WO2024217545A1 - 一种含氮四环化合物的结晶形式及其制备方法 - Google Patents

一种含氮四环化合物的结晶形式及其制备方法 Download PDF

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WO2024217545A1
WO2024217545A1 PCT/CN2024/088832 CN2024088832W WO2024217545A1 WO 2024217545 A1 WO2024217545 A1 WO 2024217545A1 CN 2024088832 W CN2024088832 W CN 2024088832W WO 2024217545 A1 WO2024217545 A1 WO 2024217545A1
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formula
compound
ray powder
crystalline form
powder diffraction
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PCT/CN2024/088832
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English (en)
French (fr)
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刘冬青
吴琪
卢玉
杜振兴
朱宁
赵祥虎
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江苏恒瑞医药股份有限公司
山东盛迪医药有限公司
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Publication of WO2024217545A1 publication Critical patent/WO2024217545A1/zh

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  • the present invention belongs to the field of medical technology and relates to a crystalline form of a nitrogen-containing tetracyclic compound and a preparation method thereof.
  • the RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPase superfamily and is widely expressed in various eukaryotic organisms.
  • RAS genes in the human body HRAS, KRAS and NARS
  • HRAS, KRAS4A, KARS4B and NRAS highly related RAS small GTPases
  • RAS proteins regulate multiple downstream pathways including RAF-MEK-ERK, PI3K/Akt/mTOR by switching between two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer, 2007, 7, 295-308).
  • the mutation rate of RAS gene is high in pancreatic cancer, colorectal cancer, non-small cell lung cancer and other tumors.
  • the activated mutant RAS protein promotes abnormal signal transduction, leading to the occurrence and development of cancer and resistance to targeted drugs.
  • KRAS mutation is the gene with the highest mutation rate among human oncogenes, accounting for 20-30% of all tumors.
  • KRAS G12C has attracted many well-known new drug research and development companies at home and abroad to participate.
  • Amgen's fastest-progressing small molecule KRAS G12C inhibitor Sotorasib (AMG510) was approved by the FDA on May 28, 2021 for use in patients with non-small cell lung cancer who have received at least one systemic treatment and carry KRAS G12C mutations
  • Eli Lilly's new generation KRAS G12C inhibitor LY3537982 has attracted more attention.
  • Eli Lilly reported the preclinical data of LY3537982 at the annual meeting of the American Association for Cancer Research (AACR) in April 2021. The data showed that LY3537982 inhibited cell activity more than 10 times that of Sotorasib and entered Phase I clinical trials in July 2021. It can be seen that highly selective, safe and effective KRAS G12C inhibitors are still needed clinically.
  • PCT/CN2022/126650 provides a KRAS G12C inhibitor, whose chemical name is (S)-4-((S)-10-acryloyl-4-chloro-2-fluoro-14-oxo-8,8a,9,10,11,12-hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazaoctinoxadiazole[3,2,1-hi]indazol-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile, having a structure shown in Formula 1,
  • the crystal form of the active pharmaceutical ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced.
  • amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.
  • the polymorphic form of the drug has different requirements for product storage, production and scale-up. Therefore, it is necessary to conduct in-depth research on the crystal form of the aforementioned compound and improve the various properties of the aforementioned compound.
  • the present disclosure provides a new crystal form of a compound represented by Formula 1, which has good stability and can be better applied in clinical practice.
  • the crystalline form A of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 8.406, 10.960, 11.530, 18.216 and 22.849.
  • the crystalline form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.419, 8.406, 10.960, 11.530, 18.216, 21.298, 22.849 and 28.948.
  • the crystalline form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.419, 8.406, 10.960, 11.530, 18.216, 21.298, 22.433, 22.849, 28.948 and 30.452.
  • the X-ray powder diffraction pattern of Form A of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG1 .
  • the present disclosure also provides a method for preparing a crystalline form A of a compound of Formula 1, the method comprising adding the compound of Formula 1 into a solvent a, and stirring for crystallization; the solvent a is selected from one or more of ethyl acetate and n-heptane.
  • the crystalline form C of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 9.150, 12.034, 17.860, 19.920, 23.604 and 23.997.
  • Form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536 and 28.038.
  • Form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 9.150, 11.840, 12.034, 17.860, 19.920, 23.604, 23.997, 25.803, 27.536, 28.038, 30.743 and 31.353.
  • the X-ray powder diffraction pattern of Form C of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 2 .
  • the present disclosure also provides a method for preparing a crystalline form C of the compound represented by Formula 1, the method comprising:
  • Method 1 adding the compound of formula 1 into solvent I, stirring and crystallizing, wherein the solvent I is selected from one or more of isopropanol, ethanol, and n-propanol;
  • Method 2 dissolving the compound of formula 1 in 1,4-dioxane, adding solvent II, stirring and crystallizing, wherein the solvent II is selected from one or more of isopropanol, methyl tert-butyl ether, n-heptane, isopropyl acetate, dichloromethane and cyclohexane;
  • the crystalline form D of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 9.096, 11.735, 12.094, 17.928 and 23.968.
  • the crystalline form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 9.096, 11.735, 12.094, 14.894, 16.002, 17.928, 19.870, 23.397 and 23.968.
  • the crystalline form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 9.096, 11.735, 12.094, 14.894, 16.002, 17.928, 19.870, 23.397, 23.968, 24.917 and 29.556.
  • the X-ray powder diffraction pattern of Form D of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG3 .
  • the present disclosure also provides a method for preparing a crystalline form D of a compound of formula 1, the method comprising adding the compound of formula 1 to a solvent b, stirring and crystallizing; the solvent b is selected from one or more of n-butanol and tert-butanol. kind.
  • the crystalline form E of the compound represented by Formula 1 provided in the present disclosure has characteristic peaks at 7.296, 10.626, 17.905, 23.131 and 25.377 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the crystalline form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.296, 10.626, 11.393, 12.647, 17.905, 20.706, 23.131 and 25.377.
  • Form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.296, 10.626, 11.393, 12.647, 16.030, 17.905, 20.706, 21.483, 23.131, 24.729, 25.377 and 27.267.
  • the X-ray powder diffraction pattern of Form E of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 4 .
  • the present disclosure also provides a method for preparing a crystalline form E of a compound represented by Formula 1, the method comprising:
  • Method 1 dissolving the compound of formula 1 in methanol and evaporating the solvent
  • Method 2 Add the compound of formula 1 into 10% water/methanol and stir.
  • the crystalline form F of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 9.947, 15.672, 18.740, 20.712, 23.910 and 28.351.
  • Form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.935, 9.947, 10.339, 15.672, 18.740, 19.933, 20.712, 23.910, 25.504, 26.139 and 28.351.
  • Form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.935, 9.947, 10.339, 11.651, 11.990, 15.672, 16.642, 18.740, 19.933, 20.712, 21.471, 23.910, 25.504, 26.139, 27.660, 28.351 and 28.898.
  • the X-ray powder diffraction pattern of Form F of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG5 .
  • the present disclosure also provides a method for preparing the crystalline form F of the compound represented by Formula 1, the method comprising:
  • Method 1 Add the compound of formula 1 into purified water and stir in a 50°C-5°C heating-cooling cycle;
  • Method 2 Dissolve the compound of formula 1 in 80% acetone/water, add purified water and stir.
  • the temperature rise and fall of 50°C-5°C refers to repeated temperature rise from 5°C to 50°C and then temperature drop from 50°C to 5°C. In some embodiments, the temperature is dropped from 50°C to 5°C within 1 hour and then raised from 5°C to 50°C within 1 hour.
  • the crystalline form G of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 10.701, 11.896, 12.669, 17.822, 25.246 and 27.288.
  • the crystalline form G of the compound represented by Formula 1 has an X-ray diffraction angle of 2 ⁇ .
  • the line powder diffraction pattern has characteristic peaks at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.378, 25.246, 27.288 and 32.704.
  • the crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.457, 10.701, 11.896, 12.669, 17.822, 20.532, 21.015, 21.378, 22.429, 24.516, 25.246, 27.288 and 32.704.
  • the X-ray powder diffraction pattern of Form G of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG6 .
  • the present disclosure also provides a method for preparing the crystalline form G of the compound represented by Formula 1, the method comprising:
  • Method 1 Add the compound of formula 1 into methanol, and heat and cool cyclically from 50°C to 5°C with stirring;
  • Method three adding the crystalline form E of the compound of formula 1 into solvent IV and stirring, wherein the solvent IV is selected from one or more of isopropyl ether, methyl tert-butyl ether, cyclohexane, isopropyl acetate and water.
  • solvent IV is selected from one or more of isopropyl ether, methyl tert-butyl ether, cyclohexane, isopropyl acetate and water.
  • the crystalline form H of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 7.961, 13.533, 15.180, 15.879 and 20.619.
  • the crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595 and 25.444.
  • the crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.961, 13.533, 15.180, 15.879, 15.946, 20.619, 20.902, 22.595, 25.444, 29.305 and 30.671.
  • the X-ray powder diffraction pattern of Form H of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 7 .
  • the present disclosure also provides a method for preparing the crystalline form H of the compound of Formula 1, the method comprising the steps of adding the compound of Formula 1 into ether and slurrying.
  • the method for preparing the crystalline form H of the compound of Formula 1 disclosed herein further comprises the step of adding the crystalline form E of the compound of Formula 1 into diethyl ether and slurrying.
  • the crystalline form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 8.996, 12.286, 18.112, 19.719 and 24.005.
  • the crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 8.996, 12.286, 15.616, 16.690, 18.112, 19.719, 22.812 and 24.005.
  • the crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ of 8.996, 12.286, 15.616, 16.690, 17.786, 18.112, 19.719, 22.812, There are characteristic peaks at 24.005, 26.757 and 27.698.
  • the X-ray powder diffraction pattern of Form I of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG8 .
