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WO2022127904A1 - 一种吲唑类衍生物的药学上可接受的盐、结晶形式及其制备方法 - Google Patents

一种吲唑类衍生物的药学上可接受的盐、结晶形式及其制备方法 Download PDF

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WO2022127904A1
WO2022127904A1 PCT/CN2021/139125 CN2021139125W WO2022127904A1 WO 2022127904 A1 WO2022127904 A1 WO 2022127904A1 CN 2021139125 W CN2021139125 W CN 2021139125W WO 2022127904 A1 WO2022127904 A1 WO 2022127904A1
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formula
compound represented
pharmaceutically acceptable
crystal form
maleate
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PCT/CN2021/139125
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English (en)
French (fr)
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王林
邵启云
冯君
贺峰
赵苗苗
杜振兴
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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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Priority to CN202180084474.7A priority Critical patent/CN116615418A/zh
Publication of WO2022127904A1 publication Critical patent/WO2022127904A1/zh

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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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms

Definitions

  • the present disclosure relates to a pharmaceutically acceptable salt, a crystalline form and a preparation method of an indazole derivative, belonging to the field of medicine.
  • Breast cancer is one of the most common malignant tumors in women. According to the 2012 GLOBALCAN statistics (CA CANCER J CLIN 2015; 65:87–108), there are about 1.7 million new cancer cases and 520,000 deaths worldwide every year. Both morbidity and mortality rank first among female malignant tumors. According to the 2017 China Cancer Registry Annual Report released by the National Cancer Center, breast cancer ranks first in the incidence of female malignant tumors, with about 279,000 new cases each year, and an annual increase of about 2%.
  • Endocrine therapy plays an important role in the treatment of this part of breast cancer patients.
  • Endocrine therapy is mainly divided into three categories, namely aromatase inhibitor (AI), which can inhibit the conversion of androgens into estrogen, reduce the level of estrogen in the body, and selective estrogen receptor modulator (selective estrogen receptor modulator).
  • SERM selective estrogen receptor modulator
  • SERM selective estrogen receptor degrader
  • SELD selective estrogen receptor degrader
  • endocrine therapy is the treatment of choice for estrogen receptor-positive breast cancer
  • about 30% of patients receiving adjuvant therapy will relapse, and almost all patients with metastatic breast cancer will develop drug resistance and progress.
  • the mechanisms of resistance to endocrine therapy are mainly divided into two categories. One is focused on the estrogen receptor signaling pathway itself, including the activating mutation, amplification, and fusion with other genes of the gene ESR1 encoding the estrogen receptor. Other mechanisms include the activation of signaling pathways that cross-react with the estrogen receptor signaling pathway, such as the growth factor receptor pathway, etc. (Nat Rev Clin Oncol. 2015 Oct. 2015). ; 12(10):573-83).
  • ESR1 gene mutations may be one of the mechanisms of drug resistance in estrogen-positive breast cancer (Nat Rev Clin Oncol. 2015 Oct;12(10):573-83 and Nat Genet 2013;45:1439-45).
  • ESR1 gene mutations were found in patients with estrogen receptor-positive metastatic breast cancer, and the mutation rate was about 30%.
  • ER Y537S and ER D538G mutations were found in 29% of the ctDNA of patients with estrogen receptor-positive metastatic breast cancer that progressed after AIs therapy.
  • PFS progression free survival
  • OS overall survival
  • ESR1 gene mutations mostly occur in metastatic estrogen receptor-positive breast cancer patients who have progressed after AIs therapy. These patients are no longer sensitive to AIs therapy. Therefore, it is necessary to develop estrogen receptors targeting ESR1 gene mutations. antagonist.
  • the first-in-class estrogen receptor covalent binding antagonist H3B-6545 developed by Eisai Company has strong inhibitory activity on wild-type and mutant estrogen receptors, and can bind to the receptor through covalent binding. To exert longer-term efficacy, clinical phase I and II trials are currently underway.
  • WO2016196346 and WO2016196342 patents for estrogen receptor antagonists with mutations in the ESR1 gene are currently underway.
  • PCT/CN2020/096744 provides an indazole derivative whose chemical name is (E)-1-morpholinyl-4-((1-(((5-((Z)-4,4,4 -Trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl ) amino) but-2-en-1-one (Formula I), providing patients with a new treatment option.
  • the present disclosure provides a pharmaceutically acceptable salt of a compound represented by formula (I), the pharmaceutically acceptable salt is selected from maleate or hydrochloride,
  • the present disclosure provides a maleic acid salt of a compound shown in formula (I), wherein the mol ratio of compound shown in formula (I) to maleic acid is 1:2-2:1.
  • the present disclosure provides a maleate salt of a compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to maleic acid is 1:1.
  • the present disclosure also provides a method for preparing the pharmaceutically acceptable salt of the aforementioned formula (I), comprising: the step of forming a salt between the compound of formula (I) and an acid selected from maleic acid, hydrochloric acid or their solution, the solvent used in the salt-forming reaction is selected from water, methanol, n-propanol, isopropanol, ethanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, butanone, methyl tert-butyl ether, acetonitrile, One or more of 1,4-dioxane, ethyl acetate and n-hexane.
  • the present disclosure further provides Form I of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 16.448, 16.956, 19.332, 20.135, 21.645, 22.257 and 22.696 .
  • the present disclosure further provides Form I of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 7.853, 16.448, 16.956, 19.332, 20.135, 20.835, 21.645, 22.257, 22.696 and a characteristic peak at 25.879.
  • the present disclosure further provides Form I of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 6.643, 7.853, 16.448, 16.956, 18.671, 19.332, 20.135, 20.835, 21.645 , 22.257, 22.696, 25.879 and 29.015 have characteristic peaks.
  • the present disclosure further provides Form II of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 7.440, 15.005, 15.503, 17.599, 18.763, 20.471 and 26.259 .
  • the present disclosure further provides Form II of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 7.440, 8.724, 15.005, 15.503, 17.599, 18.136, 18.763, 20.471, 26.259 and a characteristic peak at 28.925.
  • the present disclosure further provides Form II of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 7.440, 8.724, 15.005, 15.503, 17.599, 18.136, 18.763, 20.471, 22.600 , 23.556, 24.643, 26.259 and 28.925 have characteristic peaks.
  • the present disclosure further provides Form III of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 6.830, 16.440, 17.358, 19.295, 19.919, 20.946 and 26.340 .
  • the present disclosure further provides Form III of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 6.830, 7.916, 16.440, 17.358, 19.295, 19.919, 20.946, 23.702, 25.820 and characteristic peaks at 26.340.
  • the present disclosure further provides Form III of the maleate salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 6.830, 7.916, 14.150, 16.440, 17.358, 19.295, 19.919, 20.946, 22.943 , 23.702, 25.820, 26.340 and 29.177 have characteristic peaks.
  • Another aspect of the present disclosure provides a method for preparing the I crystal form of the maleate salt of the compound represented by formula (I), the method comprising the following steps:
  • Another aspect of the present disclosure provides a method for preparing the II crystal form of the maleate salt of the compound represented by the formula (I), the method comprising the following steps:
  • Another aspect of the present disclosure provides a method for preparing the maleate salt form III of the compound represented by formula (I), the method comprising raising the temperature of the maleate salt form I of the compound represented by formula (I) to 110°C.
  • the present disclosure provides a hydrochloride salt of a compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1.
  • the present disclosure provides a hydrochloride salt of the compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:1.
  • the present disclosure further provides a crystal form of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 6.253, 12.578, 13.583, 18.151, 19.174, 20.027 and 26.978.
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • the present disclosure further provides a crystal form of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 6.253, 8.647, 11.210, 12.578, 13.583, 18.151, 19.174, 20.027, 26.676 and There is a characteristic peak at 26.978.
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • the present disclosure further provides a crystal form of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 6.253, 8.647, 11.210, 12.578, 13.583, 18.151, 19.174, 20.027, 24.105, There are characteristic peaks at 25.004, 25.375, 26.676 and 26.978.
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • the present disclosure further provides the b crystal form of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 12.613, 15.871, 16.013, 17.839, 18.144, 19.186 and 20.074.
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • the present disclosure further provides the b crystal form of the hydrochloride salt of the compound represented by formula (I), the X-ray powder diffraction pattern of which is 12.613, 15.871, 16.013, 17.839, 18.144, 19.186, 20.074, 20.773, 21.186 and There is a characteristic peak at 26.977.
  • the mol ratio of the compound shown in the formula (I) and hydrochloric acid is 1:2-2:1, preferably 1:1.
  • the present disclosure further provides the b crystal form of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 12.613, 15.871, 16.013, 17.839, 18.144, 19.186, 20.074, 20.773, 21.186, There are characteristic peaks at 22.512, 24.181, 26.599 and 26.977.
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • the present disclosure further provides the crystal form c of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 15.515, 17.137, 19.743, 20.471, 21.525, 23.442 and 25.987.
  • the present disclosure further provides the crystal form c of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 7.353, 13.066, 14.042, 15.515, 17.137, 19.743, 20.471, 21.525, 23.442 and There is a characteristic peak at 25.987.
