WO2020233226A1 - 四氢噻吩并吡啶化合物的b晶型及制法、组合物和应用 - Google Patents

四氢噻吩并吡啶化合物的b晶型及制法、组合物和应用 Download PDF

Info

Publication number
WO2020233226A1
WO2020233226A1 PCT/CN2020/081091 CN2020081091W WO2020233226A1 WO 2020233226 A1 WO2020233226 A1 WO 2020233226A1 CN 2020081091 W CN2020081091 W CN 2020081091W WO 2020233226 A1 WO2020233226 A1 WO 2020233226A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
crystal
compound
formula
tetrahydrothienopyridine
Prior art date
Application number
PCT/CN2020/081091
Other languages
English (en)
French (fr)
Inventor
岑国栋
杨茂廷
谭少军
Original Assignee
成都施贝康生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都施贝康生物医药科技有限公司 filed Critical 成都施贝康生物医药科技有限公司
Priority to EP20808820.3A priority Critical patent/EP3985009B1/en
Publication of WO2020233226A1 publication Critical patent/WO2020233226A1/zh
Priority to US17/750,688 priority patent/US20220289761A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 medicinal chemistry, and specifically relates to a tetrahydrothienopyridine compound (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-
  • S tetrahydrothienopyridine compound
  • S 2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-
  • the B crystal form of methyl tetrahydrothiophene [3,2-c] pyridine-5(4H) yl) acetate and its preparation method, composition and application.
  • CVD cardiovascular disease
  • cardiovascular and cerebrovascular thrombotic diseases such as ischemic stroke (IS) and hemorrhagic stroke (HS) are the most lethal diseases.
  • IS ischemic stroke
  • HS hemorrhagic stroke
  • a recently completed cross-sectional survey of the burden of stroke disease in China conducted by Ness-China shows that as of 2013, the crude stroke incidence rate in my country has reached an astonishing 345.1 cases per 100,000 people per year. The level indicates that China has become a country with a high incidence of thrombosis. Therefore, the prevention, control and treatment of cardio-cerebral thrombosis diseases are even more important in this severe situation.
  • clopidogrel The key physiological pathway of thrombosis is through platelet adhesion and aggregation. Therefore, platelet aggregation inhibitory drugs play an important role in the treatment of thrombosis, and they are also a hot research topic.
  • Sanofi's clopidogrel (Polivix) is the most representative anticoagulant drug. Due to its good safety and rapid inhibition of platelet aggregation, it is used in the current clinical first-line treatment and prevention of thrombotic diseases. It has a wide range of applications. Unfortunately, due to the efficacy of clopidogrel, especially among Asians, there are significant individual differences, namely clopidogrel resistance (CPGR), which limits the application of clopidogrel. In 2010, Farid et al.
  • CPGR clopidogrel resistance
  • crystal structure of the active ingredient for pharmaceuticals often affects the chemical stability of the drug.
  • the difference in crystallization conditions and storage conditions may result in changes in the crystal structure of the compound, sometimes accompanied by other forms.
  • the crystal form of the drug thereby affecting the stability, water solubility, storage properties, etc. of the pharmaceutical preparation, thereby affecting the safety and reliability of the drug. Therefore, it is necessary to conduct in-depth research on the crystal form of the compound of formula I.
  • Providing a crystal form of a compound of formula I that has good stability, high safety, is suitable for industrial production, and has a good pharmaceutical prospect, has become an urgent problem for those skilled in the art.
  • One of the objectives of the present invention is to provide a tetrahydrothienopyridine compound (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6 ,7,7a-Tetrahydrothiophene[3,2-c]pyridine-5(4H)yl) crystalline form B of methyl acetate, which solves the problem of high impurity, low content, poor crystal form stability and incapability of making medicine in the prior art The problem.
  • the second objective of the present invention is to provide a method for preparing the B crystal form.
  • the third objective of the present invention is to provide a pharmaceutical composition containing the B crystal form.
  • the fourth objective of the present invention is to provide the application of the B crystal form.
  • the structure of the present invention is the crystalline form B of the tetrahydrothienopyridine compound represented by formula I, using Cu-K ⁇ radiation, the X-ray powder diffraction expressed at 2 ⁇ angles is 11.21 ⁇ 0.2°, 12.61 ⁇ 0.2 °, 14.69 ⁇ 0.2°, 16.14 ⁇ 0.2°, 17.81 ⁇ 0.2°, 20.22 ⁇ 0.2°, 22.10 ⁇ 0.2°, there are characteristic peaks;
  • X-ray powder diffraction expressed in 2 ⁇ angles is at 11.21 ⁇ 0.2°, 12.61 ⁇ 0.2°, 14.69 ⁇ 0.2°, 16.14 ⁇ 0.2°, 17.81 ⁇ 0.2°, 20.22 ⁇ 0.2°, There are characteristic peaks at 22.10 ⁇ 0.2°, 23.24 ⁇ 0.2°, 27.68 ⁇ 0.2°, 28.57 ⁇ 0.2°.
  • X-ray powder diffraction expressed in 2 ⁇ angles is at 11.21 ⁇ 0.2°, 12.61 ⁇ 0.2°, 14.69 ⁇ 0.2°, 16.14 ⁇ 0.2°, 17.81 ⁇ 0.2°, 19.42 ⁇ 0.2°, There are characteristic peaks at 20.22 ⁇ 0.2°, 20.76 ⁇ 0.2°, 22.10 ⁇ 0.2°, 23.24 ⁇ 0.2°, 24.31 ⁇ 0.2°, 27.01 ⁇ 0.2°, 27.68 ⁇ 0.2°, 28.57 ⁇ 0.2°, 31.09 ⁇ 0.2°.
  • the differential scanning calorimetry spectrum of the crystal form B has an endothermic peak at 151.71 ⁇ 5°C.
  • thermogravimetric analysis TGA
  • thermogravimetric analysis spectrum of the crystal form B is shown in FIG. 3.
  • the single crystal structure of the compound of formula I is provided.
  • the crystal system of the crystal is a monoclinic system, and the space group it belongs to is the P21 group.
  • the single crystal of the B crystal form has an X-ray single crystal diffraction pattern as shown in FIG. 4.
  • the crude product of the compound of formula I in any crystal form or amorphous form is dissolved in a solvent in any manner, and then cooled or concentrated to crystallize it. The crystals are filtered, washed, and dried to obtain.
  • the crude product of the compound of formula I means that the mass content of the compound of formula I is less than 98%.
  • the solvent is selected from any one or more of alcohols, ketones, nitriles, ethers, esters, and sulfones with carbon atoms less than or equal to 7; or any one or more of them and water Mixed solvents.
  • the alcohols include methanol, ethanol, isopropanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and pentanol;
  • the ketones include acetone, methyl ethyl Ketones, methyl isopropyl ketone;
  • the nitriles include acetonitrile;
  • the ethers include diethyl ether, isopropyl ether, methyl tert-butyl ether, and anisole;
  • the esters include methyl tetrahydrofuran and ethyl formate , Ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate;
  • the sulfones include dimethyl sulfoxide.
  • the conditions for cooling and crystallization are from -20°C to room temperature for standing and crystallization.
  • the condition of concentration and crystallization is that the solvent is concentrated by the rotary evaporator at an external temperature of 35°C for crystallization.
  • the filter cake is washed with the crystallization solvent corresponding to ice, preferably the crystallization solvent corresponding to 0°C.
  • the drying is drying in air at 35°C under normal pressure.
  • the pharmaceutical composition of the present invention comprises the above-mentioned crystal form B of the compound, and one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle administered with the therapeutic agent, and it is suitable for contact with humans and/or other substances within the scope of reasonable medical judgment Animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the other arterial circulatory system disorders include stroke, acute coronary syndrome, atherosclerosis, myocardial infarction and confirmed peripheral artery disease.
  • the present invention has the following beneficial effects:
  • the present invention creatively discovered that the compound of formula I (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydrothiophene [3,
  • the crude product of single isomer of 2-c]-pyridine-5(4H) methyl acetate is refined and crystallized to obtain a product with less impurities, good stability, good crystallinity, reproducibility and operability.
  • the preparation method of the crystal form B is simple, the solvent is controllable, cheap and easy to obtain, the crystallization conditions are mild, and the crystal form is stable, which is suitable for industrial production.
  • crystal form B also has unexpected technical effects: it has a stronger anti-ADP-induced platelet aggregation effect. Compared with the crystal form reported in the prior art, it has a significant difference and has the potential for further development of medicine. The dominant crystal form. In addition, crystal form B also has unexpectedly better fluidity, which makes it have better tableting performance, and is more conducive to the control of the difference in tablet weight of the finished product, thereby further ensuring the effectiveness and safety of the medication.
  • Figure 1 is the XRPD pattern of the crystal form B of the compound of formula I.
  • Fig. 2 is a DSC chart of the crystal form B of the compound of formula I.
  • Figure 3 is a TGA chart of the crystal form B of compound of formula I.
  • Fig. 4 is a single crystal diffraction pattern of the crystal form B of the compound of formula I.
  • the X-ray diffraction method is based on the four general principles of the 2015 edition of the Pharmacopoeia of the People’s Republic of China: Method 2: The X-ray powder diffraction spectrum of the sample is measured under the following conditions.
  • the instrument and its model the Netherlands PANalytical Empyrean X-ray powder diffractometer; test condition: monochromatic Cu-K ⁇ rays , Scan mode: 0/20, scan range: 0-50°, tube pressure: 35Kv, tube flow 30mA, scan speed 8°/min.
  • the DSC spectrum of the sample is measured under the following conditions according to the 0661 thermal analysis method of the four general rules of the 2015 edition of the Pharmacopoeia of the People's Republic of China, the instrument and its model: American TA Instruments DSC Q20 Differential Scanning Calorimeter; Test conditions: purge gas: nitrogen, initial temperature: 0°C, termination temperature 200°C, heating rate: 20°C/min.