  • the present disclosure also provides a method for preparing the crystalline form I of the compound of Formula 1, the method comprising the steps of adding the compound of Formula 1 into n-pentanol and slurrying.
  • the crystal form J of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 8.928, 12.055, 17.726, 19.533, 22.991 and 23.657.
  • the crystalline form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 8.928, 11.725, 12.055, 16.671, 17.726, 19.533, 22.991, 23.657 and 26.826.
  • Form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.024, 8.928, 11.725, 12.055, 15.762, 16.671, 17.726, 19.533, 22.991, 23.657, 26.826 and 27.446.
  • the X-ray powder diffraction pattern of Form J of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 9 .
  • the present disclosure also provides a method for preparing the crystalline form J of the compound of Formula 1, the method comprising the steps of adding the compound of Formula 1 to isoamyl alcohol and slurrying.
  • the crystal form K of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 9.306, 12.132, 17.933 and 20.058.
  • the crystalline form K of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.121, 9.306, 12.132, 17.933, 20.058, 24.077 and 34.192.
  • the X-ray powder diffraction pattern of Form K of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 10 .
  • the present disclosure also provides a method for preparing the crystalline form K of the compound represented by Formula 1, wherein the method is selected from any of the following methods:
  • Method 1 Add the compound of formula 1 into 7% water/ethanol and stir;
  • Method 2 Dissolve the compound of formula 1 in 1,4-dioxane or 10% water/acetone, add ethanol and stir;
  • Method 4 Dissolve the compound of formula 1 in acetonitrile, heat to 65°C to dissolve, and cool down;
  • the crystalline form L of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 10.645, 16.725, 17.050, 19.513 and 19.780.
  • the crystalline form L of the compound represented by Formula 1 has an X-ray diffraction angle of 2 ⁇ .
  • the line powder diffraction pattern has characteristic peaks at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780 and 21.862.
  • the crystalline form L of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.580, 10.645, 14.011, 14.586, 16.725, 17.050, 19.513, 19.780, 21.862, 26.362, 26.952 and 27.932.
  • the X-ray powder diffraction pattern of the crystalline form L of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 11 .
  • the present disclosure also provides a method for preparing the crystalline form L of the compound of Formula 1, the method comprising the steps of adding the crystalline form F of the compound of Formula 1 into water and stirring at 95°C.
  • the crystalline form M of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 8.313, 11.772, 15.173, 18.762, 20.945 and 25.849.
  • the crystalline form M of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.595, 8.313, 11.772, 12.680, 13.791, 15.173, 17.320, 18.762, 20.945, 25.849 and 26.857.
  • the crystalline form M of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.595, 8.313, 11.772, 12.680, 13.359, 13.791, 15.173, 16.626, 17.320, 18.762, 19.506, 20.945, 25.849, 26.857, 29.605 and 30.545.
  • the X-ray powder diffraction pattern of the crystalline form M of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 12 .
  • the present disclosure also provides a method for preparing a crystalline form M of a compound represented by Formula 1, the method comprising:
  • Method 1 Add the compound of formula 1 into isopropyl acetate and stir;
  • Method 2 Dissolve the compound of formula 1 in isopropyl acetate, add n-heptane and stir.
  • the crystalline form N of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 6.324, 13.092, 13.626, 14.699, 19.483, 22.429 and 27.407.
  • the crystalline form N of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.324, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, 22.429, 23.287 and 27.407.
  • the crystalline form N of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.324, 12.664, 13.092, 13.626, 14.699, 15.566, 19.483, 20.724, 22.429, 23.287, 25.042, 26.840, 27.407 and 30.152.
  • the X-ray powder diffraction pattern of Form N of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 13 .
  • the present disclosure also provides a method for preparing a crystalline form N of a compound represented by Formula 1, the method comprising:
  • Method 1 adding the compound of formula 1 into solvent V, stirring and crystallizing, wherein the solvent V is selected from water and methyl isobutyl ketone;
  • Method 2 dissolving the compound of formula 1 in solvent VI, adding seed crystals for crystallization, wherein the solvent VI is selected from one or more of methyl isobutyl ketone and isopropyl acetate;
  • Method 3 Dissolve the compound of formula 1 in ethyl acetate, add n-heptane and stir.
  • the crystalline form O of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 7.224, 8.423, 11.843, 16.829, 19.735 and 20.425.
  • the X-ray powder diffraction pattern of Form O of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 14 .
  • the present disclosure also provides a method for preparing a crystalline form O of a compound of Formula 1, the method comprising: dissolving the compound of Formula 1 in 2-butanone, adding water, stirring for 2 hours, and centrifuging.
  • the crystalline form P of the compound represented by Formula 1 provided in the present disclosure has characteristic peaks at 7.848, 16.342, 19.613, 21.305 and 24.786 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the crystalline form P of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.848, 13.063, 16.342, 19.613, 21.305, 23.584 and 24.786.
  • the X-ray powder diffraction pattern of the crystalline form P of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 15 .
  • the present disclosure also provides a method for preparing a crystalline form P of a compound of Formula 1, the method comprising: dissolving the compound of Formula 1 in 2-butanone, adding water, stirring for 24 hours, and centrifuging.
  • the crystalline form Q of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 7.921, 8.455, 15.468, 18.035, 22.224 and 26.015.
  • the X-ray powder diffraction pattern of Form Q of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 16 .
  • the present disclosure also provides a method for preparing a crystalline form Q of a compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in 2-butanone, adding water, stirring for 2 hours, centrifuging, and drying.
  • the crystalline form R of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 9.598, 11.283, 13.705, 15.045, 19.714 and 24.020.
  • the crystalline form R of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 8.248, 9.598, 11.283, 12.828, 13.705, 15.045, 15.539, 19.714, 22.430, 24.020 and 26.248.
  • the crystalline form R of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 8.248, 9.598, 9.884, 11.283, 11.748, 12.828, 13.705, 15.045, 15.539, 16.670, 17.686, 19.714, 20.791, 22.430, 24.020, 25.017 and 26.248.
  • the X-ray powder diffraction pattern of Form R of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 17 .
  • the present disclosure also provides a method for preparing a crystalline form R of a compound represented by Formula 1, the method comprising:
  • Step 1 dissolve the compound of formula 1 in 2-butanone, add water, heat at 50°C and stir to crystallize.
  • Step 2 Add the crystals obtained in step 1 into water and stir at 60°C to crystallize.
  • the crystalline form S of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 10.810, 13.597, 14.706, 19.971 and 22.751.
  • the crystalline form S of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.465, 10.810, 11.872, 13.597, 14.706, 15.563, 19.971, 22.751, 23.881 and 26.322.
  • the crystalline form S of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.465, 10.810, 11.872, 12.996, 13.597, 14.706, 15.563, 16.385, 19.971, 20.914, 22.751, 23.881, 25.414, 26.322, 29.235 and 32.963.
  • the X-ray powder diffraction pattern of Form S of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 18 .
  • the present disclosure also provides a method for preparing a crystalline form S of a compound represented by Formula 1, the method comprising:
  • Step 1 adding the compound of formula 1 into methyl isobutyl ketone, stirring and crystallizing;
  • Step 2 Dry the crystals in step 1 at 100°C in vacuum.
  • the crystalline form T of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 6.431, 19.884, 21.207, 21.993, 24.138, 24.924 and 25.111.
  • the X-ray powder diffraction pattern of Form T of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 19 .
  • the present disclosure also provides a method for preparing a crystalline form T of a compound of Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in isopropanol and evaporating the solvent.
  • the crystalline form U of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 6.843, 7.185, 8.193, 13.870, 14.416 and 20.769.
  • the crystalline form U of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.843, 7.185, 8.193, 13.870, 14.416, 16.683, 18.102, 18.721 and 20.769.
  • the X-ray powder diffraction pattern of Form U of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 20 .
  • the present disclosure also provides a method for preparing the crystalline form U of the compound of Formula 1, the method comprising the steps of adding the compound of Formula 1 to 90% methanol/water and slurrying.
  • the crystalline form B of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 8.587, 10.089, 11.875, 16.987, 21.717, and 23.436.
  • Form B of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.545, 8.587, 10.089, 11.117, 11.875, 16.601, 16.987, 17.056, 18.838, 19.285, 21.287, 21.717, and 23.436.
  • Form B of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , and has characteristic peaks at 7.545, 8.587, 10.089, 11.117, 11.875, 15.809, 16.601, 16.987, 17.056, 18.397, 18.515, 18.838, 19.285, 21.287, 21.717, 22.527, 22.881, 23.436, 26.541, 29.276, and 30.437.
  • the X-ray powder diffraction pattern of Form B of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 22 .
  • the present disclosure also provides a method for preparing the crystalline form B of the compound of Formula 1, the method comprising the steps of adding the crystalline form E of the compound of Formula 1 into ethyl acetate and stirring.
  • the crystalline form ⁇ of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 6.622, 9.944, 11.103, 17.932, 22.143, and 25.120.
  • the crystalline form ⁇ of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 6.622, 9.944, 11.103, 15.927, 17.932, 20.112, 22.143, 23.602, 25.120, and 29.026.
  • the X-ray powder diffraction pattern of Form ⁇ of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 23 .
  • the present disclosure also provides a method for preparing the crystalline form ⁇ of the compound of Formula 1, the method comprising adding the crystalline form N of the compound of Formula 1 into a solvent c and stirring; the solvent c is selected from one or more of methanol, 50% methanol/water, 7% water/ethanol, and 50% acetonitrile/methanol.
  • the crystalline form ⁇ of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 7.683, 12.400, 15.616, 19.040, 22.856, and 24.802.
