WO2024022435A1 - 一种5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噁吖庚英化合物的晶型及其制备方法 - Google Patents
一种5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噁吖庚英化合物的晶型及其制备方法 Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine compound Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 36
- 238000001228 spectrum Methods 0.000 claims description 21
- 230000004584 weight gain Effects 0.000 claims description 7
- 235000019786 weight gain Nutrition 0.000 claims description 7
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 208000037844 advanced solid tumor Diseases 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 12
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- 241001465754 Metazoa Species 0.000 description 6
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- RQQIRMLGKSPXSE-WIPMOJCBSA-N [1-acetyloxy-2-[[(2s,3r,5s,6s)-2,6-dihydroxy-3,4,5-triphosphonooxycyclohexyl]oxy-hydroxyphosphoryl]oxyethyl] acetate Chemical compound CC(=O)OC(OC(C)=O)COP(O)(=O)OC1[C@H](O)[C@H](OP(O)(O)=O)C(OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O RQQIRMLGKSPXSE-WIPMOJCBSA-N 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
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- SGEUNORSOZVTOL-CABZTGNLSA-N (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(OC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F SGEUNORSOZVTOL-CABZTGNLSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 101100297694 Arabidopsis thaliana PIP2-7 gene Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
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- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229940124607 PI3Kα inhibitor Drugs 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 101150063858 Pik3ca gene Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 101100456541 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) MEC3 gene Proteins 0.000 description 1
- 101100483663 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UFD1 gene Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
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- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical group O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 238000001543 one-way ANOVA Methods 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
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- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- C07B2200/07—Optical isomers
-
- 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
Definitions
- the present invention relates to a crystal form of 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine compound and a preparation method thereof, and also includes the following steps: Application in the preparation of medicines for treating related diseases. Specifically related to the crystal form of the compound of formula (I) and its preparation method.
- Phosphatidylinositol-3-kinase is composed of the regulatory subunit p85 or p101, and the catalytic subunit p110 (divided into four subtypes: p110a, p110b, p110g, and p110d)
- Lipid kinase catalyzes the phosphorylation of the 3'-OH inositol ring of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (phosphatidylinositol 3,4,5-trisphosphate, PIP3) and activates downstream Akt, etc., which plays a key role in cell proliferation, survival and metabolism. In tumor cells, PI3K is overexpressed, leading to rapid proliferation and growth of tumor cells.
- PI3K ⁇ is widely distributed in the body. Abnormal activation of PI3K ⁇ has also been found in a variety of solid tumors. Mutations in the PIK3CA gene also exist in different solid tumors, which all lead to the occurrence and development of tumors. PI3K ⁇ mainly regulates insulin and other related blood sugar regulatory pathways in normal physiological functions. Therefore, inhibition of wild-type PI3K ⁇ has also been clinically proven to cause side effects such as hyperglycemia. Therefore, inhibitors targeting mutated PI3K ⁇ play an important role in clinical safety.
- GDC-0077 is a highly selective PI3K ⁇ inhibitor developed by Roche. It also has the function of degrading mutant PI3K ⁇ protein, which brings new hope for the clinical development of higher safety PI3K inhibitors.
- the invention provides the A crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.25 ⁇ 0.20°, 8.74 ⁇ 0.20°, 10.46 ⁇ 0.20°,
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.25 ⁇ 0.20°, 7.78 ⁇ 0.20°, 8.74 ⁇ 0.20°, 10.46 ⁇ 0.20°, 18.48 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.25 ⁇ 0.20°, 7.78 ⁇ 0.20°, 8.74 ⁇ 0.20°, 10.46 ⁇ 0.20°, 14.99 ⁇ 0.20°, 16.25 ⁇ 0.20°, 17.50 ⁇ 0.20°, 18.48 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.25 ⁇ 0.20°, 8.74 ⁇ 0.20°, and/or 10.46 ⁇ 0.20°, and/or 6.65 ⁇ 0.20°, and/or 7.78 ⁇ 0.20°, and/or 12.60 ⁇ 0.20°, and/or 13.26 ⁇ 0.20°, and/or 13.87 ⁇ 0.20°, and/or 14.44 ⁇ 0.20°, and/or 14.99 ⁇ 0.20 °, and/or 15.53 ⁇ 0.20°, and/or 16.25 ⁇ 0.20°, and/or 17.50 ⁇ 0.20°, and/or 18.48 ⁇ 0.20°, and/or 19.01 ⁇ 0.20°, and/or 19.78 ⁇ 0.20°, and/or 20.55 ⁇ 0.20°, and/or 21.01 ⁇ 0.20°, and/or 21.33 ⁇ 0.20°, and/or 23.72 ⁇ 0.20°, and/or 23.96 ⁇ 0.20°
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.2511°, 6.6532°, 7.7817°, 8.7418°, 10.4626°, 12.5958°, 13.2601°, 13.8718 °, 14.4446°, 14.9927°, 15.5346°, 16.2492°, 17.5047°, 18.4752°, 19.0069°, 19.7791°, 20.5468°, 21.0093°, 21.3325°, 23.7228°, 23.9609°, 24.45 79°, 24.7921°, 25.0236°, 25.6910°, 26.0008°, 26.2926°, 26.7249°, 27.3381°, 27.5777°, 28.1708°, 28.5699°.
