WO2016131406A1 - Forme cristalline d'un inhibiteur oral des protéines kinases activées par des signaux mitogènes (mapk) et procédé de préparation de cette dernière - Google Patents

Forme cristalline d'un inhibiteur oral des protéines kinases activées par des signaux mitogènes (mapk) et procédé de préparation de cette dernière Download PDF

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Publication number
WO2016131406A1
WO2016131406A1 PCT/CN2016/073770 CN2016073770W WO2016131406A1 WO 2016131406 A1 WO2016131406 A1 WO 2016131406A1 CN 2016073770 W CN2016073770 W CN 2016073770W WO 2016131406 A1 WO2016131406 A1 WO 2016131406A1
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crystal form
ray powder
powder diffraction
preparation
diffraction pattern
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PCT/CN2016/073770
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English (en)
Chinese (zh)
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陈敏华
张炎锋
陆飞
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 WO2016131406A1 publication Critical patent/WO2016131406A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzene
  • the crystal form of imidazolium-6-carboxamide and a preparation method thereof is particularly useful.
  • Binimetinib (MEK162), an anticancer drug, is an oral mitogen-activated protein kinase inhibitor developed by Array Biopharma and is currently in Phase III clinical trials in the United States for the NRAS gene. Treatment of mutant melanoma, BRAF mutant melanoma, and patients with recurrent low-grade plasma ovarian cancer.
  • the chemical name of the drug is: 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole- 6-carboxamide, the structural formula of which is represented by formula (I).
  • the inventors of the present invention surprisingly discovered two crystal forms of the compound of formula (I) during the course of the study. Moreover, the crystal form of the invention has good stability, solubility and wettability meet the requirements of medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the crystalline germanium provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.3 ° ⁇ 0.2 °, 28.3 ° ⁇ 0.2 °, and 11.1 ° ⁇ 0.2 °.
  • the crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 16.2° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 18.9° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 16.2° ⁇ 0.2°, 11.7 ° ⁇ 0.2 °, and 18.9 ° ⁇ 0.2 °. There are characteristic peaks.
  • the crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 23.7° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 22.7° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a 2theta value of 23.7° ⁇ 0.2°, 9.4 ° ⁇ 0.2 °, 22.7 ° ⁇ 0.2 °. There are characteristic peaks.
  • the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern is basically as shown in FIG. 1 . Shown.
  • the crystal form A provided by the present invention is characterized in that an endothermic peak begins to appear near the temperature of 221 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 2 .
  • the crystal form A provided by the present invention is characterized in that it has a weight loss gradient of about 0.7% when heated to 200 ° C, and its thermogravimetric analysis chart is basically as shown in FIG. 3 .
  • the crystal form A provided by the present invention is characterized in that the crystal form A is an anhydride.
  • Another object of the present invention is to provide a process for the preparation of Form A, characterized in that a compound of the formula (I) is added to a positive solvent and added by an anti-solvent addition or added to a suitable crystallization solvent, and the temperature is lowered by volatilization, heating or Prepared by suspension stirring.
  • the positive solvent used in the anti-solvent addition includes alcohols, ethers, ketones, hydrocarbyl nitriles, and amides
  • the anti-solvents include alcohols, esters, halogenated alkanes, and water.
  • positive solvents include, but are not limited to, alcohols, ethers, ketones, acetonitrile, dimethylformamide
  • antisolvents include, but are not limited to, ethanol, ethyl acetate, dichloromethane, and water.
  • the crystallization solvent used for volatilization, heating, cooling or suspension stirring includes alcohols, ketones, halogenated alkanes, alkanes, ethers, aromatic hydrocarbons, esters, carboxylic acids, hydrocarbyl nitriles, water, amides.
  • alcohols include, but are not limited to, methanol, ethanol, isopropanol, ketones including but not limited to methyl ethyl ketone, methyl isobutyl ketone, halogenated alkanes including but not limited to dichloromethane, chloroform, alkanes including but not limited to Heptane, octane, ethers include, but are not limited to, methyl tert-butyl ether, aromatic hydrocarbons including, but not limited to, toluene, xylene, esters including but not limited to ethyl acetate, isopropyl acetate, carboxylic acids including But not limited to acetic acid, hydrocarbyl nitriles include, but are not limited to, acetonitrile, and amides include, but are not limited to, dimethylformamide.
  • Another object of the invention is to provide a crystalline form of the compound of formula (I), Form B.
  • the crystalline germanium provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 25.3 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, and 16.8 ° ⁇ 0.2 °.
  • the crystal form B provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 17.2° ⁇ 0.2°, 29.7° ⁇ 0.2°, and 32.5° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 17.2° ⁇ 0.2°, 29.7° ⁇ 0.2°, 32.5 ° ⁇ 0.2°. There are characteristic peaks.
  • the crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern is one or two of 2theta values of 25.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 23.0° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 25.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 23.0 ° ⁇ 0.2°. There are characteristic peaks.
  • crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern thereof is substantially as shown in FIG.
  • the crystal form B provided by the present invention is characterized in that an endothermic peak begins to appear near the temperature of 89 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 5 .
  • the crystal form B provided by the present invention is characterized in that it has a weight loss gradient of about 21.6% when heated to 120 ° C, and the thermogravimetric analysis chart is basically as shown in FIG. 6 .
  • the present invention provides the crystalline form B, characterized in that the crystalline form B is a diacetic acid solvate.
  • Another object of the present invention is to provide a process for the preparation of Form B comprising dissolving a solid of the compound (I) in acetic acid
  • the toluene solvent is added by an anti-solvent addition method, and the mixture is stirred and crystallized.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of Form A or Form B or a mixture thereof and a pharmaceutically acceptable excipient.
  • the crystalline form A or the crystalline form B of the compound of the formula (I) or a mixture thereof can be used for the preparation of a medicament for treating cancer, in particular, a pharmaceutical preparation for melanoma and ovarian cancer. .
  • the crystal form provided by the invention has good stability and remarkable process purification effect. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form provided by the invention has low wettability, meets the requirements of bioavailability and efficacy, does not require special drying conditions in the preparation process, simplifies the preparation process and post-treatment process of the drug, and is not easily affected by humidity, and the storage condition The requirements are not harsh, and it is convenient for long-term storage, which greatly reduces the cost of material storage and quality control, and has strong economic value.
  • Figure 1 is an XRPD pattern of Form A
  • Figure 2 is a DSC diagram of Form A
  • Figure 3 is a TGA diagram of Form A
  • Figure 4 is an XRPD pattern of Form B
  • Figure 5 is a DSC diagram of Form B
  • Figure 6 is a TGA diagram of Form B
  • Figure 7 is a 1 H NMR chart of Form B
  • Figure 8 is a DVS diagram of Form A
  • Figure 9 is a comparison of XRPD under different conditions of Form A (XRPD before test from top to bottom, XRPD placed at 5 °C for 11 months, XRPD placed at 25 °C, 60% RH for 11 months, 11 months of XRPD placed at 40 ° C, 75% RH)
  • Figure 10 is a comparison of XRPD under different conditions of Form B (XRPD before test from top to bottom, XRPD placed at room temperature for 2 weeks)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the starting compounds of the formula (I) can be obtained by known preparation methods, for example, according to the patent CN101633645B.
  • 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 X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1, and its XRPD pattern is shown in Fig. 1.
  • the wetting weight gain is not less than 15%
  • Humidity Wet 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 crystalline form A of the present invention had a weight gain of 0.14% after equilibration at 80% humidity, and was of no or almost no wettability. This property indicates that the crystal form is not susceptible to humidity or deliquescence, facilitating its long-term storage placement.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 7. Its DSC diagram is shown in Figure 5, and its TGA diagram is shown in Figure 6. The 1 H NMR chart is shown in Figure 7, and the 1 H NMR data is as follows:
  • the crystal form B sample was placed at room temperature and the XRPD and HPLC purity of the Form B sample was measured after two weeks.
  • the experimental results are shown in Table 9.
  • the XRPD comparison chart under different conditions of Form B is shown in Figure 10 (from top to bottom, XRPD before test, and XRPD for 2 weeks at room temperature).
  • Form B significantly improves the chemical purity of the sample and effectively removes many impurities in the sample.

