WO2017063572A1 - 细胞凋亡诱导剂的新晶型及其制备方法 - Google Patents

细胞凋亡诱导剂的新晶型及其制备方法 Download PDF

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WO2017063572A1
WO2017063572A1 PCT/CN2016/102022 CN2016102022W WO2017063572A1 WO 2017063572 A1 WO2017063572 A1 WO 2017063572A1 CN 2016102022 W CN2016102022 W CN 2016102022W WO 2017063572 A1 WO2017063572 A1 WO 2017063572A1
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solvent
ray powder
powder diffraction
diffraction pattern
formula
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PCT/CN2016/102022
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English (en)
French (fr)
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陈敏华
张炎锋
陆飞
张晓宇
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苏州晶云药物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of chemical medicine, in particular to a novel crystal form of an apoptosis inducing agent and a preparation method thereof.
  • Apoptosis is the most basic biological process for multicellular organisms to maintain their structural stability and balance of internal environment functions and growth.
  • Apoptosis is a feature of escaping cancer.
  • One of the main ways by which cancer cells evade apoptosis is by up-regulating the anti-apoptotic proteins of the Bcl-2 family.
  • Bcl-2 protein In various cancers and conditions of the immune system, overexpression of Bcl-2 protein is associated with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis, or a combination thereof.
  • Bcl-2 is involved in many hematological malignancies and is associated with poor prognosis in acute myeloid leukemia (AML). Patients with relapsed/refractory (R/R) AML usually have a poor prognosis and short survival.
  • ABT199 also known as Venetoclax, is a selective, potent, orally administered small molecule Bcl-2 inhibitor.
  • Venetoclax is a selective, potent, orally administered small molecule Bcl-2 inhibitor.
  • ABT199 The chemical name of ABT199 is 4-(4- ⁇ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl ⁇ piperazin-1-yl) -N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ sulfonyl)-2-(1H-pyrrolo[2,3-b Pyridine-5-yloxy)benzamide having the structural formula shown in Formula I.
  • the crystal form is known to be an important factor affecting the quality of the drug. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, the development of new crystal forms that are more suitable for application is of great significance for drug development.
  • Example 5 of CN103153993A wherein the solid ABT199 obtained is amorphous.
  • CN103328474A discloses crystalline forms of ABT199 comprising 2 anhydrates, 2 hydrates and various solvates. Both the anhydrate and the hydrate in the patent are obtained by drying the solvate.
  • ABT199 is provided as a new anhydrate and hydrate form. These anhydrates and hydrates can be directly crystallized from a solvent, and have good stability, low wettability, and uniform particle size distribution, which are important for drug development.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide an anhydrate and a hydrate form of the compound of the formula (I) which can be directly decrystallized from a solvent, and are respectively named as crystal forms B and D of ABT199. F, G.
  • the present invention adopts the following technical solutions:
  • the invention provides crystal form B of ABT199, and its X-ray powder diffraction pattern at 25 ° C (CuK ⁇ radiation
  • the shot has a characteristic peak at a 2 ⁇ value of 5.3 ° ⁇ 0.2 °, 11.3 ° ⁇ 0.2 °, and 6.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form B also has characteristic peaks at one or more of 2 ⁇ values of 16.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 10.2° ⁇ 0.2°; preferably, the present invention
  • the X-ray powder diffraction pattern of Form B also has characteristic peaks at 2 ⁇ values of 16.8 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, 10.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form B also has a characteristic peak at one or more of 2 ⁇ values of 15.7° ⁇ 0.2°, 5.9° ⁇ 0.2°, 22.8° ⁇ 0.2°; preferably, this
  • the X-ray powder diffraction pattern of Form B of the invention also has characteristic peaks at 2 ⁇ values of 15.7 ° ⁇ 0.2 °, 5.9 ° ⁇ 0.2 °, and 22.8 ° ⁇ 0.2 °.
  • said Form B has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C at a 2 ⁇ value of 5.3 ° ⁇ 0.2 °, 11.3 ° ⁇ 0.2 °, 6.7 ° ⁇ 0.2 Characteristic peaks are found in °, 16.8 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, 10.2 ° ⁇ 0.2 °, 15.7 ° ⁇ 0.2 °, 5.9 ° ⁇ 0.2 °, and 22.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form B is as shown in FIG.
  • the crystalline form B provided by the present invention begins to exhibit an endothermic peak near heating to about 130 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • the present invention provides Form B having a weight loss gradient of about 10.3% upon heating to 145 ° C, the thermogravimetric analysis of which is illustrated in FIG.
  • Another technical solution of the present invention provides a method for preparing ABT199 crystal form B, which comprises: placing a free form of ABT199 in an alkyl ether-based organic solvent, and obtaining a solid by stirring or volatilizing.
  • alkyl ether solvent is methyl tert-butyl ether.
  • the present invention provides Form D of ABT199 having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C having characteristic peaks at 2 ⁇ values of 12.7 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, and 22.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form D is also at a 2 ⁇ value of 6.3 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, One or more of 22.9 ° ⁇ 0.2 ° has a characteristic peak; preferably, the X-ray powder diffraction pattern of the crystalline form D of the present invention is also a 2 ⁇ value of 6.3 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, 22.9 ° ⁇ There is a characteristic peak at 0.2°.
  • the X-ray powder diffraction pattern of Form D also has a characteristic peak at one or more of 2 ⁇ values of 11.4° ⁇ 0.2°, 16.4° ⁇ 0.2°, and 19.9° ⁇ 0.2°; preferably, this
  • the X-ray powder diffraction pattern of Form B of the invention also has characteristic peaks at 2 ⁇ values of 11.4 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, and 19.9 ° ⁇ 0.2 °.
  • said Form D has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C at a 2 ⁇ value of 12.7 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, 22.3 ° ⁇ 0.2 Characteristic peaks at °, 6.3 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, 22.9 ° ⁇ 0.2 °, 11.4 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °, and 19.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form D is as shown in FIG.
  • the crystalline form D provided by the present invention begins to exhibit an endothermic peak near heating to 147 ° C, the differential scanning calorimetry diagram being substantially as shown in FIG.
  • the present invention provides Form D having a weight loss gradient of about 2.9% upon heating to 180 ° C, the thermogravimetric analysis of which is shown in FIG.
  • Another technical solution of the present invention is to provide a method for preparing ABT199 crystal form D, which comprises any one of the following methods:
  • ABT199 is placed in a mixed solvent of tetrahydrofuran and an anti-solvent, and the mixture is stirred to obtain a solid.
  • the anti-solvent includes, but is not limited to, one or more of water, an alkane, and an alkyl ether, preferably one or more of water, n-heptane, and methyl tert-butyl ether.
  • the present invention provides Form F of ABT199 having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C having characteristic peaks at 2 ⁇ values of 12.4 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, and 5.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form F also has characteristic peaks at one or more of 2 ⁇ values of 17.5° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.0° ⁇ 0.2°; preferably, the present invention
  • the X-ray powder diffraction pattern of Form F also has characteristic peaks at 2 ⁇ values of 17.5 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, and 19.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form F also has a characteristic peak at one or more of 2 ⁇ values of 21.3° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 17.9° ⁇ 0.2°; preferably, The X-ray powder diffraction pattern of the inventive Form F also has characteristic peaks at 2 ⁇ values of 21.3 ° ⁇ 0.2 °, 24.2 ° ⁇ 0.2 °, and 17.9 ° ⁇ 0.2 °.
  • said Form F has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C at a 2 ⁇ value of 17.5 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 5.9 ° ⁇ 0.2 Characteristic peaks at °, 12.4 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, 24.2 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form F is as shown in FIG.
  • the crystalline form F provided by the present invention begins to exhibit an endothermic peak near heating to 210 ° C, the differential scanning calorimetry diagram being substantially as shown in FIG.
  • the present invention provides Form F having a weight loss gradient of about 4.8% upon heating to 200 ° C, the thermogravimetric analysis of which is shown in FIG.
  • Another technical solution of the present invention is to provide a method for preparing ABT199 crystal form F, which comprises any one of the following methods:
  • ABT199 is placed in a mixed solvent of acetic acid and water, and the mixture is stirred to obtain a solid.
