WO2018177276A1 - 一种微管蛋白抑制剂的a晶型 - Google Patents

一种微管蛋白抑制剂的a晶型 Download PDF

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WO2018177276A1
WO2018177276A1 PCT/CN2018/080617 CN2018080617W WO2018177276A1 WO 2018177276 A1 WO2018177276 A1 WO 2018177276A1 CN 2018080617 W CN2018080617 W CN 2018080617W WO 2018177276 A1 WO2018177276 A1 WO 2018177276A1
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butyl
methylene
dione
fluorophenyl
tert
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PCT/CN2018/080617
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English (en)
French (fr)
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唐田
彭江华
靳如意
杨经安
佘琴
石涛
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深圳海王医药科技研究院有限公司
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    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • 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 belongs to the technical field of medicine, in particular to a new crystal form of a tubulin inhibitor.
  • anti-tumor drugs have made considerable contributions to prolonging the survival time of patients and improving their quality of life.
  • drugs acting on microtubules have a very important position in oncology drugs.
  • the current clinical drugs are affected by the following unfavorable problems: poor water solubility, unfavorable drug administration, and easy to cause allergic reactions, serious toxic side effects, and acquired drug resistance, resulting in reduced efficacy, complicated chemical structure, and difficulty in synthesis.
  • the sources are scarce, limiting their further use.
  • Chinese patent application CN106565686A discloses a novel small molecule tubulin inhibitor of simple structure. Since the drug molecules of different crystal forms have significant differences in solubility, melting point, dissolution rate, bioavailability, etc., preparation of a drug crystal form having a certain melting point, good chemical stability, high temperature resistance, etc. will be beneficial to the drug. Preparation and application of the formulation.
  • VDA-1 has the structure shown in formula (I):
  • Form A of the VDA-1 are characterized by melting point, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and infrared spectroscopy (IR).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • IR infrared spectroscopy
  • the A crystal form when X-ray powder diffraction is performed with a Cu radiation source, the A crystal form includes characteristic diffraction peaks at 6.6 ⁇ 0.2, 9.7 ⁇ 0.2, and 16.0 ⁇ 0.2 (°) at 2 ⁇ , and the relative of these peaks The intensity (I/I 0 ) is greater than or equal to 30%. Further, the crystal may further comprise, in X-ray powder diffraction, at 13.4 ⁇ 0.2, 16.3 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 25.5 ⁇ 0.2, 25.9 ⁇ 0.2, 26.5 at 2 ⁇ . Characteristic diffraction peaks of ⁇ 0.2 (°), the relative intensities of these peaks are all greater than or equal to 16% (see Figure 1). Where " ⁇ 0.2°" is the allowable measurement error range.
  • the Form A of the present invention can be characterized by an X-ray powder diffraction pattern. It is characterized in that its X-ray powder diffraction pattern has the characteristic peak represented by the above 2 ⁇ , as shown in Table 1, and its relative intensity is close to the following values.
  • the term "proximity” as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative intensity is highly dependent on the measurement conditions.
  • the relative intensity value may be a value within a certain range, preferably a range selected from the range of ⁇ 25% of the value shown in Table 1, and more preferably a range of ⁇ 10% of the value shown in Table 1.
  • the above A crystal form has the X-ray powder diffraction pattern shown in Fig. 1.
  • the present invention characterizes the Form A of VDA-1 using differential scanning calorimetry (DSC) techniques (see Figure 2), wherein the maximum endotherm with differential scanning calorimetry is 146.5 °C.
  • DSC differential scanning calorimetry
  • the invention uses thermogravimetric analysis technology to characterize the crystal form of VDA-1 (see Fig. 3), wherein the thermogravimetric diagram (TG) shows a weight loss of 1.0% at 127.1 °C, indicating that the adsorbed water is lost at this temperature. . The weight loss at 235.9 ° C exceeded 16%, indicating that the compound degraded as the temperature increased.
  • Another object of the present invention is to provide a process for the preparation of VDA-1 Form A.
  • a final object of the present invention is to provide the use of VDA-1 Form A for the preparation of a medicament for the treatment of hyperproliferative diseases.