  • the crystalline form ⁇ of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 7.683, 11.501, 12.400, 14.114, 15.616, 16.527, 19.040, 22.856, 24.200, 24.802, 26.963, and 29.420.
  • the crystalline form ⁇ of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , and has characteristic peaks at 7.683, 11.501, 12.400, 14.114, 15.616, 16.527, 19.040, 19.592, 19.861, 21.815, 22.856, 24.200, 24.802, 26.963, 28.023, 29.420, 31.500, and 33.726.
  • the X-ray powder diffraction pattern of the crystalline form ⁇ of the compound represented by Formula 1, expressed in terms of a diffraction angle 2 ⁇ , is shown in FIG. 24 .
  • the present disclosure also provides a method for preparing the crystalline form ⁇ of the compound of Formula 1, the method comprising the steps of adding the crystalline form B of the compound of Formula 1 into propylene glycol methyl ether and stirring.
  • the present disclosure also provides a pharmaceutical composition, which contains any one or more of the aforementioned crystalline forms A to U, crystalline form ⁇ or crystalline form ⁇ , and a pharmaceutical excipient selected from pharmaceutically acceptable excipients.
  • the present disclosure also provides a pharmaceutical composition, which is prepared from any one or more of the aforementioned crystal forms A to U, crystal form ⁇ or crystal form ⁇ , and an optional pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any one or more of the aforementioned crystalline forms A to U, crystalline form ⁇ or crystalline form ⁇ with a pharmaceutically acceptable excipient.
  • the present disclosure also provides use of any one or more of the aforementioned crystalline forms A to U, crystalline form ⁇ or crystalline form ⁇ , or the aforementioned composition in the preparation of a drug for preventing and/or treating tumors.
  • the tumor is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial cancer, esophageal cancer, essential thrombocythemia, Ewing's tumor, testicular cancer, glioma, heavy chain disease, Hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesot
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present 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 (including the case where the number exceeding 1 decimal place is rounded off), specifically -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.
  • the numerical values in the present disclosure such as the data of the measured and calculated content of the relevant substances, inevitably have a certain degree of error. Generally speaking, ⁇ 10% is within the reasonable error range. There is a certain degree of error variation depending on the context where it is used, and the error variation does not exceed ⁇ 10%, and can be ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2% or ⁇ 1%, preferably ⁇ 5%.
  • the starting material used in the crystal preparation method of the present invention can be a compound in any form, and specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.
  • the drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and the drying can be carried out under normal pressure or reduced pressure.
  • the crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals, Inducing crystallization, etc.
  • the cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed during the crystallization process.
  • the "differential scanning calorimetry or DSC” described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • Hygroscopic weight gain due to moisture absorption is less than 15% but not less than 2%;
  • weight gain due to moisture absorption is less than 2% but not less than 0.2%;
  • moisture gain is less than 0.2%.
  • excipients include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • Figure 1 is the XRPD spectrum of Compound 1 Form A.
  • Figure 2 is the XRPD spectrum of Compound 1 Form C.
  • Figure 3 is the XRPD spectrum of Compound 1 Form D.
  • FIG4 is an XRPD spectrum of Compound 1 Form E.
  • Figure 5 is the XRPD spectrum of Compound 1 Form F.
  • Figure 6 is the XRPD spectrum of Compound 1 Form G.
  • FIG. 7 is an XRPD spectrum of Compound 1 Form H.
  • Figure 8 is the XRPD spectrum of Compound 1 Form I.
  • Figure 9 is the XRPD spectrum of Compound 1 Form J.
  • Figure 10 is the XRPD spectrum of Compound 1 Form K.
  • Figure 11 is the XRPD spectrum of Compound 1 Form L.
  • Figure 12 is the XRPD spectrum of Compound 1 Form M.
  • FIG13 is an XRPD spectrum of Compound 1 Form N.
  • Figure 14 is the XRPD spectrum of Compound 1 Form O.
  • Figure 15 is the XRPD spectrum of Compound 1 Form P.
  • Figure 16 is the XRPD spectrum of Compound 1 Form Q.
  • Figure 17 is the XRPD spectrum of Compound 1 Form R.
  • Figure 18 is the XRPD spectrum of Compound 1 Form S.
  • Figure 19 is the XRPD spectrum of Compound 1 Form T.
  • Figure 20 is the XRPD spectrum of Compound 1 Form U.
  • Figure 21 is the XRPD spectrum of the amorphous form of Compound 1.
  • Figure 22 is the XRPD spectrum of Compound 1 Form B.
  • Figure 23 is the XRPD spectrum of Compound 1 Form ⁇ .
  • Figure 24 is the XRPD spectrum of Compound 1 Form ⁇ .
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC-MS (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO QExactive).
  • HPLC High performance liquid chromatography
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clearland QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of eluent for column chromatography used for purifying the compound and the developing solvent system for thin layer chromatography include: A: petroleum ether/ethyl acetate system, B: dichloromethane/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.
  • TLC thin layer chromatography
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range (2 ⁇ range): 3° ⁇ 45°.
  • DSC is differential scanning calorimetry: the measurement was carried out 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 spectrum (mostly 25-350°C), and a nitrogen purge rate of 50mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min. The specific temperature range referred to the corresponding spectrum (mostly 25-350°C), and a nitrogen purge rate of 50mL/min.
  • DVS dynamic moisture adsorption
  • SMSDVS Session in Water
  • the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%) (the specific range of humidity is subject to the corresponding graph, and most of the methods used are listed here).
  • the judgment standard is dm/dt not greater than 0.002%.
  • reaction solution was cooled to room temperature, diluted with dichloromethane (50mL), washed with water (30mL), saturated sodium carbonate solution (10mL), and saturated sodium chloride solution (10mL) in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1b (2.8g), which was directly used in the next step without purification.
  • the crude compound 1b (2.8 g, 10.25 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL), methanol (10 mL) and water (10 mL), and lithium hydroxide (2.15 g, 51.26 mmol) was added, and the mixture was stirred at 40°C for 1 hour.
  • reaction solution was concentrated under reduced pressure to remove most of the solvent, water was added, and the mixture was extracted with ethyl acetate (150 mL ⁇ 6), and the organic phases were combined, washed with dilute hydrochloric acid and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude compound 1c (1.4 g), which was used directly in the next step without purification.
  • reaction solution was concentrated under reduced pressure and diluted with ethyl acetate, and washed successively with water, saturated sodium carbonate solution and saturated sodium chloride solution.
  • the organic phase was dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1f (600 mg, yield: 54.9%).
  • the crude compound 1k (41 mg, 56.4 ⁇ mol) was suspended in 2 mL of ethyl acetate, 1 mL of tetrahydrofuran and 2 mL of water, and anhydrous potassium carbonate (24 mg, 173.6 ⁇ mol) was added.
  • Acryloyl chloride (5.4 mg, 59.6 ⁇ mol) was added under ice bath. After reacting for 5 minutes, the mixture was extracted with ethyl acetate (5 mL ⁇ 2).
  • H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 medium (Hyclone, SH30809.01) (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV).
  • RPMI1640 medium Hyclone, SH30809.01
  • complete medium 10% fetal bovine serum
  • H358 cells were seeded in a 96-well plate at a density of 1200 cells/well using complete medium, with 100 ⁇ L of cell suspension per well, and cultured overnight in a 37°C, 5% CO 2 cell culture incubator.
  • 10 ⁇ L of the compound to be tested prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold gradient dilution starting from 10 ⁇ M.
  • a blank control containing 0.5% DMSO was set up, and the well plate was placed in a 37°C, 5% CO 2 cell culture incubator for 120 hours. On the seventh day, the 96-well cell culture plate was removed, and 50 ⁇ L of CellTiter- Luminescent Cell Viability Assay (Promega, G7573) was placed at room temperature for 10 minutes and then analyzed using a multi-function microplate reader (PerkinElmer, En 2105) to read the luminescent signal value, and use Graphpad Prism software to calculate the IC50 value of the inhibitory activity of the compound.
  • CellTiter- Luminescent Cell Viability Assay Promega, G7573
  • MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in DMEM/HIGH GLUCOSE (GE, SH30243.01) medium (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV) and 2.5% horse serum (Biyuntian Biotechnology, C0262).
  • DMEM/HIGH GLUCOSE GE, SH30243.01
  • medium i.e., complete medium
  • fetal bovine serum Core
  • horse serum horse serum
  • MIA PaCa-2 cells were seeded in a 96-well plate at a density of 500 cells/well using complete medium, 90 ⁇ L of cell suspension per well, and cultured overnight in a 37°C, 5% CO 2 cell culture incubator.
  • the product was defined as crystal form G by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 6, and the position of its characteristic peaks is shown in Table 10.
  • the DSC spectrum shows that the peak temperature of the endothermic peak is 237.35°C.
  • the TGA spectrum shows that the weight loss is 0.59% at 30°C-100°C and 0.43% at 100°C-270°C.
  • DVS detection shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 1.04%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain is about 1.21%; under extreme conditions (90% RH), the moisture absorption weight gain is about 1.60%.
  • the desorption process of the sample basically coincided with the adsorption process, and the crystal form was retested after DVS detection, and the crystal form did not change.
  • the moisture absorption weight gain is about 0.55%; under extreme conditions (90% RH), the moisture absorption weight gain is about 0.73%.
  • the desorption process of the sample basically coincides with the adsorption process, and the crystal form is retested after DVS detection, and the crystal form has not changed.
  • the moisture absorption weight gain is about 3.06%; under extreme conditions (90% RH), the moisture absorption weight gain is about 3.18%.
  • the desorption process of the sample basically coincides with the adsorption process, and the crystal form is retested after DVS detection, and the crystal form has not changed.
  • Example 43 Study on the stability of factors affecting crystal form
  • the free crystal forms C, F, G, H, L, M and N were spread out in the open and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C) and high humidity (75% RH, 92.5% RH) conditions.
  • the sampling period was 30 days.

