WO2015110077A1 - 化合物A单苯甲酸盐的晶型α及其制备方法和含有该晶型的药物组合物 - Google Patents

化合物A单苯甲酸盐的晶型α及其制备方法和含有该晶型的药物组合物 Download PDF

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WO2015110077A1
WO2015110077A1 PCT/CN2015/071525 CN2015071525W WO2015110077A1 WO 2015110077 A1 WO2015110077 A1 WO 2015110077A1 CN 2015071525 W CN2015071525 W CN 2015071525W WO 2015110077 A1 WO2015110077 A1 WO 2015110077A1
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compound
monobenzoate
crystal form
diffraction pattern
solution
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PCT/CN2015/071525
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English (en)
French (fr)
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王为波
李同双
谭颂德
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上海复尚慧创医药研究有限公司
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Priority to MX2016009667A priority Critical patent/MX366651B/es
Priority to BR112016017087-3A priority patent/BR112016017087B1/pt
Priority to RU2016134404A priority patent/RU2677660C2/ru
Publication of WO2015110077A1 publication Critical patent/WO2015110077A1/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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 field of preparation of pharmaceutical compounds, in particular to a crystal form of a dipeptidyl peptidase-IV inhibitor compound A monobenzoate and a preparation method thereof, and a pharmaceutical composition containing the same.
  • Dipeptidyl peptidase IV is a serine protease that specifically hydrolyzes the Xaa-Pro or Xaa-Ala dipeptide of the N-terminus of a polypeptide or protein.
  • DPP-IV is an atypical serine protease with a Ser-Asp-His catalytic triad at the C-terminal region that differs from a typical serine protease in a reverse order.
  • DPP-IV has a variety of physiologically relevant substrates, such as inflammatory chemokines, regulated on activation normal T-cell expressed and secreted (RANTES), eosinophilic chemokines and macrophages.
  • RANTES normal T-cell expressed and secreted
  • eosinophilic chemokines and macrophages.
  • Cell-derived chemokines neuropeptides such as neuropeptide Y (NPY) and P5 substances, vasoactive peptides, incretins such as glucagon-like peptide-l (GLP-1) And glucose-dependent insulinotropic polypeptide (GIP).
  • GLP-1 glucagon-like peptide-l
  • GIP glucose-dependent insulinotropic polypeptide
  • DPP-IV inhibitors may be effective against diseases associated with DPP-IV activity, such as type 2 diabetes, diabetic dyslipidemia, impaired glucose tolerance (IGT), and impaired fasting plasma Glucose (IFG). ), metabolic acidosis, ketosis, appetite regulation and obesity.
  • diseases associated with DPP-IV activity such as type 2 diabetes, diabetic dyslipidemia, impaired glucose tolerance (IGT), and impaired fasting plasma Glucose (IFG).
  • IGT impaired glucose tolerance
  • IGF impaired fasting plasma Glucose
  • DPP-IV inhibitor Alogliptin has a clinically good therapeutic effect on type 2 diabetes and is approved for marketing in the United States. Therefore, DPP-IV inhibitors are currently considered to be the new treatment route for the treatment of type 2 diabetes.
  • PCT/CN2010/080370 describes a series of DPP-IV inhibitors of new mother core structures.
  • compound A its chemical name is: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-tri Pyrazin-4(5H)-yl)methyl)-4-fluorobenzonitrile, molecular formula: C 17 H 19 FN 6 O, molecular weight: 342, chemical formula: (I):
  • One of the objects of the present invention is to provide a stable dipeptidyl peptidase-IV (DPP-IV) reversible competitive inhibitor compound A monobenzoate with excellent stability and water solubility. Crystal form.
  • DPP-IV dipeptidyl peptidase-IV
  • Compound A The chemical name of Compound A is: (R)-2-((3-(3-Aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazine-4 ( 5H)-yl)methyl)-4-fluorobenzonitrile, molecular formula: C 17 H 19 FN 6 O, molecular weight: 342, the chemical structural formula of the compound A monobenzoate is the following formula (IA),
  • the crystal form ⁇ of the above-mentioned dipeptidyl peptidase-IV inhibitor compound A monobenzoate has characteristic peaks at 9.13°, 16.02°, 18.13° and 23.91° in the X-ray diffraction diagram at 2 ⁇ angles, and the error is ⁇ 0.2°.
  • the compound A monobenzoate is represented by an angle of 2 ⁇ in the X-ray diffraction diagram at 5.98°, 9.13°, 16.02°, 16.78°, 17.47°, 18.13°, 19.69°, 20.08°, 20.78°, 21.10°. Characteristic peaks at 21.60°, 23.33°, 23.91°, 24.70°, 25.46°, 26.63°, 27.29°, 27.92°, 28.45°, 29.30°, 30.85°, 32.63° and 33.48°. It should be noted that different samples of a particular crystal form have the same major XRPD peak, but small peaks in the powder pattern may vary. Moreover, each 2 theta angle error is typically within ⁇ 0.2° when considered by one of ordinary skill in the art.
