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WO2022100586A1 - Forme cristalline de composé spirocyclique contenant de l'oxétane, son procédé de préparation et son utilisation - Google Patents

Forme cristalline de composé spirocyclique contenant de l'oxétane, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022100586A1
WO2022100586A1 PCT/CN2021/129643 CN2021129643W WO2022100586A1 WO 2022100586 A1 WO2022100586 A1 WO 2022100586A1 CN 2021129643 W CN2021129643 W CN 2021129643W WO 2022100586 A1 WO2022100586 A1 WO 2022100586A1
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Prior art keywords
crystal form
compound
formula
etoac
angles
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PCT/CN2021/129643
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English (en)
Chinese (zh)
Inventor
李翼
刘宁
姚婷
于涛
吴成德
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022100586A1 publication Critical patent/WO2022100586A1/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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a crystal form of an oxetane-containing spiro compound, a preparation method and an application thereof, in particular to a crystal form of a compound of formula (I), a preparation method and an application thereof.
  • Ras/Raf/MEK/ERK pathway is a classic mitogen activated protein kinase (MAPK) signaling cascade, which is involved in the signaling of various growth factors, cytokines, mitogens and hormone receptors after activation Transduction is one of the most important signal transduction pathways controlling cell growth, differentiation and survival.
  • MAPK mitogen activated protein kinase
  • Extracellular regulated protein kinases are major players and downstream key nodes in the Ras/Raf/MEK/ERK pathway, and their functions can be found in many human cancers. overactive. As the terminal signaling kinase of this pathway, ERK has not yet been found to have drug resistance mutations. Therefore, drugs targeting ERK kinase are expected to overcome the drug resistance problem after upstream target inhibitor treatment and become a more potential therapeutic strategy. But so far, research on ERK inhibitors is still in the clinical stage, and no ERK inhibitors have been approved for marketing as drugs. In conclusion, there is an urgent need to develop safe and effective ERK inhibitor drugs to meet the needs of tumor treatment.
  • ERKs Extracellular regulated protein kinases
  • the present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 17.39 ⁇ 0.20° and 23.88 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 13.57 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.39 ⁇ 0.20°, 19.37 ⁇ 0.20 °, 22.22 ⁇ 0.20°, 23.88 ⁇ 0.20° and 25.85 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 13.57 ⁇ 0.20°, 14.51 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.39 ⁇ 0.20 °, 19.37 ⁇ 0.20°, 22.22 ⁇ 0.20°, 23.88 ⁇ 0.20° and 25.85 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 9.99 ⁇ 0.20°, 13.57 ⁇ 0.20°, 14.51 ⁇ 0.20°, 15.61 ⁇ 0.20 degrees degrees ° and 37.72 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16°, 9.99°, 13.57°, 14.51°, 15.61°, 16.95°, 17.39°, 18.27° , 19.37°, 19.71°, 21.40°, 21.97°, 22.22°, 23.88°, 25.02°, 25.85°, 26.50°, 27.36°, 28.72°, 30.39°, 31.19°, 31.53°, 31.97°, 32.57°, 33.05 ° and 37.72°.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 17.39 ⁇ 0.20°, and/or 23.88 ⁇ 0.20°, and/or 13.57 ⁇ 0.20°, and/or 16.95 ⁇ 0.20°, and/or 19.37 ⁇ 0.20°, and/or 22.22 ⁇ 0.20°, and/or 25.85 ⁇ 0.20°, and/or 9.99 ⁇ 0.20°, and/or 14.51 ⁇ 0.20° , and/or 15.61 ⁇ 0.20°, and/or 18.27 ⁇ 0.20°, and/or 19.71 ⁇ 0.20°, and/or 21.40 ⁇ 0.20°, and/or 21.97 ⁇ 0.20°, and/or 25.02 ⁇ 0.20°, and /or 26.50 ⁇ 0.20°, and/or 27.36 ⁇ 0.20°, and/or 28.72 ⁇ 0.20°, and/or 30.39 ⁇ 0.20°, and/or 31
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
  • the differential scanning calorimetry curve of the differential scanning calorimetry curve has an onset of an endothermic peak at 225.5 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2 .
  • thermogravimetric analysis curve (TGA) of the above-mentioned crystal form A has a weight loss of 2.41% at 200 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned A crystal form is shown in FIG. 3 .
  • the present invention also provides a method for preparing the crystal form A of the compound of formula (I), comprising:
  • the organic solvent is ethanol, MeOH, ACN, acetone, EtOAc, dioxane, toluene, H 2 O, THF:H 2 O (v/v, 1:1), EtOH:H 2 O (v/v, 2:1), Acetone:EtOAc (v/v, 1:1), DMF:EtOAc (v/v, 5:95), DMF: H2O (v/v, 5:1) 95), acetone: H2O (v/v, 95:5), dioxane: H2O (v/v, 97:3), THF, DCM:EtOAc (v/v, 2:1) .
  • the crystal form A of the compound of the present invention is stable, less affected by light, heat and humidity, and has a broad prospect for medicine; the crystal form A of the compound of formula (I) can significantly inhibit tumor growth under the administration dose, showing a dose-dependent manner; There was no significant weight loss, and the tolerance was good.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOH for ethanol
  • MeOH for methanol
  • 2-MeTHF 2-methyl Tetrahydrofuran
  • Dioxane for dioxane
  • ACN for acetonitrile
  • Toluene for toluene
  • Acetone for acetone
  • EtOAc for ethyl acetate
  • THF tetrahydrofuran
  • FIG. 5 Tumor growth curve of human colon cancer HCT-116 model animal after administration of solvent and compound A crystal form of formula (I) respectively;
  • Fig. 6 Body weight change rate (%) of human colon cancer HCT-116 xenograft tumor model animals during administration.
  • the XRPD test was performed using an X'Pert3 X-ray diffractometer from PANalytical. The test parameters are shown in Table 2.
  • the DSC spectra were collected on a TA 2500 differential scanning calorimeter, and the test parameters are shown in Table 3.
  • TGA was collected on a TA 5500 thermogravimetric analyzer, and the test parameters are shown in Table 4.
  • Dynamic moisture adsorption (DVS) curves were collected on a DVS Intrinsic instrument from SMS (Surface Measurement Systems), UK. The relative humidity at 25°C was corrected for the deliquescence points of lithium chloride (LiCl), magnesium nitrate [Mg( NO3 ) 2 ] and potassium chloride (KCl). The test parameters are shown in Table 5.
  • Hygroscopic classification ⁇ W% deliquescence Absorbs enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% hygroscopic 15%> ⁇ W% ⁇ 2% slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25°C/80%RH.
  • the synthetic route is as follows:
  • step 1
  • the crude product was obtained by concentration under reduced pressure.
  • Dioxane (500 mL) and water (2.5 L) were added to the crude product, stirred at 25° C. for 0.5 hours, and the filter cake was collected by filtration.
  • the filter cake was dissolved in ethanol (2000 mL), stirred at 25° C. for 1 hour, and the filter cake was collected by filtration.
  • the filter cake was dissolved in ethanol (2000 mL), stirred at 75° C. for 1 hour, cooled to 25° C., and the filter cake was collected by filtration.
  • the crude product was dissolved in dioxane (500 mL) and stirred for 10 minutes, then deionized water (2.5 L) was added to continue stirring for 0.5 hour, and the filter cake was collected by filtration.
  • the filter cake was dissolved in deionized water (1 L) and stirred for 1 hour, and the filter cake was collected by filtration.
  • the filter cake was dissolved in absolute ethanol (2L), stirred at 25°C for 1 hour, and the filter cake was collected by filtration.
  • the filter cake was dissolved in absolute ethanol (2L), stirred at 85°C for 1 hour, filtered to collect the filter cake, and the filter cake was vacuum dried at 45°C to obtain the compound of formula (I).
  • test sample marked S1-condition-time is used for content and related substance detection; the test sample marked S2-condition-time is used as a preparation sample, and the test sample marked S3-condition-time is used for XRPD detection .
  • Table 9 shows the results of the solid stability experiment of crystal form A.
  • HCT-116 cells Human colon cancer HCT-116 cells were cultured in monolayer in vitro, and the culture conditions were McCoy's 5a medium plus 10% fetal bovine serum, and cultured in a 5% CO2 incubator at 37°C. Conventional digestion treatment with trypsin-EDTA was passaged three times a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded;
  • Vehicle group 5% DMSO+95% (10% HP- ⁇ -CD).
  • Test compound group weigh the quantitative test compound into a dispensing bottle, add a corresponding volume of DMSO and vortex to obtain a clear solution, add a corresponding volume of 10% HP- ⁇ -CD and vortex to obtain a clear solution solution. Compounds were formulated every three days.
  • Tumor diameter was measured twice a week with a vernier caliper.
  • TGI (%) The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%).
  • the crystal form of compound A of formula (I) can significantly inhibit tumor growth under the administration dose, showing a dose-dependent manner; the body weight of the animals does not decrease significantly during the administration process, and the tolerance is good.