  • the TGA spectrum of the sample is measured under the following conditions according to the 0661 thermal analysis method of the four general principles of the "Pharmacopeia of the People's Republic of China" 2015 edition, the instrument and its model: American TA Instruments TGA Q500 thermogravimetric analyzer; test conditions : Purge gas: nitrogen, initial temperature: 0°C, end temperature 800°C, heating rate: 20°C/min.
  • the four general rules 0451 X-ray diffraction method Method 1
  • the X-ray single crystal diffraction spectrum of the sample is measured under the following conditions, the instrument and its model: PANalytical, Netherlands Empyrean X-ray powder diffractometer; test condition: monochromatic Cu-K ⁇ rays Scan mode: 0/20, scan range: 0-50°, tube pressure: 35Kv, tube flow 30mA.
  • the various crystal form characterization data of the present invention is affected by various factors such as detection equipment and conditions, and the peak position or relative intensity of the measured X-ray powder diffraction pattern may exist.
  • the relative position of the peaks rather than their relative intensity, which is also well known in the field of crystallography. It is worth noting that due to temperature changes, sample movement, or instrument calibration, the peak position of the characteristic peak can be moved within an appropriate range, and the measurement error of the 2 ⁇ value is recognized as ⁇ 0.2°.
  • the DSC can be used to analyze the transition temperature when the crystal absorbs or releases heat due to the crystallization phenomenon or crystal melting.
  • the error of the transformation temperature and the melting point should be within 5°C according to the known crystallography, and should be within 3°C under normal circumstances.
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • the crystal is at approximately 11.21 ⁇ 0.2°(7.90), 12.61 ⁇ 0.2°(7.02), 14.69 ⁇ 0.2°(6.03), 16.14 ⁇ 0.2°(5.49), 17.81 ⁇ 0.2°(4.98), 19.42 ⁇ 0.2°(4.57) ), 20.22 ⁇ 0.2°(4.39), 20.76 ⁇ 0.2°(4.27), 22.10 ⁇ 0.2°(4.02), 23.24 ⁇ 0.2°(3.83), 24.31 ⁇ 0.2°(3.66), 27.01 ⁇ 0.2°(3.30), There are characteristic peaks at 27.68 ⁇ 0.2°(3.22), 28.57 ⁇ 0.2°(3.12), and 31.09 ⁇ 0.2°(2.88).
  • the DSC spectrum is shown in Figure 2, with one and only one sharp melting endothermic peak at 151.71°C, and the TGA spectrum is shown in Figure 3. This crystal form is defined as the B crystal form.
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • This example provides a method for preparing the crystal form of compound B of formula I of the present invention, specifically:
  • This example is a comparative example, and provides a method for preparing crystal forms in the prior art (CN 104245707), specifically:
  • This example is a comparative example, and provides a method for preparing crystal forms in the prior art (CN 104245707), specifically:
  • This example is a comparative example, and provides a method for preparing crystal forms in the prior art (CN 104245707), specifically:
  • Chromatographic conditions and system suitability test use octadecylsilane bonded silica gel as filler, water (adjust pH to 3.8 with phosphoric acid): acetonitrile (45:55) as mobile phase, detection wavelength is 220nm; theoretical tower The number of plates should not be less than 2000, the resolution should not be less than 2.0, and the separation from other adjacent impurity peaks should meet the requirements.
  • Test solution Take an appropriate amount of the compound of each example, accurately weigh it, and dissolve it with absolute ethanol and dilute it quantitatively to make a solution containing about 1 mg per 1 ml as the test solution.
  • Control solution accurately measure 1ml of the reference solution of the compound represented by formula I, put it in a 100ml volumetric flask, dilute to the mark with absolute ethanol, and shake well to obtain.
  • Reference substance Standard substance of the compound of formula I calibrated provided by Chengdu Shibeikang Biomedical Technology Co., Ltd.
  • Determination method According to the high performance liquid chromatography "Chinese Pharmacopoeia” 2015 edition of the four general rules 0512, accurately measure 10 ⁇ l each of the test solution and the control solution, respectively inject into the liquid chromatograph, and record the chromatogram.
  • Example 1 99.82 ⁇ 0.10 ⁇ 0.30 2
  • Example 2 99.92 ⁇ 0.10 ⁇ 0.30 2
  • Example 3 99.94 ⁇ 0.10 ⁇ 0.30 2
  • Example 4 99.89 ⁇ 0.10 ⁇ 0.30 2
  • Example 5 99.87 ⁇ 0.10 ⁇ 0.30 2
  • Example 6 99.91 ⁇ 0.10 ⁇ 0.30 2
  • Example 7 99.88 ⁇ 0.10 ⁇ 0.30 2 Comparative Preparation Example 1 96.89 >0.50 >0.45 5
  • Comparative preparation example 2 96.43 >0.50 >0.45 5
  • Comparative Preparation Example 3 97.73 >0.50 >0.45 5
  • the purity of the type B crystal prepared by the present invention is greater than 99%, and the maximum single impurity is less than 0.1%, which meets the requirements of the ICH impurity standards for raw materials.
  • the diastereomers are metabolic components in the body.
  • the impurity requirements can be relatively relaxed; compared with the comparison of various preparation examples, the type B crystal prepared by the present invention has a higher content, a lower maximum single impurity content, and a smaller number of impurities.
  • the crystal compound of each comparative preparation example did not meet the requirements for medicinal use.
  • the type B crystal samples obtained in each embodiment and each comparative preparation example were placed in an open and flat position, and the samples were examined under the conditions of light (4500 Lux), heating at 40°C, 60°C, and high humidity for 5 days and 10 days. Day stability.
  • the detection was carried out according to the detection method of Experiment 1, and the HPLC purity detection results are shown in the following table.
  • Example 5 99.87 99.87 99.86
  • Example 6 99.91 99.91 99.90
  • Example 7 99.88 99.88 99.87
  • Comparative Preparation Example 1 96.89 96.80 96.75
  • Comparative preparation example 2 96.43 96.35 96.27
  • Comparative Preparation Example 3 97.73 97.70 97.65
  • the crystalline compound of the comparative preparation example is more sensitive to temperature; the type B crystal prepared in each example of the present invention is compared with the crystalline compound of the comparative preparation example, the type B crystal prepared in each embodiment of the present invention The stability is better, which is significantly better than the crystalline compound of the comparative preparation example.
  • the crystalline compound of the comparative preparation example is more sensitive to high temperature; the type B crystal prepared in each embodiment of the present invention is compared with the crystalline compound of the comparative preparation example, the type B prepared in each embodiment of the present invention The crystal stability is better, which is significantly better than the crystal compound of the comparative preparation example.
  • the crystalline compound of the comparative preparation example is also more sensitive to high humidity; the B-type crystal prepared in each embodiment of the present invention is compared with the crystalline compound of the comparative preparation example, the B prepared in each embodiment of the present invention The crystal form has better stability and is significantly better than the crystal form compound of the comparative preparation example.
  • the crystal form of compound B of formula I obtained in Example 1 and the stability of the crystal form were investigated by grinding and heating.
  • the melting point data is as follows:
  • Measurement method Fix the iron ring on the iron stand, place the watch glass directly under the funnel, adjust the watch glass so that its origin is perpendicular to the funnel, and slowly add multiple batches of materials from the funnel to the edge of the watch glass If the material cannot be contained, it becomes a regular cone. This is to stop feeding, measure the height h of the material with a ruler, and then measure the outer diameter R of the watch glass.
  • the formula: tang ⁇ 2h/R. Calculating the ⁇ value is the angle of repose.
  • Example 1 The mixture prepared in Example 1 has better fluidity than the mixture prepared with the crystal form of the comparative preparation example, which is more conducive to the control of the difference in tablet weight during tablet compression, and is more conducive to the stability of the tablet. Automated and commercialized production, the results show that the crystal form B of Example 1 has a significant advantage in fluidity (**P ⁇ 0.01).
  • Test method Two kinds of tablets of different crystal forms of the compound of formula (I) with the same content were prepared by using the same type and weight of auxiliary materials and the same powder compression process.
  • the other is to compare the crystalline tablets of the preparation example, and compare the efficacy of the two crystalline tablets against platelet aggregation.
  • Example 1 group and the comparative preparation example were all orally administered 30 mg (in pure Formula (I) compound calculation, same content) tablets, blood was collected from dogs before administration and 6 hours after administration to collect platelet-rich plasma; platelet aggregation was induced by 20 ⁇ M ADP, and platelet aggregation instrument was used to measure the aggregation rate in platelet-rich plasma;
  • Example 1 and the comparative preparation example were all orally administered 30 mg (calculated as the pure compound of formula (I), the same content) tablets, before and after administration 6
  • Blood was collected from dogs at a young age to collect platelet-rich plasma; 20 ⁇ M ADP was used to induce platelet aggregation, and the platelet aggregation instrument was used to determine the small blood aggregation rate in platelet-rich plasma.
  • Example 1 crystal form B
  • Example 1 has a stronger anti-ADP-induced platelet aggregation effect (* P ⁇ 0.05), it has a significant advantage and is a superior crystal form with potential for further development of medicinal use, and it is worthy of further in-depth study.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