  • the X-ray diffraction detection conditions are:
  • the Shimadzu PXRD-600 X-ray diffractometer was used to measure the 2 ⁇ range: 5°-40° in the Cu target K ⁇ 1 ray, tube current voltage: 40.0 kV, current: 30.0 mA, step size 0.02°.
  • the infrared spectrum mainly reflects the characteristic absorption peak of the functional group of the compound, and the absorption peak may have a change or a range of intervals. It can be understood that various functional groups of the compound, such as -CN group, keto group, -NH 2 , etc. may appear.
  • the infrared diffraction range should be interpreted as the infrared absorption peak range of the crystal form of the present invention. Therefore, the infrared diffraction absorption peak is not limited to the above specific numerical values and possible error ranges.
  • Test instrument Avatar 330 infrared spectrophotometer produced by Nikola, USA.
  • Test method KBr tablet method.
  • the crystal form ⁇ of the compound A monobenzoate has high stability and is stored at 40 ° C for 6 months. The content does not change substantially, and the crystal form does not change. Further, the crystal form ⁇ of the compound A monobenzoate has better stability with respect to the hydrochloride, sulfate and methanesulfonate of the compound A and the compound A, and the safety and effectiveness of the drug are sufficiently ensured.
  • Another object of the present invention is to provide a process for preparing a crystal form ⁇ of the above compound A monobenzoate, which is simple in process and can be realized under normal temperature conditions.
  • the compound A can be prepared according to the method disclosed in PCT/CN2010/080370, and the specific synthesis route and main reaction conditions are as follows:
  • the preparation method of the crystal form ⁇ of the compound A monobenzoate comprises the following steps:
  • Configure 95% methanol solution Add 91.2 mL of methanol to a 200 mL beaker, add 4.8 mL of water, stir well, and set aside.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound A monobenzoate crystal form a, and one or more pharmaceutically acceptable carriers.
  • the carrier comprises various medicinal excipients, packaging materials, delivery tools, etc., and is selected according to the needs of the preparation, for example, the auxiliary materials include a filler, a disintegrating agent, a binder, a lubricant, etc., and can be applied to oral, inhalation, non-gastrointestinal. Dosing or topical use; dosage forms include, but are not limited to, injections, solution preparations, tablets, capsules, granules and the like.
  • the pharmaceutical composition can be used for the preparation of a medicament for causing DPP-IV to cause a related disease, particularly type 2 diabetes.
  • the present invention has the following outstanding advantages and beneficial effects:
  • the crystal form of the compound A monobenzoate of the present invention has a high purity, and is easier to configure and use the pharmaceutical composition.
  • the stability of the crystalline form ⁇ of the compound A monobenzoate of the present invention is high, and the content does not change substantially after being stored at 40 ° C for 6 months, and the crystal form does not change, which is more conducive to the preparation of the pharmaceutical composition and use.
  • the crystal form ⁇ of the compound A monobenzoate of the present invention has better stability than the hydrochloride, sulfate and methanesulfonate of the compound A and the compound A, and is more advantageous for the clinical application of the compound A. .
  • the crystal form of the compound A monobenzoate of the present invention has excellent solubility in a conventional solvent and a gastric acid environment solution, and is highly soluble in water, 0.1 mol/L hydrochloric acid, and is easier to be a drug. Formulation use.
  • the method for preparing the crystal form ⁇ of the compound A monobenzoate of the invention is simple, rapid, and can be prepared under normal temperature conditions, and is easier to industrially produce.
  • Figure 1 is an X-ray diffraction pattern of the crystal form ⁇ of the compound A monobenzoate of the present invention.
  • Step C Methyl 2-(2-(2-bromo-5-fluorobenzylaminothiocarboxamide) decyl)propionate (4)
  • Step D 4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)- Ketone (5)
  • Step E 4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (6)
  • Step F (R)-tert-Butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro -1,2,4-triazin-3-yl)piperidin-3-carbamate (8)
  • Step G (R)-tert-Butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro -1,2,4-triazin-3-yl)piperidin-3-carbamate (9)
  • Step H (R)-2-((3-(3-Aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)- Methyl)-4-fluorobenzonitrile (10, Compound A)
  • Configure 95% methanol solution Add 91.2 mL of methanol to a 200 mL beaker, add 4.8 mL of water, stir well, and set aside.
  • Configure 95% methanol solution Add 22.8 mL of methanol to a 50 mL beaker, add 1.2 mL of water, stir well, and set aside.
  • Example 1 Compound 7.5 mg of Example 1 was taken in a 50 mL volumetric flask, dissolved in 70% by volume aqueous acetonitrile solution and diluted to the mark as a compound A reference solution; and 12.5 mg of benzoic acid was used. In a 25 mL volumetric flask, dissolve it in a 70% by volume aqueous solution of acetonitrile and dilute to the mark. Take 1 mL in a 25 mL volumetric flask, dissolve it in a 70% acetonitrile aqueous solution and dilute to the mark to obtain a benzoic acid reference solution.
