WO2016124137A1 - Phosphate de l'inhibiteur du récepteur du facteur de croissance épidermique, forme cristalline du phosphate et procédé de préparation - Google Patents

Phosphate de l'inhibiteur du récepteur du facteur de croissance épidermique, forme cristalline du phosphate et procédé de préparation Download PDF

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WO2016124137A1
WO2016124137A1 PCT/CN2016/073342 CN2016073342W WO2016124137A1 WO 2016124137 A1 WO2016124137 A1 WO 2016124137A1 CN 2016073342 W CN2016073342 W CN 2016073342W WO 2016124137 A1 WO2016124137 A1 WO 2016124137A1
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compound
formula
phosphate
crystalline form
preparation
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PCT/CN2016/073342
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English (en)
Chinese (zh)
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陈敏华
张炎锋
刘凯
夏楠
张晓宇
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苏州晶云药物科技有限公司
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Publication of WO2016124137A1 publication Critical patent/WO2016124137A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 relates to the field of chemical medicine, in particular to N-(2-(2-dimethylaminoethyl-methylamino)-4-methoxy-5-(4-(1-methylindol-3-yl) a pyrimidine-2-yl)aminophenyl)prop-2-enamide phosphate, a crystal form thereof, and a process for the preparation thereof.
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • EGFR-TKI Growth factor receptor tyrosine kinase inhibitor
  • the chemical name of the compound of formula (I) is N-(2-(2-dimethylaminoethyl-methylamino)-4-methoxy-5-(4-(1-methylindol-3-yl)pyrimidine 2-yl)aminophenyl)prop-2-enamide.
  • a suitable drug salt can improve the solubility of the drug, increase the physicochemical stability, and improve the physical properties such as melting point, hygroscopicity, and crystallization type after the salt is formed, and has a further development of the pharmaceutical dosage form.
  • the original research company used the mesylate salt of the compound of formula (I) for clinical research.
  • methanesulfonic acid is highly biotoxic and, if selected, is not suitable for use in medicine. (P. Heinrich Stahl, Camille G. Wermuth (Eds.). (2002). Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 294-302)
  • the phosphate provided by the invention has high solubility, low wettability, high biosafety, meets medicinal requirements, and has simple preparation method, and is suitable for drug research and industrial production.
  • the phosphate of the compound of formula (I) provided by the present invention is in a crystalline form and is designated as Form A in the present invention.
  • the X-ray powder diffraction pattern of Form A provided by the present invention has characteristic peaks at 2theta values of 9.8 ° ⁇ 0.2 °, 10.9 ° ⁇ 0.2 °, and 16.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A provided by the present invention has a characteristic peak at a 2theta value of 7.5 ° ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, and 24.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A provided by the present invention has a value of 2theta in 2theta There are characteristic peaks at 8.2 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, and 17.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A provided by the present invention has a value of 7.5 ° ⁇ 0.2 °, 8.2 ° ⁇ 0.2 °, 9.8 ° ⁇ 0.2 °, 10.9 ° ⁇ 0.2 °, 16.4 °. Characteristic peaks are present at ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, 19.5° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A provided by the present invention is substantially as shown in FIG.
  • crystal form A provided by the present invention begins to exhibit an endothermic peak when heated to about 235 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the crystal form A provided by the present invention has a weight loss gradient of about 1.5% when heated to 200 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .
  • Another object of the present invention is to provide a process for the preparation of a crystalline form A of a compound of the formula (I), which comprises reacting a compound of the formula (I) with phosphoric acid in a ketone or an alcohol solvent, and stirring and crystallization.
  • the alcohol solvent is preferably an alcohol having a carbon number of less than 6, more preferably methanol or ethanol.
  • the ketone solvent is preferably a ketone having a carbon number of less than 6, more preferably acetone.
  • the molar ratio of the compound of the formula (I) to phosphoric acid is 1:1.
  • the phosphate of the compound of the formula (I) provided by the present invention in particular the crystalline form A of the phosphate of the compound of the formula (I), can be used for the preparation of a medicament for the treatment of cancer, in particular for the treatment of a medicament for the treatment of non-small cell lung cancer.
