WO2016169030A1 - Fumarate et cristaux de composé de pyridylamine - Google Patents

Fumarate et cristaux de composé de pyridylamine Download PDF

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Publication number
WO2016169030A1
WO2016169030A1 PCT/CN2015/077308 CN2015077308W WO2016169030A1 WO 2016169030 A1 WO2016169030 A1 WO 2016169030A1 CN 2015077308 W CN2015077308 W CN 2015077308W WO 2016169030 A1 WO2016169030 A1 WO 2016169030A1
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WIPO (PCT)
Prior art keywords
compound
formula
iii
crystal
tumor
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PCT/CN2015/077308
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English (en)
Chinese (zh)
Inventor
赵锐
孟庆义
李新路
张喜全
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正大天晴药业集团股份有限公司
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Priority to CA2983475A priority Critical patent/CA2983475C/fr
Priority to PCT/CN2015/077308 priority patent/WO2016169030A1/fr
Priority to AU2015392050A priority patent/AU2015392050B2/en
Priority to RU2017138440A priority patent/RU2684278C1/ru
Publication of WO2016169030A1 publication Critical patent/WO2016169030A1/fr

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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 invention relates to a fumarate of a pyridylamine compound and a crystal thereof, and belongs to the field of medicinal chemistry.
  • Tyrosine kinases (Protein rosine Kinases, PTKs) play an extremely important role in the signal transduction pathway in cells. It is involved in the regulation, signaling and development of normal cells, and is also closely related to the proliferation, differentiation, migration and apoptosis of tumor cells. Therefore, inhibiting the activity of tyrosine kinase has a positive effect on inhibiting and treating tumors.
  • the tyrosine kinase family has multiple subtypes, including the epidermal growth factor receptor subtype (EGFR), the vascular endothelial growth factor receptor subtype (VEGFR), the platelet-derived growth factor receptor subtype (PDGFR), and the anaplastic lymphocyte.
  • Tumor kinase (ALK) and the like have been found to have abnormal activation and expression of ALK kinase in various tumor cells (such as non-small cell lung cancer, breast cancer, and malignant glioma).
  • Crizotinib (XALKORITM) is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Pfizer Inc., and was first marketed in the United States in August 2011 (Nat. Rev. Drug Discov. 10, 895- 896, 2011). The drug is mainly used for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma (ALK).
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • ALK anaplastic lymphoma
  • CN102850328A discloses a pyridinamine compound having a chemical structure such as formula (II) which is an analog of Crizotinib and which has a good inhibitory effect on ALK.
  • formula (II) which is an analog of Crizotinib and which has a good inhibitory effect on ALK.
  • the compound of the formula (II) has problems such as easy moisture absorption and degradation, and storage conditions are severe.
  • the stability, hygroscopicity, and bioavailability of the drug as a therapeutic agent during processing, manufacturing, storage, etc. are critical to drug development; and, from obtaining a commercially viable production method From the standpoint of the production of a pharmaceutical composition containing the active compound, the chemical stability, solid state stability and shelf life of the active ingredient are all very important factors. Therefore, it is important to provide a suitable form of a drug having the desired properties for drug production and storage.
  • the present invention provides a compound of formula (III) having the structure: a fumarate salt of a compound of formula (II):
  • the present invention also provides a process for preparing a compound of the formula (III), which comprises the steps of: dissolving a compound of the formula (II) in an organic solvent, and adding a solution of fumaric acid in ethanol at 0 to 80 ° C to obtain a reaction. a compound of formula (III).
  • a solution of fumaric acid in ethanol is added with stirring for 0.5 to 2 hours.
  • the solid is precipitated in the reaction liquid, it is filtered and dried, preferably Vacuum drying is selected.
  • the organic solvent is selected from one or more of the group consisting of methanol, ethanol, dichloromethane, and acetone.
  • the molar ratio of fumaric acid to the compound of formula (II) is from 1.2 to 1.5:1.
  • the concentration of the fumaric acid in ethanol solution added is from 1.0 mol/L to 2.0 mol/L, preferably from 1.0 mol/L to 1.5 mol/L.
  • the reaction is preferably carried out at 0 to 50 ° C; in other embodiments, the reaction is further preferably carried out at 20 to 50 ° C.
  • the compound of formula (III) can be prepared by dissolving a compound of formula (II) in ethanol and adding a solution of fumaric acid in ethanol at 20-50 ° C with stirring. The reaction is carried out for 0.5 to 2 hours, and the reaction liquid precipitates a solid, which is filtered and dried in vacuo to give a compound of formula (III).
  • the fumaric acid can be replaced with a different inorganic or organic acid, and different acid addition salts of the compound of formula (II) can be prepared in a manner similar to that described above.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutically acceptable carrier can be either solid or liquid.
