s,1H),8.53(s,1H),8.33-8.30(m,2H),7.94(s,1H),7.53(d,J＝8.2Hz,1H),7.26-7.22(m,2H),7.17-7.13(m,1H),7.01(s,1H),6.72-6.65(m,1H),6.36-6.31(m,1H),5.83-5.80(m,1H),3.89(s,3H),3.30-3.21(m,4H),2.81(s,6H),2.62(s,3H),2.33(s,3H)；m/z(ES+)(M+H) +＝503.3。
方法2：将化合物D-AZD9291(5.02g,1mmol)加入到丙酮(45mL)和水(4.5mL)中，然后将此溶液升温到50℃，将甲磺酸(0.96g,1mmol)的丙酮溶液(10mL)滴加到上述溶液中，加完后，将此混合液在50℃搅拌2个小时，热过滤，将滤液室温下静置析晶10个小时，然后过滤，收集固体，用丙酮与水的混合物洗涤(V 丙酮/V 水＝10/1)，然后在真空干燥箱中40℃干燥，获得晶型物。 1H-NMR(400MHz,d 6-DMSO)δ9.54(s,1H),9.22(s,1H),8.78(s,1H),8.53(s,1H),8.33-8.30(m,2H),7.94(s,1H),7.53(d,J＝8.2Hz,1H),7.26-7.22(m,2H),7.17-7.13(m,1H),7.01(s,1H),6.72-6.65(m,1H),6.36-6.31(m,1H),5.83-5.80(m,1H),3.89(s,3H),3.30-3.21(m,4H),2.81(s,6H),2.62(s,3H),2.33(s,3H)；m/z(ES+)(M+H) +＝503.3。
其中，中间体A的合成，路线如下：
Figure PCTCN2018087902-appb-000008
化合物2的合成：氮气保护下，向500mL的三口瓶中加入化合物1(15g,128.2mmol)和260mL的四氢呋喃，然后降温到0℃，分 批加入氢化钠(7.7g,192.0mmol)，加完后，0℃反应1小时，然后将氘代碘甲烷(27.8g,192.0mmol)滴加到反应液中，保持反应液的温度在0℃。加完氘代碘甲烷后，缓慢升温到室温，继续反应10小时，将冰水(200mL)滴加到反应混合物中，保持反应体系0℃，此混合物用乙酸乙酯萃取(100mL×3)，将有机相混合，干燥，过柱得15g混合物2。m/z(ES+)(M+H) +＝135.1。
中间体A的合成：氮气保护下，向250mL的三口瓶中加入化合物2(15g,111.9mmol)、化合物3(20.0g,134.3mmol)、三氯化铁(21.7g,134.3mmol)和150mL的DME，然后回流过夜，反应结束后，将反应体系降温到室温，过滤，滤饼用50mL的甲醇洗涤3次，然后将有机相旋干，过柱得到13.1g的中间体A。 1H-NMR(400MHz,d 6-DMSO)δ7.35(2H,m),7.64(1H,dd),7.88(1H,d),8.45-8.52(1H,m),8.56(1H,s),8.62(1H,d)；m/z(ES+)(M+H) +＝247.1。
中间体B的合成，路线如下：
Figure PCTCN2018087902-appb-000009
B1-2的合成：原料B1-1称取50g，加入500ml甲醇全溶解，加入Pd/C 10g，35℃下氢化反应两天。点板监控，原料反应完毕，处理。直接滤除Pd/C，旋干甲醇相得到粗品39g，直接投下一步。
B1-3的合成：原料B1-2取39g，加入到500ml的浓硫酸中，冰盐浴下加入。控制温度在10℃以下搅拌全溶。保持温度10℃以下加入1ep硝酸钾，室温下搅拌过夜。次日，倒入冰水中，用氨水调节 PH>7，乙酸乙酯萃取，干燥，过柱，得到44g产品。 1H-NMR(CDCl 3)δ7.39(d,J＝7.2Hz,1H),6.63(d,J＝12.4Hz,1H),3.94(s,3H),3.90(broad,2H)。
B1-4的合成：原料B1-3取20g，加入到500ml的二氯甲烷中，冰盐浴冷却到-5℃。滴加1.1eq的二碳酸二叔丁酯的二氯甲烷溶液，滴毕，加入0.2eq的DMAP。自然升温到室温，搅拌过夜。次日，点板，反应完毕，过柱，得到24g黄色固体。 1H-NMR(CDCl 3)δ8.89(s,1H),6.97(s,1H),6.71(d,J＝12.4Hz,1H),3.97(s,3H),1.53(s,9H)；m/z(ES+)(M+H) +＝285.0。