- the XRPD pattern of the above-mentioned crystal form A is basically as shown in Figure 1.
- the present invention also provides the above-mentioned crystal form A, whose XRPD pattern is basically as shown in Figure 1.
- the differential scanning calorimetry curve of the above-mentioned Form A has an endothermic peak starting point at 90.5 ⁇ 3.0°C and 181.7 ⁇ 3.0°C respectively.
- the DSC pattern of the above-mentioned crystal form A is shown in Figure 2.
- the DSC pattern of the above-mentioned crystal form A is basically as shown in Figure 2.
- the weight loss of the thermogravimetric analysis curve of the above-mentioned crystal form A reaches 2.55% at 110.0 ⁇ 3.0°C.
- the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.
- the TGA spectrum of the above-mentioned crystal form A is basically as shown in Figure 3.
- the hygroscopic weight gain of the above-mentioned crystal form A at 25° C. and 80% RH is 1.093%.
- the DVS pattern of the above-mentioned crystal form A is basically as shown in Figure 7.
- the present invention also provides the B crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.48 ⁇ 0.20°, 21.84 ⁇ 0.20°, 24.90 ⁇ 0.20°,
- the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.48 ⁇ 0.20°, 9.38 ⁇ 0.20°, 13.25 ⁇ 0.20°, 19.42 ⁇ 0.20°, 21.84 ⁇ 0.20°, 24.90 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.4752°, 9.3771°, 10.9011°, 13.2511°, 16.3529°, 18.9134°, 19.4248°, 21.8375 °, 24.8988°, 26.6143°, 27.6851°.
- the XRPD pattern of the above-mentioned B crystal form is basically as shown in Figure 4.
- the present invention also provides the above-mentioned B crystal form, and its XRPD pattern is basically as shown in Figure 4.
- the differential scanning calorimetry curve of the above-mentioned B crystal form has the starting point of an endothermic peak at 83.5 ⁇ 3.0°C.
- the DSC pattern of the above-mentioned B crystal form is shown in Figure 5.
- the DSC pattern of the above crystal form B is basically as shown in Figure 5.
- thermogravimetric analysis curve of the above-mentioned B crystal form has a weight loss of 6.73% at 135.0 ⁇ 3.0°C.
- the TGA spectrum of the above-mentioned B crystal form is shown in Figure 6.
- the TGA spectrum of the above crystal form B is basically as shown in Figure 6.
- the hygroscopic weight gain of the above-mentioned B crystal form at 25°C and 80% RH is 5.731%.
- the DVS spectrum of the above-mentioned crystal form B is shown in Figure 8.
- the DVS pattern of the above-mentioned crystal form B is basically as shown in Figure 8.
- the present invention also provides the application of the above-mentioned crystal form A and crystal form B in preparing drugs for treating advanced solid tumors.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method/conditions, etc.
- the error in the determination of the 2 ⁇ value can be ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal form, and it is within the scope of this application.
- the expression "substantially as shown" in a specific XRPD pattern means that the position of the diffraction peak in the XRPD pattern is basically within the range of visual inspection or with the help of a selected diffraction peak list ( ⁇ 0.20°, 2 ⁇ ). Same as above.
