WO2020216188A1 - 化合物晶型、其制备方法、药物组合物以及应用 - Google Patents
化合物晶型、其制备方法、药物组合物以及应用 Download PDFInfo
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- WO2020216188A1 WO2020216188A1 PCT/CN2020/085695 CN2020085695W WO2020216188A1 WO 2020216188 A1 WO2020216188 A1 WO 2020216188A1 CN 2020085695 W CN2020085695 W CN 2020085695W WO 2020216188 A1 WO2020216188 A1 WO 2020216188A1
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- PCKYITPVOLEZKL-UHFFFAOYSA-N COc(c(OCCCCCC(O)=O)cc1ncc2)cc1c2Oc(ccc(NC(C1(CC1)C(Nc(cc1)ccc1F)=O)=O)c1)c1F Chemical compound COc(c(OCCCCCC(O)=O)cc1ncc2)cc1c2Oc(ccc(NC(C1(CC1)C(Nc(cc1)ccc1F)=O)=O)c1)c1F PCKYITPVOLEZKL-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- the present invention relates to the field of pharmaceutical technology, in particular to the compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy] -6-Methoxy-7-quinolinyl]oxy]hexanoic acid, the three crystal forms, the preparation method of the crystal forms, the pharmaceutical composition containing the three crystal forms, and the three crystal forms in the treatment of factors Application in diseases caused by abnormal activity of protein kinase AXL and/or VEGFR2.
- 6-[[4-[2-Fluoro-4-[[1-[(4-Fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinoline Hydroxy]hexanoic acid is an anti-tumor drug, which mainly acts on AXL and vascular endothelial growth factor receptor (VEGFR2 or KDR), and is a new type of multi-target receptor tyrosine Kinase inhibitors are suitable for various clinical indications such as acute myeloid leukemia, colon cancer, gastric cancer, lung cancer, thyroid cancer, prostate cancer, hepatocellular carcinoma, kidney cancer and so on.
- VEGFR2 or KDR vascular endothelial growth factor receptor
- the present invention provides a compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl] for the treatment of value-added diseases such as cancer Amino]phenoxy]-6-methoxy-7-quinolinyl]oxy]hexanoic acid.
- One aspect of the present invention provides 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methyl
- the X-ray powder diffraction pattern of the crystal form AB expressed in 2 ⁇ angles is at 4.6 ⁇ 0.1°, 6.7 ⁇ 0.1°, 10.7 ⁇ 0.1°, 16.2 ⁇ 0.1°, 17.0 ⁇ 0.1°, 17.4 ⁇ 0.1°
- the X-ray powder diffraction pattern of the crystal form AB expressed in 2 ⁇ angles is at 4.6 ⁇ 0.1°, 6.7 ⁇ 0.1°, 9.3 ⁇ 0.1°, 9.7 ⁇ 0.1°, 10.7 ⁇ 0.1°, 11.6 ⁇ 0.1°, 13.4 ⁇ 0.1° ⁇ 13.8 ⁇ 0.1° ⁇ 15.3 ⁇ 0.1° ⁇ 16.2 ⁇ 0.1° ⁇ 17.0 ⁇ 0.1° ⁇ 17.4 ⁇ 0.1° ⁇ 18.6 ⁇ 0.1° ⁇ 19.5 ⁇ 0.1° ⁇ 20.7 ⁇ 0.1° ⁇ 21.9 ⁇ 0.1° ⁇ 22.3 ⁇ 0.1° ⁇ 22.5 ⁇ 0.1° ⁇ 23.4 ⁇ 0.1° ⁇ 23.8 ⁇ 0.1° ⁇ 24.4 ⁇ 0.1° ⁇ 25.1 ⁇ 0.1° ⁇ 26.0 ⁇ 0.1° ⁇ 26.8 ⁇ 0.1° ⁇ 27.7 ⁇ 0.1° ⁇ 29.7 ⁇ 0.1° ⁇ 32.8 There are diffraction peaks at ⁇ 0.1° and 33.1 ⁇ 0.1°.