  • the X-ray diffraction was measured by a Shimadzu PXRD-600 X-ray diffractometer at a Cu target K ⁇ 1 ray, a tube current voltage of 40.0 kV, a current of 30.0 mA, and a step size of 0.02° to determine a 2 ⁇ range: 5° to 40°.
  • Test instrument Avatar 330 infrared spectrophotometer produced by Nikola, USA Test method: KBr tableting method.
  • the accelerated test of this embodiment is carried out under abnormal conditions according to the guidance of the Chinese Pharmacopoeia 2010 edition second appendix XIXC "Guidelines for the stability test of drug substance in pharmaceutical preparations", through the process of transportation and preservation of drugs.
  • the stability under transient conditions under extreme conditions may be simulated and the long-term stability of the sample under specified storage conditions may be preliminarily predicted.
  • the specific experimental steps and experimental results are as follows:
  • the crystal form ⁇ of the compound A monobenzoate prepared in the third embodiment of the present invention is filled into a double-layer medicinal polyethylene plastic bag, heat-sealed, packaged with an aluminum-plastic composite film, heat-sealed, and placed in an accelerated test box.
  • a double-layer medicinal polyethylene plastic bag heat-sealed, packaged with an aluminum-plastic composite film, heat-sealed, and placed in an accelerated test box.
  • the temperature 40 ° C ⁇ 2 ° C, relative humidity RH 75 ⁇ 5% placed for 6 months, the purity and crystal form were measured at 0 days and 6 months respectively:
  • the crystal form detection method is the same as the method of the third embodiment.
  • the purity of the crystal form ⁇ of the compound A monobenzoate did not change substantially, maintaining high purity, and the crystal form did not undergo crystal transformation, indicating that the crystal form has excellent chemical stability. .
  • the solubility determination was carried out, and the crystal form ⁇ of the compound A monobenzoate prepared in Example 3 of the present invention was taken into a fine powder, and the sample was weighed. Strongly shake for 30 seconds every 5 minutes at 25 ° C ⁇ 2 ° C, a certain volume of solvent; observe the dissolution within 30 minutes, such as no visible solute particles or droplets, ie It is considered to be completely dissolved.
  • the crystal form has excellent solubility in a conventional solvent and a gastric acid environment solution, and it is very easy to use a pharmaceutical preparation.
  • the crystal form ⁇ of the compound A monobenzoate has better stability with respect to the hydrochloride, sulfate and methanesulfonate of the compound A and the compound A.
