WO2019109995A1 - 一种作为fgfr和vegfr抑制剂化合物的盐型、晶型及其制备方法 - Google Patents
一种作为fgfr和vegfr抑制剂化合物的盐型、晶型及其制备方法 Download PDFInfo
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a crystalline form as a FGFR and VEGFR inhibitor compound and a process for the preparation thereof.
- Fibroblast growth factor has been recognized as an important mediator of many physiological processes such as developmental morphogenesis and angiogenesis.
- the fibroblast growth factor receptor (FGFR) family is composed of four members (FGFR1-FGFR4), which are composed of extracellular immunoglobulin (Ig)-like domains, hydrophobic transmembrane regions, and regions including tyrosine kinases.
- Ig immunoglobulin
- the glycoprotein consisting of the cytoplasmic part.
- FGF binding results in FGFR dimerization followed by activation of receptor autophosphorylation and downstream signaling pathways. Receptor activation is sufficient to regenerate and activate specific downstream signaling partners involved in the regulation of diverse processes such as cell growth, cell metabolism, and cell survival.
- the FGF/FGFR signaling pathway has multiple effects in many biological processes critical for tumor cell proliferation, migration, invasion, and angiogenesis.
- Vinyl carbazoles are known in the field of cancer treatment, see WO 0210137 and WO2003101968.
- FGFR inhibitors are also known in the art, see WO 2002022598.
- the present invention provides a crystalline form A of a compound of formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.26 ⁇ 0.2 °, 10.47 ⁇ 0.2 °, 20.98 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above Form A has characteristic diffraction peaks at the following 2 theta angles: 5.26 ⁇ 0.2 °, 7.65 ⁇ 0.2 °, 10.47 ⁇ 0.2 °, 19.74 ⁇ 0.2 °, 20.33 ⁇ 0.2 °, 20.98 ⁇ 0.2 °, 26.30 ⁇ 0.2 °, 26.91 ⁇ 0.2 °.
- the XRPD pattern analysis data of the above A crystal form is as shown in Table 1:
- the differential scanning calorimetry curve of the above A crystal form has a starting point of one endothermic peak at 42.97 ° C ⁇ 3 ° C, 139.63 ° C ⁇ 3 ° C and 203.56 ° C ⁇ 3 ° C, respectively, at 147.45 The starting point of one exothermic peak at °C ⁇ 3 °C.
- the DSC pattern of the above Form A is shown in Figure 2.
- thermogravimetric analysis curve of the above A crystal form has a weight loss of 7.074% at 120.00 ° C ⁇ 3 ° C, and a weight loss of 0.4317% at 212.99 ° C ⁇ 3 ° C.
- the TGA pattern of the above Form A is shown in Figure 3.
- the present invention provides a crystalline form B of a compound of formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 11.10 ⁇ 0.2 °, 18.00 ⁇ 0.2 °, 19.84 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.31 ⁇ 0.2°, 11.10 ⁇ 0.2°, 11.73 ⁇ 0.2°, 13.94 ⁇ 0.2°, 14.77 ⁇ 0.2 °, 16.52 ⁇ 0.2 °, 18.00 ⁇ 0.2 °, 19.84 ⁇ 0.2 °.
- the XRPD pattern of the above B crystal form is shown in FIG.
- the XRPD pattern analysis data of the above B crystal form is as shown in Table 2:
- the present invention provides a crystalline form C of a compound of formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 10.19 ⁇ 0.2 °, 22.84 ⁇ 0.2 °, 24.39 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 10.19 ⁇ 0.2°, 11.32 ⁇ 0.2°, 18.73 ⁇ 0.2°, 19.71 ⁇ 0.2°, 22.84 ⁇ 0.2 °, 24.39 ⁇ 0.2 °, 32.10 ⁇ 0.2 °, 34.02 ⁇ 0.2 °.
- the XRPD pattern of the above C crystal form is shown in FIG.
- the XRPD pattern analysis data of the above C crystal form is as shown in Table 3:
- the present invention provides a crystalline form of the compound of formula (I) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 8.04 ⁇ 0.2 °, 11.55 ⁇ 0.2 °, 24.06 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.04 ⁇ 0.2°, 11.55 ⁇ 0.2°, 14.92 ⁇ 0.2°, 15.46 ⁇ 0.2°, 18.04 ⁇ 0.2. °, 19.03 ⁇ 0.2 °, 22.52 ⁇ 0.2 °, 24.06 ⁇ 0.2 °.
- the XRPD pattern of the above D crystal form is shown in FIG.
- the XRPD pattern analysis data of the above D crystal form is as shown in Table 4:
- the present invention provides a crystalline form E of a compound of formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.30 ⁇ 0.2 °, 15.93 ⁇ 0.2 °, 18.79 ⁇ 0.2 °.
- the above-mentioned E crystal form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 5.30 ⁇ 0.2°, 10.62 ⁇ 0.2°, 11.16 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.93 ⁇ 0.2°, 17.33 ⁇ 0.2°, 18.79 ⁇ 0.2°, 32.16 ⁇ 0.2°.
- the above E crystal form has an XRPD pattern as shown in FIG.
- the XRPD pattern analysis data of the above E crystal form is as shown in Table 5:
- the present invention provides a compound of the formula (II),
- the present invention provides a crystalline form of Form F of a compound of formula (II), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 4.98 ⁇ 0.2 °, 7.49 ⁇ 0.2 °, 19.18 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above F crystal form has characteristic diffraction peaks at the following 2 theta angles: 4.98 ⁇ 0.2 °, 7.49 ⁇ 0.2 °, 9.82 ⁇ 0.2 °, 12.15 ⁇ 0.2 °, 17.27 ⁇ 0.2 °, 19.18 ⁇ 0.2 °, 20.10 ⁇ 0.2 °, 21.79 ⁇ 0.2 °.
- the XRPD pattern of the above F crystal form is shown in FIG.
- the XRPD pattern analysis data of the above F crystal form is as shown in Table 6:
- the differential scanning calorimetry curve of the above F crystal form has a starting point of one endothermic peak at 172.77 ° C ⁇ 3 ° C and 277.05 ° C ⁇ 3 ° C, respectively, at 284.37 ° C ⁇ 3 ° C The starting point of an exothermic peak.
- the DSC pattern of the above F crystal form is shown in FIG.
- thermogravimetric analysis curve of the above F crystal form loses 3.578% at 153.13 ° C ⁇ 3 ° C.
- the TGA pattern of the above F crystal form is shown in FIG.
- the present invention provides a crystalline form of G of the compound of formula (II), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 7.39 ⁇ 0.2 °, 19.07 ⁇ 0.2 °, 20.04 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above G crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.39 ⁇ 0.2°, 19.07 ⁇ 0.2°, 20.04 ⁇ 0.2°, 21.05 ⁇ 0.2°, 21.76 ⁇ 0.2 °, 25.64 ⁇ 0.2 °, 26.23 ⁇ 0.2 °, 27.16 ⁇ 0.2 °.
- the XRPD pattern of the above G crystal form is shown in FIG.
- the XRPD pattern analysis data of the above G crystal form is as shown in Table 7:
- the differential scanning calorimetry curve of the above G crystal form has a starting point of an endothermic peak at 278.70 ° C ⁇ 3 ° C, and a starting point of an exothermic peak at 285.46 ° C ⁇ 3 ° C.
- the DSC pattern of the above G crystal form is shown in FIG.
- thermogravimetric analysis curve of the above G crystal form loses 3.870% at 120 ° C ⁇ 3 ° C, and loses 1.170% at 221.76 ° C ⁇ 3 ° C.
- the TGA pattern of the above G crystal form is shown in FIG.
- the present invention provides a crystalline form of the compound of formula (II) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.95 ⁇ 0.2°, 7.30 ⁇ 0.2°, 19.01 ⁇ 0.2°.
- the X-ray powder diffraction pattern of the above H crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.2°, 7.30 ⁇ 0.2°, 11.99 ⁇ 0.2°, 14.36 ⁇ 0.2°, 16.66 ⁇ 0.2. °, 18.26 ⁇ 0.2 °, 19.01 ⁇ 0.2 °, 21.49 ⁇ 0.2 °.
- the XRPD pattern of the above H crystal form is shown in FIG.
- the XRPD pattern analysis data of the above H crystal form is as shown in Table 8:
- the differential scanning calorimetry curve of the above H crystal form has a starting point of one endothermic peak at 172.97 ° C ⁇ 3 ° C and 277.33 ° C ⁇ 3 ° C, respectively, at 283.38 ° C ⁇ 3 ° C The starting point of the exothermic peak.
- the DSC pattern of the above H crystal form is shown in FIG.
- thermogravimetric analysis curve of the above H crystal form loses 0.8819% at 120 ° C ⁇ 3 ° C, and loses 2.892% at 206.30 ° C ⁇ 3 ° C.
- the TGA pattern of the above H crystal form is shown in FIG.
- the present invention provides a compound of the formula (III),
- the present invention provides a crystalline form I of a compound of formula (III), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.73 ⁇ 0.2 °, 11.66 ⁇ 0.2 °, 19.51 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above Form I has characteristic diffraction peaks at the following 2 theta angles: 6.73 ⁇ 0.2 °, 11.66 ⁇ 0.2 °, 14.28 ⁇ 0.2 °, 14.99 ⁇ 0.2 °, 16.39 ⁇ 0.2 °, 19.51 ⁇ 0.2 °, 23.34 ⁇ 0.2 °, 25.61 ⁇ 0.2 °.