  • the present disclosure further provides the crystal form c of the hydrochloride salt of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 6.970, 7.353, 9.527, 13.066, 14.042, 15.515, 17.137, 19.743, 20.471, There are characteristic peaks at 21.525, 23.442, 25.987 and 29.252.
  • Another aspect of the present disclosure provides a method for preparing the a-crystal form of the hydrochloride salt of the compound represented by formula (I), the method comprising the following steps:
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • Another aspect of the present disclosure provides a method for preparing the b crystal form of the hydrochloride salt of the compound represented by formula (I), the method comprising the following steps:
  • compound shown in formula (I) is dissolved in at least one solvent selected from isopropanol, isopropyl ether, n-hexane, ethyl acetate and acetonitrile,
  • the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:2-2:1, preferably 1:1.
  • Another aspect of the present disclosure provides a method for preparing the crystal form c of the hydrochloride salt of the compound represented by formula (I), the method comprising the following steps:
  • the preparation method of the crystal form described in the present disclosure further comprises the steps of filtration, washing or drying.
  • the present disclosure also provides a pharmaceutical composition prepared from the pharmaceutically acceptable salt or the crystal form of the pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I).
  • the present disclosure also provides a pharmaceutical composition, comprising the following components: i) a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I) or a crystalline form of a pharmaceutically acceptable salt, and ii) optionally selected from a pharmaceutically acceptable salt acceptable carrier, diluent or excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the steps of mixing the aforementioned component i) and component ii).
  • the present disclosure also provides a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I) or a crystal form of a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I), or the aforementioned composition, or prepared by the aforementioned method Use of the obtained composition in the preparation of estrogen receptor modulators.
  • the present disclosure also provides the pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I) or the crystal form of the pharmaceutically acceptable salt of the aforementioned compound represented by the formula (I) or the aforementioned composition or prepared by the aforementioned method.
  • Use of the composition in the preparation of a medicament for the prevention and/or treatment of an estrogen receptor-mediated or dependent disease or condition preferably the estrogen receptor-mediated or dependent disease or condition is cancer, more Breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer are preferred, and breast cancer is most preferred.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in this disclosure refers to the diffraction angle, and ⁇ is the Bragg angle, in degrees or degrees; 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 in the present disclosure includes, but is not limited to, stirring crystallization, beating crystallization and volatile crystallization.
  • the preparation method of the crystal form described in the present disclosure also includes steps such as filtration and drying.
  • the drying temperature mentioned in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and drying under normal pressure or under reduced pressure is possible.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured with an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • XRPD is X-ray powder diffraction detection: the measurement is carried out with a BRUKER D8Discover X-ray diffractometer, specific information collected: Cu anode (40kV, 40mA), Cu-K ⁇ rays Scanning mode: ⁇ /2 ⁇ , scanning range (2 ⁇ range): 3 ⁇ 50°.
  • DSC is differential scanning calorimetry: METTLER TOLEDO DSC 3+ differential scanning calorimeter is used for measurement, the heating rate is 10°C/min, and the specific temperature range refers to the corresponding spectrum (mostly 25-300 or 25-350°C), nitrogen purge Speed 50mL/min.
  • TGA thermogravimetric analysis: METTLER TOLEDO TGA 2 type thermogravimetric analyzer was used for detection, the heating rate was 10°C/min, the specific temperature range was referred to the corresponding spectrum (mostly 25-300°C), and the nitrogen purge rate was 50mL/min.
  • DVS dynamic moisture adsorption: SMS DVS Advantage is used for detection. At 25°C, the humidity changes from 50%-95%-0%-95%-50% in steps of 10% (the last step is 5%) (the specific humidity range is The corresponding spectrum shall prevail, and most of the methods are listed here), and the judgment standard is that dm/dt is not more than 0.002%.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • the second step (Z)-(1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H -Indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)carbamate tert-butyl ester 1f
  • the third step (Z)-(1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H -Indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)-1-amine 1g
  • the fourth step (E)-1-morpholinyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrafluoro) Hydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropane base)amino)but-2-en-1-one 1i
  • Test Example 1 Determination of Inhibitory Effect of Compound of Formula I on Estrogen Receptor Reporter Gene Activity
  • the purpose of this experiment is to test the inhibitory effect of the disclosed compounds on the activity of the estrogen receptor reporter gene, and to evaluate the in vitro activity of the compounds according to the IC 50 size.
  • MCF7 cells (ATCC, HTB-22) expressing the estrogen receptor response element-controlled luciferase reporter gene ERE-luc (synthesized by Jinweizhi Biotechnology Co., Ltd.) MCF7/ERE-luc containing 10% fetal bovine serum and 500 ⁇ g /ml G418 in MEM (GE Healthcare, SH30024.01) medium for culture.
  • ERE-luc the estrogen receptor response element-controlled luciferase reporter gene
  • MCF7/ERE-luc containing 10% fetal bovine serum and 500 ⁇ g /ml G418 in MEM (GE Healthcare, SH30024.01) medium for culture.
  • MCF7/ERE-luc cells were seeded in a 96-well plate at a density of 30,000 cells/well using incomplete MEM medium containing 10% activated carbon-treated fetal bovine serum (BioSun, BS-0004-500).
  • the 96-well plate was taken out, and 100 ⁇ l of ONE-Glo TM Luciferase Assay system (Promega, E6110) was added to each well to detect the activity of luciferase. After 3 minutes at room temperature until the cells were fully lysed, the multi-labeled microplate was used for enzyme labeling. The luminescence signal value was read by an instrument (PerkinElmer, VICTOR 3), and the IC50 value of the inhibitory activity of the compound was calculated according to the concentration of the compound and the luminescence signal value with Graphpad Prism software.
  • the inhibitory effect of the compounds in the present disclosure on the activity of the estrogen receptor reporter gene was determined by the above experiments, and the chemiluminescence signal value was plotted with the logarithmic concentration of the compound using Graghpad Prism, and the IC50 value of the compound of formula I was determined to be 1 nM .
  • the disclosed compounds have a significant inhibitory effect on the estrogen receptor reporter gene.
  • Test Example 2 Inhibitory effect of the compounds of the present disclosure on the proliferation of MCF7 cells
  • the purpose of this experiment is to determine the inhibitory activity of the disclosed compounds on the proliferation of MCF7 cells, and to evaluate the in vitro activity of the compounds according to the IC 50 size.
  • MCF7 cells (ATCC, HTB-22) were cultured in MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum.
  • MEM GE Healthcare, SH30024.01
  • MCF7 cells were seeded in a 96-well plate at a density of 3,000 cells/well in complete medium, 100 ⁇ l of cell suspension per well, and placed in a cell incubator at 37°C and 5% CO 2 overnight. The next day, the medium was aspirated, and each well was replaced with 135 ⁇ l of MEM incomplete medium containing 2% fetal bovine serum. At the same time, 15 ⁇ l of different concentrations of the compounds to be tested prepared in incomplete medium were added to each well.
  • the final concentration of the compounds was 9 concentration points of 4-fold serial dilution starting from 100 nM, set up blank control containing 0.5% DMSO, and placed in a cell incubator at 37 °C, 5% CO 2 for 144 hours.
  • the IC 50 value of the compound was obtained as 0.5 nM, and the result showed that the compound of the present disclosure has a significant inhibitory effect on the proliferation of MCF7 cells.
  • Test Example 3 Experimental Biological Evaluation of Expression of ER ⁇ Mutant MCF7 Cell Proliferation Inhibition
  • the purpose of this experiment was to determine the inhibitory activity of the disclosed compounds on the proliferation of MCF7 cells expressing ER ⁇ mutants.
  • mutants ER ⁇ Y537S and ER ⁇ D538G of human estrogen receptor ⁇ (ER ⁇ ) protein were obtained by double-primer PCR using the cDNA (Accession No. NM000125) of the wild-type ESR1 gene as a template for site-directed mutagenesis.
  • the primer sequences used for mutation are as follows (the underlined nucleotides are the sites of mutation): Y537S: F-AAG AAC GTG GTG CCC CTC T C T GAC CTG CTG CTG GAG ATG; R-CAT CTC CAG CAG GTC A G A GAG GGG CAC CAC GTT CTT; D538G: F-AAC GTG GTG CCC CTC TAT G G C CTG CTG CTG GAG ATG CTG; R-CAG CAT CTC CAG CAG CAG G C C ATA GAG GGG CAC CAC GTT.
  • the cDNA of mutant ESR1 was cloned into the target lentiviral vector pCDH-CMV-MCS-EF1-Puro.
  • the lentiviral plasmids carrying the mutant ESR1 gene sequences and lentiviral packaging plasmids were then transfected into HEK-293T cells (ATCC, CRL-3216) by Lipofectamine 3000 Transfection Reagent (ThermoFisher Scientific, Cat# L3000075).
  • the virus-containing medium supernatant was filtered and ultracentrifuged to obtain the virus pellet, resuspended and dissolved with an appropriate amount of medium, added to MCF7 cells (ATCC, HTB-22), and added to the final concentration Incubate overnight with 8 ⁇ g/ml polybrene.
  • MCF7 cells ATCC, HTB-22
  • puromycin was added to the cell culture medium for resistance screening, and about two weeks later, the MCF7 cell line capable of stably expressing ER ⁇ Y537S and ER ⁇ D538G mutants was obtained.