本发明公开了结构如式I如示的四氢噻吩并吡啶化合物的B晶型及制法、组合物和应用，解决现有技术中杂质多，含量低，晶型稳定性差，无法成药的问题。所述B晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、20.22±0.2°、22.10±0.2°处有特征峰。本发明的B晶型杂质少、稳定性好，结晶度好，重现性，适合工业化生产；还具有预料不到的更强的抗ADP诱导的血小板聚集作用和更良好的流动性。

Description

四氢噻吩并吡啶化合物的B晶型及制法、组合物和应用 技术领域
本发明属于药物化学技术领域，具体涉及四氢噻吩并吡啶化合物(S)-2-(2-氯苯基)-2-((S)-2-氧代-2,6,7,7a-四氢噻吩[3,2-c]并吡啶-5(4H)基)乙酸甲酯的B晶型，及制法、组合物和应用。
技术背景
据《中国心血管病报告2017》数据显示，我国心血管病(CVD)患病率及死亡率近年来一直处于上升阶段，推算CVD现患人数2.9亿，其中脑卒中1300万，冠心病1100万，心力衰竭450万，高血压2.7亿。而发表在《心脏病学》(JAMA Cardiology)的最新调查数据显示，2016年因CVD导致的总体死亡人数在我国高达397万，占居民疾病死亡总数的40％以上，已经成为我国居民因病死亡的首要因素，高于肿瘤致死人数。其中，心脑血管血栓性疾病如：缺血性脑卒中(IS)，出血性脑卒中(HS)则是最主要的高致死性疾病。同时，最近完成的一项由Ness-China主持的中国卒中疾病负担横断面调查研究结果显示，截止至2013年，脑卒中发病率粗率在我国已达到了每10万人每年中发病345.1例的惊人水平，预示着中国现已成为血栓病的高发国家。因此，对心脑血栓类疾病的防控和治疗在此种严峻形势下更显得尤为重要。
血栓形成的关键生理途径是通过血小板黏附、聚集而完成。因此，血小板聚集抑制类药物在治疗血栓病中发挥着重要作用,也是人们研究的热点。Sanofi公司的氯吡格雷(波立维)作为其中最具有代表性的抗凝血药物，由于其良好的安全性和能快速抑制血小板聚集的优点，在目前的防治血栓类疾病的临床一线治疗和预防中有着广泛的应用。但遗憾的是由于氯吡格雷得药效，特别是在亚洲人中存在显著的个体差异性，即氯吡格雷抵抗(CPGR)，使得氯吡格雷的应用受到限制。2010年Farid等人对氯吡格雷的代谢体内代谢进行了细致而全面的研究(J.Clin.Pharmacol 2010；50:126-142)，揭示了CPGR的成因是由于个体肝脏内CYP酶活性差异化导致，具体表现为氯吡格雷在部分患者的肝脏内无法被正常代谢，无法产生式I结构的代谢产物及其光学异构体，因而阻断了氯吡格雷被后续地进一步被代谢为活性成分，无法发挥抗凝作用。式I结构的化合物化学名为：(S)-2-(2-氯苯基)-2-((S)-2-氧代-2,6,7,7a-四氢噻吩[3,2-c]并吡啶-5(4H)基)乙酸甲酯。
Figure PCTCN2020081091-appb-000001
根据该代谢途径，药学研究者对氯吡格雷进行了一系列的结构优化，希望能借此克服CPGR，但遗憾的是包括维卡格雷、普拉格雷等诸多大胆的尝试都因结构修饰所带来的副作用而均未能取得令人满意的成果。而在另一方面，印度IPCA实验室通过专利CN 104245707启发性地简单公开了一种式I结构化合物的制备方法及其成药性的初步研究，由于该化合物即为氯吡格雷的正常CYP酶代谢产物，可以预见的，该化合物能够克服CPGR并在继承氯吡格雷的传统药效同时，将其于由结构改变带来的不可控的其它风险降至最低，但遗憾的是，该专利并未深入研究该化合物的结晶形式，仅仅通过消旋混合物进行选择性析出式I结构的晶型，虽然和非对映异构体比较，手性纯度较高；但其他杂质多，含量低，晶型稳定性差，且无法成药。
本领域技术人员公知，药用活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件和储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型，从而影响药物制剂的稳定性、水溶性、储存性等，进而影响药品的安全性和可靠性。因此，对式I结构化合物晶型的深入研究很有必要。提供一种稳定性好、安全性高、适于工业生产，且具有良好成药前景的式I结构化合物的晶型，成为了本领域技术人员亟待解决的问题。
发明内容
本发明的目的之一在于，提供一种式I结构的四氢噻吩并吡啶化合物(S)-2-(2-氯苯基)-2-((S)-2-氧代-2,6,7,7a-四氢噻吩[3,2-c]并吡啶-5(4H)基)乙酸甲酯的B晶型，解决现有技术中杂质多，含量低，晶型稳定性差，无法成药的问题。
本发明的目的之二在于，提供该B晶型的制备方法。
本发明的目的之三在于，提供一种包含该B晶型的药物组合物。
本发明的目的之四在于，提供该B晶型的应用。
为实现上述目的，本发明采用的技术方案如下：
本发明所述的一种结构如式I所示的四氢噻吩并吡啶化合物的B晶型，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、20.22±0.2°、22.10±0.2°处有特征峰；
Figure PCTCN2020081091-appb-000002
进一步地，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、20.22±0.2°、22.10±0.2°、23.24±0.2°、27.68±0.2°、28.57±0.2° 处有特征峰。
进一步地，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、19.42±0.2°、20.22±0.2°、20.76±0.2°、22.10±0.2°、23.24±0.2°、24.31±0.2°、27.01±0.2°、27.68±0.2°、28.57±0.2°、31.09±0.2°处有特征峰。
进一步地，所述B晶型的X-射线粉末衍射图如图1所示。
进一步地，所述B晶型的差示扫描量热分析图谱在151.71±5℃处有吸热峰。
进一步地，所述B晶型的差示扫描量热分析图谱如图2所示。
经热重分析(TGA)可知，本发明的B晶型在100℃前以及100～170℃间均无明显失重，表明本晶型中不含易挥发溶剂、吸附水以及结晶水；
进一步地，所述B晶型的热重分析图谱如图3所示。
在本发明的一个优选的实施例中提供了式I化合物的单晶结构，根据X射线单晶衍射数据表明，该晶体的晶系为单斜晶系，其所属空间群为P21群，晶格常数
Figure PCTCN2020081091-appb-000003
Figure PCTCN2020081091-appb-000004
α＝90°，β＝102.618(6)°，γ＝90°；所述B晶型的单晶具有如图4所示的X射线单晶衍射图谱。
本发明所述的一种制备上述的式I化合物的B晶型的方法，将任意晶型或无定型的式I化合物的粗品以任意方式溶解于溶剂中，而后冷却或者浓缩使其析晶，过滤结晶并洗涤，干燥，即得。