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Abstract

本公开涉及一种含氮的四环化合物的结晶形式及其制备方法。具体而言,本公开提供(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(式1)的晶型C、晶型F、晶型G、晶型H、晶型L、晶型M、晶型N、晶型R及晶型S,其具备良好的稳定性,可更好地用于临床治疗。

Description

一种含氮四环化合物的结晶形式及其制备方法 技术领域
本公开属于医药技术领域,涉及一种含氮四环化合物的结晶形式及其制备方法。
背景技术
RAS(Rat Sarcoma Viral Oncogene Homolog)家族属于小GTP酶超家族,广泛表达于各类真核生物。人体中有三种RAS基因(HRAS、KRAS和NARS),可表达为四种高度相关的RAS小GTP酶(HRAS、KRAS4A、KARS4B和NRAS)。其作为GDP-GTP调控的二元开关发生作用。通常情况下它们有两种表现形式:非激活状态下的GDP(二磷酸鸟苷)结合形式和激活状态下的GTP(三磷酸鸟苷)结合形式。RAS蛋白通过在两种活性状态间切换,来调控包括RAF-MEK-ERK、PI3K/Akt/mTOR在内的多个下游通路,从而影响细胞的生长、增殖和分化(Nat Rev Cancer,2007,7,295-308)。RAS基因在胰腺癌、结直肠癌、非小细胞肺癌等多种肿瘤中突变率较高,激活的突变RAS蛋白会促进异常信号转导,从而导致癌症发生和发展,以及对靶向药产生耐药性。其中KRAS突变是人类致癌基因中突变率最高的基因,占所有肿瘤的20~30%。
KRAS G12C吸引了国内外众多知名的新药研发企业参与其中。虽然进展最快的安进的小分子KRAS G12C抑制剂Sotorasib(AMG510)已于2021年5月28日被FDA批准上市,用于至少接受过一次系统治疗且携带KRAS G12C突变的非小细胞肺癌患者,但礼来的新一代KRAS G12C抑制剂LY3537982更加备受关注。礼来在2021年4月美国癌症研究协会(AACR)年会上报告了LY3537982的临床前数据,数据显示,LY3537982较Sotorasib的细胞活性抑制高出了10余倍,已于2021年7月进入临床一期。可见,临床上仍需高选择性、安全和有效的KRAS G12C抑制剂。
PCT/CN2022/126650提供一种KRAS G12C抑制剂,其化学名为(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈,具有式1所示结构,
作为药用活性成分的晶型往往影响到该药物的化学稳定性,结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化,有时还会伴随着产生其他形态的晶型。一般来说,无定形的药物产品没有规则的晶型结构,往往具有其它缺陷,比如产物稳定性较差,析晶较细,过滤较难,易结块,流动性差等。药物的多晶型对产品储存、生产及放大有不同的要求。因此,深入研究前述化合物的晶型,改善前述化合物的各方面性质是很有必要的。
发明内容
本公开提供一种式1所示化合物的新晶型,其具备良好的稳定性,可更好地应用于临床,
本公开提供的式1所示化合物的晶型A,以衍射角2θ角度表示的X-射线粉末衍射图,在8.406、10.960、11.530、18.216和22.849处有特征峰。
在一些实施方案中,式1所示化合物的晶型A,以衍射角2θ角度表示的X-射线粉末衍射图,在7.419、8.406、10.960、11.530、18.216、21.298、22.849和28.948处有特征峰。
在一些实施方案中,式1所示化合物的晶型A,以衍射角2θ角度表示的X-射线粉末衍射图,在7.419、8.406、10.960、11.530、18.216、21.298、22.433、22.849、28.948和30.452处有特征峰。
在一些实施方案中,式1所示化合物的晶型A,以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
本公开还提供一种制备式1所示化合物晶型A的方法,所述方法包括将式1化合物加入溶剂a中,搅拌析晶;所述溶剂a选自乙酸乙酯、正庚烷中的一种或多种。
本公开提供的式1所示化合物的晶型C,以衍射角2θ角度表示的X-射线粉末衍射图,在9.150、12.034、17.860、19.920、23.604和23.997处有特征峰。
在一些实施方案中,式1所示化合物的晶型C,以衍射角2θ角度表示的X-射线粉末衍射图,在9.150、11.840、12.034、17.860、19.920、23.604、23.997、25.803、27.536和28.038处有特征峰。
在一些实施方案中,式1所示化合物的晶型C,以衍射角2θ角度表示的X-射线粉末衍射图,在9.150、11.840、12.034、17.860、19.920、23.604、23.997、25.803、27.536、28.038、30.743和31.353处有特征峰。
在一些实施方案中,式1所示化合物的晶型C,以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
本公开还提供一种制备式1所示化合物晶型C的方法,所述方法包括:
方法一:将式1化合物加入溶剂I中,搅拌析晶,所述溶剂I选自异丙醇、乙醇、正丙醇中的一种或多种;
方法二:将式1化合物溶解于1,4-二氧六环中,加入溶剂II搅拌析晶,所述溶剂II选自异丙醇、甲基叔丁基醚、正庚烷、乙酸异丙酯、二氯甲烷、环己烷中的一种或多种;
方法三:将式1化合物溶解于溶剂III中,搅拌析晶,所述溶剂III选自丙酮、四氢呋喃、1,4-二氧六环、乙酸异丙酯、二氯甲烷、四氢呋喃/乙醇(v/v=2:1)中的一种或多种。
本公开提供的式1所示化合物的晶型D,以衍射角2θ角度表示的X-射线粉末衍射图,在9.096、11.735、12.094、17.928和23.968处有特征峰。
在一些实施方案中,式1所示化合物的晶型D,以衍射角2θ角度表示的X-射线粉末衍射图,在9.096、11.735、12.094、14.894、16.002、17.928、19.870、23.397和23.968处有特征峰。
在一些实施方案中,式1所示化合物的晶型D,以衍射角2θ角度表示的X-射线粉末衍射图,在9.096、11.735、12.094、14.894、16.002、17.928、19.870、23.397、23.968、24.917和29.556处有特征峰。
在一些实施方案中,式1所示化合物的晶型D,以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开还提供一种制备式1所示化合物晶型D的方法,所述方法包括将式1化合物加入溶剂b中,搅拌析晶;所述溶剂b选自正丁醇、叔丁醇中的一种或多 种。
本公开提供的式1所示化合物的晶型E,以衍射角2θ角度表示的X-射线粉末衍射图,在7.296、10.626、17.905、23.131和25.377处有特征峰。
在一些实施方案中,式1所示化合物的晶型E,以衍射角2θ角度表示的X-射线粉末衍射图,在7.296、10.626、11.393、12.647、17.905、20.706、23.131和25.377处有特征峰。
在一些实施方案中,式1所示化合物的晶型E,以衍射角2θ角度表示的X-射线粉末衍射图,在7.296、10.626、11.393、12.647、16.030、17.905、20.706、21.483、23.131、24.729、25.377和27.267处有特征峰。
在一些实施方案中,式1所示化合物的晶型E,以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开还提供一种制备式1所示化合物晶型E的方法,所述方法包括:
方法一:将式1化合物溶于甲醇,挥发溶剂;
方法二:将式1化合物加入10%水/甲醇中,搅拌。
本公开提供的式1所示化合物的晶型F,以衍射角2θ角度表示的X-射线粉末衍射图,在9.947、15.672、18.740、20.712、23.910和28.351处有特征峰。
在一些实施方案中,式1所示化合物的晶型F,以衍射角2θ角度表示的X-射线粉末衍射图,在7.935、9.947、10.339、15.672、18.740、19.933、20.712、23.910、25.504、26.139和28.351处有特征峰。
在一些实施方案中,式1所示化合物的晶型F,以衍射角2θ角度表示的X-射线粉末衍射图,在7.935、9.947、10.339、11.651、11.990、15.672、16.642、18.740、19.933、20.712、21.471、23.910、25.504、26.139、27.660、28.351和28.898处有特征峰。
在一些实施方案中,式1所示化合物的晶型F,以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开还提供一种制备式1所示化合物晶型F的方法,所述方法包括:
方法一:将式1化合物加入纯化水中,50℃-5℃循环升-降温搅拌;
方法二:将式1化合物溶解于80%丙酮/水中,加入纯化水搅拌。
本公开中50℃-5℃升降-温为多次反复从5℃升温至50℃,再从50℃降温5℃操作。在一些实施方案中,1小时内使温度由50℃降至5℃,再在1小时内从5℃升温至50℃。
本公开提供的式1所示化合物的晶型G,以衍射角2θ角度表示的X-射线粉末衍射图,在10.701、11.896、12.669、17.822、25.246和27.288处有特征峰。
在一些实施方案中,式1所示化合物的晶型G,以衍射角2θ角度表示的X-射 线粉末衍射图,在7.457、10.701、11.896、12.669、17.822、20.532、21.378、25.246、27.288和32.704处有特征峰。
在一些实施方案中,式1所示化合物的晶型G,以衍射角2θ角度表示的X-射线粉末衍射图,在7.457、10.701、11.896、12.669、17.822、20.532、21.015、21.378、22.429、24.516、25.246、27.288和32.704处有特征峰。
在一些实施方案中,式1所示化合物的晶型G,以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开还提供一种制备式1所示化合物晶型G的方法,所述方法包括:
方法一:将式1化合物加入甲醇中,50℃-5℃循环升降温搅拌;
方法二:将式1化合物溶解于80%丙酮/水中,加入甲醇/水(V/V=4:3),搅拌;
方法三:将式1化合物的晶型E加入溶剂IV中,搅拌,所述溶剂IV选自异丙醚、甲基叔丁基醚、环己烷、乙酸异丙酯、水中的一种或多种。
本公开提供的式1所示化合物的晶型H,以衍射角2θ角度表示的X-射线粉末衍射图,在7.961、13.533、15.180、15.879和20.619处有特征峰。
在一些实施方案中,式1所示化合物的晶型H,以衍射角2θ角度表示的X-射线粉末衍射图,在7.961、13.533、15.180、15.879、15.946、20.619、20.902、22.595和25.444处有特征峰。
在一些实施方案中,式1所示化合物的晶型H,以衍射角2θ角度表示的X-射线粉末衍射图,在7.961、13.533、15.180、15.879、15.946、20.619、20.902、22.595、25.444、29.305和30.671处有特征峰。
在一些实施方案中,式1所示化合物的晶型H,以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开还提供一种制备式1所示化合物晶型H的方法,所述方法包括将式1化合物加入乙醚中,打浆的步骤。
在一些实施方案中,本公开制备式1所示化合物晶型H的方法还包括将式1化合物晶型E加入乙醚中,打浆的步骤。
本公开提供的式1所示化合物的晶型I,以衍射角2θ角度表示的X-射线粉末衍射图,在8.996、12.286、18.112、19.719和24.005处有特征峰。
在一些实施方案中,式1所示化合物的晶型I,以衍射角2θ角度表示的X-射线粉末衍射图,在8.996、12.286、15.616、16.690、18.112、19.719、22.812和24.005处有特征峰。
在一些实施方案中,式1所示化合物的晶型I,以衍射角2θ角度表示的X-射线粉末衍射图,在8.996、12.286、15.616、16.690、17.786、18.112、19.719、22.812、 24.005、26.757和27.698处有特征峰。
在一些实施方案中,式1所示化合物的晶型I,以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
本公开还提供一种制备式1所示化合物晶型I的方法,所述方法包括将式1化合物加入正戊醇中,打浆的步骤。
本公开提供的式1所示化合物的晶型J,以衍射角2θ角度表示的X-射线粉末衍射图,在8.928、12.055、17.726、19.533、22.991和23.657处有特征峰。
在一些实施方案中,式1所示化合物的晶型J,以衍射角2θ角度表示的X-射线粉末衍射图,在8.928、11.725、12.055、16.671、17.726、19.533、22.991、23.657和26.826处有特征峰。
在一些实施方案中,式1所示化合物的晶型J,以衍射角2θ角度表示的X-射线粉末衍射图,在6.024、8.928、11.725、12.055、15.762、16.671、17.726、19.533、22.991、23.657、26.826和27.446处有特征峰。
在一些实施方案中,式1所示化合物的晶型J,以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本公开还提供一种制备式1所示化合物晶型J的方法,所述方法包括将式1化合物加入异戊醇中,打浆的步骤。
本公开提供的式1所示化合物的晶型K,以衍射角2θ角度表示的X-射线粉末衍射图,在9.306、12.132、17.933和20.058处有特征峰。
在一些实施方案中,式1所示化合物的晶型K,以衍射角2θ角度表示的X-射线粉末衍射图,在6.121、9.306、12.132、17.933、20.058、24.077和34.192处有特征峰。
在一些实施方案中,式1所示化合物的晶型K,以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
本公开还提供一种制备式1所示化合物晶型K的方法,所述方法选自下述任一方法:
方法一:将式1化合物加入7%水/乙醇中,搅拌;
方法二:将式1化合物溶于1,4-二氧六环或10%水/丙酮,加入乙醇搅拌;
方法三:将式1化合物溶于乙酸乙酯/乙醇(v/v=1:1),50℃-5℃升降温,搅拌;
方法四:将式1化合物溶于乙腈,65℃加热溶解,降温;
本公开提供的式1所示化合物的晶型L,以衍射角2θ角度表示的X-射线粉末衍射图,在10.645、16.725、17.050、19.513和19.780处有特征峰。
在一些实施方案中,式1所示化合物的晶型L,以衍射角2θ角度表示的X-射 线粉末衍射图,在6.580、10.645、14.011、14.586、16.725、17.050、19.513、19.780和21.862处有特征峰。
