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WO2023193563A1 - 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 - Google Patents

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 Download PDF

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WO2023193563A1
WO2023193563A1 PCT/CN2023/080068 CN2023080068W WO2023193563A1 WO 2023193563 A1 WO2023193563 A1 WO 2023193563A1 CN 2023080068 W CN2023080068 W CN 2023080068W WO 2023193563 A1 WO2023193563 A1 WO 2023193563A1
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crystal form
compound
methanol
volume ratio
temperature
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PCT/CN2023/080068
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English (en)
French (fr)
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夏烨青
黄汉敏
李汉然
郭青
石涛
冯汉林
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深圳海王医药科技研究院有限公司
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Publication of WO2023193563A1 publication Critical patent/WO2023193563A1/zh

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    • 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
    • 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 present invention belongs to the field of medical technology, and specifically relates to a new crystal form of a thienopyridine compound, its preparation method, and a pharmaceutical composition containing the crystal form of the compound.
  • polymorphism The phenomenon that the same substance has two or more spatial arrangements and unit cell parameters and forms multiple crystal forms is called polymorphism.
  • Many crystallized drugs have polymorphism. Different crystal forms of the same drug may be significantly different in appearance, solubility, melting point, dissolution, bioavailability, etc., thus affecting the stability, bioavailability and efficacy of the drug.
  • Drug polymorphism is one of the important factors affecting drug quality and clinical efficacy. Therefore, when developing drugs with polymorphic forms, special attention should be paid to their crystal form analysis.
  • Chinese patent application CN113336768A discloses a series of potential thienopyridine small molecule anti-cancer compounds, including the compound 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl))amine Formyl)cyclopropane-1-carboxamide)phenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride .
  • the structural formula of this compound is shown as formula (I).
  • An object of the present invention is to provide a new crystal form of the compound, namely compound 2-(4-(7-(2-fluoro-4-(1-((4- Fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethylvaline
  • the crystalline form A of acid ester hydrochloride, the structural formula of this compound is shown in formula (I).
  • the new crystal form has high chemical stability, high temperature resistance, high humidity resistance, good solubility, and high bioavailability.
  • Its pharmaceutical composition has good dissolution rate and is suitable for the development of preparations.
  • the crystal form of Compound A was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and infrared spectroscopy (IR). This crystal form has the necessary requirements for the preparation of pharmaceutical preparations. of performance.
  • Another object of the present invention is to provide a method for preparing a new crystal form of the compound.
  • Another object of the present invention is to provide pharmaceutical compositions containing the crystalline form of the compound.
  • a crude product of the compound (shown as formula (I)) is first prepared, and then the crude product of the compound is crystallized and trans-crystallized by recrystallization and trans-crystallization to obtain the crystal form of the compound.
  • crystal form A By conducting X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), infrared spectroscopy (IR), etc. on the substance, it was confirmed that the crystal obtained is a new type of The crystal is called crystal form A.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • IR infrared spectroscopy
  • the X-ray powder diffraction pattern of the crystal form of compound A has characteristic diffraction peaks at the following 2 ⁇ ° positions: 8.01 ⁇ 0.20°, 10.38 ⁇ 0.20°, 10.86 ⁇ 0.20° ⁇ 12.99 ⁇ 0.20° ⁇ 13.44 ⁇ 0.20° ⁇ 14.94 ⁇ 0.20° ⁇ 16.02 ⁇ 0.20° ⁇ 17.76 ⁇ 0.20° ⁇ 18.83 ⁇ 0.20° ⁇ 20.11 ⁇ 0.20° ⁇ 20.36 ⁇ 0.20° ⁇ 22.20 ⁇ 0.20° ⁇ 23.13 ⁇ 0.20°, 24.70 ⁇ 0.20°, 24.92 ⁇ 0.20°, 25.40 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.89 ⁇ 0.20°, 28.94 ⁇ 0.20°.
  • the relative intensities (I/I 0 ) of these peaks are all greater than or equal to 30%. .
  • the X-ray powder diffraction pattern of the compound A crystal form also has characteristic diffraction peaks at the following 2 ⁇ ° positions: 6.29 ⁇ 0.20°, 9.55 ⁇ 0.20°, 12.55 ⁇ 0.20°, 14.10 ⁇ 0.20°, 14.30 ⁇ 0.20°, 17.19 ⁇ 0.20°, 19.16 ⁇ 0.20°, 22.43 ⁇ 0.20°, 26.11 ⁇ 0.20°, 29.51 ⁇ 0.20°.
  • the relative intensities (I/I0) of these peaks are all greater than or equal to 15%.
  • the X-ray powder diffraction pattern of the compound A crystal form also has characteristic diffraction peaks at the following 2 ⁇ ° positions: 15.42 ⁇ 0.20°, 23.79 ⁇ 0.20°, 24.15 ⁇ 0.20°, 30.65 ⁇ 0.20°, 31.09 ⁇ 0.20°, 32.56 ⁇ 0.20°, 36.34 ⁇ 0.20°, and 38.68 ⁇ 0.20°.
