WO2017114452A1 - 喹啉类化合物的盐，其晶型、制备方法、组合物与应用 - Google Patents

喹啉类化合物的盐，其晶型、制备方法、组合物与应用 Download PDF

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WO2017114452A1
WO2017114452A1 PCT/CN2016/112942 CN2016112942W WO2017114452A1 WO 2017114452 A1 WO2017114452 A1 WO 2017114452A1 CN 2016112942 W CN2016112942 W CN 2016112942W WO 2017114452 A1 WO2017114452 A1 WO 2017114452A1
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sph1772
ditartrate
salt
solvent
crystalline form
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PCT/CN2016/112942
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English (en)
French (fr)
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余建鑫
郝宇
张晶
赵菲
张乐多
刘振营
李供省
王余吉
陈娜
白蕊
范艺
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上海医药集团股份有限公司
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Priority to JP2018534625A priority Critical patent/JP6659850B2/ja
Priority to EP16881241.0A priority patent/EP3398951B1/en
Priority to ES16881241T priority patent/ES2877799T3/es
Priority to US16/067,144 priority patent/US10344035B2/en
Priority to DK16881241.0T priority patent/DK3398951T3/da
Publication of WO2017114452A1 publication Critical patent/WO2017114452A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • 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 salt of a quinoline compound, a crystal form, a preparation method, a composition and use thereof.
  • SPH1772 The compound 3-(1-methyl-1H-pyrazol-4-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3] Zizo[4,5-b]pyrazin-1-yl)methyl)quinoline, abbreviated as SPH1772 (structure shown below), which is disclosed in patent CN104109166A.
  • SPH1772 is a highly potent and selective research oral irreversible inhibitor of the hepatocyte growth factor (HGF) receptor tyrosine kinase c-Met.
  • HGF hepatocyte growth factor
  • SPH1772 is being developed to treat several solid tumors, including non-small cell lung cancer (NSCLC), liver cancer, colon and ovarian cancer, and various other cancers.
  • Polymorphism (the appearance of different crystal forms) is a property of certain molecular and molecular complexes. Single molecules may result in various polymorphs having different crystal structures and physical properties, such as melting point, thermal behavior (eg, by thermogravimetric analysis - "TGA”, or differential scanning calorimetry (DSC)) , X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint and solid state nuclear magnetic resonance (NMR) spectrum.
  • TGA thermogravimetric analysis - "TGA”
  • DSC differential scanning calorimetry
  • XRPD or powder XRD X-ray powder diffraction
  • NMR solid state nuclear magnetic resonance
  • the present invention provides a salt of a quinoline compound, a crystal form, a preparation method, a composition and use thereof.
  • the SPH1772 ditartrate or its crystal form A of the present invention can exhibit the following excellent properties: high stability, good bioavailability, excellent pharmacokinetic properties, and excellent in vivo efficacy over SPH1772 free base.
  • the present invention provides a ditartrate salt of a quinoline compound SPH1772,
  • the tartaric acid in the ditartrate of the quinoline compound SPH1772 is preferably L-tartaric acid (ie, the structure of the ditartrate of the quinoline compound SPH1772 is
  • the present invention provides a crystalline form A of SPH1772 ditartrate as described above, which has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 7.5 ⁇ 0.2 °, 9.2 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 16.6. Characteristic peaks at ⁇ 0.2°, 20.3 ⁇ 0.2°, and 28.8 ⁇ 0.2°; the target type used in the X-ray powder diffraction is a Cu target.
  • the crystal form A of the SPH1772 ditartrate salt has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ having a characteristic peak at a value as shown in the left column of Table 1:
  • Table 1 List of XRPD peaks for Form A of SPH1772 ditartrate
  • the characteristic peaks and relative intensity values of the crystal form A of the SPH1772 ditartrate salt in the X-ray powder diffraction pattern represented by the diffraction angle of 2 ⁇ are shown in Table 1.
  • the crystal form A of the SPH1772 ditartrate salt is represented by an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the crystalline form A of the SPH1772 ditartrate has a melting point of 202 °C.
  • the DSC of Form A of the SPH1772 ditartrate salt exhibits a major endothermic peak at 199.4 °C (DSC is differential scanning calorimetry).
  • the alcohol solvent is preferably methanol; the ester solvent is preferably ethyl acetate; the ether solvent is preferably tetrahydrofuran; the ketone
  • the solvent is preferably acetone.
  • the volume-to-mass ratio of the organic solvent to the SPH1772 is preferably 40 mL/g to 80 mL/g, more preferably 60 to 70 mL/g; and the molar ratio of the SPH1772 to the tartaric acid is preferably 1:2.0 to 1: 2.2, more preferably 1:2.1; the temperature of the reaction is preferably 40 to 60 ° C, more preferably 50 ° C; the reaction time is preferably 24 h to 72 h, more preferably 24 h to 48 h.
  • the step of adding the tartaric acid to the "mixture of the compound SPH1772 and the organic solvent” and reacting is preferred to include the step of adding the tartaric acid to the "mixture of the compound SPH1772 and the organic solvent" and reacting.
  • the talic acid is preferably added for 1 to 5 minutes, more preferably 2 minutes; the tartaric acid may also participate in the reaction as a "solution of the organic solvent of tartaric acid” in the "solution of the organic solvent of tartaric acid”
  • the volume molar ratio of the organic solvent to the tartaric acid is preferably 3.5:1 to 4.5:1 mL/mmol, more preferably 4:1 mL/mmol.
  • the addition rate of "solution of the organic solvent of tartaric acid” is preferably from 1 to 5 ml/min, more preferably from 2.5 ml/min.
  • the compound SPH1772 and the organic solvent are preferably mixed in such a manner that the compound SPH1772 is added to the organic solvent to obtain "a mixture of the compound SPH1772 and the organic solvent.”
  • the step of the following treatment may be further included after the end of the reaction: the reaction liquid is filtered to obtain the crystal form A of the SPH1772 ditartrate.
  • the filtering may further comprise an operation of washing the filter cake with the organic solvent.
  • the filtration may further include an operation of drying the filter cake; the drying is preferably vacuum drying; and the vacuum drying temperature is preferably 40 to 60 ° C, more preferably 50 ° C.
  • the invention provides a preparation method of crystal form B of SPH1772 ditartrate, which is prepared by any of the following methods:
  • the anti-solvent is methyl ethyl ketone (MEK) ).
  • the 1,4-dioxane solution of the crystalline form A of the SPH1772 ditartrate prepared above can be subjected to a room temperature volatilization crystallization experiment.
  • PVP polyvinylpyrrolidone
  • the gas-liquid permeation crystallization experiment is a conventional method for preparing a crystal form in the art, and the specific operation is: placing a small vessel opening containing a "saturated solution of a good solvent of a compound" in an anti-solvent.
  • the large vessel In the large vessel, the large vessel is sealed and allowed to stand. When solids are precipitated, the solid can be collected; wherein the small vessel cannot be immersed in the anti-solvent in the large vessel.
  • the preparation method of the saturated solution of the good solvent of the crystalline form A of the SPH1772 ditartrate salt may be SPH1772
  • the crystal form A of the ditartrate is uniformly mixed with the good solvent, and the supernatant liquid is taken; wherein the mass ratio of the crystal form A of the SPH1772 ditartrate to the good solvent is preferably 4-6 mg. /mL.
  • the normal temperature volatile crystallization test is a conventional method for preparing a crystal form in the art, and the specific operation is: sealing the vessel containing the "clear solution of the solvent of the compound" with a sealing film, and placing it at room temperature. A few holes (such as 2 to 4) are punctured on the sealing film and then naturally volatilized, and after evaporation, a solid is obtained.
  • the preparation method of the 1,4-dioxane solution of the crystalline form A of the SPH1772 ditartrate can be:
  • the crystal form A of the SPH1772 ditartrate is mixed with 1,4-dioxane, and the clear liquid can be obtained;
  • the mass volume of the crystalline form A and the 1,4-dioxane of the SPH1772 ditartrate The ratio is preferably 5 to 10 mg/mL.
  • the high polymer induced crystallization test is a conventional method for preparing a crystal form in the art, and the specific operation is: mixing a saturated solution of the solvent of the compound with the high polymer (generally using ultrasonic to mix it) Sufficiently, cover the vessel with a parafilm and pour holes in it, and volatilize at room temperature to collect solids.
  • the volume-mass ratio of the saturated solution of the crystalline form A of the SPH1772 ditartrate to the high polymer is preferably 0.75:1. ⁇ 1.5:1.
  • the present invention also provides a crystalline form B of SPH1772 ditartrate prepared by the preparation of Form B of SPH1772 ditartrate described above.
  • the invention provides a preparation method of the crystalline form C of SPH1772 ditartrate: the method comprises the following steps: performing the gas-solid osmosis crystallization experiment of the crystalline form A of the SPH1772 ditartrate; wherein the solvent is N , N-dimethylformamide.
  • the gas-solid osmosis crystallization experiment is a conventional method for preparing a crystal form in the art, and the specific operation is: placing a small vessel opening containing a compound in a large vessel filled with a solvent, sealing the large vessel , stand still, when there is solid precipitation, collect solids.
  • the mass ratio of the crystalline form A of the SPH1772 ditartrate to the solvent is preferably 4 to 7 mg/mL, more preferably 5 mg/mL. .
  • the present invention also provides a preparation method of the crystalline form C of the SPH1772 ditartrate described above. Form C of SPH1772 ditartrate.
  • the invention provides a preparation method of the crystal form D of the SPH1772 ditartrate: the method comprises the following steps: the crystal form A of the SPH1772 ditartrate prepared above is subjected to a gas-solid osmosis crystallization experiment; wherein the solvent is DMSO.
  • the mass to volume ratio of the crystalline form A of the SPH1772 ditartrate to the solvent is preferably 4 to 7 mg/mL, more preferably 5 mg/mL. .
  • the present invention also provides a crystalline form D of SPH1772 ditartrate prepared by the preparation of Form D of SPH1772 ditartrate described above.
  • the present invention provides the use of the di-tartrate salt of SPH1772 to prepare a tyrosine kinase c-Met inhibitor as described above.
  • the present invention provides the use of the ditartrate salt of SPH1772 as described above for the preparation of a medicament for the treatment and/or prevention of a disease associated with overexpression or activity of tyrosine kinase c-Met.
  • the present invention provides the use of a crystalline form A of SPH1772 ditartrate as described above for the preparation of a tyrosine kinase c-Met inhibitor.
  • the present invention provides a use of the crystalline form A of SPH1772 ditartrate as described above for the preparation of a medicament for the treatment and/or prevention of a disease associated with overexpression or activity of the tyrosine kinase c-Met.
  • the invention also provides a pharmaceutical composition comprising an effective amount of a ditartrate salt of SPH 1772, and a pharmaceutically acceptable adjuvant.
  • the invention also provides a pharmaceutical composition comprising an effective amount of Form A of SPH1772 ditartrate, and a pharmaceutically acceptable adjuvant.
  • the present invention provides one or more of the crystalline form B of SPH1772 ditartrate as described above, the crystalline form C of SPH1772 ditartrate as described above, and the crystalline form D of SPH1772 ditartrate as described above.
  • tyrosine kinase c-Met inhibitors In the preparation of tyrosine kinase c-Met inhibitors.
  • the present invention provides one or more of the crystalline form B of SPH1772 ditartrate as described above, the crystalline form C of SPH1772 ditartrate as described above, and the crystalline form D of SPH1772 ditartrate as described above.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form B of SPH1772 ditartrate as described above, the crystalline form C of SPH1772 ditartrate as described above, and the crystalline form D of SPH1772 ditartrate as described above.
  • a pharmaceutical composition comprising the crystalline form B of SPH1772 ditartrate as described above, the crystalline form C of SPH1772 ditartrate as described above, and the crystalline form D of SPH1772 ditartrate as described above.
  • pharmaceutical composition comprising the crystalline form B of SPH1772 ditartrate as described above, the crystalline form C of SPH1772 ditartrate as described above, and the crystalline form D of SPH1772 ditartrate as described above.