式I化合物的粗品指式I化合物的质量含量小于98％。
所述溶剂选自碳原子数小于等于7的醇类、酮类、腈类、醚类、酯类、砜类的任意一种或几种；或它们中的任意一种或几种与水的混合溶剂。
优选地，所述醇类包括甲醇、乙醇、异丙醇、1-丙醇、2-丙醇、1-丁醇、2-丁醇、戊醇；所述酮类包括丙酮、甲基乙基酮、甲基异丙基酮；所述腈类包括乙腈；所述醚类包括乙醚、异丙醚、甲基叔丁基醚、苯甲醚；所述酯类包括甲基四氢呋喃、甲酸乙酯、乙酸乙酯、乙酸丙酯、乙酸丁酯、乙酸异丙酯、乙酸异丁酯；所述砜类包括二甲基亚砜。
冷却析晶的条件为-20℃至常温下静置析晶。
浓缩析晶的条件为旋转蒸发仪在外温35℃下浓缩溶剂进行析晶。
在某些特定的实施例中，采用冰的对应结晶溶剂对过滤滤饼进行洗涤，优选为0℃对应结晶溶剂。
所述干燥为常压下35℃空气中干燥。
本发明所述的一种药物组合物，其包含上述的化合物的B晶型，以及一种或多种药学上 可接受的载体。所述“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
本发明所述的式I化合物的B晶型在制备预防或治疗因血小板高聚集引起的心、脑及其他动脉循环障碍疾病中的药物中的用途。所述其他动脉循环系统障碍疾病包括脑卒中、急性冠脉综合症、动脉粥样硬化、心肌梗死和确诊的外周动脉疾病。
与现有技术相比，本发明具有以下有益效果：
本发明创造性地发现，对式I化合物(S)-2-(2-氯苯基)-2-((S)-2-氧代-2,6,7,7a-四氢噻吩[3,2-c]并吡啶-5(4H)基)乙酸甲酯的单一异构体粗品进行精制结晶，可获得了一种杂质少、稳定性好，结晶度好，重现性和操作性等方面具有优异优势的晶型：B晶型。且B晶型的制备方法简单，溶剂可控且廉价易得，结晶条件温和，晶型稳定，适合工业化生产。
此外，B晶型还具有预料不到的技术效果：具有更强的抗ADP诱导的血小板聚集作用，与现有技术报道的晶型相比，具有显著性差异，是具备进一步开发的药用潜力的优势晶型。此外，B晶型还具备预料不到的更良好的流动性，使其具备更好的压片性能，更有利于成品的片重差异控制，从而进一步保证用药的有效性和安全性。
附图说明
图1为式I化合物B晶型的XRPD图谱。
图2为式I化合物B晶型的DSC图谱。
图3为式I化合物B晶型的TGA图谱。
图4为式I化合物B晶型的单晶衍射图谱。
具体实施方式
以下以具体的实施例对本发明的技术方案，但本发明的保护范围不限于所述的实施例范围。所采用的试剂均为市售产品。
本发明实施例中，依据《中华人民共和国药典》2015版四部通则0451X射线衍射法：第二法，样品的X-射线粉末衍射光谱在下述条件下测定，仪器及其型号：荷兰帕纳科Empyrean X射线粉末衍射仪；测试条件：单色Cu-Kα射线
Figure PCTCN2020081091-appb-000005
,扫描方式：0/20，扫描范围：0-50°，管压：35Kv，管流30mA，扫描速度8°/分钟。
本发明实施例中，依据《中华人民共和国药典》2015版四部通则0661热分析法，样品的DSC谱图在下述条件下测定，仪器及其型号：美国TA仪器DSC Q20差示扫描量热仪；测试条件：吹扫气：氮气，初始温度：0℃，终止温度200℃，升温速率：20℃/分钟。
本发明实施例中，依据《中华人民共和国药典》2015版四部通则0661热分析法，样品的TGA谱图在下述条件下测定，仪器及其型号：美国TA仪器TGA Q500热重分析仪；测试条件：吹扫气：氮气，初始温度：0℃，终止温度800℃，升温速率：20℃/分钟。
本发明实施例中，依据《中华人民共和国药典》2015版四部通则0451X射线衍射法：第一法，样品的X-射线单晶衍射光谱在下述条件下测定，仪器及其型号：荷兰帕纳科Empyrean X射线粉末衍射仪；测试条件：单色Cu-Kα射线
Figure PCTCN2020081091-appb-000006
扫描方式：0/20，扫描范围：0-50°管压：35Kv，管流30mA。
本领域技术人员应当理解，本发明所述的各种晶型表征数据，由于受到检测设备及条件等各种因素的影响，所测得的X射线粉末衍射图谱的出峰位置或者相对强度会存在一定差异，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度，这在晶体学领域内也是公知。值得注意的是由于温度的变化、样品移动、或仪器的标定等，特征峰的出峰位置可以在适当范围内进行移动，其中2θ值的测定误差公认为±0.2°。
另外，通过DSC可以分析当晶体由于转晶现象或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，转晶温度和熔点的误差根据晶体学公知在应限定5℃之内，正常情况下应在3℃之内。
本发明实施例中所用的式I所示单一异构体化合物粗品为参照专利号CN 104245707公开的实施例2方法制备而成。
实施例1
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取5.0g式I所示单一异构体化合物粗品加入100mL茄型瓶中，加入40mL丙酮，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于100mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.58g固体，收率为58％。该结晶在约11.21±0.2°(7.90)、12.61±0.2°(7.02)、14.69±0.2°(6.03)、16.14±0.2°(5.49)、17.81±0.2°(4.98)、19.42±0.2°(4.57)、20.22±0.2°(4.39)、20.76±0.2°(4.27)、22.10±0.2°(4.02)、23.24±0.2°(3.83)、24.31±0.2°(3.66)、27.01±0.2°(3.30)、27.68±0.2°(3.22)、28.57±0.2°(3.12)、和31.09±0.2°(2.88)处有特征峰。DSC谱图见图2，有且仅有一处尖锐熔融吸热峰151.71℃，TGA图谱见图3，将此晶型定义为B晶型。
实施例2
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取100mg式I所示单一异构体化合物粗品，加入10mL茄型瓶中，加入5mL丙酮，在60℃下震荡溶解，趁热过滤，滤液置入洁净的5mL茄型瓶中缓慢静置降温至室温，得到式I所示 化合物单晶，结晶度高，单晶衍射图谱见图4，单晶低温研磨后，其X射线粉末衍射图谱以及DSC图谱经研究对比，确定产物为B晶型。
实施例3