  • the relative intensities (I/I 0 ) of these peaks are all greater than or equal to 5% (see Figure 1).
  • the crystal form of Compound A of the present invention is characterized by X-ray powder diffraction patterns, and the relative intensity of the characteristic diffraction peaks is close to the following values.
  • the term "close” here refers to the uncertainty in relative intensity measurements. Those skilled in the art understand that relative intensity uncertainties are very dependent on the measurement conditions.
  • the relative intensity value may vary, for example, within a range of ⁇ 25% or preferably within a range of ⁇ 10%.
  • the crystal form of Compound A of the present invention has the X-ray powder diffraction pattern shown in Figure 1.
  • the present invention uses differential scanning calorimetry (DSC) technology to characterize the crystal form of Compound A (see Figure 2).
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry spectrum shows that the test sample has two absorbers at 111.1°C and 197.4°C. Hot peak.
  • the present invention uses thermogravimetric analysis (TG) technology to characterize the crystal form of Compound A (see Figure 3).
  • the thermogravimetric analysis spectrum shows that the weight loss of the test sample is 2.55% in the range from room temperature to 136.0°C; 136.0°C to 136.0°C.
  • the weight loss in the range of 204.0°C is 1.32%; the weight loss in the range of 204.0°C to 481.0°C is 53.58%; the weight loss in the range of 481.0°C to 700.0°C is 42.31%. This shows that as the temperature increases, the compound degrades.
  • the present invention uses infrared spectrum (IR) technology to characterize the A crystal form (see Figure 4).
  • the infrared spectrum shows that the test sample is at 3356cm -1 , 3070cm -1 , 3027cm -1 , 2963cm -1 , 2879cm -1 , 2785cm -1 , 2683cm -1 , 2618cm -1 , 1752cm -1 , 1693cm -1 , 1642cm -1 , 1602cm -1 , 1556cm -1 , 1507cm -1 , 1495cm -1 , 1469cm -1 , 1407cm -1 , 1327cm - 1.
  • the method for preparing the A crystal form includes the following steps: adding 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl))aminomethyl Acyl)cyclopropane-1-carboxamide)phenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride
  • the crude product is added to tetrahydrofuran, ethyl acetate, C1-C4 alkyl alcohol, C3-C4 alkyl ketone or a mixed solvent thereof and water, and heated and refluxed until dissolved; after the solution is clarified, start to cool down until a solid precipitates, filter and collect the solid , and dry the solid, trans-crystallize it in methanol, and finally dry it with air to obtain crystal form A.
  • the solvent is preferably tetrahydrofuran; the alcohol is selected from methanol, ethanol, propanol and isopropanol, with methanol being preferred; the ketone is selected from acetone, methyl ethyl ketone, etc., with acetone being preferred.
  • the volume ratio (V/V) of tetrahydrofuran, ethyl acetate, C1-C4 alkyl alcohol, C3-C4 alkyl ketone and water is 3:1 to 15:1, preferably 9:1; the volume ratio of the crude product to the solvent The proportion is calculated in g/mL, and the weight-to-volume ratio is 1:4-20.
  • Tetrahydrofuran is preferably 1:10, and methanol is preferably 1:8.
  • the solution is preferably heated to 50-90°C, more preferably tetrahydrofuran is heated to 80°C, and methanol is heated to 70°C; according to this embodiment, solidification takes 2 to 16 hours, more preferably 12 hours.
  • the solidification temperature is 0 to 30°C, preferably 15 to 25°C.
  • the solid obtained by recrystallization The ratio with methanol is calculated in g/mL, and the weight-to-volume ratio is 1:1 to 10, preferably 1:2; the beating temperature is 10 to 50°C, preferably 20 to 30°C; the beating time is 1 to 10 hours, more preferably 4 Hour.
  • the obtained suspension is filtered to obtain white powder and dried at a drying temperature of 30 to 70°C, preferably 50°C.
  • a pharmaceutical composition which contains the above-mentioned crystal form A and optional pharmaceutically acceptable excipients.
  • the pharmaceutical composition can be further formulated into a form for administration according to conventional preparation methods, including oral or parenteral administration.
  • the form available for administration should contain a therapeutically effective amount of Form A.
  • therapeutically effective dose means that at this dose, the compound of the present invention can improve or alleviate the symptoms of the disease, or can inhibit and block the development of the disease.
  • pharmaceutical excipients refers to various carriers and/or excipients used in pharmaceutical production and formulation. It is all substances included in pharmaceutical preparations except active ingredients.
  • the crystal form of the present invention can be used alone to prepare drugs for treating cell proliferation diseases, or can be prepared in combination with other therapeutic drugs to achieve synergistic effects.