  • the crude product of VDA-1 is first prepared, and then the crude material is crystallized by the recrystallization method of the present invention to obtain a new crystal form, and the melting point measurement, X-ray is performed on the crystal.
  • a process for preparing the VDA-1A crystalline form comprises: adding a crude VDA-1 to ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide and tetrahydrofuran In a mixed solvent or added to a mixed solvent of C3-C4 alkyl ketone and tetrahydrofuran, heated to reflux until dissolved; after the solution is clarified, the temperature is lowered to precipitate a solid, and the solid is collected by filtration, and the collected solid is air-dried to obtain A crystal. type.
  • the ketone is selected from the group consisting of acetone, methyl ethyl ketone and n-butyl ketone, etc., a preferred solvent mixture of ethyl acetate and tetrahydrofuran, a mixed solvent of acetone and tetrahydrofuran; ethyl acetate, dimethyl sulfoxide, N, N - the volume ratio (V / V) of dimethylformamide, ketone and tetrahydrofuran is 1:1 to 1:5; the ratio of the crude product to the solvent is 1 (g) by weight to volume ratio (W/V). : 5 to 30 (ml), preferably 1:10 (g/ml).
  • the solution is preferably heated to 50 to 80 ° C, more preferably ethyl acetate, a mixed solvent of a C3-C4 alkyl ketone and a tetrahydrofuran, and heated to 60 ° C; according to this embodiment, the precipitation is carried out for 2 to 8 hours, more preferably 4 hours.
  • the precipitation temperature is 0 to 40 ° C, preferably 5 to 15 ° C.
  • the drying temperature is 30 to 60 ° C, preferably 45 ° C.
  • a pharmaceutical composition comprising Form A of Form V of the present invention, the pharmaceutical composition comprising the novel crystalline form compound and optionally a pharmaceutically acceptable carrier and/or form Agent.
  • the pharmaceutical composition can be further formulated into a form for administration according to a conventional formulation method, including an oral or parenteral administration form.
  • a therapeutically effective amount of Form A of VDA-1 should be included.
  • therapeutically effective amount is meant that at this dose, the compounds of the invention are capable of ameliorating or alleviating the symptoms of the disease, or are capable of inhibiting or blocking the progression of the disease.
  • the A crystal form of VDA-1 can be used alone for the preparation of a medicament for treating a proliferative disease, or can be prepared in combination with other therapeutic agents to synergistically.
  • the present invention produces (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]-6-(( E)-3-(3-fluorophenyl)-2-propenylene)piperazin-2,5-dione (VDA-1) Form A, which has a stable morphology and a defined melting point, chemically stable Good in properties and high in temperature resistance, the A crystal form of VDA-1 has the properties required for preparation of the preparation, and is convenient to store, simple in production operation, and easier to control in quality.
  • the crystalline form A of VDA-1 of the present invention is for treating a hyperproliferative disease.
  • the hyperproliferative disease is cancer, including but not limited to non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer. , pancreatic cancer, ovarian cancer, breast cancer, glioma, brain cancer or neck cancer.
  • Figure 1 is an X-ray diffraction pattern of Form A of VDA-1;
  • Figure 2 is a DSC pattern of Form A of VDA-1
  • Figure 3 is a TG map of Form A of VDA-1
  • Figure 4 is an IR spectrum of Form A of VDA-1
  • Figure 5 is an HPLC chromatogram of Form A of VDA-1.
  • the preparation method of the crude VDA-1 includes the steps (1) to (3):
  • Example 2.1 The method according to Example 2.1, wherein the solvent, the heating temperature, the precipitation temperature and time, and the drying temperature are as shown in Table 2, respectively.
  • Example 2.9 and 2.11 had high solvent residues, which affected the quality.
  • the sample of Example 2.10 was hygroscopic and was also a challenge to the formulation process.
  • the crystalline form obtained in Example 2.1, the VDA-1A crystalline form is the predominant crystalline form.
  • Detection conditions Cu target K ⁇ ray, voltage 40kV, current 40mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scatter slit 7.5mm, 2 ⁇ range: 3° to 50°, step size 0.02 °, each step of stay time 40S.