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取1.0g式I所示单一异构体化合物粗品加入100mL茄型瓶中，加入35mL乙腈，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于100mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.42g固体，收率为42％。其X射线粉末衍射和DSC图谱经研究对比，确定产物为B晶型。
实施例4
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取1.0g式I所示单一异构体化合物粗品加入50mL茄型瓶中，加入15mL乙醇，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于50mL烧杯中搅拌，并缓慢降温至室温，并在-20℃下静置析晶。干燥得0.45g固体，收率为45％。其X射线粉末衍射和DSC图谱经研究对比，确定产物为B晶型。
实施例5
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取1.0g式I所示单一异构体化合物粗品加入50mL茄型瓶中，加入20mL乙醚，升温至30℃搅拌溶解，基本溶清，趁热过滤，滤液置于50mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.45g固体，收率为45％。其X射线粉末衍射和DSC图谱经研究对比，确定产物为B晶型。
实施例6
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取1.0g式I所示单一异构体化合物粗品加入50mL茄型瓶中，加入30mL四氢呋喃，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于50mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.38g固体，收率为38％。其X射线粉末衍射和DSC图谱经研究对比，确定产物为B晶型。
实施例7
本实施例提供了本发明的式I结构化合物B晶型的制备方法，具体为：
取1.0g式I所示单一异构体化合物粗品加入50mL茄型瓶中，加入20mLDMSO，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于50mL烧杯中搅拌，并缓慢降温至室温，冰 浴搅拌过夜析晶。干燥得0.28g固体，收率为28％。其X射线粉末衍射和DSC图谱经研究对比，确定产物为B晶型。
对比制备例1
本实施例为对比例，提供了现有技术(CN 104245707)中晶型的制备方法，具体为：
取1.0g式I所示消旋混合物粗品(按CN 104245707公开的实施例1的方法制备)加入100mL茄型瓶中，加入30mL乙酸乙酯，1.5mL甲醇，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于100mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.32g固体，收率为32％。经X-射线粉末衍射图谱对比和熔点检测(熔程为135.0-138.0℃)，确定为CN 104245707所述晶型。
对比制备例2
本实施例为对比例，提供了现有技术(CN 104245707)中晶型的制备方法，具体为：
取1.0g式I所示消旋混合物粗品(按CN 104245707公开的实施例1的方法制备)加入100mL茄型瓶中，加入30mL乙酸乙酯，3mL甲醇，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于100mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.38g固体，收率为38％。。经X-射线粉末衍射图谱对比和熔点检测(熔程为134.5-138.0℃)，确定为CN104245707所述晶型。
对比制备例3
本实施例为对比例，提供了现有技术(CN 104245707)中晶型的制备方法，具体为：
取5.0g式I所示消旋混合物粗品(按CN 104245707公开的实施例1的方法制备)加入100mL茄型瓶中，加入30mL乙酸乙酯，6mL甲醇，升温至60℃搅拌溶解，基本溶清，趁热过滤，滤液置于100mL烧杯中搅拌，并缓慢降温至室温，搅拌过夜析晶。干燥得0.41g固体，收率为41％。经X-射线粉末衍射图谱对比和熔点检测(熔程为135.0-138.0℃)，确定为CN104245707所述晶型。
试验1，实施例晶型有关物质测定
对各实施例及各对比制备例得到的式I所示的化合物晶型进行HPLC分析。
仪器与设备：安捷伦Agilent-1100高效液相色谱仪；
色谱条件与系统适用性试验：用十八烷基硅烷键合硅胶为填充剂，以水(用磷酸调pH值至3.8)：乙腈(45：55)为流动相，检测波长为220nm；理论塔板数不得低于2000，分离度不得低于2.0，与其他相邻杂质峰的分离度应符合要求。
供试品溶液：取各实施例化合物适量，精密称定，加无水乙醇溶解并定量稀释制成每1ml中约含1mg的溶液作为供试品溶液。
对照溶液：精密量取式I所示的化合物的对照品溶液1ml，置100ml容量瓶中，加无水乙醇稀释至刻度，摇匀，即得。对照品：由成都施贝康生物医药科技有限公司提供的标定的式I化合物的标准品。
测定方法：按照高效液相色谱法《中国药典》2015年版四部通则0512，精密量取供试品溶液和对照溶液各10μl，分别注入液相色谱仪，记录色谱图。
表1，实施例晶型有关物质测定结果
编号 含量(％) 最大单杂(％) 非对映异构体(％) 杂质数
实施例1 99.82 <0.10 <0.30 2
实施例2 99.92 <0.10 <0.30 2
实施例3 99.94 <0.10 <0.30 2
实施例4 99.89 <0.10 <0.30 2
实施例5 99.87 <0.10 <0.30 2
实施例6 99.91 <0.10 <0.30 2
实施例7 99.88 <0.10 <0.30 2
对比制备例1 96.89 >0.50 >0.45 5
对比制备例2 96.43 >0.50 >0.45 5
对比制备例3 97.73 >0.50 >0.45 5
表1可以看出，本发明制备得的B型晶的纯度均大于99％，且最大单杂<0.1％，符合原料药ICH杂质标准要求，非对映异构体为体内代谢成分，按照ICH杂质要求，可相对放宽标准；和对比各制备例比较，本发明制备得的B型晶，含量更高，最大单杂含量更低，杂质个数更少。
按照原料药ICH杂质要求，各对比制备例晶型化合物不符合药用要求。
试验2，实施例晶型稳定性考察
将各实施例及各对比制备例所得B型结晶样品，分别敞口平摊放置，考察在光照(4500Lux)，加热40℃、60℃，高湿75％、90％条件下样品5天和10天的稳定性。按照试验1的检测方法进行检测，HPLC纯度检测结果见下表。
表2，实施例光照(4500Lux)条件下的测定结果
编号 0天(％) 5天(％) 10天(％)
