WO2018049634A1 - Abt-199加成盐及其晶型、其制备方法和药物组合物 - Google Patents

Abt-199加成盐及其晶型、其制备方法和药物组合物 Download PDF

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WO2018049634A1
WO2018049634A1 PCT/CN2016/099139 CN2016099139W WO2018049634A1 WO 2018049634 A1 WO2018049634 A1 WO 2018049634A1 CN 2016099139 W CN2016099139 W CN 2016099139W WO 2018049634 A1 WO2018049634 A1 WO 2018049634A1
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abt
monohydrochloride
crystal form
crystal
powder diffraction
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PCT/CN2016/099139
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English (en)
French (fr)
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盛晓红
盛晓霞
郑剑锋
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杭州领业医药科技有限公司
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Priority to US16/333,243 priority Critical patent/US10759798B2/en
Priority to CN201680056774.3A priority patent/CN108137578B/zh
Priority to PCT/CN2016/099139 priority patent/WO2018049634A1/zh
Publication of WO2018049634A1 publication Critical patent/WO2018049634A1/zh

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to the field of medicinal chemical crystallization technology.
  • the present application relates to crystalline forms of ABT-199 hydrochloride and methods of making and using same, as well as pharmaceutical compositions comprising the crystalline forms.
  • ABT-199 is a novel drug for the treatment of chronic lymphocytic leukemia developed by Abbott, a B-cell lymphoma factor-2 (BCL-2) inhibitor.
  • ABT-199 also known as GDC-0199 or GDC-199
  • GDC-0199 has the chemical name 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]pyridin-5-yloxy)benzamide
  • the English name is Venetoclax
  • the molecular formula is C 45 H 50 ClN 7 O 7 S
  • the molecular weight is 868.44
  • its chemical structural formula is as follows Shown as follows:
  • Patent CN103328474A describes a preparation method of ABT-199 compound and various crystal forms of ABT-199 compound in free state, ABT-199 monohydrochloride salt crystal form (in the present invention, for the sake of distinction, the crystal form is named ABT-199 Hydrate crystal form I), hydrate of ABT-199 monohydrochloride (in the present invention, for the sake of distinction, this crystal form is named as crystal form II of ABT-199 hydrochloride), ABT-199 sulfate
  • ABT-199 Hydrate crystal form I hydrate of ABT-199 monohydrochloride
  • crystal form II of ABT-199 hydrochloride
  • ABT-199 sulfate The preparation methods and their PXRD characterization maps, and their pharmaceutical compositions are described.
  • the crystal form I of ABT-199 hydrochloride disclosed in the patent CN103328474A has the disadvantage of poor stability, and is easily converted into ABT-199 hydrochloride crystal form II when exposed to air; the inventors discovered ABT-199 hydrochloric acid during the research.
  • Salt crystal form II has the disadvantage of low solubility in water and poor stability at high temperatures.
  • the crystalline form of the present invention has one or more improved properties, particularly in the presence of good solubility and stability.
  • the ABT-199 salt of the present invention has at least one or more superior properties compared to the known ABT-199 monohydrochloride solid form.
  • Specific improved properties include, for example, higher solubility, higher dissolution rate, better stability, better flowability, and advantageous processing and handling characteristics.
  • the novel solid form of the present invention has higher solubility and better stability.
  • the present invention provides Form A of ABT-199 monohydrochloride (referred to simply as "Form A" in the present invention).
  • the crystal form A is an ethanol solvate of ABT-199 monohydrochloride, and its structural formula is as shown in the following formula (I):
  • the X-ray powder diffraction pattern of the crystal form A expressed in terms of 2 ⁇ angle has the following characteristic peaks: 4.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.0 ⁇ 0.2. ° and 19.0 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form A represented by the 2 ⁇ angle has characteristic peaks at the following positions: 4.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 9.4 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.2 ⁇ 0.2. °, 18.0 ⁇ 0.2 °, 19.0 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 20.8 ⁇ 0.2 °, 23.0 ⁇ 0.2 °, 24.7 ⁇ 0.2 ° and 27.0 ⁇ 0.2 °.
  • the crystal form A has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the crystalline form A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form A has characteristic peaks at wave numbers of 1669, 1522, 1431, 1418, 1269, 1173, 1105, 985, 756, and 660 cm -1 .
  • the present invention provides a process for the preparation of Form A, which comprises the steps of: forming a suspension of ABT-199 monohydrochloride solid in ethanol or a mixed solvent of ethanol and another organic solvent, said other solvent It is selected from the group consisting of water, alkanes (including chlorinated alkanes), C 4 -C 5 esters, C 4 -C 6 ethers (including cyclic ethers), acetonitrile, tetrahydrofuran or mixtures thereof, stirred and crystallized, and the precipitated crystals are separated and dried.
  • Form A of the ABT-199 monohydrochloride salt was obtained.
  • the additional solvent is selected from the group consisting of water, n-heptane, methyl tert-butyl ether, tetrahydrofuran or mixtures thereof.
