WO2018157741A1 - Sb-939的盐的晶型及其制备方法和用途 - Google Patents

Sb-939的盐的晶型及其制备方法和用途 Download PDF

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WO2018157741A1
WO2018157741A1 PCT/CN2018/076607 CN2018076607W WO2018157741A1 WO 2018157741 A1 WO2018157741 A1 WO 2018157741A1 CN 2018076607 W CN2018076607 W CN 2018076607W WO 2018157741 A1 WO2018157741 A1 WO 2018157741A1
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solvent
crystalline form
ray powder
powder diffraction
present
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PCT/CN2018/076607
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English (en)
French (fr)
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陈敏华
张炎锋
高慧
刘启月
张晓宇
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苏州科睿思制药有限公司
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Priority to CN201880011239.5A priority Critical patent/CN110291071B/zh
Publication of WO2018157741A1 publication Critical patent/WO2018157741A1/zh

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystalline form of a salt of SB-939, a preparation method thereof and use thereof.
  • Histone Deacetylase (HDAC) inhibitors can inhibit DNA replication and RNA transcription of tumor cells, and can achieve the purpose of treating and preventing tumors.
  • HDAC Histone Deacetylase
  • HDAC inhibitors combined with demethylating drugs may have synergistic effects on the original cell epigenetics of acute myeloid leukemia (AML), which can restore the expression of tumor suppressor genes in vivo.
  • AML acute myeloid leukemia
  • SB-939 is an effective oral inhibitor of HDAC being developed by MEI Pharmaceuticals. SB-939 is clinically used for the treatment of prostate cancer, acute myeloid leukemia, and myelodysplastic syndrome, and has achieved good results.
  • the chemical name of SB-939 is: (2E)-3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxypropene Amide (hereinafter referred to as "compound (I)”), its chemical structural formula is as follows:
  • the present invention provides new crystalline forms CS7, CS9, CS1 and CS3 of the dihydrochloride salt of SB-939.
  • the new crystal form provided by the invention has low wettability, good stability, high purity, low degradation, high solubility and good mechanical stability. It provides a new and better choice for the preparation of drugs containing SB-939, which is very important for drug development.
  • the main object of the present invention is to provide a crystal form of a salt of the compound (I), a preparation method thereof and use thereof.
  • the present invention provides the crystal form CS7 of the dihydrochloride salt of the compound (I) (hereinafter referred to as "crystal form CS7").
  • the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks at diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, and 14.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 19.4° ⁇ 0.2°, 16.5° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks at diffraction angle 2 ⁇ values of 19.4° ⁇ 0.2°, 16.5° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 22.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, and 18.7° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS7 has characteristic peaks at diffraction angle 2 ⁇ values of 22.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS7 has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 14.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 16.5°. Characteristic peaks are present at ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS7 is as shown in FIG.
  • the crystalline form CS7 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to near 122 ° C to begin the first endothermic peak. Its DSC curve is shown in Figure 2.
  • the present invention provides a crystalline form CS7 having a mass loss gradient of about 9.3% when heated to about 120 ° C when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • the present invention also provides a method for preparing a crystalline form CS7, characterized in that the method comprises:
  • the alcohol solvent in the method (1) is preferably isopropanol
  • the ester solvent is preferably isopropyl acetate.
  • the alcohol solvent in the method (2) is preferably isopropanol, and the ester solvent is preferably ethyl acetate.
  • the present invention also provides a crystal form CS9 of a dihydrochloride salt of the compound (I) (hereinafter referred to as "crystal form CS9").
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 25.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 11.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS9 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 23.9° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 9.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 23.9° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 9.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 20.3° ⁇ 0.2°, 24.6 ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 20.3° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a diffraction angle 2 ⁇ of 25.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 11.9° ⁇ 0.2°, 23.9° ⁇ 0.2°, 17.0°. There are characteristic peaks at ⁇ 0.2°, 9.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 is at one or two of the diffraction angle 2 ⁇ values of 7.9° ⁇ 0.2°, 23.4° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 26.7° ⁇ 0.2°. Or characteristic peaks at three or four places.
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 7.9° ⁇ 0.2°, 23.4° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 26.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a diffraction angle 2 ⁇ of 25.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 11.9° ⁇ 0.2°, 23.9° ⁇ 0.2°, 17.0°. ⁇ 0.2°, 9.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, 24.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 7.9° ⁇ 0.2°, 23.4° ⁇ 0.2°, 25.5° ⁇ 0.2°, 26.7° ⁇ 0.2 There are characteristic peaks at °.
  • the X-ray powder diffraction pattern of Form CS9 is as shown in FIG.
  • the crystal form CS9 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 228 ° C to start the first exothermic peak. Its DSC curve is shown in Figure 6.
  • the present invention provides a crystalline form CS9 having a mass loss gradient of about 0.7% when heated to about 120 ° C when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • the present invention also provides a method for preparing a crystalline form CS9, characterized in that the method comprises:
  • the nitrile solvent in the method (2) is preferably acetonitrile.
  • the present invention also provides a crystal form CS1 of a dihydrochloride salt of the compound (I) (hereinafter referred to as "crystal form CS1").
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 10.6° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 15.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 6.9° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 27.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 6.9° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 27.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 13.9° ⁇ 0.2° and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 13.9° ⁇ 0.2° and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ of 10.6° ⁇ 0.2°, 24.6° ⁇ 0.2°, 15.9° ⁇ 0.2°, 6.9° ⁇ 0.2°, 25.7°. There are characteristic peaks at ⁇ 0.2°, 27.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS1 is as shown in FIG.
  • the crystal form CS1 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 145 ° C to start the first endothermic peak. Its DSC curve is shown in Figure 10.
  • the crystalline form CS1 provided by the present invention when subjected to thermogravimetric analysis (TGA), has a mass loss gradient of about 6.1% when heated to near 120 °C. Its TGA curve is shown in Figure 11.
  • the present invention also provides a method for preparing a crystalline form CS1, characterized in that the method comprises:
  • the ketone solvent in the method (1) is preferably acetone.
  • the alcohol solvent in the method (2) is preferably methanol
  • the nitrile solvent is preferably acetonitrile
  • the ketone solvent is preferably acetone
  • the amide solvent is preferably dimethylacetamide.
  • the ether solvent is preferably methyl tert-butyl ether
  • the ester solvent is preferably isopropyl acetate.
  • the present invention also provides a crystal form CS3 of a dihydrochloride salt of the compound (I) (hereinafter referred to as "crystal form CS3").
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, and 25.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 9.7° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 9.7° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 20.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 20.0° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 20.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 20.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a diffraction angle 2 ⁇ of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 25.0° ⁇ 0.2°, 9.7° ⁇ 0.2°, and 15.0°. There are characteristic peaks at ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 20.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS3 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 13.9° ⁇ 0.2° and 23.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 13.9° ⁇ 0.2° and 23.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a diffraction angle 2 ⁇ of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.7° ⁇ 0.2°, 15.0° ⁇ 0.2°, 25.0°. Characteristic peaks are present at ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 13.9° ⁇ 0.2°, 23.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS3 is as shown in FIG.
  • the crystalline form CS3 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 229 ° C to start an exothermic peak, DSC The curve is shown in Figure 14.
  • the crystalline form CS3 provided by the present invention when subjected to thermogravimetric analysis (TGA), has a mass loss gradient of about 3.0% when heated to near 120 °C. Its TGA curve is shown in Figure 15.
  • the present invention also provides a method for preparing a crystalline form CS3, characterized in that the method comprises:
  • the alcohol solvent in the method (1) is preferably methanol
  • the ether solvent is preferably methyl tert-butyl ether
  • the sulfoxide solvent is preferably dimethyl sulfoxide
  • the ketone solvent is preferably It is methyl isobutyl ketone.