  • the present invention provides a crystalline form G of ABT199 having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C having characteristic peaks at 2 ⁇ values of 10.6 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, and 24.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form G also has characteristic peaks at one or more of 2 ⁇ values of 9.6° ⁇ 0.2°, 19.3° ⁇ 0.20°, 20.3° ⁇ 0.2°; preferably, the present invention
  • the X-ray powder diffraction pattern of Form G also has characteristic peaks at 2 ⁇ values of 9.6 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, and 20.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form G has a characteristic peak at one or more of 2 ⁇ values of 11.8° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 16.5° ⁇ 0.2°; preferably, this
  • the X-ray powder diffraction pattern of the inventive Form G also has characteristic peaks at 2 ⁇ values of 11.8 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, and 16.5 ° ⁇ 0.2 °.
  • said Form G has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C at a 2 ⁇ value of 10.6 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, 24.5 ° ⁇ 0.2 Characteristic peaks at °, 9.6 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, 20.3 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, and 16.5 ° ⁇ 0.2 °.
  • CuK ⁇ radiation CuK ⁇ radiation
  • the X-ray powder diffraction pattern of Form G is as shown in FIG.
  • the crystalline form G provided by the present invention begins to exhibit an endothermic peak upon heating to around 185 ° C, the differential scanning calorimetry diagram being substantially as shown in FIG.
  • the present invention provides Form G having a weight loss gradient of about 4.4% upon heating to 200 ° C, the thermogravimetric analysis of which is illustrated in FIG.
  • Another technical solution of the present invention is to provide a method for preparing ABT199 crystal form G, which comprises any one of the following methods:
  • ABT199 is placed in a dioxane, an anti-solvent is added, and the solid is obtained by stirring to obtain a solid; or the free form of ABT199 is placed in a mixed solvent of dioxane and an anti-solvent, and the mixture is stirred to obtain a solid.
  • the anti-solvent includes, but is not limited to, one or more of water, alcohols, and aromatic hydrocarbons, preferably one or more of water, isopropanol, and toluene.
  • ABT199 is placed in acetic acid, an anti-solvent is added, and the solid is obtained by stirring; or the free form of ABT199 is placed in a mixed solvent of acetic acid and anti-solvent, and the solid is obtained by stirring.
  • the anti-solvent is one or more of an alcohol and an aromatic hydrocarbon, and preferably one or more of isopropanol and toluene.
  • ABT199 refers to the solid, semi-solid, wax or oil form of the compound of formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form B or Form D or Form F or Form G or a mixture thereof in any ratio and a pharmaceutically acceptable pharmaceutical excipient.
  • a therapeutically effective amount of Form B or Form D or Form F or Form G or a mixture thereof in any ratio is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation.
  • Pharmaceutical compositions or formulations are prepared in a manner well known in the pharmaceutical art.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms such as: solid oral preparations, including but not limited to such as powders, granules, pellets, tablets and capsules; liquid oral preparations including, but not limited to, syrups, suspensions, dispersions and emulsions And injections including, but not limited to, solutions, dispersing agents, and lyophilized formulations.
  • the dosage form may be immediate release, delayed release or slow release.
  • Release, and the immediate release preparation may be ordinary, dispersed, chewed, orally disintegrated or fast-dissolved; the sustained release preparation may form a skeleton or a reservoir system by hydrophilic or hydrophobic, or by a controlled release rate of hydrophilic and hydrophobic bonds. Or form a skeleton and reservoir system at the same time.
  • the formulation process may use, for example, direct pressure, dry granulation, wet granulation, and extrusion spheronization.
  • the formulations may be presented in a non-coating, film coating, sugar coating, powder coating, enteric or sustained release coating, and the like.
  • the route of administration is oral, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, vaginal and the like.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release;
  • dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agents, patches; dosage forms suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • formulations can be prepared by any method known in the art of pharmacy.
  • Routes of administration include oral, parenteral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, ocular, auricular, rectal, vaginal, intragastric, intracranial, intrasynovial or intra-articular. Route to give.
  • Form B or Form D or Form F or Form G or a mixture thereof in any ratio can be used to prepare a medicament for treating apoptosis dysfunction and/or overexpression related diseases of anti-apoptotic Bcl-2 family proteins Use in the formulation.
  • Form B or Form D or Form F or Form G or a mixture thereof in any ratio can be used for the preparation of a medicament for the treatment of an antitumor drug.
  • the invention provides a method of treating a disorder characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein, the method comprising administering to the patient a therapeutically effective amount of Form B or Form D Or a pharmaceutical composition of Form F or Form G or a mixture thereof in any ratio and a pharmaceutically acceptable pharmaceutical excipient.
  • the disease includes a tumor disease, an immune disease or an autoimmune disease, especially a tumor disease.
  • a tumor disease Including non-Hodgkin's lymphoma, chronic lymphoid leukemia or acute lymphocytic leukemia.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or showing a disease or condition of the disease, condition or disorder; and (3) improving the disease A disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a disease or condition of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease.
  • Preventing the disease, condition or disorder in the individual (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • polymorph refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound.
  • the phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs. It is known that a pharmaceutical compound having such a polymorph has an influence on pharmacological activity, solubility, bioavailability, stability, and the like due to its physicochemical properties. Therefore, in the case where a compound which is useful as a drug has a polymorph, it is desirable to produce a crystal compound having high usefulness from these polymorphs.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • the X-ray powder diffraction pattern was characterized by peak position and peak intensity.
  • the present invention has the following advantages compared with the prior art:
  • the invention unexpectedly discovered a new crystal form of ABT199, which has good stability, low wettability and uniform particle size distribution compared with the existing crystal form, and the crystal form can be directly crystallized in a solvent, and is contained.
  • the preparation of pharmaceutical preparations of ABT199 provides a new and better choice and is of great significance for drug development.
  • Figure 1 shows the XRPD pattern of ABT199 crystal form B.
  • Figure 2 is a DSC diagram of ABT199 crystal form B
  • FIG. 3 is a TGA diagram of ABT199 crystal form B
  • Figure 4 is a 1 H-NMR chart of Form A of ABT199
  • Figure 5 is an XRPD diagram of ABT199 crystal form D
  • FIG. 6 is a DSC diagram of ABT199 crystal form D
  • FIG. 7 is a TGA diagram of ABT199 crystal form D
  • Figure 8 is a 1 H-NMR chart of Form A of ABT199
  • Figure 9 is an XRPD diagram of ABT199 crystal form F
  • Figure 10 is a DSC diagram of ABT199 crystal form F
  • FIG. 11 is a TGA diagram of ABT199 crystal form F
  • Figure 12 is a 1 H-NMR chart of Form A of ABT199
  • Figure 13 is an XRPD diagram of ABT199 crystal form G
  • Figure 14 is a DSC diagram of the ABT199 crystal form G
  • Figure 15 is a TGA diagram of the ABT199 crystal form G
  • Figure 16 is a 1 H-NMR chart of Form A of ABT199
  • Figure 17 is a PLM diagram of anhydrate B of CN103328474A
  • Figure 18 is a PLM diagram of Form B of the present invention
  • Figure 19 is a PLM diagram of the crystal form D of the present invention
  • Figure 20 is a PLM diagram of the crystal form G of the present invention.
  • Figure 21 is an XRPD overlay before and after the grinding treatment (from the top to the bottom, the starting form F, the crystal form F after grinding, the anhydrous A in the starting CN103328474A and the anhydrate A in the ground CN103328474A after grinding) XRPD map)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the particle size distribution test of the present invention uses a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G. Set the test parameters according to the following table:
  • the polarizing microscope (PLM) pattern of the present invention was collected on an Axio Lab. A1 upright microscope manufactured by ZEISS.
  • ABT199 was weighed into a 20 mL glass vial, and 9 mL of methyl tert-butyl ether solvent was added dropwise, stirred at room temperature overnight, centrifuged, and the resulting solid was dried in vacuo.
  • the solid obtained in this example was Form B, and the X-ray powder diffraction data thereof is shown in Table 1.
  • the XRPD pattern is shown in Figure 1.