  • the preparation method has an operating temperature of 10 to 60 ° C, more preferably room temperature; and the stirring time is 1 to 7 days, more preferably 3 to 7 days.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass-to-volume ratio of the amount of the ABT-199 monohydrochloride to the amount of the solvent in the preparation method is from 10 mg/mL to 100 mg/mL, more preferably from 20 mg/mL to 50 mg/mL.
  • the crystal form A of the ABT-199 monohydrochloride of the present invention has a higher solubility in water than the known ABT-199 hydrochloride salt form II at 25 ° C, indicating the crystal of the ABT-199 monohydrochloride salt of the present invention.
  • Type A has better solubility and thus better bioavailability.
  • the crystal form A of the ABT-199 monohydrochloride of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the crystal form A of the ABT-199 monohydrochloride of the present invention has good storage stability, and can better ensure that the pharmaceutically active ingredient itself and the preparation form containing ABT-199 monohydrochloride can avoid or reduce the drug. Quality, safety, and stability issues during manufacturing and/or storage, such as non-uniform content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the present invention provides Form B of ABT-199 monohydrochloride (referred to simply as "Form B" in the present invention).
  • the crystal form B is an anhydride of ABT-199 monohydrochloride, and its structural formula is as shown in the following formula (II):
  • the X-ray powder diffraction pattern of the crystal form B expressed in terms of 2 ⁇ angle has the following characteristic peaks: 4.6 ⁇ 0.2°, 9.9 ⁇ 0.2°, 12.2 ⁇ 0.2°, 13.3 ⁇ 0.2°, 18.0 ⁇ 0.2 ° and 20.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form B represented by the 2 ⁇ angle has characteristic peaks at the following positions: 4.6 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.1 ⁇ 0.2°, 9.9 ⁇ 0.2°, 12.2 ⁇ 0.2 °, 13.3 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 20.8 ⁇ 0.2 °, 22.0 ⁇ 0.2 ° and 27.0 ⁇ 0.2 °.
  • the crystalline form B has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the crystalline form B has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form B has characteristic peaks at wave numbers of 1669, 1573, 1431, 1367, 1229, 1205, 1143, 985, 866, and 811 cm -1 .
  • the crystalline form B has the following single crystal structure information:
  • the present invention provides a process for the preparation of Form B, which employs any of the following methods:
  • the crystal form II of ABT-199 monohydrochloride salt form A or ABT-199 hydrochloride is heated from room temperature to 130 ° C at a temperature increase rate of 5 to 20 ° C / min, and is maintained at 5 to 35 at this temperature.
  • the solvent was removed from minute to complete, and then cooled to room temperature at a cooling rate of 5 to 20 ° C /min to obtain the crystal form B.
  • the ABT-199 hydrochloride salt form II has an X-ray powder diffraction pattern as shown in FIG.
  • the holding time is 20 to 35 minutes, more preferably 20 to 30 minutes;
  • the heating rate is 5 to 10 ° C / min.
  • the cooling rate is 10 to 20 ° C / minute.
  • the ABT-199 hydrochloride salt form II has an X-ray powder diffraction pattern as shown in FIG.
  • the ambient temperature is between 140 and 150 °C.
  • the time of the placement is 20 to 30 minutes.
  • the crystalline form B of the ABT-199 monohydrochloride of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the crystalline form B of the ABT-199 monohydrochloride of the present invention has good storage stability, can better ensure that the pharmaceutically active ingredient itself and the formulation form containing ABT-199 monohydrochloride can avoid or reduce the manufacture of the drug and/or Or problems in quality, safety, and stability during storage, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the present invention provides a crystalline form C of ABT-199 monohydrochloride (referred to simply as "Form C" in the present invention).
  • the crystal form C is a dihydrate of ABT-199 monohydrochloride, and its structural formula is as shown in the following formula (III):
  • the X-ray powder diffraction pattern of the crystal form C expressed in terms of 2 ⁇ angle has the following characteristic peaks: 4.6 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 17.2 ⁇ 0.2°, and 17.8 ⁇ 0.2. °.
  • the X-ray powder diffraction pattern of the crystal form C expressed in the 2 ⁇ angle has characteristic peaks at the following positions: 4.6 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.8 ⁇ 0.2 °, 18.5 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 21.2 ⁇ 0.2 °, 23.6 ⁇ 0.2 ° and 27.0 ⁇ 0.2 °.
  • the crystal form C has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • crystalline form C has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form C has characteristic peaks at wave numbers of 1669, 1605, 1522, 1418, 1367, 1346, 1250, 1173, 904, and 842 cm -1 .
  • the present invention provides a process for the preparation of Form C comprising the steps of: ABT-199 monohydrochloride solid in dichloromethane, methanol, water-saturated ester/alkane, C 3 -C 4 ketone A suspension is formed in the mixture or a mixture thereof, and the crystals are stirred and the precipitated crystals are separated and dried to obtain the crystal form C of the ABT-199 monohydrochloride.