- the XRPD pattern of the above I crystalline form is shown in FIG.
- the XRPD pattern analysis data of the above I crystal form is as shown in Table 9:
- the differential scanning calorimetry curve of the above I crystal form has a starting point of one endothermic peak at 32.94 ° C ⁇ 3 ° C and 204.62 ° C ⁇ 3 ° C, respectively.
- the DSC pattern of the above I crystalline form is shown in FIG.
- thermogravimetric analysis curve of the above I crystal form loses 0.8601% at 85.39 ° C ⁇ 3 ° C, and loses 2.264% at 184.93 ° C ⁇ 3 ° C.
- the TGA pattern of the above Form I is shown in FIG.
- the present invention provides a compound of the formula (IV),
- the present invention provides a J crystal form of the compound of formula (IV), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 4.99 ⁇ 0.2 °, 11.32 ⁇ 0.2 °, 19.95 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above J crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.99 ⁇ 0.2°, 6.90 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.73 ⁇ 0.2°, 11.32 ⁇ 0.2 °, 14.41 ⁇ 0.2 °, 16.73 ⁇ 0.2 °, 19.95 ⁇ 0.2 °.
- the XRPD pattern of the above J crystal form is shown in FIG.
- the XRPD pattern analysis data of the above J crystal form is as shown in Table 10:
- the differential scanning calorimetry curve of the above J crystal form has a starting point of one endothermic peak at 33.34 ° C ⁇ 3 ° C and 194.84 ° C ⁇ 3 ° C, respectively.
- the DSC pattern of the above J crystal form is shown in FIG.
- thermogravimetric analysis curve of the above J crystal form loses 1.357% at 120 ° C ⁇ 3 ° C, and loses 0.8330% at 177.11 ° C ⁇ 3 ° C.
- the TGA pattern of the above J crystal form is shown in FIG.
- the present invention provides a process for the preparation of a crystalline form of a compound of formula (I), (II), (III) or (IV), which comprises separately adding a compound of formula (I), (II), (III) or (IV), respectively. It is obtained by heating or stirring or recrystallization in a solvent.
- the solvent is selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, ethyl acetate-ethanol, isopropanol or ethanol-water.
- the agitation temperature is from 35 °C to 45 °C.
- the beating time is from 12 hours to 36 hours.
- the weight ratio of the above compound to the solvent is from 1:10 to 1:15.
- the invention also provides a preparation method of the crystal form of the compound G of the formula (II), which comprises adding the compound of the formula (I) to ethanol, adding hydrochloric acid/ethyl acetate to the reaction bottle, heating and stirring, cooling to room temperature, filtering. Got it.
- the compound G of the formula (II) is heated at a temperature of from 85 ° C to 95 ° C.
- 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, combinations thereof with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
- rt stands for room temperature
- THF tetrahydrofuran
- NMP N-methylpyrrolidone
- MeSO 3 H stands for methanesulfonic acid
- DME ethylene glycol dimethyl ether
- DCM stands for dichloromethane
- Xphos stands for 2-bicyclohexylphosphine-2'4'6'-triisopropylbiphenyl
- EtOAc stands for ethyl acetate
- MeOH stands for methanol
- acetone stands for acetone
- 2-Me-THF 2-methyltetrahydrofuran
- IPA stands for isopropyl Alcohol
- m-CPBA stands for 3-chloroperoxybenzoic acid
- Pd(dppf)Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
- DIEA stands for N,N -diisopropy
- XRPD X-ray powder diffractometer
- Test method Approximately 10-20 mg samples were used for XRPD detection.
- DSC Differential Scanning Calorimeter
- Test method Take a sample (about 1mg) and put it in a DSC aluminum pot for testing. Heat the sample from 30 °C (room temperature) to 300 °C (or 350) at a heating rate of 10 °C/min under 50 mL/min N 2 . °C).
- TGA Thermal Gravimetric Analyzer
- Test method The sample (2-5 mg) was placed in a TGA platinum pot for testing, and the sample was heated from room temperature to 300 ° C or weight loss by 20% at a heating rate of 10 ° C / min under 25 mL / min N 2 .
- Test conditions Samples (10-15 mg) were placed in a DVS sample pan for testing.
- the hygroscopicity evaluation is classified as follows:
- Humidity classification Wet weight gain* deliquescence Absorb sufficient water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% Humidity 15%> ⁇ W% ⁇ 2% Slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
- the compound of the present invention has excellent FGFR1 kinase inhibitory activity and SNU-16 cell inhibitory activity, and can be used as a small molecule tyrosine kinase inhibitor; has an antitumor activity against cell proliferation and angiogenesis, and is excellent for anti-tumor activity. Mammals (including humans) have excellent effects.
- the solubility data of several salts of the present invention showed that the solubility of the hydrochloride in the aqueous phase was the largest, and the solubility of the three salts was similar in the simulated intestinal fluid and the simulated gastric juice; the solubility of the free base in the three biological media was good, but in the water Extremely difficult to dissolve.
- the G crystal form, the I crystal form, and the J crystal form have excellent stability under thermal stability and acceleration conditions, and slightly generate impurities under illumination conditions, and have good stability under light-shielding conditions.
- Figure 1 XRPD spectrum of Cu-K alpha radiation of the crystalline form of Compound A of formula (I).
- Figure 4 XRPD spectrum of Cu-K alpha radiation of Form B of Compound (I).
- Figure 5 XRPD spectrum of Cu-K alpha radiation of Form C of Compound (I).
- Figure 7 XRPD spectrum of Cu-K alpha radiation of Form E of Compound (I).
- Figure 8 XRPD spectrum of Cu-K alpha radiation of the crystalline form of Compound F of formula (II).
- Figure 11 XRPD spectrum of Cu-K ⁇ radiation of the compound G crystal form of formula (II).
- Figure 14 XRPD spectrum of Cu-K alpha radiation of the compound H crystal form of formula (II).
- Figure 17 XRPD pattern of Cu-K alpha radiation of Form I of Formula (III).
- Figure 21 XRPD spectrum of Cu-K alpha radiation of Compound J form of Formula (IV).
- Example 1A To a solution of Example 1A (20 g, 120 mmol) of trimethyl orthoformate (400 ml) was slowly added dropwise with formic acid (40 ml) at 0 ° C, stirring at this temperature for 30 minutes, then dripping Concentrated sulfuric acid (1.2 ml) was added, and the dropwise addition was completed. The mixture was heated to 50 ° C for 30 minutes, and then cooled to 25 ° C for 3 hours. After cooling to room temperature, it was added to water (100 ml), EtOAc (EtOAc (EtOAc) Concentration in vacuo gave Example 1B which was used directly in the next step.
- formic acid 40 ml
- Concentrated sulfuric acid 1.2 ml
- Example 1B To a solution of Example 1B (8 g, 38 mmol) in tetrahydrofuran (120 mL), EtOAc (EtOAc, EtOAc) Stir under 1 hour. It was quenched with water (4 ml), EtOAc (EtOAc)EtOAc.
- Example 1C To a solution of Example 1C (5 g, 27 mmol) m. After cooling to room temperature, it was filtered and evaporated in vacuo.
- Example 1D To a solution of Example 1D (2.7 g, 5 mmol) in tetrahydrofuran (80 mL), sodium hydrogen (600 mg, 60%, 14.5 mmol) was added portionwise at 5 ° C under nitrogen. After stirring for 30 minutes, Example 1J (2 g, 10.6 mmol) was added, followed by heating to 70 ° C and stirring for 16 hours. After cooling to room temperature, it was poured into ice water (50 ml), EtOAc (EtOAc m. Filtration, concentration in vacuo, and the residue was purified by column chromatography.
- EtOAc EtOAc
- Example 1E 900 mg, 1.53 mmol
- acetone 4 ml
- water 4 ml
- p-toluenesulfonic acid 291 mg, 1.53 mmol
- Example 1H To a solution of Example 1H (748 mg, 1.63 mmol) in dichloromethane (12 mL), EtOAc (m. , 1.63 mmol, DMAP (20 mg, 0.16 mmol), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, the pH was adjusted to about 7 with 1M hydrochloric acid, and extracted with dichloromethane (20 mL EtOAc). Purification by silica gel column chromatography to give Example 1I as a yellow solid. LCMS (ESI) m / z: 559 [M + 1] +.
- Example 1J 50 mg, 90 ⁇ mol
- tetrahydro-2hydro-pyran-4-amine 18 mg, 180 ⁇ mol
- 1,2-dichloroethane 2.5 mL
- acetic acid about 0.1 ml
- Sodium cyanoborohydride (12 mg, 180 ⁇ mol) was added to the reaction mixture at room temperature, stirring was continued for 1 hour, water (5 ml) was added, and dichloromethane (20 ml x 3) was added for extraction. Washed with brine (20 ml), dried over sodium sulfate, filtered and evaporated. Solid samples were used for chiral column resolution to give Example 1K-R configuration (8 mg), Example 1K-S configuration (8 mg).
- Chiral column method chiral column, Chiralcel OJ-H 250 ⁇ 4.6 mm ID, 5 ⁇ m; mobile phase, methanol (0.05% DEA (diethylamine))-CO 2 from 5% to 40%; flow rate, 2.35 mL/ Min; wavelength, 280 nm.
- Example 1K-S 15 mg, 23 [mu]mol
- methanol 1 ml
- methanol 3 ml
- the reaction solution was stirred at 40 ° C for 3 hours.