  • the DSC chart is shown in Figure 2.
  • An endothermic peak begins to appear near heating to 130 °C.
  • Its TGA pattern is shown in Figure 3 with a weight loss gradient of about 10.3% when heated to 145 °C.
  • 1 H-NMR is shown in Figure 4.
  • ABT199 14.7 mg was weighed into a 20 mL glass vial, dissolved in 14.0 mL of methyl t-butyl ether, and evaporated to give a solid at room temperature.
  • the solid obtained in this example was found to be Form B, and the X-ray powder diffraction data thereof is shown in Table 2.
  • ABT199 208.6 mg was weighed into a 20 mL glass vial, and 10 mL of a mixed solvent of tetrahydrofuran and water in a volume ratio of 1:2 was added thereto, stirred at 50 ° C overnight, and centrifuged to obtain a solid.
  • ABT199 24.9 mg was weighed into a 1.5 mL glass vial, dissolved in 0.1 mL of tetrahydrofuran, and 0.6 mL of the anti-solvent methyl tert-butyl ether was added dropwise, stirred at room temperature overnight, and centrifuged to obtain a solid.
  • ABT199 15.0 mg was weighed into a 1.5 mL glass vial, 0.2 mL of tetrahydrofuran was added thereto, 0.2 mL of anti-solvent water was added dropwise, and the mixture was stirred at 50 ° C overnight, and centrifuged to obtain a solid.
  • ABT199 14.8 mg was weighed into a 1.5 mL glass vial, 0.2 mL of acetic acid was added to dissolve, 0.2 mL of anti-solvent water was added dropwise, and the mixture was stirred at 50 ° C overnight, and centrifuged to obtain a solid.
  • the solid obtained in this example was found to be Form F, and its X-ray powder diffraction data is shown in Table 7.
  • the DSC chart is shown in Figure 10.
  • An endothermic peak begins to appear near 200 °C.
  • Its TGA pattern is shown in Figure 11, with a weight loss gradient of about 4.8% when heated to 200 °C.
  • the solid obtained in this example was found to be Form F, and its X-ray powder diffraction data is shown in Table 8. Its XRPD diagram is shown in Figure 9.
  • the solid obtained in this example was found to be crystalline form F, 1 H NMR as shown in Fig. 12, and X-ray powder diffraction data thereof are shown in Table 9.
  • ABT199 200.1 mg was weighed into a 20 mL glass vial, and 5 mL of a mixed solvent of acetic acid and toluene in a volume ratio of 1:49 was added thereto, stirred at room temperature overnight, and centrifuged to obtain a solid.
  • the solid obtained in this example was examined as Form G, and the X-ray powder diffraction data thereof is shown in Table 12. Its DSC chart is shown in Figure 14. An endothermic peak begins to appear near heating to 185 °C. Its TGA pattern is shown in Figure 15, with a weight loss gradient of about 4.4% when heated to 200 °C. 1 H NMR is shown in Figure 16.
  • each of the anhydrous B in CN103328474A, the crystalline form B of the present invention, the crystalline form D, the crystalline form F and the crystalline form G solid are placed at a constant temperature of 25 ° C / 60% RH and 40 ° C / 75% RH, respectively.
  • Samples were taken for the XRDD test at the initial placement and after the time shown in the table below. The results obtained are shown in Tables 13 and 14.
  • the crystal form B of the present invention According to the results of the long-term stability test and the accelerated stability test of Tables 13 and 14, the crystal form B of the present invention, the crystal form D, the crystal form F, and the form G were left unchanged for 9 months.
  • the anhydrate B has undergone crystal transformation in the 3-month long-term stability test and the 1-month accelerated stability test, and is converted into the hydrate C in CN103328474A. Therefore, the crystal forms B, D, G and F of the present invention exhibit better stability than the anhydrate B, and are more suitable for long-term storage and storage as a crystalline bulk drug or a drug, and are more developed and Practical value.
  • each of the anhydrous B of CN103328474A, the crystalline form B of the present invention, the crystalline form D, the crystalline form F and the crystalline form G solid sample were respectively subjected to DVS (Dynamic Moisture Absorption Test), and the results are shown in Table 15. According to the test results, the hygroscopicity of the crystalline form B, the crystalline form D, the crystalline form F and the crystalline form G of the present invention at 80% RH and 25 ° C was lower than that of the anhydrous B in CN103328474A.
  • Anhydrate B in CN103328474A is hygroscopic, and Form B and Form F of the present invention are slightly hygroscopic, and Form D and Form G are none. Or almost no wettability, and the crystal form B, the crystal form D, the form F and the form G of the present invention did not change in the DVS test. It can be seen that Form B, Form D, Form F and Form G have lower hygroscopicity than Anhydrate B in CN103328474A, and the stability is very good, suitable for later product development and storage. .
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • Mv represents the average particle size by volume
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the crystal grains B, C and G of the present invention have an average particle diameter of about 20 ⁇ m and are normally distributed, and have a uniform particle dispersion property.
  • CN103328474A anhydrate B has different particle sizes, large differences, no normal distribution, and poor particle uniformity.
  • the polarized microscope sample test method is as follows: place about 0.5 mg of the sample onto the glass slide, add a small amount of mineral oil to disperse the sample, cover the cover slip and gently press with the fingertip to ensure that the slide and the cover slip are There are no bubbles at the tip. Adjust the eyepiece and objective of the microscope and fine tune the moving sample stage to focus on the sample.
  • CN103328474A Polarized light microscope (PLM) results for anhydrous B, Form B, Form D and Form G of the present invention are shown in Figures 17, 18, 19 and 20.
  • the solid morphology of the crystal form B, the crystal form D and the crystal form G of the present invention are also fine rods and uniform distribution, while the CN103328474A anhydrate B has obvious agglomeration and agglomeration.
  • the particle properties of the crystal form D and the crystal form G are not easily agglomerated or agglomerated, and the crystal morphology is regular.
  • the crystal form B, the crystal form D and the crystal form G of the present invention Compared with CN103328474A anhydrate B, it has a more uniform particle size distribution and a more regular crystal morphology, which helps to improve the performance of the drug during the process, and simplifies the post-treatment process such as powder homogenization. Drug development offers better options.
  • the crystal form F of the present invention and the anhydrous substance A of CN103328474A were each about 20 mg, respectively, and manually ground for 5 minutes in a mortar, and the sample XRPD test was performed before and after the grinding.
  • the test results are shown in Fig. 21. It can be seen that the crystal form F of the present invention has a decreased crystallinity after grinding, but the crystallinity is not lost, and the CN103328474A anhydrate A has been subjected to grinding and the test result is amorphous. It can be seen that the crystalline form F of the present invention has better mechanical grinding resistance than the anhydrous A in CN103328474A, so that it can maintain good stability and reliability during the post-treatment of tablets and the like.
  • the crystal form B of the present invention and the CN103328474A anhydrate A solid were each mixed 5 mg.
  • different water activities were set, and the stirring test at room temperature was carried out. After stirring overnight, the crystal form was examined, and it was found that crystal form B was obtained under the other water activities except that the mixture was stirred in pure water to obtain an amorphous shape. It can be seen that the crystal form B of the present invention can stably exist under various water activity conditions, and is suitable for later development.