B1-5的合成：原料B1-4取13.5g，加入到200ml的DMA中，搅拌下全溶。再加入2eq的N,N,N’-三甲基乙二胺和3eq的DIEA，升温到110℃搅拌过夜。次日，反应完毕。处理，得到22g油状物粗品，直接投下一步。 1H-NMR(CDCl 3)δ8.54(s,1H),6.85(s,1H),6.60(s,1H),3.90(s,3H),3.22(t,J＝6.8Hz,2H),2.81(s,3H),2.55(t,J＝7.2Hz,2H),2.26(s,6H),1.49(s,9H)；m/z(ES+)(M+H) +＝369.3。
B1-6的合成：原料B1-5取22g，加入到400ml的乙酸乙酯中，搅拌下全溶，再加入4.07g的Pd/C，20℃下氢化反应过夜。次日，原料反应完毕，直接滤除Pd/C，浓缩，得到粗品17g黑色油状物，直接投下一步。 1H-NMR(CDCl 3)δ7.517(s,1H),6.941(s,1H),6.61(s,1H),4.10(m,2H),3.76(s,3H),2.92(m,2H),2.62(s,3H),2.40(m,2H),2.27(s,6H),1.49(s,9H)；m/z(ES+)(M+H) +＝339.4。
B1-7的合成：原料B1-6有17.3g，加入500ml的二氯甲烷和1.2eq的DIEA，冰盐浴冷却到-5℃，氩气保护。滴加1.1eq的丙烯酰氯，滴毕，自然升温到室温。3小时后，反应完毕。直接低温下旋蒸浓缩除去溶剂。得到23g左右粗品。直接投下一步。
中间体B的合成：原料B1-7有23g，加入到50ml的THF中，冰盐浴冷却到-5℃。浓盐酸100ml，控制温度低于10℃，搅拌2小时后，点板反应完毕。处理，过柱。得到5.2g产品。 1H-NMR(CDCl 3)δ10.10(s,1H),7.97(s,1H),6.68(s,1H),6.41-6.21(m,2H),5.65(m,1H),3.81(s,3H),3.76(s,2H),2.82(m,2H),2.65(s,3H),2.20(s,6H)；m/z(ES+)(M+H) +＝293.3。
对制备得到的式(Ⅰ)或式(Ⅱ)所示化合物的晶型进行X-射线粉末衍射分析，得到的X射线粉末衍射图谱见图1所示。X-射线粉末衍射峰数据如表1所示。本发明方法1和方法2获得的晶型物的X射线粉末衍射图谱一致。
表1
Figure PCTCN2018087902-appb-000010
Figure PCTCN2018087902-appb-000011
在表1中，X-射线粉末衍射峰的2θ角度值，其误差范围为±0.2°。应该理解，X射线粉末衍射图的2θ值可在机器之间和样品之间稍有变化，其数值范围可能相差在±0.2个单位内，因此所引用的数值不能解释为绝对值。
考虑到2θ角度的表示的峰的强度有高有低，尤其是一些峰的强度低于最强峰的20％，其表征的数据准确度受仪器条件的影响较大，可能出现较大的误差，因此可以选取峰强高于20％的峰值作为本发明晶型的特征峰。
制备得到的式(Ⅰ)或式(Ⅱ)所示化合物的晶型的熔点为239～240℃(熔点仪测试)。DSC(差示扫描量热法)显示其熔点在249℃～254℃之间。
进一步还测定了式(Ⅰ)或式(Ⅱ)所示化合物的晶型的稳定性，所用仪器为药品加速稳定性试验箱；加速试验条件为40℃，相对湿度75％。测试结果见表2。
表2
Figure PCTCN2018087902-appb-000012
Figure PCTCN2018087902-appb-000013
将式(Ⅰ)或式(Ⅱ)所示化合物的晶型物在药品加速稳定性试验箱完成六个月的加速试验后，取样进行X-射线粉末衍射分析，得到的X射线粉末衍射图谱见图2所示。
对比图1和图2可以得出，图1与图2图形一致，2θ角度值在仪器的误差范围内保持一致，表明本发明的晶型物在经过6个月的加速试验后，晶型保持一致。
以上实验结果说明，本晶型理化性质稳定，氘代率能够保持不变，此氘代AZD9291晶型非常适合在接下来制剂等药物研发方面的应用。
同时，我们还对本发明的氘代AZD9291甲磺酸盐晶型物进行了差示扫描量热法(DSC)和热重分析法(TGA)等研究，研究结果如图3所示。从DSC-TGA图可以看出，本发明的晶型物溶剂残留很低，样品纯度高。非常适用于后续药学研究。
并且，将本发明的氘代AZD9291甲磺酸盐晶型物用于大鼠的口服生物利用度试验，其口服生物利用度可达到30.9％。口服生物利用度高，证明此晶型物适用于口服制剂的开发。
采用本发明方法1或方法2制得的式(Ⅰ)或式(Ⅱ)所示化合物的晶型，在室温下放置1个月未见吸潮等性状改变。同时，通过加速实验，发现其理化性质也非常稳定。通过HPLC检测(HPLC图谱见图4)，HPLC检测数据如表3。其纯度高达99.83％，同时，每一个单一杂质的含量均在0.1％以下，非常适合用于后续的原料药和制剂的研发以及后续药物代谢动力学实验与动物学实验。
表3
Figure PCTCN2018087902-appb-000014
Figure PCTCN2018087902-appb-000015