  • cell proliferation diseases Mainly refers to cancer, including but not limited to non-small cell lung cancer, progressive large cell lymphoma, liver cancer, gastric cancer, colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer, diffuse large B-cell lymphoma, glioma, esophagus cancer, brain or neck cancer.
  • the A crystal form of 3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride has high chemical stability, high temperature resistance, and high humidity resistance.
  • It has the properties required for preparation of preparations, and is simple to produce, convenient to store, and easier to control quality. It has been verified by experiments that the dissolution rate of the preparation formula composition containing the crystal form A of the compound is above 80% in 15 minutes.
  • Figure 1 is the X-ray powder diffraction pattern of the new crystal form A obtained in Example 1 of the present invention.
  • FIG. 2 is a differential scanning calorimetry (DSC) spectrum of the new crystal form A obtained in Example 1 of the present invention
  • FIG. 3 is a thermogravimetric analysis (TG) spectrum of the new crystal form A obtained in Example 1 of the present invention.
  • Figure 4 is an infrared (IR) spectrum of the new crystal form A obtained in Example 1 of the present invention.
  • Figure 5 is an HPLC pattern of the new crystal form A obtained in Example 1 of the present invention.
  • Figure 6 is a plasma concentration-time curve of td32-4 obtained by in vivo conversion of the new crystal form A obtained in Example 1 of the present invention and the crude product (dose 200 mg/kg).
  • the raw materials and reagents used in the present invention are all commercially available products.
  • the compound of the present invention 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3,
  • the crude product of 2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride is prepared by (N-3-fluoro 4-((2-(1- (2-hydroxymethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane -1,1-Dimethylamide) is prepared from raw materials.
  • the raw material compound is abbreviated as td32-4, and the reaction formula is:
  • Boc-glycine (3.77g, 17.4mmol)
  • 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (abbreviation EDCI, 4g, 20.9mmol)
  • 4-Dimethylaminopyridine (abbreviation DMAP, 1.59g, 13.0mmol) was added to 60mL of anhydrous tetrahydrofuran. After reacting for 30 minutes, td32-4 (5g, 8.7mmol) was added to the reaction system, transferred to room temperature, and reacted 24 Hour.
  • step 1) Use the intermediate compound prepared in step 1) as raw material, dissolve it in 30 mL of anhydrous acetone, add 2 mL of concentrated hydrochloric acid, and react at 40°C for 5 hours to produce a white precipitate. Filter it, wash the precipitate with 20 mL of anhydrous acetone, and vacuum After drying, the compound of the present invention 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[ Crude product of 3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride. White solid 4.46g, yield: 91.1%, HPLC purity: 97.2%, LC-MS: 675.8[M+H] + .
  • the obtained compound is 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3 , 2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride, crystal form A, and its properties are identified as shown in Figures 1 to 5.
  • Detection conditions Cu target K ⁇ ray, voltage 40kV, current 40mA, emission slit 1/8°, anti-scatter slit 1/4°, anti-scatter slit 7.5mm, 2 ⁇ ° range: 3°-60°, step size 0.02°, dwell time 40s per step.
  • Atmosphere N2, 40mL/min;
  • Scanning procedure Raise the temperature from room temperature to 205°C at 10°C/min, and record the heating curve;
  • Test sample mass 2.14mg (use aluminum sample pan).
  • thermogravimetric analyzer from NETZSCH, Germany
  • Atmosphere air, 20mL/min;
  • Heating rate 10°C/min.
  • the obtained compound is 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3 , 2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl) ethyl valine ester hydrochloride A crystal form.
  • the obtained compound is 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3 , 2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl) ethyl valine ester hydrochloride A crystal form.
  • the type of mixed solvent used in the experiment is preferably tetrahydrofuran/water; the alcohol solvent used is preferably methanol; the ketone solvent used is preferably acetone.
  • the volume ratio (V/V) of the mixed solvent and water is 3:1 to 15:1, preferably 9:1; the ratio of the crude product to the solvent is calculated in g/mL, and the weight to volume ratio is 1:4 to 20 , tetrahydrofuran is preferably 1:10, and methanol is preferably 1:8.
  • the solution is preferably heated to 50-90°C, more preferably tetrahydrofuran is heated to 80°C, and methanol is heated to 70°C; according to this embodiment, solidification takes 2 to 16 hours, more preferably 12 hours.
  • the solidification temperature is 0 to 30°C, preferably 15 to 25°C.
  • the beating temperature is 10 to 50 ° C, preferably 20 to 30 ° C; the beating time is 1 to 10 hours, more preferably 4 hours.
  • the obtained suspension is filtered to obtain white powder and dried at a drying temperature of 30 to 70°C, preferably 50°C.