  • Test basis People's Republic of China (2015 edition four) 0451 X-ray powder diffraction method
  • Test sample quality Sample 1: 2.48mg (using aluminum sample tray)
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • thermogravimetric analyzer
  • Test conditions atmosphere: air, 20ml / min;
  • Test basis General rules for thermal analysis JY/T 014-1996
  • Test basis GB/T 6040-2002 General rules for infrared spectrum analysis
  • Mobile phase A water-mobile phase acetonitrile B (80:20)
  • Test basis "Chinese Pharmacopoeia" two appendix VD high performance liquid chromatography
  • Example 2.1 The stability of the crystal form A obtained in Example 2.1 was examined (10-day accelerated test), and the crystal form A was placed at 60 ° C, humidity of 92.5%, and light conditions, and the results are shown in the following table.
  • VDA-1 crystal form A Take the prescribed amount of polysorbate-80, while stirring, add VDA-1 crystal form A, stir to dissolve VDA-1, and pass the solution through a microfiltration membrane for positive pressure filtration until the solution is clear, the determined content is 98.36. % and pH are 6.14. After passing the test, the solution is filled in an antibiotic-controlled bottle in a clean condition, 0.5 ml (including VDA-1) per bottle, and the rubber stopper and aluminum cover are obtained.
  • the prepared injection was allowed to stand at 40 ° C for 7 days and 0 days, and the effect of the addition of acid and the addition of different acids, and the different processes of the same formulation, such as nitrogen and no nitrogen, on the stability of the injection of Form A were compared.
  • Y2 indicates the standard colorimetric liquid yellow No. 2 (in accordance with the Chinese Pharmacopoeia 2015 edition, supervised by Shanghai Pharmaceutical Inspection Institute)
  • Example 5.3 no acid is added in Example 5.3. After 7 days at 40 °C, the related substances are significantly increased, the VDA-1 content is decreased, and other indexes are not significantly changed. 13% hydrochloric acid (Example 5.2) or 50% citric acid is added (implementation)