实施例1 99.82 99.82 99.82
实施例2 99.92 99.92 99.92
实施例3 99.94 99.94 99.94
实施例4 99.89 99.89 99.89
实施例5 99.87 99.87 99.86
实施例6 99.91 99.91 99.90
实施例7 99.88 99.88 99.87
对比制备例1 96.89 96.80 96.75
对比制备例2 96.43 96.35 96.27
对比制备例3 97.73 97.70 97.65
表2可以看出，本发明各实施例制备得的B型晶、对比制备例晶型化合物在光照(4500Lux)条件下均较为稳定，相比较而言，本发明各实施例制备得的B型晶稳定性更好。
表3加热40℃条件下的稳定性结果
编号 0天(％) 5天(％) 10天(％)
实施例1 99.82 99.82 99.81
实施例2 99.92 99.92 99.91
实施例3 99.94 99.93 99.93
实施例4 99.89 99.89 99.88
实施例5 99.87 99.87 99.87
实施例6 99.91 99.91 99.90
实施例7 99.88 99.88 99.88
对比制备例1 96.89 96.31 95.35
对比制备例2 96.43 96.01 94.78
对比制备例3 97.73 97.22 96.13
表3可以看出，对比制备例的晶型化合物对温度较为敏感；本发明各实施例制备得的B型晶与对比制备例的晶型化合物比较，本发明各实施例制备得的B型晶稳定性更好，显著优于对比制备例的晶型化合物。
表4加热60℃条件下的稳定性结果
编号 0天(％) 5天(％) 10天(％)
实施例1 99.82 99.79 99.77
实施例2 99.92 99.87 99.84
实施例3 99.94 99.90 99.88
实施例4 99.89 99.87 99.86
实施例5 99.87 99.85 99.85
实施例6 99.91 99.89 99.88
实施例7 99.88 99.85 99.84
对比制备例1 96.89 95.45 94.37
对比制备例2 96.43 95.23 93.89
对比制备例3 97.73 96.60 95.23
表4可以看出，对比制备例的晶型化合物对高温更为敏感；本发明各实施例制备得的B型晶与对比制备例的晶型化合物比较，本发明各实施例制备得的B型晶稳定性更好，显著优于对比制备例的晶型化合物。
表5高湿90％的稳定性结果
编号 0天(％) 5天(％) 10天(％)
实施例1 99.82 99.82 99.81
实施例2 99.92 99.92 99.91
实施例3 99.94 99.94 99.94
实施例4 99.89 99.89 99.89
实施例5 99.87 99.87 99.86
实施例6 99.91 99.91 99.90
实施例7 99.88 99.88 99.87
对比制备例1 96.89 96.75 96.69
对比制备例2 96.43 96.33 96.23
对比制备例3 97.73 97.66 97.58
表5可以看出，对比制备例的晶型化合物对高湿也较为敏感；本发明各实施例制备得的B型晶与对比制备例的晶型化合物比较，本发明各实施例制备得的B型晶稳定性更好，显著优于对比制备例的晶型化合物。
试验3、熔点数据的测定
将实施例1所得式I化合物B晶型以及进行研磨、加热处理考察其晶型稳定性，熔点数据如下：
表6，实施例熔点数据
Figure PCTCN2020081091-appb-000007
表6可以看出，众所周知，稳定性越好的晶型，熔点越高，熔点不同，晶型不同；可见本发明各实施例1制备得的B型晶，熔点高于对比制备例化合物，进一步说明B型晶稳定性更好，显著优于对比制备例的晶型化合物。
试验4、实施例的压片性能研究
试验方法：
①将原料粉碎后过80目。
②按上述按照同样的处方称取原辅料，将原料和部分乳糖混合后，将原料、乳糖混合物，剩余乳糖、微晶纤维素、玉米淀粉和交联聚维酮混合均匀后，再加入硬脂酸镁混合均匀。
③物料流动性的测定
测定方法：将铁圈固定在铁架台上，将表面皿放在漏斗正下方，调整表面皿使其原点与漏斗成垂直线，将多批物料从漏斗缓缓加入，一直加到表面皿的边缘盛不下物料，即成规则的圆锥体为止，这是停止加料，用尺子测定物料高度h，再测定表面皿外直径R，公式：tangθ＝2h/R。算出θ値既是休止角。
表7制剂处方组成
Figure PCTCN2020081091-appb-000008
表8，总混颗粒休止角检测结果：
  对比制备例1 实施例1
休止角 38.3°±0.5 30.5°±0.7**
注：对比制备例比较，**表示P<0.01。
结论：试验结果见表8，用实施例1制备的混合物料比用对比制备例的晶型制备的混合物料流动性更好，更有利于压片时片重差异的控制，更有利于片子的自动化和商业化生产，结果说明实施例1的B晶型在流动性上具有显著的优势(**P<0.01)。
试验5、实施例的药效学作用研究
试验方法：通过同样型号和重量的辅料，同样的粉末压片工艺，制备同样含量的式(I)化合物的不同晶型的两种片剂，一种是实施例1(B晶型)的片剂；另一种是对比制备例的晶型的片剂，比较两种晶型片剂抗血小板聚集的疗效。
8只雄性比格犬，体重差异不超过1kg，按体重随机分为两组，每组4只，分两周期给药，第一周期实施例1组和对比制备例均口服给予30mg(以纯的式(I)化合物计算，相同的含量)片剂，给药前、给药后6小时犬取血收集富血小板血浆；以20μM ADP诱导血小板聚集，血小板聚集仪测定富血小板血浆中聚集率；
洗脱14天后，动物交叉，第二周期同样，实施例1组和对比制备例均口服给予30mg(以纯的式(I)化合物计算，相同的含量)片剂，给药前、给药后6小时犬取血收集富血小板血浆；以20μM ADP诱导血小板聚集，血小板聚集仪测定富血小板血浆中血小聚集率。
试验结果见9：
表9，实施例药效学试验结果(n＝8)
Figure PCTCN2020081091-appb-000009
注：对比制备例比较，*表示P<0.05
结论：试验结果见表9，和对比制备例比较，给药前无显著性差异，但给药后6小时，实施例1(B晶型)具有更强的抗ADP诱导的血小板聚集作用(*P<0.05)，具有显著性的优势，是具备进一步开发的药用潜力的优势晶型，值得进一步的深入研究。
本发明公开和提出的(S)-2-(2-氯苯基)-2-((S)-2-氧代-2,6,7,7a-四氢噻吩[3,2-c]并吡啶-5(4H)基)乙酸甲酯的B晶型及其制备方法，本领域技术人员可通过借鉴本文内容，适当改变原料、工艺参数等环节实现。本发明的方法与产品已通过较佳实施例子进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和产品进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，他们都被视为包括在本发明精神、范围和内容中。