  • the obtained crystal form A was subjected to a stability investigation (10-day accelerated test), and the purity, maximum single impurities, total impurities and 0-day data of the crystal form A were compared under high temperature of 60°C, high humidity of 92.5%, and light conditions. . Experimental results show that the purity is slightly reduced under light conditions, and the obtained crystal form is stable under other conditions. This shows that crystal form A has higher stability under high temperature and high humidity conditions.
  • the solubility test in water was performed on the crystal form A and the crude product prepared in Example 1.
  • the solubility test method refers to the test method in the second part of the 2020 edition of the Chinese Pharmacopoeia.
  • Test method Weigh the test sample ground into fine powder or measure the liquid test sample, place it in a certain volume of solvent at 25°C ⁇ 2°C, shake vigorously for 30 seconds every 5 minutes; observe the dissolution within 30 minutes If there are no visible solute particles or droplets, it is considered to be completely dissolved.
  • test sample was weighed into a glass bottle, add PEG400, vortex, mix, and sonicate to obtain a clear solution.
  • Crystal Form A prepared in Example 1 can be rapidly converted into td32-4 in the body when administered at a dose of 200 mg/kg.
  • Example 1 When administered at a dose of 200 mg/kg, it can be rapidly converted into td32-4 in the body.
  • the oral bioavailability F 32.6% was calculated based on the exposure of the converted td32-4.
  • Prescription 1 Tablet prescription containing 5% of crystal form A prepared in Example 1
  • Preparation method The above ingredients are mixed according to conventional preparation methods and directly compressed into tablets.
  • Prescription 2 Tablet prescription containing 5% of the crude product of Example 1
  • Preparation method The above ingredients are mixed according to conventional preparation methods and directly compressed into tablets.

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Abstract

本发明公开了化合物2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的晶型A、制备方法以及其药物组合物。该晶型的化学稳定性高、耐高温、耐高湿、溶解性好、且生物利用度高，其药物组合物具有良好的溶出度，适用于制剂的开发。该化合物的结构式如式（I）所示：

Description

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 技术领域
本发明属于医药技术领域，具体地说，涉及一种噻吩并吡啶化合物的新晶型，其制备方法，以及含有该化合物晶型的药物组合物。
背景技术
同一物质具有两种或两种以上的空间排列和晶胞参数，形成多种晶型的现象称为多晶现象(polymorphism)。许多结晶药物都存在多晶现象，同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，从而影响了药物的稳定性、生物利用度及疗效。药物多晶型现象是影响药品质量与临床疗效的重要因素之一，因此对存在多晶型的药物进行研发时，应对其晶型分析予以特别的关注。