  • the prescription of Example 5.4) is significantly better than the prescription without acid (Example 5.3), while the prescription for adjusting the pH with 13% hydrochloric acid is superior to the prescription for adjusting the pH with 50% citric acid.
  • the same prescription process is different, such as implementation.
  • the content of nitrogen-passing sample and the related substances did not change much after being placed at 40 °C for 7 days.
  • the content of nitrogen-free samples decreased and the related substances increased significantly.
  • the stability of nitrogen-passing samples was better than that of nitrogen-free samples.
  • 5.1 is the formulation and preparation process of VDA-1 injection (through nitrogen).

Abstract

本发明提供(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮(VDA-1)的A晶型，其具有稳定的形态和确定的熔点，化学稳定性好，耐高温，适于制药用途，用于治疗过度增殖性疾病。

Description

一种微管蛋白抑制剂的A晶型 技术领域
本发明属于医药技术领域，具体地说，涉及一种微管蛋白抑制剂的新晶型。
背景技术
作为肿瘤治疗的主要手段，抗肿瘤药物为延长患者的生存时间以及改善其生命质量做出了相当的贡献。其中作用于微管的药物(微管抑制剂)，又在肿瘤药物中具有相当重要的地位。但是目前的临床药物，受到如下不良问题的影响：较差的水溶性，不利于给药且易造成过敏反应、严重的毒副作用以及获得性耐药性，导致疗效降低、化学结构复杂难于合成，从而来源稀少，限制了它们进一步的使用。
中国专利申请CN106565686A公开了一种新的结构简单的小分子微管蛋白抑制剂。由于不同晶型的药物分子，在溶解度，熔点、溶出度、生物有效性等方面有显著差异，因此制备一种具有确定熔点，化学稳定性好，耐高温等优点的药物晶型将有利于药物制剂的制备和应用。
发明内容
本发明的一个目的是提供一种微管蛋白抑制剂的新晶型，即(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮(简称VDA-1)的晶型A，VDA-1具有如式(I)所示的结构：
Figure PCTCN2018080617-appb-000001
所述VDA-1的晶型A的特征通过熔点、X-射线粉末衍射(XRD)、差示扫描量热分析(DSC)、热重分析(TG)、红外光谱(IR)进行了表征，该晶型具备制备药物制剂所需要的性能。
具体地，当用Cu辐射源进行X-射线粉末衍射时，所述的A晶型包括在位 于2θ为6.6±0.2、9.7±0.2、16.0±0.2(°)的特征衍射峰，这些峰的相对强度(I/I 0)均大于或等于30％。更进一步地，所述结晶在X-射线粉末衍射中还可以进一步包含位于2θ为13.4±0.2、16.3±0.2、16.6±0.2、17.1±0.2、18.1±0.2、25.5±0.2、25.9±0.2、26.5±0.2(°)的特征衍射峰，这些峰的相对强度均大于或等于16％(见图1)。其中“±0.2°”为允许的测量误差范围。
本发明的A晶型可以通过X-射线粉末衍射图谱进行表征。其特征在于其X射线粉末衍射图谱具有上述2θ表示的特征峰，如表1所示，其相对强度接近下列数值。
表1
Figure PCTCN2018080617-appb-000002
此处的术语“接近”是指相对强度测量值的不确定性。本领域技术人员理解相对强度的不确定性非常依赖于测量条件。相对强度值可以是一定范围内的数值，优选地为选自表1所示数值±25％的范围，更优选地为表1所示数值±10％的范围。
上述A晶型具有图1所示的X射线粉末衍射图谱。