Claims (10)

  1. 一种结构如式I所示的四氢噻吩并吡啶化合物的B晶型，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、20.22±0.2°、22.10±0.2°处有特征峰；
    Figure PCTCN2020081091-appb-100001
  2. 根据权利要求1所述的四氢噻吩并吡啶化合物的B晶型，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、20.22±0.2°、22.10±0.2°、23.24±0.2°、27.68±0.2°、28.57±0.2°处有特征峰。
  3. 根据权利要求2所述的四氢噻吩并吡啶化合物的B晶型，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.21±0.2°、12.61±0.2°、14.69±0.2°、16.14±0.2°、17.81±0.2°、19.42±0.2°、20.22±0.2°、20.76±0.2°、22.10±0.2°、23.24±0.2°、24.31±0.2°、27.01±0.2°、27.68±0.2°、28.57±0.2°、31.09±0.2°处有特征峰。
  4. 根据权利要求1所述的四氢噻吩并吡啶化合物的B晶型，其特征在于，所述晶型的X-射线粉末衍射图如图1所示。
  5. 根据权利要求4所述的四氢噻吩并吡啶化合物的B晶型，其特征在于，所述晶型的差示扫描量热分析图谱在151.71±5℃处有吸热峰。
  6. 根据权利要求5所述的四氢噻吩并吡啶化合物的B晶型，其特征在于，所述晶型的差示扫描量热分析图谱如图2所示。
  7. 根据权利要求7所述的四氢噻吩并吡啶化合物的B晶型，其特征在于，所述晶型的热重分析图谱如图3所示。
  8. 一种制备如权利要求1-7任意一项所述的四氢噻吩并吡啶化合物的B晶型的方法，其特征在于：将任意晶型或无定型的式I化合物的粗品以任意方式溶解于溶剂中，而后冷却或者浓缩使其析晶，过滤结晶并洗涤，干燥，即得。
  9. 一种药物组合物，其包含权利要求1-7中任意一项所述的四氢噻吩并吡啶化合物的B晶型，以及一种或多种药学上可接受的载体。
  10. 权利要求1-7中任意一项所述的四氢噻吩并吡啶化合物的B晶型在制备预防或治疗因血小板高聚集引起的心、脑及其他动脉循环障碍疾病中的药物中的用途。
PCT/CN2020/081091 2019-05-17 2020-03-25 四氢噻吩并吡啶化合物的b晶型及制法、组合物和应用 WO2020233226A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP20808820.3A EP3985009B1 (en) 2019-05-17 2020-03-25 B crystal form of tetrahydrothienopyridine compound, preparation method therefor, composition and application
US17/750,688 US20220289761A1 (en) 2019-05-17 2022-05-23 Crystalline form b of tetrahydrothienopyridine compound, preparation method, composition and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910412233.5 2019-05-17
CN201910412233.5A CN111943958B (zh) 2019-05-17 2019-05-17 四氢噻吩并吡啶化合物的b晶型及制法、组合物和应用