  • the comparative accelerated test was carried out under the same conditions, and the crystal form ⁇ of the compound A monobenzoate had better stability with respect to the hydrochloride, sulfate and methanesulfonate of the compound A and the compound A.
  • the above materials were uniformly mixed according to a conventional method, and then divided into 1000 equal portions and filled into ordinary gelatin capsules to obtain 1000 capsules.

Abstract

本发明属于药物化合物的制备领域，具体涉及一种二肽基肽酶-IV抑制剂化合物A单苯甲酸盐的晶型α及其制备方法，以及含有该晶型的药物组合物。

Description

化合物A单苯甲酸盐的晶型α及其制备方法和含有该晶型的药物组合物 技术领域
本发明属于药物化合物的制备领域，具体涉及一种二肽基肽酶-IV抑制剂化合物A单苯甲酸盐的晶型α及其制备方法，以及含有该晶型的药物组合物。
背景技术
二肽基肽酶IV(Dipeptidyl peptidase IV，DPP-IV)是丝氨酸蛋白酶，能特异性水解多肽或蛋白质N末端的Xaa-Pro或Xaa-Ala二肽。DPP-IV是非典型丝氨酸蛋白酶，其C末端区域的Ser-Asp-His催化三联体与典型丝氨酸蛋白酶不同，为逆序排列。
DPP-IV有多种生理学相关底物，如炎症趋化因子类、正常T细胞表达和分泌因子(regulated on activation normal T-cell expressed and secreted，RANTES)、嗜酸细胞活化趋化因子和巨噬细胞衍生趋化因子、神经肽类如神经肽Y(neuropeptide Y，NPY)和P5物质、血管活性肽、肠降血糖素如胰高糖素样肽(glucagon-like peptide-l，GLP-1)和葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic polypeptide，GIP)。
抑制体内DPP-IV可使内源性GLP-1(7-36)水平上升，减少其拮抗物GLP-1(9-36)的生成。因此，DPP-IV抑制剂可能对与DPP-IV活性相关的疾病有效，例如2型糖尿病，糖尿病血脂异常，糖耐量降低(Impaired Glucose Tolerance，IGT)，空腹血糖受损(Impaired Fasting Plasma Glucose，IFG)，代谢性酸中毒，酮病，食欲调节和肥胖。
DPP-IV抑制剂阿格列汀(Alogliptin)在临床上对于2型糖尿病表现为良好的治疗效果，在美国获批上市。因此，DPP-IV抑制剂目前被认为是新的治疗2型糖尿病的治疗途径。
PCT/CN2010/080370描述了一系列的新母核结构的DPP-IV抑制剂。其 中，包括化合物A，其化学名称为：(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苯腈，分子式：C17H19FN6O，分子量：342，化学结构式为下式(I)：
Figure PCTCN2015071525-appb-000001
为了改善该化合物的药用性质，对具有有利的稳定性性质研究可以有效地用于药物组合物中通过抑制DPP-IV而治疗病态的患者。
发明内容
本发明的目的之一在于提供一种稳定的二肽基肽酶-IV(Dipeptidyl peptidase-IV，DPP-IV)可逆的竞争性抑制剂化合物A单苯甲酸盐的稳定和水溶解性优异的晶型。
化合物A的化学名称为：(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苯腈，分子式：C17H19FN6O，分子量：342，化合物A单苯甲酸盐的化学结构式为下式(IA)，
Figure PCTCN2015071525-appb-000002
上述二肽基肽酶-IV抑制剂化合物A单苯甲酸盐的晶型α在X射线衍射图中以2θ角表示在9.13°、16.02°、18.13°和23.91°处有特征峰，误差为±0.2°。
具体的，化合物A单苯甲酸盐在X射线衍射图中以2θ角表示在5.98°、9.13°、16.02°、16.78°、17.47°、18.13°、19.69°、20.08°、20.78°、21.10°、21.60°、23.33°、23.91°、24.70°、25.46°、26.63°、27.29°、27.92°、28.45°、29.30°、30.85°、32.63°和33.48°处有特征峰。应注意：特定晶型的不同样品具有同样的主要XRPD峰，但是在粉末图中的小峰可能有变化。此外，当由本领域普通技术人员考虑时，各2θ角误差通常在±0.2°以内。
更为具体优选的，所述化合物A单苯甲酸盐的晶型α的X射线衍射图如附图1所示。
X射线衍射检测条件为：
采用岛津PXRD-600型X射线衍射仪，在Cu靶Kα1射线，管流电压：40.0kV，电流：30.0mA，步长0.02°条件下测定2θ范围：5°-40°。
上述化合物A单苯甲酸盐的晶型α在红外衍射图中以波数cm-1表示，在2937.35cm-1、2854.53cm-1、2231.20cm-1、1683.03cm-1、1609.46cm-1、1591.62cm-1、1418.00cm-1、1303.96cm-1、1278.17cm-1、722.02cm-1附近有特征吸收峰。应注意：特定晶型的不同样品具有同样的主要红外衍射吸收峰，但可能存在操作误差，当由本领域普通技术人员采用相应方法得到的同晶型样品采用相同的仪器进行考虑时，吸收峰误差通常在±0.2cm-1以内。但是，红外光谱主要体现的是化合物功能基团的特征吸收峰，吸收峰可能有变化或存在区间范围，可以理解本化合物各官能基团，如-CN基，酮基，-NH2等可能出现的红外衍射范围均应解释为本发明晶型的红外吸收峰范围。所以，红外衍射吸收峰不局限于上述特定数值和可能误差范围。
更为具体优选的，所述化合物A单苯甲酸盐的红外衍射图如附图2所示。
红外衍射检测条件：