  • the alcohol solvent in the method (2) is preferably ethanol
  • the nitrile solvent is preferably acetonitrile
  • the ester solvent is preferably ethyl acetate
  • the alkane solvent is preferably n-heptane.
  • 0 to 10 ° C is preferably 4 ° C
  • the 40 to 80 ° C is preferably 50 ° C.
  • the SB-939 free form or the dihydrochloride salt of SB-939 refers to the solid, semi-solid, wax or oil form of the compound (I) or its dihydrochloride salt, without limitation, the SB-939 Dihydrochlorides include, but are not limited to, the crystalline forms CS7, CS9, CS1 and CS3 of the present invention.
  • the "room temperature” is not an accurate temperature value and refers to a temperature range of 10 to 30 °C.
  • the gas-solid permeation method in the present invention means that the starting material is placed in a closed environment having a specific solvent atmosphere, and the starting material is not directly contacted with the solvent, but is prepared by indirect contact of the solvent volatilization diffusion with the starting material. A new solid form method.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction patterns typically vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having the same or similar characteristic peaks as those in the maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the novel crystalline forms CS7, CS9, CS1, and CS3 of the present invention are pure, single, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the crystal form provided by the invention has low wettability and can overcome the disadvantages caused by high wettability, such as the weight change of the water absorption due to the change of the weight of the raw material, which is beneficial to the long-term storage of the medicine and the storage of the material. Quality control costs.
  • the crystal forms CS7, CS9 and CS1 of the present invention have hygroscopicity of 0.14%, 0.65% and 0.15%, respectively, and have low wettability, which can well prevent the crystal form instability during the preparation and/or storage of the drug and The problem that the preparation is unprocessable caused by external factors such as environmental moisture is beneficial to accurate quantification and later transportation and storage in the preparation of the preparation;
  • the crystal form provided by the invention has good stability, thereby ensuring that the quality standard of the sample is consistent and controllable, and meets the stringent requirements for the crystal form in the pharmaceutical application and the preparation process.
  • the crystalline form CS7 of the present invention can be stably placed for at least 6 months under conditions of 25 ° C / 60% relative humidity and / or 40 ° C / 75% relative humidity, and at least one stable at 60 ° C / 75% relative humidity. month.
  • the crystalline form CS9 of the present invention can be stably placed for at least 6 months under conditions of 25 ° C / 60% relative humidity and at least stable for 2 weeks under conditions of 40 ° C / 75% relative humidity.
  • the crystalline form CS1 of the present invention can be stably placed at least for one month at 25 ° C / 60% relative humidity, and more preferably at least for 6 months.
  • the crystalline form CS3 of the present invention is stable for at least one month at 25 ° C / 60% relative humidity.
  • the crystal form of the present invention has a purity of more than 99%, and is exposed to open at 25 ° C / 60% relative humidity for 1 month. More preferably, the purity is substantially unchanged after 6 months of standing, and degradation is not easy, and has good Chemical stability. Therefore, the crystal form of the present invention has good stability, which is favorable for preservation of the sample and stabilization of the preparation;
  • the crystal form provided by the invention has good mechanical stability and reduces the risk of crystal transformation during grinding or tableting in the preparation of the preparation.
  • the crystal forms CS7, CS9, CS1 and CS3 of the invention have high grinding stability, and the grinding and pulverization of the raw material medicine are often required in the processing of the preparation, and the high grinding stability can reduce the crystallinity change of the raw material medicine during the processing of the preparation. And the risk of crystal transformation.
  • the crystal form provided by the present invention has good solubility and solubility in water is higher than 10 mg/mL.
  • High solubility can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug, and high doses can be used after oral administration to achieve the desired therapeutic blood concentration, which is beneficial to the absorption of the drug in the human body, thereby achieving The ideal bioavailability and efficacy of the drug meet the medicinal requirements.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS7, CS9, CS1 or CS3 of the present invention, and at least one pharmaceutically acceptable carrier, diluent or Shape agent.
  • the present invention provides the use of the crystalline form CS7, CS9, CS1 or CS3 of SB-939 for the preparation of a medicament for the treatment of prostate cancer and/or acute myeloid leukemia and/or myelodysplastic syndrome diseases.
  • Figure 1 is an XRPD pattern of a crystalline form CS7 obtained according to Example 1 of the present invention.
  • Example 2 is a DSC chart of a crystalline form CS7 obtained according to Example 1 of the present invention.
  • Figure 3 is a TGA diagram of a crystalline form CS7 obtained in accordance with Example 1 of the present invention.
  • Example 4 is an XRPD pattern of a crystalline form CS7 obtained according to Example 2 of the present invention.
  • Figure 5 is an XRPD pattern of a crystalline form CS9 obtained according to Example 3 of the present invention.
  • Figure 6 is a DSC chart of a crystalline form CS9 obtained according to Example 3 of the present invention.
  • Figure 7 is a TGA diagram of a crystalline form CS9 obtained in accordance with Example 3 of the present invention.
  • Figure 8 is an XRPD pattern of a crystalline form CS9 obtained according to Example 4 of the present invention.
  • Figure 9 is an XRPD pattern of a crystal form CS1 obtained according to Example 5 of the present invention.
  • Figure 10 is a DSC chart of a crystalline form CS1 obtained according to Example 5 of the present invention.
  • Figure 11 is a TGA diagram of a crystalline form CS1 obtained according to Example 5 of the present invention.
  • Figure 12 is an XRPD pattern of a crystal form CS1 obtained according to Example 8 of the present invention.
  • Figure 13 is an XRPD pattern of a crystalline form CS3 obtained in accordance with Example 13 of the present invention.
  • Figure 14 is a DSC chart of a crystalline form CS3 obtained in accordance with Example 13 of the present invention.
  • Figure 15 is a TGA diagram of a crystalline form CS3 obtained in accordance with Example 13 of the present invention.
  • Figure 16 is an XRPD pattern of a crystalline form CS3 obtained in accordance with Example 18 of the present invention.
  • Figure 17 is a DVS diagram of the crystalline form CS7 of the present invention.
  • Figure 18 is an XRPD overlay of the DVS before and after DVS of the crystalline form CS7 of the present invention (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS).
  • Figure 19 is a DVS diagram of the crystalline form CS9 of the present invention.
  • Figure 20 is a DVS diagram of the crystal form CS1 of the present invention.
  • Figure 21 is an XRPD overlay of the DVS before and after the DCS of the crystal form CS1 of the present invention (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS).
  • Figure 22 is a DVS diagram of the crystalline form CS3 of the present invention.
  • Figure 23 is an XRPD overlay of the crystalline form CS7 of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 24 is an XRPD overlay of the crystalline form CS7 of the present invention before and after being placed at 40 ° C / 75% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 25 is an XRPD overlay of the crystalline form CS7 of the present invention before and after placement at 60 ° C / 75% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 26 is an XRPD overlay of the crystalline form CS9 of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 27 is an XRPD overlay of the crystalline form CS9 of the present invention before and after placement at 40 ° C / 75% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 28 is an XRPD overlay of the crystalline form CS1 of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 29 is an XRPD overlay of the crystalline form CS3 of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 30 is an XRPD overlay of the crystal form CS7 before and after polishing according to the present invention (the lower figure shows the XRPD pattern before polishing, and the upper figure shows the XRPD pattern after grinding).
  • Figure 31 is an XRPD overlay of the crystal form CS9 before and after polishing according to the present invention (the figure below shows the XRPD pattern before grinding, and the upper figure shows the XRPD pattern after grinding).
  • Figure 32 is an XRPD overlay of the crystal form CS1 of the present invention before and after polishing (the lower figure shows the XRPD pattern before polishing, and the upper figure shows the XRPD pattern after grinding).
  • Figure 33 is an XRPD overlay of the crystal form CS3 before and after polishing according to the present invention (the lower figure shows the XRPD pattern before polishing, and the upper figure shows the XRPD pattern after grinding).
