WO2023193563A1 - Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée - Google Patents

Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
compound
methanol
volume ratio
temperature
Prior art date
Application number
PCT/CN2023/080068
Other languages
English (en)
Chinese (zh)
Inventor
夏烨青
黄汉敏
李汉然
郭青
石涛
冯汉林
Original Assignee
深圳海王医药科技研究院有限公司
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 深圳海王医药科技研究院有限公司 filed Critical 深圳海王医药科技研究院有限公司
Publication of WO2023193563A1 publication Critical patent/WO2023193563A1/fr

Links

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
    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline A d'un composé chlorhydrate d'ester de valine 2-(4-(7-(2-fluoro-4-(1- ((4-fluorophényl)carbamoyl)cyclopropane-1-carboxamide)phénoxy)thiéno[3,2-b]pyridin-2-yl)-1H-pyrazolyl-1-yl)éthylique, et son procédé de préparation et une composition pharmaceutique associée. La forme cristalline a une stabilité chimique élevée, est résistante à la température et l'humidité élevées, a une bonne solubilité et une grande biodisponibilité ; et la composition pharmaceutique de la forme cristalline a une bonne vitesse de dissolution, et est appropriée pour le développement de préparations. La formule développée du composé est telle que représentée par la formule (I).
PCT/CN2023/080068 2022-04-06 2023-03-07 Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée WO2023193563A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210358212.1A CN114644642B (zh) 2022-04-06 2022-04-06 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
CN202210358212.1 2022-04-06

Publications (1)

Publication Number Publication Date
WO2023193563A1 true WO2023193563A1 (fr) 2023-10-12

Family

ID=81997101

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/080068 WO2023193563A1 (fr) 2022-04-06 2023-03-07 Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée

Country Status (2)

Country Link
CN (1) CN114644642B (fr)
WO (1) WO2023193563A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114644642B (zh) * 2022-04-06 2023-05-12 深圳海王医药科技研究院有限公司 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

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777655A (zh) * 2014-12-25 2016-07-20 深圳海王药业有限公司 萘普替尼对甲苯磺酸盐的α晶型及制备方法和含有其的药物组合物
WO2018056872A1 (fr) * 2016-09-21 2018-03-29 Alghamdi Zainab Saeed Composé pour inhiber la croissance et la prolifération de cellules de cancer du foie humain et son procédé de synthèse
CN108299399A (zh) * 2018-02-01 2018-07-20 深圳海王医药科技研究院有限公司 一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物
CN108530464A (zh) * 2017-03-02 2018-09-14 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂
CN109384799A (zh) * 2018-11-12 2019-02-26 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂化合物的晶型a及制备方法和含有其的药物组合物
CN113336768A (zh) * 2020-02-18 2021-09-03 深圳海王医药科技研究院有限公司 一种多靶点酪氨酸激酶抑制剂
CN114644642A (zh) * 2022-04-06 2022-06-21 深圳海王医药科技研究院有限公司 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

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777655A (zh) * 2014-12-25 2016-07-20 深圳海王药业有限公司 萘普替尼对甲苯磺酸盐的α晶型及制备方法和含有其的药物组合物
WO2018056872A1 (fr) * 2016-09-21 2018-03-29 Alghamdi Zainab Saeed Composé pour inhiber la croissance et la prolifération de cellules de cancer du foie humain et son procédé de synthèse
CN108530464A (zh) * 2017-03-02 2018-09-14 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂
CN108299399A (zh) * 2018-02-01 2018-07-20 深圳海王医药科技研究院有限公司 一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物
CN109384799A (zh) * 2018-11-12 2019-02-26 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂化合物的晶型a及制备方法和含有其的药物组合物
CN113336768A (zh) * 2020-02-18 2021-09-03 深圳海王医药科技研究院有限公司 一种多靶点酪氨酸激酶抑制剂
CN114644642A (zh) * 2022-04-06 2022-06-21 深圳海王医药科技研究院有限公司 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

Also Published As

Publication number Publication date
CN114644642B (zh) 2023-05-12
CN114644642A (zh) 2022-06-21

Similar Documents

Publication Publication Date Title
WO2011095059A1 (fr) Polymorphes du dasatinib, leurs procédés de préparation et leurs compositions pharmaceutiques
US8933114B2 (en) Polymorphic forms of asenapine maleate and processes for their preparation
WO2018059556A1 (fr) Forme polymorphe d'un composé inhibiteur de kinase, composition pharmaceutique le contenant, son procédé de préparation et son utilisation
WO2017152707A1 (fr) Formes cristallines de sel de mésylate de dérivé de pyridinyl-aminopyrimidine, procédés de préparation et applications associés
WO2023193563A1 (fr) Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée
US9884856B2 (en) Crystal form of Dabrafenib mesylate and preparation method thereof
JP2022522395A (ja) 選択的エストロゲン受容体分解剤の新規な塩
WO2019149254A1 (fr) Forme cristalline d'un composé immunitaire à petites molécules, son procédé de préparation et composition pharmaceutique la contenant
WO2019205812A1 (fr) Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation
WO2022258060A1 (fr) Forme cristalline de lanifibranor et son procédé de préparation
WO2019134455A1 (fr) Nouvelle forme cristalline d'acalabrutinib, son procédé de préparation et son utilisation
WO2018214877A1 (fr) Forme cristalline de dézocine et procédé de préparation associé
WO2021000687A1 (fr) Procédé de préparation d'une forme cristalline de pac-1
CN108948018B (zh) 苯并二氮*衍生物及其盐和相关晶体形式、制备方法和用途
US9598413B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
CN113045554A (zh) 一种非索替尼晶型及其制备方法
JP2022517396A (ja) Ｅｇｆｒ阻害剤の塩、結晶形及びその製造方法
US20160090385A1 (en) Crystalline forms of n,n-dicyclopropyl-4-(1,5-dimethyl-1h-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboximide for the treatment of myeloproliferative disorders
US20160130272A1 (en) Crystalline forms of n,n-dicyclopropyl-4-(1,5-dimethyl-1h-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboximide for the treatment of myeloproliferative disorders
WO2018177276A1 (fr) Forme cristalline d'inhibiteur de tubuline
WO2017076358A1 (fr) Nouvelle forme cristalline de sel de composé imidazolyl-biphényl et son procédé de préparation
JP2022507558A (ja) チエノピリドン誘導体のカリウム塩一水和物及びその調製方法
WO2023061372A1 (fr) Sel de malate de dérivé de xanoméline, forme cristalline a, procédé de préparation correspondant et utilisation associée
CN114630668B (zh) 一种Aprocitentan晶型及其制备方法和用途
WO2022067724A1 (fr) Cocristal d'inhibiteur de sglt-2 et de sarcosine, procédé pour sa préparation et utilisation correspondante

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: 23784127

Country of ref document: EP

Kind code of ref document: A1