本发明采用差示扫描量热(DSC)技术对VDA-1的A晶型进行表征(见图2)，其中具有差示扫描量热的吸热最大值在146.5℃。该吸热过程在DSC谱图上表现为一吸热峰；
本发明采用热重分析技术对VDA-1的A晶型进行表征(见图3)，其中其特征在于热重谱图(TG)显示在127.1℃失重1.0％，说明该温度下有吸附水失去。在235.9℃失重超过16％，说明随着温度升高，该化合物降解了。
本发明的化合物的A晶型的红外图谱如图4所示，其中在3228、3064、2966、 2911、2732、2589、1707、1686、1664、1639、1597、1499、1411、1375、1350、1272、1149、1049、1022、952、937、810、773、677、443(cm -1)有较强吸收峰。
本发明的另一个目的是提供VDA-1晶型A的制备方法。
本发明的再一个目的是提供含有所述VDA-1晶型A的药物组合物。
本发明的最后一个目的是提供VDA-1晶型A在制备治疗过度增殖性疾病的药物中的应用。
根据本发明的一个方面，先制备所述VDA-1的粗品，然后通过本发明所述的重结晶方法对该物质粗品进行结晶，获得新晶型，通过对该结晶进行熔点测量、X-射线粉末衍射、DSC、TG、IR等检测和分析，确证获得的结晶是一种新型的结晶，本发明将其称为VDA-1的A晶型。
根据本发明的另一方面，制备所述VDA-1A晶型的方法包括：将VDA-1的粗品，加入到乙酸乙酯、二甲基亚砜、N,N-二甲基甲酰胺和四氢呋喃的混合溶剂中或加入到C3-C4烷基酮和四氢呋喃的混合溶剂中，加热回流至溶解；溶液澄清后开始降温，至析出固体，过滤收集固体，将收集的固体鼓风干燥即得A晶型。所述的酮选自丙酮、甲基乙基酮和正丁酮等，优选的溶剂乙酸乙酯和四氢呋喃的混合溶剂、丙酮和四氢呋喃的混合溶剂；乙酸乙酯、二甲基亚砜、N,N-二甲基甲酰胺、酮与四氢呋喃的体积比(V/V)为1:1～1:5；所述的粗品与溶剂的配比为重量体积比(W/V)为1(g)：5～30(ml)，优选为1:10(g/ml)。将溶液优选加热到50～80℃，更优选乙酸乙酯、C3-C4烷基酮与四氢呋喃混合溶剂加热至60℃；根据此实施方案，析固进行2～8小时，更优选为4小时。析固温度为0～40℃，优选5～15℃。析固完全后过滤，烘干温度为30～60℃，优选为45℃。
根据本发明的又一方面，提供含有本发明VDA-1的A晶型的药物组合物，该药物组合物含有所述新晶型化合物和任选的药学上可接受的载体和/或赋形剂。
所述药物组合物可进一步按照常规制剂方法配制成可供给药的形式，包括经口或胃肠外给药形式。在可供给药的形式中，应包含治疗有效量的VDA-1的A晶型。所谓“治疗有效量“是指在该剂量下，本发明的化合物能够改善或减轻疾病症状，或能够抑制或阻断疾病的发展。
根据经验并考虑本领域的标准方法和参考文献，本领域技术人员可以容易 地选择各种载体和/或赋形剂并确定其用量。
根据本发明的再一方面，VDA-1的A晶型可单独用于制备治疗过渡性增殖疾病的药物，也可以和其他治疗药物联合制备，协同作用。
有益效果：本发明制备得到了(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮(VDA-1)的A晶型，其具有稳定的形态和确定的熔点，化学稳定性好，耐高温，VDA-1的A晶型具备了制备制剂所需要的性能，且贮存方便，生产操作更为简便，质量更易控制。
本发明VDA-1的A晶型，用于治疗过度增殖性疾病，优选地，所述的过度增殖性疾病为癌症，包括但不限于非小细胞肺癌、结肠直肠癌、顽固性非小细胞肺癌、胰腺癌、卵巢癌、乳腺癌、神经胶质瘤、脑癌或颈部癌症。
附图说明
图1是VDA-1的A晶型的X射线衍射图谱；
图2是VDA-1的A晶型的DSC图谱；
图3是VDA-1的A晶型的TG图谱；
图4是VDA-1的A晶型的IR图谱；
图5是VDA-1的A晶型的HPLC图谱。
具体实施方式
下文以具体实施例进一步说明本发明，但不对本发明的范围形成任何限制。
所有原料和试剂均为普通商购。
制备VDA-1粗品
实施例1
VDA-1粗品的制备方法包括步骤(1)～(3)：
(1)
Figure PCTCN2018080617-appb-000003
化合物A的合成参考中国专利CN1684955中实施例2的方法制备而成。
(2)
Figure PCTCN2018080617-appb-000004
1L干燥的单口烧瓶中加入3-氟苯甲醛0.10mol，甲酰基亚甲基三苯基磷烷0.11mmol和甲苯(200ml)。反应体系回流16小时然后浓缩。粗产物经柱层析纯化(洗脱剂：石油醚/乙酸乙酯的体积比:100/1至80/20)得到化合物3，ESI：[M+H]151.0。
(3)
Figure PCTCN2018080617-appb-000005