  • the solid carrier can include one or more of a flavoring agent, a lubricant, a solubilizing agent, a suspending agent, a filler, a binder, a tablet disintegrating agent, or an encapsulating material.
  • Suitable solid carriers include, for example, magnesium stearate, talc, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone.
  • Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups and the like.
  • Suitable liquid carriers for oral and parenteral administration include water, alcohols, oils and the like.
  • the invention also provides the use of a compound of formula (III) for the manufacture of a medicament for the prevention or treatment of a tumor.
  • the compound of the formula (III) of the present invention can be used alone or in combination with other drugs for the preparation of an antitumor drug.
  • the tumor may be lung cancer, preferably ALK positive primary or metastatic non-small cell lung cancer.
  • the invention also provides a type A crystal of the compound of formula (III),
  • the X-ray powder diffraction spectrum has diffraction peaks at about 6.3°, 11.7°, 12.5°, 14.1°, 22.6°, and 23.3° by 2 ⁇ values; typically, the X-ray powder diffraction spectrum is represented by 2 ⁇ values. There are diffraction peaks at about 6.3°, 11.7°, 12.5°, 14.1°, 19.7°, 21.2°, 22.6°, 23.3°, 23.8°, and 25.5°; more typically, X-ray powder diffraction spectra are represented by 2 ⁇ values.
  • the differential scanning calorimetry (DSC) measurement chart of a typical example of the type A crystal of the compound of the formula (III) provided by the present invention has an absorption peak at about 227.5 °C.
  • a typical example of the type A crystal of the compound of formula (III) provided by the present invention has an infrared (IR) spectrum as shown in FIG.
  • Another aspect of the present invention provides a crystal composition wherein the compound of the formula (III) has a type A crystal of 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% by weight of the crystal composition. the above.
  • Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a Form A crystal of the compound of formula (III) above, or a crystalline composition as described above.
  • Another aspect of the present invention provides a crystal of Form A of the above compound of the formula (III), the above crystalline composition, or the use of the above pharmaceutical composition for the preparation of a medicament for preventing or treating a tumor, preferably for preparation for prevention
  • the use in a medicament for treating lung cancer is further preferably used in the preparation of a medicament for treating ALK-positive primary or metastatic non-small cell lung cancer.
  • Another aspect of the present invention provides a method of preparing a type A crystal of the above compound of the formula (III) or the above crystal composition, comprising:
  • the organic solvent is a lower alcohol, preferably a C 1 - C 4 alkyl alcohol, more preferably methanol; in the step (a), it may be heated to 40 ° C to 65 ° C, preferably 50 ° C to 60 ° C;
  • the ratio of the compound of the formula (III) to the organic solvent is preferably from 1 g/50 ml to 1 g/10 ml, more preferably from 1 g/15 ml to 1 g/10 ml; and in the step (a), the preferred stirring rate is from 300 to 500 rpm.
  • the second solvent is acetone, tetrahydrofuran, dioxane or water;
  • the volume ratio of the second solvent in step (b) to the organic solvent in step (a) It may be from 1 to 3:1, preferably 2:1; in step (c), it may be cooled to -15 ° C to 0 ° C, preferably to 0 ° C.
  • the above method of preparing a type A crystal of a compound of formula (III) may further comprise:
  • step (d) vacuum drying at 45 ° C or blast drying at 45 ° C under normal pressure may be employed.
  • the present invention also provides a B-type crystal of the compound of the formula (III),
  • the X-ray powder diffraction spectrum has diffraction peaks at about 23.0°, 24.9°, 25.9°, 27.0°, 28.9°, 29.5°, 38.1°, and 38.8° by 2 ⁇ values; typically, X-ray powder
  • the diffraction spectrum has diffraction peaks at about 18.7°, 23.0°, 24.9°, 25.9°, 27.0°, 28.0°, 28.9°, 29.5°, 36.0°, 38.1°, and 38.7°.
  • the differential scanning calorimetry (DSC) measurement chart of a typical example of the type B crystal of the compound of the formula (III) provided by the present invention has an absorption peak at about 230.6 °C.
  • a typical example of a type B crystal of the compound of formula (III) provided by the present invention has an infrared (IR) spectrum as shown in FIG.
  • Another aspect of the present invention provides a crystal composition wherein the compound of the formula (III) has a B-type crystal of 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% by weight of the crystal composition. the above.
  • Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a Form B crystal of a compound of formula (III) above, or a crystalline composition as described above.
  • Another aspect of the present invention provides a use of a type B crystal of the compound of the above formula (III), the above crystal composition, or the above pharmaceutical composition for the preparation of a medicament for preventing or treating a tumor, preferably for preparation for prevention