- a selected diffraction peak list ⁇ 0.20°, 2 ⁇ .
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- SXRD single crystal X-ray diffraction
- the grown single crystal is used to collect diffraction intensity data with a Bruker D8venture diffractometer.
- the light source is CuK ⁇ radiation.
- the scanning method is: ⁇ / ⁇ scanning.
- the direct method Shelxs97 is further used to analyze the crystal structure, and the absolute configuration can be confirmed. .
- the solvent used in the present invention is commercially available.
- the compound of formula (I) can well inhibit the activity of PI3K ⁇ kinase, and can also well inhibit the cell proliferation activity in HCC1954 cells with PIK3CA mutations; the crystal form of compound A of formula (I) is stable.
- Test method Spread an appropriate amount of sample evenly on the single crystal silicon sample plate, and conduct XRPD testing using the parameters described below.
- DSC Differential Scanning Calorimeter
- TGA Thermal Gravimetric Analyzer
- Dynamic moisture adsorption curves were collected on a DVS Intrinsic instrument from the British SMS (Surface Measurement Systems) company. The relative humidity at 25°C was measured with lithium chloride (LiCl), magnesium nitrate [Mg(NO 3 ) 2 ] and potassium chloride (KCl) deliquescent point correction.
- LiCl lithium chloride
- Mg(NO 3 ) 2 magnesium nitrate
- KCl potassium chloride
- the hygroscopicity evaluation categories are as follows:
- ⁇ W% represents the hygroscopic weight gain at 25°C/80%RH.
- Figure 1 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form A of the compound of formula (I);
- Figure 2 is the DSC spectrum of the crystal form A of the compound of formula (I);
- Figure 3 is the TGA spectrum of the crystal form A of compound (I);
- Figure 4 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form B of the compound of formula (I);
- Figure 5 is the DSC spectrum of the crystal form B of the compound of formula (I);
- Figure 6 is the TGA spectrum of the crystal form B of compound (I).
- Figure 7 is the DVS spectrum of the crystal form A of the compound of formula (I);
- Figure 8 is the DVS spectrum of the crystal form B of the compound of formula (I);
- Figure 9 is an ellipsoid diagram of the three-dimensional structure of the compound of formula (I).
- the purified compound was added to aqueous hydrochloric acid solution (6M, 100mL), and then 300mL of methylene chloride was added for extraction. Add sodium carbonate to the water phase to adjust pH until solid precipitates. The aqueous phase was continuously extracted with 300 mL of dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-2.
- the hygroscopic weight gain of the crystalline form A of the compound of formula (I) at 25°C and 80% RH is 1.093%.
- the hygroscopic weight gain of compound B crystal form of formula (I) at 25°C and 80% RH is 5.731%.
- Example 8 Single crystal X-ray diffraction detection and analysis of the compound of formula (I)
- Single crystal culture process Add 10 mg of compound of formula (I) to 2 mL of ethanol, stir until the sample is completely dissolved, and obtain a colorless clear liquid. Place the sample solution in a 4 ml semi-sealed sample bottle and slowly evaporate at room temperature. Colorless needle-like crystals were obtained after two weeks. Crystals were collected and diffraction intensity data were collected using a single crystal X-ray diffractometer (SC-XRD) (D8-VENTURE). The single crystal data shows that the absolute configuration of the compound of formula (I) can be determined, and the molecular formula of the compound is C 19 H 22 F 2 N 6 O 4 . The ellipsoid diagram of the three-dimensional structure of the compound of formula (I) is shown in Figure 9. The crystal structure data of the single crystal of the compound of formula (I) are shown in Table 8.
- Cell culture Human breast cancer HCC1954 cells are cultured in a monolayer in vitro. Add 10% fetal calf serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin to the corresponding culture medium, and culture in a 37°C 5% CO 2 incubator. Passaging was performed twice a week for routine processing. When the cell saturation is 80%-90% and the number reaches the requirement, cells are collected, counted, and inoculated.
- Administration volume 10 ⁇ L/g based on mouse body weight. If body weight loss exceeds 15%, the dosing regimen should be adjusted accordingly.
- Animal grouping animals were weighed before administration, and tumor volume was measured. Patients were randomly divided into groups according to tumor volume (randomized block design).
- the relative tumor inhibitory efficacy of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%).