- the solution was removed in vacuo to give Example 1L.
- Example 1K-R configuration 15 mg, 23 micromoles
- methanol 1 mL
- acetyl chloride 1 mL
- methanol 3 mL
- Example 1 was obtained by vacuum removal of the solution.
- Example 1 was dissolved in methanol, and the mixture was dissolved with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane.
- Example 1 The solution of Example 1 was dissolved in methanol, and the mixture was separated with a saturated aqueous solution of sodium hydrogencarbonate. The organic phase was evaporated and evaporated. XRPD detects its crystalline form to give Form A of the compound of formula (I).
- the reference solution STD-1 was diluted 1, 5, 10, 100 and 1000 times, and recorded as a linear solution L1, L2, L3, L4, L5.
- the solubility of the compounds of formula (I) and their salts in four different pH media is tested.
- About 10 mg of the compound of the formula (I) to (IV) were weighed separately, and then 5.0 mL of different media (water, SGF, FaSSIF, FeSSIF) were separately added and mixed to form a suspension.
- the magnetons were added to the above suspension and placed on a magnetic stirrer for stirring. After stirring for 2 hrs, 4 hrs and 24 hrs, the sample was centrifuged, and the remaining solid sample of the lower layer was measured for XRPD, and the concentration of the upper layer was determined by HPLC and the pH was measured.
- Tables 12 and 13 The solubility results are shown in Tables 12 and 13.
- FaSSIF 1. Weigh 0.042g sodium hydroxide, 0.3438g sodium dihydrogen phosphate and 0.6186g sodium chloride, add 90mL pure water and mix well, adjust the pH to 6.5 with 1N hydrochloric acid or 1N sodium hydroxide to make up with pure water. To 100 mL, 2. Take 50 mL of the above buffer and add 0.224 g of FaSSIF/FeSSIF/FaSSGF commercial powder (Biorelevant.com), stir until dissolved, and dilute to 100 mL with purified water. Place the configured buffer at room temperature. After standing for two hours, observe that the buffer is slightly milky white and ready to use.
- FeSSIF 1. Weigh 0.404g sodium hydroxide, 0.865g glacial acetic acid, 1.1874g sodium chloride, add 90mL pure water, mix well, adjust the pH to 5.0 with 1N hydrochloric acid or 1N sodium hydroxide to 100mL with pure water. 2. Take 50 mL of the above buffer and add 1.12 g of FaSSIF/FeSSIF/FaSSGF commercial powder (Biorelevant.com), stir until dissolved, and dilute to 100 mL with purified water. Place the configured buffer at room temperature and observe that the buffer is a clear liquid after standing for two hours.
- FaSSGF FaSSGF (SGF): 1. Weigh 0.2g of sodium chloride and add 90mL of purified water to mix well. Adjust the pH to 1.8 with 1N hydrochloric acid to 100mL with pure water, and let it stand at room temperature.
- the light sample was placed in the bottom of a 40 ml glass vial, which was placed vertically in the light box.
- the total illuminance is 1.2x10 6 Lux.hr near UV 200w.hr/m 2 After sampling, it is stored in a refrigerator at -20 ° C for analysis.
- the compounds were examined under the following conditions and samples were taken at different time points to examine physical properties, HPLC analysis of the contents and total impurities.
- the research conditions and test items are shown in Tables 14 to 16 below.
- the Form I of the compound of the formula (III) has a wet weight gain of 2.134% at 25 ⁇ 1 ° C and 80 ⁇ 2% RH, and is hygroscopic.
- the J crystal form of the compound of the formula (IV) has a wet weight gain of 5.229% at 25 ⁇ 1 ° C and 80 ⁇ 2% RH, and is hygroscopic.
- Reaction buffer 50 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.01% Brij-35, 1 mM DTT, 2 mM MnCl 2
- reaction buffer 50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% BRIJ-35, 1 mM EGTA, 4 mM MnCl 2 , 2 mM DTT.
- the reaction plate was placed in a 23 ° C incubator for 60 min.
- the compounds of the present invention have a significant inhibitory effect on FGFR1.
- TGI Tumor growth inhibition
- the evolutionary growth potential of tumors was evaluated by the relationship between tumor volume and time.
- the long axis (L) and the short axis (W) of the subcutaneous tumor were measured twice a week by a caliper, and the volume of the tumor (TV) was calculated by the formula ((LxW 2 )/2).
- TGI was calculated from the median value of the tumor volume of the solvent group mice and the difference in the tumor volume of the drug group mice, expressed as a percentage of the tumor volume in the solvent control group.
- %TGI ((intermediate tumor volume (control)-intermediate tumor volume (administered group))/intermediate tumor volume (control group)) x100
- the compound of the present invention has excellent FGFR1 kinase inhibitory activity in vitro and can be used as a small molecule tyrosine kinase inhibitor; it has excellent antitumor activity against cell proliferation and angiogenesis, and is useful for treating various mammals (including humans). Have excellent results.
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Abstract
本发明公开了一类作为FGFR和VEGFR抑制剂化合物的盐型、晶型、制备方法及其医药用途。
Description
相关申请的引用
本申请主张如下优先权:
CN201711286398.X,申请日2017-12-07。
本发明涉及一种作为FGFR和VEGFR抑制剂化合物的晶型及其制备方法。