250ml干燥的单口烧瓶中加入DMF(100ml)，中间体A 5mmol，3-氟苯甲醛10mmol和碳酸铯10mmol。反应体系在25～30℃搅拌2小时，冷却至室温，然后到入冰水中。乙酸乙酯萃取，有机相用食盐水洗三次，无水硫酸钠干燥，过滤，浓缩。粗产物用二氯甲烷/甲醇(10/1)洗涤，得到VDA-1粗品，ESI：[M+H]381.2。
制备VDA-1晶体
实施例2.1
取200gVDA-1粗品加入到反应瓶中，加入2400ml的乙酸乙酯和四氢呋喃的混合溶剂中(V/V＝1:5)，搅拌下升温回流至60℃。溶解后搅拌10min，再降温至5～15℃，至固体析出再搅拌析晶4h，抽滤，滤饼用丙酮淋洗。滤饼于45℃鼓风干燥，用五氧化二磷助干。得类白色固体166g，收率83.0％，用卡尔费休测定仪检测水分为0.3％。
实施例2.2
取200gVDA-1粗品加入到反应瓶中，加入1600ml的丙酮和水的混合溶剂中(V/V＝1:3)，搅拌下升温回流至60℃。溶解后搅拌10min，再降温至5～15℃，至固体析出再搅拌析晶4h，抽滤，滤饼用丙酮淋洗。滤饼于45℃鼓风干燥，用五氧化二磷助干。得类白色固体148g，收率74.0％。用卡尔费休测定仪检测水 分为0.3％。
实施例2.3～2.8
按照实施例2.1所述的方法，其中溶剂、加热温度、析固温度和时间、干燥温度分别如表2所示。
表2
Figure PCTCN2018080617-appb-000006
结果发现实施例2.2～2.8均未获得合适的晶型。
实施例2.9～2.11
除了上述工艺之外，还考察了不同溶剂如二甲亚砜、无水乙醇、甲醇溶剂对产物晶型的影响。
实施例2.9～2.11的制备过程如下：
表3
Figure PCTCN2018080617-appb-000007
Figure PCTCN2018080617-appb-000008
用卡尔费休测定仪检测实施例2.1获得的化合物VDA-1的A晶型与实施例2.9～2.11获得的样品的水分和溶剂含量，结果见表4：
表4
Figure PCTCN2018080617-appb-000009
实施例2.9和2.11的样品溶剂残留高，影响质量，实施例2.10的样品具有引湿性，对制剂工艺也是一种挑战。因此实施例2.1获得的晶型即VDA-1A晶型为优势晶型。
实施例3检测VDA-1晶型A
实施例样品的测试条件：
3.1XRD：
检测仪器：锐影(Empyrean)X射线衍射仪
检测条件：Cu靶Kα射线，电压40kV，电流40mA，发散狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，2θ范围：3°～50°，步长0.02°，每步停留时间40S。
检测依据：中华人民共和国(2015年版四部)0451X射线粉末衍射法
检测结果：如图1所示。
3.2DSC：
检测仪器：德国NETZSCH公司DSC 214差示扫描量热仪
检测条件：气氛：N2，40ml/min
扫描程序：从室温以10℃/min升温至250℃，记录升温曲线。
检测样品质量：样品1：2.48mg(使用铝质样品盘)
检测依据：JY/T 014-1996热分析方法通则
检测结果：如图2所示。
3.3TG：
检测仪器：德国NETZSCH公司TG209热重分析仪
检测条件：气氛：空气，20ml/min；
扫描程序：室温～800℃，升温速率：10℃/min。
检测依据：热分析方法通则JY/T 014-1996
检测结果：如图3所示。
3.4红外光谱：
检测仪器：FT-IR NICOLET6700(美国)
检测条件：溴化钾压片法
检测依据：GB/T 6040-2002红外光谱分析方法通则
检测结果：如图4所示。
3.5HPLC
检测仪器：Agilent 1260series(美国)
检测条件：
色谱柱：Waters Sunfire C18
流动相A：水-流动相乙腈B(80:20)
柱温：40℃检测波长：390nm。
检测依据：《中国药典》二部附录VD高效液相色谱法
检测结果：如图5所示。
VDA-1晶型A的稳定性的考察
实施例4
对实施例2.1获得的晶型A进行稳定性考察(10天的加速试验)，将晶型A置于60℃、湿度92.5％和光照条件下，结果如下表所示。
表5：晶型A影响因素的考察结果
Figure PCTCN2018080617-appb-000010
将晶型A的水分、纯度、最大单杂及总杂与0天的数据进行对比，结果为光照条件下，晶型A的纯度略有降低，其他条件下晶型A稳定。
制备VDA-1晶型A的注射液
实施例5.1
取聚山梨酯-80，加入0.5％的经干燥处理的针用活性炭和实施例2.1获得的VDA-1晶型A，加热至50℃，恒温搅拌30min，加热过滤，至澄明度与颜色检验合格。