- T test was used for comparison between two groups.
- One-way ANOVA was used to compare three or more groups. If the F values are significantly different, multiple comparisons should be performed after ANOVA analysis. All data analyzes were performed with SPSS or Graphpad Prism. p ⁇ 0.05 is considered to be a significant difference.
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Abstract
一种5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噁吖庚英化合物的晶型及其制备方法,还包括所述晶型在制备治疗相关疾病的药物中的应用。具体公开了式(I)化合物的晶型及其制备方法。
Description
本申请主张如下优先权:
CN202210892561.1,申请日:2022年07月27日;
CN202310708131.4,申请日:2023年06月14日。
本发明涉及一种5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噁吖庚英化合物的晶型及其制备方法,还包括所述晶型在制备治疗相关疾病的药物中的应用。具体涉及式(I)化合物的晶型及其制备方法。
磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)为一种由调节亚单位p85或p101,以及催化亚单位p110(又分为p110a,p110b,p110g,p110d四种亚型)组成的脂激酶,通过催化磷脂酰肌醇4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate,PIP2)的肌醇环3’-OH磷酸化为磷脂酰肌醇3,4,5-三磷酸(phosphatidylinositol 3,4,5-trisphosphate,PIP3)而激活下游的Akt等从而对细胞的增殖、生存和代谢等起关键作用。在肿瘤细胞中,PI3K过度表达,从而导致肿瘤细胞的快速增殖和生长。
PI3K共有四个亚型,其中PI3Kα在机体中广泛分布。在多种实体瘤中也发现PI3Kα的异常活化。在不同的实体瘤中也存在着PIK3CA基因的突变,这些都导致了肿瘤的发生和发展。PI3Kα在正常生理功能中主要调节胰岛素等相关的血糖调控通路。因此,对野生型PI3Kα的抑制在临床上也验证了会引起高血糖等副作用。所以靶向突变PI3Kα的抑制剂对于临床安全性有重要作用。
GDC-0077是有Roche公司研发的高选择性PI3Kα抑制剂,同时它对突变型PI3Kα蛋白具有降解的功能,这为临床开发更高安全性的PI3K抑制剂带来了新的希望。
发明内容
本发明提供了式(I)化合物的A晶型,其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,8.74±0.20°,10.46±0.20°,
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,7.78±0.20°,8.74±0.20°,10.46±0.20°,18.48±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,7.78±0.20°,8.74±0.20°,10.46±0.20°,14.99±0.20°,16.25±0.20°,17.50±0.20°,18.48±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,8.74±0.20°,和/或10.46±0.20°,和/或6.65±0.20°,和/或7.78±0.20°,和/或12.60±0.20°,和/或13.26±0.20°,和/或13.87±0.20°,和/或14.44±0.20°,和/或14.99±0.20°,和/或15.53±0.20°,和/或16.25±0.20°,和/或17.50±0.20°,和/或18.48±0.20°,和/或19.01±0.20°,和/或19.78±0.20°,和/或20.55±0.20°,和/或21.01±0.20°,和/或21.33±0.20°,和/或23.72±0.20°,和/或23.96±0.20°,和/或24.46±0.20°,和/或24.79±0.20°,和/或25.02±0.20°,和/或25.69±0.20°,和/或26.00±0.20°,和/或26.29±0.20°,和/或26.72±0.20°,和/或27.34±0.20°,和/或27.58