  • MCF7 cells expressing ER ⁇ mutants were cultured in MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum.
  • MEM GE Healthcare, SH30024.01
  • complete medium containing 10% fetal bovine serum.
  • cells were seeded in a 96-well plate at a density of 3,000 cells/well in complete medium, 100 ⁇ l of cell suspension per well, and cultured overnight in a cell incubator at 37°C, 5% CO 2 .
  • the medium was aspirated, and each well was replaced with 135 ⁇ l of MEM incomplete medium containing 2% fetal bovine serum.
  • 15 ⁇ l of different concentrations of the compounds to be tested prepared in incomplete medium were added to each well.
  • the final concentration of the compounds was 9 concentration points of 4-fold serial dilution starting from 100 nM, set up blank control containing 0.5% DMSO, and placed in a cell incubator at 37 °C, 5% CO 2 for 144 hours.
  • IC 50 value of the inhibitory activity of the compound, the IC 50 of the inhibitory effect of the compound of the present disclosure on the proliferation of MCF7 D538G cells expressing ER ⁇ mutant is 2nM
  • the IC 50 of the inhibitory effect on the proliferation of MCF7ER ⁇ Y537S cells expressing ER ⁇ mutant is 3nM
  • mice Female, were divided into 4 groups on average, and 9 mice were divided into 1 group. They were purchased from Jisijie Laboratory Animal Co., Ltd., and the animal production license number was SCXK (Shanghai) 2013-0006.
  • mice After a night of fasting, the mice were administered by intragastric administration respectively, and the administration volume was 0.2 ml/10 g, and the administration dose of the compound of formula I was 30 mg/kg.
  • the purpose of this experiment was to determine the covalent modification of the estrogen receptor ER ⁇ wild type and ER ⁇ Y537S mutant by the compounds of the present disclosure.
  • the ligand binding domain (LBD, ligand binding domain, aa296-554) of estrogen receptor ER ⁇ wild type and ER ⁇ Y537S mutant was expressed and purified from E. coli. Add 2 ⁇ M ER ⁇ wild-type or ER ⁇ Y537S mutant protein and 10 ⁇ M compound to a buffer containing 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM TCEP, 5% glycerol, mix well, and incubate at 4°C for 24 hours. High-resolution mass spectrometry detection.
  • test compounds have good covalent modification effect on ER ⁇ wild type or ER ⁇ Y537S mutant protein.
  • the product is defined as crystal form I
  • the XRPD spectrum is shown in Figure 1
  • the peak positions are shown in Table 1.
  • DSC spectrum shows endothermic peaks at 61.47°C and 115.48°C; TGA spectrum shows 2.81% weight loss at 25°C-140°C.
  • the obtained product was characterized by 1 H-NMR, and the nuclear magnetic data showed that the molar ratio of the main component and maleic acid in the salt was 1:1.
  • the product is defined as crystal form II, as shown in Figure 2, and the peak positions are shown in Table 2.
  • the DSC spectrum shows an endothermic peak at 136.02°C; the TGA spectrum shows a weight loss of 0.58% at 25°C-85°C, 3.73% at 85°C-150°C, and 4.39% at 150°C-210°C.
  • the crystal form of compound I represented by formula I was heated to 110° C. by DSC, and detected by X-ray powder diffraction.
  • the crystal form of the product was transformed and defined as crystal form III, as shown in FIG.
  • the obtained product was characterized by 1 H-NMR, and the nuclear magnetic data showed that the molar ratio of the main component and maleic acid in the salt was 1:1.
  • Embodiment 7 the preparation of hydrochloride a crystal form
  • Embodiment 8 the preparation of hydrochloride a crystal form
  • the compound represented by formula I (1.5 g, 2.36 mmol) was added to 10 mL of butanone, stirred, heated to 60 ° C, dissolved, and then added 0.5 mL of n-hexane clear liquid, cooled to 40 ° C, and slowly added dropwise 229.36 ⁇ L concentrated Hydrochloric acid (270.41 mg, 2.60 mmol, 35%) was dissolved, then cooled to room temperature and stirred at room temperature for 24 hours. No solid was precipitated.
  • the compound hydrochloride salt of formula I was added (Example 11), and gradually A white solid was precipitated, stirred for 16 hours, and gradually formed a white cloudy liquid, which was filtered, and the filter cake was collected and dried in vacuo to obtain the title product (1 g, yield: 63%).
  • the chloride ion content was 4.99% as detected by ion chromatography, indicating that the molar ratio of the main component and hydrochloric acid in the salt was 1:1.
  • the product was found to be crystal form a by X-ray powder diffraction.
  • the DSC spectrum shows an endothermic peak at 173.48°C; the TGA spectrum shows a weight loss of 2.81% at 25°C-170°C and a weight loss of 2.07% at 170°C-200°C.
  • DVS test shows that under normal storage conditions (ie, 25°C, 60%RH), the sample has a hygroscopic weight gain of about 0.89%; under accelerated experimental conditions (ie, 70%RH), the hygroscopic weight gain of the sample is about 1.02%; under extreme conditions At low temperature (90% RH), the hygroscopic weight gain was about 1.49%.
  • the crystal form was re-measured, and the crystal form did not change.
  • Embodiment 9 the preparation of hydrochloride a crystal form
  • the chloride ion content was 5.04% as detected by ion chromatography, indicating that the molar ratio of the main component and hydrochloric acid in the salt was 1:1.
  • the product is defined as crystal form b, the XRPD spectrum is shown in Figure 5, and the peak positions are shown in Table 5.
  • the DSC spectrum shows that the endothermic peak is not obvious, and the exothermic peak peak is 183.54°C;
  • DVS test shows that under normal storage conditions (ie, 25°C, 60% RH), the sample has a hygroscopic weight gain of about 0.84%; under accelerated experimental conditions (ie, 70% RH), the hygroscopic weight gain of the sample is about 0.99%; under extreme conditions At low temperature (90% RH), the hygroscopic weight gain was about 1.8%.
  • the desorption process and the adsorption process of this sample were basically coincident during the humidity change from 0% to 95% RH. After the DVS test, the crystal form was re-measured, and the crystal form did not change.
  • the compound represented by formula I (50 mg, 78.66 ⁇ mol) was added to 2 mL of acetonitrile, stirred, and dissolved, and 7.21 ⁇ L of concentrated hydrochloric acid (12M, 86.5 mmol, 35%) was slowly added dropwise, still dissolved, and stirred at room temperature for 24 hours. After that, a white cloudy liquid gradually formed, filtered, and the filter cake was collected and dried in vacuo to obtain the title product (40 mg, yield: 75.66%). The product was found to be crystal form b by X-ray powder diffraction.
  • the DSC spectrum shows that the endothermic peaks are 94.07°C and 147.06°C; the TGA spectrum shows that the weight loss is 5.30% at 25°C-120°C.
  • DVS test shows that under normal storage conditions (ie, 25°C, 60% RH), the sample has a hygroscopic weight gain of about 8.64%; under accelerated experimental conditions (ie, 70% RH), the hygroscopic weight gain of the sample is about 9.32%; under extreme conditions (90% RH), the hygroscopic weight gain was about 12.32%.
  • the desorption process and the adsorption process of this sample were basically coincident during the humidity change from 0% to 95% RH. After the DVS test, the crystal form was re-measured, and the crystal form did not change.