- the present invention also provides a method for preparing compound 1 of crystal form AB, which includes the following steps:
- the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, t-amyl alcohol or mixed solvents containing ethanol; preferably, The mixed solvent containing ethanol is selected from tetrahydrofuran/water/ethanol, tetrahydrofuran/ethanol, DMF/ethanol.
- the X-ray powder diffraction pattern of the crystal form M expressed in 2 ⁇ angles is at 9.5 ⁇ 0.1°, 10.2 ⁇ 0.1°, 10.6 ⁇ 0.1°, 11.4 ⁇ 0.1°, 13.2 ⁇ 0.1°, 14.3 ⁇ 0.1° , 18.2 ⁇ 0.1°, 18.9 ⁇ 0.1°, 19.3 ⁇ 0.1°, 19.7 ⁇ 0.1°, 20.4 ⁇ 0.1°, 23.3 ⁇ 0.1°, 26.7 ⁇ 0.1°, 29.6 ⁇ 0.1°, there are diffraction peaks.
- the X-ray powder diffraction pattern of the crystal form M expressed in 2 ⁇ angles is at 9.5 ⁇ 0.1°, 10.2 ⁇ 0.1°, 10.6 ⁇ 0.1°, 11.4 ⁇ 0.1°, 13.2 ⁇ 0.1°, 14.3 ⁇ 0.1°, 15.2 ⁇ 0.1°, 15.7 ⁇ 0.1°, 16.4 ⁇ 0.1°, 17.4 ⁇ 0.1°, 18.2 ⁇ 0.1°, 18.9 ⁇ 0.1°, 19.3 ⁇ 0.1°, 19.7 ⁇ 0.1°, 20.4 ⁇ 0.1°, 22.1 ⁇ 0.1°, 23.3
- the present invention also provides a method for preparing compound 1 crystal form M, which includes the following steps:
- the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, t-amyl alcohol or mixed solvents containing ethanol; preferably, The mixed solvent containing ethanol is selected from tetrahydrofuran/water/ethanol, tetrahydrofuran/ethanol, DMF/ethanol.
- the X-ray powder diffraction pattern of the crystal form F expressed in 2 ⁇ angles is at 7.1 ⁇ 0.1°, 8.0 ⁇ 0.1°, 10.0 ⁇ 0.1°, 10.9 ⁇ 0.1°, 14.0 ⁇ 0.1°, 15.4 ⁇ 0.1°
- diffraction peaks at, 16.0 ⁇ 0.1°, 16.5 ⁇ 0.1°, 17.1 ⁇ 0.1°, 19.5 ⁇ 0.1°, 22.0 ⁇ 0.1°, 25.0 ⁇ 0.1°, 28.1 ⁇ 0.1°.
- the X-ray powder diffraction pattern of the crystal form F expressed in 2 ⁇ angles is at 7.1 ⁇ 0.1°, 8.0 ⁇ 0.1°, 9.0 ⁇ 0.1°, 10.0 ⁇ 0.1°, 10.9 ⁇ 0.1°, 11.3 ⁇ 0.1°, 14.0 ⁇ 0.1° ⁇ 15.4 ⁇ 0.1° ⁇ 16.0 ⁇ 0.1° ⁇ 16.5 ⁇ 0.1° ⁇ 17.1 ⁇ 0.1° ⁇ 18.0 ⁇ 0.1° ⁇ 19.5 ⁇ 0.1° ⁇ 19.8 ⁇ 0.1° ⁇ 20.4 ⁇ 0.1° ⁇ 21.4 ⁇ 0.1° ⁇ 22.0
- the present invention also provides a method for preparing the crystalline form F of compound 1, which includes the following steps:
- the present invention also provides another method for preparing crystal form F of compound 1, which includes the following steps:
- the organic solvent is selected from DMSO, ethyl acetate, methanol, ethanol or DMSO/ethyl acetate mixed solvent, DMSO/water mixed Solvent.