±0.20°,和/或28.17±0.20°,和/或28.57±0.20°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.2511°,6.6532°,7.7817°,8.7418°,10.4626°,12.5958°,13.2601°,13.8718°,14.4446°,14.9927°,15.5346°,16.2492°,17.5047°,18.4752°,19.0069°,19.7791°,20.5468°,21.0093°,21.3325°,23.7228°,23.9609°,24.4579°,24.7921°,25.0236°,25.6910°,26.0008°,26.2926°,26.7249°,27.3381°,27.5777°,28.1708°,28.5699°。
在本发明的一些方案中,上述A晶型,其XRPD图谱基本上如图1所示。
本发明还提供了上述A晶型,其XRPD图谱基本上如图1所示。
在本发明的一些方案中,上述A晶型的XRPD图谱解析数据如表1所示:
表1式(I)化合物A晶型的XRPD图谱解析数据
在本发明的一些方案中,上述A晶型的差示扫描量热曲线分别在90.5±3.0℃和181.7±3.0℃处具有一个吸热峰的起始点。
在本发明的一些方案中,上述A晶型的DSC图谱如图2所示。
在本发明的一些方案中,上述A晶型的DSC图谱基本上如图2所示。
在本发明的一些方案中,上述A晶型的热重分析曲线在110.0±3.0℃时失重达2.55%。
在本发明的一些方案中,上述A晶型的TGA图谱如图3所示。
在本发明的一些方案中,上述A晶型的TGA图谱基本上如图3所示。
在本发明的一些方案中,上述A晶型在25℃和80%RH下的吸湿增重为1.093%。
在本发明的一些方案中,上述A晶型的DVS图谱如图7所示。
在本发明的一些方案中,上述A晶型的DVS图谱基本上如图7所示。
本发明还提供了式(I)化合物的B晶型,其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.48±0.20°,21.84±0.20°,24.90±0.20°,
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.48±0.20°,9.38±0.20°,13.25±0.20°,19.42±0.20°,21.84±0.20°,24.90±0.20°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.4752°,9.3771°,10.9011°,13.2511°,16.3529°,18.9134°,19.4248°,21.8375°,24.8988°,26.6143°,27.6851°。
在本发明的一些方案中,上述B晶型,其XRPD图谱基本上如图4所示。
本发明还提供了上述B晶型,其XRPD图谱基本上如图4所示。
在本发明的一些方案中,上述B晶型的XRPD图谱解析数据如表2所示:
表2式(I)化合物B晶型的XRPD图谱解析数据
在本发明的一些方案中,上述B晶型的差示扫描量热曲线在83.5±3.0℃处具有一个吸热峰的起始点。
在本发明的一些方案中,上述B晶型的DSC图谱如图5所示。
在本发明的一些方案中,上述B晶型的DSC图谱基本上如图5所示。
在本发明的一些方案中,上述B晶型的热重分析曲线在135.0±3.0℃时失重达6.73%。
在本发明的一些方案中,上述B晶型的TGA图谱如图6所示。
在本发明的一些方案中,上述B晶型的TGA图谱基本上如图6所示。
在本发明的一些方案中,上述B晶型在25℃和80%RH下的吸湿增重为5.731%。
在本发明的一些方案中,上述B晶型的DVS图谱如图8所示。
在本发明的一些方案中,上述B晶型的DVS图谱基本上如图8所示。
本发明还提供了上述A晶型和B晶型在制备治疗晚期实体瘤的药物上的应用。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
除非另有说明,本发明化合物的差示扫描量热曲线中,向上表示放热(Exo Up)。
除非另有说明,在粉末X-射线衍射光谱(XRPD)中,峰的位置或峰的相对强度可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型,峰的位置可能存在误差,2θ值的测定误差可以为±0.2°。因此,在确定每种晶型时,应该将此误差考虑在内,在误差内也属于本申请的范围。
本发明中表述“基本上如……所示”的特定XRPD图谱是指XRPD图谱中衍射峰的位置在目视检查或借助于被选择的衍射峰列表(±0.20°,2θ)的范围内基本上相同。普通技术人员理解,强度可以随着样品而改变。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培