取处方量的聚山梨酯-80，边滴加13％盐酸溶液，边搅拌，使测定pH值在3.5-3.9范围内，加入VDA-1晶型A，搅拌使VDA-1溶解，将溶液经微孔滤膜进行正压滤过，至溶液澄明，测定其含量为99.81％和pH为3.74，合格后，将溶液在洁净条件灌装于抗生素管制瓶中，每瓶0.5ml(含VDA-1)，通氮气后，压胶塞、轧铝盖，即得。
取药用乙醇，在水浴上蒸馏，弃去初馏分，收集冷凝液。称取195g冷凝液，加注射水至1500g，加入0.3％的针用活性碳和VDA-1晶型A，加热回流30min后，放冷，脱炭，经0.22um微孔滤膜过滤至溶液澄明，在100级洁净条件下灌装于抗生素管制瓶中，每瓶1.5ml。压胶塞，轧铝盖，即得。
实施例5.2
取聚山梨酯-80，加入0.5％的经干燥处理的针用活性炭和实施例2.1获得的VDA-1晶型A，加热至50℃，恒温搅拌60min，加热过滤，至澄明度与颜色检验合格。
取处方量的聚山梨酯-80，边滴加13％盐酸溶液，边搅拌，使测定pH值在3.5-3.9范围内，加入VDA-1晶型A，搅拌使VDA-1溶解，将溶液经微孔滤膜进行正压滤过，至溶液澄明，测定含量为99.81％和pH为3.74，合格后，将溶液在洁净条件灌装于抗生素管制瓶中，每瓶0.5ml(含VDA-1)，压胶塞、轧铝盖，即得。
取药用乙醇，在水浴上蒸馏，弃去初馏分，收集冷凝液。称取195g冷凝液，加注射水至1500g，加入0.3％的针用活性碳和VDA-1晶型A，加热回流30min后，放冷，脱炭，经0.22um微孔滤膜过滤至溶液澄明，在100级洁净条件下灌装于抗生素管制瓶中，每瓶1.5ml。压胶塞，轧铝盖，即得。
实施例5.3
取聚山梨酯-80，加入0.5％的经干燥处理的针用活性炭和实施例2.1获得的VDA-1晶型A，加热至40℃，恒温搅拌30min，加热过滤，至澄明度与颜色检验合格。
取处方量的聚山梨酯-80，一边搅拌，一边加入VDA-1晶型A，搅拌使VDA-1溶解，将溶液经微孔滤膜进行正压滤过，至溶液澄明，测定含量为98.36％和pH为6.14，合格后，将溶液在洁净条件灌装于抗生素管制瓶中，每瓶0.5ml(含VDA-1)，压胶塞、轧铝盖，即得。
取药用乙醇，在水浴上蒸馏，弃去初馏分，收集冷凝液。称取195g冷凝液，加注射水至1500g，加入0.3％的针用活性碳和VDA-1晶型A，加热回流30min后，放冷，脱炭，经0.22um微孔滤膜过滤至溶液澄明，在100级洁净条件下灌装于抗生素管制瓶中，每瓶1.5ml。压胶塞，轧铝盖，即得。
实施例5.4
取聚山梨酯-80，加入0.5％的经干燥处理的针用活性炭和实施例2.1获得的VDA-1晶型A，加热至60℃，恒温搅拌60min，加热过滤，至澄明度与颜色检验合格。
取处方量的聚山梨酯-80，边滴加50％枸橼酸溶液，边搅拌，使测定pH值在4.0-5.0范围内，加入VDA-1晶型A，搅拌使VDA-1溶解，将溶液经微孔滤膜进行正压滤过，至溶液澄明，测定含量为99.16％和pH为4.50，合格后，将溶液在洁净条件灌装于抗生素管制瓶中，每瓶0.5ml(含VDA-1)，压胶塞、轧铝盖，即得。
取药用乙醇，在水浴上蒸馏，弃去初馏分，收集冷凝液。称取195g冷凝液，加注射水至1500g，加入0.3％的针用活性碳和VDA-1晶型A，加热回流30min后，放冷，脱炭，经0.22um微孔滤膜过滤至溶液澄明，在100级洁净条件下灌装于抗生素管制瓶中，每瓶1.5ml。压胶塞，轧铝盖，即得。
将所制备的注射液于40℃放置7天和0天，比较不加酸与加入不同酸、及同一处方不同工艺如通氮气与不通氮气对晶型A的注射液的稳定性的影响。
实施例5.1～5.4如表7所示：
表7
Figure PCTCN2018080617-appb-000011
Figure PCTCN2018080617-appb-000012
注：*pH值测定方法：取本品0.5g，加水4.5ml，搅拌15分钟，依法测定(中国药典2015版)，***电极后搅拌15分钟，所测定的pH值。
Y2：表示标准比色液黄色2号(符合中国药典2015版，上海药品检验所监制)
由表7可见实施例5.3不加酸，40℃放置7天后有关物质明显增加，VDA-1含量下降，其它指标没有明显变化，加入13％盐酸(实施例5.2)或50％枸橼酸(实施例5.4)的处方明显优于不加酸的处方(实施例5.3)，而用13％盐酸调节pH值的处方优于用50％枸橼酸调节pH值的处方，同一处方工艺不同，如实施例5.1和5.2，40℃放置7天后通氮气样品的含量与有关物质变化不大，不通氮气的样品含量下降、有关物质明显增加，通氮气比不通氮气的样品稳定性更好，因此选择实施例5.1为VDA-1注射剂的处方和制备工艺(通氮气)。
以上对本发明较佳实施方式的描述并不限制本发明，本领域技术人员可以根据本发明做出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

Claims (10)