- the present invention also provides a method for preparing crystalline form F of compound 1, which includes the following steps:
- crystal form F As a seed crystal, stirring and reacting at a temperature of 50 ⁇ 3° C. for 1 to 2 days to precipitate crystals, filtering the crystals, and drying the filter cake to obtain crystal form F.
- One aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one of compound 1 having crystal form AB of the present invention, compound 1 having crystal form M, and compound 1 having crystal form F, and pharmaceutically Acceptable carrier.
- the present invention also provides the crystal form AB, crystal form M and crystal form F of compound 1 and the pharmaceutical composition comprising these three crystal forms for the treatment of diseases caused by abnormal activity of protein kinase AXL and/or VEGFR2 (E.g. tumor or cancer) application in medicine.
- diseases caused by abnormal activity of protein kinase AXL and/or VEGFR2 E.g. tumor or cancer
- the pharmaceutical composition can be used to treat thyroid cancer (including medullary thyroid cancer), gastric cancer, esophageal cancer, kidney cancer (including renal carcinoma), liver cancer (including hepatocellular carcinoma), ovarian cancer, cervical cancer, large intestine Cancer, small bowel cancer, brain cancer (including astrocytic tumors, including: malignant glioma, giant cell malignant glioma, glioma sarcoma, and malignant glioma with oligodendroglial component), leukemia , Lung cancer (including non-small cell lung cancer), bone cancer, prostate cancer (including castration-resistant prostate cancer), pancreatic cancer, skin cancer, lymphoma, solid tumor, Hodgkin's disease or non-Hodgkin's lymphoma . Therefore, the present invention also relates to a method for treating diseases caused by abnormal activity of protein kinase AXL and/or VEGFR2, the treatment method comprising administering the above-mentioned pharmaceutical composition to
- the pharmaceutical composition of the present invention can be made into various dosage forms, including but not limited to various oral preparations; preferably, the pharmaceutical composition is a tablet or a capsule.
- the crystal form AB, crystal form M and crystal form F of the compound 1 of the present invention all have good chemical stability, and the yield and purity are high.
- the preparation method of the crystal form of the present invention is simple and easy to implement, can be stably produced in batches, and is beneficial to popularization and application.
- Crystal form AB, crystal form M and crystal form F are also relatively stable under high temperature, high humidity, and oxidation conditions, which are good for storage and transportation and industrial production.
- the crystal form AB, crystal form M and crystal form F (especially crystal form AB) of the present invention have high bioavailability.
- Figure 1 is a hydrogen NMR spectrum of compound 1 (using deuterated DMSO as solvent);
- Figure 2 is an XRPD pattern of compound 1 prepared according to the method in the prior art
- Figure 3 is the XRPD pattern of the crystalline form AB of compound 1;
- Figure 4 is the TGA and DSC spectra of the crystalline form AB of compound 1;
- Figure 5 is the XRPD pattern of the crystal form M of compound 1;
- Figure 6 is the TGA and DSC spectra of the crystal form M of compound 1;
- Figure 7 is the XRPD pattern of crystalline form F of compound 1;
- Figure 8 is the TGA and DSC spectra of crystal form F of compound 1;
- Figure 9 shows the comparison of the XRPD overlays of the crystalline form AB of compound 1 before the stability acceleration experiment and when the stability is accelerated for one month (from top to bottom, it is 0 month, January sealed, and opened in January);
- Figure 10 shows the comparison of the XRPD overlays of the crystalline form AB of compound 1 before the stability acceleration experiment and when the stability is accelerated for seven months (from top to bottom: 0 month, January sealed, January open);
- Figure 11 shows the XRPD pattern (small angle-sealing) of the crystalline form AB of compound 1 during the accelerated stability test for seven months;
- Figure 12 shows the XRPD pattern (small angle-open) of the crystalline form AB of compound 1 at seven months of the accelerated stability experiment.