Abstract

本发明涉及一种细胞凋亡诱导剂的新晶型及其制备方法，其结构式如式(I)所示，这些晶型能够直接从溶剂中析晶得到，且稳定性良好、引湿性低、粒度分布均一，为含ABT199的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

细胞凋亡诱导剂的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及一种细胞凋亡诱导剂的新晶型及其制备方法。
背景技术
细胞凋亡与增殖的动态平衡是多细胞生物维系其结构稳定和内环境功能平衡及生长发育最基本的生物学过程。研究表明，原癌基因Bcl-2是抑制细胞凋亡的主要原因，由其控制表达的Bcl-2蛋白，从原虫到人细胞都有阻断细胞凋亡的功能。细胞凋亡是逃避癌症的特点，癌细胞通过其逃避细胞凋亡的一种主要方法是通过上调Bcl-2家族的抗细胞凋亡蛋白。
在免疫系统的各种癌症和病症中，Bcl-2蛋白的超表达与对化疗的抗性、临床结果、疾病发展、总的预后或其组合有关。Bcl-2在许多血液系统恶性疾患中都有累及，在急性髓系白血病(AML)中耐药性和不良预后相关。复发/难治性(R/R)AML的患者通常预后很差，生存很短。ABT199，又名Venetoclax，是一个选择性、强效、口服的小分子Bcl-2抑制剂。2016年4月11日FDA批准其上市，商品名为Venclexta。ABT199的化学名称为4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺，结构式如式I所示。
Figure PCTCN2016102022-appb-000001
已知晶型是影响药品质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效产生不同的影响。因此，研发新的更适合应用的晶型对于药物开发具有非常重要的意义。
目前，CN103153993A实施例5中公开了ABT199的制备方法，其中制得的ABT199固体为无定形。CN103328474A公开了ABT199的结晶形式，包括2个无水物，2个水合物及多种溶剂合物。该专利中无水物及水合物均需通过溶剂合物干燥得到。
因此，提供ABT199新的无水物、水合物形式，这些无水物、水合物能够直接从溶剂中析晶得到，且稳定性良好、引湿性低、粒度分布均一，对药物开发具有重要意义。
发明内容
本发明所要解决的技术问题是克服现有技术的不足，提供能够直接从溶剂中析晶得到的式(Ⅰ)化合物的无水物、水合物形式，分别命名为ABT199的晶型B、D、F、G。
为解决以上技术问题，本发明采取如下技术方案：
本发明提供ABT199的晶型B，其25℃下的X射线粉末衍射图(CuKα辐 射)在2θ值为5.3°±0.2°、11.3°±0.2°、6.7°±0.2°处具有特征峰。
进一步地，晶型B的X射线粉末衍射图还在2θ值为16.8°±0.2°、20.6°±0.2°、10.2°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型B的X射线粉末衍射图还在2θ值为16.8°±0.2°、20.6°±0.2°、10.2°±0.2°处具有特征峰。
更进一步的，晶型B的X射线粉末衍射图还在2θ值为15.7°±0.2°、5.9°±0.2°、22.8°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型B的X射线粉末衍射图还在2θ值为15.7°±0.2°、5.9°±0.2°、22.8°±0.2°处具有特征峰。
在一个具体且优选的实施方案中，所述晶型B，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为5.3°±0.2°、11.3°±0.2°、6.7°±0.2°、16.8°±0.2°、20.6°±0.2°、10.2°±0.2°、15.7°±0.2°、5.9°±0.2°、22.8°±0.2°中处具有特征峰。
根据本发明的一个具体且优选方面，晶型B的X射线粉末衍射图如图1所示。
根据本发明的一个具体且优选方面，本发明提供的晶型B，在加热至130℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图2所示。
根据本发明的一个具体且优选方面，本发明提供的晶型B，在加热至145℃具有约10.3％的重量损失梯度，其热重分析图如图3所示。
本发明的另一个技术方案是提供一种ABT199晶型B的制备方法，包括：将ABT199的游离形式置于烷基醚类有机溶剂中，通过搅拌分离或挥发的方法得到固体。
进一步地，所述烷基醚类溶剂为甲基叔丁基醚。
本发明提供ABT199的晶型D，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为12.7°±0.2°、19.1°±0.2°、22.3°±0.2°处具有特征峰。
进一步地，晶型D的X射线粉末衍射图还在2θ值为6.3°±0.2°、16.8°±0.2°、 22.9°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型D的X射线粉末衍射图还在2θ值为6.3°±0.2°、16.8°±0.2°、22.9°±0.2°处具有特征峰。
更进一步的，晶型D的X射线粉末衍射图还在2θ值为11.4°±0.2°、16.4°±0.2°、19.9°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型B的X射线粉末衍射图还在2θ值为11.4°±0.2°、16.4°±0.2°、19.9°±0.2°处具有特征峰。
在一个具体且优选的实施方案中，所述晶型D，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为12.7°±0.2°、19.1°±0.2°、22.3°±0.2°、6.3°±0.2°、16.8°±0.2°、22.9°±0.2°、11.4°±0.2°、16.4°±0.2°、19.9°±0.2°处具有特征峰。
根据本发明的一个具体且优选方面，晶型D的X射线粉末衍射图如图5所示。
根据本发明的一个具体且优选方面，本发明提供的晶型D，在加热至147℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图6所示。
根据本发明的一个具体且优选方面，本发明提供的晶型D，在加热至180℃具有约2.9％的重量损失梯度，其热重分析图如图7所示。
本发明的另一个技术方案是提供一种ABT199晶型D的制备方法，所述制备方法包括下述方法中的任一种：
1)将ABT199的游离形式置于四氢呋喃中，加入反溶剂，搅拌分离得到固体；或
2)将ABT199的游离形式置于四氢呋喃与反溶剂的混合溶剂中，搅拌分离得到固体。
进一步的，所述反溶剂包括但不限于水、烷烃、烷基醚中的一种或多种，优选为水、正庚烷、甲基叔丁基醚的一种或多种。
本发明提供ABT199的晶型F，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为12.4°±0.2°、13.3°±0.2°、5.9°±0.2°处具有特征峰。
进一步地，晶型F的X射线粉末衍射图还在2θ值为17.5°±0.2°、18.5°±0.2°、19.0°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型F的X射线粉末衍射图还在2θ值为17.5°±0.2°、18.5°±0.2°、19.0°±0.2°处具有特征峰。
更进一步的，晶型F的X射线粉末衍射图还在2θ值为21.3°±0.2°、24.2°±0.2°、17.9°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型F的X射线粉末衍射图还在2θ值为21.3°±0.2°、24.2°±0.2°、17.9°±0.2°处具有特征峰。
在一个具体且优选的实施方案中，所述晶型F，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为17.5°±0.2°、13.3°±0.2°、5.9°±0.2°、12.4°±0.2°、18.5°±0.2°、19.0°±0.2°、21.3°±0.2°、24.2°±0.2°、17.9°±0.2°处具有特征峰。
根据本发明的一个具体且优选方面，晶型F的X射线粉末衍射图如图9所示。
根据本发明的一个具体且优选方面，本发明提供的晶型F，在加热至210℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图10所示。
根据本发明的一个具体且优选方面，本发明提供的晶型F，在加热至200℃具有约4.8％的重量损失梯度，其热重分析图如图11所示。
本发明的另一个技术方案是提供一种ABT199晶型F的制备方法，所述制备方法包括下述方法中的任一种：
1)将ABT199的游离形式置于乙酸中，加入水，搅拌分离得到固体；或
2)将ABT199的游离形式置于乙酸与水的混合溶剂中，搅拌分离得到固体。
本发明提供ABT199的晶型G，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为10.6°±0.2°、11.1°±0.2°、24.5°±0.2°处具有特征峰。
进一步地，晶型G的X射线粉末衍射图还在2θ值为9.6°±0.2°、19.3°±0.20°、20.3°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型G的X射线粉末衍射图还在2θ值为9.6°±0.2°、19.3°±0.2°、20.3°±0.2°处具有特征峰。