将本发明制备的氘代AZD9291甲磺酸盐晶型物敞口平摊放置在室温下的实验室，考察室温下的稳定性，纯度用HPLC检测，结果见表4。
从表中结果可知，本发明制备的晶型物室温下稳定性好，纯度用HPLC检测保持一致。
表4
Figure PCTCN2018087902-appb-000016
本发明提供的氘代AZD9291晶型，其可作为表皮生长因子受体EGFR抑制剂，特别是EGFR突变体抑制剂。
本发明提供的氘代AZD9291晶型，可用于制备调节EGFR酪氨酸激酶活性或治疗EGFR相关疾病药物，其抑制一种或多种EGFR的激活或抗性突变，例如L858R激活突变体、Exon19缺失EGFR激活突变体、T790M抗性突变体，尤其适用于癌症治疗，如非小细胞肺癌。

Claims (9)

  1. 一种氘代AZD9291的晶型，其特征在于，结构式如式(Ⅰ)或式(Ⅱ)所示：
    Figure PCTCN2018087902-appb-100001
    该晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度(单位为°)为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、15.1±0.2、16.3±0.2、18.7±0.2、22.0±0.2、25.6±0.2、26.0±0.2处具有衍射峰。
  2. 一种氘代AZD9291的晶型，其特征在于，结构式如式(Ⅰ)或式(Ⅱ)所示：
    Figure PCTCN2018087902-appb-100002
    该晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度(单位为°)为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、15.1±0.2、16.3±0.2、17.0±0.2、17.3±0.2、17.7±0.2、18.7±0.2、19.4±0.2、19.7±0.2、20.2±0.2、20.7±0.2、21.6±0.2、22.0±0.2、22.8±0.2、23.5±0.2、24.2±0.2、24.8±0.2、25.6±0.2、26.0±0.2处具有衍射峰。
  3. 一种氘代AZD9291的晶型，其特征在于，结构式如式(Ⅰ)或式(Ⅱ)所示：
    Figure PCTCN2018087902-appb-100003
    该晶型使用Cu-Kα射线测量得到的X射线粉末衍射在2θ角度(单位为°)为：7.1±0.2、8.5±0.2、9.4±0.2、10.3±0.2、12.6±0.2、14.4±0.2、15.1±0.2、15.6±0.2、16.3±0.2、17.0±0.2、17.3±0.2、17.7±0.2、18.2±0.2、18.7±0.2、19.4±0.2、19.7±0.2、20.2±0.2、20.7±0.2、21.6±0.2、22.0±0.2、22.8±0.2、23.5±0.2、24.2±0.2、24.8±0.2、25.6±0.2、26.0±0.2、26.9±0.2、27.7±0.2、28.2±0.2、29.5±0.2、30.7±0.2、31.7±0.2、32.5±0.2、33.1±0.2、33.8±0.2、34.6±0.2、34.9±0.2、35.6±0.2、37.9±0.2、38.7±0.2处具有衍射峰。
  4. 权利要求1-3任一所述的氘代AZD9291的晶型在制备用于治疗癌症的药物中的用途。
  5. 根据权利要求4所述的氘代AZD9291的晶型的用途，其中所述癌症是非小细胞肺癌。
  6. 一种如权利要求1至3任一项所述的氘代AZD9291的晶型的制备方法，包括下述步骤：
    1)将氘代AZD9291化合物加入到溶剂体系中，升温到40～80℃，然后再向所述溶剂体系中加入甲磺酸，甲磺酸的摩尔数是氘代AZD9291化合物的1～1.5倍，保持40～80℃，反应1～5小时，然后热过滤；
    2)将热过滤后的滤液在室温下自然冷却，析出晶体；
    3)过滤，收集晶体物，然后所述晶体物经洗涤、干燥，得到氘代AZD9291甲磺酸盐的晶型物。
  7. 根据权利要求6所述的晶型的制备方法，所述的溶剂体系为甲醇、乙醇、异丙醇、丙酮、乙腈、四氢呋喃、水、1,4-二氧六环、乙酸叔丁酯、丙酮/水混合液、乙醇/乙酸叔丁酯混合液、1,4-二氧六环 /水混合液中的任一种。
  8. 根据权利要求7所述的晶型的制备方法，所述的溶剂体系为乙腈或丙酮/水混合液。
  9. 根据权利要求8所述的晶型的制备方法，所述丙酮/水混合液中丙酮与水的体积比为：丙酮/水＝10:1～15:1。
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