  • 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 Q500.
  • 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 free form of SB-939 used in the following examples was prepared according to the prior art.
  • the SB-939 dihydrochloride starting material used in the following examples includes, but is not limited to, an amorphous form, a crystalline form CS7, a crystalline form CS9, a crystalline form CS1, a single form of the crystalline form CS3, or any mixture thereof.
  • the DSC curve of the crystalline form CS7 obtained in Example 1 is shown in Fig. 2, and the TGA curve is shown in Fig. 3.
  • the DSC curve is shown in Figure 6, and the TGA curve is shown in Figure 7.
  • the crystalline form CS7 of 185.1 mg of SB-939 dihydrochloride was weighed out, placed in a 20 ml vial, 5 ml of acetonitrile was added, the lid was closed and the parafilm was sealed, and stirred at room temperature overnight to obtain the crystalline form CS9.
  • the X-ray powder diffraction pattern is shown in Fig. 8, and the X-ray powder diffraction data is shown in Table 3.
  • the crystal form CS1 is a hydrate, the X-ray powder diffraction pattern thereof is shown in Fig. 9, and the X-ray powder diffraction data is shown in Table 4.
  • the DSC curve is shown in Figure 10
  • the TGA curve is shown in Figure 11.
  • the DSC curve for sample 13 is shown in Figure 14, and the TGA curve is shown in Figure 15.
  • Example 20 Study on the wettability of crystalline forms CS7, CS9, CS1 and CS3
  • the crystal form CS9 The DVS pattern of the wettability experiment is shown in Figure 19; the DVS pattern of the wettability test of the crystal form CS1 is shown in Figure 20, and the XRPD comparison chart before and after the DVS is shown in Figure 21 (the above figure shows the XRPD picture before DVS, and the figure below shows DVS).
  • the latter XRPD pattern is shown in Fig. 22; the DVS pattern of the wettability test of the crystal form CS3 is shown in Fig. 22.
  • 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%
  • Example 21 Stability Study of Forms CS7, CS9, CS1 and CS3
  • the crystal form CS7 of the present invention was placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity, respectively, and the samples before and after the placement were subjected to XRPD test. The results are shown in Table 12.
  • the results show that the crystalline form CS7 remains unchanged for at least 6 months at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and at least one month after 60 ° C / 75% relative humidity.
  • the crystal form remains unchanged.
  • the purity of the crystalline form CS7 is more than 99%, and the purity change is only 0.13% after being left for 6 months under the condition of 25 ° C / 60% relative humidity, the purity change is small, and the stability is good.
  • the crystal form CS9 of the present invention was placed open at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and the samples before and after the placement were subjected to XRPD test, and the results are shown in Table 13.
  • the results show that the crystalline form CS9 remains unchanged for at least 6 months at 25 ° C / 60% relative humidity, and remains unchanged for at least 2 weeks at 40 ° C / 75% relative humidity.
  • the purity of the crystalline form CS9 is more than 99%, and the purity change is only 0.03% after being left for 6 months under the condition of 25 ° C / 60% relative humidity, the purity is substantially unchanged, the degradation is not easy, and the stability is good.
  • the crystal form CS1 of the present invention was placed open at 25 ° C / 60% relative humidity, and the samples before and after the placement were subjected to XRPD test. The results are shown in Table 14.
  • the crystal form CS3 of the present invention was placed open at 25 ° C / 60% relative humidity, and the samples before and after the placement were subjected to XRPD test. The results are shown in Table 15.
  • the results show that the crystalline form CS3 remains unchanged for at least one month at 25 ° C / 60% relative humidity.
  • the purity of the crystalline form CS3 is more than 99%, and the purity change is only 0.01% after being left for 1 month under the condition of 25 ° C / 60% relative humidity, the purity is substantially unchanged, the impurity is not easily degraded, and the stability is good.
  • the stability of the drug is very important, especially during the commercial period. Maintaining good stability can reduce the risk of drug dissolution rate and bio-profit change due to crystal form change and impurity content increase. Safety, avoiding the toxicity of drugs caused by impurities, and preventing the occurrence of adverse drug reactions are of great significance.
  • the more stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystal, and it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent quality control of the sample and ensuring the preparation.
  • the dissolution profile of the product does not change as the storage time changes.
  • Example 22 Study on the grinding stability of crystalline forms CS7, CS9, CS1 and CS3
  • the crystal forms CS7, CS9, CS1 and CS3 of the present invention were each about 10 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 of the crystal form CS7 are shown in Fig. 30 (the figure below is the pre-grinding, the figure above is the grind), and the test result of the crystal form CS9 is shown in Fig. 31 (the figure below is the pre-grinding, the figure above is the grind), the crystal form CS1
  • the test results are shown in Fig. 32 (the figure below is the pre-grinding, the above figure is after the grinding), and the test result of the crystal form CS3 is shown in Fig. 33 (the figure below is the grinding, the upper figure is the grinding).
  • the crystal forms CS7, CS9, CS1 and CS3 of the present invention are crystallized after grinding and the crystallinity is kept good.
  • the crystalline drug with better mechanical stability has low requirements on the crystallization equipment, requires no special post-treatment conditions, is more stable in the preparation process, can significantly reduce the development cost of the drug, enhance the quality of the drug, and has strong economic value.
  • the crystal forms CS7, CS9, CS1 and CS3 of the present invention have better mechanical stability in the subsequent process, and provide more options for subsequent formulation processes.
  • the crystal forms CS7, CS9, CS1 and CS3 can be ground by subsequent dry grinding means to obtain particles having a smaller particle size.