在一些实施方案中,式1所示化合物的晶型L,以衍射角2θ角度表示的X-射线粉末衍射图,在6.580、10.645、14.011、14.586、16.725、17.050、19.513、19.780、21.862、26.362、26.952和27.932处有特征峰。
在一些实施方案中,式1所示化合物的晶型L,以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本公开还提供一种制备式1所示化合物晶型L的方法,所述方法包括将式1化合物晶型F加入水中,于95℃搅拌的步骤。
本公开提供的式1所示化合物的晶型M,以衍射角2θ角度表示的X-射线粉末衍射图,在8.313、11.772、15.173、18.762、20.945和25.849处有特征峰。
在一些实施方案中,式1所示化合物的晶型M,以衍射角2θ角度表示的X-射线粉末衍射图,在7.595、8.313、11.772、12.680、13.791、15.173、17.320、18.762、20.945、25.849和26.857处有特征峰。
在一些实施方案中,式1所示化合物的晶型M,以衍射角2θ角度表示的X-射线粉末衍射图,在7.595、8.313、11.772、12.680、13.359、13.791、15.173、16.626、17.320、18.762、19.506、20.945、25.849、26.857、29.605和30.545处有特征峰。
在一些实施方案中,式1所示化合物的晶型M,以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
本公开还提供一种制备式1所示化合物晶型M的方法,所述方法包括:
方法一:将式1化合物加入乙酸异丙酯中,搅拌;
方法二:将式1化合物溶解于乙酸异丙酯中,加入正庚烷搅拌。
本公开提供的式1所示化合物的晶型N,以衍射角2θ角度表示的X-射线粉末衍射图,在6.324、13.092、13.626、14.699、19.483、22.429和27.407处有特征峰。
在一些实施方案中,式1所示化合物的晶型N,以衍射角2θ角度表示的X-射线粉末衍射图,在6.324、13.092、13.626、14.699、15.566、19.483、20.724、22.429、23.287和27.407处有特征峰。
在一些实施方案中,式1所示化合物的晶型N,以衍射角2θ角度表示的X-射线粉末衍射图,在6.324、12.664、13.092、13.626、14.699、15.566、19.483、20.724、22.429、23.287、25.042、26.840、27.407和30.152处有特征峰。
在一些实施方案中,式1所示化合物的晶型N,以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
本公开还提供一种制备式1所示化合物晶型N的方法,所述方法包括:
方法一:将式1化合物加入溶剂V中,搅拌析晶,所述溶剂V选自水、甲基异丁基酮;
方法二:将式1化合物溶于溶剂VI中,加入晶种析晶,所述溶剂VI选自甲基异丁基酮、乙酸异丙酯的一种或多种;
方法三:将式1化合物溶于乙酸乙酯中,加入正庚烷,搅拌。
本公开提供的式1所示化合物的晶型O,以衍射角2θ角度表示的X-射线粉末衍射图,在7.224、8.423、11.843、16.829、19.735和20.425处有特征峰。
在一些实施方案中,式1所示化合物的晶型O,以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
本公开还提供一种制备式1所示化合物晶型O的方法,所述方法包括:将式1化合物溶于2-丁酮,加入水后,搅拌2小时离心。
本公开提供的式1所示化合物的晶型P,以衍射角2θ角度表示的X-射线粉末衍射图,在7.848、16.342、19.613、21.305和24.786处有特征峰。
在一些实施方案中,式1所示化合物的晶型P,以衍射角2θ角度表示的X-射线粉末衍射图,在7.848、13.063、16.342、19.613、21.305、23.584和24.786处有特征峰。
在一些实施方案中,式1所示化合物的晶型P,以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
本公开还提供一种制备式1所示化合物晶型P的方法,所述方法包括:将式1化合物溶于2-丁酮,加入水后,搅拌24小时,离心的步骤。
本公开提供的式1所示化合物的晶型Q,以衍射角2θ角度表示的X-射线粉末衍射图,在7.921、8.455、15.468、18.035、22.224和26.015处有特征峰。
在一些实施方案中,式1所示化合物的晶型Q,以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
本公开还提供一种制备式1所示化合物晶型Q的方法,包括:将式1化合物溶于2-丁酮,加入水后,搅拌2小时离心、干燥的步骤。
本公开提供的式1所示化合物的晶型R,以衍射角2θ角度表示的X-射线粉末衍射图,在9.598、11.283、13.705、15.045、19.714和24.020处有特征峰。
在一些实施方案中,式1所示化合物的晶型R,以衍射角2θ角度表示的X-射线粉末衍射图,在8.248、9.598、11.283、12.828、13.705、15.045、15.539、19.714、22.430、24.020和26.248处有特征峰。
在一些实施方案中,式1所示化合物的晶型R,以衍射角2θ角度表示的X-射线粉末衍射图,在8.248、9.598、9.884、11.283、11.748、12.828、13.705、15.045、15.539、16.670、17.686、19.714、20.791、22.430、24.020、25.017和26.248处有特征峰。
在一些实施方案中,式1所示化合物的晶型R,以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
本公开还提供一种制备式1所示化合物晶型R的方法,所述方法包括:
步骤一:将式1化合物溶于2-丁酮,加入水,50℃加热搅拌析晶。
步骤二:将步骤一中的晶体加入水中,于60℃搅拌析晶。
本公开提供的式1所示化合物的晶型S,以衍射角2θ角度表示的X-射线粉末衍射图,在10.810、13.597、14.706、19.971和22.751处有特征峰。
在一些实施方案中,式1所示化合物的晶型S,以衍射角2θ角度表示的X-射线粉末衍射图,在6.465、10.810、11.872、13.597、14.706、15.563、19.971、22.751、23.881和26.322处有特征峰。
在一些实施方案中,式1所示化合物的晶型S,以衍射角2θ角度表示的X-射线粉末衍射图,在6.465、10.810、11.872、12.996、13.597、14.706、15.563、16.385、19.971、20.914、22.751、23.881、25.414、26.322、29.235和32.963处有特征峰。
在一些实施方案中,式1所示化合物的晶型S,以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
本公开还提供一种制备式1所示化合物晶型S的方法,所述方法包括:
步骤一:将式1化合物加入甲基异丁基酮中,搅拌析晶;
步骤二:将步骤一中的晶体于100℃真空干燥。
本公开提供的式1所示化合物的晶型T,以衍射角2θ角度表示的X-射线粉末衍射图,在6.431、19.884、21.207、21.993、24.138、24.924和25.111处有特征峰。
在一些实施方案中,式1所示化合物的晶型T,以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
本公开还提供一种制备式1所示化合物晶型T的方法,所述方法包括将式1化合物溶于异丙醇中,蒸发溶剂的步骤。
本公开提供的式1所示化合物的晶型U,以衍射角2θ角度表示的X-射线粉末衍射图,在6.843、7.185、8.193、13.870、14.416和20.769处有特征峰。
在一些实施方案中,式1所示化合物的晶型U,以衍射角2θ角度表示的X-射线粉末衍射图,在6.843、7.185、8.193、13.870、14.416、16.683、18.102、18.721和20.769处有特征峰。
在一些实施方案中,式1所示化合物的晶型U,以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
本公开还提供一种制备式1所示化合物晶型U的方法,所述方法包括将式1化合物加入90%甲醇/水中,打浆的步骤。
本公开提供的式1所示化合物的晶型B,以衍射角2θ角度表示的X-射线粉末衍射图,在8.587、10.089、11.875、16.987、21.717、23.436处有特征峰。
在一些实施方案中,式1所示化合物的晶型B,以衍射角2θ角度表示的X-射线粉末衍射图,在7.545、8.587、10.089、11.117、11.875、16.601、16.987、17.056、18.838、19.285、21.287、21.717、23.436处有特征峰。
在一些实施方案中,式1所示化合物的晶型B,以衍射角2θ角度表示的X-射线粉末衍射图,在7.545、8.587、10.089、11.117、11.875、15.809、16.601、16.987、17.056、18.397、18.515、18.838、19.285、21.287、21.717、22.527、22.881、23.436、26.541、29.276、30.437处有特征峰。
在一些实施方案中,式1所示化合物的晶型B,以衍射角2θ角度表示的X-射线粉末衍射图谱如图22所示。
本公开还提供一种制备式1所示化合物晶型B的方法,所述方法包括将式1化合物的晶型E加入乙酸乙酯中,搅拌的步骤。
本公开提供的式1所示化合物的晶型α,以衍射角2θ角度表示的X-射线粉末衍射图,在6.622、9.944、11.103、17.932、22.143、25.120处有特征峰。
在一些实施方案中,式1所示化合物的晶型α,以衍射角2θ角度表示的X-射线粉末衍射图,在6.622、9.944、11.103、15.927、17.932、20.112、22.143、23.602、25.120、29.026处有特征峰。
在一些实施方案中,式1所示化合物的晶型α,以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
本公开还提供一种制备式1所示化合物晶型α的方法,所述方法包括将式1化合物晶型N加入溶剂c中,搅拌;所述溶剂c选自甲醇、50%甲醇/水、7%水/乙醇、50%乙腈/甲醇中的一种或多种。
本公开提供的式1所示化合物的晶型β,以衍射角2θ角度表示的X-射线粉末衍射图,在7.683、12.400、15.616、19.040、22.856、24.802处有特征峰。
在一些实施方案中,式1所示化合物的晶型β,以衍射角2θ角度表示的X-射线粉末衍射图,在7.683、11.501、12.400、14.114、15.616、16.527、19.040、22.856、24.200、24.802、26.963、29.420处有特征峰。
在一些实施方案中,式1所示化合物的晶型β,以衍射角2θ角度表示的X-射线粉末衍射图,在7.683、11.501、12.400、14.114、15.616、16.527、19.040、19.592、19.861、21.815、22.856、24.200、24.802、26.963、28.023、29.420、31.500、33.726处有特征峰。
在一些实施方案中,式1所示化合物的晶型β,以衍射角2θ角度表示的X-射线粉末衍射图谱如图24所示。
本公开还提供一种制备式1所示化合物晶型β的方法,所述方法包括将式1化合物晶型B加入丙二醇甲醚中,搅拌的步骤。
本公开还提供了一种药物组合物,其含有前述晶型A至晶型U、晶型α或晶型β中任意一种或多种晶型,和任选自药学上可接受的赋形剂中的药用辅料。
本公开还提供了一种药物组合物,其由前述晶型A至晶型U、晶型α或晶型β中任意一种或多种晶型,和任选药学上可接受的赋形剂制备而成。
本公开还提供了一种药物组合物的制备方法,包括将前述晶型A至晶型U、晶型α或晶型β中任意一种或多种晶型,与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述晶型A至晶型U、晶型α或晶型β中任意一种或多种晶型,或由前述组合物在制备用于预防和/或治疗肿瘤的用途。
本公开所述的用途,其中所述的肿瘤选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、结直肠癌、肺癌、肾癌、肝癌、宫颈癌、子宫内膜癌、骨髓瘤、白血病、淋巴瘤、听神经瘤、基底细胞癌、胆管癌、膀胱癌、脑癌、支气管癌、肉瘤、脊索瘤、绒毛膜癌、颅咽管瘤、囊腺癌、胚胎癌、血管内皮细胞瘤、室管膜瘤、上皮癌、食管癌、原发性血小板增多症、尤文氏瘤、睾丸癌、胶质瘤、重链病、成血管细胞瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、成神经细胞瘤、NUT中线癌、神经胶质瘤、骨癌、鼻咽癌、口腔癌、甲状腺癌、松果体瘤、真性红细胞增多症、成视网膜细胞瘤、皮脂腺癌、精原细胞瘤、皮肤癌、鳞状细胞癌、滑膜瘤、汗腺癌、瓦尔登斯特伦巨球蛋白血症和维尔姆斯瘤;优选地,所述的癌症选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、结直肠癌和肺癌。
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(包括超过1位小数的数字经过四舍五入后的情况),具体为-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。
本公开中数值如有关物质含量为测定计算的数据,不可避免存在一定程度的误差。一般而言,±10%均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化,该误差变化不超过±10%,可以为±9%、±8%、±7%、±6%、±5%、±4%、±3%、±2%或±1%,优选±5%。
本公开晶型制备方法中所用的起始原料可以是任意形式的化合物,具体形式包括但不限于:无定形、任意晶型、水合物、溶剂合物等。
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。
本公开中所述的析晶的方法有室温析晶、冷却析晶、挥发溶剂析晶、加入晶种 诱导析晶等,所述冷却的温度选自65℃以下,优选-10℃至60℃,所述析晶过程中还可以搅拌。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中,测量样品与参考物之间的温度差、热流差,以表征所有与热效应有关的物理变化和化学变化,得到样品的相变信息。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定,
潮解:吸收足量水分形成液体;
极具引湿性:引湿增重不小于15%;
有引湿性:引湿增重小于15%但不小于2%;
略有引湿性:引湿增重小于2%但不小于0.2%;
无或几乎无引湿性:引湿增重小于0.2%。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
附图说明
图1为化合物1晶型A的XRPD谱图。