成纤维细胞生长因子(FGF)已经被公认为如发育期形态发生和血管形成的许多生理学过程的重要媒介。成纤维细胞生长因子受体(FGFR)家族是由四个成员(FGFR1-FGFR4)组成,其为由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞质部分所组成的糖蛋白。FGF结合导致FGFR二聚化,随后为受体自体磷酸化和下游信号通路的激活。受体活化足以复元和活化参与如细胞生长、细胞新陈代谢和细胞存活的多元化过程调控的特定下游信号伙伴。因此,在对于肿瘤细胞增殖、迁移、入侵和血管形成关键性的许多生物过程中,该FGF/FGFR信号通路具有多效应作用。
乙烯基吲唑类在癌症治疗领域是已知的,参见WO 0210137和WO2003101968。FGFR抑制剂在此领域中也是已知的,参见WO 2002022598。
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:5.26±0.2°,10.47±0.2°,20.98±0.2°。
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:5.26±0.2°,7.65±0.2°,10.47±0.2°,19.74±0.2°,20.33±0.2°,20.98±0.2°,26.30±0.2°,26.91±0.2°。
本发明的一些方案中,上述A晶型的XRPD图谱如图1所示。
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衍射数据
本发明的一些方案中,上述A晶型的差示扫描量热曲线在42.97℃±3℃、139.63℃±3℃和203.56℃±3℃处分别具有1个吸热峰的起始点,在147.45℃±3℃处具有1个放热峰的起始点。
本发明的一些方案中,上述A晶型的DSC图谱如图2所示。
本发明的一些方案中,上述A晶型的热重分析曲线在120.00℃±3℃时失重达7.074%,在212.99℃±3℃时又失重0.4317%。
本发明的一些方案中,上述A晶型的TGA图谱如图3所示。
本发明提供了式(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:11.10±0.2°,18.00±0.2°,19.84±0.2°。
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:9.31±0.2°,11.10±0.2°,11.73±0.2°,13.94±0.2°,14.77±0.2°,16.52±0.2°,18.00±0.2°,19.84±0.2°。
本发明的一些方案中,上述B晶型的XRPD图谱如图4所示。
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衍射数据
本发明提供了式(Ⅰ)化合物的C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:10.19±0.2°,22.84±0.2°,24.39±0.2°。
本发明的一些方案中,上述C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:10.19±0.2°,11.32±0.2°,18.73±0.2°,19.71±0.2°,22.84±0.2°,24.39±0.2°,32.10±0.2°,34.02±0.2°。
本发明的一些方案中,上述C晶型的XRPD图谱如图5所示。
本发明的一些方案中,上述C晶型的XRPD图谱解析数据如表3所示:
表3式(Ⅰ)化合物C晶型的XRPD衍射数据
本发明提供了式(Ⅰ)化合物的D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:8.04±0.2°,11.55±0.2°,24.06±0.2°。
本发明的一些方案中,上述D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:8.04±0.2°,11.55±0.2°,14.92±0.2°,15.46±0.2°,18.04±0.2°,19.03±0.2°,22.52±0.2°,24.06±0.2°。
本发明的一些方案中,上述D晶型的XRPD图谱如图6所示。
本发明的一些方案中,上述D晶型的XRPD图谱解析数据如表4所示:
表4式(Ⅰ)化合物D晶型的XRPD衍射数据
本发明提供了式(Ⅰ)化合物的E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:5.30±0.2°,15.93±0.2°,18.79±0.2°。
本发明的一些方案中,上述E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:5.30±0.2°,10.62±0.2°,11.16±0.2°,14.47±0.2°,15.93±0.2°,17.33±0.2°,18.79±0.2°,32.16±0.2°。
本发明的一些方案中,上述E晶型,其XRPD图谱如图7所示。
本发明的一些方案中,上述E晶型的XRPD图谱解析数据如表5所示:
表5式(Ⅰ)化合物E晶型的XRPD衍射数据
本发明提供了式(Ⅱ)所示化合物,
本发明提供了式(Ⅱ)化合物的F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:4.98±0.2°,7.49±0.2°,19.18±0.2°。
本发明的一些方案中,上述F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:4.98±0.2°,7.49±0.2°,9.82±0.2°,12.15±0.2°,17.27±0.2°,19.18±0.2°,20.10±0.2°,21.79±0.2°。
本发明的一些方案中,上述F晶型的XRPD图谱如图8所示。
本发明的一些方案中,上述F晶型的XRPD图谱解析数据如表6所示:
表6式(Ⅱ)化合物F晶型的XRPD衍射数据
本发明的一些方案中,上述F晶型的差示扫描量热曲线在172.07℃±3℃、277.05℃±3℃处分别有1个吸热峰的起始点,在284.37℃±3℃处有一个放热峰的起始点。
本发明的一些方案中,上述F晶型的DSC图谱如图9所示。
本发明的一些方案中,上述F晶型的热重分析曲线在153.13℃±3℃时失重达3.578%。
本发明的一些方案中,上述F晶型的TGA图谱如图10所示。
本发明提供了式(Ⅱ)化合物的G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:7.39±0.2°,19.07±0.2°,20.04±0.2°。
本发明的一些方案中,上述G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:7.39±0.2°,19.07±0.2°,20.04±0.2°,21.05±0.2°,21.76±0.2°,25.64±0.2°,26.23±0.2°,27.16±0.2°。
本发明的一些方案中,上述G晶型的XRPD图谱如图11所示。
本发明的一些方案中,上述G晶型的XRPD图谱解析数据如表7所示:
表7式(Ⅱ)化合物G晶型的XRPD衍射数据
本发明的一些方案中,上述G晶型的差示扫描量热曲线在278.70℃±3℃处有吸热峰的起始点,在285.46℃±3℃处有放热峰的起始点。
本发明的一些方案中,上述G晶型的DSC图谱如图12所示。
本发明的一些方案中,上述G晶型的热重分析曲线在120℃±3℃时失重达3.870%,在221.76℃±3℃时又失重1.170%。
本发明的一些方案中,上述G晶型的TGA图谱如图13所示。
本发明提供了式(Ⅱ)化合物的H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:4.95±0.2°,7.30±0.2°,19.01±0.2°。
本发明的一些方案中,上述H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:4.95±0.2°,7.30±0.2°,11.99±0.2°,14.36±0.2°,16.66±0.2°,18.26±0.2°,19.01±0.2°,21.49±0.2°。
本发明的一些方案中,上述H晶型的XRPD图谱如图14所示。
本发明的一些方案中,上述H晶型的XRPD图谱解析数据如表8所示:
表8式(Ⅱ)化合物H晶型的XRPD衍射数据
本发明的一些方案中,上述H晶型的差示扫描量热曲线在172.97℃±3℃、277.33℃±3℃处分别有1个吸热峰的起始点,在283.38℃±3℃处有放热峰的起始点。
本发明的一些方案中,上述H晶型的DSC图谱如图15所示。
本发明的一些方案中,上述H晶型的热重分析曲线在120℃±3℃时失重达0.8819%,在206.30℃±3℃时又失重2.892%。
本发明的一些方案中,上述H晶型的TGA图谱如图16所示。
本发明提供了式(Ⅲ)所示化合物,
本发明提供了式(Ⅲ)化合物的I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:6.73±0.2°,11.66±0.2°,19.51±0.2°。
本发明的一些方案中,上述I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:6.73±0.2°,11.66±0.2°,14.28±0.2°,14.99±0.2°,16.39±0.2°,19.51±0.2°,23.34±0.2°,25.61±0.2°。
本发明的一些方案中,上述I晶型的XRPD图谱如图17所示。
本发明的一些方案中,上述I晶型的XRPD图谱解析数据如表9所示:
表9式(Ⅱ)化合物I晶型的XRPD衍射数据
本发明的一些方案中,上述I晶型的差示扫描量热曲线在32.94℃±3℃、204.62℃±3℃处分别有1个吸热峰的起始点。
本发明的一些方案中,上述I晶型的DSC图谱如图18所示。
本发明的一些方案中,上述I晶型的热重分析曲线在85.39℃±3℃时失重0.8601%,在184.93℃±3℃时又失重2.264%。
本发明的一些方案中,上述I晶型的TGA图谱如图19所示。
本发明提供了式(Ⅳ)所示化合物,
本发明提供了式(Ⅳ)化合物的J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:4.99±0.2°,11.32±0.2°,19.95±0.2°。
本发明的一些方案中,上述J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:4.99±0.2°,6.90±0.2°,9.9±0.2°,10.73±0.2°,11.32±0.2°,14.41±0.2°,16.73±0.2°,19.95±0.2°。
本发明的一些方案中,上述J晶型的XRPD图谱如图21所示。
本发明的一些方案中,上述J晶型的XRPD图谱解析数据如表10所示:
表10式(Ⅳ)化合物J晶型的XRPD衍射数据
本发明的一些方案中,上述J晶型的差示扫描量热曲线在33.34℃±3℃、194.84℃±3℃处分别有1个吸热峰的起始点。
本发明的一些方案中,上述J晶型的DSC图谱如图22所示。
本发明的一些方案中,上述J晶型的热重分析曲线在120℃±3℃时失重1.357%,在177.11℃±3℃时又失重0.8330%。
本发明的一些方案中,上述J晶型的TGA图谱如图23所示。
本发明提供了式(Ⅰ)、(Ⅱ)、(Ⅲ)或(Ⅳ)化合物晶型的制备方法,包括分别独立地将式(Ⅰ)、(Ⅱ)、(Ⅲ)或(Ⅳ)化合物加入到溶剂中加热搅拌或重结晶制得。
本发明的一些方案中,上述溶剂选自:甲醇、乙醇、丙酮、四氢呋喃、乙酸乙酯、乙酸乙酯-乙醇、异丙醇或乙醇-水。
本发明的一些方案中,上述搅拌温度为35℃~45℃。
本发明的一些方案中,上述打浆时间为12小时~36小时。
本发明的一些方案中,上述化合物与溶剂的重量比为1:10~1:15。
本发明还提供了式(Ⅱ)化合物G晶型的制备方法,包括将式(Ⅰ)化合物加入到乙醇中,将盐酸/乙酸乙酯滴加到反应瓶中加热搅拌,降温到室温,过滤制得。
本发明的一些方案中,上述式(Ⅱ)化合物G晶型加热搅拌温度为85℃~95℃。
本发明的一些方案中,上述化合物及其晶型在制备治疗酪氨酸激酶抑制剂相关病症的药物上的应用。
