WO2021078076A1 - Nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation - Google Patents

Nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation Download PDF

Info

Publication number
WO2021078076A1
WO2021078076A1 PCT/CN2020/121710 CN2020121710W WO2021078076A1 WO 2021078076 A1 WO2021078076 A1 WO 2021078076A1 CN 2020121710 W CN2020121710 W CN 2020121710W WO 2021078076 A1 WO2021078076 A1 WO 2021078076A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
eltrombopag
acetylated
ray powder
powder diffraction
Prior art date
Application number
PCT/CN2020/121710
Other languages
English (en)
Chinese (zh)
Inventor
张鹏伟
黄河
廖伟龙
李英龙
寇景平
林碧悦
陈勇
王仲清
罗忠华
黄芳芳
Original Assignee
广东东阳光药业有限公司
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 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Priority to CN202080060751.6A priority Critical patent/CN114341112A/zh
Publication of WO2021078076A1 publication Critical patent/WO2021078076A1/fr

Links

Images

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • Eltrombopag olamine is a thrombopoietin receptor agonist used to treat certain conditions that cause thrombocytopenia.
  • the structure of Eltrombopag diethanolamine salt is shown in the following formula (1).
  • Eltrombopag has a food effect
  • acetylated Eltrombopag is a prodrug of Eltrombopag and can be used to overcome the food effect of Eltrombopag.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is conducive to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
  • the present invention obtains a new crystal form of the compound through a large number of experimental studies on the prodrug of Eltrombopag: acetylated Eltrombopag, which has good stability, good release in the animal body, and simple preparation process Easy to operate and other superior properties.
  • the invention provides a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • the crystal form has good stability and the preparation method of the crystal form is simple and easy to operate.
  • the present invention provides new crystal forms of acetylated Eltrombopag: crystal form D and crystal form J.
  • the new crystal form was studied, and it was found that the crystal form D and the crystal form J have good performance in terms of stability and the like, and both can be used in the production of pharmaceutical preparations.
  • the crystal form D is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6.
  • the differential scanning calorimetry (DSC) of the crystal form D has endothermic peaks in the range of 167°C-169°C, 211°C-213°C, and 225°C-227°C.
  • the crystal form J is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7.
  • the differential scanning calorimetry (DSC) of the crystal form J has an endothermic peak in the range of 165°C to 167°C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form D or crystal form J and pharmaceutically acceptable auxiliary materials or excipients.
  • the pharmaceutical composition contains acetylated Eltrombopag, and according to the mass ratio, at least 80% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal form J.
  • the pharmaceutical composition can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs, immunoglobulin therapy or after splenectomy, and platelets in patients with chronic hepatitis C Reduce symptoms, severe aplastic anemia and other diseases that do not respond to immunosuppressive treatment.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the present invention also provides a method for preparing the acetylated Eltrombopag crystal form D or crystal form J.
  • a method for preparing acetylated Eltrombopag crystal form D includes: mixing the acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution, stirring to precipitate crystals, collecting the crystals, and removing Solvent to obtain crystal form D.
  • a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, separating out crystals, and collecting the crystals, The solvent was removed to obtain the crystal form J.
  • the crystal form D and the crystal form J provided by the present invention have good stability, are beneficial to storage, transfer, and operation in the production process, and can be used to prepare a preparation.
  • an object of the present invention is to provide a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • the crystal form has good stability and the preparation method of the crystal form is simple and easy to operate.
  • the present invention provides new crystal forms of acetylated Eltrombopag: crystal form D and crystal form J.
  • the new crystal form of the present invention was studied, and it was found that the crystal form D and the crystal form J have good performance in terms of stability, release in the body, etc., and can be used in the production of pharmaceutical preparations.
  • the crystal form D is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6.
  • the crystal form D has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 7.1, 14.2, 16.9, 19.9 , 26.0 and 28.6.
  • the crystal form D has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 6.7, 7.1, 8.8, 13.4 , 14.2, 14.6, 16.2, 16.9, 18.9, 19.9, 21.4, 26.0, 26.4, 28.6 and 30.6.
  • the relative intensity of the diffraction peak at 8.8 degrees 2 ⁇ is greater than 70%, or greater than 80%, or greater than 90%, or Greater than 99%.
  • the crystal form D has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
  • the differential scanning calorimetry (DSC) of the crystalline form D has endothermic peaks in the range of 167°C-169°C, 211°C-213°C, and 225°C-227°C.
  • the crystalline form D has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
  • thermogravimetric analysis curve (TGA) of the crystal form D shows that there is a weight loss between 30°C and 120°C, and the weight loss is about 3.66%.
  • the crystal form D has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
  • TGA pattern thermogravimetric analysis curve
  • the purity of the crystal form D is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, the purity of the crystal form D is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • Form J is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 7.9, 10.5, 12.9, 14.8 , 18.4, 20.8 and 23.8.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 5.8, 7.9, 8.8, 10.5 , 12, 12.9, 14.5, 14.8, 16.5, 18.4, 20.8, 22.8, 23.8 and 25.7.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 7.0, 7.9, 10.5, 12.9 , 13.5, 14.0, 14.8, 16.0, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 23.8, 24.7 and 27.1.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 5.8, 7.0, 7.9, 8.8 , 10.5, 12, 12.9, 13.5, 14.0, 14.5, 14.8, 16.0, 16.5, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 22.8, 23.8, 24.7 and 27.1.
  • the relative intensity of the peak at 2 ⁇ of 14.8 degrees is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
  • the crystal form J has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 4.
  • XRPD pattern X-ray powder diffraction pattern
  • the differential scanning calorimetry (DSC) of the crystalline form J has an endothermic peak in the range of 165°C to 167°C.
  • the crystalline form J has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 5.
  • thermogravimetric analysis curve (TGA) of the crystal form J shows that there is a weight loss between 30°C and 160°C, and the weight loss is about 4.56%.
  • the crystal form J has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 6.
  • the purity of the crystal form J is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%.
  • the acetylated Eltrombopag crystal form D and crystal form J of the present invention can be used for the treatment of chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy or chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs or immunoglobulin treatment is invalid Patients with thrombocytopenia, thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • ITP chronic idiopathic thrombocytopenic purpura