  • Embodiment 15 Experiment on influencing factors of hydrochloride crystal form a
  • Embodiment 16 Long-term accelerated stability experiment of hydrochloride crystal form a

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Abstract

提供一种吲唑类衍生物的药学上可接受的盐、结晶形式及其制备方法。具体而言，涉及式(I)所示化合物药学上可接受的盐的晶型及其制备方法，提供的式(I)化合物的药学上可接受的盐的晶型具备良好的稳定性，可更好地用于临床治疗。

Description

一种吲唑类衍生物的药学上可接受的盐、结晶形式及其制备方法
本申请要求申请日为2020/12/18的中国专利申请202011510169.3的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种吲唑类衍生物的药学上可接受的盐、结晶形式及其制备方法，属于医药领域。
背景技术
乳腺癌是女性最常见的恶性肿瘤之一，据2012年GLOBALCAN统计数据显示(CA CANCER J CLIN 2015；65:87–108)，全球一年约有170万新发癌症病例，52万死亡病例，无论发病率和死亡率都居女性恶性肿瘤首位。国家癌症中心发布的2017年《中国肿瘤登记年报》显示，乳腺癌居女性恶性肿瘤发病率首位，每年新发病例约27.9万，并以每年2％左右的速度递增。
约有70％的乳腺癌患者为雌激素受体(estrogen receptor，ER)阳性乳腺癌，在这部分乳腺癌患者的治疗中，内分泌治疗(endocrine therapy)占有重要地位。内分泌治疗主要分三类，分别是芳香化酶抑制剂(aromatase inhibitor，AI)，能够抑制雄激素转化为雌激素，降低体内雌激素的水平，选择性雌激素受体调节剂(selective estrogen receptor modulator，SERM)，拮抗雌激素受体的活性，和选择性雌激素受体降解剂(selective estrogen receptor degrader，SERD)，不仅可以拮抗雌激素受体的活性，还能够促进受体的降解(Pharmacol Ther.2017 Dec 28)。虽然内分泌治疗是雌激素受体阳性乳腺癌的首选治疗，但约有30％接受辅助治疗的病人会发生复发，而几乎所有的转移性乳腺癌病人都会产生耐药而发生进展。对内分泌治疗产生耐药的机制主要分两类，一类集中在雌激素受体信号通路本身，包括编码雌激素受体的基因ESR1的激活突变、扩增、与其他基因的融合，雌激素受体共调解因子和下游控制细胞周期因子的失调等，另一类机制包括与雌激素受体信号通路有交叉反应的信号通路的激活，如生长因子受体通路等(Nat Rev Clin Oncol.2015 Oct；12(10):573-83)。
2013年两项研究，在11～55％的接受过芳香化酶抑制剂治疗的雌激素受体阳性转移性乳腺癌病人中检测到了ESR1基因突变，进一步研究发现突变受体可以不依赖雌激素发生磷酸化，发挥转录作用，使雌激素依赖的MCF7接种的肿瘤在体内可以不再依赖雌 激素生长，而且突变受体会使SERM他莫昔芬(tamoxifen)和SERD氟维司群(fulvestrant)的活性降低。因此ESR1基因突变可能是雌激素阳性乳腺癌发生耐药的机制之一(Nat Rev Clin Oncol.2015 Oct；12(10):573-83 and Nat Genet 2013；45:1439-45)。在随后进行的多个研究中，都在雌激素受体阳性转移性乳腺癌病人中发现了一定比例的ESR1基因突变，突变比例大约在30％左右。在BOLERO-2临床试验中发现，经过AIs治疗后进展的雌激素受体阳性转移性乳腺癌病人的ctDNA中有29％存在ER Y537S和ER D538G突变。在依西美坦(exemestane)单用组，发生突变病人的无进展生存期(progression free survival，PFS)和总生存期(overall survival，OS)都比没有发生突变的病人短[Nat Genet 2013；45:1446-51]。
综上所述，ESR1基因突变大多发生在经过AIs治疗而进展的转移性雌激素受体阳性乳腺癌病人中，这些病人对AIs治疗不再敏感，因此需要开发针对ESR1基因突变的雌激素受体拮抗剂。
Eisai公司开发的first-in-class的雌激素受体共价结合拮抗剂H3B-6545对野生型和突变型雌激素受体都有较强的抑制活性，且能够通过和受体的共价结合发挥更长时间的药效，目前正在进行临床一二期试验。目前公开的针对ESR1基因突变的雌激素受体拮抗剂的专利有WO2016196346和WO2016196342。
PCT/CN2020/096744提供了一种吲唑类衍生物，其化学名为(E)-1-吗啉基-4-((1-(((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)甲基)环丙基)氨基)丁-2-烯-1-酮(式I)，为患者提供新的治疗选择。
Figure PCTCN2021139125-appb-000001
发明内容
本公开提供一种式(I)所示化合物的药学上可接受的盐，所述药学上可接受的盐选自马来酸盐或盐酸盐，
Figure PCTCN2021139125-appb-000002
可选的实施方案中，本公开提供一种式(I)所示化合物的马来酸盐，其中式(I)所示化 合物与马来酸的摩尔比为1:2-2:1。
可选的实施方案中，本公开提供一种式(I)所示化合物的马来酸盐，其中式(I)所示化合物与马来酸的摩尔比为1:1。
本公开还提供了一种制备前述式(I)所述的可药用盐的方法，包括：式(I)化合物与酸成盐的步骤，所述酸选自马来酸、盐酸或它们的溶液，所述成盐反应所用溶剂选自水、甲醇、正丙醇、异丙醇、乙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、丁酮、甲基叔丁基醚、乙腈、1,4-二氧六环、乙酸乙酯和正己烷中的一种或多种。
本公开进一步提供式(I)所示化合物的马来酸盐的I晶型，其X-射线粉末衍射谱图在2θ角为16.448、16.956、19.332、20.135、21.645、22.257和22.696处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的I晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的I晶型，其X-射线粉末衍射谱图在2θ角为7.853、16.448、16.956、19.332、20.135、20.835、21.645、22.257、22.696和25.879处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的I晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的I晶型，其X-射线粉末衍射谱图在2θ角为6.643、7.853、16.448、16.956、18.671、19.332、20.135、20.835、21.645、22.257、22.696、25.879和29.015处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的I晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的II晶型，其X-射线粉末衍射谱图在2θ角为7.440、15.005、15.503、17.599、18.763、20.471和26.259处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的II晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的II晶型，其X-射线粉末衍射谱图在2θ角为7.440、8.724、15.005、15.503、17.599、18.136、18.763、20.471、26.259和28.925处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的II晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的II晶型，其X-射线粉末衍射谱图在 2θ角为7.440、8.724、15.005、15.503、17.599、18.136、18.763、20.471、22.600、23.556、24.643、26.259和28.925处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的II晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的III晶型，其X-射线粉末衍射谱图在2θ角为6.830、16.440、17.358、19.295、19.919、20.946和26.340处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的III晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的III晶型，其X-射线粉末衍射谱图在2θ角为6.830、7.916、16.440、17.358、19.295、19.919、20.946、23.702、25.820和26.340处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的III晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的马来酸盐的III晶型，其X-射线粉末衍射谱图在2θ角为6.830、7.916、14.150、16.440、17.358、19.295、19.919、20.946、22.943、23.702、25.820、26.340和29.177处有特征峰。
进一步地，所述的式(I)所示化合物的马来酸盐的III晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开另一方面提供一种制备式(I)所示化合物的马来酸盐的I晶型的方法，所述方法包括以下步骤：
1)将式(I)所示化合物、马来酸溶于选自乙醇、丙酮、甲醇或水中的至少一种的溶剂中，
2)结晶析出。
进一步地，前述制备得到的式(I)所示化合物的马来酸盐的I晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开另一方面提供一种制备式(I)所示化合物的马来酸盐的II晶型的方法，所述方法包括以下步骤：
1)将式(I)所示化合物、马来酸溶于选自乙醇、异丙醚、正己烷和丁酮中的至少一种的溶剂中，
2)结晶析出。
进一步地，前述制备得到的式(I)所示化合物的马来酸盐的II晶型，其中式(I)所示化 合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开另一方面提供一种制备式(I)所示化合物的马来酸盐的III晶型的方法，所述方法包括将式(I)所示化合物的马来酸盐I晶型升温至110℃。
进一步地，前述制备得到的式(I)所示化合物的马来酸盐的III晶型，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
本公开提供一种式(I)所示化合物的盐酸盐，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1。
可选的实施方案中，本公开提供一种式(I)所示化合物的盐酸盐，其中式(I)所示化合物与盐酸的摩尔比为1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的a晶型，其X-射线粉末衍射谱图在2θ角为6.253、12.578、13.583、18.151、19.174、20.027和26.978处有特征峰。
进一步地，所述的式(I)所示化合物的盐酸盐的a晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的a晶型，其X-射线粉末衍射谱图在2θ角为6.253、8.647、11.210、12.578、13.583、18.151、19.174、20.027、26.676和26.978处有特征峰。