更进一步的，晶型G的X射线粉末衍射图还在2θ值为11.8°±0.2°、14.6°±0.2°、16.5°±0.2°中的一处或多处具有特征峰；优选的，本发明晶型G的X射线粉末衍射图还在2θ值为11.8°±0.2°、14.6°±0.2°、16.5°±0.2°处具有特征峰。
在一个具体且优选的实施方案中，所述晶型G，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为10.6°±0.2°、11.1°±0.2°、24.5°±0.2°、9.6°±0.2°、19.3°±0.2°、20.3°±0.2°、11.8°±0.2°、14.6°±0.2°、16.5°±0.2°处具有特征峰。
根据本发明的一个具体且优选方面，晶型G的X射线粉末衍射图如图13所示。
根据本发明的一个具体且优选方面，本发明提供的晶型G，在加热至185℃附近时开始出现一个吸热峰，其差示扫描量热分析图基本如图14所示。
根据本发明的一个具体且优选方面，本发明提供的晶型G，在加热至200℃具有约4.4％的重量损失梯度，其热重分析图如图15所示。
本发明的另一个技术方案是提供一种ABT199晶型G的制备方法，所述制备方法包括下述方法中的任一种：
1)将ABT199的游离形式置于二氧六环中，加入反溶剂，搅拌分离得到固体；或将ABT199的游离形式置于二氧六环与反溶剂的混合溶剂中，搅拌分离得到固体。
进一步的，所述反溶剂包括但不限于水、醇类、芳香烃类中的一种或多种，优选为水、异丙醇、甲苯中的一种或多种。
2)将ABT199的游离形式置于乙酸中，加入反溶剂，搅拌分离得到固体；或将ABT199的游离形式置于乙酸与反溶剂的混合溶剂中，搅拌分离固体得到。
进一步的，所述反溶剂为醇类、芳香烃类的一种或多种，优选为异丙醇、甲苯的一种或多种。
在本发明的晶型B、D、F、G的制备方法中：
所述ABT199游离形式是指式(I)化合物的固体、半固体、蜡或油形式。
Figure PCTCN2016102022-appb-000002
本发明提供一种包含有效治疗量的晶型B或晶型D或晶型F或晶型G或其任意比例的混合物和药学上可接受的药用辅料的药用组合物。一般是将治疗有效量的晶型B或晶型D或晶型F或晶型G或其任意比例的混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
上述药物组合物可制成一定的剂型，通过适合的途径给药。剂型如：固体口服制剂，其包括但不局限于如散剂、颗粒剂、微丸、片剂和胶囊剂；液体口服制剂，其包括但不局限于如糖浆剂、混悬剂、分散剂和乳剂；以及注射剂，其包括但不局限于如溶液剂、分散剂和冻干制剂。剂型可能是速释、迟释或缓 释，且速释制剂可能是普通、分散、咀嚼、口崩或速溶；缓释制剂可能由亲水或疏水，或由亲水和疏水结合的控制释放速率的物质来形成骨架或储库系统，或同时形成骨架和储库系统。处方工艺可能使用如直压、干法制粒、湿法制粒和挤出滚圆。制剂可能的呈现方式有不包衣、薄膜包衣、糖衣、粉末包衣、肠溶或缓释包衣等。给药途径如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。上述制剂可通过药学领域已知的任何方法来制备。给药途径包括通过口服、肠胃外、舌下、口腔、鼻内、肺部、局部、透皮、皮内、眼睛、耳部、直肠、阴道、胃内、颅内、滑膜内或关节内途径给予。
晶型B或晶型D或晶型F或晶型G或其任意比例的混合物可用于制备治疗抗细胞凋亡Bcl-2家族蛋白的细胞凋亡功能障碍和/或过度表达相关的疾病的药物制剂中的用途。晶型B或晶型D或晶型F或晶型G或其任意比例的混合物可用于制备治疗抗肿瘤药物制剂中的用途。
本发明提供治疗特征在于抗细胞凋亡Bcl-2家族蛋白的细胞凋亡功能障碍和/或过度表达的疾病的方法，该方法包括向所述患者给予治疗有效量的晶型B或晶型D或晶型F或晶型G或其任意比例的混合物和药学上可接受的药用辅料的药用组合物。
所述疾病包括肿瘤疾病、免疫性疾病或自身免疫性疾病，尤其是肿瘤疾病 包括非霍奇金淋巴瘤、慢性淋巴样白血病或急性淋巴细胞性白血病等。
本发明中的术语，如没有明确定义，按照本领域技术人员的理解取其通常的意思。
本文所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本文所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
本文所使用的术语“多晶型”是指相同化合物的不同晶型且包括但不限于包含相同化合物的水合物及溶剂合物的其它固态分子形式。同一种药物分子形成多种晶型的现象称为药物多晶型，药物多晶型是固体药物中普遍存在的现象。已知具有这样的多晶型的药物化合物由于其物理化学性质不同而对药理活性、溶解性、生物利用度及稳定性等带来影响。因此，在作为药品有用的化合物存在多晶型的情况下，希望从这些多晶型中制造有用性高的晶型化合物。
本文所使用的术语“X射线粉末衍射图”是指实验观测到的衍射图或源自其的参数。通过峰位置及峰强度表征X射线粉末衍射图。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明意外发现了ABT199的新晶型，与现有晶型相比，该晶型稳定性良好、引湿性低、粒度分布均一，并且该晶型均能直接在溶剂中结晶得到，为含 ABT199的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
附图说明
图1为ABT199晶型B的XRPD图
图2为ABT199晶型B的DSC图
图3为ABT199晶型B的TGA图
图4为ABT199晶型B的1H-NMR图
图5为ABT199晶型D的XRPD图
图6为ABT199晶型D的DSC图
图7为ABT199晶型D的TGA图
图8为ABT199晶型D的1H-NMR图
图9为ABT199晶型F的XRPD图
图10为ABT199晶型F的DSC图
图11为ABT199晶型F的TGA图
图12为ABT199晶型F的1H-NMR图
图13为ABT199晶型G的XRPD图
图14为ABT199晶型G的DSC图
图15为ABT199晶型G的TGA图
图16为ABT199晶型G的1H-NMR图
图17为CN103328474A的无水物B的PLM图
图18为本发明晶型B的PLM图
图19为本发明晶型D的PLM图
图20为本发明晶型G的PLM图
图21为研磨处理前后的XRPD叠图(从上往下依次是起始晶型F，研磨后的晶型F，起始的CN103328474A中无水物A和研磨后的CN103328474A中无水物A的XRPD图)
具体实施方式
以下结合具体的实施例对本发明做进一步详细的说明，但本发明不限于以下实施例。实施例中未注明的条件为常规条件。制备方法中作为原料的ABT199游离形式通过已知方法制备得到。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的名词解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H-NMR：液态核磁氢谱
DVS：动态水分吸附
PLM：偏光显微镜
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Kα1
Figure PCTCN2016102022-appb-000003
1.540598；Kα2
Figure PCTCN2016102022-appb-000004
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明的粒度分布测试使用Microtrac公司的S3500型激光粒度分析仪。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。根据如下表格设置试验参数：
Figure PCTCN2016102022-appb-000005
Figure PCTCN2016102022-appb-000006
*：流速60％为65mL/s的60％
本发明所述的偏光显微镜(PLM)图在由ZEISS公司生产的Axio Lab.A1正置式显微镜上采集。
实施例1
称取209.6mg ABT199游离形式加入20mL玻璃小瓶中，滴加9mL的甲基叔丁基醚溶剂，室温下搅拌过夜，离心，真空干燥所得固体。
经检测，本实施例得到的固体为晶型B，其X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，在加热至130℃附近开始出现一个吸热峰。其TGA图如图3，在加热至145℃具有约10.3％的重量损失梯度。1H-NMR如图4。
1H-NMR数据如下：1H NMR(400MHz,DMSO)δ11.68(s,1H),11.38(s,1H),8.60(t,J＝5.8Hz,1H),8.56(d,J＝2.2Hz,1H),8.04(d,J＝2.6Hz,1H),7.80(dd,J＝9.2,2.0Hz,1H),7.60–7.44(m,3H),7.34(d,J＝8.4Hz,2H),7.11(d,J＝9.4Hz,1H),7.04(d,J＝8.4Hz,2H),6.68(dd,J＝9.1,2.0Hz,1H),6.39(dd,J＝3.3,1.8Hz,1H),6.19(d,J＝2.0Hz,1H),3.85(dd,J＝11.2,3.0Hz,2H),3.25(d,J＝11.5Hz,1H),3.08(s,4H),2.76(s,2H),2.17(d,J＝23.0Hz,5H),1.95(s,2H),1.89(s,1H),1.61(d,J＝11.2Hz,2H),1.38(t,J＝6.5Hz,2H),1.26(qd,J＝12.0,4.1Hz,2H),1.11(s,2H),0.92(s,6H).