  1. 式(I)化合物(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型，所述的A晶型的X射线粉末衍射图谱具有衍射角2θ为6.6°±0.2°、9.7°±0.2°、13.4°±0.2°、16.0°±0.2°、16.3°±0.2°、16.6°±0.2°、17.1°±0.2°、18.1°±0.2°、25.5°±0.2°、25.9°±0.2°、26.5°±0.2°的特征衍射峰，
    Figure PCTCN2018080617-appb-100001
  2. 根据权利要求1所述的化合物(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型，其特征在于，所述的A晶型具有下表所示的衍射角2θ，晶面间距d，和相对强度I/I 0，且相对强度I/I 0的误差为±25％，
    Figure PCTCN2018080617-appb-100002
  3. 根据权利要求2所述的化合物(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型，其特征在于，所述的相对强度I/I 0的误差为±10％。
  4. 根据权利要求1-3任一项所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型，其特征在于，所述的A晶型的升温DSC曲线的最大吸热转变在146.5℃。
  5. 根据权利要求1-3任一项所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型，其特征在于，该晶型的热重分析图谱显示在236℃失重超过16％。
  6. 根据权利要求1-3任一项所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型，其特征在于用KBr压片测得的红外光谱图谱，其在3228cm -1、3064cm -1、2966cm -1、2911cm -1、2732cm -1、2589cm -1、1707cm -1、1686cm -1、1664cm -1、1639cm -1、1597cm -1、1499cm -1、1411cm -1、1375cm -1、1350cm -1、1272cm -1、1149cm -1、1049cm -1、1022cm -1、952cm -1、937cm -1、810cm -1、773cm -1、677cm -1、443cm -1有较强吸收峰。
  7. 制备权利要求1所述的(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型的方法，包括下述步骤：
    1)制备(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮(VDA-1)的粗品；
    2)将(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的粗品加入到溶剂中，加热回流至溶解；
    其中，所述的溶剂为乙酸乙酯、二甲基亚砜或N,N-二甲基甲酰胺与四氢呋喃的混合溶剂；或C 3-C 4烷基酮与四氢呋喃的混合溶剂，所述的C 3-C 4烷基酮选自丙酮、甲基乙基酮和正丁酮；
    乙酸乙酯、二甲基亚砜、N,N-二甲基甲酰胺、C 3-C 4烷基酮与四氢呋喃的体积比(V/V)为1:1～1:5；
    所述的粗品与溶剂的配比为重量体积比为1(g)：5～30(ml)，加热温度为50～80℃；
    3)溶液澄清后开始降温，至析出固体，过滤收集固体，将收集的固体鼓风干燥即得A晶型；
    其中析固进行2～8小时，析固温度为0～40℃，析固完全后过滤，烘干温度为30～60℃。
  8. 根据权利要求7所述的制备方法，其中步骤2)中所述的溶剂为乙酸乙酯与四氢呋喃的混合溶剂，或者丙酮与四氢呋喃的混合溶剂，粗品与所述溶剂的配比为重量体积比为1(g)：10(ml)，所述的加热温度为60℃；
    步骤3)中析固时间为4小时，析固温度5～15℃，烘干温度为45℃。
  9. 一种药物组合物，含有权利要求1所述(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型或其盐，和药学上可接受的载体。
  10. 权利要求1所述(3Z,6Z)-3-[((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基]-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮的A晶型在制备治疗过度增殖性疾病的药物中的应用。
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