图2为化合物1晶型C的XRPD谱图。
图3为化合物1晶型D的XRPD谱图。
图4为化合物1晶型E的XRPD谱图。
图5为化合物1晶型F的XRPD谱图。
图6为化合物1晶型G的XRPD谱图。
图7为化合物1晶型H的XRPD谱图。
图8为化合物1晶型I的XRPD谱图。
图9为化合物1晶型J的XRPD谱图。
图10为化合物1晶型K的XRPD谱图。
图11为化合物1晶型L的XRPD谱图。
图12为化合物1晶型M的XRPD谱图。
图13为化合物1晶型N的XRPD谱图。
图14为化合物1晶型O的XRPD谱图。
图15为化合物1晶型P的XRPD谱图。
图16为化合物1晶型Q的XRPD谱图。
图17为化合物1晶型R的XRPD谱图。
图18为化合物1晶型S的XRPD谱图。
图19为化合物1晶型T的XRPD谱图。
图20为化合物1晶型U的XRPD谱图。
图21为化合物1无定形的XRPD谱图。
图22为化合物1晶型B的XRPD谱图。
图23为化合物1晶型α的XRPD谱图。
图24为化合物1晶型β的XRPD谱图。
具体实施方式
以下将结合实施例或实验例更详细地解释本公开,本公开中的实施例或实验例仅用于说明本公开中的技术方案,并非限定本公开中的实质和范围。
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 NEO 500M核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商:Agilent,MS型号:6110/6120Quadrupole 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 QExactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200~300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH&Co.KG,Acros Organics,Aldrich Chemical Company,韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明,反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空,充入氢气,反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
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:石油醚/乙酸乙酯体系,B:二氯甲烷/甲醇体系,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。
XRPD为X射线粉末衍射检测:测定使用BRUKER D8型X射线衍射仪进行,具体采集信息:Cu阳极(40kV,40mA),射线:单色Cu-Ka射线扫描方式:θ/2θ,扫描范围(2θ范围):3°~45°。
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25-350℃),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25-350℃),氮气吹扫速度50mL/min。
DVS为动态水分吸附:检测采用SMSDVS 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1式1化合物的制备
(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈1
(参照申请号为PCT/CN2022/126650申请中实施例7-P2的制备方法)
第一步
4-溴-5-氟-1H-吲唑-7-甲酸甲酯1b
将2-氨基-4-溴-5-氟-3-甲基苯甲酸甲酯1a(2.7g,10.3mmol,采用专利申请“WO2016020836A1”中说明书第103页步骤(iv)公开的方法制备而得)溶于氯仿(50mL)中,加入醋酸酐(3.16g,30.9mmol),温度保持40℃以下,搅拌反应90分钟后加入醋酸钾(302mg,3.08mmol)、亚硝酸叔丁酯(2.12g,20.6mmol),回流反应14小时。反应液冷却至室温,用二氯甲烷(50mL)稀释,依次用水(30mL)、饱和碳酸钠溶液(10mL)、饱和氯化钠溶液洗涤(10mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得粗品标题化合物1b(2.8g),产品不经纯化直接用于下步反应。
MS m/z(ESI):272.9[M+1]。
第二步
4-溴-5-氟-1H-吲唑-7-甲酸1c
将粗品化合物1b(2.8g,10.25mmol)溶于四氢呋喃(20mL)、甲醇(10mL)和水(10mL)的混合溶剂中,加入氢氧化锂(2.15g,51.26mmol),40℃搅拌反应1小时。反应液减压浓缩除去大部分溶剂,加入水,用乙酸乙酯(150mL×6)萃取,合并有机相,依次用稀盐酸、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤除去干燥剂,滤液减压浓缩得粗品化合物1c(1.4g),产品不经纯化直接用于下步反应。
MS m/z(ESI):259.0[M+1]。
第三步
(S)-4-(4-溴-5-氟-1H-吲唑-7-羰基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯1f
将粗品化合物1c(600mg,2.32mmol)、(S)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯1d(586mg,2.54mmol,采用专利申请“WO2021118877A1”中说明书第80页的prep-aration 65公开的方法制备而得)溶于30mL N,N-二甲基甲酰胺中,冰浴下加入N,N-二异丙基乙胺(898mg,6.95mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.05g,2.78mmol),搅拌反应1小时。反应液减压浓缩后加入乙酸乙酯稀释,依次用水、饱和碳酸钠溶液、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1f(600mg,产率:54.9%)。
MS m/z(ESI):415.2[M-55]。
第四步
(S)-3-溴-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯1g
在氮气氛下,将化合物1f(600mg,1.27mmol)溶于36mL四氢呋喃中,冰浴下依次加入三苯基膦(667mg,2.54mmol)、偶氮二甲酸二乙酯(514mg,2.54mmol),保持温度搅拌反应30分钟,反应液加入饱和氯化铵溶液淬灭,用乙酸乙酯萃取(15mL×2),合并有机相,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1g(577mg,产率:99.9%)。
MS m/z(ESI):397.2[M-55]。
第五步
(S)-3-溴-4-氯-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁基酯1h
将化合物1g(630mg,1.38mmol)溶于乙腈(6mL)中,加入N-氯代丁二酰亚胺(278mg,2.08mmol),加热至60℃反应0.5小时,有固体析出,补加N-氯代丁二酰亚胺(100mg,0.75mmol),继续反应20分钟,反应液冷却至室温,加入饱和碳酸氢钠溶液,用乙酸乙酯(10mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤除去干燥剂,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1h(380mg,产率:56%)。
MS m/z(ESI):487.1[M+1]。
第六步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-4-氯-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯1j
将化合物1h(150mg,0.31mmol)、化合物1i(186mg,0.46mmol,采用专利申请“WO2021118877A1”中说明书第50页的preparation 15公开的方法制备而得)溶于5mL的甲苯中,加入双(二苯基膦苯基醚)二氯化钯(II)(43mg,0.06mmol)、 碳酸铯(300mg,0.92mmol),氮气置换,105℃搅拌反应6小时,反应液冷却至室温后过滤,滤液减压浓缩,残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1j(40mg,产率:18.6%)。
MS m/z(ESI):699.2[M+1]。
第七步
2-氨基-4-((S)-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐1k
将化合物1j(40mg,57.21μmol)溶于1mL二氯甲烷中,0℃下加入1mL三氟乙酸,搅拌反应2小时,反应液减压浓缩得到粗品标题化合物1k(41mg),产品不经纯化直接用于下步反应。
MS m/z(ESI):499.2[M+1]。
第八步
(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈1
将粗品化合物1k(41mg,56.4μmol)悬浮于2mL乙酸乙酯,1mL四氢呋喃和2mL水中,加入无水碳酸钾(24mg,173.6μmol),冰浴下加入丙烯酰氯(5.4mg,59.6μmol),反应5分钟后用乙酸乙酯(5mL×2)萃取,合并有机相,减压浓缩,得到粗品化合物1,即4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(39mg),用高效液相制备色谱法纯化(Waters-2545,色谱柱:SharpSil-TC18,30*150mm,5μm;流动相:水相(10mmol/L碳酸氢铵)和乙腈,梯度配比:乙腈30%-45%,流速:30mL/min)纯化得到标题化合物1(5mg,产率:15.1%),经X-射线粉末衍射检测,该产物为无定形,XRPD谱图如图21所示。
单一构型化合物(较短保留时间)1(5mg,产率:15.1%)
MS m/z(ESI):553.2[M+1]。
HPLC分析:保留时间2.21分钟,纯度:99%(色谱柱:ACQUITYBEH,C18,1.7μm,2.1*50mm;流动相:水(10mM碳酸氢铵),乙腈,梯度配比:乙腈10%-95%)。
1H NMR(500MHz,CD3OD):δ7.67(d,1H),7.20(t,1H),7.02(dd,1H),6.87(dd,1H),6.72-6.28(m,1H),5.81(t,1H),4.74-4.67(m,1H),4.66-4.56(m,1H),4.41(d,1H),4.30(d,-1H),4.12-4.00(m,1H),3.96(d,1H),3.49(d,1H),3.09(dd,2H),2.26-2.16(m,1H),1.94(s,1H)。
单一构型化合物(较长保留时间)1-P1(2mg,产率:6%)
MS m/z(ESI):553.2[M+1]。
HPLC分析:保留时间2.29分钟,纯度:95%(色谱柱:ACQUITYBEH,C18,1.7μm,2.1*50mm;流动相:水(10mM碳酸氢铵),乙腈,梯度配比:乙腈 10%-95%)。
1H NMR(500MHz,CD3OD):δ7.65(d,1H),7.20(t,1H),7.00(dd,1H),6.85(dd,1H),6.70-6.26(m,1H),5.81(t,1H),4.73-4.65(m,1H),4.66-4.56(m,1H),4.39(d,1H),4.30(d,1H),4.10-4.00(m,1H),3.92(d,1H),3.49(d,1H),3.12(dd,2H),2.24-2.16(m,1H),1.92(s,1H)。
测试例1 H358细胞增殖试验
以下方法用来测定本公开化合物对H358细胞增殖的抑制活性,实验方法简述如下:
H358细胞(ATCC,CRL-5807)用含有10%胎牛血清(Corning,35-076-CV)的RPMI1640培养基(Hyclone,SH30809.01)(即完全培养基)进行培养。实验第一天,使用完全培养基将H358细胞以1200个细胞/孔的密度种于96孔板,每孔100μL细胞悬液,放置37℃,5% CO2细胞培养箱培养过夜。第二天,每孔加入10μL用完全培养基配制的梯度稀释的待测化合物,化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点,设置含有0.5% DMSO的空白对照,孔板放置37℃,5% CO2的细胞培养箱培养120小时。第七天,取出96孔细胞培养板,每孔加入50μL CellTiter-Luminescent Cell Viability Assay(Promega,G7573),室温放置10分钟后,使用多功能微孔板酶标仪(PerkinElmer,En2105)读取发光信号值,用Graphpad Prism软件计算化合物抑制活性的IC50值。
表1本公开化合物对H358细胞增殖的抑制活性
结论:本公开化合物对H358细胞增殖具有抑制作用。
测试例2 MIA PaCa-2细胞增殖试验
以下方法用来测定本公开化合物对MIAPaCa-2细胞增殖的抑制活性。实验方法简述如下:
MIA PaCa-2细胞(ATCC,CRL-1420)用含有10%胎牛血清(Corning,35-076-CV)和2.5%马血清(碧云天生物技术,C0262)的DMEM/HIGH GLUCOSE(GE,SH30243.01)培养基(即完全培养基)进行培养。实验第一天,使用完全培养基将MIA PaCa-2细胞以500个细胞/孔的密度种于96孔板,每孔90μL细胞悬液,放置37℃,5% CO2细胞培养箱培养过夜。第二天,每孔加入10μL用完全培养基配制的梯度稀释的待测化合物,化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点,设置含有0.5% DMSO的空白对照,孔板放置37℃、5% CO2的细胞培养箱培养72小时。第五天,取出96孔细胞培养板,每孔加入50μL发光细胞活性检测试剂(CellTiter-Luminescent Cell Viability Assay)(Promega,G7573),室温放置10分钟后,使用多功能微孔板酶标仪(PerkinElmer,EnVision2015)读取发光信号值。用Graphpad Prism软件计算化合物抑制活性的IC50值。
表2本公开化合物对MIA PaCa-2细胞增殖的抑制活性
实施例2晶型A的制备
称取5mg式1所示化合物,加入0.5ml乙酸乙酯/正庚烷(v/v=1:1),室温搅拌2天,离心后固体真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型A,XRPD谱图如图1,其特征峰位置如表3所示。DSC谱图显示吸热峰峰值温度为156.75℃、206.08℃。TGA谱图显示30℃-140℃失重10.64%。
表3