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

Abstract

L'invention concerne une forme cristalline d'un composé spirocyclique contenant de l'oxétane, son procédé de préparation et son utilisation. La présente invention concerne en particulier une forme cristalline d'un composé de formule (I), son procédé de préparation et son utilisation.
PCT/CN2021/129643 2020-11-11 2021-11-09 Forme cristalline de composé spirocyclique contenant de l'oxétane, son procédé de préparation et son utilisation WO2022100586A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011252031.8 2020-11-11
CN202011252031 2020-11-11

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WO2022100586A1 true WO2022100586A1 (fr) 2022-05-19

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008153947A2 (fr) * 2007-06-07 2008-12-18 Amgen Inc. Modulateurs de la raf kinase et leurs méthodes d'utilisation
CN103189369A (zh) * 2010-09-01 2013-07-03 吉利德康涅狄格有限公司 吡啶酮/吡嗪酮、其制备方法及使用方法
CN103201277A (zh) * 2010-09-01 2013-07-10 吉利德康涅狄格有限公司 哒嗪酮、其制备方法及使用方法
WO2013130976A1 (fr) * 2012-03-01 2013-09-06 Array Biopharma Inc. Inhibiteurs de la sérine / thréonine kinase
CN107074874A (zh) * 2014-12-22 2017-08-18 伊莱利利公司 Erk抑制剂
WO2020228817A1 (fr) * 2019-05-15 2020-11-19 南京明德新药研发有限公司 Inhibiteur d'erk et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008153947A2 (fr) * 2007-06-07 2008-12-18 Amgen Inc. Modulateurs de la raf kinase et leurs méthodes d'utilisation
CN103189369A (zh) * 2010-09-01 2013-07-03 吉利德康涅狄格有限公司 吡啶酮/吡嗪酮、其制备方法及使用方法
CN103201277A (zh) * 2010-09-01 2013-07-10 吉利德康涅狄格有限公司 哒嗪酮、其制备方法及使用方法
WO2013130976A1 (fr) * 2012-03-01 2013-09-06 Array Biopharma Inc. Inhibiteurs de la sérine / thréonine kinase
CN107074874A (zh) * 2014-12-22 2017-08-18 伊莱利利公司 Erk抑制剂
WO2020228817A1 (fr) * 2019-05-15 2020-11-19 南京明德新药研发有限公司 Inhibiteur d'erk et son utilisation

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