  • the pharmaceutically acceptable adjuvant is a conventional pharmaceutical excipient in the art, and the selection thereof varies depending on the route of administration and the action characteristics, and preferably includes a filler, a diluent, a binder, and a wetting agent. , disintegrants, lubricants, Emulsifier, suspending agent.
  • the pharmaceutical composition can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • injection intravenous, intramuscular, subcutaneous and intracoronary
  • sublingual buccal
  • rectal transurethral
  • vaginal nasal
  • the preferred route is oral.
  • the disease associated with overexpression or activity of the tyrosine kinase c-Met is a disease caused by a change in the tyrosine kinase c-Met which is conventional in the art, preferably including cancer and muscle. Skeletal sarcoma, soft tissue sarcoma, hematopoietic malignancies and other tumors.
  • the cancer preferably includes bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer and thyroid cancer.
  • the musculoskeletal sarcoma comprises: osteosarcoma, synovial sarcoma and rhabdomyosarcoma; and the soft tissue sarcoma preferably comprises: malignant fibrous histiocytoma/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma;
  • the hematopoietic malignant tumor comprises: multiple myeloma, lymphoma, adult type T cell leukemia, acute myeloid leukemia and chronic myeloid leukemia; and the other tumors preferably include: glioblasts Tumor, astrocytoma, melanoma, mesothelioma, and embryonal carcinosarcoma.
  • the tartaric acid in the present invention is generally referred to as L-tartaric acid unless otherwise specified.
  • the ditartrate salt of SPH1772 and the tartaric acid in its A to D crystal form are generally L-tartrate.
  • the structure of L-tartaric acid is
  • the quinoline compound SPH1772 salt or a polymorph thereof (Sitrate salt of SPH1772 or its crystal form A) in the present application is said to be substantially characterized by graphical data "as shown in the figure", including, for example, a powder. X-ray diffraction pattern, FTIR spectrum and solid state NMR spectrum.
  • graphical data including, for example, a powder. X-ray diffraction pattern, FTIR spectrum and solid state NMR spectrum.
  • SPH1772 ditartrate or its crystalline form A is referred to herein as being characterized by "data as shown in the figures" and thus will be understood to include having these small variations compared to the drawings (as known to the skilled person).
  • the graphical data characterizes any crystalline form of SPH1772 ditartrate or its crystalline form A.
  • An item eg, a reaction mixture
  • room temperature usually shrinking Written as "RT”. This means that the temperature of the item is close to the temperature of the space, or the same as the temperature of the space, such as the room or fume hood in which the item is located.
  • room temperature is from about 20 ° C to about 30 ° C, or from about 22 ° C to about 27 ° C, or about 25 ° C.
  • the method or step may be referred to herein as "overnight.” This refers to, for example, the time interval of a method or step that spans the night time when the method or step may not be actively observed.
  • the time interval is from about 8 to about 20 hours, or from about 10 to 18 hours, typically about 16 hours.
  • reduced pressure refers to a pressure of from about 10 mbar to about 50 mbar.
  • isolated relates to any of the following: a SPH1772 salt of the invention or a polymorph thereof, and corresponding to the SPH1772 or SPH1772 salt polymorph physically separated from the reaction mixture formed therefrom.
  • the present invention relates to an active pharmaceutical ingredient API (e.g., the ditartrate salt of SPH 1772 or its crystalline form A) containing individual optical isomers of SPH1772, mixtures of individual enantiomers or racemates.
  • active pharmaceutical ingredient API e.g., the ditartrate salt of SPH 1772 or its crystalline form A
  • individual optical isomers of SPH1772 mixtures of individual enantiomers or racemates.
  • the ditartrate salt of SPH1772 of the present invention or its crystalline form A generally exhibits reduced hygroscopicity. Because these salts do not absorb as much water as the comparative salts in the art, they have advantages in galenical formulations.
  • the crystalline form A of the ditartrate salt of SPH 1772 of the present invention is at least partially crystalline, with a higher degree of crystallinity resulting in a more stable salt of SPH1772.
  • the ditartrate salt of SPH 1772 of the present invention has a water content of less than 0.1 to 8% by weight, more preferably 0.5 to 5% by weight, still more preferably 0.8 to 3.5% by weight.
  • the ditartrate salt of SPH1772 according to the invention or its crystalline form A is preferably present in a purely isolated form, for example in a purity of >95% by weight, preferably >98% by weight, more preferably >99% by weight.
  • the SPH1772 ditartrate salt of the present invention or its crystal form A is preferably present in the form of microparticles.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the present invention is that the SPH1772 ditartrate or its crystal form A of the present invention can exhibit the following excellent properties: high stability, good bioavailability, good pharmacokinetic properties, and superior to SPH1772 free base. In vivo efficacy.
  • Figure 1 is an XRPD pattern of Form A of SPH1772 ditartrate.
  • Figure 2 is an XRPD pattern of Form A of SPH1772.
  • Figure 3 is an XRPD pattern of Form B of SPH1772.
  • Figure 4 is an XRPD pattern of Form A of SPH1772-tartrate.
  • Figure 5 is a graph showing the drug-time concentration of the test compound in the effect Example 3 in rats.
  • Fig. 6 is a bar graph showing the drug-time concentration distribution of the test compound in the effect embodiment 3 in rats.
  • Fig. 7 is a bar graph showing the peak concentration of the test compound in the effect embodiment 3 in rats.
  • Figure 8 is a graph showing the growth curve of tumor volume of each treatment group and control group in the MHCC97H human liver cancer model.
  • Figure 9 is a graph showing tumor volume changes of each treatment group and control group in a mouse model of LU2503 human lung tumor.
  • the meaning of the unit M is mol/L
  • the meaning of nM is nmol/L
  • the meaning of mM is mmol/L.
  • the tartaric acid referred to in the following examples is L-tartaric acid.
  • Residual moisture content determined according to the Karl Fischer method as described in Ph. Eur. 6th Edition, 2008, Section 2.5.12. The assay was performed using a Mettler Toledo DL31 Karl Fischer titrator. Typically, 50 mg to 100 mg salt samples are analyzed.
  • DSC TA Q200/2000 Differential Scanning Calorimeter
  • Liquid NMR (Solution NMR): NMR spectra liquid NMR spectrometer Bruker 400M in collection, DMSO-d 6 as a solvent.
  • a three-necked round bottom flask equipped with a magnetic needle, a thermometer and a nitrogen balloon was filled with a mixture of 5.0 g (11.8 mmol) of SPH1772 and 100 ml of DMF, heated to 110 ° C, slowly dissolved in a clear solution, and stirring was continued at this temperature for 30 minutes. Heat and allow to stand at room temperature overnight. Filter and filter cake was washed with 20 ml DMF. The above filter cake was transferred to a three-necked round bottom flask equipped with a magnetic needle, a thermometer and a nitrogen balloon, and 100 ml of absolute ethanol was added. The mixture was heated to 50 ° C and stirring was continued at this temperature for 2 hours, heating was stopped and cooled to room temperature.
  • the polymorph type test was carried out under 96 conditions including anti-solvent addition, room temperature stirring, gas-solid permeation, gas-liquid permeation, slow cooling, room temperature volatilization and polymer induction.
  • the solids obtained in the test have all been isolated and characterized.
  • the anti-solvent addition method was carried out under 18 test conditions to obtain crystal form B of SPH1772-tartrate crystal form A, SPH1772, and crystal form B of SPH1772.
  • Form 10 of 10 mg of SPH1772 ditartrate was weighed into a 3 ml vial, and 2 ml of solvent was added to a 20 ml vial. After placing the 3 ml vial in a 20 ml vial, the 20 ml vial was sealed. The solid was collected after standing at room temperature for 7 days. See Table 3 for the specific experimental results.
  • Test number Solvent Crystal form SPH-B-A1 H 2 O SPH1772 ditartrate crystal form A SPH-B-A2 DCM SPH1772 ditartrate crystal form A SPH-B-A3 EtOH SPH1772 ditartrate crystal form A
  • Gas-solid permeation was carried out under 14 test conditions to obtain crystal form A of SPH1772 ditartrate, crystal form C of SPH1772 ditartrate, and crystal form D of SPH1772 ditartrate.
  • Test number Solvent Crystal form SPH-D-A1 EtOH SPH1772 ditartrate crystal form A SPH-D-A2 IPA SPH1772 ditartrate crystal form A SPH-D-A3 Ace SPH1772 ditartrate crystal form A SPH-D-A4 MIBK SPH1772 ditartrate crystal form A SPH-D-A5 EtOAc SPH1772 ditartrate crystal form A SPH-D-A6 IPAc SPH1772 ditartrate crystal form A SPH-D-A7 MTBE SPH1772 ditartrate crystal form A SPH-D-A8 THF SPH1772 ditartrate crystal form A SPH-D-A9 2-MeTHF SPH1772 ditartrate crystal form A SPH-D-A10 1,4-dioxane SPH1772 ditartrate crystal form A SPH-D-A11 ACN SPH1772 ditartrate crystal form A SPH-D-A12 CHCl 3 SPH1772
  • Test number Solvent (v:v) Crystal form SPH-E-A1* 1,4-dioxane Amorphous SPH-E-A2 2-MeTHF Amorphous SPH-E-A3* Ace Amorphous SPH-E-A4* EtOAc Amorphous SPH-E-A5* ACN Amorphous SPH-E-A6 THF/H 2 O (19:1) Amorphous
  • Test number Good solvent / anti-solvent Crystal form SPH-F-A1 (THF: H 2 O)/MEK SPH1772 ditartrate salt form B SPH-F-A2 (THF: H 2 O) / ACN Amorphous SPH-F-A3 (THF: H 2 O) / EtOH Amorphous SPH-F-A4 1,4-dioxane/MEK clarify SPH-F-A5 1,4-dioxane/n-heptane Amorphous SPH-F-A6 1,4-dioxane/EtOAc Amorphous SPH-F-A7 NMP/MeOH Form A of SPH1772
  • SPH-F-A8 NMP/toluene clarify SPH-F-A9 NMP/ACN
  • Form A of SPH1772 SPH-F-A10 DMSO/acetone clarify SPH-F-A11 DMSO/IPA clarify SPH-F-A12 DMAc/2-MeTHF clarify SPH-F-A13 DMAc/CHCl 3 clarify
  • N/A means less solids.
  • Polymer A polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hydroxypropyl methylcellulose (HPMC), methyl fiber Prime (MC), mass ratio 1:1:1:1:1:1.
  • Polymer B polycaprolactone (PCL), polyethylene glycol (PEG), polymethyl methacrylate (PMMA), sodium alginate (SA), hydroxyethyl cellulose (HEC), quality Ratio 1:1:1:1:1.
  • the polymer induction was carried out under 8 conditions, and the crystal form of SPH1772 ditartrate salt form B was obtained.
  • c-Met kinase purchased from Carna Biosciences, Inc. Cat. No. 08-151;
  • DTT solution purchased from Sigma-Aldrich, article number: 43816;
  • EDTA solution purchased from GIBCO, article number: 15575;
  • test kit HTRF kinEASE-TK kit and related components were purchased from Cisbio Bioassays, wherein the HTRF kinEASE-TK kit was numbered: 62TK0PEC;
  • In vitro kinase assays were performed using the Homogeneous Time-Resolved Fluorescence (HTRF) technique, and the test compounds were screened on c-Met kinase at ATP concentrations of Km, respectively.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the initial concentration of the test compound was selected to be 111.11 nM, and 10 gradient dilutions were selected for each compound.
  • the gradient dilution factor was 3 times, and 2 replicate wells per concentration were used for detection.
  • INCB28060 Capmatinib was used as the standard control.
  • the 1X reaction buffer required for each kinase was prepared using 5 ⁇ Enzymatic buffer in the HTRF kinEASE-TK kit.
  • 5 ⁇ compounds for example, the concentration of the compound required for the final experiment is 1 um, which is first formulated into a sample of 5 um concentration, referred to as 5 ⁇ compound.