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Abstract

本发明涉及化合物（I）的盐的晶型及其制备方法和用途。本发明提供的新晶型CS7、CS9、CS1和CS3的引湿性低、稳定性好、纯度高、不易发生降解、溶解度高且机械稳定性好。为含化合物（I）药物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

SB-939的盐的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及SB-939的盐的晶型及其制备方法和用途。
背景技术
组蛋白去乙酰化酶(Histone Deacetylase，简称HDAC)抑制剂可抑制肿瘤细胞的DNA复制和RNA转录，可达到治疗和预防肿瘤的目的。作为一类表观遗传修饰酶，HDAC对染色体的结构修饰和基因表达调控发挥着重要的作用。研究表明，HDAC抑制剂联合去甲基化药物可能会对急性髓性白血病(Acute Myeloid Leukemia，AML)原始细胞表观遗传学产生协同作用，使机体内抑癌基因的表达得以恢复。
Pracinostat，又称SB-939，是MEI制药公司正在开发的一种HDAC的有效口服抑制剂。SB-939临床用于治疗前列腺癌、急性髓性白血病、骨髓发育异常综合征，并取得了良好的效果。SB-939的化学名称为：(2E)-3-[2-丁基-1-[2-(二乙基氨基)乙基]-1H-苯并咪唑-5-基]-N-羟基丙烯酰胺(以下称为“化合物(I)”)，其化学结构式如下所示：
Figure PCTCN2018076607-appb-000001
在药物研究领域，不同的药物晶型具有不同的颜色、熔点、溶解度、溶出性能、化学稳定性、机械稳定性等，这些特性可以影响药物制剂的质量、安全性和有效性，从而导致临床药效差异。因此，晶型研究和控制成为药物研发过程中的重要研究内容。
目前没有SB-939相关的晶型信息报道，因此，需要开发SB-939的新晶型，寻找适合药用的优势晶型，以适于药物的工业化生产要求。本发明提供SB-939的二盐酸盐的新晶型CS7、CS9、CS1和CS3。本发明提供的新晶型引湿性低、稳定性好、纯度高、不易发生降解、溶解度高且机械稳定性好。为含SB-939的药物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。
发明内容
本发明的主要目的是提供化合物(I)的盐的晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物(I)的二盐酸盐的晶型CS7(以下称作“晶型CS7”)。
使用Cu-Kα辐射，所述晶型CS7的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、20.1°±0.2°、14.1°±0.2°处有特征峰。
进一步的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为19.4°±0.2°、16.5°±0.2°、22.2°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为19.4°±0.2°、16.5°±0.2°、22.2°±0.2°处均有特征峰。
更进一步的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为22.8°±0.2°、8.8°±0.2°、18.7°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS7的X射线粉末衍射在衍射角2θ值为22.8°±0.2°、8.8°±0.2°、18.7°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS7的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、20.1°±0.2°、14.1°±0.2°、19.4°±0.2°、16.5°±0.2°、22.2°±0.2°、22.8°±0.2°、8.8°±0.2°、18.7°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS7的X射线粉末衍射谱图如附图1所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS7，当进行差示扫描量热分析(DSC)时，加热至122℃附近开始出现第一个吸热峰。其DSC曲线如图2所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS7，当进行热重分析(TGA)时，加热至120℃附近时，具有约9.3％的质量损失梯度，其TGA曲线如图3所示。
根据本发明的目的，本发明还提供晶型CS7的制备方法，其特征在于，所述方法包含：
(1)将SB-939游离碱加至醇类和酯类的混合溶剂中并搅拌，后缓慢加入盐酸水溶液(摩尔比HCl:SB-939为2:1～3:1)，在室温下搅拌得到；或
(2)将SB-939的二盐酸盐溶解在纯水中，配成含有SB-939二盐酸盐的溶液，将溶液缓慢滴加到反溶剂中，室温下搅拌得到，其中，反溶剂为醇类和酯类的单一或混合溶剂。
进一步的，方法(1)中所述醇类溶剂优选为异丙醇，所述酯类溶剂优选为乙酸异丙酯。
进一步的，方法(2)中所述醇类溶剂优选为异丙醇，所述酯类溶剂优选为乙酸乙酯。
根据本发明的目的，本发明还提供化合物(I)的二盐酸盐的晶型CS9(以下称作“晶型CS9”)。
使用Cu-Kα辐射，所述晶型CS9的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、 21.2°±0.2°、11.9°±0.2°处有特征峰。
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为23.9°±0.2°、17.0°±0.2°、9.1°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为23.9°±0.2°、17.0°±0.2°、9.1°±0.2°处均有特征峰。
更进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为20.3°±0.2°、24.6±0.2°、21.6°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为20.3°±0.2°、24.6°±0.2°、21.6°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS9的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、21.2°±0.2°、11.9°±0.2°、23.9°±0.2°、17.0°±0.2°、9.1°±0.2°、20.3°±0.2°、24.6°±0.2°、21.6°±0.2°处有特征峰。
更进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为7.9°±0.2°、23.4°±0.2°、25.5°±0.2°、26.7°±0.2°中的一处或两处或三处或四处有特征峰。优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为7.9°±0.2°、23.4°±0.2°、25.5°±0.2°、26.7°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS9的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、21.2°±0.2°、11.9°±0.2°、23.9°±0.2°、17.0°±0.2°、9.1°±0.2°、20.3°±0.2°、24.6°±0.2°、21.6°±0.2°、7.9°±0.2°、23.4°±0.2°、25.5°±0.2°、26.7°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS9的X射线粉末衍射谱图如附图5所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS9，当进行差示扫描量热分析(DSC)时，加热至228℃附近开始出现第一个放热峰，其DSC曲线如附图6所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS9，当进行热重分析(TGA)时，加热至120℃附近时，具有约0.7％的质量损失梯度，其TGA曲线如附图7所示。
根据本发明的目的，本发明还提供晶型CS9的制备方法，其特征在于，所述方法包含：
(1)将SB-939的二盐酸盐溶解在N-甲基吡咯烷酮中形成溶液，将丙酮缓慢滴加到SB-939二盐酸盐的溶液中，室温搅拌并于50℃条件下干燥得到；或
(2)将SB-939的二盐酸盐加至腈类溶剂中，室温下搅拌得到。
进一步的，方法(2)中所述腈类溶剂优选为乙腈。
根据本发明的目的，本发明还提供化合物(I)的二盐酸盐的晶型CS1(以下称作“晶型CS1”)。
使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.6°±0.2°、24.6°±0.2°、15.9°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为6.9°±0.2°、25.7°±0.2°、27.4°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为6.9°±0.2°、25.7°±0.2°、27.4°±0.2°处均有特征峰。