进一步地，所述的式(I)所示化合物的盐酸盐的a晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的a晶型，其X-射线粉末衍射谱图在2θ角为6.253、8.647、11.210、12.578、13.583、18.151、19.174、20.027、24.105、25.004、25.375、26.676和26.978处有特征峰。
进一步地，所述的式(I)所示化合物的盐酸盐的a晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的b晶型，其X-射线粉末衍射谱图在2θ角为12.613、15.871、16.013、17.839、18.144、19.186和20.074处有特征峰。
进一步地，所述的式(I)所示化合物的盐酸盐的b晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的b晶型，其X-射线粉末衍射谱图在2θ角为12.613、15.871、16.013、17.839、18.144、19.186、20.074、20.773、21.186和26.977处有特征峰。
进一步地，所述的式(I)所示化合物的盐酸盐的b晶型，其中式(I)所示化合物与盐酸 的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的b晶型，其X-射线粉末衍射谱图在2θ角为12.613、15.871、16.013、17.839、18.144、19.186、20.074、20.773、21.186、22.512、24.181、26.599和26.977处有特征峰。
进一步地，所述的式(I)所示化合物的盐酸盐的b晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开进一步提供式(I)所示化合物的盐酸盐的c晶型，其X-射线粉末衍射谱图在2θ角为15.515、17.137、19.743、20.471、21.525、23.442和25.987处有特征峰。
本公开进一步提供式(I)所示化合物的盐酸盐的c晶型，其X-射线粉末衍射谱图在2θ角为7.353、13.066、14.042、15.515、17.137、19.743、20.471、21.525、23.442和25.987处有特征峰。
本公开进一步提供式(I)所示化合物的盐酸盐的c晶型，其X-射线粉末衍射谱图在2θ角为6.970、7.353、9.527、13.066、14.042、15.515、17.137、19.743、20.471、21.525、23.442、25.987和29.252处有特征峰。
本公开另一方面提供一种制备式(I)所示化合物的盐酸盐的a晶型的方法，所述方法包括以下步骤：
1)将式(I)所示化合物溶于选自乙醇、乙醚、丁酮、正己烷或异丙醇中的至少一种的溶剂中，
2)加入盐酸，结晶析出。
进一步地，前述制备得到的式(I)所示化合物的盐酸盐的a晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开另一方面提供一种制备式(I)所示化合物的盐酸盐的b晶型的方法，所述方法包括以下步骤：
1)将式(I)所示化合物溶于选自异丙醇、异丙醚、正己烷、乙酸乙酯和乙腈中的至少一种的溶剂中，
2)加入盐酸，结晶析出。
进一步地，前述制备得到的式(I)所示化合物的盐酸盐的b晶型，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
本公开另一方面提供一种制备式(I)所示化合物的盐酸盐的c晶型的方法，所述方法包括以下步骤：
1)将式(I)所示化合物溶于选自丙酮、甲醇和水中的至少一种的溶剂中，
2)加入盐酸水溶液，结晶析出。
可选的实施方案中，前述的式(I)所示化合物的药学上可接受的盐的晶型，其中，所述2θ角度的误差范围为±0.2。
在某些实施方式中，本公开所述的晶型的制备方法还包括过滤、洗涤或干燥步骤。
本公开还提供了由前述式(I)所示化合物药学上可接受的盐或药学上可接受的盐的晶型制备得到的药物组合物。
本公开还提供了一种药物组合物，包含如下组分：i)前述式(I)所示化合物药学上可接受的盐或者药学上可接受的盐的晶型，和ii)任选自药学上可接受的载体、稀释剂或赋形剂。
本公开还提供了一种药物组合物的制备方法，包括将前述组分i)和组分ii)混合的步骤。
本公开还提供了前述式(I)所示化合物的药学上可接受的盐或者前述式(I)所示化合物的药学上可接受的盐的晶型、或前述组合物、或由前述方法制备得到的组合物在制备雌激素受体调节剂中的用途。
本公开还提供了前述式(I)所示化合物的药学上可接受的盐或者前述式(I)所示化合物的药学上可接受的盐的晶型或前述组合物或由前述方法制备得到的组合物在制备预防和/或治疗雌激素受体介导的或依赖性的疾病或病症的药物中的用途，优选所述雌激素受体介导的或依赖性的疾病或病症为癌症，更优选为乳腺癌、卵巢癌、子宫内膜癌、前列腺癌或子宫癌，最优选乳腺癌。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20，可以为-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。
本公开所述的“结晶析出”包括但不限于搅拌结晶、打浆结晶和挥发结晶。
本公开所述晶型的制备方法中还包括过滤，干燥等步骤。
本公开中所述干燥温度一般为25℃-100℃，优选40℃-70℃，可以常压干燥，也可以减压干燥。
附图说明
图1.式(I)所示化合物的马来酸盐的I晶型XRPD谱图；
图2.式(I)所示化合物的马来酸盐的II晶型XRPD谱图；
图3.式(I)所示化合物的马来酸盐的III晶型XRPD谱图；
图4.式(I)所示化合物的盐酸盐的a晶型XRPD谱图；
图5.式(I)所示化合物的盐酸盐的b晶型XRPD谱图；
图6.式(I)所示化合物的盐酸盐的c晶型XRPD谱图。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。
waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)
THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
离子色谱使用Thermo Scientific Dionex Intergrion，色谱柱型号：DionexIonPacTM AS11-HC(4μm，4×250cm)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8Discover型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα射线
Figure PCTCN2021139125-appb-000003
扫描方式：θ/2θ，扫描范围(2θ范围)：3～50°。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃)，氮气吹扫速度50mL/min。
DVS为动态水分吸附：检测采用SMS DVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.002％。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1、式I化合物(E)-1-吗啉基-4-((1-(((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)甲基)环丙基)氨基)丁-2-烯-1-酮的制备
Figure PCTCN2021139125-appb-000004
第一步：(1-(((5-碘吡啶-2-基)氧基)甲基)环丙基)氨基甲酸叔丁酯1c
将氢化钠(0.4g,10.7mmol)溶于N,N-二甲基甲酰胺(20mL)，室温下加入1-(羟甲基)环丙基氨基甲酸叔丁酯1b(1.0g,5.3mmol，采用公知的方法“Journal of Organic Chemistry, 2002,67(11),3965-3968”制备而得)，加完后缓慢加入2-氟-5-碘吡啶1a(1.8g,8.0mmol)。室温搅拌2小时后停止反应。反应液减压浓缩，残余物用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物1c(2.4g)，产率：86％。
MS m/z(ESI):391.0[M+1]
第二步：(Z)-(1-(((5-(4,4,4-三氟-1-(3-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)甲基)环丙基)氨基甲酸叔丁酯1f
将3-氟-1-(四氢-2H-吡喃-2-基)-5-(4,4,4-三氟丁-1-炔-1-基)-1H-吲唑1d(1.8g,5.5mmol,采用专利申请WO2018098305中说明书第84页的实施例3公开的方法制备得到)溶于甲基四氢呋喃(40mL)，加入双联频哪醇硼酸酯(1.7g,6.6mmol)，四三苯基膦铂(137mg,0.1mmol)，抽换氩气3次，升温至85℃搅拌3小时。冷却至室温，加入化合物1c(2.0g,5.2mmol)，双三苯基磷二氯化钯(741mg,1.1mmol)，碳酸铯(3.6g,11.0mmol)和水(1mL)，室温搅拌过夜。加入碘苯1e(1.2g,6.1mmol)，氢氧化钾(1.5g,27.6mmol)，抽换氩气3次，升温至85℃搅拌2小时后冷却至室温停止反应。反应液减压浓缩，残余物用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物1f(3.0g)，产率：88％。
MS m/z(ESI):667.2[M+1]
第三步：(Z)-(1-(((5-(4,4,4-三氟-1-(3-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)甲基)环丙基)-1-胺1g
将化合物1f(1.8g,2.7mmol)溶于二氯甲烷(15mL)，加入三氟乙酸(3mL)，室温搅拌反应5小时，停止反应。反应液减压浓缩，用饱和碳酸氢钠溶液(100mL)将反应液调至pH 8左右，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物1g粗品(1.4g)，产率：89％，产物不经纯化直接进行下一步反应。
第四步：(E)-1-吗啉基-4-((1-(((5-((Z)-4,4,4-三氟-1-(3-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)甲基)环丙基)氨基)丁-2-烯-1-酮1i
将化合物1g(1.7g,2.8mmol)溶于N,N-二甲基甲酰胺(20mL)，室温下加入二异丙基乙胺(1.1g，8.5mmol)，然后加入(E)-4-溴-1-吗啡啉基丁-2-烯-1-酮1h(0.7g,2.8mmol，采用专利申请US2016347717中说明书第65页的实施例15公开的方法制备得到)，搅拌反应2小时。停止并冷却反应，加入饱和碳酸氢钠溶液(15mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，用饱和氯化钠溶液洗涤(50mL×4)，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1i(1.3g)，产率：65％。
MS m/z(ESI):720.2[M+1]
第五步：(E)-1-吗啉基-4-((1-(((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯 -1-基)吡啶-2-基)氧基)甲基)环丙基)氨基)丁-2-烯-1-酮I
将化合物1i(2.0g,2.8mmol)溶于甲醇(5mL)，加入盐酸(12N,10mL)搅拌反应3小时。停止并冷却反应，浓缩反应液，加入饱和碳酸氢钠溶液(15mL)，用二氯甲烷萃取(50mL×4)，合并有机相，依次用水洗(30mL×3)，饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1(1.3g)，产率：73％。
MS m/z(ESI):636.2[M+1]；
1H NMR(400MHz,CD 3OD)7.65(d,2H),7.49(d,1H),7.30-7.22(m,7H),6.82-6.76(m,1H),6.60-6.52(m,2H),4.15(s,2H),3.62-3.39(m,12H),0.76-0.64(m,4H)。经X-射线粉末衍射检测，该产物晶型为无定型。