表1
2θ d间隔 强度％
5.33 16.58 100.00
6.01 14.72 21.92
6.71 13.16 15.40
10.15 8.72 16.06
11.31 7.82 54.63
13.13 6.74 10.29
15.07 5.88 7.82
15.78 5.62 9.56
16.79 5.28 10.56
17.70 5.01 11.14
20.58 4.32 16.84
22.82 3.90 6.37
23.44 3.80 6.76
实施例2
称取14.7mg ABT199游离形式放入20mL玻璃小瓶中，加入14.0mL的甲基叔丁基醚溶剂溶清，室温下敞口挥发得到固体。
经检测，本实施例得到的固体为晶型B，其X射线粉末衍射数据如表2所示。
表2
2θ d间隔 强度％
5.33 16.59 100.00
5.87 15.05 44.99
6.70 13.19 17.87
10.18 8.69 12.79
11.27 7.85 41.63
13.10 6.76 5.32
13.63 6.50 6.31
15.66 5.66 7.80
16.78 5.29 11.71
17.69 5.01 9.44
20.57 4.32 15.28
22.75 3.91 8.65
23.45 3.79 6.14
24.73 3.60 1.56
29.07 3.07 1.20
实施例3
称取28.3mg ABT199游离形式，加入1mL的甲基叔丁基醚溶剂，放置于5℃条件下搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型B，其X射线粉末衍射数据如表3所示。
表3
2θ d间隔 强度％
5.31 16.65 100.00
5.90 14.98 33.91
6.69 13.22 24.40
10.16 8.71 10.51
11.27 7.85 41.61
15.65 5.66 7.48
16.71 5.30 6.58
20.56 4.32 10.56
22.80 3.90 5.05
实施例4
称取208.6mg ABT199游离形式加入20mL玻璃小瓶中，加入10mL的四氢呋喃和水体积比为1:2的混合溶剂，50℃下搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型D，其X射线粉末衍射数据如表4所示。其XRPD图如图5，其DSC图如图6，在加热至147℃附近开始出现一个吸热峰。其TGA图如图7，在加热至180℃具有约2.9％的重量损失梯度。1H NMR如图8。
1H NMR数据如下：1H NMR(400MHz,DMSO)δ11.68(s,1H),11.39(s,1H),8.59(d,J＝5.5Hz,1H),8.56(d,J＝2.2Hz,1H),8.04(d,J＝2.6Hz,1H),7.80(d,J＝9.2Hz,1H),7.59–7.43(m,3H),7.34(d,J＝8.4Hz,2H),7.11(d,J＝9.2Hz,1H),7.04(d,J＝8.4Hz,2H),6.68(d,J＝7.0Hz,1H),6.39(dd,J＝3.2,1.8Hz,1H),6.19(d,J＝1.9Hz,1H),3.85(dd,J＝11.3,3.0Hz,2H),3.25(d,J＝11.3Hz,1H),3.07(s,4H),2.75(s,2H),2.17(d,J＝22.5Hz,5H),1.95(s,2H),1.89(s,1H),1.61(d,J＝11.8Hz,2H),1.38(t,J＝6.3Hz,2H),1.26(ddd,J＝16.6,12.7,4.5Hz,2H),0.92(s,5H).
表4
2θ d间隔 强度％
6.30 14.04 100.00
6.96 12.70 1.39
7.71 11.47 2.31
11.36 7.79 16.72
11.66 7.59 19.27
12.70 6.97 37.17
13.23 6.69 10.53
14.24 6.22 21.99
16.35 5.42 15.75
16.77 5.29 7.32
17.85 4.97 5.49
18.26 4.86 3.05
19.15 4.64 48.98
19.85 4.47 15.62
21.52 4.13 6.17
22.28 4.00 44.94
22.87 3.89 17.52
23.76 3.74 1.52
25.65 3.47 8.68
26.57 3.35 8.93
27.44 3.25 2.50
28.51 3.13 9.45
32.07 2.79 0.92
实施例5
称取24.9mg ABT199游离形式加入1.5mL玻璃小瓶中，加入0.1mL的四氢呋喃溶清，滴加0.6mL的反溶剂甲基叔丁基醚，室温搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型D，其X射线粉末衍射数据如表5所示。
表5
2θ d间隔 强度％
6.28 14.08 20.69
11.35 7.79 27.39
11.66 7.59 20.59
12.68 6.98 39.21
13.27 6.67 30.53
14.27 6.21 37.22
15.50 5.72 17.54
16.37 5.41 33.64
16.77 5.29 39.73
17.84 4.97 28.10
19.17 4.63 85.10
19.88 4.47 47.33
22.27 3.99 100.00
22.85 3.89 38.62
23.97 3.71 13.21
25.63 3.48 16.36
26.64 3.35 22.45
28.49 3.13 17.04
实施例6
称取15.0mg ABT199游离形式加入1.5mL玻璃小瓶中，加入0.2mL的四氢呋喃溶清，滴加0.2mL的反溶剂水，50℃条件下搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型D，其X射线粉末衍射数据如表6所示。
表6
2θ d间隔 强度％
6.29 14.06 100.00
7.73 11.44 7.65
11.39 7.77 24.03
12.69 6.97 25.13
13.30 6.66 19.01
14.28 6.20 27.48
16.39 5.41 15.19
16.85 5.26 15.52
18.06 4.91 16.10
19.18 4.63 32.83
19.89 4.46 18.26
22.32 3.98 40.50
22.91 3.88 17.77
25.66 3.47 6.67
26.73 3.34 11.05
28.54 3.13 7.00
实施例7
称取14.8mg ABT199游离形式加入1.5mL玻璃小瓶中，加入0.2mL的乙酸溶清，滴加0.2mL的反溶剂水，50℃条件下搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型F，其X射线粉末衍射数据如表7所示。其DSC图如图10，加热至210℃附近开始出现一个吸热峰。其TGA图如图11，在加热至200℃具有约4.8％的重量损失梯度。
表7
2θ d间隔 强度％
4.94 17.88 16.76
5.89 15.01 100.00
9.79 9.03 5.96
12.44 7.11 31.97
13.25 6.68 34.67
15.29 5.79 10.30
15.83 5.60 18.68
16.69 5.31 8.07
17.46 5.08 76.46
17.94 4.94 61.47
18.56 4.78 12.23
18.98 4.68 14.73
19.68 4.51 17.06
20.19 4.40 11.96
20.93 4.24 19.72
21.33 4.17 27.44
22.80 3.90 5.95
24.26 3.67 16.38
25.25 3.53 9.26
28.28 3.16 32.21
34.76 2.58 5.28
38.13 2.36 2.78
实施例8
称取28.2mg ABT199游离形式加入1.5mL玻璃小瓶中，加入0.2mL的乙酸溶清，滴加0.4mL的反溶剂水，50℃条件下搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型F，其X射线粉末衍射数据如表8所示。其XRPD图如图9。
表8
2θ d间隔 强度％
5.92 14.94 29.75
9.80 9.03 18.51
11.05 8.01 3.51
12.45 7.11 52.07
13.31 6.65 76.43
15.24 5.81 15.84
15.80 5.61 16.22
16.01 5.54 11.53
16.67 5.32 30.07
17.51 5.06 100.00
17.99 4.93 32.52
18.54 4.79 59.49
18.93 4.69 51.79
19.61 4.53 25.31
20.09 4.42 17.46
20.96 4.24 32.53
21.23 4.19 54.34
21.56 4.12 18.99
22.19 4.01 28.75
22.65 3.93 16.86
23.77 3.74 11.78
24.17 3.68 39.56
25.23 3.53 23.00
28.18 3.17 34.71
30.37 2.94 4.26
实施例9
称取289.2mg ABT199游离形式加入20mL玻璃小瓶中，加入2mL的乙酸溶清，缓慢加入8mL的反溶剂水，于50℃条件下搅拌一周，过滤后用约20mL的水洗涤，后放置于150℃的烘箱中干燥2小时后得到固体。
经检测，本实施例得到的固体为晶型F，1H NMR如图12，其X射线粉末衍射数据如表9所示。
1H NMR数据如下：1H NMR(400MHz,DMSO)δ11.69(s,1H),8.74–8.53(m,2H),8.04(d,J＝2.6Hz,1H),7.80(dd,J＝9.2,2.0Hz,1H),7.59–7.45(m,3H),7.34(d,J＝8.4Hz,2H),7.07(dd,J＝28.7,8.8Hz,3H),6.68(dd,J＝9.0,2.1Hz,1H),6.39(dd,J＝3.3,1.9Hz,1H),6.19(d,J＝2.1Hz,1H),3.85(dd,J＝11.3,3.0Hz,2H),3.35–3.20(m,66H),3.07(s,4H),2.71(d,J＝34.0Hz,3H),2.50(dt,J＝3.6,1.8Hz,33H),2.22(t,J＝36.9Hz,6H),1.95(s,2H),1.89(s,1H),1.61(d,J＝10.7Hz,2H),1.39(d,J＝6.2Hz,1H),1.38–1.04(m,3H),0.92(s,6H).