- the XRPD test was performed on the solid prepared in this example, and the obtained XRPD pattern is shown in FIG. 2.
- Accelerated test Put compound 1 in a vial, put the vial into a closed container (dryer) with a relative humidity of 75% ⁇ 5% in two ways: sealed and open, and put the dryer in the incubator. Place it at 40°C ⁇ 2°C for 7 months, and take a small amount of samples for testing in 0, 1, 2, and July.
- the test results are shown in Figure 9 to Figure 12 and Table 1.
- the above experimental results show that the crystal form AB of the compound 1 obtained in the present invention has good stability and high bioavailability, and the appearance properties and particle size of the obtained crystals are more suitable for preparation of medicines.
- the crystal form AB is easy to realize in scale-up preparation, and the operation is simple, and the obtained crystal form AB itself is also a thermodynamically stable crystal form. Therefore, in terms of industrial preparation methods and quality, crystalline form AB is a more ideal compound crystal form.
- Accelerated test Put the crystal form M of compound 1 in a petri dish, put the petri dish into a closed container (dryer) with a relative humidity of 75% ⁇ 5% in an open manner, and put the desiccator into the incubator. Place it at 40°C ⁇ 2°C for 3 months, and take a small amount of samples for testing in 0, 1, 2, and 3 months.
- Accelerated test Put the crystal form F of compound 1 in a petri dish, put the petri dish in an open container (dryer) with a relative humidity of 75% ⁇ 5%, and put the desiccator into the incubator. Place it at 40°C ⁇ 2°C for 3 months, and take a small amount of samples for testing in 0, 1, 2 and 3 months.
- Table 4 shows the crystalline form of Compound AB 1 and the IC 50 for AXL of VEGF-R2.
- Form AB compound has a lower IC 50. Therefore, crystal form AB can be used as a candidate drug crystal form for clinical use.
- Table 5 shows the inhibitory effect of the crystalline form AB of Compound 1 on tumors in different tumor models.
- MOLM-13 cells were subcutaneously inoculated in mice to establish a subcutaneous xenograft tumor model of human acute myeloid leukemia. After 14 days of intragastric administration of crystal form AB, the tumor was collected and tumor volume data was collected. The tumor inhibition rate results of each dose group are shown in the above table.
- the half effective dose of KC1036 has an EC 50 of 1.5 mg/kg; after 3 mg/kg administration, tumor growth is significantly inhibited; 6 mg/kg or 6.25 mg/kg inhibits tumor growth and is administered After 14 days, some mouse tumors disappeared.
- mice were subcutaneously inoculated with NCIH-1703 cells to establish a subcutaneous xenograft tumor model of lung cancer. Animals were intragastrically given crystal form AB for 28 days, and then the tumors were collected and tumor volume data were collected.
- the tumor inhibition rate results of each dose group are shown in Table 5 above.
- the KC1036 6.25 mg/kg group can significantly inhibit tumor growth, the 12.5 mg/kg group can significantly inhibit tumor growth and some mice can see tumors begin to fade, 12.5 mg/kg, The doses of 25mg/kg and 50mg/kg significantly inhibited tumor growth and the number of tumor regression cases increased.
- the drug samples of different crystal forms of Compound 1 were added to 1% CMC-Na solution, prepared as a suspension, and administered to mice by gavage.
- the drug samples of different crystal forms of Compound 1 were formulated into solutions in DMSO/PEG400/water and administered intravenously to mice. After administration, blood samples were collected through the dorsal foot vein at different time points. After anticoagulation with sodium heparin, the plasma was extracted by centrifugation. The plasma samples were analyzed by LC-MS/MS and the plasma drug concentration was obtained. The pharmacokinetics were calculated using WinNonlin (Phoenix TM ) Kinetic parameter values. Table 6 lists the bioavailability analysis results of crystal form AB, crystal form M and crystal form F.