实施例3晶型A的制备
称取20mg式1所示化合物,加入0.5mL乙酸乙酯,50℃-5℃升降温(速率±0.75℃/min)搅拌1天,离心后固体真空干燥,得到标题产物。经X-射线粉末衍射检测,将该产物为晶型A。
实施例4晶型C的制备
称取10mg式1所示化合物,加入1mL异丙醇,室温搅拌3天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型C,XRPD谱图如图2,其特征峰位置如表4所示。DSC谱图显示吸热峰峰值温度为239.41℃。TGA谱图显示30℃-159℃失重0.50%,159℃-269℃失重5.50%。
表4

实施例5晶型C的制备
称取10mg式1所示化合物,加入溶剂,所述溶剂如下表5所示,室温溶析后继续搅拌3天,离心后固体真空干燥,得到标题产物。经X-射线粉末衍射检测,将该产物为晶型C。
表5
实施例6晶型C的制备
称取5mg式1所示化合物,加入0.05mL 1,4-二氧六环室温搅拌溶解,加入0.45ml溶剂,所述溶剂如下表6所示,搅拌析晶,室温打浆3天,离心后固体真空干燥,得到标题产物。经X-射线粉末衍射检测,将该产物为晶型C。
表6
实施例7晶型C的制备
称取10mg式1所示化合物,加入0.2mL正丙醇,60℃打浆1天,离心后固体真空干燥,得到标题产物。经X-射线粉末衍射检测,将该产物为晶型C。
实施例8晶型D的制备
称取80mg式1所示化合物,加入1mL正丁醇,50℃-5℃升降温(速率±0.75℃/min)搅拌2天,离心后固体真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型D,XRPD谱图如图3,其特征峰位置如表7所示。DSC谱图显示吸热峰峰值温度为235.17℃。TGA谱图显示30℃-119℃失重1.10%,120℃-266℃失重5.62%。
表7

实施例9:晶型D的制备
称取10mg式1所示化合物,加入0.2mL叔丁醇,60℃打浆1天,离心后固体真空干燥,得到固体。经X-射线粉末衍射检测,该产物为晶型D。
实施例10:晶型E的制备
称取10mg式1所示化合物,加入1mL甲醇,50℃加热溶解后,慢挥发得到固体。经X-射线粉末衍射检测,将该产物定义为晶型E,XRPD谱图如图4,其特征峰位置如表8所示。DSC谱图显示吸热峰峰值温度为229.16℃、259.36℃。TGA谱图显示30℃-177℃失重2.17%,177℃-260℃失重5.94%。
表8

实施例11:晶型E的制备
称取5mg式1所示化合物,加入0.2mL甲醇,50℃-5℃升降温(速率±0.75℃/min)搅拌1天,离心后固体真空干燥,得到标题产物。经X-射线粉末衍射检测,该产物为晶型E。
实施例12:晶型E的制备
称取5mg式1所示化合物,加入0.125mL 10%水/甲醇,50℃-5℃升降温(速率±0.75℃/min)搅拌1天,离心后固体真空干燥,得到标题产物。经X-射线粉末衍射检测,该产物为晶型E。
实施例13:晶型F的制备
称取1g式1所示化合物,加入13mL纯化水,50℃-5℃升降温(速率±0.75℃/min)搅拌4天,减压过滤后固体真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型F,XRPD谱图如图5,其特征峰位置如表9所示。DSC谱图显示吸热峰峰值温度为85.97℃、150.99℃、222.57℃。TGA谱图显示 30℃-101℃失重6.03%。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6.35%;在加速实验条件(即70%RH),吸湿增重约为6.44%;在极端条件下(90%RH),吸湿增重约为6.65%。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不重合,DVS检测后复测晶型,晶型未转变。
表9

实施例14:晶型F的制备
称取100mg式1所示化合物,加入1mL 80%丙酮/水,室温搅拌溶解,加入3.8mL纯化水搅拌析晶,升温至50℃继续搅拌3天,离心后40℃鼓风干燥过夜,得到固体。经X-射线粉末衍射检测,该产物为晶型F。
实施例15:晶型G的制备
称取80mg式1所示化合物,加入1mL甲醇,50℃-5℃升降温(速率±0.75℃/min)搅拌2天,离心后固体80℃真空干燥7.5h,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型G,XRPD谱图如图6,其特征峰位置如表10所示。DSC谱图显示吸热峰峰值温度为237.35℃。TGA谱图显示30℃-100℃失重0.59%,100℃-270℃失重0.43%。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1.04%;在加速实验条件(即70%RH),吸湿增重约为1.21%;在极端条件下(90%RH),吸湿增重约为1.60%。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,且DVS检测后复测晶型,晶型未转变。
表10

实施例16:晶型G的制备
称取500mg式1所示化合物,加入2mL 80%丙酮/水,室温搅拌溶解,加入8mL甲醇,6mL纯化水,继续搅拌4天后,过滤后80℃真空干燥过夜,得到固体。经X-射线粉末衍射检测,该产物为晶型G。
实施例17:晶型G的制备
称取10mg式1所示化合物E晶型,加入0.2mL溶剂,所述溶剂如下表11所示,60℃下搅拌1天,离心后80℃真空干燥过夜,得到固体。经X-射线粉末衍射检测,该产物为晶型G。
表11
实施例18:晶型H的制备
称取25mg式1所示化合物的晶型E,加入1mL乙醚,室温或50℃下打浆4小时,离心后80℃下真空干燥过夜,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型H,XRPD谱图如图7,其特征峰位置如表12所示。DSC谱图显示吸热峰峰值温度为46.77℃、221.95℃。TGA谱图显示30℃-100℃失重2.23%,100℃-220℃失重0.20%。
表12

实施例19:晶型H的制备
称取25mg式1所示化合物,加入1mL乙醚,室温下打浆5天,离心后40℃下真空干燥过夜,得到固体。经X-射线粉末衍射检测,该产物为晶型H。
实施例20:晶型I的制备
称取30mg式1所示化合物,加入0.6mL正戊醇,60℃下打浆1天,离心后40℃下真空干燥过夜,得到标题产物。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8,其特征峰位置如表13所示。DSC谱图显示吸热峰峰值温度为66.03℃、222.56℃、245.19℃。TGA谱图显示30℃-100℃失重0.97%,100℃-240℃失重8.15%。
表13

实施例21:晶型J的制备
称取30mg式1所示化合物,加入0.6mL异戊醇,60℃下打浆1天,离心后40℃下真空干燥过夜,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型J,XRPD谱图如图9,其特征峰位置如表14所示。DSC谱图显示吸热峰峰值温度为230.96℃、242.37℃。TGA谱图显示31℃-100℃失重0.46%,171℃-260℃失重7.85%。
表14

实施例22:晶型K的制备
称取10mg式1所示化合物,加入1mL 7%水/乙醇,室温搅拌3天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型K,XRPD谱图如图10,其特征峰位置如表15所示。DSC谱图显示吸热峰峰值温度为240.73℃。TGA谱图显示30℃-108℃失重1.42%,108℃-272℃失重3.32%。
表15

实施例23:晶型K的制备
称取5mg式1所示化合物,加入0.050mL 1,4-二氧六环室温搅拌溶解,加入0.450ml乙醇搅拌析晶,室温打浆3天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,该产物为晶型K。
实施例24:晶型K的制备
称取5mg式1所示化合物,加入0.075mL乙酸乙酯/乙醇混合溶剂(v/v=1:1)室温搅拌溶解,50℃-5℃升降温(速率±0.75℃/min)搅拌1天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,该产物为晶型K。
实施例25:晶型L的制备
称取10mg式1所示化合物的晶型F,加入0.5ml水,95℃搅拌2小时,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型L,XRPD谱图如图11,其特征峰位置如表16所示。DSC谱图显示吸热峰峰值温度为98.46℃、237.45℃。TGA谱图显示30℃-270℃失重2.6%。
表16

实施例26:晶型M的制备
称取10mg式1所示化合物,加入0.1ml乙酸异丙酯,室温下搅拌2天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型M,XRPD谱图如图12,其特征峰位置如表17所示。DSC谱图显示吸热峰峰值温度为254.20℃。TGA谱图显示27℃-247℃失重0.23%。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0.48%;在加速实验条件(即70%RH),吸湿增重约为0.55%;在极端条件下(90%RH),吸湿增重约为0.73%。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,且DVS检测后复测晶型,晶型未转变。
表17
实施例27:晶型M的制备
称取100mg式1所示化合物,加入2.5ml乙酸异丙酯,60℃下搅拌溶解, 降至室温后加入1mL正庚烷,室温搅拌过夜。离心后真空干燥,得到固体。经X-射线粉末衍射检测,该产物为晶型M。
实施例28:晶型N的制备
称取10mg式1所示化合物,加入0.1ml水,95℃搅拌3天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型N,XRPD谱图如图13,其特征峰位置如表18所示。DSC谱图显示吸热峰峰值温度为59.31℃、268.68℃。TGA谱图显示25℃-213℃失重2.1%。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3.00%;在加速实验条件(即70%RH),吸湿增重约为3.06%;在极端条件下(90%RH),吸湿增重约为3.18%。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,且DVS检测后复测晶型,晶型未转变。
表18

实施例29:晶型N的制备
称取10mg式1所示化合物,溶于0.5ml乙酸乙酯,加入1mL正庚烷,室温下搅拌过夜。析出固体后过滤,取固体加入水95℃搅拌过夜。离心后真空干燥,得到固体。经X-射线粉末衍射检测,该产物为晶型N。
实施例30:晶型N的制备
称取100mg式1所示化合物,溶于1.0ml甲基异丁基酮/乙酸异丙酯(v/v=1:1)混合溶液,加入5mg N晶型晶种,室温搅拌过夜。离心后固体真空干燥,得到标题产物。
实施例31:晶型N的制备
称取100mg式1所示化合物,加入1.0ml甲基异丁基酮,室温搅拌过夜。离心后真空干燥,得到固体。经X-射线粉末衍射检测,该产物为晶型N。
实施例32:晶型O的制备
称取50mg式1所示化合物,溶于0.5mL 2-丁酮,加入3.5mL水,50℃搅拌2小时,离心去上清液,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型O,XRPD谱图如图14,其特征峰位置如表19所示。
表19

实施例33:晶型P的制备
称取50mg式1所示化合物,溶于0.5mL 2-丁酮,加入3.5mL水,50℃搅拌24小时,离心去上清液,得到固体。经X-射线粉末衍射检测,将该产物定义为游离态P晶型,XRPD谱图如图15,其特征峰位置如表20所示。
表20
实施例34:晶型Q的制备
称取50mg式1所示化合物,溶于0.5mL 2-丁酮,加入3.5mL水,50℃搅拌2小时,离心取固体真空干燥,得到标题产物。经X-射线粉末衍射检测,将该产物定义为游离态Q晶型,XRPD谱图如图16,其特征峰位置如表21所示。
表21
实施例35:晶型R的制备
称取50mg式1所示化合物,溶于0.5mL 2-丁酮,加入3.5mL水,50℃搅拌2小时,离心取固体真空干燥。加入1.0mL水,60℃下搅拌12小时,离心取真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型R,XRPD谱图如图17,其特征峰位置如表22所示。
表22

实施例36:晶型S的制备
称取50mg式1所示化合物,加入0.5ml甲基异丁基酮,室温搅拌过夜。离心后100℃真空干燥过夜,得到固体。经X-射线粉末衍射检测,将该产物定义为游离态S晶型,XRPD谱图如图18,其特征峰位置如表23所示。DSC谱图显示吸热峰峰值温度为280.11℃。TGA谱图显示33℃-333℃失重0.52%。
表23

实施例37:晶型T的制备
称取式1所示化合物10mg,加入到1ml异丙醇中,溶液体系室温搅拌至澄清,0.22μm滤膜过滤,将溶液于室温下缓慢蒸发析晶,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型T,XRPD谱图如图19,其特征峰位置如表24所示。
表24