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

Abstract

La présente invention concerne une forme cristalline destinée au traitement du mélanome et du cancer de l'ovaire, et un procédé de préparation de cette dernière. La forme cristalline A et la forme cristalline B fournies par la présente invention présentent une bonne stabilité, le processus de purification de ces dernières est efficace, et la solubilité et l'hygroscopicité de ces dernières satisfont aux exigences médicales. Le procédé de préparation de la forme cristalline est simple, son coût est faible, et l'optimisation et le développement futurs du médicament présentent une valeur significative.
PCT/CN2016/073770 2015-02-16 2016-02-14 Forme cristalline d'un inhibiteur oral des protéines kinases activées par des signaux mitogènes (mapk) et procédé de préparation de cette dernière WO2016131406A1 (fr)

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CN201510084490.2 2015-02-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10485788B2 (en) * 2016-06-03 2019-11-26 Array Biopharma Inc. Pharmaceutical combinations
WO2020165565A1 (fr) 2019-02-11 2020-08-20 Johnson Matthey Public Limited Company Solvate cristallin de binimitinib avec dmso et forme cocristalline de binimitinib avec de l'acide citrique
WO2021116901A1 (fr) * 2019-12-09 2021-06-17 Biocon Limited Formes de binimétinib et procédé de préparation correspondant

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1874768A (zh) * 2003-08-29 2006-12-06 阵列生物制药公司 作为mek抑制剂的n3烷基化苯并咪唑衍生物
WO2014063024A1 (fr) * 2012-10-19 2014-04-24 Novartis Ag Préparation d'un inhibiteur de mek et formulation le contenant
CN104487089A (zh) * 2012-03-20 2015-04-01 诺华股份有限公司 组合疗法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100984613B1 (ko) * 2002-03-13 2010-09-30 어레이 바이오파마 인크. Ｍｅｋ 억제제로서의 ｎ3 알킬화 벤즈이미다졸 유도체

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1874768A (zh) * 2003-08-29 2006-12-06 阵列生物制药公司 作为mek抑制剂的n3烷基化苯并咪唑衍生物
CN104487089A (zh) * 2012-03-20 2015-04-01 诺华股份有限公司 组合疗法
WO2014063024A1 (fr) * 2012-10-19 2014-04-24 Novartis Ag Préparation d'un inhibiteur de mek et formulation le contenant

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10485788B2 (en) * 2016-06-03 2019-11-26 Array Biopharma Inc. Pharmaceutical combinations
US11376239B2 (en) * 2016-06-03 2022-07-05 Array Biopharma Inc Pharmaceutical combinations
WO2020165565A1 (fr) 2019-02-11 2020-08-20 Johnson Matthey Public Limited Company Solvate cristallin de binimitinib avec dmso et forme cocristalline de binimitinib avec de l'acide citrique
CN113316569A (zh) * 2019-02-11 2021-08-27 庄信万丰股份有限公司 比美替尼与dmso的结晶溶剂化物以及比美替尼与柠檬酸的共结晶形式
WO2021116901A1 (fr) * 2019-12-09 2021-06-17 Biocon Limited Formes de binimétinib et procédé de préparation correspondant

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