WO2023185869A1 - Forme cristalline de fumarate de dérivé pyrrolohétérocyclique et son procédé de préparation - Google Patents

Forme cristalline de fumarate de dérivé pyrrolohétérocyclique et son procédé de préparation Download PDF

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Publication number
WO2023185869A1
WO2023185869A1 PCT/CN2023/084452 CN2023084452W WO2023185869A1 WO 2023185869 A1 WO2023185869 A1 WO 2023185869A1 CN 2023084452 W CN2023084452 W CN 2023084452W WO 2023185869 A1 WO2023185869 A1 WO 2023185869A1
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Prior art keywords
formula
compound represented
cancer
crystal form
fumarate salt
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PCT/CN2023/084452
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English (en)
Chinese (zh)
Inventor
周先强
杨俊然
尤凌峰
冯君
杜振兴
王捷
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2023185869A1 publication Critical patent/WO2023185869A1/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
    • A61K31/41—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
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to a new crystal form of fumarate salt of a pyrroloheterocyclic derivative and a preparation method thereof, and belongs to the field of pharmaceuticals.
  • Mitogen-activated protein kinase plays an extremely important role in the signal transduction pathway, and extracellular signal regulated kinase (ERK) is a member of the MAPK family.
  • ERK extracellular signal regulated kinase
  • RAS-RAF-MEK-ERK step exogenous stimulation signals are transmitted to ERK, and the activated ERK is transferred into the nucleus to regulate the activity of transcription factors, thereby regulating biological functions such as cell proliferation, differentiation, and apoptosis, or through phosphorylation
  • Cytoskeletal components in the cytoplasm participate in the regulation of cell morphology and the redistribution of the cytoskeleton.
  • RAS and RAF gene mutations cause continuous activation of the MAPK-ERK signaling pathway, promoting malignant transformation and abnormal proliferation of cells, and ultimately the formation of tumors (Roberts PJ et al., Oncogene, 2007, 26(22), 3291-3310).
  • the combination of MEK inhibitors and B-RAF inhibitors can further improve the effect of B-RAF inhibitors on inhibiting tumor growth, and can significantly improve the disease-free progression and overall survival rates of melanoma patients carrying BRAF V600E and V600K mutations (Frederick DT et al. , Clinical Cancer Research, 2013.19(5), 1225-1231).
  • B-RAF/MEK inhibitors can inhibit tumors, their efficacy is short-lived.
  • B-RAF/MEK inhibitors not only inhibit tumor growth, but also regulate the immune microenvironment of tumors.
  • B-RAF/MEK inhibitors can enhance the expression of tumor-specific antigens, improve the recognition and killing of tumors by antigen-specific T cells, and promote the migration and infiltration of immune cells.
  • the expression of PD-L1 in tumor tissues was enhanced, and when combined with antibodies against checkpoint molecules (such as PD-1 antibodies, CTLA4 antibodies), it showed superior efficacy.
  • checkpoint molecules such as PD-1 antibodies, CTLA4 antibodies
  • BioMed Valley Discoveries’ BVD-523 is in the second clinical phase
  • Merck’s MK-8353 and Astex’s Astex-029 are in the first clinical phase.
  • Relevant patents include WO1999061440A1, WO2001056557A2, WO2001056993A2, WO2001057022A2, WO2002022601A1, WO2012118850A1, WO2013018733A1, WO2014179154A2, WO2015 103133A1, WO2016192063A1, WO2017180817A1, WO2018049127A1.
  • the present disclosure provides a V crystal form of the fumarate salt of the compound represented by formula (I), the fumarate salt of the compound represented by formula (I), wherein the compound represented by formula (I) and fumaric acid
  • the molar ratio of the salt is 2:1, and its X-ray powder diffraction spectrum has characteristic peaks at 2 ⁇ angles of 13.763, 14.493, 17.975, 19.549, and 25.502.
  • the V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure has an X-ray powder diffraction spectrum at 2 ⁇ angle of 11.684, 12.703, 13.763, 14.493, 16.740, 17.975, 19.549, 23.299, 23.711 There are characteristic peaks at , 25.502 and 26.448.
  • the V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure has an X-ray powder diffraction spectrum at the 2 ⁇ angle of 7.756, 8.278, 11.684, 12.703, 13.763, 14.493, 15.305, 16.740, 17.975 There are characteristic peaks at , 19.549, 21.221, 22.519, 23.299, 23.711, 24.132, 25.502, 26.448, 27.356, 29.725, 30.822, and 36.057.
  • the present disclosure provides the V crystal form of the fumarate salt of the compound represented by formula (I), wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • Another aspect of the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), including the following steps: 1) Dissolving the compound represented by formula (I) and fumaric acid in an organic In the solvent, 2) crystallizes out, wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from 10:1-2:1, and the organic solvent is selected from methanol, acetonitrile, ethanol, isopropanol, Ethyl acetate, tetrahydrofuran, acetone or mixtures thereof.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I).
  • the step of dissolving the compound represented by formula (I) and fumaric acid in an organic solvent is Operate under heating conditions, the temperature can be selected from 30-120°C, such as 35-80°C, such as 40-60°C, specifically it can be selected from 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C , 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I).
  • the crystallization step is completed under heating conditions, and the temperature can be selected from 30-120°C. example Such as 35-80°C, such as 40-60°C, specifically it can be selected from 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85 °C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from the group consisting of 20: 1-2:1, for example 10:1-2:1.
  • the crystallization step time is greater than 1.5 hours, such as greater than 3 hours, such as greater than 7 hours, For example, it is greater than 15 hours, for example, it is greater than 24 hours.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), and the organic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, Tetrahydrofuran, acetonitrile, acetone or mixtures thereof, preferably methanol.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), including the following steps: 1) adding the compound represented by formula (I) and fumaric acid in Dissolve in an organic solvent under heating conditions, 2) crystallize under heating conditions, the temperature of step 1) and step 2) is selected from 30-120°C, optionally the same or different, wherein the compound represented by formula (I)
  • the molar ratio to fumaric acid is selected from 10:1-2:1, the time of step 2) is greater than 1.5 hours, and the organic solvent is methanol, ethanol, isopropyl alcohol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or mixtures thereof.
  • the method for preparing the crystalline forms described in the present disclosure further includes filtration, washing or drying steps.