中国专利申请CN113336768A公开了一系列潜在的噻吩并吡啶类小分子抗癌化合物，其中包括化合物2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐。该化合物的结构式如式(I)所示。
虽然该专利申请公开了制备该化合物的方法，但没有公开显示任何化合物可以稳定地结晶或者纯化。在此基础上，本发明进一步研究了该噻吩并吡啶类小分子抗癌化合物的新晶型及其对药物稳定性、溶解度、生物利用度、溶出度等的影响。
发明内容
本发明的一个目的是提供一种化合物的新晶型，即化合物2-(4-(7-(2-氟-4-(1-((4- 氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的晶型A，该化合物的结构式如式(I)所示。
该新晶型的化学稳定性高、耐高温、耐高湿、溶解性好、且生物利用度高，其药物组合物具有良好的溶出度，适用于制剂的开发。
该化合物A晶型通过X-射线粉末衍射(XRPD)、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的性能。
本发明的另一个目的是提供该化合物新晶型的制备方法。
本发明的再一个目的是提供含有该化合物晶型的药物组合物。
根据本发明的一个方面，先制备所述化合物(如式(I)所示)的粗品，然后通过重结晶和转晶的方法对该物质的粗品进行结晶和转晶，获得化合物晶型。
通过对该物质进行X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)、热重分析(TG)、红外光谱(IR)等的检测和分析，确证获得的结晶是一种新型的结晶，称为A晶型。
具体地，当用Cu-Kα进行X-射线粉末衍射时，该化合物A晶型的X-射线粉末衍射图谱在下述2θ°位置具有特征衍射峰：8.01±0.20°、10.38±0.20°、10.86±0.20°、12.99±0.20°、13.44±0.20°、14.94±0.20°、16.02±0.20°、17.76±0.20°、18.83±0.20°、20.11±0.20°、20.36±0.20°、22.20±0.20°、23.13±0.20°、24.70±0.20°、24.92±0.20°、25.40±0.20°、26.72±0.20°、27.89±0.20°、28.94±0.20°，这些峰的相对强度(I/I0)均大于或等于30％。
该化合物A晶型的X-射线粉末衍射图谱还在下述2θ°位置具有特征衍射峰：6.29±0.20°、9.55±0.20°、12.55±0.20°、14.10±0.20°、14.30±0.20°、17.19±0.20°、19.16±0.20°、22.43±0.20°、26.11±0.20°、29.51±0.20°，这些峰的相对强度(I/I0)均大于或等于15％。
该化合物A晶型的X-射线粉末衍射图谱还在下述2θ°位置具有特征衍射峰：15.42±0.20°、23.79±0.20°、24.15±0.20°、30.65±0.20°、31.09±0.20°、32.56±0.20°、36.34±0.20°、38.68±0.20°，这些峰的相对强度(I/I0)均大于或等于5％(参见附图1)。
本发明的化合物A晶型通过X-射线粉末衍射图谱进行表征，特征衍射峰的相对强度接近下列数值。
表1.化合物A晶型的X-射线粉末衍射图数据
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。相对强度值可以在例如±25％范围内改变或优选在±10％范围内改变。
本发明的化合物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分析(DSC)技术对该化合物A晶型进行表征(见图2)，其差示扫描量热图谱显示，供试样品在111.1℃、197.4℃处存在两个吸热峰。
本发明采用热重分析(TG)技术对该化合物A晶型进行表征(见图3)，其热重分析图谱显示，供试品在室温至136.0℃范围内失重量为2.55％；136.0℃至204.0℃范围内失重量为1.32％；204.0℃至481.0℃范围内失重量为53.58％；481.0℃至700.0℃范围内失重量为42.31％。说明随着温度的升高，该化合物发生降解。
本发明采用红外光谱(IR)技术对A晶型进行表征(见图4)，其红外光谱显示，供试品在3356cm-1、3070cm-1、3027cm-1、2963cm-1、2879cm-1、2785cm-1、2683cm-1、2618cm-1、1752cm-1、1693cm-1、1642cm-1、1602cm-1、1556cm-1、1507cm-1、1495cm-1、1469cm-1、1407cm-1、1327cm-1、1288cm-1、1251cm-1、1200cm-1、868cm-1、829cm-1处有较强的吸收峰。
根据本发明的另一方面，制备所述A晶型的方法包括下述步骤：将2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的粗品，加入到四氢呋喃、乙酸乙酯、C1-C4烷基醇、C3-C4烷基酮或其与水的混合溶剂中，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，且干燥该固体，将所得的固体在甲醇中转晶，最后鼓风干燥即得A晶型。所述的溶剂种类优选四氢呋喃；所述的醇选自甲醇、乙醇、丙醇和异丙醇，优选甲醇；所述的酮选自丙酮和甲基乙基酮等，优选丙酮。四氢呋喃、乙酸乙酯、C1-C4烷基醇、C3-C4烷基酮与水的体积比(V/V)为3:1～15:1，优选9:1；所述的粗品与溶剂的配比按g/mL计算，重量体积比为1：4～20，四氢呋喃优选1:10，甲醇优选1:8。将溶液优选加热到50～90℃，更优选四氢呋喃加热到80℃，甲醇加热到70℃；根据此实施方案，析固2～16小时，更优选为12小时。析固温度为0～30℃，优选15～25℃。析固完全后过滤，加入甲醇打浆，进行转晶操作；重结晶所得固体 与甲醇的配比按g/mL计算，重量体积比为1：1～10，优选1:2；打浆温度10～50℃，优选20～30℃；打浆时间1～10小时，更优选为4小时。转晶结束后，将所得混悬液过滤，得到白色粉末并烘干，烘干温度为30～70℃，优选为50℃。