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/750,688 Continuation US20220289761A1 (en) 2019-05-17 2022-05-23 Crystalline form b of tetrahydrothienopyridine compound, preparation method, composition and application thereof

Publications (1)

Publication Number Publication Date
WO2020233226A1 true WO2020233226A1 (zh) 2020-11-26

Family

ID=73336829

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/081091 WO2020233226A1 (zh) 2019-05-17 2020-03-25 四氢噻吩并吡啶化合物的b晶型及制法、组合物和应用

Country Status (4)

Country Link
US (1) US20220289761A1 (zh)
EP (1) EP3985009B1 (zh)
CN (1) CN111943958B (zh)
WO (1) WO2020233226A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115327003B (zh) * 2022-08-12 2024-03-12 成都施贝康生物医药科技有限公司 一种氧化氯吡格雷有关物质的检测方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120329762A1 (en) * 2011-06-27 2012-12-27 Ashok Kumar Anti-thrombotic compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108685913B (zh) * 2018-07-31 2021-08-10 成都施贝康生物医药科技有限公司 含氧吡格雷光学异构体或其盐的组合物及制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120329762A1 (en) * 2011-06-27 2012-12-27 Ashok Kumar Anti-thrombotic compounds
CN104245707A (zh) 2011-06-27 2014-12-24 Ipca实验室有限公司 抗血栓化合物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", vol. IV, 2015
FARID ET AL., J. CLIN. PHARMACOL, vol. 50, 2010, pages 126 - 142
See also references of EP3985009A4

Also Published As

Publication number Publication date
EP3985009A4 (en) 2023-06-28
EP3985009A1 (en) 2022-04-20
EP3985009B1 (en) 2024-05-08
US20220289761A1 (en) 2022-09-15
CN111943958B (zh) 2023-05-09
CN111943958A (zh) 2020-11-17

Similar Documents

Publication Publication Date Title
US10377757B2 (en) Crystal form of JAK inhibitor and preparation method thereof
CN110577541B (zh) 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577540B (zh) 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577534B (zh) 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577538B (zh) 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110577539B (zh) 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
WO2019052133A1 (zh) Gsk1278863的晶型及其制备方法和制药用途
US11572365B2 (en) Crystal form of upadacitinib, preparation method therefor, and use thereof
EP3553058A1 (en) Crystal form of bromodomain protein inhibitor drug, preparation method and use thereof
CN107868044A (zh) 一种非溶剂化晶体及其制备方法与应用
WO2020233226A1 (zh) 四氢噻吩并吡啶化合物的b晶型及制法、组合物和应用
TWI772382B (zh) 氘代丁苯那嗪(deutetrabenazine)之類似物、其製備方法及用途
US20200181064A1 (en) Pharmaceutically acceptable salts of fatty acids
CN114644642B (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
WO2016169288A1 (zh) 一种无定形态曲札茋苷及其制备方法
CN110540542A (zh) 一种苯乙酸类化合物的钠盐、结晶形式及其制备方法
CN104447682A (zh) 比拉斯汀化合物
EP4249476A1 (en) Salt of benzothiazole compound, and crystal form and use thereof
AU2021106179A4 (en) New crystalline form of epalrestat as well as preparation method and application thereof
WO2018149309A1 (zh) 4-苯基噻唑衍生物的晶型及其制备方法
TW201739750A (zh) 一種鈉依賴性葡萄糖共轉運蛋白抑制劑的胺溶劑合物及其製備方法和應用
EP3650450B1 (en) Crystal form ii of thienopyridine derivative bisulfate and preparation method therefor and use thereof
WO2020258660A1 (zh) 盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物
CN110790675A (zh) 一种秋水仙碱化合物及其制备方法、制剂、应用与药物组合物
WO2022228352A1 (zh) 一种五环三萜类化合物结晶及其制备方法

Legal Events

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

Ref document number: 20808820

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020808820

Country of ref document: EP

Effective date: 20211217