测试仪器：美国尼高力公司生产的Avatar 330型红外分光光度计，测试方法：KBr压片法。
所述化合物A单苯甲酸盐的晶型α的稳定性高，经6个月40℃下保存， 含量基本不发生变化，晶型不发生转变。并且化合物A单苯甲酸盐的晶型α相对于化合物A、化合物A的盐酸盐、硫酸盐及甲磺酸盐均具有更好的稳定性，充分保证用药的安全性和有效性。
并且所述化合物A单苯甲酸盐的晶型α按中国药典2010年版第二部凡例中规定的溶解度方法进行实验，在常规溶剂和胃酸环境溶液中的溶解性极好，在水、0.1mol/L的盐酸中表现为极易溶解。
本发明的另一目的在于提供一种上述化合物A单苯甲酸盐的晶型α的制备方法，该方法工艺简单，常温条件下即可实现。
其中，化合物A可根据PCT/CN2010/080370公开的方法制备，具体合成路线及主要的反应条件如下：
Figure PCTCN2015071525-appb-000003
化合物A单苯甲酸盐的晶型α的制备方法包括以下步骤：
以甲醇或者甲醇和水的混合溶液作为溶剂，分别溶解苯甲酸和化合物A，往化合物A的溶液中在特定温度下滴加等摩尔的苯甲酸溶液，滴加完毕后，在15-25℃搅拌析晶10小时以上，然后再在0-10℃析晶，得化合物A单苯甲酸盐晶型α。
具体实施操作方法例如：
配置95％甲醇溶液：200mL烧杯中加入91.2mL甲醇，加入4.8mL水，搅拌均匀，备用。
取2.14g苯甲酸，室温下加入10mL 95％甲醇搅拌溶解，备用(苯甲酸的甲醇溶液)；向50mL反应瓶中加入化合物A 60g，用95％甲醇32mL搅拌溶解；使内温保持在15-25℃下滴加苯甲酸的甲醇溶液，0.5-1h滴完；滴加完毕后，15-25℃下搅拌析晶16h，再在0-10℃下析晶6h，得化合物A单苯甲酸盐的晶型α。
本发明的再一目的在于提供一种含有上述化合物A单苯甲酸盐晶型α的药物组合物，和一种以上药学上可接受的载体。
所述载体包括各种药用辅料，包材，传递工具等，根据制剂需要进行选择，例如辅料包括填充剂、崩解剂、粘合剂、润滑剂等，可以适用于口服、吸入、非肠胃给药或表面使用；剂型包括但不限于注射剂、溶液制剂、片剂、胶囊剂、颗粒剂等。
所述药物组合物可以用于制备DPP-IV引起相关疾病、特别是2型糖尿病的药物的应用。
本发明与现有技术相比具有如下突出的优点及有益效果：
1、本发明的化合物A单苯甲酸盐的晶型α的纯度高，更易于药物组合物的配置和使用。
2、本发明的化合物A单苯甲酸盐的晶型α的稳定性高，经6个月40℃下保存，含量基本不发生变化，晶型不发生转变，更利于药物组合物的制备和使用。
3、本发明的化合物A单苯甲酸盐的晶型α相对于化合物A、化合物A的盐酸盐、硫酸盐及甲磺酸盐均具有更好的稳定性，更利于化合物A的临床应用。
4、本发明的化合物A单苯甲酸盐的晶型α的在常规溶剂和胃酸环境溶液中的溶解性极好，在水、0.1mol/L的盐酸中表现为极易溶解，更易于药物制剂使用。
5、本发明制备化合物A单苯甲酸盐的晶型α的方法简单、快捷、在常温条件下即可制备，更易于产业化生产。
附图说明
图1是本发明化合物A单苯甲酸盐的晶型α的X射线衍射图谱。
图2是本发明化合物A单苯甲酸盐的晶型α的红外衍射图谱。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但发明的实施方式不限于此。
实施例1 化合物A的制备
按照WO2011079778说明书实施例2和3的方法，采用以下技术合成路线制备化合物A：
所得化合物A的1H-NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H),1.12(m,1H)。
MS:m/z,343(100％,M+1)。
Figure PCTCN2015071525-appb-000004
具体制备步骤如下：
步骤A：1-溴-4-氟-2-(异硫氰酸甲基)苯(2)
向1-溴-2-(溴甲基)-4-氟苯(1，5.36g，20.0mmol)的DMF溶液(20mL)中加入碘化钠(1.20g，8.00mmol)和硫氰酸钾(3.88g，40.0mmol)。将该 混合物在氮气氛围下加热到80℃反应12h后，冷却到室温，向其中加入100mL水，并用乙酸乙酯萃取(50mL×2)，合并有机层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩得粗品，残余物用硅胶柱色谱纯化(洗脱剂：石油醚)，得1-溴-4-氟-2-(异硫氰酸甲基)苯(2)。
步骤B：N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3)
将水合肼(80％，2.22g，35.5mmol)的1,4-二氧六环溶液(20mL)冷却到0℃，向其中加入1-溴-4-氟-2-(异硫氰酸甲基)苯(2，3.16g，12.8mmol)的1,4-二氧六环溶液(5mL)。将该混合物在室温下搅拌2h，向其中加入100mL冰水，有固体析出，抽滤、水洗，五氧化二磷干燥过夜，得N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3)。
MS:m/z,278(100％,M+1),280(100％),300(10％,M+23),302(10％)。
步骤C：甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4)
向丙酮酸(352mg，4.00mmol)的甲醇溶液(15mL)中先后加入N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3，1.112g，4.00mmol)，以及浓硫酸5滴，将该混合物加热到回流7h，蒸除大部分溶剂，残余物用乙酸乙酯萃取(150mL)，有机层先后分别用水，饱和碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩，得甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4)。
MS:m/z,362(100％,M+1),364(100％),384(60％,M+23),386(60％)。
步骤D：4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)- 酮(5)