更进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为13.9°±0.2°、19.0°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为13.9°±0.2°、19.0°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.6°±0.2°、24.6°±0.2°、15.9°±0.2°、6.9°±0.2°、25.7°±0.2°、27.4°±0.2°、13.9°±0.2°、19.0°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射谱图如附图9所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS1，当进行差示扫描量热分析(DSC)时，加热至145℃附近开始出现第一个吸热峰，其DSC曲线如附图10所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS1，当进行热重分析(TGA)时，加热至120℃附近时，具有约6.1％的质量损失梯度。其TGA曲线如附图11所示。
根据本发明的目的，本发明还提供晶型CS1的制备方法，其特征在于，所述方法包括：
(1)将SB-939游离碱加至酮类溶剂体系中搅拌，后缓慢加入盐酸水溶液(摩尔比HCl:SB-939为2:1～3:1)，在室温下搅拌得到；或
(2)将SB-939的二盐酸盐溶解在醇类或水或酰胺类正溶剂中，配成含SB-939二盐酸盐的溶液，将反溶剂缓慢滴加到溶液中，室温搅拌得到。其中，正溶剂为醇类或水时，反溶剂为腈类或酮类；正溶剂为酰胺类时，反溶剂为腈类、醚类或酯类。
进一步的，方法(1)中所述酮类溶剂优选为丙酮。
进一步的，方法(2)中所述醇类溶剂优选为甲醇，所述腈类溶剂优选为乙腈，所述酮类溶剂优选为丙酮，所述酰胺类溶剂优选为二甲基乙酰胺，所述醚类溶剂优选为甲基叔丁基醚，所述酯类溶剂优选为乙酸异丙酯。
根据本发明的目的，本发明还提供化合物(I)的二盐酸盐的晶型CS3(以下称作“晶型CS3”)。
使用Cu-Kα辐射，所述晶型CS3的X射线粉末衍射在衍射角2θ值为6.5°±0.2°、8.0°±0.2°、25.0°±0.2°处有特征峰。
进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为9.7°±0.2°、15.0°±0.2°、18.7°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为9.7°±0.2°、15.0°±0.2°、18.7°±0.2°处均有特征峰。
更进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为20.5°±0.2°、19.6°±0.2°、20.0°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为20.5°±0.2°、19.6°±0.2°、20.0°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS3的X射线粉末衍射在衍射角2θ值为6.5°±0.2°、8.0°±0.2°、25.0°±0.2°、9.7°±0.2°、15.0°±0.2°、18.7°±0.2°、20.5°±0.2°、19.6°±0.2°、20.0°±0.2°处有特征峰。
更进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为13.9°±0.2°、23.8°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为13.9°±0.2°、23.8°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS3的X射线粉末衍射在衍射角2θ值为6.5°±0.2°、8.0°±0.2°、9.7°±0.2°、15.0°±0.2°、25.0°±0.2°、18.7°±0.2°、20.5°±0.2°、19.6°±0.2°、20.0°±0.2°、13.9°±0.2°、23.8°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS3的X射线粉末衍射谱图如附图13所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS3，当进行差示扫描量热分析(DSC)时，加热至229℃附近开始出现一个放热峰，其DSC曲线如附图14所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS3，当进行热重分析(TGA)时，加热至120℃附近时，具有约3.0％的质量损失梯度。其TGA曲线如附图15所示。
根据本发明的目的，本发明还提供晶型CS3的制备方法，其特征在于，所述方法包括：
(1)将SB-939的二盐酸盐溶解在醇类或N-甲基吡咯烷酮或亚砜类正溶剂中，配成含SB-939二盐酸盐的溶液，将反溶剂缓慢滴加到溶液中，室温搅拌得到。其中，正溶剂为醇类时，反溶剂为醚类；正溶剂为N-甲基吡咯烷酮时，反溶剂为丙酮；正溶剂为亚砜类溶剂时，反溶剂为酮类溶剂；或
(2)将SB-939的二盐酸盐加至醇类、腈类、酯类和烷烃类的单一或混合溶剂中，室温搅拌，后在0-10℃条件下搅拌，最后继续在40-80℃条件下搅拌得到。
进一步的，方法(1)中所述醇类溶剂优选为甲醇，所述醚类溶剂优选为甲基叔丁基醚，所述亚砜类溶剂优选为二甲亚砜，所述酮类溶剂优选为甲基异丁基酮。
进一步的，方法(2)中所述醇类溶剂优选为乙醇，所述腈类溶剂优选为乙腈，所述酯类溶剂优选为乙酸乙酯，所述烷烃类溶剂优选为正庚烷，所述0～10℃优选为4℃，所述40～80℃优选为50℃。
在本发明的晶型CS7、CS9、CS1和CS3的制备方法中：
所述SB-939游离形式或SB-939的二盐酸盐是指化合物(I)或其二盐酸盐的固体、半固体、蜡或油形式，非限制性的，所述SB-939的二盐酸盐包括但不限于本发明的晶型CS7、CS9、CS1和CS3。所述“室温”不是精确的温度值，是指10～30℃温度范围。
本发明中所述气固渗透法是指：将起始原料置于具有特定溶剂氛围的密闭环境中，起始原料不直接与溶剂接触，而是通过溶剂挥发扩散与起始原料间接接触制备得到新固体形态的方法。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件变化而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的新晶型CS7、CS9、CS1和CS3是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体实验条件的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明提供的新晶型具有以下有益效果：
(1)本发明提供的晶型引湿性低，能够克服高引湿性带来的弊端，如因吸水发生重量变化导致原料晶型组份含量不确定，有利于药品的长期贮存，降低物料储存以及质量控制成本。尤其是本发明的晶型CS7、CS9和CS1，引湿性分别为0.14％、0.65％和0.15％，引湿性低，能够很好地避免药物在制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存；
(2)本发明提供的晶型稳定性好，从而保证样品的质量标准一致可控，符合药物应用及制剂工艺中对晶型的苛刻要求。本发明的晶型CS7在25℃/60％相对湿度和/或40℃/75％相对湿度条件下至少可稳定放置6个月，在60℃/75％相对湿度条件下至少可稳定放置1个月。本发明的晶型CS9在25℃/60％相对湿度条件下至少可稳定放置6个月，在40℃/75％相对湿度条件下至少可稳定放置2周。本发明晶型CS1在25℃/60％相对湿度下至少可稳定放置1个月，更优选的，至少可稳定放置6个月。本发明晶型CS3在25℃/60％相对湿度下至少可稳定放置1个月。此外，本发明晶型纯度大于99％，且在25℃/60％相对湿度条件下敞口放置1个月，更优选的，放置6个月后纯度基本不变，不易发生降解，具有良好的化学稳定性。因此，本发明的晶型具有良好的稳定性，有利于样品的保存和制剂的稳定；
(3)本发明提供的晶型机械稳定性好，降低制剂制备时研磨或压片过程发生转晶的风险。本发明的晶型CS7、CS9、CS1和CS3具有高的研磨稳定性，制剂加工过程中常需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
(4)本发明提供的晶型溶解性良好，在水中的溶解度高于10mg/mL。高溶解性可降低给药剂量从而降低药品的副作用并提高药品的安全性，且在口服后不需要高剂量即可达到所需的治疗血药浓度，有利于药物在人体内的吸收，从而达到理想的药物生物利用度和药效，符合药用要求。
此外，本发明提供一种药用组合物，所述药用组合物包含有效治疗量的本发明晶型CS7、CS9、CS1或CS3，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步的，本发明提供SB-939的晶型CS7、CS9、CS1或CS3在制备治疗前列腺癌和/或急性髓性白血病和/或骨髓发育异常综合征疾病的药物中的用途。
附图说明
图1为根据本发明实施例1所得晶型CS7的XRPD图。
图2为根据本发明实施例1所得晶型CS7的DSC图。
图3为根据本发明实施例1所得晶型CS7的TGA图。
图4为根据本发明实施例2所得晶型CS7的XRPD图。
图5为根据本发明实施例3所得晶型CS9的XRPD图。
图6为根据本发明实施例3所得晶型CS9的DSC图。
图7为根据本发明实施例3所得晶型CS9的TGA图。
图8为根据本发明实施例4所得晶型CS9的XRPD图。
图9为根据本发明实施例5所得晶型CS1的XRPD图。
图10为根据本发明实施例5所得晶型CS1的DSC图。
图11为根据本发明实施例5所得晶型CS1的TGA图。