根据本发明的又一方面，提供一种药物组合物，该药物组合物含有上述A晶型和任选的药学上可接受药用辅料。
所述药物组合物可进一步按照常规制剂方法配置成可供给药的形式，包括经口或肠胃外给药的形式。在可供给药的形式中，应包含治疗有效量的A晶型。所谓的“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，或能够抑制和阻断疾病的发展。
术语“药用辅料”是指药品生产和处方调配时所使用的各种载体和/或赋形剂，是除活性成分外，包含在药物制剂中的所有物质。
根据本发明的再一方面，本发明的晶型可单独用于制备治疗细胞增殖性疾病的药物，也可以和其他治疗药物联合制备，协同作用。
本发明的2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的A晶型，用于治疗细胞增殖性疾病，所述的细胞增殖性疾病主要指癌症，包括但不限于非小细胞肺癌、渐变性大细胞淋巴瘤、肝癌、胃癌、结直肠癌、乳腺癌、胰腺癌、卵巢癌、弥漫大B细胞淋巴瘤、神经胶质瘤、食道癌、脑癌或颈部癌症。
本发明制备得到的2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的A晶型，具有化学稳定性高、耐高温、耐高湿的特点，具备了制备制剂所需要的性能，且生产简便、储存方便、质量更易控制，经试验验证，含有所述化合物晶型A的制剂配方组合物，15分钟溶出度均在80％以上。
附图说明
图1是本发明实施例1所得的新晶型A的X-射线粉末衍射图谱；
图2是本发明实施例1所得的新晶型A的差示扫描量热分析(DSC)图谱；
图3是本发明实施例1所得的新晶型A的热重分析(TG)图谱；
图4是本发明实施例1所得的新晶型A的红外(IR)图谱；
图5是本发明实施例1所得的新晶型A的HPLC图谱。
图6是本发明实施例1所得的新晶型A与粗品在体内转化所得的td32-4的血药浓度-时间曲线(剂量200mg/kg)。
具体实施方式
本发明所使用的原料和试剂均为市售产品。
制备粗品
本发明化合物2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐粗品的制备是以(N-3-氟4-((2-(1-(2-羟甲基)-1H-吡唑-4-基)噻吩并[3,2-b]吡啶-7-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)为原料制备而得，该原料化合物简称td32-4，反应式为：
制备步骤：
1)合成中间化合物：2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基(叔丁氧羰基)缬氨酸酯
0℃条件下，将Boc-甘氨酸(3.77g,17.4mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(缩写EDCI，4g,20.9mmol)、4-二甲氨基吡啶(缩写DMAP，1.59g,13.0mmol)加入到60mL的无水四氢呋喃中，反应30分钟后，将td32-4(5g,8.7mmol)加入反应体系，转移至室温，反应24小时。反应液过滤，向滤液中加入200mL 1mol/L的稀盐酸溶液，搅拌析出白色固体，抽滤，烘干固体。中间体粗品用水/乙醇(V/V＝1/1)体系重结晶处理，得到中间化合物2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基(叔丁氧羰基)缬氨酸酯，白色固体5.33g，收率：79.1％。
2)合成本发明化合物的粗品
以步骤1)制备而得的中间化合物为原料，将其溶于30mL无水丙酮中，加入浓盐酸2mL，40℃反应5小时，产生白色沉淀，抽滤，用20mL无水丙酮洗涤沉淀，真空干燥得到本发明化合物2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的粗品。白色固体4.46g，收率：91.1％，HPLC纯度：97.2％，LC-MS：675.8[M+H]+。
实施例1
称取100g 2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐粗品，加入到反应瓶中，加入1000mL四氢呋喃和水的混合溶液(V四氢呋喃：V水＝9:1)，搅拌下升温回流至80℃。溶解后再搅拌30min，随后降温至15～25℃，搅拌析晶12h，抽滤，烘干滤饼得固体80g；将所得固体加入到反应瓶中，加入160ml甲醇，20～25℃打浆4h，抽滤；所得滤饼于50℃鼓风干燥，得到白色粉末76g，两步总收率76％。得到的化合物为2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的A晶型，其性状鉴定如图1～图5所示。
实施例样品测试条件：
(一)X-射线粉末衍射(XRPD)：
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，发射狭缝1/8°，防散射狭缝1/4°，防散射狭缝7.5mm，2θ°范围：3°-60°，步长0.02°，每步停留时间40s。
检测依据：《中华人民共和国药典》2020年版四部0451X射线衍射法
检测结果：如图1。
(二)差示扫描量热(DSC)：
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205℃，记录升温曲线；
检测样品质量：2.14mg(使用铝制样品盘)。
检测依据：JY/T 0589.3-2020热分析方法通则第3部分差示扫描量热法
检测结果：如图2。