将由钠(273mg，11.88mmol)和干燥甲醇(30mL)新鲜制备的甲醇钠(0.4M)溶于甲醇30mL，向其中加入甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4，1.434g，3.96mmol)，将该混合物加热回流22h，蒸除大部分溶剂，残余物用水100mL稀释，用2N浓盐酸调节pH为1-2，乙酸乙酯萃取(50mL×2)，合并萃取层用饱和食盐水洗涤，无水硫酸钠干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20％-30％)， 得4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5)。
MS:m/z,330(65％,M+1),332(60％,M+23)。
步骤E：4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(6)
将4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5，914mg，2.77mmol)悬浮于乙醇15mL中，先后加入氢氧化钠(111mg，2.77mmol)和碘甲烷(787mg，5.54mmol)。将该混合物于室温搅拌10分钟得澄清黄色溶液，反应用水100mL稀释，乙酸乙酯萃取(30mL×2)，合并萃取层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩，残余物用硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20-25％)得4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(6)。
1HNMR(400MHz,DMSO,ppm):δ7.73(m,1H),7.16(br,1H),7.05(d,1H),5.09(s,2H),2.56(s,3H),2.32(s,3H)。
MS：m/z,344(100％,M+1),346(100％)。
步骤F：(R)-叔丁基1-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4,5-二氢 -1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(8)
将4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(6，180mg，0.523mmol)与(R)-叔丁基哌啶-3-氨基甲酸酯(7，208mg，1.04mmol)研磨5分钟，在氮气氛围下加热到135℃反应13h，反应混合物用硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝10-50％)得(R)-叔丁基1-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(8)。
MS:m/z,496(100％,M+1),498(100％)。
步骤G：(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4,5-二氢 -1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(9)
向碳酸钠(53mg，0.50mmol)、醋酸钯(3mg，0.013mmol)和N-甲基吡咯烷酮0.5mL的混合物中加入异丙醇3滴和水2滴，将该混合物在室温下搅拌5分钟，向其中加入(R)-叔丁基1-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(8，246mg，0.496mmol) 的NMP溶液(1.0mL)，并加热到140℃，再加入K4[Fe(CN)6]·3H2O(209mg，0.496mmol)，在140℃下加热12h，冷却到室温，加入水10mL，乙酸乙酯萃取(20mL×2)，合并有机层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20-35％)，得(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(9)。
MS:m/z,418(20％),443(100％,M+1),465(95％,M+23)。
步骤H：(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)- 基)甲基)-4-氟苄腈(10，化合物A)
向(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(9，37mg)的二氯甲烷溶液1mL中加入三氟醋酸0.5mL，室温搅拌1h，用饱和碳酸氢钠溶液中和，二氯甲烷萃取(10mL×3)，合并有机层用无水硫酸钠干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：二氯甲烷/甲醇/氨水＝92:6:2)，得(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苄腈(10)。
1HNMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H),1.12(m,1H)。
MS:m/z,343(100％,M+1)。
实施例2 化合物A单苯甲酸盐的晶型α的制备
配置95％甲醇溶液：200mL烧杯中加入91.2mL甲醇，加入4.8mL水，搅拌均匀，备用。
取2.14g苯甲酸，室温下加入10mL 95％甲醇搅拌溶解，备用(苯甲酸的甲醇溶液)；向50mL反应瓶中加入化合物A 60g、95％甲醇32mL搅拌溶解，使内温保持在20℃下滴加苯甲酸的甲醇溶液，1h滴完；滴加完毕后，20℃搅拌析晶16h，再在4℃析晶6h，得化合物A单苯甲酸盐晶型α。
实施例3 化合物A单苯甲酸盐的晶型α的制备
配置95％甲醇溶液：50mL烧杯中加入22.8mL甲醇，加入1.2mL水，搅拌均匀，备用。
取2.14g苯甲酸，室温下加入10mL 95％甲醇搅拌溶解，备用；向50mL反应瓶中加入化合物A 60g、95％甲醇32mL搅拌溶解，使内温保持在15℃下滴加苯甲酸的甲醇溶液，0.8h滴完；滴加完毕后，15℃搅拌析晶16h，再在5℃析晶6h，得化合物A单苯甲酸盐晶型α(本品)。
通过以下方法确定所得化合物为化合物A单苯甲酸盐：