图12为根据本发明实施例8所得晶型CS1的XRPD图。
图13为根据本发明实施例13所得晶型CS3的XRPD图。
图14为根据本发明实施例13所得晶型CS3的DSC图。
图15为根据本发明实施例13所得晶型CS3的TGA图。
图16为根据本发明实施例18所得晶型CS3的XRPD图。
图17为本发明晶型CS7的DVS图。
图18为本发明晶型CS7的DVS前后的XRPD叠图(上图为DVS前的XRPD图，下图为DVS后的XRPD图)。
图19为本发明晶型CS9的DVS图。
图20为本发明晶型CS1的DVS图。
图21为本发明晶型CS1的DVS前后的XRPD叠图(上图为DVS前的XRPD图，下图为DVS后的XRPD图)。
图22为本发明晶型CS3的DVS图。
图23为本发明晶型CS7在25℃/60％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图24为本发明晶型CS7在40℃/75％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图25为本发明晶型CS7在60℃/75％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图26为本发明晶型CS9在25℃/60％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图27为本发明晶型CS9在40℃/75％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图28为本发明晶型CS1在25℃/60％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图29为本发明晶型CS3在25℃/60％相对湿度条件下放置前后的XRPD叠图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图30为本发明晶型CS7研磨前后的XRPD叠图(下图为研磨前的XRPD图，上图为研磨后的XRPD图)。
图31为本发明晶型CS9研磨前后的XRPD叠图(下图为研磨前的XRPD图，上图为研磨后的XRPD图)。
图32为本发明晶型CS1研磨前后的XRPD叠图(下图为研磨前的XRPD图，上图为研磨后的XRPD图)。
图33为本发明晶型CS3研磨前后的XRPD叠图(下图为研磨前的XRPD图，上图为研磨后的XRPD图)。
具体实施方式
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
采集数据所用的仪器及方法：
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
Figure PCTCN2018076607-appb-000002
1.540598；
Figure PCTCN2018076607-appb-000003
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：N 2
本发明所述的热重分析(TGA)图在TA Q500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：N 2
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：N 2,200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
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用到的SB-939游离形式是根据现有技术制备得到。以下实施例中所用的SB-939二盐酸盐原料包含但不限于无定形形式、晶型CS7、晶型CS9、晶型CS1、晶型CS3的单一形式或它们的任意混合。
实施例1～2：晶型CS7的制备
实施例1：
称取200.1毫克的SB-939游离碱固体，加至2.5毫升的体积比为1:1的异丙醇和乙酸异丙酯混合体系中，搅拌并缓慢滴加200微升6摩尔/升的盐酸水溶液，室温下搅拌24h，离心收集固体，真空干燥后得到晶型CS7。晶型CS7为水合物，其X射线粉末衍射图谱如图1，X射线粉末衍射数据如表1所示。
实施例1所得晶型CS7的DSC曲线如图2所示，TGA曲线如图3所示。
表1
衍射角2θ d值 相对强度(％)
6.42 13.77 100.00
8.86 9.98 5.76
9.29 9.52 2.20
9.71 9.11 2.16
11.38 7.77 2.16
12.86 6.88 0.76
13.80 6.42 3.25
14.12 6.27 11.92
14.67 6.04 1.05
15.78 5.62 2.14
16.14 5.49 0.70
16.50 5.37 11.69
18.67 4.75 5.14
19.36 4.59 13.96
20.13 4.41 26.73
20.84 4.26 4.42
21.18 4.19 3.00
22.24 4.00 9.69
22.79 3.90 9.22
24.76 3.60 4.02
26.43 3.37 5.42
26.64 3.35 3.33
27.00 3.30 2.82
27.48 3.25 3.82
27.92 3.20 4.77
28.21 3.16 3.86
28.95 3.08 1.42
29.58 3.02 6.39
30.03 2.98 5.56
30.69 2.91 1.43
31.44 2.85 2.40
32.01 2.80 1.51
32.54 2.75 6.69
34.56 2.60 1.41
36.07 2.49 7.15
36.79 2.44 3.09
39.02 2.31 2.12
实施例2
称取10.3毫克的SB-939二盐酸盐原料，室温下溶解于0.3毫升的水中，搅拌并迅速加入3毫升的体积比为1:1的异丙醇和乙酸乙酯的混合溶剂体系，继续搅拌至有大量固体析出，离心收集固体得到晶型CS7，其X射线粉末衍射图谱如图4所示。
实施例3～4：晶型CS9的制备
实施例3：
称取163.7毫克的SB-939二盐酸盐原料，室温下溶解于1.5毫升的N-甲基吡咯烷酮中，搅拌并缓慢加入2毫升的丙酮，继续搅拌至有大量固体析出，离心收集固体，于50℃条件下真空干燥24小时得到晶型CS9。晶型CS9为无水物，其X射线粉末衍射图谱如图5所示，X射线粉末衍射数据如表2所示。
其DSC曲线如图6所示，TGA曲线如图7所示。
表2
衍射角2θ d值 相对强度(％)
4.24 20.85 7.03
7.92 11.16 28.10
9.08 9.74 76.14
10.73 8.24 3.57
11.94 7.41 74.07
14.08 6.29 31.59
14.74 6.01 15.43
15.33 5.78 8.17
16.34 5.43 21.17
17.02 5.21 77.63
17.39 5.10 17.63
18.19 4.88 23.70
19.29 4.60 17.60
19.47 4.56 26.38
19.82 4.48 23.62
20.30 4.38 83.65
20.63 4.30 22.99
21.22 4.19 98.13
21.57 4.12 61.80
23.42 3.80 48.24
23.88 3.73 78.01
24.58 3.62 66.41
25.47 3.50 63.06
25.93 3.44 100.00
26.70 3.34 50.23
27.22 3.28 20.79
27.42 3.25 33.40
27.81 3.21 12.07
28.38 3.14 30.53
28.94 3.09 20.09
29.49 3.03 4.43
30.00 2.98 18.14
30.85 2.90 39.70
31.12 2.87 24.31
31.69 2.82 7.92
32.48 2.75 16.64
32.59 2.75 18.74
33.06 2.71 5.32
33.89 2.65 10.81
34.20 2.62 9.13
34.75 2.58 7.28
35.19 2.55 21.07
35.52 2.53 9.64
36.54 2.46 8.49
36.87 2.44 8.18
37.65 2.39 1.37
实施例4
称取185.1毫克的SB-939二盐酸盐的晶型CS7，置于20毫升的小瓶中，加入5毫升乙腈，盖上盖子并封上封口膜，于室温下搅拌过夜得到晶型CS9。其X射线粉末衍射图谱如图8所示，X射线粉末衍射数据如表3所示。
表3
衍射角2θ d值 强度％
3.25 27.16 1.95
3.35 26.34 30.42
7.35 12.02 12.81
7.85 11.26 45.14
9.08 9.74 46.33
11.88 7.45 87.13
12.47 7.10 8.84
14.06 6.30 20.21
14.70 6.03 23.26
16.40 5.40 16.30
16.99 5.22 44.18
18.14 4.89 12.39
19.45 4.56 28.37
20.28 4.38 74.93
21.15 4.20 99.77
21.51 4.13 100.00
23.37 3.81 57.18
23.83 3.73 68.23
24.58 3.62 59.79
25.48 3.50 41.25
25.94 3.44 96.01
26.72 3.34 51.11
28.43 3.14 21.32
29.85 2.99 8.31
30.93 2.89 20.08
31.61 2.83 15.45
32.54 2.75 12.59
33.83 2.65 22.56
35.22 2.55 11.50
实施例5～12：晶型CS1的制备
实施例5：
称取20.4毫克的SB-939游离碱固体，加入1毫升的丙酮，搅拌并缓慢滴加112微升的 1摩尔/升的盐酸水溶液，室温下搅拌过夜。离心收集固体，真空干燥得到晶型CS1。晶型CS1为水合物，其X射线粉末衍射图谱如图9所示，X射线粉末衍射数据如表4所示。