实施例38:晶型U的制备
称取式1所示化合物20mg,于0.18ml甲醇与0.02ml水的混合溶液中搅拌24小时,过滤后,将产品50℃烘干16h,得到固体。经X-射线粉末衍射检测,将该产物定义为晶型U,XRPD谱图如图20,其特征峰位置如表25所示。
表25
实施例39:游离态B晶型的制备
称取10mg式1所示化合物的晶型E,加入0.5ml乙酸乙酯,室温搅拌2天,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为游离态B晶型,XRPD谱图如图22,其特征峰位置如表26所示。
表26
实施例40:晶型α的制备
称取10mg式1所示化合物晶型N,加入0.2ml甲醇,室温下搅拌析晶,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为游离态晶型α,XRPD谱图如图23,其特征峰位置如表27所示。DSC谱图显示吸热峰峰值温度为42.51℃、262.81℃。TGA谱图显示30℃-316℃失重3.43%。
表27
实施例41:晶型α的制备
称取10mg式1所示化合物晶型N,加入0.2ml溶剂,所述溶剂如下表27所示,室温下搅拌析晶,离心后真空干燥,得到固体。经X-射线粉末衍射检测,该产物为游离态晶型α。
表28
实施例42:晶型β的制备
称取10mg式1所示化合物的晶型B,加入0.1mL丙二醇甲醚,室温搅拌析晶,离心后真空干燥,得到固体。经X-射线粉末衍射检测,将该产物定义为游离态晶型β,XRPD谱图如图24,其特征峰位置如表29所示。DSC谱图显示吸热峰峰值温度为157.49℃、221.33℃。TGA谱图显示30℃-187℃失重7.16%。
表29

实施例43:晶型影响因素稳定性研究
将游离态晶型C、晶型F、晶型G、晶型H、晶型L、晶型M、晶型N敞口平摊放置,分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(75% RH、92.5% RH)条件下样品的稳定性,取样考察期为30天。
表30晶型C的影响因素稳定性研究

表31晶型F的影响因素稳定性研究
表32晶型G的影响因素稳定性研究

表33晶型H的影响因素稳定性研究
表34晶型L的影响因素稳定性研究

表35晶型M的影响因素稳定性研究
表36晶型N的影响因素稳定性研究

结论:影响因素实验表明:在光照、高温(40℃、60℃)、高湿(75% RH、92.5%RH)条件下30天,晶型C、晶型F、晶型G、晶型H、晶型L、晶型M、晶型N的物理和化学稳定性均良好。
实施例44:游离态晶型长期加速稳定性研究
将晶型C、晶型F、晶型G、晶型H、晶型L、晶型M、晶型N放置25℃/60%RH和40℃/75%RH条件考察稳定性。
表37晶型C的长期加速稳定性研究
表38晶型F的长期加速稳定性研究
表39晶型G的长期加速稳定性研究

表40晶型H的长期加速稳定性研究
表41晶型L的长期加速稳定性研究
表42晶型M的长期加速稳定性研究

表43晶型N的长期加速稳定性研究
结论:长期加速实验表明:在25℃/60RH和40℃/75RH条件下6个月,晶型C、晶型F、晶型G、晶型H、晶型L、晶型M、晶型N的物理化学稳定性均良好。

Claims (31)

  1. 一种式1所示化合物的晶型C,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在9.150、12.034、17.860、19.920、23.604和23.997处有特征峰,优选在9.150、11.840、12.034、17.860、19.920、23.604、23.997、25.803、27.536和28.038处有特征峰,更优选在9.150、11.840、12.034、17.860、19.920、23.604、23.997、25.803、27.536、28.038、30.743和31.353处有特征峰,
  2. 根据权利要求1所述的晶型C,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  3. 一种如权利要求1或2所述的晶型C的制备方法,所述方法包括:
    方法一:将式1化合物加入溶剂I中,搅拌析晶,所述溶剂I选自异丙醇、乙醇、正丙醇中的一种或多种;
    方法二:将式1化合物溶解于1,4-二氧六环中,加入溶剂II搅拌析晶,所述溶剂II选自异丙醇、甲基叔丁基醚、正庚烷、乙酸异丙酯、二氯甲烷、环己烷中的一种或多种;
    方法三:将式1化合物溶解于溶剂III中,搅拌析晶,所述溶剂III选自丙酮、四氢呋喃、1,4-二氧六环、乙酸异丙酯、二氯甲烷、四氢呋喃/乙醇(v/v=2:1)中的一种或多种。
  4. 一种式1所示化合物的晶型F,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在9.947、15.672、18.740、20.712、23.910和28.351处有特征峰,优选在7.935、9.947、10.339、15.672、18.740、19.933、20.712、23.910、25.504、26.139和28.351处有特征峰,更优选在7.935、9.947、10.339、11.651、11.990、15.672、16.642、18.740、19.933、20.712、21.471、23.910、25.504、26.139、27.660、28.351和28.898处有特征峰。
  5. 根据权利要求4所述的晶型F,其特征在于,以衍射角2θ角度表示的X-射 线粉末衍射图谱如图5所示。
  6. 一种如权利要求4或5所述的晶型F的制备方法,所述方法包括:
    方法一:将式1化合物加入纯化水中,50℃-5℃循环升降温搅拌;
    方法二:将式1化合物溶解于80%丙酮/水中,加入纯化水搅拌。
  7. 一种式1所示化合物的晶型G,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在10.701、11.896、12.669、17.822、25.246和27.288处有特征峰,优选在7.457、10.701、11.896、12.669、17.822、20.532、21.378、25.246、27.288和32.704处有特征峰,更优选在7.457、10.701、11.896、12.669、17.822、20.532、21.015、21.378、22.429、24.516、25.246、27.288和32.704处有特征峰。
  8. 根据权利要求7所述的晶型G,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  9. 一种如权利要求7或8所述的晶型G的制备方法,所述方法包括:
    方法一:将式1化合物加入甲醇中,50℃-5℃循环升降温搅拌;
    方法二:将式1化合物溶解于80%丙酮/水中,加入甲醇/水(V/V=4:3),搅拌;
    方法三:将式1化合物的晶型E加入溶剂IV中,搅拌,所述溶剂IV选自异丙醚、甲基叔丁基醚、环己烷、乙酸异丙酯、水中的一种或多种。
  10. 一种式1所示化合物的晶型H,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在7.961、13.533、15.180、15.879和20.619处有特征峰,优选在7.961、13.533、15.180、15.879、15.946、20.619、20.902、22.595和25.444处有特征峰,更优选在7.961、13.533、15.180、15.879、15.946、20.619、20.902、22.595、25.444、29.305和30.671处有特征峰。
  11. 根据权利要求10所述的晶型H,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  12. 一种如权利要求10或11所述的晶型H的制备方法,所述方法包括将式1化合物加入乙醚中,搅拌的步骤。
  13. 一种式1所示化合物的晶型L,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在10.645、16.725、17.050、19.513和19.780处有特征峰,优选在6.580、10.645、14.011、14.586、16.725、17.050、19.513、19.780和21.862处 有特征峰,更优选在6.580、10.645、14.011、14.586、16.725、17.050、19.513、19.780、21.862、23.529、26.952和27.932处有特征峰。
  14. 根据权利要求13所述的晶型L,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
  15. 一种如权利要求13或14所述的晶型L的制备方法,所述方法包括将式1化合物晶型F加入水中,于95℃搅拌的步骤。
  16. 一种式1所示化合物的晶型M,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在8.313、11.772、15.173、18.762、20.945和25.849处有特征峰,优选在7.595、8.313、11.772、12.680、13.791、15.173、17.320、18.762、20.945、25.849和26.857处有特征峰,更优选在7.595、8.313、11.772、12.680、13.359、13.791、15.173、16.626、17.320、18.762、19.506、20.945、25.849、26.857、29.605和30.545处有特征峰。
  17. 根据权利要求16所述的晶型M,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
  18. 一种如权利要求16或17所述的晶型M的制备方法,所述方法包括:
    方法一:将式1化合物加入乙酸异丙酯中,搅拌;
    方法二:将式1化合物溶解于乙酸异丙酯中,加入正庚烷搅拌。
  19. 一种式1所示化合物的晶型N,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在6.324、13.092、13.626、14.699、19.483、22.429和27.407处有特征峰,优选在6.324、13.092、13.626、14.699、15.566、19.483、20.724、22.429、23.287和27.407处有特征峰,更优选在6.324、12.664、13.092、13.626、14.699、15.566、19.483、20.724、22.429、23.287、25.042、26.840、27.407和30.152处有特征峰。
  20. 根据权利要求19所述的晶型N,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
  21. 一种如权利要求19或20所述的晶型N的制备方法,所述方法包括:
    方法一:将式1化合物加入溶剂V中,搅拌析晶,所述溶剂V选自水、甲基异丁基酮;
    方法二:将式1化合物溶于溶剂VI中,加入晶种析晶,所述溶剂VI选自甲 基异丁基酮、乙酸异丙酯的一种或多种;
    方法三:将式1化合物溶于乙酸乙酯,加入正庚烷,搅拌。
  22. 一种式1所示化合物的晶型R,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在9.598、11.283、13.705、15.045、19.714和24.020处有特征峰,优选在8.248、9.598、11.283、12.828、13.705、15.045、15.539、19.714、22.430、24.020和26.248处有特征峰,更优选在8.248、9.598、9.884、11.283、11.748、12.828、13.705、15.045、15.539、16.670、17.686、19.714、20.791、22.430、24.020、25.017和26.248处有特征峰
  23. 根据权利要求22所述的晶型R,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
  24. 一种如权利要求22或23所述的晶型R的制备方法,所述方法包括:
    步骤一:将式1化合物溶于2-丁酮,加入水,搅拌析晶。
    步骤二:将步骤一中的晶体加入水中,于60℃搅拌析晶。
  25. 一种式1所示化合物的晶型S,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图,在10.810、13.597、14.706、19.971和22.751处有特征峰,优选在6.465、10.810、11.872、13.597、14.706、15.563、19.971、22.751、23.881和26.322处有特征峰,更优选在6.465、10.810、11.872、12.996、13.597、14.706、15.563、16.385、19.971、20.914、22.751、23.881、25.414、26.322、29.235和32.963处有特征峰
  26. 根据权利要求25所述的晶型S,其特征在于,以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
  27. 一种如权利要求25或26所述的晶型S的制备方法,所述方法包括:
    步骤一:将式1化合物加入甲基异丁基酮中,搅拌析晶;
    步骤二:将步骤一中的晶体于100℃真空干燥。
  28. 根据权利要求1-2、4-5、7-8、10-11、13-14、16-17、19-20、22-23、25-26任一项所述的晶型,所述2θ角误差范围为±0.20。
  29. 一种药物组合物,含有权利要求1-2、4-5、7-8、10-11、13-14、16-17、19-20、22-23、25-26任一项所述的晶型和任选自药学上可接受的赋形剂。
  30. 一种药物组合物的制备方法,包括将权利要求1-2、4-5、7-8、10-11、13-14、16-17、19-20、22-23、25-26任一项所述的晶型和药学上可接受的赋形剂混合的步骤。
  31. 权利要求1-2、4-5、7-8、10-11、13-14、16-17、19-20、22-23、25-26任一项所述的晶型,或权利要求26所述的药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途。
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