测试例1：式I化合物对雌激素受体报告基因活性的抑制作用的测定
1、实验目的
本实验的目的是测试本公开化合物对雌激素受体报告基因活性的抑制作用，根据IC 50大小评价化合物的体外活性。
2、实验方法
表达雌激素受体反应元件控制的荧光素酶报告基因ERE-luc(金唯智生物科技有限公司合成)的MCF7细胞(ATCC，HTB-22)MCF7/ERE-luc使用含有10％胎牛血清和500μg/ml G418的MEM(GE Healthcare，SH30024.01)培养基进行培养。实验第一天，使用含有10％活性炭处理的胎牛血清(BioSun，BS-0004-500)的MEM不完全培养基将MCF7/ERE-luc细胞以30,000个/孔的密度种于96孔板，每孔100μl细胞悬液，放置37℃，5％CO 2的细胞培养箱培养过夜。第二天，每孔加入10μl用不完全培养基配制的β-雌二醇和不同浓度的待测化合物，β-雌二醇的终浓度是0.1nM，化合物的终浓度是从10μM开始进行10倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，放置37℃，5％CO 2的细胞培养箱培养20小时。第三天，取出96孔板，每孔加入100μl ONE-Glo TM Luciferase Assay system(Promega，E6110)检测荧光素酶的活性，室温放置3分钟至细胞充分裂解后，使用多标记微孔板酶标仪(PerkinElmer，VICTOR 3)读取发光信号值，用Graphpad Prism软件根据化合物的浓度和发光信号值计算化合物抑制活性的IC 50值。
3、测试结果
本公开中化合物对雌激素受体报告基因活性的抑制作用通过以上的试验进行测定，用Graghpad Prism对化学发光信号值与化合物的对数浓度作图，测得式I化合物的IC 50值为1nM。
因此，本公开化合物对雌激素受体报告基因具有明显的抑制作用。
测试例2：本公开化合物对MCF7细胞增殖的抑制效应
1、实验目的
本实验的目的是测定本公开化合物对MCF7细胞增殖的抑制活性，根据IC 50大小评价化合物的体外活性。
2、实验方法
MCF7细胞(ATCC，HTB-22)用含有10％胎牛血清的MEM(GE Healthcare，SH30024.01)完全培养基进行培养。实验第一天，使用完全培养基将MCF7细胞以3,000个/孔的密度种于96孔板，每孔100μl细胞悬液，放置37℃，5％CO 2的细胞培养箱培养过夜。第二天吸掉培养基，每孔更换为135μl含有2％胎牛血清的MEM不完全培养基，同时每孔加入15μl用不完全培养基配制的不同浓度的待测化合物，化合物的终浓度是从100nM开始进行4倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，放置37℃，5％CO 2的细胞培养箱培养144小时。第八天，取出96孔细胞培养板，每孔加入150μl
Figure PCTCN2021139125-appb-000005
Luminescent Cell Viability Assay(Promega，G7573)，室温放置10分钟后，使用多标记微孔板酶标仪(PerkinElmer，VICTOR 3)读取发光信号值，用Graphpad Prism软件根据化合物的浓度和发光信号值计算化合物抑制活性的IC 50值。
3、数据分析
用Graghpad Prism对化学发光信号值与化合物的对数浓度作图，得出化合物的IC 50值为0.5nM，结果显示本公开化合物对MCF7细胞增殖具有明显的抑制作用。
测试例3：表达ERα突变体MCF7细胞增殖抑制实验生物学评价
1、实验目的
本实验的目的是测定本公开化合物对表达ERα突变体MCF7细胞增殖的抑制活性。
2、实验方法
定点突变和细胞系构建
人雌激素受体α(estrogen receptorα，ERα)蛋白的突变体ERαY537S与ERαD538G使用双引物PCR的方式以野生型ESR1基因的cDNA(Accession No.NM000125)为模板进行定点突变获得。突变所使用的引物序列如下(下划线标出的核苷酸为突变的位点)：Y537S:F-AAG AAC GTG GTG CCC CTC T CT GAC CTG CTG CTG GAG ATG；R-CAT CTC CAG CAG CAG GTC A GA GAG GGG CAC CAC GTT CTT；D538G:F-AAC GTG GTG CCC CTC TAT G GC CTG CTG CTG GAG ATG CTG；R-CAG CAT CTC CAG CAG CAG G CC ATA GAG GGG CAC CAC GTT。将突变体ESR1的cDNA克隆至目标慢病毒载体 pCDH-CMV-MCS-EF1-Puro上。然后将带有突变体ESR1基因序列的慢病毒质粒以及慢病毒包装质粒通过Lipofectamine 3000 Transfection Reagent(ThermoFisher Scientific，Cat# L3000075)转染到HEK-293T细胞(ATCC，CRL-3216)中。转染后48小时，将带有病毒的培养基上清过滤、超速离心获得病毒沉淀，用适量的培养基重悬溶解后，加入到MCF7细胞(ATCC，HTB-22)中，并加入终浓度为8μg/ml的polybrene孵育过夜。转染两天后，在细胞培养液中加入1μg/ml的嘌呤霉素进行抗性筛选，约两周后得到能够稳定表达ERαY537S与ERαD538G突变体的MCF7细胞系。
细胞增殖抑制实验
将表达ERα突变体的MCF7细胞用含有10％胎牛血清的MEM(GE Healthcare，SH30024.01)完全培养基进行培养。实验第一天，使用完全培养基将细胞以3,000个/孔的密度种于96孔板，每孔100μl细胞悬液，放置37℃，5％CO 2的细胞培养箱培养过夜。第二天吸掉培养基，每孔更换为135μl含有2％胎牛血清的MEM不完全培养基，同时每孔加入15μl用不完全培养基配制的不同浓度的待测化合物，化合物的终浓度是从100nM开始进行4倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，放置37℃，5％CO 2的细胞培养箱培养144小时。第八天，取出96孔细胞培养板，每孔加入150μl
Figure PCTCN2021139125-appb-000006
Luminescent Cell Viability Assay(Promega，G7573)，室温放置10分钟后，使用多标记微孔板酶标仪(PerkinElmer，VICTOR 3)读取发光信号值，用Graphpad Prism软件根据化合物的浓度和发光信号值计算化合物抑制活性的IC 50值，本公开化合物对表达ERα突变体MCF7 D538G细胞增殖的抑制效应的IC 50为2nM，对表达ERα突变体MCF7ERαY537S细胞增殖的抑制效应的IC 50为3nM，结果显示本公开化合物对表达ERα突变体MCF7细胞增殖具有明显的抑制作用。
测试例4、本公开化合物的BALB/C裸鼠药代动力学测试
1、摘要
以BALB/C裸鼠为受试动物，应用LC/MS/MS法测定了BALB/C裸鼠灌胃给予式I化合物后不同时刻血浆中的药物浓度。研究本公开式I化合物在BALB/C裸鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
式I化合物。
2.2试验动物
BALB/C裸鼠36只，雌性，平均分成4组，9只为1组，购自杰思捷实验动物有限 公司提供，动物生产许可证号SCXK(沪)2013-0006。
2.3药物配制
称取适量样品，加5％体积的DMSO、5％体积的吐温80和90％体积的生理盐水配制成0.1mg/mL的无色澄清透明液体。
2.4给药
禁食一夜后分别灌胃给药，给药体积0.2ml/10g，式I化合物给药剂量为30mg/kg。
3、操作
Balb/C裸鼠36只，雌性；禁食一夜后灌胃给药。于给药后0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0h采血0.1ml(每个时间点3只动物)，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。测定不同浓度的药物灌胃给药后裸鼠血浆中的待测化合物含量：取给药后各时刻的裸鼠血浆25μL，加入内标溶液喜树碱40μL(100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液0.5μL进行LC/MS/MS分析。
4、BALB/C裸鼠药代动力学参数结果
本公开式I化合物的药代动力学参数如下：
Figure PCTCN2021139125-appb-000007
结论：本公开化合物的药代吸收良好，具有明显的药代吸收效果。
测试例5、雌激素受体ERα野生型和ERαY537S突变型共价修饰生物学评价
1、实验目的
本实验的目的是测定本公开化合物对雌激素受体ERα野生型和ERαY537S突变型的共价修饰作用。
2、实验方法
雌激素受体ERα野生型和ERαY537S突变型的配体结合区域(LBD,ligand binding domain,aa296-554)由大肠杆菌表达并纯化。将2μM ERα野生型或ERαY537S突变型蛋白和10μM化合物加入到含有50mM Tris-HCl,pH7.5,150mM NaCl,1mM TCEP,5％glycerol的缓冲液中混匀，置于4℃孵育24小时后，进行高分辨质谱检测。或者将1μM ERα野生型或ERαY537S突变型蛋白和3μM化合物加入到含有50mM Tris-HCl,pH7.5, 150mM NaCl,1mM TCEP,5％glycerol的缓冲液中混匀，置于37℃孵育15分钟后，进行高分辨质谱检测。在质谱检测结果图谱中分子量为蛋白与化合物之和的峰即为共价修饰产物，通过计算未结合化合物蛋白与总蛋白的比值算出共价修饰的百分比。
共价修饰24小时后共价修饰比：
Figure PCTCN2021139125-appb-000008
结论：测试化合物对ERα野生型或ERαY537S突变型蛋白均具有很好的共价修饰作用。
实施例2、马来酸盐I晶型的制备
称量10mg式(I)化合物和3.0mg马来酸配体，加入500ul乙醇溶剂搅拌溶清，搅拌2天，慢挥发，逐渐析出固体，过滤，真空干燥固体，所得产物 1H-NMR显示化合物与马来酸的摩尔比为1:1。
经X-射线粉末衍射检测，将该产物定义为晶型I，XRPD谱图如图1，峰位置如表1所示。
表1.马来酸盐I晶型峰位置
Figure PCTCN2021139125-appb-000009
Figure PCTCN2021139125-appb-000010
DSC谱图显示吸热峰峰值61.47℃、115.48℃；TGA谱图显示25℃-140℃失重2.81％。
实施例3、马来酸盐I晶型的制备
称量10mg式(I)化合物和3.0mg马来酸配体，加入500ul10％水/丙酮溶剂搅拌溶清，搅拌2天，慢挥发，逐渐析出固体，过滤，真空干燥固体，核磁数据表明该盐中式(I)所示化合物与马来酸的摩尔比为1:1。经X-射线粉末衍射检测为晶型I。
实施例4、马来酸盐I晶型的制备
称量10mg式(I)化合物和3.0mgq马来酸配体，加入500ul10％水/甲醇溶剂搅拌溶清，搅拌2天，慢挥发，逐渐析出固体，过滤，真空干燥固体，核磁数据表明该盐中式(I)所示化合物与马来酸的摩尔比为1:1。经X-射线粉末衍射检测为晶型I。
实施例5、马来酸盐II晶型的制备
将式I所示化合物(25mg，39.33umol)加入1.5mL乙醇和正己烷(V/V＝1:1)混合溶剂中，搅拌，滴加0.5mL马来酸(4.57mg，39.33umol)丁酮溶液，搅拌溶清，加入0.5mL 正己烷搅拌，0.5小时后逐渐形成白色浑浊液，在室温下搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(25mg，收率：100％)。
所得产物 1H-NMR表征，核磁数据表明该盐中主成分与马来酸的摩尔比为1:1。
1H NMR(400MHz,CD 3OD)δ7.73-7.64(m,2H),7.52(dd,1H),7.32(dd,2H),7.26(d,4H),7.22(dt,1H),6.82(d,1H),6.75-6.63(m,2H),6.27(s,2H),4.41(s,2H),4.01(d,2H),3.69-3.61(m,8H),3.50-3.35(m,2H),1.19-1.17(m,2H),1.16-1.05(m,2H).