  • the present disclosure provides a composition prepared from the V crystal form of the fumarate salt of the compound represented by formula (I).
  • composition contains the following components: i) the V crystal form of the fumarate salt of the compound represented by formula (I); and ii) one or more pharmaceutically acceptable carriers, diluents or excipients.
  • Another aspect of the present disclosure provides a preparation method of the above-mentioned pharmaceutical composition, including the following steps: Mix the ingredients.
  • the present disclosure also provides the V crystal form of the fumarate salt of the compound represented by formula (I), or the composition prepared by the aforementioned method in the preparation of drugs for the treatment or prevention of cancer, inflammation, or other proliferative diseases.
  • the cancer is selected from the group consisting of melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, and bladder cancer , prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumors, myeloma, astrocytoma and glioma.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in this disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20, which can be -0.20, -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, -0.04, -0.03, -0.02, -0.01 , 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • Crystallization as described in this disclosure includes, but is not limited to, stirring crystallization, beating crystallization and volatilization crystallization.
  • the drying temperature mentioned in the publication is generally 25°C to 100°C, preferably 40°C to 70°C. Drying can be done under normal pressure or under reduced pressure.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High-performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a Bruker D8 Discovery X-ray diffractometer. Specific collection information: Cu anode (40kV, 40mA), Cu-K ⁇ ray Scanning mode: ⁇ /2 ⁇ , scanning range (2 ⁇ range): 5 ⁇ 50°.
  • DSC is differential scanning calorimetry: the measurement is performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding chart (mostly 25-300 or 25-350°C), nitrogen purge speed 50mL/min.
  • TGA thermogravimetric analysis: the METTLER TOLEDO TGA2 thermogravimetric analyzer is used for detection, with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding chart (mostly 25-300°C), and the nitrogen purge rate is 50mL/min.
  • DVS dynamic moisture adsorption: the detection uses SMS DVS Advantage. At 25°C, the humidity changes from 50%-95%-0%-95%-50% in steps of 10% (the last step is 5%) (specific range of humidity Subject to the corresponding chart, most methods of use are listed here), and the judgment standard is that dm/dt is not greater than 0.002%.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: In the methylene chloride/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • Ion chromatography Thermo Scientific Dionex Intergrion ion chromatograph and chromatographic column DionexIonPacTM AS11-HC (4 ⁇ m, 4*250cm) were used for detection.
  • Example 1 (Preparation method of Example 10 in WO2020200069A1)
  • compound 1e (4.0g, 8.51mmol) was dissolved in 50mL of 1,4-dioxane, and 4,4,4',4',5,5,5',5'- were added in sequence Octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.24g, 12.76mmol), potassium acetate (3.34g, 34.04mmol) and [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (1.24g, 1.70mmol), stirred at 90°C for 2 hours. Cool, filter through diatomaceous earth, concentrate the filtrate, and purify by column chromatography with eluent system C to obtain the title compound If (2.0 g), yield: 45%.
  • compound 1f (98.6 mg, 0.19 mmol), pre-prepared 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine 1i, [1,1′ - Bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.02 mmol), cesium carbonate (124 mg, 0.2 mmol) mixture was suspended in 20 mL of 1,4-dioxane and 4 mL of water, heated to The reaction was stirred at 80°C for 14 hours.
  • Dissolve compound 1j (100 mg, 0.17 mmol) in 20 mL of methylene chloride, add 1 mL of trifluoroacetic acid dropwise, complete the addition, and stir for 4 hours. Adjust the pH to 7 with saturated sodium bicarbonate, extract with dichloromethane (20 mL ⁇ 2), combine the organic phases, concentrate under reduced pressure, and purify with column chromatography using eluent system A to obtain the title compound 1 (15 mg), yield: 18%. The product was tested by X-ray powder diffraction and found to be amorphous. Type, XRPD spectrum is shown in Figure 1.
  • the TGA spectrum is shown in Figure 4.
  • the weight loss is 0.44% at 25°C-140°C, and the weight loss is 8.46% at 140°C-270°C.
  • the DVS spectrum is shown in Figure 5. Under normal storage conditions (i.e. 25°C humidity 60%), the water absorption is approximately 0.18%; under accelerated test conditions (i.e. humidity 70%), the water absorption is approximately 0.23%; under extreme conditions (i.e. humidity 90%) %), water absorption is about 0.44%. During the humidity change process from 0% to 95%, the desorption process and adsorption process of the sample basically coincided; the X-ray powder diffraction comparison before and after DVS showed that the crystal form did not change before and after DVS (see Figure 6).
  • the fumarate V crystal form of the compound represented by formula (I) was placed flat in the open and examined under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%). Regarding the stability of the sample, the sampling inspection period is 30 days.
  • the fumarate V crystal form of the compound represented by formula (I) was placed at 25°C, 60% RH and 40°C, 75% RH to examine its stability.
  • the long-term/accelerated stability experiment shows that the physical and chemical properties of the fumarate V crystal form of the compound represented by formula (I) are good when placed under long-term accelerated stability conditions for 6 months.
  • Embodiment 5 preparation of ⁇ crystal form of hydrobromide salt of compound represented by formula (I)
  • Embodiment 6 preparation of ⁇ crystal form of hydrobromide salt of compound represented by formula (I)
  • hydrobromide ⁇ crystal form of the compound represented by formula (I) and the hydrobromide beta crystal form of the compound represented by formula (I) are placed flat in the open, and the stability of the samples under high temperature (40°C, 60°C) conditions is investigated. nature, the sampling inspection period is 30 days.
  • Example 8 the hydrobromide ⁇ crystal form of the compound represented by formula (I), the hydrobromide beta crystal form of the compound represented by formula (I), and the fumarate V crystal form of the compound represented by formula (I) in physiological media dispersion phenomenon
  • Excessive fumarate crystal form V of the compound represented by formula (I) and hydrobromide ⁇ and ⁇ crystal form samples (target concentration approximately 5 mg/ml) of the compound represented by formula (I) were placed in FaSSGF, FeSSIF, and FaSSIF physiological systems respectively.
  • the relevant media were equilibrated at 37°C and 120rpm for 1h and 24h, and the observed phenomena are shown in Table 8.
  • the fumarate crystal form V of the compound represented by formula (I) has good dispersion behavior in physiological media.