(三)热重分析(TG)：
检测仪器：德国NETZSCH公司TG209F1热重分析仪
检测条件：
气氛：空气，20mL/min；
扫描程序：室温～700℃；
升温速率：10℃/min。
检测依据：热分析方法通则第4部分：热重法JY/T 0589.4-2020
检测结果：如图3。
(四)红外光谱(IR)：
检测仪器：FT-IR NICOLET 6700(美国)
检测条件：溴化钾压片法
检测依据：GB/T 6040-2019红外光谱分析方法通则
检测结果：如图4。
(五)高效液相色谱(HPLC)：
检测仪器：Agilent 1260Infinity II高效液相色谱仪(美国)
检测条件：
色谱柱：Poroshell 120EC-C18
流动相：水/乙腈(80:20)
柱温：30℃；检测波长：254nm。
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。
实施例2
称取100g 2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐粗品，加入到反应瓶中，加入800mL甲醇和水的混合溶液(V甲醇：V水＝9:1)，搅拌下升温回流至70℃。溶解后再搅拌30min，随后降温至15～25℃，搅拌析晶12h，抽滤，烘干滤饼得固体75g；将所得固体加入到反应瓶中，加入150ml甲醇，20～25℃打浆4h，抽滤；所得滤饼于50℃鼓风干燥，得到白色粉末71g，两步 总收率71％。得到的化合物为2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的A晶型。
实施例3
称取100g 2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐粗品，加入到反应瓶中，加入1500ml四氢呋喃溶液，搅拌下升温回流至80℃。溶解后再搅拌30min，随后降温至15～25℃，搅拌析晶12h，抽滤，烘干滤饼得固体85g；将所得滤饼加入到反应瓶中，加入170ml甲醇，20～25℃打浆4h，抽滤；所得滤饼于50℃鼓风干燥，得到白色粉末81，两步总收率81％。得到的化合物为2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的A晶型。
实施例4
分别称取50g 2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐粗品，加入到反应瓶中，分别采用表2的实验条件按照实施例1的实验操作制备本发明的化合物A晶型，总收率如表2所示。
表2


实验结论：实验所用的混合溶剂的类型，优选四氢呋喃/水；所用醇类溶剂，优选甲醇；所用酮类溶剂，优选丙酮。混合溶剂与水的体积比(V/V)为3:1～15:1，优选9:1；所述的粗品与溶剂的配比按g/mL计算，重量体积比为1：4～20，四氢呋喃优选1:10，甲醇优选1:8。将溶液优选加热到50～90℃，更优选四氢呋喃加热到80℃，甲醇加热到70℃；根据此实施方案，析固2～16小时，更优选为12小时。析固温度为0～30℃，优选15～25℃。析固完全后过滤，加入甲醇打浆，进行转晶操作；重结晶所得固体与甲醇的配比按g/mL计算，重量体积比为1：1～10，优选1:2；打浆温度10～50℃，优选20～30℃；打浆时间1～10小时，更优选为4小时。转晶结束后，将所得混悬液过滤，得到白色粉末并烘干，烘干温度为30～70℃，优选为50℃。
实施例5稳定性试验
2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的A晶型的稳定性考察。
将获得的A晶型进行稳定性考察(10天加速试验)，在高温60℃、高湿92.5％、光照条件下对A晶型的纯度、最大单杂以及总杂和0天的数据进行对比。实验结果显示，光照条件下，纯度略有降低，其他条件下显示获得的晶型稳定。说明A晶型在高温、高湿条件下稳定性较高。
表3.A晶型影响因素试验结果
将2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的粗品进行稳定性考察(10天加速试验)，在高温40℃、60℃条件下对粗品的纯度、最大单杂以及总杂和0天的数据进行对比。实验结果显示，粗品在60℃条件下存放5天、10天，纯度降低较多，稳定性低于相同条件下存放的A晶型。
表4.粗品的影响因素试验结果
实施例6溶解性测试
对实施例1制备所得的晶型A和粗品进行水中的溶解度测试，溶解度测试方法参考2020版中国药典第二部中的试验方法。
试验方法：称取研成细粉的供试品或量取液体供试品，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列名词术语表示：
晶型A和粗品在水中的溶解度测试结果如表5所示：
表5.晶型A和粗品在水中的溶解度测试结果
实验结果表明，本发明所得化合物的晶型A在水中的溶解性明显好于该化合物的粗品，更能满足制剂开发的各项指标要求。
实施例7生物利用度测试
实验材料：SD雄性鼠，SPF级。上海西普尔-必凯实验动物有限公司。其它试剂均为市售产品。
(1)溶液配制
称取供试品适量至玻璃瓶中，加入PEG400，涡旋振荡，混匀，超声得澄清溶液。供试品以200mg/kg剂量经灌胃给与实验动物(n＝3)。
(2)试验方法
给药前称重SD大鼠，根据体重，计算给药量。通过灌胃口服给药。按0,0.25,0.5,1,2,4,8,12,24小时间隔，经颌下静脉或其他方式采血，每个样品采集约0.20mL，EDTA-K2抗凝，采集后放置冰上。并于1小时之内离心分离血 浆(离心条件：6800g，6min，2-8℃)。血浆样本于-40至-20℃条件保存待分析。本发明涉及的化合物，静脉给药4小时后全部转化为td32-4，其数据视为100％生物利用度，用作计算口服生物利用度。
(3)实验结果
实施例1制备的晶型A：在200mg/kg剂量给药时，在体内能迅速转化成td32-4，按照转化而来的td32-4的暴露量计算口服生物利用度F＝54.3％