  • ITP chronic idiopathic thrombocytopenic purpura
  • immunoglobulin treatment is invalid Patients with thrombocytopenia, thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form D or crystal form J and pharmaceutically acceptable excipients or excipients.
  • a therapeutically effective amount of acetylated Eltrombopag crystal form D or/and crystal form J is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is It is prepared in a well-known manner in the pharmaceutical field.
  • the pharmaceutical composition or preparation can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy, and patients with chronic hepatitis C that are ineffective in the treatment of glucocorticoid drugs or immunoglobulin.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-10% of the crystal form D or the crystal form J of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-5% of the crystal form D or crystal form J of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-1% of the crystal form D or the crystal form J of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-0.5% of the crystal form D or the crystal form J of the total weight of the composition.
  • a pharmaceutical composition contains acetylated Eltrombopag, and at least 90% of the acetylated Eltrombopag is in the acetylated Eltrombopag crystal form D or crystal.
  • a pharmaceutical composition contains acetylated Eltrombopag, in terms of mass ratio, wherein at least 95% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal Type J.
  • a pharmaceutical composition contains acetylated Eltrombopag, and at least 97% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal. Type J.
  • a pharmaceutical composition contains acetylated Eltrombopag, in terms of mass ratio, wherein at least 99% of acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal Type J.
  • the purity of crystal form D in the pharmaceutical composition is at least 80%. In some embodiments, the purity of the crystalline form D in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the purity of the crystal form J in the pharmaceutical composition is at least 80%. In some embodiments, the purity of the crystalline form J in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the pharmaceutical composition containing acetylated Eltrombopag crystal form D or crystal form J of the present invention can be used to prepare glucocorticoid drugs, immunoglobulin treatment ineffective or chronic idiopathic thrombocytopenia after splenectomy Thrombocytopenia in patients with ITP, as well as thrombocytopenia in patients with chronic hepatitis C, and pharmaceutical preparations for severe aplastic anemia that do not respond to immunosuppressive therapy.
  • the pharmaceutical composition containing acetylated Eltrombopag crystal form D or crystal form J of the present invention can be used to treat chronic idiopathic thrombocytopenia after glucocorticoid drugs, immunoglobulin therapy, or chronic idiopathic thrombocytopenia after splenectomy Thrombocytopenia in patients with chronic hepatitis C (ITP), thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • ITP chronic hepatitis C
  • thrombocytopenia in patients with chronic hepatitis C
  • severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • the crystal form D or crystal form J provided by the present invention has better stability, and a more stable crystal form is of great significance for improving the quality of the medicine.
  • the crystal form D and crystal form J provided by the invention have good stability, are not easy to deliquesce under high humidity conditions, and are convenient for long-term storage and placement of the medicine.
  • the crystal form provided by the invention has good stability, can well avoid crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and drug efficacy, and has strong economic value.
  • the present invention proposes a method for preparing the aforementioned acetylated Eltrombopag crystal form D or crystal form J.
  • a method for preparing acetylated Eltrombopag crystal form D includes: mixing the acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution, stirring to precipitate crystals, collecting the crystals, and removing Solvent to obtain crystal form D.
  • a method for preparing acetylated Eltrombopag crystal form D includes: mixing acetylated Eltrombopag with tetrahydrofuran, and after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution dropwise to precipitate crystals, The crystals are collected and the solvent is removed to obtain crystal form D.
  • the anti-solvent is water or methanol, or a combination thereof.
  • the mass-volume ratio of the solvent of the acetylated Eltrombopag and tetrahydrofuran is 1:2 to 1:20; more preferably 1:3 ⁇ 1:5.
  • a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, separating out crystals, and collecting the crystals, The solvent was removed to obtain the crystal form J.
  • a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, dissolving by heating, and after the dissolution is complete, reducing the temperature to 0°C to 20°C to precipitate Crystals, crystals are collected, and the solvent is removed to obtain crystal form J.
  • the good solvent is ethylene glycol dimethyl ether, acetone, tetrahydrofuran, a mixed solvent of acetone and ethyl acetate, a mixed solvent of acetone and methyl ethyl ketone, and a mixed solvent of acetone and acetonitrile.
  • the good solvent is a mixed solvent
  • the volume ratio of acetone to ethyl acetate, methyl ethyl ketone or acetonitrile is 1:1.
  • the mass-volume ratio of the acetylated Eltrombopag to the good solvent is 1:20 to 1:50; more preferably 1:25 to 1:40.
  • the “crystal form” of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention
  • the “crystal form” of should be understood as falling within the protection scope of the present invention.
  • the present invention tests various parameters on a sample containing a certain "crystal form” that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different, and the experimental error or the value of the difference may be less than or equal to 10°C, or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than It is equal to 1°C, so the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the mass unit is grams and the volume unit is milliliters.
  • RH means relative humidity
  • Figure 1 X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form D.
  • FIG. 1 Differential scanning calorimetry (DSC) graph of acetylated Eltrombopag Form D.
  • Figure 4 X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form J.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • test instrument In the present invention, the test instrument and method
  • the X-ray powder diffraction (XRPD) pattern was collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 10mm. Using ⁇ - ⁇ Continuous scanning mode, to obtain an effective 2 ⁇ range of 3° ⁇ 40°.
  • the DSC measurement was performed in TA Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.
  • the TGA measurement was performed in TA Instruments TM model Q500.
  • the operation step is to peel the empty crucible, take about 10 mg of solid sample, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purge, and record the spectrum.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation appartenant au domaine de la chimie médicinale. La forme cristalline a une bonne stabilité et facilite des opérations dans des processus de stockage, de transfert et de production, se libère aisément chez les animaux, et peut être utilisée pour préparer les préparations.
PCT/CN2020/121710 2019-10-21 2020-10-17 Nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation WO2021078076A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080060751.6A CN114341112A (zh) 2019-10-21 2020-10-17 乙酰化艾曲波帕的新晶型及其制备方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910998955 2019-10-21
CN201910999095.5 2019-10-21
CN201910999095 2019-10-21
CN201910998955.3 2019-10-21