经X-射线粉末衍射检测，该产物定义为晶型II，如图2，峰位置如表2所示。
DSC谱图显示吸热峰峰值136.02℃；TGA谱图显示25℃-85℃失重0.58％，85℃-150℃失重3.73％，150℃-210℃失重4.39％。
表2.马来酸盐II晶型峰位置
Figure PCTCN2021139125-appb-000011
Figure PCTCN2021139125-appb-000012
实施例6、马来酸盐III晶型的制备
将式I所示化合物I晶型经DSC升温至110℃，经X-射线粉末衍射检测，该产物晶型发生转变，定义为晶型III，如图3，峰位置如表3所示。所得产物 1H-NMR表征，核磁数据表明该盐中主成分与马来酸的摩尔比为1:1。
表3.马来酸盐III晶型峰位置
Figure PCTCN2021139125-appb-000013
实施例7、盐酸盐a晶型的制备
将式I所示化合物(25mg，39.33μmol)加入到2mL乙醇和乙醚(V/V＝1:1)的混合溶剂中，搅拌，溶清，缓慢滴加入3.28μL浓盐酸(12M，39.33mmol，35％)，出现白色浑浊液，逐渐变成黏稠状，继续搅拌，0.5小时后逐渐形成白色浑浊液，在室温下搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(23mg，收率：80％)。经X-射线粉末衍射检测，该产物定义为晶型a，如图4，峰位置如表4所示。
表4.盐酸盐a晶型峰位置
Figure PCTCN2021139125-appb-000014
Figure PCTCN2021139125-appb-000015
实施例8、盐酸盐a晶型的制备
将式I所示化合物(1.5g，2.36mmol)加入到10mL丁酮中，搅拌，加热至60℃，溶清，再加入0.5mL正己烷清液，冷却至40℃，缓慢滴加入229.36μL浓盐酸(270.41mg，2.60mmol，35％)，溶清，随后冷却至室温，并在室温下搅拌24小时，无固体析出，加入式I所示化合物盐酸盐晶种(实施例11)，逐渐析出白色固体，搅拌16小时，逐渐形成白色浑浊液，过滤，收集滤饼，真空干燥，得到标题产物(1g，收率：63％)。
经离子色谱检测，氯离子含量为4.99％，表明该盐中主成分与盐酸的摩尔比为1:1。
经X-射线粉末衍射检测，将该产物为晶型a。
DSC谱图显示吸热峰峰值173.48℃；TGA谱图显示25℃-170℃失重2.81％，170℃-200℃失重2.07％。DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.89％；在加速实验条件(即70％RH)，吸湿增重约为1.02％；在极端条件下(90％RH)，吸湿增重约为1.49％。DVS检测后复测晶型，晶型未转变。
实施例9、盐酸盐a晶型的制备
将式I所示化合物(25mg，39.33μmol)加入到2mL异丙醇中，搅拌溶清，滴加入3.28μL浓盐酸(12M，39.33mmol，35％)，出现白色浑浊液，逐渐变成黏稠状，继续搅拌，0.5小时后逐渐形成白色浑浊液，在室温下搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(23mg，收率：80％)。经X-射线粉末衍射检测，该产物为晶型a。
实施例10、盐酸盐a晶型的制备
将式I所示化合物(25mg，39.33μmol)加入到2mL丁酮中，搅拌溶清，滴加入3.28μL浓盐酸(12M，39.33mmol，35％)，出现白色浑浊液，逐渐变成黏稠状，继续搅拌，0.5小时后逐渐形成白色浑浊液，在室温下搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(23mg，收率：80％)。经X-射线粉末衍射检测，该产物为晶型a。
实施例11、盐酸盐b晶型的制备
将式I所示化合物(1.2g，1.89mmol)加入到30mL异丙醇、异丙醚和正己烷(V/V/V＝1:1:1)混合溶剂中，搅拌，溶清，滴加入173.05μL浓盐酸(12M，2.07mmol，35％)，溶清，室温下搅拌24小时，逐渐形成白色浑浊液，过滤，收集滤饼，真空干燥，得到标题产物(1.1g，收率：86.69％)。
经离子色谱检测，氯离子含量为5.04％，表明该盐中主成分与盐酸的摩尔比为1:1。
经X-射线粉末衍射检测，该产物定义为晶型b，XRPD谱图如图5，峰位置如表5所示。
DSC谱图显示吸热峰不明显，放热峰峰值为183.54℃；TGA谱图显示25℃-145℃失重0.58％，145℃-180℃失重1.10％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.84％；在加速实验条件(即70％RH)，吸湿增重约为0.99％；在极端条件下(90％RH)，吸湿增重约为1.8％。在0％-95％RH湿度变化过程中，该样品的解吸附过程与吸附过程基本重合。DVS检测后复测晶型，晶型未转变。
表5.盐酸盐b晶型峰位置
Figure PCTCN2021139125-appb-000016
Figure PCTCN2021139125-appb-000017
实施例12、盐酸盐b晶型的制备
将式I所示化合物(50mg，78.66umol)加入到2mL正己烷和乙酸乙酯(V/V＝1:1)的混合溶剂中，搅拌溶清，缓慢滴加入6.55μL浓盐酸(12M，78.66mmol，35％)，出现白色浑浊液，逐渐变成黏稠状，继续搅拌，0.5小时后逐渐形成白色浑浊液，在室温下搅拌16小时，过滤，收集滤饼，真空干燥，得到标题产物(45mg，收率：85.12％)。经X-射线粉末衍射检测，该产物为晶型b。
实施例13、盐酸盐b晶型的制备
将式I所示化合物(50mg，78.66μmol)加入到2mL乙腈中，搅拌，溶清，缓慢滴加入7.21μL浓盐酸(12M，86.5mmol，35％)，仍然溶清，室温下搅拌24小时，后逐渐形 成白色浑浊液，过滤，收集滤饼，真空干燥，得到标题产物(40mg，收率：75.66％)。经X-射线粉末衍射检测，该产物为晶型b。
实施例14、盐酸盐c晶型的制备
称量15mg式I所示化合物，加入500μl溶剂搅拌澄清，加入1M盐酸水溶液26μL无析出，慢挥发得产物，经X-射线粉末衍射检测，定义产物为晶型c。XRPD谱图如图6，峰位置如表6所示。
DSC谱图显示吸热峰峰值为94.07℃、147.06℃；TGA谱图显示25℃-120℃失重5.30％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为8.64％；在加速实验条件(即70％RH)，吸湿增重约为9.32％；在极端条件下(90％RH)，吸湿增重约为12.32％。在0％-95％RH湿度变化过程中，该样品的解吸附过程与吸附过程基本重合。DVS检测后复测晶型，晶型未转变。
表6.盐酸盐c晶型峰位置
Figure PCTCN2021139125-appb-000018
实施例15、盐酸盐晶型a影响因素实验
取式1化合物盐酸盐晶型a于开口的洁净称量瓶中，考察在高温(40℃、60℃)、光照(4500lx±500lx)、高湿(90％±5％RH、75％±5％RH)条件下样品的稳定性，取样考察期为30天，结果如下表7所示。
表7.式I化合物盐酸盐晶型a影响因素30天试验结果
Figure PCTCN2021139125-appb-000019
实验结果显示，式I化合物盐酸盐晶型a在光照、40℃、60℃、75％RH、90％RH条件下物理和化学性质稳定性良好。
实施例16、盐酸盐晶型a长期加速稳定性实验
式I所示化合物盐酸盐晶型a进行6个月的长期(25℃、60％RH)、加速(40℃、75％RH)稳定性考察，结果如下表8。
表8
Figure PCTCN2021139125-appb-000020
结果显示，盐酸盐晶型a样品在长期(25℃、60％RH)、加速(40℃、75％RH)条件下放置6个月，物理化学稳定性良好。

Claims (21)

  1. 一种式(I)所示化合物的药学上可接受的盐，所述药学上可接受的盐选自马来酸盐和盐酸盐，
    Figure PCTCN2021139125-appb-100001
  2. 一种根据权利要求1所述的式(I)所示化合物的马来酸盐，所述的式(I)所示化合物的马来酸盐，其中式(I)所示化合物与马来酸的摩尔比为1:2-2:1，优选1:1。
  3. 根据权利要求2所述的式(I)所示化合物的马来酸盐，所述的式(I)所示化合物的马来酸盐的I晶型，其中式(I)所示化合物与马来酸的摩尔比为1:1，其X-射线粉末衍射谱图在2θ角为16.448、16.956、19.332、20.135、21.645、22.257和22.696处有特征峰，优选X-射线粉末衍射谱图在2θ角为7.853、16.448、16.956、19.332、20.135、20.835、21.645、22.257、22.696和25.879处有特征峰，更优选X-射线粉末衍射谱图在2θ角为6.643、7.853、16.448、16.956、18.671、19.332、20.135、20.835、21.645、22.257、22.696、25.879和29.015处有特征峰。