  • SPH1772 SPH1772 Form A and two c-Met tyrosine tartrate Form A kinase inhibition IC 50 is lower than the positive reference compound INCB28060, show inhibitory activity in vitro than INCB28060.
  • H1993 human lung cancer cells purchased from ATCC, article number: CRL-5909;
  • RPMI 1640 purchased from GIBCO, article number 11875-093;
  • Strep/pen purchased from GIBCO, article number: 15240-062;
  • Fetal bovine serum FBS purchased from GIBCO, article number: 10099-141;
  • CCK-8 Cell Counting Kit-8 (CCK-8) reagent to inhibit the proliferation of tumor cells by compound SPH1772 and its different salt forms on human lung cancer H1993 cell line to evaluate the test compound.
  • the inhibitory activity of the cell line in vitro proliferation was evaluated.
  • CCK-8 is a kit for detecting cell proliferation, cell survival and cytotoxicity and is an alternative to the MTT method.
  • the initial concentration of the test compound was selected to be 111.11 nM, 9 gradient dilution concentrations were selected, and the gradient dilution factor was 3 times. Two replicate wells per concentration were used for detection, and INCB28060 (Capmatinib) was used as a standard control.
  • the crystal form A of SPH1772 and the crystal form A of SPH1772 ditartrate have better proliferation inhibitory activity against H1993 cells than the positive reference compound INCB28060, and the inhibition of proliferation of H1993 cell line is stronger under the nM level.
  • Analytical and animal laboratory compounds are supplied by the Central Research Institute. Acetonitrile is an HPLC pure reagent (Merck), and formic acid (HCOOH) is an HPLC pure reagent produced by CNW. Other analytical pure organic reagents were supplied by Shanghai Pharmaceutical Reagent Co., Ltd. of China Pharmaceuticals (Group). The analytical pure water was prepared from deionized water through a MilliQ pure water meter.
  • the liquid-mass spectrometry system (LC/MS/MS) consisted of a Waters AcQuity UPLC tandem API4000Q-trap mass spectrometer.
  • SD rats were divided into 3 groups, 3 in each group, and 20 ⁇ mol/kg SPH1772 ditartrate crystal form A, SPH1772 crystal form A and INCB28060 hydrochloride (8 mL/kg, 2.5 mM) were administered by gavage, respectively.
  • 0.4 mL of blood was taken from the fundus venous plexus of rats before and 5, 15, 30, 60, 90, 120, 240, 360, 480, 720, and 1440 min after administration.
  • the blood sample was centrifuged at 8000 rpm for 5 min, and the plasma was stored in a centrifuge tube at -20 ° C for storage.
  • Plasma sample treatment 50 ⁇ L of plasma sample, 200 ⁇ L of internal standard acetonitrile (propranolol (PRO), 2.5 ng/ml) was added to precipitate the protein. The mixture was vortexed for 10 min, centrifuged at 6000 g for 10 min, and the supernatant was diluted 5 times with the mobile phase, and then injected in a 96-well plate.
  • internal standard acetonitrile propranolol (PRO), 2.5 ng/ml
  • Liquid Chromatography System Acquity UPLC LC System (including binary infusion pump, autosampler, column oven, degasser), Waters, USA.
  • MS/MS system API 4000Q-Trap triple quadrupole mass spectrometer with electrospray ionization source (ESI), Applied Biosystems, USA
  • Analytical column BEH C18column, 1.7 ⁇ m particle size, 50 x 2.1 mm I.D., Waters, USA
  • the ion source is an electrospray ionization source (Turbo Ionspray, ESI); source ejection voltage is 5500V; temperature 500 deg.] C; ion source gas 1 (N 2) pressure of 50 psi; ion source gas 2 (N 2) pressure of 50 psi; gas curtain Gas (N 2 ) pressure is 20 psi; collision gas pressure (CAD) is Medium; scanning time is 100 ms; positive ion mode detection; scanning mode is multi-reaction monitoring (MRM), ion reaction and collision energy for quantitative analysis (CE) ), the de-clustered voltage (DP) is shown in the following table:
  • the standard curve of SPH1772 in rat plasma has a linear range of 0.01-22.5 ⁇ M and a lower limit of quantification of 0.01 ⁇ M.
  • the standard curve of INCB28060 hydrochloride in rat plasma has a linear range of 0.002 to 5 ⁇ M and a lower limit of quantification of 0.002 ⁇ M. See Table 12 to Table 14 for the pharmacokinetic parameters of Form A of SPH1772 ditartrate and Form A of A and SPH1772 and INCB28060 hydrochloride.
  • the drug-time concentration curve of the test compound is shown in Fig. 5.
  • the histogram of the drug-time concentration (AUC(0-t)) distribution of the test compound in the rat is shown in Fig. 6; the test compound is in the rat body.
  • the distribution of peak concentration (Cmax) is shown in column 7.
  • BALB/c nude mice were subcutaneously inoculated with MHCC97H cells to establish a subcutaneous transplantation tumor model of human liver cancer.
  • the test was divided into crystal form A (0.05 mg/kg, 0.5 mg/kg and 5 mg/kg) of SPH1772 ditartrate, positive control INC280 hydrochloride (5 mg/kg) and Vehicle group (vehicle control group), each group 10 Only, intragastric administration, once a day, for a total of 21 days.
  • the efficacy was evaluated based on the relative tumor inhibition rate (TGI) and the tumor delay time, and the safety was evaluated based on the animal's body weight change and death.
  • TGI tumor inhibition rate
  • mice Female, 7-9 weeks (the age of mice at the time of tumor cell inoculation), weighing 19.5-23.9 g, 75 animals. Purchased from Shanghai Lingchang Biotechnology Co., Ltd., animal certificate number: 2013001816956. Feeding environment: SPF level.
  • MHCC97H (Zhongshan Hospital, Fudan University) cell culture in DMEM containing 10% fetal bovine serum In the liquid. MHCC97H cells in the exponential growth phase were collected and resuspended in PBS to a suitable concentration for subcutaneous tumor inoculation in mice.
  • mice Seventy-five female mice were subcutaneously inoculated with 0.2 ml of 1 ⁇ 10 7 MHCC97H cells resuspended in PBS and Matrigel (1:1). When the average tumor volume was 157 mm 3 , they were randomly grouped according to tumor size.
  • the tumor volume calculation formula is: long diameter ⁇ short diameter 2 /2.
  • TGI Relative tumor inhibition rate
  • TGI 1 - T / C (%).
  • T/C% is the relative tumor growth rate, that is, the percentage of tumor volume or tumor weight relative to the treatment group and the control group at a certain time point.
  • T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively.
  • T/C% T RTV /C RTV *100%
  • T RTV treatment group mean RTV
  • C RTV vehicle control group mean RTV
  • RTV V t /V 0
  • V 0 is the group when the animal the tumor volume
  • V t is the tumor volume after treatment of the animal
  • T/C% T TW /C TW ⁇ 100%
  • T TW mean tumor weight at the end of the treatment group
  • C TW mean tumor weight at the end of the vehicle control experiment).
  • the median tumor volume of the vehicle control mice on the 25th day after administration was 1815 mm 3 .
  • the average tumor volume was 469 mm 3 on the 25th day after administration, and the relative tumor inhibition rate TGI (%) was 74%.
  • the average tumor volume was 60 mm 3 on the 25th day after administration, and the relative tumor inhibition rate TGI (%) was 97%.
  • SPH 1772 ditartrate of Form A (5mg / kg) treated group at day 25 after dosing mean tumor volume of 22mm 3, the relative rate of tumor inhibition TGI (%) was 99%.
  • the lung tumor xenograft model LU2503 was used for this pharmacodynamic experiment. There is a gene deletion in exon 14 of the MET gene of this model. At the same time, the model has mild cachexia and has a tendency to collapse.
  • mice From The lung tumor xenograft model LU2503 (R11P6) tumor-bearing mice were collected from tumor tissue, and the tumor pieces cut into 2-3 mm in diameter were inoculated subcutaneously in the right anterior scapula of BALB/c nude mice. When the average tumor volume reached approximately 139 mm 3 , mice were randomly assigned to 6 experimental groups according to tumor volume, 8 in each group, 4 per cage. The day of grouping is defined as day 0. Dosing begins on day 0 and ends on day 20. The experiment ended on the 21st.
  • the test was divided into crystal form A (0.3 mg/kg, 3 mg/kg and 30 mg/kg) of SPH1772 ditartrate, positive control INC280 (30 mg/kg), positive control Crizotinib (30 mg/kg) and solvent group. Only, intragastric administration, once a day, for a total of 21 days.
  • BALB/c mice female, 8-9 weeks (week age at the time of tumor cell inoculation), 52 rats. Purchased from Nanjing Biomedical Research Institute of Nanjing University, license number: SCXK (Su) 2015-0001; quality certificate number: 201602064. Feeding environment: SPF level.
  • the tumor volume calculation formula is: long diameter ⁇ short diameter 2 /2.
  • Group 1 On the 21st day after group therapy, Group 1 (INC280, 30 mg/kg, QD*21), Group 2 (solvent, QD*21), Group 3 (Form A of SPH1772 ditartrate, 0.3 mg/ Kg, QD*21), Group 4 (SPH1772 ditartrate crystal form A, 3 mg/kg, QD*21), Group 5 (SPH1772 ditartrate crystal form A, 30 mg/kg, QD*21)
  • the percentage change in body weight of the tumor-bearing mice of Group 6 was -5.00%, -9.86%, -1.61%, -1.88%, -2.01%, and 3.26%, respectively.
  • Table 19 is at Antitumor effect of lung tumor xenograft model LU2503
  • Form A of SPH1772 ditartrate was treated as a monotherapy with statistically significant resistance at doses of 0.3 mg/kg, 3 mg/kg, and 30 mg/kg.
  • the lung tumor xenograft model LU2503 has a better effect than INC280 and Crizotinib.

