WO2021037185A1 - Inhibiteur de tyrosine kinase ayant une faible teneur en impuretés - Google Patents

Inhibiteur de tyrosine kinase ayant une faible teneur en impuretés Download PDF

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Publication number
WO2021037185A1
WO2021037185A1 PCT/CN2020/111995 CN2020111995W WO2021037185A1 WO 2021037185 A1 WO2021037185 A1 WO 2021037185A1 CN 2020111995 W CN2020111995 W CN 2020111995W WO 2021037185 A1 WO2021037185 A1 WO 2021037185A1
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WIPO (PCT)
Prior art keywords
formula
compound represented
pharmaceutically acceptable
solvent
acceptable salt
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PCT/CN2020/111995
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English (en)
Chinese (zh)
Inventor
张全良
邱振均
曹永兴
韦艳丽
Original Assignee
江苏恒瑞医药股份有限公司
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Publication of WO2021037185A1 publication Critical patent/WO2021037185A1/fr

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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to tyrosine kinase inhibitors with low impurity content, pharmaceutical compositions and preparation methods.
  • Receptor tyrosine kinases are a class of transmembrane proteins involved in signal transduction. They are expressed in a variety of cells and regulate cell growth, differentiation and angiogenesis. Studies have shown that more than 50% of proto-oncogenes and oncogene products have tyrosine kinase activity, and their abnormal expression will lead to tumorigenesis. In addition, they are also resistant to tumor invasion and metastasis, tumor angiogenesis, and tumor chemotherapy. Sex is closely related.
  • WO2011029265 discloses an effective tyrosine kinase inhibitor and a preparation method thereof, the structure of which is shown in formula I,
  • CN102933574A describes the dimaleate salt form of the compound, which has improved physicochemical properties, pharmacokinetic properties, and good bioavailability.
  • CN103974949A describes the crystalline form I of the dimaleate salt of this compound.
  • WO2017186140 describes the preparation method of this compound.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • the impurity content of the compound may be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%, 0.09%, 0.08% %, 0.07%, 0.06%, 0.05% or less, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
  • the pharmaceutically acceptable salt of the compound represented by formula I is maleate, preferably dimaleate.
  • the particle size D90 of the compound described in the present disclosure is less than 20 ⁇ m, for example, less than 15 ⁇ m, or less than 14 ⁇ m, or less than 13 ⁇ m, or less than 12 ⁇ m, or less than 10 ⁇ m, or less than 9 ⁇ m, or less than 8 ⁇ m, or less than 7 ⁇ m , Or less than 6 ⁇ m, or less than 5 ⁇ m, or less than 4 ⁇ m, or less than 3 ⁇ m.
  • the particle size D50 of the compound is less than 5 ⁇ m, preferably less than 4 ⁇ m, or less than 3 ⁇ m, or less than 2 ⁇ m, or less than 1 ⁇ m.
  • Another aspect of the present disclosure also provides a method for preparing the compound represented by formula I or a pharmaceutically acceptable salt thereof, which comprises the step of recrystallizing the compound represented by formula I or a pharmaceutically acceptable salt thereof using a solvent.
  • the solvent may be A mixed solvent of methanol and other solvents, the other solvents are selected from one or more of acetone, ethyl acetate and tetrahydrofuran, preferably acetone and/or tetrahydrofuran.
  • the impurity content of the compound is less than 0.2%, for example, it can be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%. %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or less, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
  • the volume ratio of methanol to other solvents may be 1:1 to 1:50, preferably 1:3 to 1:20.
  • the volume ratio of the compound represented by formula I or its pharmaceutically acceptable salt to the solvent may range from 1:5 to 1:200.
  • the method of recrystallization is not particularly limited, and it can be performed by a usual recrystallization operation method.
  • the raw materials can be heated and dissolved in an organic solvent and then slowly cooled and allowed to stand for crystallization, or stirring and crystallization can be adopted. After the crystallization is completed, the desired crystals can be obtained by filtering and drying.
  • the recrystallization process can be carried out at room temperature without heating, which largely avoids the degradation of the compound represented by formula I and ensures that the compound represented by formula I or its pharmaceutically acceptable salt And the stability of the pharmaceutical composition and the operability of the production process.
  • the prepared salt of the compound represented by formula I has a small particle size, which is convenient for preparation of the formulation.
  • the compound represented by formula I is relatively soluble in other solvents, for example, ethanol or isopropanol, it can basically only be completely dissolved under heating conditions, which can easily cause degradation of the compound represented by formula I, resulting in purity reduce.
  • seed crystals can optionally be added to accelerate the speed of crystallization.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof is the maleate salt of the compound represented by formula I, and the method further comprises combining the compound represented by formula I or a pharmaceutically acceptable salt thereof with The step of mixing maleic acid and solvent.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof is the dimaleate salt of the compound represented by formula I.
  • the solvent in the mixing step is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, or tetrahydrofuran, preferably methanol.
  • the compound represented by the formula I has high solubility in methanol, and the dissolution rate is relatively fast, and the dissolved compound represented by the formula I is not easy to precipitate in methanol, which is beneficial to industrial production.
  • the preparation method includes:
  • the method further includes the step of separating crystals of the compound represented by formula I or its pharmaceutically acceptable salt.
  • the isolated compound represented by formula I or its pharmaceutically acceptable salt has an impurity content of less than 0.2%, For example, it can be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or more Low, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
  • the methanol solution containing the dimaleate salt of the compound represented by formula I in the step (1) is mixed with other solvents in the step (2) for recrystallization.
  • the step (1) does not include the operation of removing the methanol solvent.
  • the method for separating the compound represented by formula I or its pharmaceutically acceptable salt described in the present disclosure is a conventional separation method in the art, such as centrifugation, filtration and the like.
  • Another aspect of the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I described in the present disclosure or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may also contain other pharmaceutically acceptable excipients.
  • Another aspect of the present disclosure also provides a pharmaceutical composition.
  • the compound of formula I or a pharmaceutically acceptable salt thereof prepared by the method described in the present disclosure or the method described in the present disclosure is combined with one or more pharmaceutically acceptable salts. It is made by mixing acceptable excipients.
  • the content of impurities or substances described in the present disclosure can be obtained through HPLC detection.
  • the relative retention time of each impurity is: impurity-A 0.31min; impurity-B 1.08min; impurity-C 0.86min.
  • the ratio of the impurities described in the present disclosure to the compound represented by formula I or a pharmaceutically acceptable salt thereof is a weight ratio.
  • the "D10” mentioned in the present disclosure refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 10%.
  • D50 refers to the particle size when the cumulative particle size distribution percentage of a sample reaches 50%.
  • D90 refers to the particle size when the cumulative particle size distribution percentage of a sample reaches 90%.
  • Example 1 According to the method of Example 1, 0.5 kg of compound of formula I was added to obtain a total of 601.8 g of compound of formula I dimaleate, with a yield of 86%.
  • the impurity content of the dimaleate product of the formula I compound recrystallized with methanol solvent is significantly lower than that of products prepared from other solvents.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de tyrosine kinase ayant une faible teneur en impuretés. En particulier, la présente invention concerne un composé tel que présenté dans la formule I ou un sel pharmaceutiquement acceptable de celui-ci, dont la teneur en impuretés est inférieure à 0,2 %.
PCT/CN2020/111995 2019-08-30 2020-08-28 Inhibiteur de tyrosine kinase ayant une faible teneur en impuretés WO2021037185A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910812526 2019-08-30
CN201910812526.2 2019-08-30