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。
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。
本发明采用下述缩略词:r.t.代表室温;THF代表四氢呋喃;NMP代表N-甲基吡咯烷酮;MeSO
3H代表甲烷磺酸;DME代表乙二醇二甲醚;DCM代表二氯甲烷;Xphos代表2-双环己基膦-2’4’6’-三异丙基联苯;EtOAc代表乙酸乙酯;MeOH代表甲醇;acetone代表丙酮;2-Me-THF代表2-甲基四氢呋喃;IPA代表异丙醇;m-CPBA代表3-氯过氧苯甲酸;Pd(dppf)Cl
2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯;;DIEA 代表N,N-二异丙基乙胺;DMSO代表二甲基亚砜;HEPES代表4-羟乙基哌嗪乙磺酸;EGTA代表乙二醇双(2-氨基乙基醚)四乙酸;THP代表四氢吡喃基。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:布鲁克D8 advance X-射线衍射仪
测试方法:大约10~20mg样品用于XRPD检测。
详细的XRPD参数如下:
光管电压:40kV,光管电流:40mA
发散狭缝:0.60mm
探测器狭缝:10.50mm
防散射狭缝:7.10mm
扫描范围:4-40deg
步径:0.02deg
步长:0.12秒
样品盘转速:15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:TA Q2000差示扫描量热仪
测试方法:取样品(约1mg)置于DSC铝锅内进行测试,在50mL/min N
2条件下,以10℃/min的升温速率,加热样品从30℃(室温)到300℃(或350℃)。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TA Q5000IR热重分析仪
测试方法:取样品(2~5mg)置于TGA铂金锅内进行测试,在25mL/min N
2条件下,以10℃/min的升温速率,加热样品从室温到300℃或失重20%。
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)
仪器型号:SMS DVS Advantage动态蒸汽吸附仪
测试条件:取样品(10~15mg)置于DVS样品盘内进行测试。
详细的DVS参数如下:
温度:25℃
平衡:dm/dt=0.01%/min(最短:10min,最长:180min)
干燥:0%RH下干燥120min
RH(%)测试梯级:10%
RH(%)测试梯级范围:0%-90%-0%
引湿性评价分类如下:
引湿性分类 | 引湿增重* |
潮解 | 吸收足量水分形成液体 |
极具引湿性 | ΔW%≥15% |
有引湿性 | 15%>ΔW%≥2% |
略有引湿性 | 2%>ΔW%≥0.2% |
无或几乎无引湿性 | ΔW%<0.2% |
*在25±1℃和80±2%RH下的引湿增重。
高效液相色谱(High Performance Liquid Chromatograph,HPLC)
化合物含量分析方法的色谱条件参见表11。
表11 HPLC分析含量测定方法
技术效果
本发明化合物优异的体外FGFR1激酶抑制活性和SNU-16细胞抑制活性,可以作为小分子的络氨酸激酶抑制剂;具有抑制细胞增殖及血管生成,具有优良的抗肿瘤活性,对用于治疗各种哺乳动物(包括人类)有优良的效果。
本发明几种盐溶解度数据显示,在水相中盐酸盐溶解度最大,在模拟肠液和模拟胃液中,三种盐的溶解度接近;游离碱在三种生物媒介中溶解性均较好,但水中极难溶解。G晶型、I晶型和J晶型热稳定性和加速条件下稳定性优异,光照条件下略有杂质生成,避光条件下稳定性良好。
图1:式(Ⅰ)化合物A晶型的Cu-Kα辐射的XRPD谱图。
图2:式(Ⅰ)化合物A晶型的DSC谱图。
图3:式(Ⅰ)化合物A晶型的TGA谱图。
图4:式(Ⅰ)化合物B晶型的Cu-Kα辐射的XRPD谱图。
图5:式(Ⅰ)化合物C晶型的Cu-Kα辐射的XRPD谱图。
图6:式(Ⅰ)化合物D晶型的Cu-Kα辐射的XRPD谱图。
图7:式(Ⅰ)化合物E晶型的Cu-Kα辐射的XRPD谱图。
图8:式(Ⅱ)化合物F晶型的Cu-Kα辐射的XRPD谱图。
图9:式(Ⅱ)化合物F晶型的DSC谱图。
图10:式(Ⅱ)化合物F晶型的TGA谱图。
图11:式(Ⅱ)化合物G晶型的Cu-Kα辐射的XRPD谱图。
图12:式(Ⅱ)化合物G晶型的DSC谱图。
图13:式(Ⅱ)化合物G晶型的TGA谱图。
图14:式(Ⅱ)化合物H晶型的Cu-Kα辐射的XRPD谱图。
图15:式(Ⅱ)化合物H晶型的DSC谱图。
图16:式(Ⅱ)化合物H晶型的TGA谱图。
图17:式(Ⅲ)化合物I晶型的Cu-Kα辐射的XRPD谱图。
图18:式(Ⅲ)化合物I晶型的DSC谱图。
图19:式(Ⅲ)化合物I晶型的TGA谱图。
图20:式(Ⅲ)化合物I晶型的DVS等温线。
图21:式(Ⅳ)化合物J晶型的Cu-Kα辐射的XRPD谱图。
图22:式(Ⅳ)化合物J晶型的DSC谱图。
图23:式(Ⅳ)化合物J晶型的TGA谱图。
图24:式(Ⅳ)化合物J晶型的DVS等温线。
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。
实施例1的制备
实施例1A
0℃条件下,向6-甲酸甲酯-1-甲基吡啶(20克,0.13摩尔)的N,N-二甲基亚砜(200毫升)的溶液中加入碘单质(33.5克,0.13毫摩尔)和三氟乙酸(35.3毫升,0.4毫摩尔),搅拌1小时,然后升温到140℃下搅拌2.5小时。冷却到0℃后,饱和硫代硫酸钠溶液(30毫升)淬灭,搅拌30分钟,水层用乙酸乙酯(150毫升×3)萃取,结合有机层饱和食盐水(50毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过硅胶快速色谱法硅胶柱层析纯化纯化得到实施例1A。
1H NMR(400MHz,CHLOROFORM-d)ppm:10.14(s,1H),9.36(s,1H),8.47(dd,J=1.3,8.0Hz,1H),8.03(d,J=8.0Hz,1H),4.05-3.94(s,3H).
实施例1B
0℃条件下,向实施例1A(20克,120毫摩尔)的原甲酸三甲酯(400毫升)的溶液中,慢慢滴加甲酸(40毫升),该温度下搅拌30分钟,然后滴加浓硫酸(1.2毫升),滴加完成,升温到50℃搅拌30分钟,然后再降温到25℃搅拌3小时。冷却到室温,加到水(100毫升)中,水层用乙酸乙酯(200毫升×3)萃取,合并有机相,用饱和食盐水(100毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩得到实施例1B,直接用于下一步。
实施例1C
0℃氮气保护下,向实施例1B(8克,38毫摩尔)的四氢呋喃(120毫升)溶液中,分批加入四氢 铝锂(4.4克,114毫摩尔),加入完成之后,在该温度下搅拌1小时。用水(4.4毫升),15%氢氧化钠(4.4毫升)然后再加水(13.2毫升)淬灭,搅拌30分钟过滤,真空浓缩得到实施例1C,直接用于下一步。
实施例1D
向实施例1C(5克,27毫摩尔)的二氯甲烷(120毫升)溶液中,加入二氧化锰(19克,216毫摩尔),然后升温到40℃搅拌16小时。冷却到室温后,过滤,真空浓缩,残余物通过硅胶快速色谱法硅胶柱层析纯化得到实施例1D。
1H NMR(400MHz,CHLOROFORM-d)ppm 10.1(s,1H),9.04-9.13(m,1H),8.22(dd,J=2.01,8.03Hz,1H),7.75(d,J=8.03Hz,1H),5.44(s,1H),3.43(s,6H).
实施例1E
在5℃氮气保护下,向实施例1D(2.7克,5毫摩尔)的四氢呋喃(80毫升)溶液中分批加入钠氢(600毫克,60%,14.5毫摩尔),完成之后,该温度下搅拌30分钟,加入实施例1J(2克,10.6毫摩尔),然后加热到70℃搅拌16小时。冷却到室温后,倒入冰水(50毫升)中,水层用乙酸乙酯(40毫升×3)萃取,合并有机相,用饱和食盐水(20毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过柱层析纯化得到实施例1E。
此混合物通过手性HPLC拆分得到顺反异构体,手性柱:Chiralcel OD-3 150×4.6mm I.D.,3μm,流动相:乙醇(0.05%DEA)-CO
2,从5%到40%,流速:2.5mL/min,波长:220nm。
实施例1F
室温下,向实施例1E(900毫克,1.53毫摩尔)的丙酮(4毫升),水(4毫升)混合溶液中,加入一水合对甲苯磺酸(291毫克,1.53毫摩尔),反应液加热至50℃搅拌10小时。反应完毕,加入水(4毫升),加入二氯甲烷(30毫升x3)萃取,合并有机相,用饱和食盐水(20毫升)洗涤,并用硫酸钠干燥,过滤并蒸发得到实施例1F,为黄色固体。LCMS(ESI)m/z:541[M+1]
+.
实施例1G
氮气保护下,室温向实施例1F(850毫克,1.57毫摩尔)的甲醇(8毫升)溶液中,分批加入硼氢化钠(119毫克,3.14毫摩尔),搅拌1小时。加入水(30毫升)淬灭,加入乙酸乙酯(40毫升x3)萃取,有机相合并用饱和食盐水(20毫升)洗涤,并用硫酸钠干燥,过滤并蒸发,得到实施例1G,为黄色液体。LCMS(ESI)m/z:543[M+1]
+.
实施例1H
室温氮气保护下,往实施例1G(900毫克,粗品)的甲醇(2毫升)溶液中,加入新鲜配制的乙酰氯(2毫升),甲醇(6毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即为实施例1H,为黄色固体。LCMS(ESI)m/z:459[M+1]
+.
实施例1I
室温氮气保护下,往实施例1H(748毫克,1.63毫摩尔)的二氯甲烷(12毫升)溶液中,加入三乙胺(495毫克,4.89毫摩尔),二碳酸二叔丁酯(356毫克,1.63毫摩尔),DMAP(20毫克,0.16毫摩尔),反应液在室温下搅拌30分钟。反应完毕,用1M盐酸调节pH至7左右,加入二氯甲烷(20毫升x3)萃取,有机相合并用饱和食盐水(20毫升)洗涤,并用硫酸钠干燥,过滤并蒸发,残余物通过快速色谱法硅胶柱层析纯化纯化得到实施例1I,为黄色固体。LCMS(ESI)m/z:559[M+1]
+.
实施例1J
室温下,往实施例1I(280毫克,0.5毫摩尔)的二氯甲烷(6毫升)溶液中,分批加入戴斯-马丁试剂(318.毫克,0.75毫摩尔),反应液在室温搅拌2个小时,反应完,反应液用冰水浴冷却,析出白色固体,过滤,滤液蒸干得实施例1J,为黄色固体。LCMS(ESI)m/z:557[M+1]
+.
实施例1K
室温下,往实施例1J(50毫克,90微摩尔),四氢化-2氢-吡喃-4胺(18毫克,180微摩尔)的1,2-二氯乙烷(2.5毫升)溶液中,加入醋酸(约0.1毫升)至pH为5左右,搅拌2个小时。氰基硼氢化钠(12毫克,180微摩尔)室温下加入到反应液中,继续搅拌1个小时,加入水(5毫升),加入二氯甲烷(20毫升x3)萃取,有机相合并用饱和食盐水(20毫升)洗涤,并用硫酸钠干燥,过滤并蒸发,残余物通过快速色谱法硅胶柱层析纯化得到实施例1K。固体样品用于手性柱拆分得到实施例1K-R构型(8毫克),实施例1K-S构型(8毫克)。
LCMS(ESI)m/z:642[M+1]
+.
手性柱方法:手性柱,Chiralcel OJ-H 250×4.6mm I.D.,5μm;流动相,甲醇(0.05%DEA(二乙胺))-CO
2从5%到40%;流速,2.35mL/min;波长,280nm。
实施例1L
室温氮气保护下,往实施例1K-S构型(15毫克,23微摩尔)(按照实施例1K的制备方法,放大200毫克规模的反应,得到1K-S构型产物15毫克)的甲醇(1毫升)溶液中,加入新鲜配置的乙酰氯(1毫升),甲醇(3毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即为实施例1L。LCMS(ESI)m/z:542[M+1]
+.