Abstract

本发明公开了一种喹啉类化合物的盐，其晶型、制备方法、组合物与应用。本发明的SPH1772二酒石酸盐或其晶型A可表出以下的优异的性质：稳定性高，生物利用率好，药动学性质优异，比SPH1772游离碱优异的体内药效。

Description

喹啉类化合物的盐，其晶型、制备方法、组合物与应用
本申请要求申请日为2015年12月31日的中国专利申请CN201511030013.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种喹啉类化合物的盐，其晶型、制备方法、组合物与应用。
背景技术
化合物3-(1-甲基-1H-吡唑-4-基)-6-(6-(1-甲基-1H-吡唑-4-基)-1H-[1,2,3]***并[4，5-b]吡嗪-1-基)甲基)喹啉，简称SPH1772(结构如下式所示)，该化合物已经公开于专利CN104109166A中。SPH1772是肝细胞生长因子(HGF)受体酪氨酸激酶c-Met的高效选择性的研究性口服不可逆抑制剂。SPH1772正在被开发治疗若干实体肿瘤，包括非小细胞肺癌(NSCLC)、肝癌、肠癌和卵巢癌，和各种其他癌症。
Figure PCTCN2016112942-appb-000001
多晶型现象(不同晶体形式的出现)是某些分子和分子复合体的性质。单分子可能导致具有不同晶体结构和物理性质的各种多晶型，所述物理性质像熔点、热行为(例如通过热重分析-“TGA”、或差示扫描量热法(DSC)测定)、X射线粉末衍射(XRPD或粉末XRD)图、红外线吸收指纹以及固态核磁共振(NMR)光谱。这些技术中的一种或多种可以用于区别化合物的不同多晶型物。
发现可以提供具有合意加工性质的材料，所述的合意处理性质如易于处理、易于加工、存储稳定性和易于提纯或用作促进转化成其他多晶型物的合意的中间晶体形式。可药用化合物或其盐的多晶型物和溶剂化物也可提供改进药物的性能特征的机会。其扩展了制剂研究员可用于例如通过向产品提供不同的性质(例如，更佳加工或处理特征，改善的溶解特征，或改善的储存期限)来制剂优化的材料清单。至少出于这些原因，需要SPH1772游离碱和其盐的固态形式。
发明内容
本发明提供了一种喹啉类化合物的盐，其晶型、制备方法、组合物与应用。本发明的SPH1772二酒石酸盐或其晶型A可表出以下的优异的性质：稳定性高，生物利用率好，药动学性质优异，比SPH1772游离碱优异的体内药效。
本发明提供了一种喹啉类化合物SPH1772的二酒石酸盐，
Figure PCTCN2016112942-appb-000002
所述的喹啉类化合物SPH1772的二酒石酸盐中的酒石酸优选为L-酒石酸(即所述的喹啉类化合物SPH1772的二酒石酸盐的结构为
Figure PCTCN2016112942-appb-000003
本发明提供了一种如上所述的SPH1772二酒石酸盐的晶型A，其以衍射角为2θ表示的X-射线粉末衍射图在7.5±0.2°、9.2±0.2°、14.5±0.2°、16.6±0.2°、20.3±0.2°和28.8±0.2°处有特征峰；所述的X-射线粉末衍射中使用的靶型为Cu靶。
优选地，所述的SPH1772二酒石酸盐的晶型A以衍射角为2θ表示的X-射线粉末衍射图在如表1左侧栏所示的数值处有特征峰：
表1：SPH1772二酒石酸盐的晶型A的XRPD峰列表
2θ°[±0.2°] 相对强度％
7.089 30.7
7.541 100.0
9.150 31.2
11.019 28.8
14.163 22.3
14.545 75.7
16.589 29.4
17.130 24.5
17.825 10.6
19.752 8.1
20.283 32.9
21.389 24.9
21.598 21.7
22.783 12.8
23.161 6.3
25.314 29.5
25.789 22.3
26.670 8.5
26.927 8.9
28.264 6.3
28.758 25.1
29.348 10.5
31.248 3.4
32.305 6.5
33.048 3.1
33.842 4.6
35.343 3.5
38.305 4.4
作为优选，所述的SPH1772二酒石酸盐的晶型A在以衍射角为2θ表示的X-射线粉末衍射图的特征峰和相对强度值如表1所示。
作为优选，所述的SPH1772二酒石酸盐的晶型A在以衍射角为2θ表示的X-射线粉末衍射图如图1所示。
作为优选，所述的SPH1772二酒石酸盐的晶型A的熔点为202℃。
作为优选，所述的SPH1772二酒石酸盐的晶型A的DSC显示199.4℃处有主要吸热峰(DSC为差示扫描量热法)。
本发明中喹啉类化合物SPH1772二酒石酸盐的制备，本领域技术人员根据本申请实施例公开的内容及及本领域常识进行制备。
本发明还提供了所述的SPH1772二酒石酸盐的晶型A的制备方法，包括以下步骤：有机溶剂中，将化合物SPH1772与酒石酸进行反应，即可；其中，所述的有机溶剂为醇类溶剂、酯类溶剂、DCM:MeOH＝6:1～9:1v/v、醚类溶剂或酮类溶剂。
所述的SPH1772二酒石酸盐的晶型A的制备方法中，所述的醇类溶剂优选甲醇；所述的酯类溶剂优选乙酸乙酯；所述的醚类溶剂优选四氢呋喃；所述的酮类溶剂优选丙酮。所述的有机溶剂与所述的SPH1772的体积质量比优选40mL/g～80mL/g，更优选60～70mL/g；所述的SPH1772与所述的酒石酸的摩尔比优选1:2.0～1:2.2，更优选1:2.1；所述的反应的温度优选40～60℃，更优选50℃；所述的反应的时间优选24h～72h，更优选24h～48h。
所述的SPH1772二酒石酸盐的晶型A的制备方法中，优选包括以下步骤：将所述的酒石酸加入到“所述的化合物SPH1772和所述的有机溶剂的混合物”中，反应即可。所述的酒石酸的加入时间优选1～5min，更优选2min；所述的酒石酸还可以以“酒石酸的所述有机溶剂的溶液”形式参与反应，所述“酒石酸的所述有机溶剂的溶液”中，所述的有机溶剂与所述的酒石酸的体积摩尔比优选3.5:1～4.5:1mL/mmol，更优选4:1mL/mmol。当所述的酒石酸以“酒石酸的所述有机溶剂的溶液”形式参与反应时，“酒石酸的所述有机溶剂的溶液”的加入速率优选为1～5ml/min，更优选为2.5ml/min。所述的化合物SPH1772和所述的有机溶剂的混合方式优选为将所述的化合物SPH1772加入到所述的有机溶剂中，得到“所述的化合物SPH1772和所述的有机溶剂的混合物”。
所述的SPH1772二酒石酸盐的晶型A的制备方法中，所述的反应结束之后还可包括后以下处理的步骤：将反应液过滤，得到所述的SPH1772二酒石酸的晶型A，即可。其中，所述的过滤之后还可进一步包括用所述的有机溶剂洗涤滤饼的操作。所述的过滤之后还可进一步包括干燥滤饼的操作；所述的干燥优选真空干燥；所述的真空干燥的温度优选40～60℃，更优选50℃。
本发明提供了一种SPH1772二酒石酸盐的晶型B的制备方法，其由以下任一方法制备：
方法一：将上述制备得到的SPH1772二酒石酸盐的晶型A进行气液渗透结晶实验，即可；其中，良溶剂为THF:H2O＝19:1v/v；反溶剂为丁酮(MEK)。
方法二，将上述制备得到的SPH1772二酒石酸盐的晶型A的1,4-二氧六环溶液，进行常温挥发结晶实验，即可。
方法三，将上述制备得到的SPH1772二酒石酸盐的晶型A进行高聚物诱导结晶实验，即可；其中，当高聚物为聚乙烯吡咯烷酮(PVP)：聚乙烯醇(PVA)：聚氯乙烯(PVC)：聚醋酸乙烯酯(PVAC)：羟丙基甲基纤维素(HPMC)：甲基纤维素(MC)的质量比为1:1:1:1:1:1时，溶剂为1,4-二氧六环；当高聚物为聚己内酯(PCL)：聚乙二醇(PEG)：聚甲基丙基酸甲酯(PMMA)：海藻酸钠(SA)：羟乙基纤维素(HEC)的质量比为1:1:1:1:1时，溶剂为1,4-二氧六环，或四氢呋喃：水＝19:1v/v。
本发明需要说明，气液渗透结晶实验是本领域中常规的一种晶型的制备方法，具体操作为：将装有“化合物的良溶剂的饱和溶液”的小器皿开口置于装有反溶剂的大器皿中，将大器皿密封、静置，当有固体析出的时候，收集固体即可；其中，小器皿不可以没入到大器皿中的反溶剂中。
本发明所述的SPH1772二酒石酸盐的晶型B的制备方法的方法一中，优选与以下步骤：所述的SPH1772二酒石酸盐的晶型A的良溶剂的饱和溶液的制备方法可以为将SPH1772二酒石酸盐的晶型A与所述的良溶剂混合均匀，取上层清液即可；其中，所述的SPH1772二酒石酸盐的晶型A与所述的良溶剂的质量体积比优选4～6mg/mL。
本发明需要说明，常温挥发结晶试验是本领域中常规的一种晶型的制备方法，具体操作为：将装有“化合物的溶剂的澄清溶液”的器皿用封口膜密封，置于室温下，将封口膜上刺几个(如2～4个)小孔后放置自然挥发，挥干后得到固体，即可。
本发明所述的SPH1772二酒石酸盐的晶型B的制备方法的方法二中，所述的SPH1772二酒石酸盐的晶型A的1,4-二氧六环溶液的制备方法可以为：将所述的SPH1772二酒石酸盐的晶型A与1,4-二氧六环混合，取澄清液即可；所述的SPH1772二酒石酸盐的晶型A与1,4-二氧六环的质量体积比优选5～10mg/mL。
本发明需要说明，高聚物诱导结晶试验是本领域中常规的一种晶型的制备方法，具体操作为：将化合物的溶剂的饱和溶液与高聚物混合充分后(一般采用超声使其混合充分)，用封口膜盖住器皿并在上面扎孔，置于室温条件下挥发，收集固体，即可。
本发明所述的SPH1772二酒石酸盐的晶型B的制备方法的方法三中，所述的SPH1772二酒石酸盐的晶型A的饱和溶液与所述的高聚物的体积质量比优选0.75:1～1.5:1。
本发明还提供了一种由上所述的SPH1772二酒石酸盐的晶型B的制备方法制得的SPH1772二酒石酸盐的晶型B。
本发明提供了一种SPH1772二酒石酸盐的晶型C的制备方法：其包括以下步骤：将所述的SPH1772二酒石酸盐的晶型A进行气固渗透结晶实验，即可；其中，溶剂为N,N-二甲基甲酰胺。
本发明需要说明，气固渗透结晶实验是本领域中常规的一种晶型的制备方法，具体操作为：将装有化合物的小器皿开口置于装有溶剂的大器皿中，将大器皿密封、静置，当有固体析出的时候，收集固体即可。
本发明所述的SPH1772二酒石酸盐的晶型C的制备方法中，所述的SPH1772二酒石酸盐的晶型A与所述的溶剂的质量体积比优选4～7mg/mL，更优选5mg/mL。
本发明还提供了一种由上所述的SPH1772二酒石酸盐的晶型C的制备方法制得的 SPH1772二酒石酸盐的晶型C。
本发明提供了一种SPH1772二酒石酸盐的晶型D的制备方法：其包括以下步骤：将上述制备得到的SPH1772二酒石酸盐的晶型A进行气固渗透结晶实验，即可；其中，溶剂为DMSO。
本发明所述的SPH1772二酒石酸盐的晶型D的制备方法中，所述的SPH1772二酒石酸盐的晶型A与所述的溶剂的质量体积比优选4～7mg/mL，更优选5mg/mL。
本发明还提供了一种由上所述的SPH1772二酒石酸盐的晶型D的制备方法制得的SPH1772二酒石酸盐的晶型D。
本发明提供一种如上所述的SPH1772的二酒石酸盐制备酪氨酸激酶c-Met抑制剂的应用。
本发明提供一种如上所述的SPH1772的二酒石酸盐在制备治疗和/或预防与酪氨酸激酶c-Met的过表达或活性相关疾病的药物中的应用。
本发明提供一种如上所述的SPH1772二酒石酸盐的晶型A制备酪氨酸激酶c-Met抑制剂的应用。
本发明提供一种如上所述的SPH1772二酒石酸盐的晶型A在制备治疗和/或预防与酪氨酸激酶c-Met的过表达或活性相关疾病的药物中的应用。
本发明还提供一种药物组合物，其包括有效量的SPH1772的二酒石酸盐，以及药学上可接受辅料。
本发明还提供一种药物组合物，其包括有效量的SPH1772二酒石酸盐的晶型A，以及药学上可接受辅料。