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Abstract
Description
Claims (10)
- 化合物1的晶型AB,所述晶型AB以2θ角度表示的X射线粉末衍射图谱在4.6±0.1°、6.7±0.1°、10.7±0.1°、16.2±0.1°、17.0±0.1°、17.4±0.1°、19.5±0.1°、20.7±0.1°、21.9±0.1°、22.5±0.1°、23.8±0.1°、25.1±0.1°处具有衍射峰;进一步地,所述晶型AB以2θ角度表示的X射线粉末衍射图谱在4.6±0.1°、6.7±0.1°、9.3±0.1°、9.7±0.1°、10.7±0.1°、11.6±0.1°、13.4±0.1°、13.8±0.1°、15.3±0.1°、16.2±0.1°、17.0±0.1°、17.4±0.1°、18.6±0.1°、19.5±0.1°、20.7±0.1°、21.9±0.1°、22.3±0.1°、22.5±0.1°、23.4±0.1°、23.8±0.1°、24.4±0.1°、25.1±0.1°、26.0±0.1°、26.8±0.1°、27.7±0.1°、29.7±0.1°、32.8±0.1°、33.1±0.1°处具有衍射峰;进一步地,所述晶型AB以2θ角度表示的X射线粉末衍射图谱如图3所示;进一步地,所述晶型AB的TGA图谱和DSC图谱如图4所示。
- 一种制备化合物1的晶型AB的方法,所述方法包括以下步骤:(1)将化合物1加到醇溶剂中,在75~80℃的温度下加热溶解;(2)在低于-5℃的温度下析出晶体,在-10~-15℃的温度下搅拌以进一步析出晶体;(3)将晶体过滤,干燥,得到晶型AB;优选地,所述醇溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、叔戊醇或含有乙醇的混合溶剂;优选地,所述含有乙醇的混合溶剂选自四氢呋喃/水/乙醇、四氢呋喃/乙醇、DMF/乙醇。
- 化合物1的晶型M,所述晶型M以2θ角度表示的X射线粉末衍射图谱在9.5±0.1°、10.2±0.1°、10.6±0.1°、11.4±0.1°、13.2±0.1°、14.3±0.1°、18.2±0.1°、18.9±0.1°、19.3±0.1°、19.7±0.1°、20.4±0.1°、23.3±0.1°、26.7±0.1°、29.6±0.1°处具有衍射峰;进一步地,所述晶型M以2θ角度表示的X射线粉末衍射图谱在9.5±0.1°、10.2±0.1°、10.6±0.1°、11.4±0.1°、13.2±0.1°、14.3±0.1°、15.2±0.1°、15.7±0.1°、16.4±0.1°、17.4±0.1°、18.2±0.1°、18.9±0.1°、19.3±0.1°、19.7±0.1°、20.4±0.1°、22.1±0.1°、23.3±0.1°、24.2±0.1°、25.3±0.1°、25.7±0.1°、26.7±0.1°、27.2±0.1°、27.7±0.1°、28.8±0.1°、29.6±0.1°处具有衍射峰;进一步地,所述晶型M以2θ角度表示的X射线粉末衍射图谱如图5所示;进一步地,所述晶型M的TGA图谱和DSC图谱如图6所示。
- 一种制备化合物1的晶型M的方法,所述方法包括以下步骤:(1)将化合物1加到醇溶剂中,加热使化合物1溶解;(2)在10~30℃的温度下搅拌以析出晶体;(3)将晶体过滤,干燥,得到晶型M;优选地,所述醇溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、叔戊醇或含有乙醇的混合溶剂;优选地,所述含有乙醇的混合溶剂选自四氢呋喃/水/乙醇、四氢呋喃/乙醇、DMF/乙醇。