  • Still another object of the present invention is to provide a pharmaceutical composition which is prepared by using a crystalline form A of the compound of the formula (I) as an active ingredient and adding a usual excipient for the drug.
  • Another object of the present invention is to provide a use of the phosphate crystal form A of the compound of the formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of cancer.
  • the phosphate crystal form A of the compound of the formula (I) provided by the invention has higher biosafety, overcomes the problem of great toxicity of the methanesulfonate salt, and is more suitable for drug development;
  • the phosphate crystal form A of the compound of the formula (I) provided by the invention has lower hygroscopicity, and overcomes the problem that the mesylate salt has high wettability and high humidity is deliquescent;
  • the phosphate crystal form A of the compound of the formula (I) provided by the present invention has higher solubility than the free base of the compound of the formula (I), and satisfies the bioavailability and the efficacy requirement.
  • Figure 1 is an XRPD pattern of the crystalline form A of the compound of formula I;
  • Figure 2 is a DSC chart of the crystalline form A of the compound of formula I;
  • Figure 3 is a TGA diagram of the crystalline form A of the compound of formula I;
  • Figure 4 is a 1 H NMR chart of the crystalline form A of the compound of formula I;
  • Figure 5 is a DVS diagram of the crystalline form A of the compound of formula I;
  • Figure 6 is a DVS diagram of the crystalline form B of the compound of formula I;
  • Figure 7 is a XRPD comparison of the one month stability test of the compound of formula I for the crystalline form A of the compound of formula I under different test conditions (from top to bottom, the starting sample is XRPD, 5 ° C, 25 ° C / 60% RH and XRPD of the sample after being placed at 40 ° C / 75% RH for 1 month;
  • Figure 8 is a comparison of XRPD of the 3-month stability test of the compound of the formula I for the phosphate crystal form A under different test conditions (from top to bottom, the starting sample is XRPD, 5 ° C, 25 ° C / 60% RH and XRPD of the sample after 3 months of placement at 40 ° C / 75% RH.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the solid obtained in this example was a phosphate crystal form A of the compound of the formula (I), and the X-ray powder diffraction data thereof are shown in Table 1. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.
  • the solid obtained in this example was a phosphate crystal form A of the compound of the formula (I), and its X-ray powder diffraction data is shown in Table 2.
  • the phosphate crystal form A of the compound of the formula (I) and the free base were respectively made into a saturated solution by using H 2 O and a simulated gastric fluid (SGF) of pH 1.8, respectively, after 1 hour, 4 hours and 24 hours, respectively.
  • the content was determined by high performance liquid chromatography (HPLC) after an hour.
  • HPLC high performance liquid chromatography
  • the invention overcomes the problem that the free base has low solubility and is unstable in the biological medium by means of phosphate formation, and the effect of improving bioavailability is achieved.
  • Application CN103702990A The compound (I) mesylate salt Form B has a weight gain of 6.16% after equilibration at 80% relative humidity, a high wettability, and deliquescence occurs after equilibration at 95% relative humidity.
  • the invention overcomes the problem that the mesylate salt has high wettability and deliquescent by means of phosphate formation.
  • Deliquescence absorbs a sufficient amount of water to form a liquid
  • the wetting weight gain is not less than 15%
  • the wetting weight gain is less than 15% but not less than 2%;
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%.
  • the phosphate crystal A of the compound of the formula (I) obtained by the present invention is placed at 5 ° C, 25 ° C / relative humidity 60%, and 40 ° C / relative humidity of 75% for 3 months, respectively at the end of January and March
  • Each sample was taken once, focusing on the stability of related substances and crystal forms.
  • the test showed that Form A had good stability, the HPLC purity data is summarized in Table 5, and the XRPD comparison chart is shown in Figures 7 and 8.
  • the phosphate crystal A of the compound of the formula (I) was very stable. Stabilization refers to the analysis by liquid phase, XRPD, etc., that is, no degradation is found, and no transition to other crystal forms is detected.