Abstract

La présente divulgation concerne une forme cristalline de fumarate d'un dérivé pyrrolohétérocyclique et son procédé de préparation. Plus particulièrement, la présente invention concerne une forme cristalline V de fumarate d'un composé représenté par la formule (I) et son procédé de préparation. La forme cristalline V de fumarate du composé de formule (I) fournie par la présente invention a une bonne stabilité, et peut être mieux utilisée pour un traitement clinique.
PCT/CN2023/084452 2022-03-28 2023-03-28 Forme cristalline de fumarate de dérivé pyrrolohétérocyclique et son procédé de préparation WO2023185869A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016192063A1 (fr) * 2015-06-03 2016-12-08 Changzhou Jiekai Pharmatech Co. Ltd Composés hétérocycliques utilisés comme inhibiteurs d'erk
CN107922387A (zh) * 2015-06-15 2018-04-17 阿沙纳生物科学公司 Erk1与erk2的杂环抑制剂及其在癌症治疗中的应用
WO2020200069A1 (fr) * 2019-03-29 2020-10-08 江苏恒瑞医药股份有限公司 Dérivé pyrrolohétérocyclique, son procédé de préparation et son application en médecine
WO2022068860A1 (fr) * 2020-09-29 2022-04-07 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé pyrrolo-hétérocyclique et son procédé de préparation
CN114315837A (zh) * 2020-09-29 2022-04-12 江苏恒瑞医药股份有限公司 一种erk抑制剂的结晶形式及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016192063A1 (fr) * 2015-06-03 2016-12-08 Changzhou Jiekai Pharmatech Co. Ltd Composés hétérocycliques utilisés comme inhibiteurs d'erk
CN107922387A (zh) * 2015-06-15 2018-04-17 阿沙纳生物科学公司 Erk1与erk2的杂环抑制剂及其在癌症治疗中的应用
WO2020200069A1 (fr) * 2019-03-29 2020-10-08 江苏恒瑞医药股份有限公司 Dérivé pyrrolohétérocyclique, son procédé de préparation et son application en médecine
WO2022068860A1 (fr) * 2020-09-29 2022-04-07 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé pyrrolo-hétérocyclique et son procédé de préparation
CN114315837A (zh) * 2020-09-29 2022-04-12 江苏恒瑞医药股份有限公司 一种erk抑制剂的结晶形式及其制备方法

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