  • the use in a medicament for treating lung cancer is further preferably used in the preparation of a medicament for treating ALK-positive primary or metastatic non-small cell lung cancer.
  • Another aspect of the present invention provides a method of preparing a B-type crystal of the above compound of the formula (III) or the above crystal composition, comprising:
  • step (a) it may be heated to 40 ° C to 70 ° C, preferably to reflux; the preferred stirring rate is 300-500 r / min; preferably the ratio of the compound of the formula (III) to anhydrous methanol is 1 g / 50 ml - 1 g /10 ml, further preferably 1 g / 15 ml - 1 g / 10 ml.
  • stepwise cooling may be cooled to 15 ° C to 25 ° C, and further cooled to -5 ° C to -20 ° C; preferably cooled to room temperature and further cooled to -18 ° C.
  • the above method of preparing a Form B crystal of a compound of formula (III) may further comprise:
  • Step (c) may be carried out by vacuum drying at 45 ° C or blast drying at 45 ° C under normal pressure.
  • the X-ray powder diffraction spectrum of the sample was measured under the following conditions: Apparatus: Bruker D2 X-ray diffractometer; test conditions: 30 kV 10 mA; slit: 0.6 mm/3 mm/0.8 mm; target type: Cu; angle range : 5-40°; step length 0.1s/0.02°.
  • 1 H NMR was measured under the following conditions: test unit: China Pharmaceutical University Analytical Testing Center; instrument: BRUKER AV-500 type nuclear magnetic resonance apparatus; solvent: DMSO-d6; internal standard: TMS; temperature: 303K.
  • the DSC spectrum was measured under the following conditions: Apparatus: Mettler type 1 differential thermal analyzer; temperature range: 30-270 ° C; temperature rising rate: 10 ° C / min.
  • the IR spectrum is measured under the following conditions: instrument: Perkin Elmer spetrum 100 type infrared spectrometer; instrument calibration: correcting the wavenumber of the instrument with the infrared spectrum absorption peak of the polystyrene film; Method: KBr tableting method.
  • the ethanol used is anhydrous ethanol unless otherwise specified.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to the crystal.
  • the dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting.
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.
  • the compound of the formula (II) can be produced by referring to the method disclosed in CN201210128875.0.
  • Figure 1 is an X-ray powder diffraction pattern of Form A crystal of the compound of the formula (III) obtained in Example 3.
  • Example 2 is an X-ray powder diffraction pattern of a B-type crystal of the compound of the formula (III) obtained in Example 5.
  • Example 3 is a graph showing a type A crystal differential scanning calorimetry (DSC) measurement of the compound of the formula (III) obtained in Example 3.
  • Example 4 is a B-type crystal differential scanning calorimetry (DSC) measurement chart of the compound of the formula (III) obtained in Example 5.
  • Figure 5 is an infrared (IR) spectrum of Form A crystal of the compound of formula (III) prepared in Example 3.
  • Figure 6 is a B-type crystal infrared (IR) spectrum of the compound of formula (III) prepared in Example 5.
  • 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-pyridinamine can be used according to Organic Process Research&Development, 2011, 15(5): 1018 Prepared by the method disclosed in the literature of -1026 or WO2007066187.
  • the fumaric acid is replaced by a different organic or inorganic acid by the method of Example 2 to provide a series of acid addition salts of the compound of formula (II).
  • HPLC detection conditions are as follows:
  • Liquid Chromatograph Shimadzu Ultra Fast High Resolution Liquid Chromatograph Prominence UFLC XR
  • PDA wavelength range 260 ⁇ 275nm Detection cell temperature: 40 ° C
  • the type A crystal of the compound of the formula (III) prepared in Example 3 and the compound of the formula (III) prepared in Example 5 were prepared by referring to the method for influencing the drug substance in the Appendix XIX C of the Chinese Pharmacopoeia 2010 (Part 2).
  • the B-type crystals were subjected to a high temperature test (40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%) and a strong light irradiation test (45001 x ⁇ 5001 x).
  • the investigation time was 10 days, and the total amount of impurities was sampled on the 0th day and the 10th day to examine the stability.
  • the test results are shown in Table 4.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un fumarate, un cristal de type A et un cristal de type B d'un composé de pyridylamine représenté par la formule structurale (III), un procédé de préparation associé, des compositions médicamenteuses et des compositions cristallines contenant le composé et les cristaux associés, et leurs utilisations dans la préparation de médicaments pour la prévention ou le traitement de tumeurs.
PCT/CN2015/077308 2015-04-23 2015-04-23 Fumarate et cristaux de composé de pyridylamine WO2016169030A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA2983475A CA2983475C (fr) 2015-04-23 2015-04-23 Fumarate et cristaux de compose de pyridylamine
PCT/CN2015/077308 WO2016169030A1 (fr) 2015-04-23 2015-04-23 Fumarate et cristaux de composé de pyridylamine
AU2015392050A AU2015392050B2 (en) 2015-04-23 2015-04-23 Fumarate of pyridylamine compound and crystals thereof
RU2017138440A RU2684278C1 (ru) 2015-04-23 2015-04-23 Фумарат пиридиламина и его кристаллы