Abstract

La présente invention concerne une forme cristalline de phosphate A du composé de formule (I), et un procédé de préparation de la forme cristalline de phosphate A. La forme cristalline de phosphate A possède des propriétés avantageuses telles qu'une bonne solubilité, une faible hygroscopicité et une faible aptitude au développement du procédé. Le procédé de préparation est simple et de coût réduit, et présente une valeur considérable pour l'optimisation et le développement futurs du médicament.
PCT/CN2016/073342 2015-02-05 2016-02-03 Phosphate de l'inhibiteur du récepteur du facteur de croissance épidermique, forme cristalline du phosphate et procédé de préparation WO2016124137A1 (fr)

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CN201510059564.7A CN104961731A (zh) 2015-02-05 2015-02-05 一种表皮生长因子受体抑制剂的磷酸盐、其晶型及制备方法
CN201510059564.7 2015-02-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017218892A1 (fr) * 2016-06-17 2017-12-21 Beta Pharma, Inc. Sels pharmaceutiques de n-(2-(2-(diméthylamino)éthoxy)-4-méthoxy-5-((4-(1-méthyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phényl)acrylamide et leurs formes cristallines
CN110483486A (zh) * 2019-09-17 2019-11-22 鲁南制药集团股份有限公司 一种奥西替尼酮咯酸盐晶型及其制备方法

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CN104961731A (zh) * 2015-02-05 2015-10-07 苏州晶云药物科技有限公司 一种表皮生长因子受体抑制剂的磷酸盐、其晶型及制备方法
RU2603960C1 (ru) * 2015-11-19 2016-12-10 Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") Дихлорацетат n1,n2-дизамещенного n4-[4-(1-метил-1н-индол-3-ил)-пиримидин-2-ил]-5-метоксибензол-1,2,4-триамина в качестве модулятора egfr для лечения рака
RU2733412C2 (ru) * 2016-03-22 2020-10-01 Цзянсу Хансох Фармасьютикал Груп Ко., Лтд. Поликристаллическая форма свободного основания или соли присоединения кислоты ингибитора egfr, способ её получения и применение
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
CN106432231B (zh) * 2016-09-09 2018-06-12 无锡佰翱得生物科学有限公司 Azd9291的药用盐、及其晶型和制备方法
CN107176954B (zh) 2017-06-02 2019-01-11 无锡双良生物科技有限公司 一种egfr抑制剂的药用盐及其晶型、制备方法和应用
CA3067044A1 (fr) * 2017-06-16 2018-12-20 Beta Pharma, Inc. Formulations pharmaceutiques de n-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1h-indole-3-yl)pyrimidine-2-yl)amino)phenyl)acrylamide et de sels de ce dernier
CN113801101A (zh) * 2020-06-15 2021-12-17 鲁南制药集团股份有限公司 Azd9291-2-酮戊二酸盐及其制备方法
CN113929663A (zh) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 Azd9291-2-吲哚甲酸盐及其制备方法
CN113929664A (zh) * 2020-07-13 2022-01-14 鲁南制药集团股份有限公司 Azd9291-3,5-吡啶二羧酸盐及其制备方法
CN113968845A (zh) * 2020-07-24 2022-01-25 鲁南制药集团股份有限公司 Azd9291-没食子酸盐及其制备方法
TW202222795A (zh) * 2020-11-19 2022-06-16 大陸商上海翰森生物醫藥科技有限公司 一種含吲哚類衍生物的鹽、晶型及其製備方法和應用

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CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症
CN104961731A (zh) * 2015-02-05 2015-10-07 苏州晶云药物科技有限公司 一种表皮生长因子受体抑制剂的磷酸盐、其晶型及制备方法

Patent Citations (2)

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CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症
CN104961731A (zh) * 2015-02-05 2015-10-07 苏州晶云药物科技有限公司 一种表皮生长因子受体抑制剂的磷酸盐、其晶型及制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017218892A1 (fr) * 2016-06-17 2017-12-21 Beta Pharma, Inc. Sels pharmaceutiques de n-(2-(2-(diméthylamino)éthoxy)-4-méthoxy-5-((4-(1-méthyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phényl)acrylamide et leurs formes cristallines
US10844045B2 (en) 2016-06-17 2020-11-24 Beta Pharma, Inc. Pharmaceutical salts N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide and crystalline forms thereof
CN110483486A (zh) * 2019-09-17 2019-11-22 鲁南制药集团股份有限公司 一种奥西替尼酮咯酸盐晶型及其制备方法
CN110483486B (zh) * 2019-09-17 2024-01-26 鲁南制药集团股份有限公司 一种奥西替尼酮咯酸盐晶型及其制备方法

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