实施例1的粗品：在200mg/kg剂量给药时，在体内能迅速转化成td32-4，按照转化而来的td32-4的暴露量计算口服生物利用度F＝32.6％
通过2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐晶型A与粗品的药代动力学数据可以看出，本发明中化合物的晶型A在体内表现出明显优于粗品的药代动力学性质，在200mg/kg剂量时，晶型A的生物利用度明显高于同剂量下的粗品。
实施例8压力/研磨对晶型的影响
称取100mg实施例1的A晶型，直接用压片机压制成片(7.1kN,8.5kN)，此时所用压片机压力远高于压片时的主压力。将所得药品研磨后测定XPRD，结果显示2θ°位置的特征衍射峰未发生显著变化，说明该晶型在压片、研磨过程中稳定，符合制剂需求。
实施例9固体药物制剂的制备
处方1：含5％实施例1制备所得A晶型的片剂处方

制法：上述成分按照常规制剂方法进行混合、直接压片。
处方2：含5％实施例1的粗品的片剂处方
制法：上述成分按照常规制剂方法进行混合、直接压片。
实施例10固体药物制剂性能测试
按照2010版药典溶出度试验测试处方1、处方2的溶解度、可压性及崩解度。结果显示，在辅料一致的条件下，处方1在15分钟溶出度达到80％以上，而处方2的溶出度低于80％；且处方1的可压性和崩解度均优于处方2，证明晶型A比粗品更能满足制剂的各项指标要求。
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. 化合物2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐的晶型A，所述化合物的结构式如式(I)所示，
    其特征在于，当使用Cu-Kα辐射时，所述化合物晶型A的X-射线粉末衍射图谱的数据为：

  2. 如权利要求1所述的化合物晶型A，其特征在于，所述化合物晶型A的热重分析图谱显示在室温至136.0℃范围内失重量为2.55％；136.0℃至204.0℃范围内失重量为1.32％；204.0℃至481.0℃范围内失重量为53.58％；481.0℃至700.0℃范围内失重量为42.31％。
  3. 如权利要求1所述的化合物晶型A，其特征在于，所述化合物晶型A的差示扫描量热谱图在111.1℃和197.4℃处存在两个吸热峰。
  4. 如权利要求1或2所述的化合物晶型A，其特征在于，用溴化钾压片测得的所述化合物晶型A的红外吸收图谱，所述晶型在3356cm-1、3070cm-1、3027cm-1、2963cm-1、2879cm-1、2785cm-1、2683cm-1、2618cm-1、1752cm-1、1693cm-1、1642cm-1、1602cm-1、1556cm-1、1507cm-1、1495cm-1、1469cm-1、1407cm-1、1327cm-1、1288cm-1、1251cm-1、1200cm-1、868cm-1、829cm-1有吸收峰。
  5. 一种如权利要求1所述的化合物晶型A的制备方法，包括以下步骤：
    1)将2-(4-(7-(2-氟-4-(1-((4-氟苯基)氨甲酰基)环丙烷-1-甲酰胺)苯氧基)噻吩并[3,2-b]吡啶-2-基)-1H-吡唑基-1-基)乙基缬氨酸酯盐酸盐粗品加入到溶剂中，加热回流至溶解，获得所述化合物溶液；
    所述溶剂为选自有机溶剂四氢呋喃、乙酸乙酯、C1-C4烷基醇和C3-C4烷基酮中的一种，或所述一种有机溶剂与水的混合溶剂；
    所述混合溶剂中，所述有机溶剂与水的体积比为3:1～15:1；
    所述化合物粗品与所述溶剂的重量体积比为1g:(4～20)mL；
    所述加热的温度为50℃～90℃；
    2)待所述化合物溶液澄清后，对该化合物溶液进行降温直至析出固体；
    析固时间为2小时～16小时，析固温度为0℃～30℃；
    3)过滤并收集所述固体，随后将所述固体烘干；
    4)向所述固体加入甲醇，打浆，使所述固体在甲醇中转晶，获得混悬液；
    所述固体与所述打浆甲醇的重量体积比为1g:(1～10)mL；转晶温度为10℃～50℃；转晶时间1小时～10小时；
    5)将步骤4)获得的混悬液过滤，得到白色粉末，鼓风干燥，获得所述化合物晶型A；干燥温度为30℃～70℃。
  6. 一种如权利要求5所述的制备方法，其中所述的C1-C4烷基醇选自甲醇、乙醇、丙醇、异丙醇中的一种；所述的C3-C4烷基酮选自丙酮和甲基乙基酮中的一种。
  7. 一种如权利要求5所述的制备方法，其中步骤1)中所述的C1-C4烷基醇为甲醇；所述的C3-C4烷基酮为丙酮。
  8. 一种如权利要求5所述的制备方法，其中步骤1)所述溶剂为四氢呋喃与水以体积比为9:1的混合溶剂；所述化合物粗品与所述混合溶剂的重量体积比为1g：10mL，加热温度为80℃；
    步骤2)中析固时间为12小时；析固温度为15℃～25℃；
    转晶固体与打浆甲醇的重量体积比为1g：2mL；转晶温度为20℃～30℃；转晶时间为4小时；
    烘干温度为50℃。
  9. 一种如权利要求5所述的制备方法，其中步骤1)所述溶剂为甲醇与水以体积比为9:1的混合溶剂；所述化合物粗品与所述混合溶剂的重量体积比为1g：8mL，加热温度为70℃；
    步骤2)中析固时间为12小时；析固温度为15℃～25℃；
    转晶固体与打浆甲醇的重量体积比为1g：2mL；转晶温度为20℃～30℃；转晶时间为4小时；
    烘干温度为50℃。
  10. 一种含有如权利要求1所述的化合物晶型A的药物组合物。
PCT/CN2023/080068 2022-04-06 2023-03-07 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 WO2023193563A1 (zh)

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