Publications (1)

Publication Number Publication Date
WO2021078076A1 true WO2021078076A1 (fr) 2021-04-29

Family

ID=75620392

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/121710 WO2021078076A1 (fr) 2019-10-21 2020-10-17 Nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN114341112A (fr)
WO (1) WO2021078076A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1444477A (zh) * 2000-05-25 2003-09-24 史密丝克莱恩比彻姆公司 血小板生成素模拟物
WO2011089214A1 (fr) * 2010-01-22 2011-07-28 Ascendis Pharma As Lieurs de précurseurs à base de carbamates liés à des supports
CN102149282A (zh) * 2008-05-20 2011-08-10 纽罗吉斯克斯公司 碳酸酯前药及其使用方法
CN102448942A (zh) * 2009-04-01 2012-05-09 普利瓦赫尔瓦茨卡有限公司 艾曲波帕和艾曲波帕盐的多晶型物及其制备方法
WO2013072921A2 (fr) * 2011-09-13 2013-05-23 Glenmark Generics Limited Procédé de préparation de composés substitués de l'acide 3'-hydrazino-biphényl-3-carboxylique
CN109096195A (zh) * 2018-09-27 2018-12-28 上海雅本化学有限公司 一种艾曲波帕的制备方法
WO2019071111A1 (fr) * 2017-10-06 2019-04-11 Teva Pharmaceuticals Usa, Inc. Formes à l'état solide d'eltrombopag choline
US10336706B2 (en) * 2014-09-05 2019-07-02 Hetero Research Foundation Crystalline form of Eltrombopag free acid