Publications (1)

Publication Number Publication Date
WO2021037185A1 true WO2021037185A1 (fr) 2021-03-04

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ID=74685178

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TW (1) TW202115027A (fr)
WO (1) WO2021037185A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012122865A2 (fr) * 2011-03-11 2012-09-20 上海恒瑞医药有限公司 Sel pharmaceutiquement acceptable de (e)-n-[4-[[3-chloro-4-(2-pyridylméthoxy)phényl]amino]-3-cyano-7-éthoxy-6-quinolyl]-3-[(2r)-1-méthylpyrrolidine-2-yl]prop-2-énamide, son procédé de préparation et son utilisation médicale
WO2014008794A1 (fr) * 2012-07-12 2014-01-16 江苏恒瑞医药股份有限公司 Forme cristallisée i du dimaléate inhibiteur de tyrosine kinase et ses méthodes de préparation
WO2017186140A1 (fr) * 2016-04-28 2017-11-02 江苏恒瑞医药股份有限公司 Procédé de préparation d'un inhibiteur de tyrosine kinase et d'un dérivé correspondant
WO2019080830A1 (fr) * 2017-10-24 2019-05-02 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un dérivé de quinoléine
CN110840892A (zh) * 2018-08-21 2020-02-28 江苏恒瑞医药股份有限公司 酪氨酸激酶抑制剂与cdk4/6抑制剂联合在制备预防或治疗肿瘤疾病的药物中的用途
CN110960529A (zh) * 2018-09-30 2020-04-07 江苏恒瑞医药股份有限公司 一种降低了毒性杂质含量的酪氨酸激酶抑制剂的原料药
WO2020083188A1 (fr) * 2018-10-22 2020-04-30 江苏恒瑞医药股份有限公司 Forme cristalline de maléate d'inhibiteur de tyrosine kinase et son procédé de préparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012122865A2 (fr) * 2011-03-11 2012-09-20 上海恒瑞医药有限公司 Sel pharmaceutiquement acceptable de (e)-n-[4-[[3-chloro-4-(2-pyridylméthoxy)phényl]amino]-3-cyano-7-éthoxy-6-quinolyl]-3-[(2r)-1-méthylpyrrolidine-2-yl]prop-2-énamide, son procédé de préparation et son utilisation médicale
WO2014008794A1 (fr) * 2012-07-12 2014-01-16 江苏恒瑞医药股份有限公司 Forme cristallisée i du dimaléate inhibiteur de tyrosine kinase et ses méthodes de préparation
WO2017186140A1 (fr) * 2016-04-28 2017-11-02 江苏恒瑞医药股份有限公司 Procédé de préparation d'un inhibiteur de tyrosine kinase et d'un dérivé correspondant
WO2019080830A1 (fr) * 2017-10-24 2019-05-02 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un dérivé de quinoléine
CN110840892A (zh) * 2018-08-21 2020-02-28 江苏恒瑞医药股份有限公司 酪氨酸激酶抑制剂与cdk4/6抑制剂联合在制备预防或治疗肿瘤疾病的药物中的用途
CN110960529A (zh) * 2018-09-30 2020-04-07 江苏恒瑞医药股份有限公司 一种降低了毒性杂质含量的酪氨酸激酶抑制剂的原料药
WO2020083188A1 (fr) * 2018-10-22 2020-04-30 江苏恒瑞医药股份有限公司 Forme cristalline de maléate d'inhibiteur de tyrosine kinase et son procédé de préparation

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