养出的单晶用Bruker D8venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:φ/ω扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。
化合物依据本领域常规命名原则或者使用软件命名,市售化合物采用供应商目录名称。
技术效果
式(I)化合物能够很好的抑制PI3Kα激酶活性,在PIK3CA突变的HCC1954细胞中也能够很好地抑制细胞的增殖活性;式(I)化合物A晶型稳定。
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:PANalytical(帕纳科)公司的Empyrean型X射线衍射仪
测试方法:将适量样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试。
试验参数如表3:
表3 XRPD仪器参数
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:TA Discovery DSC 2500差示扫描量热仪
试验参数如表4:
表4 DSC仪器参数
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TA Discovery TGA 5500热重分析仪
试验参数如表5:
表5 TGA仪器参数
本发明动态水分吸附分析(Dynamic Vapor Sorption,DVS)方法
动态水分吸附(曲线在英国SMS(Surface Measurement Systems)公司的DVS Intrinsic仪器上采集。在25℃时的相对湿度用氯化锂(LiCl),硝酸镁[Mg(NO3)2]和氯化钾(KCl)的潮解点校正。
表6 DVS仪器参数
引湿性评价分类如下:
吸收足量水分形成液体:潮解;ΔW%≥15%:极具引湿性;15%>ΔW%≥2%:有引湿性;2%>ΔW%≥0.2%:略有引湿性;ΔW%<0.2%:无或几乎无引湿性。ΔW%表示在25℃/80%RH下的吸湿增重。
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图;
图2为式(I)化合物A晶型的DSC谱图;
图3为式(I)化合物A晶型的TGA谱图;
图4为式(I)化合物B晶型的Cu-Kα辐射的XRPD谱图;
图5为式(I)化合物B晶型的DSC谱图;
图6为式(I)化合物B晶型的TGA谱图;
图7为式(I)化合物A晶型的DVS谱图;
图8为式(I)化合物B晶型的DVS谱图;
图9为式(I)化合物立体结构椭球图。
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实验例1:式(I)化合物的制备
合成路线:
步骤1:化合物1-2的合成
在预先干燥过的反应瓶中加入1-1(4.0g,9.82mmol),然后加入四氢呋喃(200mL),最后加入劳森试剂(7.94g,19.64mmol)。反应在20℃并搅拌12小时。反应完成后,向反应液中滴加水淬灭反应,然后用二氯甲烷(100mL*3)萃取,合并有机相,用100mL饱和氯化钠溶液洗涤,再用无水硫酸钠干燥。过滤后直接减压浓缩得粗品。粗产品通过硅胶柱层析分离(二氯甲烷:甲醇=20:1)纯化。纯化后的化合物加入盐酸水溶液(6M,100mL),再加入300mL二氯甲烷萃取。水相加入碳酸钠调节pH直至有固体析出。水相继续用二氯甲烷300mL萃取,收集有机相,无水硫酸钠干燥后减压浓缩得到化合物1-2。
1H NMR(400MHz,CDCl3)δ=8.08(d,J=8.8Hz,1H),8.05-7.98(m,1H),7.39-7.25(m,1H),7.12-7.08(m,1H),6.77-6.44(m,1H),6.35(dd,J=2.4,8.7Hz,1H),6.15(d,J=2.5Hz,1H),4.85-4.72(m,1H),4.65(dd,J=4.0,9.5Hz,1H),4.48-4.39(m,1H),4.34(dd,J=2.5,5.0Hz,2H),4.25-4.15(m,3H),1.59(d,J=6.5Hz,3H);MS:m/z=424.1[M+1]+。
步骤2:式(I)化合物的合成
在预先干燥过的反应瓶中加入1-2(20.00mg,47.23μmol),加入乙醇(5mL),加入碳酸钾(32.64mg,236.16μmol)和O-甲基羟胺盐酸盐(19.72mg,236.16μmol),反应在80℃搅拌12小时。反应完成后,将反应液减压浓缩,加入10mL水,然后用二氯甲烷(10mL*3)萃取,合并有机相。有机相再用10mL饱和氯化钠溶液洗涤,再用无水硫酸钠干燥。有机相减压浓缩,得到式(I)化合物。