苯甲酸的鉴别方法：按照《中国药典》2010版第二部附录III“一般鉴别试验”项下“苯甲酸盐”试验法进行试验。取本品约0.1g，置10mL容量瓶中，加水溶剂并稀释到刻度，摇匀，精密量取5mL至10mL烧杯中，调节溶液对酚酞呈中性，滴加三氯化铁溶液，观察到赭色沉淀，空白对照未有此现象。
HPLC出峰时间和含量鉴别：取实施例1的化合物A 7.5mg于50mL容量瓶中，用体积比70％的乙腈水溶液溶解并稀释至刻度，作为化合物A对照品溶液；以及12.5mg苯甲酸于25mL容量瓶中，用体积比70％的乙腈水溶液溶解并稀释至刻度，取1mL于25mL容量瓶中，用体积比70％的乙腈水溶液溶解并稀释至刻度，作为苯甲酸对照品溶液；取本品约10mg于50mL容量瓶中，用体积比70％的乙腈水溶液溶解并稀释至刻度，作为本品供试品溶液。采用色谱条件(仪器：Agilent 1200 HPLC仪，色谱柱：Agilent Eclipse Plus C18，5μm，4.6×250mm，检测波长：229nm，流动相：0.1％的磷酸-乙腈：水＝3：7，流速1.0mL/min，进样量20μL)分析。结果发现，主峰保留时间和对照品保留时间一致，并通过峰面积计算化合物A和苯甲酸的含量，本品中化合物A和苯甲酸的摩尔比为1:1。
所得化合物A单苯甲酸盐的晶型α的X射线衍射图谱、红外衍射图谱分别如图1和图2所示。
X射线衍射检测条件：
X射线衍射采用岛津PXRD-600型X射线衍射仪，在Cu靶Kα1射线，管流电压：40.0kV，电流：30.0mA，步长0.02°条件下测定2θ范围：5°-40°。
红外衍射检测条件：
测试仪器：美国尼高力公司生产的Avatar 330型红外分光光度计，测 试方法：KBr压片法。
实施例4 稳定性实验
本实施例的加速试验是根据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》的指导在超常条件下进行的，通过对药品在运输、保存过程中可能会遇到的短暂的超常条件下的稳定性进行模拟考察，并可初步预测样品在规定的贮存条件下的长期稳定性。具体实验步骤和实验结果如下：
将本发明实施例3制备得到的化合物A单苯甲酸盐的晶型α装入双层药用聚乙烯塑料袋中，热封，外加铝塑复合膜包装，热封，置于加速实验箱中，在温度40℃±2℃，相对湿度RH 75±5％下放置6个月，分别于0天和6个月末测定纯度和晶型情况：
纯度检测方法参照《中国药典》2010版第二部附录VD的高效液相色谱法，仪器：Agilent高效液相色谱仪，色谱柱C18，5μm，流速：1mL/min，检测波长：229nm，流动相：0.1％的磷酸-乙腈：水＝3：7。
晶型检测方法同实施例3检测方法。
通过6个月的加速试验后，化合物A单苯甲酸盐的晶型α的纯度基本不发生变化，保持高纯度，晶型不发生转晶变化，说明该晶型物具有优异的化学稳定性。
实施例5 溶解性实验
按照《中国药典》2010版第二部凡例对溶解度的指导进行溶解度测定，取本发明实施例3制备得到的化合物A单苯甲酸盐的晶型α，研成细粉，称取样品，置于25℃±2℃、一定容量的溶剂中，每隔5分钟强力振摇30秒钟；观察30分钟内的溶解情况，如无目视可见的溶质颗粒或液滴时，即 视为完全溶解。
药品的近似溶解度以下名词术语表示：
Figure PCTCN2015071525-appb-000006
实验方法及结果如下：
Figure PCTCN2015071525-appb-000007
从上述结果可以表明，该晶型在常规溶剂和胃酸环境溶液中的溶解性极好，非常易于药物制剂的使用。
实施例6 稳定性对比实验
根据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》的指导，以化合物A单苯甲酸盐的晶型α和化合物A、化合物A的盐酸盐、硫酸盐及甲磺酸盐在同等条件下进行影响因素高温试验和加速实验，保存数日后，结果如下：
(一)高温实验
依据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》，精密称取化合物A单苯甲酸盐的晶型α25mg，裸露放入培养皿中，置于40℃的高温试验箱中，放置0天、5天、10天取样测定，结果见表1。
表1高温实验结果(40±2℃)
Figure PCTCN2015071525-appb-000008
通过上述结果可以看出：化合物A单苯甲酸盐的晶型α在高温条件下比较稳定。
同等条件下进行对比高温试验，化合物A单苯甲酸盐的晶型α相对于化合物A、化合物A的盐酸盐、硫酸盐及甲磺酸盐均具有更好的稳定性。
(二)加速实验
依据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》，精密称取化合物A单苯甲酸盐的晶型α20mg，装入双层药用聚乙烯塑料袋中，热封，外加铝塑复合膜包装，热封。置加速试验箱中，于40℃，RH75±5％条件下放置0、6月后取样测定，结果见表2。
表2加速实验结果(40℃±2℃，RH75±5％)
Figure PCTCN2015071525-appb-000009
通过上述结果可以看出：化合物A单苯甲酸盐的晶型α在40℃，RH75±5％条件下加速试验6个月，其指标与0月基本一致，说明本品在加速40℃下稳定。
同等条件下进行对比加速试验，化合物A单苯甲酸盐的晶型α相对于化合物A、化合物A的盐酸盐、硫酸盐及甲磺酸盐均具有更好的稳定性。
实施例7药物组合物的制备
化合物A单苯甲酸盐(晶型α)  6.78g
糊精                       84.00g
按常规方法，将上述物质混合均匀后，分1000等份分别装入普通明胶胶囊，得到1000颗胶囊。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种二肽基肽酶-IV抑制剂化合物A单苯甲酸盐的晶型α，所述化合物A单苯甲酸盐化学结构式如下式(IA)所示：
    Figure PCTCN2015071525-appb-100001
  2. 权利要求1的化合物A单苯甲酸盐的晶型α，其特征在于，所述化合物A单苯甲酸盐的晶型α在X射线衍射图中以2θ角表示在9.13°、16.02°、18.13°和23.91°处有特征峰，误差为±0.2°。