本发明提供一种如上所述的SPH1772二酒石酸盐的晶型B、如上所述的SPH1772二酒石酸盐的晶型C和如上所述的SPH1772二酒石酸盐的晶型D中的一种或几种，在制备酪氨酸激酶c-Met抑制剂的应用。
本发明提供一种如上所述的SPH1772二酒石酸盐的晶型B、如上所述的SPH1772二酒石酸盐的晶型C和如上所述的SPH1772二酒石酸盐的晶型D中的一种或几种，在制备治疗和/或预防与酪氨酸激酶c-Met的过表达或活性相关的疾病的药物中的应用。
本发明还提供一种药物组合物，其包括如上所述的SPH1772二酒石酸盐的晶型B、如上所述的SPH1772二酒石酸盐的晶型C和如上所述的SPH1772二酒石酸盐的晶型D中的一种或几种，以及药学上可接受辅料。
本发明中，所述的药学上可接受辅料为本领域中的常规药用辅料，其选择因施用途径和作用特点而异，较佳的包括填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、 乳化剂、助悬剂。
本发明中，所述的药物组合物可以口服、注射(静脉、肌肉、皮下和冠状动脉内)、舌下、经颊、经直肠、经尿道、经***、经鼻、吸入或局部途径施用。优选的途径是口服。
本发明中，所述的与酪氨酸激酶c-Met的过表达或活性相关疾病为本领域中常规的由酪氨酸激酶c-Met的变化所引起的疾病，较佳的包括癌症、肌肉骨骼肉瘤、软组织肉瘤、造血***恶性肿瘤和其他肿瘤。所述的癌症较佳的包括膀胱癌、乳腺癌、***、结肠癌、食道癌、胃癌、头颈癌、肾癌、肺癌、肝癌、鼻咽癌、卵巢癌、胰腺癌、***癌和甲状腺癌；所述的肌肉骨骼肉瘤较佳的包括：骨肉瘤、滑膜肉瘤和横纹肌肉瘤；所述的软组织肉瘤较佳的包括：恶性纤维组织细胞瘤/纤维肉瘤、平滑肌肉瘤和卡波济氏肉瘤；所述的造血***恶性肿瘤较佳的包括：多发性骨髓瘤、淋巴瘤、成人型T细胞白血病、急性骨髓性白血病和慢性粒细胞白血病；所述的其他肿瘤较佳的包括：胶质母细胞瘤、星形细胞瘤、黑色素瘤、间皮瘤和胚胎性癌肉瘤。
本发明中的酒石酸如无特殊说明，一般指L-酒石酸。例如，所述的SPH1772的二酒石酸盐以及其A～D晶型中的的酒石酸一般均为L-酒石酸盐。L-酒石酸的结构为
Figure PCTCN2016112942-appb-000004
本申请中喹啉类化合物SPH1772盐或其多晶型(SPH1772的二酒石酸盐或其晶型A)称为大体上通过“如图中所示”的图形数据表征，这些数据包括(例如)粉末X射线衍射图、FTIR光谱和固态NMR光谱。技术人员将理解，由于技术人员熟知的诸如仪器响应的变化和样品浓度和纯度变化之类因素，数据的这些图示可能经受诸如峰相对强度和峰位置之类的小变化。尽管如此，技术人员将容易能够将本文图中的图形数据与未知结晶形式产生的图形数据比较并且确认两组图形数据是表征相同的晶体形式或还是两种不同的晶体形式。SPH1772二酒石酸盐或其晶型A在本文被称为通过“如图中所示”图形数据表征，因此将被理解为可包括用具有与附图相比的这些小变化(如技术人员熟知)的图形数据表征的SPH1772二酒石酸盐或其晶型A的任何结晶形式。
术语XRPD和PXRD在科学文献中被粉末X射线衍射分析领域技术人员互换地使用，并且本申请在这两种表述或其缩写之间未做区别。
如本文中所用，除非另外说明，否则使用铜Ka辐射波长
Figure PCTCN2016112942-appb-000005
进行XRPD测定。
物品(例如反应混合物)可能在本文中特征在于处于、或允许达到“室温”，通常缩 写为“RT”。这意味着物品的温度接近于空间的温度，或与空间的温度相同，该空间例如该物品所位于的房间或通风橱。典型地，室温为约20℃至约30℃，或约22℃至约27℃，或约25℃。
方法或步骤在本文可以被称为“过夜”。这是指例如方法或步骤的时间间隔，其跨越方法或步骤可能未被积极地观察时的夜晚时间。该时间间隔为约8至约20小时，或约10至18小时，典型地约16小时。
如本文中所用，术语“减压”是指约10mbar至约50mbar的压力。
如本文中所用，术语“分离”是关于以下任一种：本发明的SPH1772盐或其多晶型，并且对应于从其形成的反应混合物中物理分离的所述SPH1772或SPH1772盐多晶型。
本发明涉及活性药用成分API(例如SPH1772的二酒石酸盐或其晶型A)含有SPH1772的个别光学异构体，个别对映体的混合物或外消旋体。
本发明的SPH1772的二酒石酸盐或其晶型A通常呈现降低的吸湿性。因为这些盐不像本领域中比较性盐那样强的吸水，所以他们在盖仑制剂中具有优点。
优选地，本发明的SPH1772的二酒石酸盐的晶型A至少呈部分结晶形式，更高程度的结晶度导致SPH1772更稳定的盐。
优选地，本发明的SPH1772的二酒石酸盐的水含量小于0.1至8重量％、更优选地0.5至5重量％、还更优选0.8至3.5重量％。
根据本发明SPH1772的二酒石酸盐或其晶型A优选以分离和基本上纯的形式例如>95重量％、优选>98重量％、更优选>99重量％的纯度存在。
本发明的SPH1772二酒石酸盐或其晶型A优选以微粒形式存在。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的SPH1772二酒石酸盐或其晶型A可表出以下的优异的性质：稳定性高，生物利用率好，药动学性质好，比SPH1772游离碱优异的体内药效。
附图说明
图1为SPH1772二酒石酸盐的晶型A的XRPD图。
图2为SPH1772的晶型A的XRPD图。
图3为SPH1772的晶型B的XRPD图。
图4为SPH1772一酒石酸盐的晶型A的XRPD图。
图5为效果实施例3中受试化合物在大鼠体内的药-时浓度曲线。
图6为效果实施例3中受试化合物在大鼠体内的药-时浓度分布柱状图。
图7为效果实施例3中受试化合物在大鼠体内达峰浓度柱状图。
图8为MHCC97H人源肝癌模型中各治疗组和对照组小鼠肿瘤体积的生长变化曲线。
图9为LU2503人源肺肿瘤小鼠模型中各治疗组和对照组的肿瘤体积变化曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本申请效果实施例中，单位M的含义为mol/L，nM的含义为nmol/L，mM的含义为mmol/L。
除了特别声明，下述实施例中涉及的酒石酸为L-酒石酸。
除了特别声明，本发明的实施例涉及的设备及测试方法如下：
XRPD图：在PANalytacal Empyrean粉末X射线衍射仪上分析样品；测定条件如下：
Figure PCTCN2016112942-appb-000006
残余水分含量：根据如Ph.Eur.第6版，2008，章节2.5.12中所述Karl Fischer方法测定。使用Mettler Toledo DL31Karl Fischer滴定器进行测定。通常，分析50mg至100mg盐样品。
IR：漫反射模式的Perkin Elmer型
DSC：TA Q200/2000差示扫描量热仪；
TGA：TA Q500/5000热重分析仪
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铂金盘，敞开 铝盘，压盖
温度范围 室温-设定温度 25℃–设定温度
扫描速率(℃/分钟) 10 10
保护气体 氮气 氮气
熔点：Lab India Visual熔化范围装置；
HPLC：高效液相色谱
高效液相色谱在Agilent 1100和1260HPLC上采集。
Figure PCTCN2016112942-appb-000007
液态核磁(Solution NMR)：液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d6作为溶剂。
实施例1：SPH1772的晶型A
向配备有磁针、温度计和氮气球的三颈圆底烧瓶装填5.0g(11.8mmol)SPH1772和100ml DMF的混合物加热至110℃，慢慢溶解至澄清溶液，在此温度下继续搅拌30分钟，停止加热并在室温下静置过夜。过滤，滤饼用20ml DMF洗涤。将上述滤饼转移至配备有磁针、温度计和氮气球的三颈圆底烧瓶，加入100ml无水乙醇。混合物加热至50℃，并在此温度下继续搅拌2小时，停止加热并在冷却至室温。过滤，滤饼用20ml无水乙醇洗涤。置于真空干燥箱内50℃干燥2小时以提供4.0g(80％)白色产品。SPH1772的晶型A的XRPD峰列表如下所示：XRPD图如图2所示。
2θ°[±0.2°] 相对强度％
9.374 31.0
10.811 42.6
12.219 1.6
14.321 100.0
16.239 72.2
18.813 11.3
19.546 44.8
21.682 12.3
23.673 9.5
24.813 7.0
27.005 29.4
28.567 1.6
35.797 1.9
38.200 1.9
DSC显示273.0℃处的主要吸热峰。
IR(cm-1)：3432.3，1618.2，1575.9，1541.7，1195.9，1126.6，1099.6，917.8，817.7和616.9。
残余溶剂-未检测到。
熔点＝270.5℃。
1H NMR(δppm，DMSO-d6，400MHz)9.22(s，1H)，9.17(d，J＝2.4Hz，1H)，8.64(s，1H)，8.46(d，J＝1.6Hz，1H)，8.37(s，1H)，8.31(s，1H)，8.07(s，1H)，7.99(d，J＝8.8Hz，1H)，7.84(d，J＝1.2Hz，1H)，7.76(dd，J1＝8.4Hz，J2＝2.0Hz，1H)，6.15(s，2H)，3.95(s，3H)，3.90(s，3H)。
实施例2：SPH1772二酒石酸盐的晶型A的制备
将乙酸乙酯(10ml)加入SPH1772游离碱250.8mg(0.59mmol)并且该混合物在室温下搅拌以获得白色悬浊液，经历两分钟的过程添加187.5mg(1.25mmol)酒石酸在乙酸乙酯(5ml)中的溶液。该混合物在50℃下搅拌24小时。过滤，滤饼用MeOH(5ml)漂洗，将固体样品转移至50℃真空烘箱干燥过夜，得370.5mg(86.3％收率)的白色固体。
DSC显示199.4℃下的主要吸热峰。
XRPD图如图1所示，具体XRPD峰列表如下：
2θ°[±0.2°] 相对强度％
7.089 30.7
7.541 100.0
9.150 31.2
11.019 28.8
14.163 22.3
14.545 75.7
16.589 29.4
17.130 24.5
17.825 10.6
19.752 8.1
20.283 32.9
21.389 24.9
21.598 21.7
22.783 12.8
23.161 6.3
25.314 29.5
25.789 22.3
26.670 8.5
26.927 8.9
28.264 6.3
28.758 25.1
29.348 10.5
31.248 3.4
32.305 6.5
33.048 3.1
33.842 4.6
35.343 3.5
38.305 4.4
IR(cm-1)：3415.3，3225.4，3117.1，2356.6，1742.6，1714.0，1579.5，1541.8，1191.2，1135.7，1076.4，873.7和608.2。
残余溶剂-未检测到。
熔点＝202℃。
1H NMR表明存在酒石酸盐。
1H NMR(δppm，DMSO-d6，400MHz)9.22(s，1H)，9.18(d，J＝0.4Hz，1H)，8.64(s，1H)，8.46(d，J＝0.4Hz，1H)，8.37(s，1H)，8.31(s，1H)，8.07(s，1H)，7.99(d，J＝0.8Hz，1H)，7.84(d，J＝1.2Hz，1H)，7.76(dd，J1＝8.4Hz，J2＝2.0Hz，1H)，6.16(s，2H)，4.33(s，4H)，3.95(s，3H)，3.90(s，3H)。