1H NMR(400MHz,CDCl3)δ=8.11-7.98(m,1H),7.19(s,1H),6.78-6.45(m,1H),6.39(ddd,J=2.4,8.8,13.2Hz,1H),6.24(dd,J=2.4,16.4Hz,1H),4.86-4.73(m,1H),4.68-4.57(m,3H),4.49-4.39(m,1H),4.33(br d,J=3.3Hz,2H),4.24-4.16(m,2H),3.94-3.83(m,2H),3.79(s,3H),1.45(d,J=6.5Hz,3H);MS:m/z=437.2[M+1]+。
实施例2:式(I)化合物A晶型的制备
称量100mg式(I)化合物,加入正庚烷(2mL,20v)形成悬浮液,再加入甲基叔丁基醚(0.2mL,2V),最后加入乙醇(0.2mL,2V),室温搅拌16小时后,过滤,滤饼减压干燥得到式(I)化合物A晶型。
称量53g式(I)化合物,加入正庚烷(1060mL,20v)形成悬浮液,再加入甲基叔丁基醚(106mL,2V),
搅拌下加入乙醇(106mL,2V),最后加入水(1060mL,20v),室温(约25℃)搅拌116小时,补加式(I)化合物A晶型(约5g),继续搅拌约95小时。过滤,滤饼减压干燥得到式(I)化合物A晶型。
实施例3:式(I)化合物B晶型的制备
称量100mg式(I)化合物,加入正庚烷(1mL,10v)形成悬浮液,再加入甲醇(0.1mL,1V),25℃搅拌16小时后,过滤,滤饼减压干燥得到式(I)化合物B晶型。
实施例4:晶型竞争实验
称量式(I)化合物(约0.5g)在下列四组溶剂中过饱和后,取上清液作为A晶型和B晶型竞争性研究的溶剂。四组混合溶剂分别为:
第一组:水(2mL)
第二组:正庚烷:甲叔醚:乙醇=2mL:0.2mL:0.2mL
第三组:正庚烷:甲叔醚:95%乙醇=2mL:0.2mL:0.2mL
第四组:正庚烷:甲叔醚:90%乙醇=2mL:0.2mL:0.2mL
从上述四组过饱和溶液中分别取1mL上层清液开展下述研究,加入等质量的A晶型(50mg)和B晶型(50mg)分别在25℃和50℃条件下进行搅拌;5天后取溶液中的固体样品进行XRPD的表征考察晶型的变化情况。
结果表明,在25℃和50℃条件下,各实验体系中得到的式(I)化合物A晶型。
实施例5:式(I)化合物A晶型的固体稳定性试验
称取20mg式(I)化合物A晶型于40mL玻璃瓶中,用锡箔纸封好瓶口,再用针头扎些密集小孔,保证环境温湿度充分与样品接触(光照条件直接敞口即可)。将样品放置于相应的影响因素试验条件下(60℃;25℃/92.5%RH;紫外光+可见光)和加速条件下(40℃/75%RH和60℃/75%RH)。在5天、10天、1个月、2个月、3个月时间点取样分析。
表7式(I)化合物A晶型的固体稳定性试验结果
结果表明,式(I)化合物A晶型在高温高湿光照和加速条件下,晶型稳定。
实施例6:式(I)化合物A晶型的引湿性研究
实验材料:
SMS DVS intrinsic动态水分吸附仪
实验方法:
取式(I)化合物A晶型(10~30mg)置于DVS样品盘内进行测试。
实验结果:
式(I)化合物A晶型的DVS谱图如图7所示,ΔW=1.093%。
实验结论:
式(I)化合物A晶型在25℃和80%RH下的吸湿增重为1.093%。
实施例7:式(I)化合物B晶型的引湿性研究
实验材料:
SMS DVS intrinsic动态水分吸附仪
实验方法:
取式(I)化合物B晶型(10~30mg)置于DVS样品盘内进行测试。
实验结果:
式(I)化合物B晶型的DVS谱图如图8所示,ΔW=5.731%。
实验结论:
式(I)化合物B晶型在25℃和80%RH下的吸湿增重为5.731%。
实施例8:式(I)化合物的单晶X射线衍射检测分析
单晶培养过程:取10mg式(I)化合物加入2mL乙醇,搅拌至样品全部溶解,得到无色清液,将样品溶液置于4ml半密封样品瓶中,在室温下缓慢挥发。两周后得到无色针状晶体。收集晶体,用单晶X射线衍射仪(SC-XRD)(D8-VENTURE)收集衍射强度数据。单晶数据显示,可以确定式(I)化合物的绝对构型,该化合物的分子式为C19H22F2N6O4。式(I)化合物的立体结构椭球图见图9。式(I)化合物单晶的晶体结构数据见表8。
表8式(I)化合物单晶的晶体数据
实验例1:体内药效评价
1.实验目的:评价受试药在人乳腺癌细胞HCC1954细胞皮下异种移植肿瘤模型上的体内药效。
2.实验设计:
(1)细胞培养:人乳腺癌HCC1954细胞体外单层培养,相应培养基中加10%胎牛血清,100U/mL青霉素和100μg/mL链霉素,37℃5%CO2孵箱培养。一周两次进行常规处理传代。当细胞饱和度为80%-90%,数量达到要求时,收取细胞,计数,接种。
(2)动物:Balb/c nud,雌性,6~8周龄,体重18~20克。共需45只(包括分组剩余鼠)。由上海吉辉实验动物饲养有限公司或其他有资质的实验动物供应商提供
(3)肿瘤接种:将0.2mL(5×106个)HCC1954细胞(PBS:Matrixgel=1:1)皮下接种于每只小鼠的右后背,药效实验中肿瘤平均体积达到100-150mm3时开始分组给药。实验分组和给药方案见下表9。
表9动物实验分组和给药方案:
注:
1.N:每组小鼠数目