表9
2θ d间隔 强度％
5.89 15.01 56.49
9.27 9.54 20.20
9.75 9.07 20.10
12.45 7.11 65.79
13.22 6.70 100.00
15.27 5.80 22.32
15.80 5.61 18.83
16.67 5.32 32.29
17.45 5.08 98.98
17.93 4.95 34.15
18.61 4.77 58.35
18.90 4.69 54.93
19.66 4.51 38.40
20.08 4.42 17.19
20.94 4.24 27.07
21.33 4.17 80.25
22.18 4.01 20.95
24.28 3.67 38.92
25.23 3.53 19.77
28.29 3.15 34.66
29.90 2.99 3.97
实施例10
称取203.5mg ABT199游离形式加入20mL玻璃小瓶中，加入10mL的二氧六环和异丙醇体积比为1:4的混合溶剂中，室温下搅拌过夜，离心，150℃条件下真空干燥得到固体。
经检测，本实施例得到的固体为晶型G，其X射线粉末衍射数据如表10所示。其XRPD图如图13。
表10
2θ d间隔 强度％
5.31 16.64 61.86
8.73 10.12 5.85
9.58 9.23 33.82
10.63 8.32 42.08
11.11 7.96 26.48
11.81 7.49 25.64
14.61 6.06 60.38
15.57 5.69 20.21
16.10 5.50 24.39
16.55 5.36 17.72
17.63 5.03 9.62
18.73 4.74 9.28
19.32 4.59 33.04
19.87 4.47 74.94
20.37 4.36 73.05
20.97 4.24 69.54
23.94 3.72 15.42
24.47 3.64 100.00
25.32 3.52 43.84
25.71 3.47 31.81
27.13 3.29 19.18
29.42 3.04 17.28
30.84 2.90 7.69
31.41 2.85 4.86
33.93 2.64 7.53
36.19 2.48 9.84
38.38 2.35 4.55
实施例11
称取23.0mg ABT199游离形式加入1.5mL玻璃小瓶中，加入0.5mL的二 氧六环溶剂中，滴加反溶剂水0.4mL，室温下搅拌过夜，离心，140℃条件下真空干燥得到固体。
经检测，本实施例得到的固体为晶型G，其X射线粉末衍射数据如表11所示。
表11
2θ d间隔 强度％
8.82 10.02 19.37
9.56 9.25 58.06
10.66 8.30 45.01
11.10 7.97 33.93
11.80 7.50 32.76
12.97 6.82 10.87
14.61 6.06 59.46
14.83 5.98 70.05
15.58 5.69 17.84
15.89 5.58 24.98
16.54 5.36 43.88
17.67 5.02 29.65
18.78 4.72 20.23
19.30 4.60 75.91
19.88 4.47 100.00
20.30 4.38 95.69
20.98 4.23 57.33
24.50 3.63 83.64
25.57 3.48 38.22
26.88 3.32 8.97
29.37 3.04 11.47
32.19 2.78 6.65
36.32 2.47 4.52
实施例12
称取200.1mg ABT199游离形式加入20mL玻璃小瓶中，加入5mL的乙酸和甲苯体积比为1:49的混合溶剂中，室温下搅拌过夜，离心得到固体。
经检测，本实施例得到的固体为晶型G，其X射线粉末衍射数据如表12所示。其DSC图如图14，在加热至185℃附近开始出现一个吸热峰。其TGA图如图15，在加热至200℃具有约4.4％的重量损失梯度。1H NMR如图16。
1H NMR数据如下：1H NMR(400MHz,DMSO)δ11.68(s,1H),11.59–11.34(m,1H),8.58(d,J＝15.5Hz,2H),8.04(d,J＝2.5Hz,1H),7.80(d,J＝9.0Hz,1H),7.50(t,J＝10.7Hz,2H),7.34(d,J＝8.4Hz,2H),7.12(s,1H),7.04(d,J＝8.4Hz,2H),6.68(d,J＝8.7Hz,1H),6.39(s,1H),6.19(s,1H),3.85(d,J＝8.7Hz,2H),3.07(s,3H),2.74(s,2H),2.67(s,1H),2.33(s,1H),2.15(s,4H),1.95(s,3H),1.61(d,J＝11.8Hz,2H),1.39(d,J＝6.8Hz,2H),1.26(d,J＝8.4Hz,2H),0.92(s,5H).
表12
2θ d间隔 强度％
5.26 16.81 42.15
8.73 10.13 12.99
9.56 9.25 100.00
10.67 8.29 45.12
11.12 7.95 58.41
11.81 7.49 24.75
14.64 6.05 72.59
16.54 5.36 40.08
19.24 4.61 56.40
19.95 4.45 72.05
20.26 4.38 84.84
24.50 3.63 56.10
25.62 3.48 17.64
29.22 3.06 7.19
实施例13
晶型的稳定性研究：
各取CN103328474A中的无水物B，本发明的晶型B，晶型D，晶型F和晶型G固体约20毫克分别放置于25℃/60％RH和40℃/75％RH恒温恒湿箱中。并在起始放置时和放置如下表所示时间后分别取样进行晶型XRPD测试。所得结果如表13和14所示。
表13长期稳定性试验
Figure PCTCN2016102022-appb-000007
Figure PCTCN2016102022-appb-000008
表14加速稳定性试验
Figure PCTCN2016102022-appb-000009
根据表13和14长期稳定性试验及加速稳定性试验结果来看，本发明晶型B，晶型D，晶型F，晶型G放置9个月后晶型没有发生变化。而无水物B在3个月长期稳定性试验和1个月加速稳定性试验中均已发生转晶，转变为CN103328474A中的水合物C。因此，与无水物B相比，本发明的晶型B、D、G和F表现出更好的稳定性，更适于作为晶型原料药或者药品来长期放置与贮存，更具有开发和实用价值。
实施例14
引湿性研究：
各取CN103328474A的无水物B，本发明的晶型B，晶型D，晶型F和晶型G固体样品约10毫克分别做DVS(动态水分吸附测试)，结果如表15所示。根据测试结果可知，在80％RH，25℃的条件下，本发明的晶型B，晶型D，晶型F和晶型G的吸湿性均低于CN103328474A中的无水物B。
表15
Figure PCTCN2016102022-appb-000010
Figure PCTCN2016102022-appb-000011
参考中国2015年《药典》通则9103中关于引湿性定义，CN103328474A中无水物B属于有引湿性，本发明晶型B和晶型F属于略有引湿性，晶型D和晶型G属于无或几乎无引湿性，并且本本发明的晶型B、晶型D、晶型F和晶型G在DVS试验中晶型均未发生改变。可见晶型B，晶型D，晶型F和晶型G相比于CN103328474A中的无水物B而言，均具有更低的引湿性，并且稳定性表现很好，适合后期产品开发及储存。
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例15
晶型的颗粒属性研究：
取10–30mg样品加入10mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使样品量指示图达到合适位置，开始实验，粒径分布测试结果如表16所示。
表16
Figure PCTCN2016102022-appb-000012
Mv：表示按照体积计算的平均粒径
SD：表示标准偏差
D10：表示粒径分布中(体积分布)占10％所对应的粒径
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径