1H NMR(400MHz,METHANOL-d
4)ppm 9.04(s,1H),8.50(br.s.,2H),8.23(d,J=7.03Hz,1H),7.64(d,J=8.03Hz,1H),7.49(d,J=8.53Hz,1H),7.18-7.26(m,2H),7.04(s,2H),6.12(q,J=6.53Hz,1H),4.53(s,2H),4.08(dd,J=4.02,11.54Hz,2H),3.56-3.66(m,7H),2.15(d,J=11.04Hz,2H),1.83(d,J=6.53Hz,4H),1.18(t,J=7.03Hz,9H).
实施例1
如实施例1L中描述的方法,室温氮气保护下,往实施例1K-R构型(15毫克,23微摩尔)(放大200毫克规模的反应,得到1K-R构型产物15毫克)的甲醇(1毫升)溶液中,加入新鲜配置的乙酰氯(1毫升),甲醇(3毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即得到实施例1。LCMS(ESI)m/z:542[M+1]
+.
1H NMR(400MHz,METHANOL-d
4)ppm 8.95-9.12(m,1H),8.44-8.59(m,1H),8.25(br.s.,1H),7.68(br.s.,1H),7.51(d,J=8.78Hz,1H),7.25(d,J=15.06Hz,2H),6.91-7.10(m,1H),6.13(d,J=5.77Hz,1H),4.54(br.s.,2H),4.07(d,J=10.54Hz,2H),3.42-3.57(m,3H),2.15(d,J=10.79Hz,2H),1.83(m,5H).
将实施例1溶解到甲醇里,用饱和碳酸氢钠水溶液解离,二氯甲烷萃取后有机相旋干,得到式(Ⅰ)化合物。
实施例2:式(Ⅰ)化合物A晶型的制备
将实施例1溶解到甲醇里,用饱和碳酸氢钠水溶液解离,二氯甲烷萃取后有机相旋干,再加入少量甲醇打浆纯化,过滤后得到固体。XRPD检测其晶型状态,得到式(Ⅰ)化合物的A晶型。
实施例3:式(Ⅰ)化合物B晶型的制备
称取30mg式(Ⅰ)化合物加入玻璃瓶中,加入400μL甲醇,使其成悬浊液。将上述悬浊液样品置于磁力搅拌器上(40℃)进行避光搅拌试验。悬浊液样品在40℃下搅拌2天后离心,然后将残留样品置 于真空干燥箱中(40℃)干燥过夜,XRPD检测其晶型状态,得到式(Ⅰ)化合物的B晶型。
实施例4:式(Ⅰ)化合物C晶型的制备
称取30mg式(Ⅰ)化合物加入玻璃瓶中,加入400μL乙酸乙酯-乙醇(3:2),使其成悬浊液。将上述悬浊液样品置于磁力搅拌器上(40℃)进行避光搅拌试验。悬浊液样品在40℃下搅拌2天后离心,然后将残留样品置于真空干燥箱中(40℃)干燥过夜,XRPD检测其晶型状态,得到式(Ⅰ)化合物的C晶型。
实施例5:式(Ⅰ)化合物D晶型的制备
称取30mg式(Ⅰ)化合物加入玻璃瓶中,加入400μL丙酮,使其成悬浊液。将上述悬浊液样品置于磁力搅拌器上(40℃)进行避光搅拌试验。悬浊液样品在40℃下搅拌2天后离心,然后将残留样品置于真空干燥箱中(40℃)干燥过夜,XRPD检测其晶型状态,得到式(Ⅰ)化合物的D晶型。
实施例6:式(Ⅰ)化合物E晶型的制备
称取30mg式(Ⅰ)化合物加入玻璃瓶中,加入400μL异丙醇,使其成悬浊液。将上述悬浊液样品置于磁力搅拌器上(40℃)进行避光搅拌试验。悬浊液样品在40℃下搅拌2天后离心,然后将残留样品置于真空干燥箱中(40℃)干燥过夜,XRPD检测其晶型状态,得到式(Ⅰ)化合物的E晶型。
实施例7:式(Ⅱ)化合物的F晶型的制备
称取60mg式(Ⅰ)化合物加入到玻璃瓶中,加入磁子,置于磁力搅拌器上,加入1.8mL的乙酸乙酯加热到50℃使其溶清,然后缓慢加入适量的盐酸的乙醇(1.2mL)溶液(式(Ⅰ)化合物和酸的摩尔比为1:2);并观察现象,加入盐酸后,50℃下搅拌2小时后,室温搅拌过夜,有沉淀产生,离心。然后将残留样品置于真空干燥箱中(40℃)干燥,XRPD检测其晶型状态,得到式(Ⅱ)化合物的F晶型。
实施例8:式(Ⅱ)化合物G晶型的制备
称取30mg式(Ⅰ)化合物的盐酸盐(实施例1)加入玻璃瓶中,加入400μL的甲醇。将溶解样品快速离心,取上清液于离心管中,铝箔纸包扎管口,扎小孔,置于通风橱中挥发;将悬浊液样品置于磁力搅拌器上(40℃)搅拌(避光)。2天后快速离心分离,并将上清液置于通风橱中挥发干。收集上述离心所得残留样品及挥发所得的固体置于30℃真空干燥箱中干燥过夜,XRPD检测其晶型状态,得到式(Ⅱ)化合物的G晶型。
实施例9:式(Ⅱ)化合物G晶型的制备
将乙醇(1.25L)加入装有式(Ⅰ)化合物(41.7g)三口烧瓶(3L)中;反应液加热到90℃,将盐酸/乙酸乙酯(38.4mL)滴加到反应瓶中;在90℃条件下搅拌2小时后,将反应液降到室温搅拌20小时;将反应液过滤,得到的固体用0.1L的乙醇洗涤;最终得到的固体通过旋转蒸发仪(50℃,6小时)蒸掉含有的少量乙醇溶液;最终得到式(Ⅱ)化合物的G晶型。
实施例10:式(Ⅱ)化合物H晶型的制备
称取30mg式(Ⅰ)化合物的盐酸盐(实施例1)加入玻璃瓶中,加入400μL的乙醇。将溶解样品快速离心,取上清液于离心管中,铝箔纸包扎管口,扎小孔,置于通风橱中挥发;将悬浊液样品置于磁力搅拌器上(40℃)搅拌(避光)。2天后快速离心分离,并将上清液置于通风橱中挥发干。收集上述离心所得残留样品及挥发所得的固体置于30℃真空干燥箱中干燥过夜,XRPD检测其晶型状态,得到式(Ⅱ)化合物的H晶型。
实施例11:式(Ⅲ)化合物的I晶型的制备
称取60mg式(Ⅰ)化合物加入到玻璃瓶中,加入磁子,置于磁力搅拌器上,加入1.8mL的乙酸乙酯加热到50℃使其溶清,然后缓慢加入适量的柠檬酸的乙醇(1.2mL)溶液(式(Ⅰ)化合物和酸的摩尔比为1:2);并观察现象,加入盐酸后,50℃下搅拌2小时后,室温搅拌过夜,有沉淀产生,离心。然后将残留样品置于真空干燥箱中(40℃)干燥,XRPD检测其晶型状态,得到式(Ⅲ)化合物的I晶型。
实施例12:式(Ⅳ)化合物的J晶型的制备
称取60mg式(Ⅰ)化合物加入到玻璃瓶中,加入磁子,置于磁力搅拌器上,加入1.8mL的乙酸乙酯加热到50℃使其溶清,然后缓慢加入适量的L-苹果酸的乙醇(1.2mL)溶液(式(Ⅰ)化合物和酸的摩尔比为1:2);并观察现象,加入盐酸后,50℃下搅拌2小时后,室温搅拌过夜,有沉淀产生,离心。然后将残留样品置于真空干燥箱中(40℃)干燥,XRPD检测其晶型状态,得到式(Ⅳ)化合物的J晶型。
实验例1:式(Ⅰ)、(Ⅱ)、(Ⅲ)或(Ⅳ)化合物的溶解度试验
对照品溶液的制备(以式(Ⅰ)化合物作为对照样品)
称取式(Ⅰ)化合物大约5mg,准确称量,置于样品瓶中,加入乙腈10mL,超声5min,放冷至室温后混合均匀。平行配制2份,分别标记为STD-1和STD-2。
线性溶液的制备
将对照品溶液STD-1逐级稀释1,5,10,100和1000倍,记作线性溶液L1,L2,L3,L4,L5。
式(Ⅰ)化合物及其盐的溶解度试验
测试式(Ⅰ)化合物及其盐在4个不同pH媒介中的溶解度。分别称取大约10mg的式(Ⅰ)~(Ⅳ)化合物,然后分别加入5.0mL不同的媒介(水,SGF,FaSSIF,FeSSIF),混匀成混悬液。将磁子加入到上述混悬液中,置于磁力搅拌器上进行搅拌。搅拌2hrs,4hrs及24hrs后取样离心,下层残留固体样品测定XRPD,上层样品用HPLC测定其浓度并测定其pH值。溶解度结果见表12、13。
表12式(Ⅰ)、(Ⅱ)化合物在4种媒介中的溶解度试验结果
注:<LOQ代表低于检测限
·FaSSIF:1.称量0.042g氢氧化钠,0.3438g磷酸二氢钠和0.6186g氯化钠加入90mL纯净水混合均匀后,用1N盐酸或者1N氢氧化钠调pH=6.5用纯净水定容至100mL,2.取50mL上述缓冲液再加入0.224g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com),搅拌直至溶解,用纯净水定容至100mL。将配置的缓冲液放置室温,静止两小时后观察缓冲液为轻微的乳白色,即可使用。
·FeSSIF:1.称量0.404g氢氧化钠,0.865g冰乙酸,1.1874g氯化钠加入90mL纯净水混合均匀后,用1N盐酸或者1N氢氧化钠调pH=5.0用纯净水定容至100mL;2.取50mL上述缓冲液再加入1.12g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com),搅拌直至溶解,用纯净水定容至100mL。将配置的缓冲液放置室温,静止两小时后观察缓冲液为透明液体,即可使用。
·FaSSGF(SGF):1.称量0.2g氯化钠加入90mL纯净水混合均匀后,用1N盐酸调pH=1.8用纯净水定容至100mL,静止至室温.