2.给药容积:根据小鼠体重10μL/g。如果体重下降超过15%,给药方案应做出相应调整。
3.QD:每天一次。
4.溶媒(Vehicle):10%二甲亚砜/10%聚乙二醇/80%水
动物分组:给药前称重动物,测量瘤体积。根据瘤体积随机分组(随机区组设计)。
实验指标:实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次(或隔天)用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b2,a和b分别表示肿瘤的长径和短径。
化合物的相对肿瘤抑制疗效用TGI(%)或相对肿瘤增殖率T/C(%)评价。
数据分析:T检验用于两组间比较。三组或多组间比较用one-way ANOVA。如果F值有显著性差异,应在ANOVA分析之后再进行多重比较。用SPSS或Graphpad Prism进行所有数据分析。p<0.05认为有显著性差异。
3.实验结果见表10。
表10式(I)化合物在小鼠HCC1954体内药效模型中的药效结果
结论:式(I)化合物在小鼠HCC1954体内药效模型中展示出了剂量依赖性的肿瘤生长抑制作用。
Claims (10)
- 式(I)化合物的A晶型,其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,8.74±0.20°,10.46±0.20°,
- 根据权利要求1所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,7.78±0.20°,8.74±0.20°,10.46±0.20°,18.48±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.25±0.20°,7.78±0.20°,8.74±0.20°,10.46±0.20°,14.99±0.20°,16.25±0.20°,17.50±0.20°,18.48±0.20°。
- 根据权利要求3所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.2511°,6.6532°,7.7817°,8.7418°,10.4626°,12.5958°,13.2601°,13.8718°,14.4446°,14.9927°,15.5346°,16.2492°,17.5047°,18.4752°,19.0069°,19.7791°,20.5468°,21.0093°,21.3325°,23.7228°,23.9609°,24.4579°,24.7921°,25.0236°,25.6910°,26.0008°,26.2926°,26.7249°,27.3381°,27.5777°,28.1708°,28.5699°。
- 根据权利要求1~4任意一项所述的A晶型,还具有以下任意一项或多项特征:(1)其XRPD图谱基本上如图1所示;(2)其差示扫描量热曲线分别在90.5±3.0℃和181.7±3.0℃处具有一个吸热峰的起始点;(3)其DSC图谱基本上如图2所示;(4)其热重分析曲线在110.0±3.0℃时失重达2.55%;(5)其TGA图谱基本上如图3所示;(6)其在25℃和80%RH下的吸湿增重为1.093%;(7)其DVS图谱基本上如图7所示。
- 式(I)化合物的B晶型,其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.48±0.20°,21.84±0.20°,24.90±0.20°,
- 根据权利要求6所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.48±0.20°,9.38±0.20°,13.25±0.20°,19.42±0.20°,21.84±0.20°,24.90±0.20°。
- 根据权利要求7所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.4752°,9.3771°,10.9011°,13.2511°,16.3529°,18.9134°,19.4248°,21.8375°,24.8988°,26.6143°,27.6851°。
- 根据权利要求6~8任意一项所述的B晶型,还具有以下任意一项或多项特征:(1)其XRPD图谱基本上如图4所示;(2)其差示扫描量热曲线在83.5±3.0℃处具有一个吸热峰的起始点;(3)其DSC图谱基本上如图5所示;(4)其热重分析曲线在135.0±3.0℃时失重达6.73%;(5)其TGA图谱基本上如图6所示;(6)其在25℃和80%RH下的吸湿增重为5.731%;(7)其DVS图谱基本上如图8所示。
- 根据权利要求1~5任意一项所述的A晶型或根据权利要求6~9任意一项所述的B晶型在制备治疗晚期实体瘤的药物上的应用。
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