D90：表示粒径分布中(体积分布)占90％所对应的粒径
上述试验结果来看，本发明的晶型B、晶型D和晶型G的平均粒径在20μm左右并呈正态分布，具有均一性良好的颗粒分散属性。而CN103328474A无水物B的颗粒大小不一，相差较大，不呈正态分布，颗粒均一性差。
偏光显微镜样品测试方法为：放置约0.5mg的样品至载玻片上，滴加少量的矿物油使样品分散，覆盖上盖玻片后轻轻用指尖按压，确保载玻片与盖玻片指尖没有气泡。调整显微镜的目镜和物镜，并微调移动样品台，聚焦至样品清晰。CN103328474A无水物B、本发明的晶型B、晶型D和晶型G的偏光显微镜(PLM)结果如图17、18、19和20所示。从PLM图像能清晰的发现，本发明的晶型B、晶型D和晶型G固体形貌也均是细小棒状且分布均匀，而CN103328474A无水物B有明显的团聚、结块的现象。本发明的晶型B，晶型D和晶型G的颗粒属性不易团聚或者结块，且晶体形貌规则。
从粒度分布以及形貌研究数据可以发现，本发明晶型B、晶型D和晶型G 与CN103328474A无水物B相比，具有更均一的粒径分布，更规则的晶体形貌，有助于提升药物在工艺过程中的排杂性能，简化粉体均一化等后处理过程，，为药物开发提供更好的选择。
实施例16
晶型F的研磨稳定性研究：
取本发明的晶型F和CN103328474A无水物A各约20毫克左右，分别用研钵手动研磨5分钟，研磨前后对进行样品XRPD测试。测试结果见图21，由此可见，本专利晶型F经过研磨后结晶度下降，但未失去结晶性，而CN103328474A无水物A经过研磨后测试结果为无定形。可见，本发明的晶型F与CN103328474A中的无水物A相比具有更好地抗机械研磨的特性，使其可以在压片等后期制剂处理过程中保持很好的稳定性和可靠性。
实施例17
晶型F的热力学稳定性研究：
取CN103328474A无水物A，本发明的晶型D、晶型F、晶型G各约5毫克，加入到4毫升体积比为1:9的N,N-二甲基甲酰胺与乙醇的混合溶剂中。在50℃条件下搅拌过夜，测得结果如表17所示。在50℃条件下，CN103328474A中的无水物A、本发明的晶型D和G均变成本发明的晶型F。可见本发明的晶型F在测试条件下更稳定。
表17
Figure PCTCN2016102022-appb-000013
实施例18
晶型B在不同水活度下的稳定性研究：
取本发明晶型B和CN103328474A无水物A固体各5毫克混合，通过调节水和甲基叔丁基醚混合溶剂的不同体积比，设置不同水活度，进行室温下混悬搅拌试验。搅拌过夜后检测晶型，发现除了在纯水里搅拌得到无定形外，其余水活度下都得到晶型B。可见本发明晶型B在各个水活度条件下都能稳定存在，适合后期开发。
表18
Figure PCTCN2016102022-appb-000014
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (23)

  1. 一种式(I)化合物的晶型B，
    Figure PCTCN2016102022-appb-100001
    其特征在于，其X射线粉末衍射图(CuKα辐射)在2θ值为5.3°±0.2°、11.3°±0.2°、6.7°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型B，其特征还在于，其X射线粉末衍射图还在2θ值为16.8°±0.2°、20.6°±0.2°、10.2°±0.2°中的一处或多处具有衍射峰。
  3. 根据权利要求1或2所述的晶型B，其特征还在于，其X射线粉末衍射图还在2θ值为15.7°±0.2°、5.9°±0.2°、22.8°±0.2°中的一处或多处具有衍射峰。
  4. 根据权利要求1至3任一项所述的晶型B的制备方法，其特征在于，所述方法包括：将式(I)化合物的游离形式置于烷基醚类有机溶剂中，通过搅拌分离或挥发的方法得到固体。
  5. 根据权利要求4所述的制备方法，其特征在于，所述烷基醚类溶剂为甲基叔丁基醚。
  6. 一种式(I)化合物的晶型D，其特征在于，其X射线粉末衍射图(CuKα辐射)在2θ值为12.7°±0.2°、19.1°±0.2°、22.3°±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型D，其特征还在于，其X射线粉末衍射图还在6.3°±0.2°、16.8°±0.2°、22.9°±0.2°中的一处或多处具有衍射峰。
  8. 根据权利要求6或7所述的晶型D，其特征还在于，其X射线粉末衍射图还在11.4°±0.2°、16.4°±0.2°、19.9°±0.2°中的一处或多处具有衍射峰。
  9. 根据权利要求6至8任一项所述的晶型D的制备方法，其特征在于，所述方法包括下述方法中的任一种：
    1)将式(I)化合物的游离形式置于四氢呋喃中，加入反溶剂，搅拌分离得到固体；或
    2)将式(I)化合物的游离形式置于四氢呋喃与反溶剂的混合溶剂中，搅拌分离得到固体；
    所述反溶剂为水、烷烃、烷基醚中的一种或多种。
  10. 根据权利要求9所述的制备方法，其特征在于，所述反溶剂为水、正庚烷、甲基叔丁基醚的一种或多种。
  11. 一种式(I)化合物的晶型F，其特征在于，其X射线粉末衍射图(CuKα辐射)在2θ值为12.4°±0.2°、13.3°±0.2°、5.9°±0.2°处具有特征峰。
  12. 根据权利要求11所述的晶型F，其特征还在于，其X射线粉末衍射图还在17.5°±0.2°、18.5°±0.2°、19.0°±0.2°中的一处或多处具有衍射峰。
  13. 根据权利要求11或12所述的晶型F，其特征还在于，其X射线粉末衍射图还在21.3°±0.2°、24.2°±0.2°、17.9°±0.2°中的一处或多处具有衍射峰。
  14. 根据权利要求11至13任一项所述的晶型F的制备方法，其特征在于，所述方法包括下述方法中的任一种：
    1)将式(I)化合物的游离形式置于乙酸中，加入水，搅拌分离得到固体；或
    2)将式(I)化合物的游离形式置于乙酸与水的混合溶剂中，搅拌分离得到 固体。
  15. 一种式(I)化合物的晶型G，其特征在于，其X射线粉末衍射图(CuKα辐射)在2θ值为10.6°±0.2°、11.1°±0.2°、24.5°±0.2°处具有特征峰。
  16. 根据权利要求15所述的晶型G，其特征还在于，其X射线粉末衍射图还在9.6°±0.2°、19.3°±0.2°、20.3°±0.2°中的一处或多处具有衍射峰。
  17. 根据权利要求15或16所述的晶型G，其特征还在于，其X射线粉末衍射图还在11.8°±0.2°、14.6°±0.2°、16.5°±0.2°中的一处或多处具有衍射峰。
  18. 根据权利要求15至17任一项所述的晶型G的制备方法，其特征在于，所述方法包括：将式(I)化合物的游离形式置于二氧六环中，加入反溶剂，搅拌分离得到固体；或将式(I)化合物的游离形式置于二氧六环与反溶剂的混合溶剂中，搅拌分离得到固体；所述反溶剂为水、醇类、芳香烃类中的一种或多种。
  19. 根据权利要求18所述的晶型G的制备方法，所述反溶剂为水、异丙醇、甲苯中的一种或多种。
  20. 根据权利要求15至17任一项所述的晶型G的制备方法，其特征在于，所述方法包括：将式(I)化合物的游离形式置于乙酸中，加入反溶剂，搅拌分离固体得到；或将式(I)化合物的游离形式置于乙酸与反溶剂的混合溶剂中，搅拌分离固体得到。所述反溶剂为醇类、芳香烃类中的一种或多种。
  21. 根据权利要求20所述的晶型G的制备方法，其特征在于，所述反溶剂为异丙醇、甲苯中的一种或多种。
  22. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1至3中的任一项的晶型B或权利要求6至8中的任一项的晶型D或权利要求11至13 中的任一项的晶型F或权利要求15至17中的任一项的晶型G或其混合物及药学上可接受的辅料。
  23. 权利要求1至3中的任一项的晶型B或权利要求6至8中的任一项的晶型D或权利要求11至13中的任一项的晶型F或权利要求15至17中的任一项所述的晶型G或其混合物或权利要求22所述的药用组合物用于制备治疗抗肿瘤药物制剂中的用途。
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