实施例3SPH1772酒石酸盐的多晶型研究
本实施例中使用的SPH1772二酒石酸盐的晶型A均为实施例2制备得到。
多晶型试验设置在96种条件下进行，包括反溶剂添加、室温搅拌法、气固渗透、气液渗透、缓慢降温、常温挥发和高聚物诱导等方法。试验中所得固体已全部分离表征。
(1)反溶剂添加法：
称取15毫克SPH1772二酒石酸盐的晶型A于20毫升小瓶中，加入相应良溶剂溶解固体后，边搅拌边逐滴添加反溶剂，有固体析出后离心分离固体。若加入15毫升反溶剂且搅拌过夜后仍无固体析出，则放置室温挥发分离出固体。具体反应的结果见表2：
表2反溶剂添加的溶剂及晶型种类
Figure PCTCN2016112942-appb-000008
Figure PCTCN2016112942-appb-000009
注：表中acetone:H2O＝4:1,v/v；*表示固体由5℃搅拌过夜得到；**表示固体由室温挥发得到。
反溶剂添加法在18种试验条件下进行，获得晶型包括SPH1772一酒石酸盐晶型A、SPH1772的晶型A、SPH1772的晶型B。
(2)气固渗透的方法：
称取10毫克SPH1772二酒石酸盐的晶型A于3毫升小瓶中，另在20毫升小瓶中加入2毫升溶剂，将3毫升小瓶敞口置于20毫升小瓶中后，将20毫升小瓶密封。室温下静置7天后收集固体。具体实验结果参见表3。
表3、气固渗透试验的溶剂及获得晶型
试验编号 溶剂 晶型
SPH-B-A1 H2O SPH1772二酒石酸盐晶型A
SPH-B-A2 DCM SPH1772二酒石酸盐晶型A
SPH-B-A3 EtOH SPH1772二酒石酸盐晶型A
SPH-B-A4 MeOH SPH1772二酒石酸盐晶型A
SPH-B-A5 ACN SPH1772二酒石酸盐晶型A
SPH-B-A6 THF SPH1772二酒石酸盐晶型A
SPH-B-A7 CHCl3 SPH1772二酒石酸盐晶型A
SPH-B-A8 MEK SPH1772二酒石酸盐晶型A
SPH-B-A9 Acetone SPH1772二酒石酸盐晶型A
SPH-B-A10 DMF SPH1772二酒石酸盐晶型C
SPH-B-A11 EtOAc SPH1772二酒石酸盐晶型A
SPH-B-A12 1,4-Dioxane SPH1772二酒石酸盐晶型A
SPH-B-A13 IPA SPH1772二酒石酸盐晶型A
SPH-B-A14 DMSO SPH1772二酒石酸盐晶型D
气固渗透在14种试验条件下进行，获得晶型包括SPH1772二酒石酸盐的晶型A、SPH1772二酒石酸盐的晶型C、SPH1772二酒石酸盐的晶型D。
(3)室温搅拌法：
称取15毫克SPH1772二酒石酸盐的晶型A于1.5毫升小瓶中，加入1.0毫升不同溶剂或混合溶剂配成浑浊液，置于设定温度为25℃的磁力搅拌(转速为800rpm)，约3.5天后离心分离固体，搅拌后变为澄清的样品则放置室温下挥发分离出固体。具体结果见表4：
表4室温搅拌试验的溶剂及获得晶型
Figure PCTCN2016112942-appb-000010
Figure PCTCN2016112942-appb-000011
其中，aw表示水活度
室温搅拌在19种条件下进行，获得晶型为SPH1772二酒石酸盐的晶型A。
(4)50℃搅拌试验：
称量15毫克每份的SPH1772二酒石酸盐的晶型A至1.5毫升玻璃小瓶中，分别加入0.5毫升表5中所列的溶剂，得到悬浮液在50℃下搅拌3.5天后，离心收集固体并进行XRPD测试。试验结果见表5。
表5 50℃搅拌试验的溶剂及获得晶型如下表：
试验编号 溶剂 晶型
SPH-D-A1 EtOH SPH1772二酒石酸盐晶型A
SPH-D-A2 IPA SPH1772二酒石酸盐晶型A
SPH-D-A3 acetone SPH1772二酒石酸盐晶型A
SPH-D-A4 MIBK SPH1772二酒石酸盐晶型A
SPH-D-A5 EtOAc SPH1772二酒石酸盐晶型A
SPH-D-A6 IPAc SPH1772二酒石酸盐晶型A
SPH-D-A7 MTBE SPH1772二酒石酸盐晶型A
SPH-D-A8 THF SPH1772二酒石酸盐晶型A
SPH-D-A9 2-MeTHF SPH1772二酒石酸盐晶型A
SPH-D-A10 1,4-dioxane SPH1772二酒石酸盐晶型A
SPH-D-A11 ACN SPH1772二酒石酸盐晶型A
SPH-D-A12 CHCl3 SPH1772二酒石酸盐晶型A
SPH-D-A13 MEK SPH1772二酒石酸盐晶型A
SPH-D-A14 MeOH 无定形
50℃搅拌在14种条件下进行，获得晶型为SPH1772二酒石酸盐的晶型A。
(5)缓慢降温试验：
称取30毫克SPH1772二酒石酸盐的晶型A于3毫升小瓶中，加入1.0毫升不同的溶剂，在50℃搅拌约2小时并过滤后得其饱和溶液，将该溶液以0.1℃/分钟降温至5℃后析出固体。未析出固体的样品至室温下进行挥发分离出固体。具体结果见表6。
表6缓慢降温试验的溶剂及获得晶型
试验编号 溶剂(v:v) 晶型
SPH-E-A1* 1,4-dioxane 无定形
SPH-E-A2 2-MeTHF 无定形
SPH-E-A3* acetone 无定形
SPH-E-A4* EtOAc 无定形
SPH-E-A5* ACN 无定形
SPH-E-A6 THF/H2O(19:1) 无定形
注：*表示固体通过室温敞口挥发得到。
缓慢降温在6种条件下进行，获得晶型为SPH1772酒石酸盐无定型。
(6)气液渗透试验：
称取15毫克SPH1772二酒石酸盐的晶型A于3毫升小瓶中，分别加入2.5毫升表7中的溶剂，过滤取上清液于3毫升小瓶中，另取20毫升的小瓶并向其中加入约3毫升的反溶剂，将3毫升小瓶敞口置于20毫升小瓶中，密封并于室温下静置。当观察到有固体析出时则取出固体测XRPD。具体结果见表7。
表7气液渗透试验的溶剂及获得晶型
试验编号 良溶剂/反溶剂 晶型
SPH-F-A1 (THF:H2O)/MEK SPH1772二酒石酸盐晶型B
SPH-F-A2 (THF:H2O)/ACN 无定形
SPH-F-A3 (THF:H2O)/EtOH 无定形
SPH-F-A4 1,4-dioxane/MEK 澄清
SPH-F-A5 1,4-dioxane/n-heptane 无定形
SPH-F-A6 1,4-dioxane/EtOAc 无定形
SPH-F-A7 NMP/MeOH SPH1772的晶型A
SPH-F-A8 NMP/toluene 澄清
SPH-F-A9 NMP/ACN SPH1772的晶型A
SPH-F-A10 DMSO/acetone 澄清
SPH-F-A11 DMSO/IPA 澄清
SPH-F-A12 DMAc/2-MeTHF 澄清
SPH-F-A13 DMAc/CHCl3 澄清
注：THF:H2O＝19:1,v/v。
气液扩散在13种条件下进行，获得晶型包括SPH1772二酒石酸盐晶型B、SPH1772游离碱晶型A。
(7)常温挥发结晶试验：
称取15毫克化合物SPH1772二酒石酸盐的晶型A于3毫升小瓶中，加入1.5毫升-3.0毫升相应溶剂或混合溶剂配制成澄清溶液，或过滤后得到澄清液，置于在室温下用封口膜密封，刺2～4个小孔后放置自然挥发，挥干后得到固体。
表8常温挥发结晶试验的溶剂及获得晶型
Figure PCTCN2016112942-appb-000012
注：N/A表示固体量少。
常温挥发在5种条件下进行，获得晶型为SPH1772酒石酸盐晶型B。
(8)高聚物诱导结晶试验：
称取15毫克化合物，分别配制成表9中所列溶于相应的良溶剂的饱和溶液，分装1.5-3.0毫升每份的饱和溶液至装有2毫克相应混合聚合物的3毫升小瓶中。超声使其混合充分后，用封口膜盖住小瓶并在上面扎孔，置于室温条件下挥发，收集所得固体进行XRPD测试。实验结具体结果见表9。
表9高聚物诱导结晶试验的溶剂及获得晶型
Figure PCTCN2016112942-appb-000013
Figure PCTCN2016112942-appb-000014
注：高聚物A：聚乙烯吡咯烷酮(PVP)，聚乙烯醇(PVA)，聚氯乙烯(PVC)，聚醋酸乙烯酯(PVAC)，羟丙基甲基纤维素(HPMC)，甲基纤维素(MC)，质量比1:1:1:1:1:1。高聚物B：聚己内酯(PCL)，聚乙二醇(PEG)，聚甲基丙基酸甲酯(PMMA)，海藻酸钠(SA)，羟乙基纤维素(HEC)，质量比1:1:1:1:1。
高聚物诱导在8种条件下进行，获得晶型为SPH1772二酒石酸盐晶型B。
本实施例中，根据XRPD结果：试验中共得到四种二酒石酸盐晶型(A～D)，鉴定结果表明SPH1772二酒石酸盐的晶型A为无水晶型，SPH1772二酒石酸盐的晶型B和晶型C为SPH1772二酒石酸盐的歧化晶型，SPH1772二酒石酸盐的晶型D为DMSO溶剂合物。由于SPH1772二酒石酸盐的晶型B、晶型C和晶型D可能的弱稳定性，SPH1772二酒石酸盐的晶型A为优选晶型。同时还得到SPH1772一酒石酸盐的晶型A和SPH1772的晶型B，SPH1772一酒石酸盐的晶型A为无水晶型，SPH1772的晶型B为DMAc溶剂合物。
具体表征数据如下：
(1)SPH1772一酒石酸盐的晶型A
DSC显示209.2℃处的主要吸热峰。残余溶剂：丙酮、乙酸乙酯-未检测到。熔点＝202.1℃。1H NMR确认SPH1772一酒石酸盐的晶型A。
1H NMR(δppm，DMSO-d6，400MHz)9.22(s，1H)，9.18(d，J＝0.4Hz，1H)，8.64(s，1H)，8.46(d，J＝0.4Hz，1H)，8.37(s，1H)，8.31(s，1H)，8.07(s，1H)，7.99(d，J＝0.8Hz，1H)，7.84(d，J＝1.2Hz，1H)，7.76(dd，J1＝8.4Hz，J2＝2.0Hz，1H)，6.15(s，2H)，4.28(s，2H)，3.93(s，3H)，3.90(s，3H)。
XRPD图如图4所示，具体XRPD峰列表如下：
2θ°[±0.2°] 相对强度％
6.892 19.8
12.924 20.2
13.525 21.3
14.512 100.0
15.639 37.3
16.990 14.4
17.912 14.9
19.098 11.0
21.024 18.9
(2)SPH1772的晶型B
熔点为263.2℃。DSC显示113.9℃、171.7℃和268.8℃处有主要吸热峰。残余溶剂：DMAc＝51.5％。1H NMR确认SPH1772的晶型B
1H NMR(δppm，DMSO-d6，400MHz)9.22(s，1H)，9.17(d，J＝2.4Hz，1H)，8.64(s，1H)，8.46(d，J＝1.6Hz，1H)，8.37(s，1H)，8.31(s，1H)，8.07(s，1H)，7.99(d，J＝8.8Hz，1H)，7.84(d，J＝1.2Hz，1H)，7.76(dd，J1＝8.4Hz，J2＝2.0Hz，1H)，6.15(s，2H)，3.95(s，3H)，3.90(s，3H)，2.94(s，15H)，2.79(s，15H)，1.96(s，15H)。
XRPD图如图3所示，XRPD峰列表如下：
2-θ°[±0.2°] 相对强度％
10.511 24.3
13.156 19.6
17.057 100.0
18.631 27.0
28.781 3.1
效果实施例1：c-Met酪氨酸激酶活性的抑制活性
材料与试剂：
c-Met激酶，购自Carna Biosciences,Inc.货号：08-151；
二甲基亚砜，购自Sigma-Aldrich，货号：D8418；
ATP，购自Sigma-Aldrich，货号：A7699；
DTT溶液，购自Sigma-Aldrich，货号：43816；
EDTA溶液，购自GIBCO，货号：15575；