表13式(Ⅲ)、(Ⅳ)化合物在4种媒介中的溶解度试验结果
结论:生物媒介中几种盐溶解度数据显示,在水相中盐酸盐溶解度最大,在模拟肠液和模拟胃液中,三种盐的溶解度接近;游离碱在三种生物媒介中溶解性均较好,但水中极难溶解。
实验例2:G晶型、I晶型和J晶型的固体稳定性试验
分别精确称量约10毫克G晶型、I晶型或J晶型置于40毫升玻璃样品瓶的底部,摊成薄薄的一层, 敞口样品用铝箔纸封瓶口,并在铝箔纸上扎些小孔,保证样品能与环境空气充分接触,密闭样品用瓶盖封闭,并缠上封口膜。每个条件时间点样品平行称量两份,并另外取适量样品(不称量)用于XRPD检测,准备好的样品于各条件下放置,分别于时间点到达后取样分析。0天对照品样品平行称量5份,密闭保存于-20℃的冰箱内等待分析。同样方法准备光照样品置于40毫升玻璃样品瓶的底部,玻璃瓶敞口竖放于光照箱。另外分别取适量两个样品做为避光样品,敞口竖放,玻璃瓶外用锡箔纸包裹。总照度1.2x10
6Lux.hr近紫外200w.hr/m
2照满后取样保存于-20℃的冰箱内等待分析。
考察化合物在如下条件放置并在不同的时间点取样检测物理性质,HPLC分析含量和总的杂质。研究条件和检测项目如下表14~16。
表14式(Ⅱ)化合物G晶型的固体稳定性试验
表15式(Ⅲ)化合物I晶型的固体稳定性试验
表16式(Ⅳ)化合物J晶型的固体稳定性试验
结论:影响因素和加速实验均显示,G晶型、I晶型和J晶型热稳定性和加速条件下稳定性优异,光照条件下略有杂质生成,避光条件下稳定性良好。
实验例3.式(Ⅲ)化合物的I晶型的的引湿性试验
实验材料:
SMS DVS Advantage动态蒸汽吸附仪
实验方法:
取式(Ⅲ)化合物的I晶型10~15mg置于DVS样品盘内进行测试。
实验结果:
式(Ⅲ)化合物的I晶型的DVS谱图如图20所示,△W=2.134%。
实验结论:
式(Ⅲ)化合物的I晶型在25±1℃和80±2%RH下的引湿增重为2.134%,有引湿性。
实验例4.式(Ⅳ)化合物的J晶型的的引湿性试验
实验材料:
SMS DVS Advantage动态蒸汽吸附仪
实验方法:
取式(Ⅳ)化合物的J晶型10~15mg置于DVS样品盘内进行测试。
实验结果:
式(Ⅳ)化合物的J晶型的DVS谱图如图24所示,△W=5.227%。
实验结论:
式(Ⅳ)化合物的J晶型在25±1℃和80±2%RH下的引湿增重为5.227%,有引湿性。
实验例5:本发明化合物的体外酶活性测试
实验目的:
通过Z′-LYTE
TM Detection Kinase Assay检测酶活性,以化合物的IC
50值为指标,来评价化合物对FGFR1的抑制作用。
实验材料:
FGFR1(Invitrogen#PV4105)
Tyr4(Invitrogen-PR5053U)
ATP(Sigma-A7699)
DMSO(Sigma cat#34869-100ML)
反应缓冲液:50mM Hepes(pH 7.5),10mM MgCl
2,1mM EGTA,0.01%Brij-35,1mM DTT,2mM MnCl
2
384反应板(Corning Costar 3573)
384化合物板(Greiner#781280)
Development reagent B(Invitrogen#PR5193D)
Development Buffer(Invitrogen#PR4876B)
离心机(Eppendorf#5810R)
电子加样枪(Eppendorf)
Multidrop液体工作站(ThermoScientific)
Bravo自动液体工作站(Agilent)
Envision(Perkin Elmer)
实验步骤和方法:
A.准备酶/底物混和液
0.6nM FGFR1,2μm Tyr4 peptide及10μm ATP于反应缓冲液(50mM Hepes,pH7.5,10mM MgCl
2,0.01%BRIJ-35,1mM EGTA,4mM MnCl
2,2mM DTT)。
B.化合物加样:
a.用DMSO将化合物稀释成10mM,3倍稀释,11个梯度,双复孔.
b.在Bravo自动液体工作站转移化合物1:25稀释到中间板中。然后再转移2.5ul至反应板中,保证DMSO终浓度为1%。
c.转移酶/底物缓冲液5μl于每孔中
d.使用Multidrop液体工作站依次加入ATP溶液到每孔中
e.1000rpm离心1分钟
f.将反应板放置于23℃恒温箱中反应60min。
C.显色反应实验:
a.配制1:128配制Development regent B与Development Buffer的混和液
b.于每孔加入5ul,1000rpm离心1分钟
c.离心后将反应板置于恒温箱(23℃)90分钟,取出后在Envision(Perkin Elmer)读板仪中读数
D.分析数据:使用XLFIT(IDBS)分析数据,计算化合物的IC
50值。
实验结果见表17:
表17 Z′-LYTE
TM检测IC
50测试结果
供试样品 | FGFR1 |
实施例1 | AAA |
注:50nM<A≤1μm,10nM<AA≤50nM,AAA≤10nM,N/A表示未测。
结论:本发明化合物对FGFR1的抑制作用显著。
实验例6:本发明化合物的肿瘤生长抑制(TGI)分析
肿瘤的演化生长势通过肿瘤体积与时间的关系来进行评价的。皮下肿瘤的长轴(L)和短轴(W)通过测径器每周测定两次,肿瘤的体积(TV)通过公式((LxW
2)/2)进行计算。TGI由溶剂组小鼠肿瘤体积的中值和药物组组小鼠肿瘤体积中值得差值来进行计算,以溶剂对照组肿瘤体积中值得百分比来表示,
通过下述公式进行计算:
%TGI=((中间肿瘤体积(对照)-中间肿瘤体积(给药组))/中间肿瘤体积(对照组))x100
原始统计分析是通过重复方差测定分析来完成。接下来通过Scheffe psot h℃实验方法进行多重比较。单独溶剂(0.5%甲基纤维素+0.2%吐温水溶液)为阴性对照。
实验结果见表18:
FGFR1/2高表达的人源肿瘤肝癌移植模型 | TGI%(末次给药) | |
实施例1 | 5mg/kg,BID | 85 |
本发明化合物优异的体外FGFR1激酶抑制活性,可以作为小分子的络氨酸激酶抑制剂;具有抑制细胞增殖及血管生成,具有优良的抗肿瘤活性,对用于治疗各种哺乳动物(包括人类)有优良的效果。
Claims (63)
- 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:5.26±0.2°,7.65±0.2°,10.47±0.2°,19.74±0.2°,20.33±0.2°,20.98±0.2°,26.30±0.2°,26.91±0.2°。
- 根据权利要求2所述的A晶型,其XRPD图谱如图1所示。
- 根据权利要求1~3任意一项所述的A晶型,其差示扫描量热曲线在42.97℃±3℃、139.63℃±3℃和203.56℃±3℃处分别具有1个吸热峰的起始点,在147.45℃±3℃处具有1个放热峰的起始点。
- 根据权利要求4所述的A晶型,其DSC图谱如图2所示。
- 根据权利要求1~3任意一项所述的A晶型,其热重分析曲线在120.00℃±3℃时失重达7.074%,在212.99℃±3℃时又失重0.4317%。
- 根据权利要求6所述的A晶型,其TGA图谱如图3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:11.10±0.2°,18.00±0.2°,19.84±0.2°。
- 根据权利要求8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:9.31±0.2°,11.10±0.2°,11.73±0.2°,13.94±0.2°,14.77±0.2°,16.52±0.2°,18.00±0.2°,19.84±0.2°。
- 根据权利要求9所述的B晶型,其XRPD图谱如图4所示。
- 式(Ⅰ)化合物的C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:10.19±0.2°,22.84±0.2°,24.39±0.2°。
- 根据权利要求11所述的C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:10.19±0.2°,11.32±0.2°、18.73±0.2°,19.71±0.2°,22.84±0.2°,24.39±0.2°,32.10±0.2°,34.02±0.2°。
- 根据权利要求12所述的C晶型,其XRPD图谱如图5所示。
- 式(Ⅰ)化合物的D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:8.04±0.2°,11.55±0.2°,24.06±0.2°。
- 根据权利要求14所述的D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:8.04±0.2°,11.55±0.2°,14.92±0.2°,15.46±0.2°,18.04±0.2°,19.03±0.2°,22.52±0.2°,24.06±0.2°。
- 根据权利要求15所述的D晶型,其XRPD图谱如图6所示。
- 式(Ⅰ)化合物的E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:5.30±0.2°,15.93±0.2°,18.79±0.2°。
- 根据权利要求17所述的E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:5.30±0.2°,10.62±0.2°,11.16±0.2°,14.47±0.2°,15.93±0.2°,17.33±0.2°,18.79±0.2°,32.16±0.2°。
- 根据权利要求18所述的E晶型,其XRPD图谱如图7所示。
- 式(Ⅱ)化合物的F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:4.98±0.2°,7.49±0.2°,19.18±0.2°。
- 根据权利要求21所述的F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:4.98±0.2°,7.49±0.2°,9.82±0.2°,12.15±0.2°,17.27±0.2°,19.18±0.2°,20.10±0.2°,21.79±0.2°。
- 根据权利要求22所述的F晶型,其XRPD图谱如图8所示。
- 根据权利要求21~23任意一项所述的F晶型,其差示扫描量热曲线在172.07℃±3℃、277.05℃±3℃处分别有1个吸热峰的起始点,在284.37℃±3℃处有一个放热峰的起始点。
- 根据权利要求24所述的F晶型,其DSC图谱如图9所示。