其DSC曲线如图10所示，TGA曲线如图11所示。
表4
衍射角2θ d值 相对强度(％)
5.15 17.17 8.55
6.91 12.79 29.33
8.24 10.73 0.68
9.14 9.67 5.37
9.53 9.28 8.39
10.39 8.51 57.70
10.58 8.36 100.00
11.33 7.81 1.94
12.09 7.32 4.36
12.66 6.99 5.61
12.96 6.83 2.69
13.90 6.37 17.84
14.12 6.27 8.73
14.85 5.97 3.12
15.93 5.56 30.15
18.37 4.83 9.91
18.74 4.73 13.01
19.04 4.66 15.07
19.84 4.48 7.00
20.86 4.26 9.86
22.21 4.00 16.40
22.99 3.87 9.36
23.46 3.79 10.66
23.97 3.71 14.27
24.26 3.67 18.44
24.64 3.61 43.15
25.70 3.47 22.23
26.20 3.40 13.50
26.66 3.34 12.90
27.44 3.25 19.08
28.61 3.12 8.36
29.06 3.07 6.25
29.80 3.00 6.71
30.16 2.96 8.53
30.99 2.89 4.33
32.38 2.76 4.54
33.41 2.68 14.07
34.57 2.59 4.72
35.30 2.54 7.92
36.01 2.49 2.47
36.89 2.44 2.66
实施例6～12：
称取约10毫克的SB-939二盐酸盐原料，如表5所示，溶解于一定体积的正溶剂中，逐滴加入反溶剂。添加反溶剂后，继续搅拌至有大量固体析出，离心干燥并收集固体。实施例6～12所得固体分别被标记为样品6～12。经检测，样品6～12均为晶型CS1。选取样品9测试表征，其X射线粉末衍射图如图12，数据如表6所示。
表5
Figure PCTCN2018076607-appb-000004
表6
衍射角2θ d值 相对强度(％)
5.01 17.64 8.78
6.79 13.01 44.30
9.51 9.30 5.95
10.25 8.63 38.39
10.49 8.43 100.00
11.27 7.85 7.33
12.64 7.00 12.32
13.81 6.41 31.15
15.88 5.58 44.36
18.37 4.83 14.65
18.71 4.74 21.92
19.03 4.66 16.71
19.77 4.49 11.87
20.91 4.25 15.06
22.35 3.98 14.20
22.91 3.88 14.93
23.44 3.80 15.95
23.91 3.72 33.52
24.30 3.66 27.42
24.73 3.60 51.39
25.88 3.44 50.36
26.66 3.34 15.13
27.39 3.26 23.67
29.05 3.07 9.61
29.94 2.98 5.31
33.47 2.68 11.25
34.59 2.59 8.13
35.41 2.54 5.18
37.26 2.41 10.74
实施例13～19：晶型CS3的制备
实施例13～14：
称取一定质量的SB-939二盐酸盐原料，如表7所示，室温下溶于正溶剂中，搅拌并逐滴加入反溶剂，继续搅拌至有大量固体析出，离心干燥并收集固体。实施例13～14所得固体分别被标记为样品13～14。经检测，样品13～14均为晶型CS3。选取样品13测试表征，其X射线粉末衍射图如图13，数据如表8所示。
样品13的DSC曲线如图14所示，TGA曲线如图15所示。
表7
Figure PCTCN2018076607-appb-000005
表8
衍射角2θ d值 相对强度(％)
4.14 21.32 12.66
5.07 17.44 6.79
6.45 13.70 32.24
7.96 11.10 68.37
9.69 9.13 25.78
10.78 8.21 4.28
12.66 6.99 6.08
13.32 6.65 10.02
13.82 6.41 24.95
14.98 5.91 54.18
15.43 5.74 13.96
16.41 5.40 15.68
17.47 5.08 2.48
18.02 4.92 8.41
18.73 4.74 41.63
19.02 4.67 7.20
19.65 4.52 52.81
19.96 4.45 36.89
20.54 4.32 38.59
21.32 4.17 8.21
22.03 4.03 17.45
22.80 3.90 9.98
23.86 3.73 25.44
24.56 3.62 40.77
24.95 3.57 100.00
25.58 3.48 13.69
26.13 3.41 3.69
27.10 3.29 15.31
27.40 3.25 16.02
28.03 3.18 6.86
29.13 3.07 11.40
29.66 3.01 7.10
30.52 2.93 8.76
30.92 2.89 27.00
31.96 2.80 12.73
32.69 2.74 9.81
33.22 2.70 7.99
33.57 2.67 14.62
34.05 2.63 3.31
35.56 2.52 5.02
37.38 2.41 1.94
37.81 2.38 6.18
实施例15：
称取10.7毫克的SB-939二盐酸盐原料，溶于0.5毫升的二甲亚砜正溶剂中，配成含SB-939二盐酸盐的二甲亚砜溶液，搅拌并将SB-939二盐酸盐的二甲亚砜溶液逐滴滴加至3.0毫升的甲基异丁基酮反溶剂中，继续搅拌至有大量固体析出，离心干燥并收集固体得到晶型CS3。
实施例16～19：
称取一定质量的SB-939二盐酸盐晶型CS1，室温下在表9所示的溶剂中搅拌3天，后 在4℃条件下搅拌7天，最后在50℃的热台上搅拌6天，离心，真空干燥并收集固体。实施例16～19所得的固体分别标记为样品16～19，经检测，样品16～19均为晶型CS3。选取样品17测试表征，其X射线粉末衍射图如图16，数据如表10所示。
表9
Figure PCTCN2018076607-appb-000006
表10
衍射角2θ d值 相对强度％
1.83 48.29 1.27
1.92 46.10 0.52
2.48 35.67 6.42
2.93 30.20 13.78
3.61 24.50 20.26
3.89 22.73 18.31
4.19 21.10 22.10
5.16 17.14 20.70
5.31 16.65 25.83
6.43 13.74 28.98
6.88 12.84 23.73
7.87 11.24 83.44
9.70 9.12 32.70
10.64 8.31 24.18
12.75 6.94 20.14
13.31 6.65 25.80
13.71 6.46 27.04
13.88 6.38 27.02
14.86 5.96 36.06
15.20 5.83 23.29
16.55 5.36 23.06
18.03 4.92 16.34
18.70 4.75 44.07
19.60 4.53 27.82
20.06 4.43 32.54
20.53 4.33 25.15
21.40 4.15 9.15
21.95 4.05 18.12
22.67 3.92 9.99
23.71 3.75 20.76
24.43 3.64 23.67
25.03 3.56 100.00
25.68 3.47 15.05
26.87 3.32 19.20
27.52 3.24 9.32
实施例20：晶型CS7、CS9、CS1和CS3的引湿性研究
在25℃条件下，取本发明的晶型CS7、CS9、CS1和CS3各约10mg进行动态水分吸附(DVS)测试其引湿性，实验结果如表11所示。晶型CS7的引湿性实验的DVS图如图17所示，DVS前后XRPD对比图如图18(上图为DVS前的XRPD图，下图为DVS后的XRPD图)所示；晶型CS9的引湿性实验的DVS图如图19所示；晶型CS1的引湿性实验的DVS图如图20所示，DVS前后XRPD对比图如图21(上图为DVS前的XRPD图，下图为DVS后的XRPD图)所示；晶型CS3的引湿性实验的DVS图如图22所示。
表11
Figure PCTCN2018076607-appb-000007
结果表明，本发明的晶型CS7、CS9、CS1和CS3具有较低的引湿性，且DVS前后本 发明晶型CS7和晶型CS1未发生改变，能够克服药物晶型高引湿性带来的弊端，简化含本发明晶型CS7、CS9、CS1和CS3药物的制备与后处理工艺，如制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，适合药用。
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21：晶型CS7、CS9、CS1和CS3的稳定性研究
晶型CS7的稳定性研究：
取本发明的晶型CS7分别置于25℃/60％相对湿度，40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，对放置前后的样品进行XRPD测试。结果如表12所示。
表12
Figure PCTCN2018076607-appb-000008
结果表明，晶型CS7在25℃/60％相对湿度和40℃/75％相对湿度条件下至少放置6个月晶型保持不变，在60℃/75％相对湿度条件下至少放置一个月后晶型保持不变。晶型CS7的纯度大于99％，且在25℃/60％相对湿度条件下放置6个月后纯度变化仅为0.13％，纯度变化小，具有良好的稳定性。
晶型CS9的稳定性研究：