  4. 根据权利要求2所述的式(I)所示化合物的马来酸盐，所述的式(I)所示化合物的马来酸盐的II晶型，其中式(I)所示化合物与马来酸的摩尔比为1:1，其X-射线粉末衍射谱图在2θ角为7.440、15.005、15.503、17.599、18.763、20.471和26.259处有特征峰，优选X-射线粉末衍射谱图在2θ角为7.440、8.724、15.005、15.503、17.599、18.136、18.763、20.471、26.259和28.925处有特征峰，更优选X-射线粉末衍射谱图在2θ角为7.440、8.724、15.005、15.503、17.599、18.136、18.763、20.471、22.600、23.556、24.643、26.259和28.925处有特征峰。
  5. 根据权利要求2所述的式(I)所示化合物的马来酸盐，所述的式(I)所示化合物的马来酸盐的III晶型，其中式(I)所示化合物与马来酸的摩尔比为1:1，其X-射线粉末衍射谱图在2θ角为6.830、16.440、17.358、19.295、19.919、20.946和26.340处有特征峰，优选X-射线粉末衍射谱图在2θ角为6.830、7.916、16.440、17.358、19.295、19.919、20.946、 23.702、25.820和26.340处有特征峰，更优选X-射线粉末衍射谱图在2θ角为6.830、7.916、14.150、16.440、17.358、19.295、19.919、20.946、22.943、23.702、25.820、26.340和29.177处有特征峰。
  6. 一种制备根据权利要求3所述的式(I)所示化合物的马来酸盐的I晶型的方法，所述方法包括以下步骤：
    1)将式(I)所示化合物、马来酸溶于选自乙醇、丙酮、甲醇或水中的至少一种的溶剂中，
    2)结晶析出。
  7. 一种制备根据权利要求4所述的式(I)所示化合物的马来酸盐的II晶型的方法，所述方法包括以下步骤：
    1)将式(I)所示化合物、马来酸溶于选自乙醇、异丙醚、正己烷和丁酮中的至少一种的溶剂中，
    2)结晶析出。
  8. 一种制备根据权利要求5所述的式(I)所示化合物的马来酸盐的III晶型的方法，所述方法包括将式(I)所示化合物的马来酸盐I晶型升温至110℃的步骤。
  9. 一种根据权利要求1所述的式(I)所示化合物的盐酸盐，所述的式(I)所示化合物的盐酸盐，其中式(I)所示化合物与盐酸的摩尔比为1:2-2:1，优选1:1。
  10. 根据权利要求9所述的式(I)所示化合物的盐酸盐，所述的式(I)所示化合物的盐酸盐的a晶型，其中式(I)所示化合物与盐酸的摩尔比为1:1，其X-射线粉末衍射谱图在2θ角为6.253、12.578、13.583、18.151、19.174、20.027和26.978处有特征峰，优选X-射线粉末衍射谱图在2θ角为6.253、8.647、11.210、12.578、13.583、18.151、19.174、20.027、26.676和26.978处有特征峰，更优选X-射线粉末衍射谱图在2θ角为6.253、8.647、11.210、12.578、13.583、18.151、19.174、20.027、24.105、25.004、25.375、26.676和26.978处有特征峰。
  11. 根据权利要求9所述的式(I)所示化合物的盐酸盐，所述的式(I)所示化合物的盐酸 盐的b晶型，其中式(I)所示化合物与盐酸的摩尔比为1:1，其X-射线粉末衍射谱图在2θ角为12.613、15.871、16.013、17.839、18.144、19.186和20.074处有特征峰，优选X-射线粉末衍射谱图在2θ角为12.613、15.871、16.013、17.839、18.144、19.186、20.074、20.773、21.186和26.977处有特征峰，更优选X-射线粉末衍射谱图在2θ角为12.613、15.871、16.013、17.839、18.144、19.186、20.074、20.773、21.186、22.512、24.181、26.599和26.977处有特征峰。
  12. 根据权利要求9所述的式(I)所示化合物的盐酸盐，所述的式(I)所示化合物的盐酸盐的c晶型，其X-射线粉末衍射谱图在2θ角为15.515、17.137、19.743、20.471、21.525、23.442和25.987处有特征峰，优选X-射线粉末衍射谱图在2θ角为7.353、13.066、14.042、15.515、17.137、19.743、20.471、21.525、23.442和25.987处有特征峰，更优选X-射线粉末衍射谱图在2θ角为6.970、7.353、9.527、13.066、14.042、15.515、17.137、19.743、20.471、21.525、23.442、25.987和29.252处有特征峰。
  13. 一种制备根据权利要求10所述的式(I)所示化合物的盐酸盐的a晶型的方法，所述方法包括以下步骤：
    1)将式(I)所示化合物溶于选自乙醇、乙醚、丁酮、正己烷或异丙醇中的至少一种的溶剂中，
    2)加入盐酸，结晶析出。
  14. 一种制备根据权利要求11所述的式(I)所示化合物的盐酸盐的b晶型的方法，所述方法包括以下步骤：
    1)将式(I)所示化合物溶于选自异丙醇、异丙醚、正己烷、乙酸乙酯和乙腈中的至少一种的溶剂中，
    2)加入盐酸，结晶析出。
  15. 一种制备根据权利要求12所述的式(I)所示化合物的盐酸盐的c晶型的方法，所述方法包括以下步骤：
    1)将式(I)所示化合物溶于选自丙酮、甲醇和水中的至少一种的溶剂中，
    2)加入盐酸水溶液，结晶析出。
  16. 根据权利3-5所述的式(I)所示化合物的马来酸盐的晶型、根据权利要求10-12所述的式(I)所示化合物的盐酸盐的晶型，其中，所述2θ角度的误差范围为±0.2。
  17. 根据权利要求1、2、9所述的式(I)所示化合物的药学上可接受的盐，
    或根据权利要求3-5、10-12、16所述的式(I)所示化合物的药学上可接受盐的晶型，或根据权利要求6-8、13-15所述的方法制备得到的式(I)所示化合物的药学上可接受盐的晶型的任意一种或其混合物制备得到的组合物。
  18. 一种药物组合物，其包含如下组分：
    i)根据权利要求1、2、9所述的式(I)所示化合物的药学上可接受的盐，
    或根据权利要求3-5、10-12、16所述的式(I)所示化合物的药学上可接受盐的晶型，或根据权利要求6-8、13-15所述的方法制备得到的式(I)所示化合物的药学上可接受盐的晶型的任意一种或其混合物；和
    ii)一种或多种药学上可接受的载体、稀释剂或赋形剂。
  19. 一种制备药物组合物的方法，包括将根据权利要求1、2、9所述的式(I)所示化合物的药学上可接受的盐，或根据权利要求3-5、10-12、16所述的式(I)所示化合物的药学上可接受盐的晶型，或根据权利要求6-8、13-15所述的方法制备得到的式(I)所示化合物的药学上可接受盐的晶型的任意一种或其混合物与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
  20. 根据权利要求1、2、9所述的式(I)所示化合物的药学上可接受的盐、
    或根据权利要求3-5、10-12、16所述的式(I)所示化合物的药学上可接受盐的晶型、或根据权利要求6-8、13-15所述的方法制备得到的式(I)所示化合物的药学上可接受盐的晶型的任意一种或其混合物、或根据权利要求17、18所述的组合物在制备预防和/或治疗雌激素受体介导的或依赖性的疾病或病症的药物中的用途。
  21. 根据权利要求1、2、9所述的式(I)所示化合物的药学上可接受的盐、或根据权利要求3-5、10-12、16所述的式(I)所示化合物的药学上可接受盐的晶型、或根据权利要求6-8、13-15所述的方法制备得到的式(I)所示化合物的药学上可接受盐的晶型的任意一种或其混合物、或根据权利要17、18所述的组合物在制备预防和/或治疗雌激素受体介导的 或依赖性的疾病或病症的药物中的用途，优选所述雌激素受体介导的或依赖性的疾病或病症为癌症，更优选为乳腺癌、卵巢癌、子宫内膜癌、前列腺癌或子宫癌，最优选乳腺癌。
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WO2020253762A1 (zh) * 2019-06-19 2020-12-24 江苏恒瑞医药股份有限公司 吲唑类衍生物、其制备方法及其在医药上的应用

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