检测试剂盒HTRF kinEASE-TK kit及相关组分，购自Cisbio Bioassays，其中HTRF kinEASE-TK kit货号为：62TK0PEC；
96孔化合物板，购自Thermo Scientific，货号：267245；
384孔检测板，购自Greiner Bio-One，货号：784075；
其他常规化学药品购自国药集团化学试剂有限公司。
体外激酶分析采用均相时间分辨荧光HTRF(Homogeneous Time-Resolved Fluorescence)技术，在ATP浓度为Km情况下，分别在c-Met激酶上对受试化合物进行筛选。(其中，Km代表米氏常数，单位是mol/L，酶促反应速度是最大反应速度一半时ATP的浓度。)
检测过程中，受试化合物初始浓度均选择为111.11nM，各化合物均选择10个梯度稀释浓度，梯度稀释倍数为3倍，每浓度2个复孔进行检测，采用INCB28060(Capmatinib)作为标准对照。
所有样品采用DMSO配制成10-2M的贮备液，小量分装后保存于-80℃备用。
实验方法：
1、配制1×反应缓冲液(购买的反应缓冲液为高浓度的，使用时需要稀释，稀释成最终实验时所需浓度称为1x反应缓冲液。)
采用HTRF kinEASE-TK kit中的5×Enzymatic buffer，配制适合每种激酶所需要的1×反应缓冲液。
2、5×化合物的配制与转移(例如：最终实验所需化合物浓度为1um，先配制成5um浓度的样品，称为5×化合物。)
1)化合物稀释：取10mM的受试化合物储存液，在96孔化合物板中，用DMSO将化合物分多步稀释，获得为初始浓度100×的化合物，之后再以此浓度化合物为第一个浓度，采用DMSO进行3倍梯度稀释，共稀释10个浓度；之后分别取1ul的梯度稀释液加入19ul的1×反应缓冲液中，配制成5×化合物备用；
2)5×化合物的转移：从96孔板中转移2ul的5×化合物进入384孔板中；无化合物对照孔中加入2ul的如下液体：1ul的DMSO加入19ul的1×反应缓冲液；Min对照孔中加入2ul的250mM的EDTA。
本效果实施例中，受试化合物的c-Met酪氨酸激酶活性的抑制活性数据如表10所示：
表10受试化合物对c-Met酪氨酸激酶活性的抑制活性数据
Figure PCTCN2016112942-appb-000015
Figure PCTCN2016112942-appb-000016
SPH1772的晶型A和SPH1772二酒石酸盐的晶型A的c-Met酪氨酸激酶抑制IC50比阳性参照化合物INCB28060更低，表明体外抑制活性高于INCB28060。
效果实施例2人肺癌H1993细胞的增殖抑制活性
材料与试剂：
Cell Counting Kit-8试剂盒，购自Dojindo，货号：CK04；
H1993人肺癌细胞，购自ATCC，货号：CRL-5909；
RPMI 1640，购自GIBCO，货号：11875-093；
Strep/pen，购自GIBCO，货号：15240-062；
胎牛血清FBS，购自GIBCO，货号：10099-141；
96孔细胞培养板，购自Corning，货号：3599；
96孔化合物板，购自Thermo Scientific，货号：267245；
其他常规化学药品购自国药集团化学试剂有限公司。
本效果实施例中，我们采用Cell Counting Kit-8(CCK-8)试剂，在人肺癌H1993细胞株上进行了化合物SPH1772及其不同盐型对肿瘤细胞增殖的抑制筛选，以评价受试化合物对该细胞株体外增殖的抑制活性。
CCK-8是检测细胞增殖、细胞存活和细胞毒性的试剂盒，为MTT法的替代方法。检测过程中，受试化合物的初始浓度选择为111.11nM，选择9个梯度稀释浓度，梯度稀释倍数为3倍，每浓度2个复孔进行检测，采用INCB28060(Capmatinib)作为标准对照。
所有样品采用DMSO配制成10-2M的贮备液，小量分装后保存于-80℃备用。
实验方法：
1、细胞培养与接种：实验第一天，取正常培养的细胞，在其指数生长状态下，消化分散后按照5.5×104cells/mL(表示55000个细胞每毫升)的密度，接种于96孔细胞培养板中，每孔接种90μl；接种完成后将微孔板放置于37摄氏度，5％的CO2的条件下培养过夜；
2、加药处理细胞：实验的第二天，从培养箱中取出微孔板，向微孔板中的每个孔中各加入10×化合物，每孔加入10μL，其中每个给药浓度2个复孔，每个化合物共9个给药浓度。根据不同的细胞株，各化合物的起始浓度有所不同。
3、数据的采集：化合物与细胞共同孵育72小时后，将含有细胞的微孔板从培养箱中取出，向每孔中加入10μl Cell Counting Kit-8反应液，将微孔板放入培养箱孵育2-3个 小时。于Flexstation 3上测定在450nm处的吸光度值，设定650nm为参比波长。
4、按下列公式对化合物的体外抑制活性进行计算：细胞增殖抑制率：抑制率(％)＝(信号值对照－信号值给药)/信号值对照×100％。并根据各浓度的抑制率，采用LOGIT法计算50％抑制浓度(50％inhibitory concentration，IC50)。
表11：受试化合物对H1993细胞株的体外增殖抑制作用
化合物 IC50(nM)
INCB28060 2.1
SPH1772二酒石酸盐的晶型A 0.7
SPH1772的晶型A 0.5
SPH1772的晶型A和SPH1772二酒石酸盐的晶型A对H1993细胞的增殖抑制活性优于阳性参照化合物INCB28060，在nM水平以下就对H1993细胞株的体外增殖有较强的抑制作用。
效果实施例3大鼠体内药物动力学分析
药物、动物及试剂：
分析用和动物实验用化合物由中央研究院药化室提供。乙腈为HPLC纯试剂(Merck)，甲酸(HCOOH)为CNW公司生产的HPLC纯试剂。其它分析纯有机试剂均由中国医药(集团)上海化学试剂公司提供。分析用纯水由去离子水经MilliQ纯水仪制备而成。
SD大鼠，雄性，180～200g，由上海西普尔必凯实验动物有限公司提供。
实验仪器：液相-质谱联用分析***(LC/MS/MS)由Waters AcQuity UPLC串联API4000Q-trap质谱检测器组成。
实验方法：
所有样品均使用DMSO超声加热至澄清，并配制成25nM溶液。
所有样品均按照20μmol/kg的剂量给药。
SD大鼠分为3组，每组3只，分别灌胃给予20μmol/kgSPH1772二酒石酸盐的晶型A、SPH1772的晶型A和INCB28060盐酸盐(8mL/kg，2.5mM)，分别于给药前和给药后5、15、30、60、90、120、240、360、480、720、1440min于大鼠眼底静脉丛取血0.4mL。血样于8000rpm离心5min，取血浆于离心管中-20℃保存备用。
血浆样品处理：血浆样品50μL，加入200μL含内标的乙腈(***(PRO)，2.5ng/ml)沉淀蛋白。涡旋10min，6000g离心10min，取上清用流动相5倍稀释后，于96孔板中进样。
样品测定方法：
1、仪器
液相色谱***：Acquity UPLC液相色谱***(包括二元输液泵、自动进样器、柱温箱、脱气机)，美国Waters公司。
MS/MS***：API 4000Q-Trap型三重四极杆串联质谱仪，配备电喷雾电离源(ESI)，美国Applied Biosystems公司
数据采集：Analyst 1.5.1软件，美国Applied Biosystems公司
2、LC条件
分析柱：BEH C18column，1.7μm粒径，50x 2.1mm I.D.，美国Waters公司
流速：0.3ml/min；进样量：2μl；柱温45℃。采用的梯度洗脱程序为：
时间(min) A(1MmNH4FA-0.025％FA-H2O) B(1MmNH4FA-0.025％FA-METH)
0 95％ 5％
0.5 95％ 5％
1 5％ 95％
2 5％ 95％
2.5 95％ 5％
3 95％ 5％
3、MS条件
离子源为电喷雾电离源(Turbo Ionspray，ESI)；源喷射电压为5500V；温度为500℃；离子源气体1(N2)压力为50psi；离子源气体2(N2)压力为50psi；气帘气体(N2)压力为20psi；碰撞气压力(CAD)为Medium；扫描时间为100ms；正离子方式检测；扫描方式为多反应监测(MRM)，用于定量分析的离子反应及碰撞能量(CE)、去簇电压(DP)如下表所示：
Figure PCTCN2016112942-appb-000017
SPH1772在大鼠血浆中标准曲线线性范围为0.01～22.5μM，定量下限0.01μM。INCB28060盐酸盐在大鼠血浆中标准曲线线性范围为0.002～5μM，定量下限0.002μM。SPH1772二酒石酸盐的晶型A、SPH1772的晶型A和INCB28060盐酸盐的体药代参数参见表12～表14。受试化合物的药-时浓度曲线如图5所示，受试化合物在大鼠体内药-时浓度(AUC(0-t))分布柱状图如图6所示；受试化合物在大鼠体内的达峰浓度(Cmax)的分布柱状图7所示。
表12SPH1772二酒石酸盐的晶型A在大鼠体内血浆药物浓度
Figure PCTCN2016112942-appb-000018
Figure PCTCN2016112942-appb-000019
表13SPH1772的晶型A在大鼠体内血浆药物浓度
Figure PCTCN2016112942-appb-000020
表14INCB28060盐酸盐的晶型A在大鼠体内血浆药物浓度
Figure PCTCN2016112942-appb-000021
表15受试化合物在大鼠体内主要PK数据：
Figure PCTCN2016112942-appb-000022
如表所示，剂量为20μmol/Kg时，SPH1772的晶型A的AUC(0-24h)为4057.55μM*min，SPH1772二酒石酸盐的晶型A的AUC(0-24h)为8802.13μM*min。与SPH1772的晶型A相比，SPH1772二酒石酸盐的晶型A相应的AUC值增加了2.17倍，达峰浓度增加了1.80倍。相同摩尔剂量下，SPH1772二酒石酸盐晶型A表现出了比SPH1772的晶型A更加优异的药动性质，总体来说INCB28060盐酸盐在大鼠体内的暴露量不如SPH1772的晶型A及SPH1772二酒石酸盐的晶型A。
效果实施例4SPH1772二酒石酸盐的晶型A在人源肝癌MHCC97H细胞株异种移植BALB/c裸小鼠动物模型中的抗肿瘤作用评价
4.1实验方法
BALB/c裸小鼠皮下接种MHCC97H细胞，建立人肝癌皮下移植肿瘤模型。试验分为SPH1772二酒石酸盐的晶型A(0.05mg/kg、0.5mg/kg和5mg/kg)、阳性对照INC280盐酸盐(5mg/kg)及Vehicle组(溶媒对照组)，每组10只，灌胃给药，每天给药一次，共给药21天。根据相对肿瘤抑制率(TGI)及肿瘤延迟时间进行疗效评价，根据动物体重变化和死亡情况进行安全性评价。
4.2实验动物
BALB/c Nude小鼠，雌性，7-9周(肿瘤细胞接种时的小鼠周龄)，体重19.5-23.9g，75只。购自上海灵畅生物科技有限公司，动物合格证编号：2013001816956。饲养环境：SPF级。
4.3细胞和相关试剂
MHCC97H(复旦大学附属中山医院)细胞培养在含10％胎牛血清的DMEM培养 液中。收集指数生长期的MHCC97H细胞，PBS重悬至适合浓度用于小鼠皮下肿瘤接种。
4.4动物造模和分组
75只雌性小鼠右侧皮下接种0.2毫升重悬于PBS和基质胶(1:1)中的1×107MHCC97H细胞。待肿瘤平均体积157mm3时，根据肿瘤大小随机分组。肿瘤体积计算公式为：长径×短径2/2。
4.5结果判断标准