  3. 权利要求1的化合物A单苯甲酸盐的晶型α，其特征在于，所述化合物A单苯甲酸盐的晶型α的红外衍射图中以波数cm-1表示，在2937.35cm-1、2854.53cm-1、2231.20cm-1、1683.03cm-1、1609.46cm-1、1591.62cm-1、1418.00cm-1、1303.96cm-1、1278.17cm-1、722.02cm-1有特征吸收峰，误差为±0.2cm-1。
  4. 权利要求2的化合物A单苯甲酸盐的晶型α，其特征在于，所述化合物A单苯甲酸盐的晶型α的红外衍射图中以波数cm-1表示，在2937.35cm-1、2854.53cm-1、2231.20cm-1、1683.03cm-1、1609.46cm-1、1591.62cm-1、1418.00cm-1、1303.96cm-1、1278.17cm-1、722.02cm-1有特征吸收峰，误差为±0.2cm-1。
  5. 权利要求1至4中任一项的化合物A单苯甲酸盐的晶型α，其特征在于，在X射线衍射图中以2θ角表示在5.98°、9.13°、16.02°、16.78°、17.47°、18.13°、19.69°、20.08°、20.78°、21.10°、21.60°、23.33°、23.91°、24.70°、25.46°、 26.63°、27.29°、27.92°、28.45°、29.30°、30.85°、32.63°和33.48°处有特征峰，误差为±0.2°。
  6. 权利要求5的化合物A单苯甲酸盐的晶型α，其特征在于，所述化合物A单苯甲酸盐的晶型α的X射线衍射图如附图1所示。
  7. 权利要求5的化合物A单苯甲酸盐的晶型α，其特征在于，所述化合物A单苯甲酸盐的晶型α的红外衍射图如附图2所示。
  8. 权利要求6的化合物A单苯甲酸盐的晶型α，其特征在于，所述化合物A单苯甲酸盐的晶型α的红外衍射图如附图2所示。
  9. 一种权利要求1-8中任一项的化合物A单苯甲酸盐的晶型α的制备方法，其特征在于，包括如下步骤：以甲醇或者甲醇和水的混合溶液作为溶剂，分别溶解苯甲酸和化合物A，往化合物A的溶液中在15-25℃下滴加等摩尔的苯甲酸溶液，滴加完毕后，在15-25℃下搅拌析晶10小时以上，然后再在0-10℃下析晶，得化合物A单苯甲酸盐的晶型α。
  10. 一种药物组合物，其特征在于，所述药物组合物中含有权利要求1-8中任一项的二肽基肽酶-IV抑制剂化合物A单苯甲酸盐的晶型α，和一种以上药学可接受的载体。
PCT/CN2015/071525 2014-01-24 2015-01-26 化合物A单苯甲酸盐的晶型α及其制备方法和含有该晶型的药物组合物 WO2015110077A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018219295A1 (zh) * 2017-05-31 2018-12-06 深圳信立泰药业股份有限公司 二肽基肽酶iv抑制剂的氘代1,2,4-三嗪衍生物

Families Citing this family (3)

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Publication number Priority date Publication date Assignee Title
WO2017008684A1 (zh) * 2015-07-15 2017-01-19 深圳信立泰药业股份有限公司 化合物A的晶型α及其制备方法和含有该晶型的药物组合物
CN106349215B (zh) * 2015-07-15 2022-02-08 深圳信立泰药业股份有限公司 一种化合物a苯甲酸盐的无定形及其制备方法和含有该无定形的药物组合物
CN109692164A (zh) * 2017-10-20 2019-04-30 深圳信立泰药业股份有限公司 化合物a或其盐的药物组合物及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102791701A (zh) * 2009-12-30 2012-11-21 上海复尚慧创医药研究有限公司 作为二肽基肽酶iv(dpp-iv)抑制剂的3-(3-氨基哌啶-1-基)-5-氧代-1,2,4-三嗪衍生物

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006068978A2 (en) * 2004-12-21 2006-06-29 Takeda Pharmaceutial Company Limited Dipeptidyl peptidase inhibitors
TW200745079A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
CN101360723A (zh) * 2005-09-16 2009-02-04 武田药品工业株式会社 制备嘧啶二酮衍生物的方法
TW200838536A (en) * 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
FR2933979B1 (fr) * 2008-07-15 2012-08-24 Pf Medicament Derives de triazines et uraciles, leur preparation et leur application en therapeutique humaine
CN103068392A (zh) * 2010-05-12 2013-04-24 Mapi医药公司 苯甲酸阿格列汀的多晶形物
CN103172615A (zh) * 2013-03-29 2013-06-26 山东罗欣药业股份有限公司 苯甲酸阿格列汀晶型化合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102791701A (zh) * 2009-12-30 2012-11-21 上海复尚慧创医药研究有限公司 作为二肽基肽酶iv(dpp-iv)抑制剂的3-(3-氨基哌啶-1-基)-5-氧代-1,2,4-三嗪衍生物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018219295A1 (zh) * 2017-05-31 2018-12-06 深圳信立泰药业股份有限公司 二肽基肽酶iv抑制剂的氘代1,2,4-三嗪衍生物

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