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PCT/CN2015/077308 WO2016169030A1 (fr) 2015-04-23 2015-04-23 Fumarate et cristaux de composé de pyridylamine

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WO2016169030A1 true WO2016169030A1 (fr) 2016-10-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020233710A1 (fr) * 2019-05-22 2020-11-26 正大天晴药业集团股份有限公司 Composition pharmaceutique de composé d'amine pyridine et son application dans le cancer du poumon non à petites cellules ros1-positif

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850328A (zh) * 2011-07-01 2013-01-02 中国科学院上海药物研究所 吡啶类化合物、其制备方法、包含该化合物的药物组合物及其用途
CN103263416A (zh) * 2013-04-28 2013-08-28 杭州鸿运华宁生物医药工程有限公司 一种吡啶胺化合物在制备适于口服给药的治疗肺癌的药物中的应用
CN104557869A (zh) * 2013-10-25 2015-04-29 正大天晴药业集团股份有限公司 一种吡啶胺化合物富马酸盐的晶型
CN104557870A (zh) * 2013-10-25 2015-04-29 正大天晴药业集团股份有限公司 一种吡啶胺化合物的富马酸盐

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RU2387650C2 (ru) * 2005-12-05 2010-04-27 Пфайзер Продактс Инк. Полиморфы с-met/hgfr ингибитора
JP2014526524A (ja) * 2011-09-21 2014-10-06 テリジーン リミテッド キナーゼ阻害剤としてのピリジン化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850328A (zh) * 2011-07-01 2013-01-02 中国科学院上海药物研究所 吡啶类化合物、其制备方法、包含该化合物的药物组合物及其用途
CN103263416A (zh) * 2013-04-28 2013-08-28 杭州鸿运华宁生物医药工程有限公司 一种吡啶胺化合物在制备适于口服给药的治疗肺癌的药物中的应用
CN104557869A (zh) * 2013-10-25 2015-04-29 正大天晴药业集团股份有限公司 一种吡啶胺化合物富马酸盐的晶型
CN104557870A (zh) * 2013-10-25 2015-04-29 正大天晴药业集团股份有限公司 一种吡啶胺化合物的富马酸盐

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020233710A1 (fr) * 2019-05-22 2020-11-26 正大天晴药业集团股份有限公司 Composition pharmaceutique de composé d'amine pyridine et son application dans le cancer du poumon non à petites cellules ros1-positif
CN113747900A (zh) * 2019-05-22 2021-12-03 正大天晴药业集团股份有限公司 吡啶胺化合物的药物组合物及其在ros1阳性非小细胞肺癌中的应用
CN113747900B (zh) * 2019-05-22 2024-04-02 正大天晴药业集团股份有限公司 吡啶胺化合物的药物组合物及其在ros1阳性非小细胞肺癌中的应用

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AU2015392050A1 (en) 2017-11-23
CA2983475C (fr) 2023-03-28
AU2015392050B2 (en) 2020-01-23
RU2684278C1 (ru) 2019-04-05

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