相对肿瘤抑制率TGI(％)：TGI＝1-T/C(％)。T/C％为相对肿瘤增值率，即在某一时间点，治疗组和对照组相对肿瘤体积或瘤重的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)或瘤重(TW)。
计算公式如下：T/C％＝TRTV/CRTV*100％(TRTV：治疗组平均RTV；CRTV：溶媒对照组平均RTV；RTV＝Vt/V0，V0为分组时该动物的瘤体积，Vt为治疗后该动物的瘤体积)。或T/C％＝TTW/CTW×100％(TTW：治疗组实验终结时平均瘤重；CTW：溶媒对照组实验终结时平均瘤重)。
4.6实验终点
末次给药后1.5h和24h，取血取瘤，称瘤重，拍照。
4.7统计分析
所有实验结果以平均瘤体积±SEM(平均标准误差)表示。不同组间的统计分析选择最佳药物治疗点(通常是在最后一次给药后)。用独立样本T检验方法比较治疗组相对肿瘤体积和瘤重与对照组相比有无显著性差异。所有的数据均用SPSS 18.0进行分析。p<0.05为具有显著性差异。
4.8实验结果
溶媒对照组小鼠在给药后第25天平均肿瘤体积为1815mm3。SPH 1772二酒石酸盐的晶型A(0.05mg/kg)治疗组在给药后第25天平均肿瘤体积为469mm3，相对肿瘤抑制率TGI(％)为74％。SPH 1772二酒石酸盐的晶型A(0.5mg/kg)治疗组在给药后第25天平均肿瘤体积为60mm3，相对肿瘤抑制率TGI(％)为97％。SPH 1772二酒石酸盐的晶型A(5mg/kg)治疗组在给药后第25天平均肿瘤体积为22mm3，相对肿瘤抑制率TGI(％)为99％。INC280(5mg/kg)治疗组在给药后第25天平均肿瘤体积为166mm3，相对肿瘤抑制率TGI(％)为91％。瘤重分析结果与相对瘤体积分析结果基本吻合。各治疗组和对照组肿瘤生长情况见表16、表17和图8。
Figure PCTCN2016112942-appb-000023
Figure PCTCN2016112942-appb-000024
表17各组瘤重表
Figure PCTCN2016112942-appb-000025
SPH1772二酒石酸盐的晶型A在上述MHCC97H人源肝癌模型研究中，各治疗组均无动物死亡，没有表现明显的药物毒性，治疗期间耐受良好。
效果实施例5：SPH1772二酒石酸盐的晶型A在人源肺肿瘤小鼠模型LU2503中的抗肿瘤作用评价
5.1模型信息
来源于女性患者的
Figure PCTCN2016112942-appb-000026
肺肿瘤异种移植模型LU2503被用于该药效学实验。该模型的MET基因14号外显子存在基因缺失。同时，该模型具有轻微恶病质，且具有肿瘤破溃倾向。
5.2实验方法
从
Figure PCTCN2016112942-appb-000027
肺肿瘤异种移植模型LU2503(R11P6)荷瘤小鼠收取肿瘤组织，切成直径为2-3mm的瘤块接种于BALB/c裸鼠右前肩胛处皮下。当平均肿瘤体积达到约139mm3时，根据肿瘤体积将小鼠随机分入6个实验组，每组8只，每笼4只。分组当天定义为 第0天。给药开始于第0天，结束于第20天。该实验于第21日结束。试验分为SPH1772二酒石酸盐的晶型A(0.3mg/kg、3mg/kg和30mg/kg)、阳性对照INC280(30mg/kg)、阳性对照Crizotinib(30mg/kg)及溶剂组，每组8只，灌胃给药，每天给药一次，共给药21天。
5.3实验动物
BALB/c小鼠，雌性，8-9周(肿瘤细胞接种时的小鼠周龄)，52只。购自南京大学南京生物医药研究院，许可证号：SCXK(苏)2015-0001；质量合格证号：201602064。饲养环境：SPF级。
5.4动物分组
待肿瘤平均体积139mm3时，根据肿瘤大小随机分组。肿瘤体积计算公式为：长径×短径2/2。
5.5结果判断标准同4.5。
5.6实验终点同4.6。
5.7统计分析同4.7。
5.8实验结果
在分组治疗后第21天，第1组(INC280,30mg/kg,QD*21)、第2组(溶剂,QD*21)、第3组(SPH1772二酒石酸盐的晶型A,0.3mg/kg,QD*21)、第4组(SPH1772二酒石酸盐的晶型A,3mg/kg,QD*21)、第5组(SPH1772二酒石酸盐的晶型A,30mg/kg,QD*21)和第6组(Crizotinib,30mg/kg,QD*21)荷瘤鼠体重改变百分比分别为-5.00％、-9.86％、-1.61％、-1.88％、-2.01％和3.26％。
在分组治疗后第21天，溶剂组的平均肿瘤体积达到1886.32mm3。其他组的肿瘤完全消退，相对肿瘤增值率(T/C％)均为0.00％，均具有统计学显著的抗LU2503肿瘤生长的作用(P<0.05)。各治疗组和溶剂处理组荷瘤鼠在不同时间点的肿瘤体积见表18、表19和图9。
表18各治疗组和溶剂处理组荷瘤鼠的肿瘤体积
Figure PCTCN2016112942-appb-000028
Figure PCTCN2016112942-appb-000029
注释：数据以“平均值±标准误差”表示
表19在
Figure PCTCN2016112942-appb-000030
肺肿瘤异种移植模型LU2503中的抑瘤效果
Figure PCTCN2016112942-appb-000031
本研究中，SPH1772二酒石酸盐的晶型A作为单药治疗，在0.3mg/kg、3mg/kg和30mg/kg剂量时均具有统计学显著的抗
Figure PCTCN2016112942-appb-000032
肺肿瘤异种移植模型LU2503生长的作用，且相同给药剂量下，SPH1772二酒石酸盐的晶型A抗
Figure PCTCN2016112942-appb-000033
肺肿瘤异种移植模型LU2503生长的作用，要优于INC280和Crizotinib。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (11)

  1. 一种喹啉类化合物SPH1772的二酒石酸盐，
    Figure PCTCN2016112942-appb-100001
  2. 如权利要求1所述的喹啉类化合物SPH1772的二酒石酸盐，其特征在于，所述的酒石酸为L-酒石酸。
  3. 如权利要求1或2所述的喹啉类化合物SPH1772二酒石酸盐的晶型A，其特征在于，以衍射角为2θ表示的X-射线粉末衍射图在7.5±0.2°、9.2±0.2°、14.5±0.2°、16.6±0.2°、20.3±0.2°和28.8±0.2°处有特征峰；所述的X-射线粉末衍射中使用的靶型为Cu靶。
  4. 如权利要求3所述的喹啉类化合物SPH1772二酒石酸盐的晶型A，其特征在于，所述的SPH1772二酒石酸盐的晶型A的熔点为202℃，和/或，所述的SPH1772二酒石酸盐的晶型A的DSC显示199.4℃处有主要吸热峰。
  5. 如权利要求3或4所述的喹啉类化合物SPH1772二酒石酸盐的晶型A的制备方法，其特征在于，包括以下步骤：有机溶剂中，将化合物SPH1772与酒石酸进行反应，即可；其中，所述的有机溶剂为醇类溶剂、酯类溶剂、DCM:MeOH＝6:1～9:1v/v、醚类溶剂或酮类溶剂。
  6. 如权利要求5所述的制备方法，其特征在于，
    所述的醇类溶剂为甲醇；
    和/或，所述的酯类溶剂为乙酸乙酯；
    和/或，所述的醚类溶剂为四氢呋喃；
    和/或，所述的酮类溶剂为丙酮；
    和/或，所述的有机溶剂与所述的SPH1772的体积质量比为40mL/g～80mL/g；
    和/或，所述的SPH1772与所述的酒石酸的摩尔比为1:2.0～1:2.2；
    和/或，所述的反应的温度为40～60℃；
    和/或，所述的反应的时间为24h～72h；
    和/或，所述的SPH1772二酒石酸盐的晶型A的制备方法包括以下步骤：将所述的酒石酸加入到“所述的化合物SPH1772和所述的有机溶剂的混合物”中，反应即可；
    和/或，所述的SPH1772二酒石酸盐的晶型A的制备方法中，所述的反应结束之后 还包括后以下处理的步骤：将反应液过滤，得到所述的SPH1772二酒石酸的晶型A，即可。
  7. 如权利要求5或6所述的制备方法，其特征在于，
    所述的有机溶剂与所述的SPH1772的体积质量比为60～70mL/g；
    和/或，所述的SPH1772与所述的酒石酸的摩尔比为1:2.1；
    和/或，所述的反应的温度为50℃；
    和/或，所述的反应的时间为24h～48h；
    和/或，当所述的酒石酸以“酒石酸的所述有机溶剂的溶液”形式参与反应时，所述“酒石酸的所述有机溶剂的溶液”中，所述的有机溶剂与所述的酒石酸的体积摩尔比为3.5:1～4.5:1mL/mmol，优选4:1mL/mmol；
    和/或，当所述的酒石酸以“酒石酸的所述有机溶剂的溶液”形式参与反应时，“酒石酸的所述有机溶剂的溶液”的加入速率为1～5ml/min，优选2.5ml/min。
  8. 如权利要求1或2所述的SPH1772的二酒石酸盐的晶型，包括SPH1772的二酒石酸盐的晶型B、SPH1772的二酒石酸盐晶型C和SPH1772的二酒石酸盐的晶型D，其特征在于，
    所述的SPH1772的二酒石酸盐的晶型B由下述方法一至方法三中的任一方法制备：
    方法一：将权利要求3或4所述的SPH1772二酒石酸盐的晶型A进行气液渗透结晶实验，即可；其中，良溶剂为THF:H2O＝19:1v/v；反溶剂为丁酮；
    方法二，将权利要求3或4所述的SPH1772二酒石酸盐的晶型A的1,4-二氧六环溶液，进行常温挥发结晶实验，即可；
    方法三，将权利要求3或4所述的SPH1772二酒石酸盐的晶型A进行高聚物诱导结晶实验，即可；其中，当高聚物为聚乙烯吡咯烷酮:聚乙烯醇:聚氯乙烯:聚醋酸乙烯酯:羟丙基甲基纤维素:甲基纤维素的质量比为1:1:1:1:1:1时，溶剂为1,4-二氧六环；当高聚物为聚己内酯：聚乙二醇:聚甲基丙基酸甲酯:海藻酸钠:羟乙基纤维素的质量比为1:1:1:1:1时，溶剂为1,4-二氧六环，或四氢呋喃:水＝19:1v/v；
    所述的SPH1772的二酒石酸盐的晶型C由下述方法制备：将权利要求3或4所述的SPH1772二酒石酸盐的晶型A进行气固渗透结晶实验，即可；其中，溶剂为N,N-二甲基甲酰胺；
    所述的SPH1772的二酒石酸盐的晶型D由下述方法制备：将权利要求3或4所述的SPH1772二酒石酸盐的晶型A进行气固渗透结晶实验，即可；其中，溶剂为DMSO。
  9. 如权利要求1或2所述的SPH1772的二酒石酸盐、如权利要求3或4所述的 SPH1772的二酒石酸盐的晶型A、如权利要求8所述的SPH1772的二酒石酸盐的晶型B、如权利要求8所述的SPH1772的二酒石酸盐的晶型C和如权利要求8所述的SPH1772的二酒石酸盐的晶型D中的一种或多种，在制备酪氨酸激酶c-Met抑制剂中的应用。
  10. 如权利要求1或2所述的SPH1772的二酒石酸盐、如权利要求3或4所述的SPH1772的二酒石酸盐的晶型A、如权利要求8所述的SPH1772的二酒石酸盐的晶型B、如权利要求8所述的SPH1772的二酒石酸盐的晶型C和如权利要求8所述的SPH1772的二酒石酸盐的晶型D中的一种或多种，在制备治疗和/或预防与酪氨酸激酶c-Met的过表达或活性相关疾病的药物中的应用。
  11. 一种药物组合物，其特征在于，包括如权利要求1或2所述的SPH1772的二酒石酸盐、如权利要求3或4所述的SPH1772的二酒石酸盐的晶型A、如权利要求8所述的SPH1772的二酒石酸盐的晶型B、如权利要求8所述的SPH1772的二酒石酸盐的晶型C和如权利要求8所述的SPH1772的二酒石酸盐的晶型D中的一种或多种，以及药学上可接受的辅料。
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