取本发明的晶型CS9置于25℃/60％相对湿度和40℃/75％相对湿度下敞口放置，对放置前后的样品进行XRPD测试，结果如表13所示。
表13
Figure PCTCN2018076607-appb-000009
结果表明，晶型CS9在25℃/60％相对湿度条件下至少放置6个月晶型保持不变，在40℃/75％相对湿度条件下至少放置2周晶型保持不变。晶型CS9的纯度大于99％，且在25℃/60％相对湿度条件下放置6个月后纯度变化仅为0.03％，纯度基本不变，不易发生降解，具有良好的稳定性。
晶型CS1的稳定性研究：
取本发明的晶型CS1置于25℃/60％相对湿度下敞口放置，对放置前后的样品进行XRPD测试。结果如表14所示。
表14
Figure PCTCN2018076607-appb-000010
结果表明，晶型CS1在25℃/60％相对湿度条件下至少放置6个月晶型保持不变，晶型CS1的纯度大于99％，且在25℃/60％相对湿度条件下放置6个月后纯度变化仅为0.47％，纯度变化小，具有良好的稳定性。
晶型CS3的稳定性研究：
取本发明的晶型CS3置于25℃/60％相对湿度下敞口放置，对放置前后的样品进行XRPD测试。结果如表15所示。
表15
Figure PCTCN2018076607-appb-000011
结果表明，晶型CS3在25℃/60％相对湿度条件下至少放置1个月晶型保持不变。晶型CS3的纯度大于99％，且在25℃/60％相对湿度条件下放置1个月后纯度变化仅为0.01％， 纯度基本不变，不易降解产生杂质，具有良好的稳定性。
药物的稳定性至关重要，尤其在市售有效期内，保持较好的稳定性能够减少药物由于晶型变化和杂质含量增加而导致药物溶出速率及生物利度改变的风险，对保证药物疗效和安全性，避免杂质带来的药物毒性问题，防止药物不良反应的发生具有重要意义。更稳定的晶型在结晶工艺过程中更加可控，不容易出现混晶，且在制剂工艺及储存过程中，不容易转变成其它晶型，从而保证样品的质量标准一致可控，并确保制剂产品的溶出曲线不会随着储存的时间变化而发生改变。
结果表明，本发明晶型CS7、CS9、CS1和CS3具有良好的稳定性，符合药物应用及制剂工艺中对晶型的苛刻要求。
实施例22：晶型CS7、CS9、CS1和CS3的研磨稳定性研究
取本发明晶型CS7、CS9、CS1和CS3各约10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。晶型CS7的测试结果见图30(下图为研磨前，上图为研磨后)，晶型CS9的测试结果见图31(下图为研磨前，上图为研磨后)，晶型CS1的测试结果见图32(下图为研磨前，上图为研磨后)，晶型CS3的测试结果见图33(下图为研磨前，上图为研磨后)。从图中可以看出，本发明晶型CS7、CS9、CS1和CS3经过研磨后晶型不变且结晶度保持良好。
更好的机械稳定性表现在一定机械应力的作用下，仍可保持稳定的物理化学性质。具有较好的机械稳定性的晶型药物对结晶设备要求低，无需特别的后处理条件，在制剂过程中更加稳定，可显著降低药物的开发成本，提升药物质量，具有很强的经济价值。
上述结果表明，本发明的晶型CS7、CS9、CS1和CS3在后续的工艺过程中具备更好的机械稳定性，为后续制剂工艺提供更多选择。例如，可以通过后续干法研磨手段对晶型CS7、CS9、CS1和CS3进行研磨从而得到粒径更小的颗粒。
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 (22)

  1. 一种化合物(I)的二盐酸盐的晶型CS7，其特征在于，其X射线粉末衍射图在2θ值为6.4°±0.2°、20.1°±0.2°、14.1°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS7，其特征还在于，其X射线粉末衍射图在2θ值为19.4°±0.2°、16.5°±0.2°、22.2°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1或2所述的晶型CS7，其特征还在于，其X射线粉末衍射图在2θ值为22.8°±0.2°、8.8°±0.2°、18.7°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种权利要求1所述的晶型CS7的制备方法，其特征在于，所述方法为：
    (1)将SB-939游离碱加至醇类和酯类的混合溶剂中并搅拌，后加入盐酸水溶液(摩尔比HCl:SB-939为2:1～3:1)，在室温下搅拌得到；或
    (2)将SB-939的二盐酸盐溶解在纯水中，配成含有SB-939二盐酸盐的溶液，将溶液滴加至反溶剂中，室温下搅拌得到，其中，反溶剂为醇类和酯类的单一或混合溶剂。
  5. 根据权利要求4所述的制备方法，其特征在于：
    方法(1)中所述醇类溶剂为异丙醇，所述酯类溶剂为乙酸异丙酯；
    方法(2)中所述醇类溶剂为异丙醇，所述酯类溶剂为乙酸乙酯。
  6. 一种化合物(I)的二盐酸盐的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为25.9°±0.2°、21.2°±0.2°、11.9°±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型CS9，其特征还在于，其X射线粉末衍射图在2θ值为23.9°±0.2°、17.0°±0.2°、9.1°±0.2°中的一处或两处或三处具有特征峰。
  8. 根据权利要求6或7所述的晶型CS9，其特征还在于，其X射线粉末衍射图在2θ值为20.3°±0.2°、24.6°±0.2°、21.6°±0.2°中的一处或两处或三处具有特征峰。
  9. 一种权利要求6所述的晶型CS9的制备方法，其特征在于，所述方法为：
    (1)将SB-939的二盐酸盐溶解在N-甲基吡咯烷酮溶剂中形成溶液，将丙酮滴加至SB-939二盐酸盐的溶液中，室温搅拌并于50℃条件下干燥得到；或
    (2)将SB-939的二盐酸盐加至腈类溶剂中，室温下搅拌得到。
  10. 根据权利要求9所述的制备方法，其特征在于：方法(2)中所述腈类溶剂为乙腈。
  11. 一种化合物(I)的二盐酸盐的晶型CS1，其特征在于，其X射线粉末衍射图在2θ值为10.6°±0.2°、24.6°±0.2°、15.9°±0.2°处具有特征峰。
  12. 根据权利要求11所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2θ值为6.9°±0.2°、25.7°±0.2°、27.4°±0.2°中的一处或两处或三处具有特征峰。
  13. 根据权利要求11或12所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2θ值为13.9°±0.2°、19.0°±0.2°的一处或两处具有特征峰。
  14. 一种权利要求11所述的晶型CS1的制备方法，其特征在于，所述方法为：
    (1)将SB-939游离碱加至酮类溶剂体系中搅拌，后加入盐酸水溶液(摩尔比HCl:SB-939为2:1～3:1)，在室温下搅拌得到；或
    (2)将SB-939的二盐酸盐溶解在醇类或水或酰胺类正溶剂中，配成含SB-939二盐酸盐的溶液，将反溶剂滴加至溶液中，室温搅拌得到，其中，正溶剂为醇类或水时，反溶剂为腈类或酮类；正溶剂为酰胺类时，反溶剂为腈类、醚类或酯类。
  15. 根据权利要求14所述的制备方法，其特征在于：
    方法(1)中所述酮类溶剂为丙酮；
    方法(2)中所述醇类溶剂为甲醇，所述腈类溶剂为乙腈，所述酮类溶剂为丙酮，所述酰胺类溶剂为二甲基乙酰胺，所述醚类溶剂为甲基叔丁基醚，所述酯类溶剂为乙酸异丙酯。
  16. 一种化合物(I)的二盐酸盐的晶型CS3，其特征在于，其X射线粉末衍射图在2θ值为6.5°±0.2°、8.0°±0.2°、25.0°±0.2°处具有特征峰。
  17. 根据权利要求16所述的晶型CS3，其特征还在于，其X射线粉末衍射图在2θ值为9.7°±0.2°、15.0°±0.2°、18.7°±0.2°中的一处或两处或三处具有特征峰。
  18. 根据权利要求16或17所述的晶型CS3，其特征还在于，其X射线粉末衍射图在2θ值为20.5°±0.2°、19.6°±0.2°、20.0°±0.2°的一处或两处或三处具有特征峰。
  19. 一种权利要求16所述的晶型CS3的制备方法，其特征在于，所述方法为：
    (1)将SB-939的二盐酸盐溶解在醇类或N-甲基吡咯烷酮或亚砜类正溶剂中，配成含SB-939二盐酸盐的溶液，将反溶剂滴加至溶液中，室温搅拌得到，其中，正溶剂为醇类时，反溶剂为醚类；正溶剂为N-甲基吡咯烷酮时，反溶剂为丙酮；正溶剂为亚砜类溶剂时，反溶剂为酮类溶剂；或
    (2)将SB-939的二盐酸盐加至醇类、腈类、酯类和烷烃类的单一或混合溶剂中，室温搅拌，后在0～10℃条件下搅拌，最后继续在40～80℃条件下搅拌得到。
  20. 根据权利要求19所述的制备方法，其特征在于：
    方法(1)中所述醇类溶剂为甲醇，所述醚类溶剂为甲基叔丁基醚，所述亚砜类溶剂为二甲亚砜，所述酮类溶剂为甲基异丁基酮；
    方法(2)中所述醇类溶剂为乙醇，所述腈类溶剂为乙腈，所述酯类溶剂为乙酸乙酯，所述烷烃类溶剂为正庚烷，所述0～10℃为4℃，所述40～80℃为50℃。
  21. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的晶型CS7或权利要求6所述的晶型CS9或权利要求11所述的晶型CS1或权利要求16所述的晶型CS3及药学上可接受的载体、稀释剂或赋形剂。
  22. 权利要求1所述的晶型CS7或权利要求6所述的晶型CS9或权利要求11所述的晶型CS1或权利要求16所述的晶型CS3，在制备治疗前列腺癌和/或急性髓性白血病和/或骨髓发育异常综合征疾病的药物中的用途。
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