- 根据权利要求21~23任意一项所述的F晶型,其热重分析曲线在153.13℃±3℃时失重达3.578%。
- 根据权利要求26所述的F晶型,其TGA图谱如图10所示。
- 式(Ⅱ)化合物的G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:7.39±0.2°,19.07±0.2°,20.04±0.2°。
- 根据权利要求28所述的G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:7.39±0.2°,19.07±0.2°,20.04±0.2°,21.05±0.2°,21.76±0.2°,25.64±0.2°,26.23±0.2°,27.16±0.2°。
- 根据权利要求29所述的G晶型,其XRPD图谱如图11所示。
- 根据权利要求28~30任意一项所述的G晶型,其差示扫描量热曲线在278.70℃±3℃处有吸热峰的起始点,在285.46℃±3℃处有放热峰的起始点。
- 根据权利要求31所述的G晶型,其DSC图谱如图12所示。
- 根据权利要求28~30任意一项所述的G晶型,其热重分析曲线在120℃±3℃时失重达3.870%,在221.76℃±3℃时又失重1.170%。
- 根据权利要求33所述的G晶型,其TGA图谱如图13所示。
- 式(Ⅱ)化合物的H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:4.95±0.2°,7.30±0.2°,19.01±0.2°。
- 根据权利要求35所述的H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:4.95±0.2°,7.30±0.2°,11.99±0.2°,14.36±0.2°,16.66±0.2°,18.26±0.2°,19.01±0.2°,21.49±0.2°。
- 根据权利要求36所述的H晶型,其XRPD图谱如图14所示。
- 根据权利要求35~37任意一项所述的H晶型,其差示扫描量热曲线在172.97℃±3℃、277.33℃±3℃处分别有1个吸热峰的起始点,在283.38℃±3℃处有放热峰的起始点。
- 根据权利要求38所述的H晶型,其DSC图谱如图15所示。
- 根据权利要求35~37任意一项所述的H晶型,其热重分析曲线在120℃±3℃时失重达0.8819%,在206.30℃±3℃时又失重2.892%。
- 根据权利要求40所述的H晶型,其TGA图谱如图16所示。
- 式(Ⅲ)化合物的I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:6.73±0.2°,11.66±0.2°,19.51±0.2°。
- 根据权利要求43所述的I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:6.73±0.2°,11.66±0.2°,14.28±0.2°,14.99±0.2°,16.39±0.2°,19.51±0.2°,23.34±0.2°,25.61±0.2°。
- 根据权利要求44所述的I晶型,其XRPD图谱如图17所示。
- 根据权利要求43~45任意一项所述的I晶型,其差示扫描量热曲线在32.94℃±3℃、204.62℃±3℃处分别有1个吸热峰的起始点。
- 根据权利要求46所述的I晶型,其DSC图谱如图18所示。
- 根据权利要求43~45任意一项所述的I晶型,其热重分析曲线在85.39℃±3℃时失重0.8601%,在184.93℃±3℃时又失重2.264%。
- 根据权利要求48所述的I晶型,其TGA图谱如图19所示。
- 式(Ⅳ)化合物的J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:4.99±0.2°,11.32±0.2°,19.95±0.2°。
- 根据权利要求51所述的J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:4.99±0.2°,6.90±0.2°,9.9±0.2°,10.73±0.2°,11.32±0.2°,14.41±0.2°,16.73±0.2°,19.95±0.2°。
- 根据权利要求52所述的J晶型,其XRPD图谱如图21所示。
- 根据权利要求51~53任意一项所述的J晶型,其差示扫描量热曲线在33.34℃±3℃、194.84℃±3℃处分别有1个吸热峰的起始点。
- 根据权利要求54所述的J晶型,其DSC图谱如图22所示。
- 根据权利要求51~53任意一项所述的J晶型,其热重分析曲线在120℃±3℃时失重1.357%,在177.11℃±3℃时又失重0.8330%。
- 根据权利要求56所述的J晶型,其TGA图谱如图23所示。
- 式(Ⅰ)、(Ⅱ)、(Ⅲ)或(Ⅳ)化合物晶型的制备方法,包括分别独立地将式(Ⅰ)、(Ⅱ)、(Ⅲ)或(Ⅳ)化合物加入到溶剂中加热搅拌或重结晶制得。
- 根据权利要求58所述的制备方法,其中,溶剂选自:甲醇、乙醇、丙酮、四氢呋喃、乙酸乙酯、乙酸乙酯-乙醇、异丙醇或乙醇-水。
- 根据权利要求58所述的制备方法,其中,搅拌温度为35℃~45℃。
- 根据权利要求58所述的制备方法,其中,打浆时间为12小时~36小时。
- 根据权利要求58所述的制备方法,其中,化合物与溶剂的重量比为1:10~1:15。
- 根据权利要求20、42或50所述的化合物,或根据权利要求1~19、21~41、43~49或52~57任意一项所述的晶型在制备治疗酪氨酸激酶抑制剂相关病症的药物上的应用。
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WO2022033472A1 (zh) * | 2020-08-11 | 2022-02-17 | 河南迈英诺医药科技有限公司 | Fgfr抑制剂化合物及其用途 |
WO2024137742A1 (en) | 2022-12-20 | 2024-06-27 | Blueprint Medicines Corporation | Compounds and compositions as fgfr3 degraders and uses thereof |
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WO2021138391A1 (en) * | 2019-12-30 | 2021-07-08 | Tyra Biosciences, Inc. | Indazole compounds |
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CN100420687C (zh) * | 2002-12-20 | 2008-09-24 | 霍夫曼-拉罗奇有限公司 | 作为选择性kdr和fgfr抑制剂的吡啶并[2,3-d]嘧啶衍生物 |
UA96969C2 (en) * | 2006-12-21 | 2011-12-26 | Астразенека Аб | Acylaminopyrazoles as fgfr inhibitors |
GB201209613D0 (en) * | 2012-05-30 | 2012-07-11 | Astex Therapeutics Ltd | New compounds |
CN105906630B (zh) * | 2015-04-06 | 2018-10-23 | 四川百利药业有限责任公司 | 用作fgfr抑制剂的n-(1h-吡唑-5-基)嘧啶并吡唑-4,6-二取代胺类化合物 |
CN107137407B (zh) * | 2016-03-01 | 2021-07-27 | 江苏恒瑞医药股份有限公司 | 一种vegfr抑制剂在制备治疗胰腺癌的药物中的用途 |
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WO2002010137A2 (en) | 2000-07-31 | 2002-02-07 | Signal Pharmaceuticals, Inc. | Indazole derivatives as jnk inhibitors |
WO2002022598A1 (en) | 2000-09-11 | 2002-03-21 | Chiron Corporation | Quinolinone derivatives as tyrosine kinase inhibitors |
WO2003101968A1 (fr) | 2002-05-31 | 2003-12-11 | Eisai Co., Ltd. | Compose de pyrazole et composition medicinale le contenant |
WO2017024968A1 (zh) * | 2015-08-07 | 2017-02-16 | 南京明德新药研发股份有限公司 | 作为fgfr和vegfr抑制剂的乙烯基化合物 |
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WO2022033472A1 (zh) * | 2020-08-11 | 2022-02-17 | 河南迈英诺医药科技有限公司 | Fgfr抑制剂化合物及其用途 |
JP7511294B2 (ja) | 2020-08-11 | 2024-07-05 | ホーナン メディノ ファーマシューティカル テクノロジー カンパニー リミテッド | Fgfr阻害剤化合物及びその使用 |
WO2024137742A1 (en) | 2022-12-20 | 2024-06-27 | Blueprint Medicines Corporation | Compounds and compositions as fgfr3 degraders and uses thereof |
Also Published As
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CN116283940A (zh) | 2023-06-23 |
CN111448185A (zh) | 2020-07-24 |
US11078194B2 (en) | 2021-08-03 |
JP2021505625A (ja) | 2021-02-18 |
EP3722282A4 (en) | 2021-04-14 |
EP3722282A1 (en) | 2020-10-14 |
US20200361913A1 (en) | 2020-11-19 |
JP6974618B2 (ja) | 2021-12-01 |
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