- 化合物1的晶型F,所述晶型F以2θ角度表示的X射线粉末衍射图谱在7.1±0.1°、8.0±0.1°、10.0±0.1°、10.9±0.1°、14.0±0.1°、15.4±0.1°、16.0±0.1°、16.5±0.1°、17.1±0.1°、19.5±0.1°、22.0±0.1°、25.0±0.1°、28.1±0.1°处具有衍射峰;进一步地,所述晶型F以2θ角度表示的X射线粉末衍射图谱在7.1±0.1°、8.0±0.1°、9.0±0.1°、10.0±0.1°、10.9±0.1°、11.3±0.1°、14.0±0.1°、15.4±0.1°、16.0±0.1°、16.5±0.1°、17.1±0.1°、18.0±0.1°、19.5±0.1°、19.8±0.1°、20.4±0.1°、21.4±0.1°、22.0±0.1°、22.8±0.1°、24.4±0.1°、25.0±0.1°、26.2±0.1°、27.7±0.1°、28.1±0.1°、29.6±0.1°、33.5±0.1°处具有衍射峰;进一步地,所述晶型F以2θ角度表示的X射线粉末衍射图谱如图7所示;进一步地,所述晶型F的TGA图谱和DSC图谱如图8所示。
- 一种制备化合物1的晶型F的方法,所述方法包括以下步骤:(1)将权利要求1所述的晶型AB加到二甲基乙酰胺中,溶清,一边搅拌一边加入反溶剂——水,搅拌析晶;(2)将晶体分离,在22~30℃的温度下真空干燥后,然后在45~60℃的温度下真空干燥。
- 一种制备化合物1的晶型F的方法,所述方法包括以下步骤:(1)将化合物1加入到有机溶剂中,在20~60℃的温度下搅拌,使化合物1溶解或配成混悬液;(2)以晶型F为晶种,在20~60℃的温度下搅拌以析出晶体;(3)将晶体过滤,干燥,得到晶型F;所述有机溶剂选自DMSO、乙酸乙酯、甲醇、乙醇或DMSO/乙酸乙酯 混合溶剂、DMSO/水混合溶剂。
- 一种制备化合物1的晶型F的方法,所述方法包括以下步骤:(1)将权利要求1所述的晶型AB加到乙酸乙酯中,加热至50±3℃,配制成固液混悬体系;(2)以晶型F作为晶种,在50±3℃的温度下搅拌反应1~2天,析出晶体,将晶体过滤,将滤饼干燥,得到晶型F。
- 一种药物组合物,所述药物组合物包括具有权利要求1所述晶型AB的化合物1、具有权利要求3所述晶型M的化合物1或具有权利要求5所述晶型F的化合物1中的至少一种以及药学上可接受的载体;优选地,所述药物组合物为片剂或胶囊剂。
- 根据权利要求1或2所述的晶型AB、权利要求3或4所述的晶型M、权利要求5或6所述的晶型F以及权利要求9所述的药物组合物在制备用于治疗因蛋白激酶AXL和/或VEGFR2的活性异常所引起的疾病的药物中的应用;进一步地,所述因蛋白激酶AXL和/或VEGFR2的活性异常所引起的疾病包括:甲状腺癌、胃癌、食道癌、肾癌、肝癌、卵巢癌、宫颈癌、大肠癌、小肠癌、脑癌、白血病、肺癌、骨癌、前列腺癌、胰腺癌、皮肤癌、淋巴瘤、实体瘤、何杰金氏病、非何杰金氏淋巴瘤;其中,甲状腺癌包括甲状腺髓样癌;肾癌包括肾癌瘤;肝癌包括肝细胞癌;脑癌包括星形细胞肿瘤,其中,星形细胞肿瘤包括恶性胶质瘤、巨细胞恶性胶质瘤、神经胶质肉瘤和具有少突神经胶质组分的恶性胶质瘤;肺癌包括非小细胞肺癌;前列腺癌包括去势抵抗性前列腺癌。
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WO2018072614A1 (zh) | 2016-10-18 | 2018-04-26 | 北京康辰药业股份有限公司 | 一种喹啉基取代的羧酸化合物或其药学上可接受的盐、其药物组合物及应用 |
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