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1444477A (zh) * 2000-05-25 2003-09-24 史密丝克莱恩比彻姆公司 血小板生成素模拟物
CN102149282A (zh) * 2008-05-20 2011-08-10 纽罗吉斯克斯公司 碳酸酯前药及其使用方法
CN102448942A (zh) * 2009-04-01 2012-05-09 普利瓦赫尔瓦茨卡有限公司 艾曲波帕和艾曲波帕盐的多晶型物及其制备方法
WO2011089214A1 (fr) * 2010-01-22 2011-07-28 Ascendis Pharma As Lieurs de précurseurs à base de carbamates liés à des supports
WO2013072921A2 (fr) * 2011-09-13 2013-05-23 Glenmark Generics Limited Procédé de préparation de composés substitués de l'acide 3'-hydrazino-biphényl-3-carboxylique
US10336706B2 (en) * 2014-09-05 2019-07-02 Hetero Research Foundation Crystalline form of Eltrombopag free acid
WO2019071111A1 (fr) * 2017-10-06 2019-04-11 Teva Pharmaceuticals Usa, Inc. Formes à l'état solide d'eltrombopag choline
CN109096195A (zh) * 2018-09-27 2018-12-28 上海雅本化学有限公司 一种艾曲波帕的制备方法

Also Published As

Publication number Publication date
CN114341112A (zh) 2022-04-12

Similar Documents

Publication Publication Date Title
US10457666B2 (en) Stable crystal form of tipiracil hydrochloride and crystallization method for the same
WO2021129589A1 (fr) Nouvelle forme cristalline de kd-025 et son procédé de préparation
BR112019021447A2 (pt) sal fumarato, forma cristalina i do referido sal, métodos para preparação dos mesmos, composição farmacêutica compreendendo o sal e a forma cristalina i e uso do sal fumarato, da forma cristalina i e da composição farmacêutica
WO2021104022A1 (fr) Nouvelle forme cristalline de tropifexor et son procédé de préparation
WO2021078076A1 (fr) Nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation
WO2021104021A1 (fr) Nouvelle forme cristalline de tropifexor et son procédé de préparation
WO2021078077A1 (fr) Nouvelle forme cristalline d'eltrombopag acétylé et son procédé de préparation
WO2021057834A1 (fr) Forme cristalline de composé ester et son procédé de préparation
CN103059013B (zh) 达沙替尼一水合物的晶型及其制备方法
TW201917117A (zh) 一種炔基吡啶類脯胺醯羥化酶抑制劑的晶型及其製備方法
WO2018233678A1 (fr) Composé de dexrabéprazole sodique et composition pharmaceutique correspondante
TWI762825B (zh) 酪胺酸激酶抑制劑的一馬來酸鹽的晶型及其製備方法
WO2017028762A1 (fr) Forme cristalline d'un composé cyclique de type naphtalène
WO2019137325A1 (fr) Nouvelle forme cristalline de phosphate de baricitinib et son procédé de préparation
CN102659644B (zh) 2-氨基乙磺酸的晶型及制备工艺
JP2017530107A (ja) ナトリウム・グルコース共輸送体２阻害薬のｌ−プロリン化合物、およびｌ−プロリン化合物の一水和物および結晶
JP5801715B2 (ja) １−（２’−シアノ−２’−デオキシ−β−Ｄ−アラビノフラノシル）シトシン・一塩酸塩の新規安定形結晶
CN110903219A (zh) 酰胺衍生物的盐及其制备方法
WO2018086473A1 (fr) Eutectique d'aprémilast et son procédé de préparation
CN112543634A (zh) Ebna1抑制剂晶体形式及其制备和使用方法
CN105985252B (zh) 一种门冬氨酸鸟氨酸晶型iv及其制备方法
CN112638865A (zh) 药物共晶体及其制备方法
WO2021136491A1 (fr) Forme cristalline d'inhibiteur de la dipeptidyl-peptidase iv, son procédé de préparation et son application
WO2023185638A1 (fr) Forme cristalline d'un dérivé de quinoléine et son procédé de préparation
CN109206410A (zh) 一种酪氨酸激酶抑制剂的二马来酸盐的晶型及其制备方法

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: 20880218

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20880218

Country of ref document: EP

Kind code of ref document: A1