  • the solvent is selected from the group consisting of dichloromethane, methanol, water-saturated ethyl acetate, water-saturated n-heptane, methyl ethyl ketone or a mixture thereof.
  • the preparation method has an operating temperature of 10 to 60 ° C, more preferably room temperature.
  • the agitation time is from 1 to 7 days, more preferably from 3 to 7 days.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass-to-volume ratio of ABT-199 monohydrochloride to solvent in the preparation method is from 10 mg/mL to 100 mg/m, more preferably from 20 mg/mL to 50 mg/mL.
  • the known ABT-199 monohydrochloride salt form II can not maintain the original crystal form, and converts to the crystal form C of the ABT-199 monohydrochloride salt of the invention. While Form C of the ABT-199 monohydrochloride of the present invention remained crystalline under the same experimental conditions.
  • the crystal form C of the ABT-199 monohydrochloride of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the crystalline form C of the ABT-199 monohydrochloride of the present invention has good storage stability, can better ensure that the pharmaceutically active ingredient itself and the formulation form containing ABT-199 monohydrochloride can avoid or reduce the manufacture of the drug and/or Or quality, safety and stability problems during storage, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • Form 1 (abbreviated as "Form 1" in the present invention) of ABT-199 dihydrochloride, the structural formula of which is represented by the following formula (IV):
  • Form 1 is an anhydride of ABT-199 dihydrochloride.
  • the X-ray powder diffraction pattern of Form 1 expressed in 2 ⁇ angle has the following characteristic peaks: 4.5 ⁇ 0.2°, 9.9 ⁇ 0.2°, 12.4 ⁇ 0.2°, 16.5 ⁇ 0.2°, 19.0 ⁇ 0.2 ° and 20.7 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the Form 1 expressed in terms of 2 ⁇ angle has characteristic peaks at the following positions: 4.5 ⁇ 0.2°, 9.9 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.5 ⁇ 0.2 °, 16.7 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 19.0 ⁇ 0.2 °, 19.6 ⁇ 0.2 °, 20.7 ⁇ 0.2 °, 22.9 ⁇ 0.2 °, and 25.2 ⁇ 0.2 °.
  • the crystal form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the Form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form 1 has characteristic peaks at wave numbers of 1687, 1618, 1569, 1447, 1351, 1312, 1275, 1238, 1172, 1091, 831, 790, and 659 cm -1 .
  • the present invention provides a process for the preparation of Form 1, which comprises the steps of: in a solvent selected from the group consisting of C 1 -C 4 alcohols, C 3 -C 4 ketones, acetonitrile or mixtures thereof, the molar ratio is 1:2 to 1:2.5 ABT-199 and 37% hydrochloric acid solution were mixed and stirred, and the solid was separated to obtain crystal form 1 of the ABT-199 dihydrochloride.
  • the solvent is selected from the group consisting of isopropanol, acetone, acetonitrile or mixtures thereof.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the agitation time is from 1 to 7 days, more preferably from 3 to 7 days.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass-to-volume ratio of the ABT-199 free base to the solvent in the preparation method is from 40 mg/mL to 100 mg/mL, more preferably from 40 mg/mL to 80 mg/mL.
  • the starting material ABT-199 can be prepared by the method described in the synthesis of the compound of the example of the patent document 04-CN103328474A, which is incorporated herein by reference in its entirety in its entirety in Amorphous or crystalline.
  • the crystal form 1 has the following beneficial effects:
  • the crystalline form 1 of the ABT-199 dihydrochloride salt of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the ABT-199 dihydrochloride salt form 1 of the present invention has good storage stability, can better ensure that the pharmaceutically active ingredient itself and the formulation dosage form containing ABT-199 monohydrochloride can avoid or reduce the manufacture of the drug and/or Problems such as quality, safety and stability during storage, such as uneven content of active ingredients and impurities. Avoid special and expensive packaging.
  • the present inventors also developed crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, crystal of ABT-199 monohydrochloride.
  • Form L Form M, Form N and methods for their preparation.
  • the crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I, of the above ABT-199 monohydrochloride salt, Form J, Form K, Form L, Form M, Form N have one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology Good thermal and storage stability, low hygroscopicity, good flowability and favorable processing and handling characteristics.
  • the crystal form D of the ABT-199 monohydrochloride is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 5.8 ⁇ 0.2°, 7.3 ⁇ 0.2°, 11.4 ⁇ 0.2°, There are characteristic peaks at 11.8 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.7 ⁇ 0.2°, and 24.8 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form D of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a solvent, stirring and crystallization at a certain temperature, and crystallizing the precipitated crystal Separation and drying gave the crystal form D of the ABT-199 monohydrochloride.
  • the solvent is selected from the group consisting of a mixed solvent of 1,4-dioxane and water, and the temperature is 10 to 60 °C.
  • the crystal form E of the ABT-199 monohydrochloride is characterized in that the X-ray powder diffraction pattern of Cu-K ⁇ radiation is 4.6 ⁇ 0.2°, 8.3 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.3. Characteristic peaks at ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.8 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.5 ⁇ 0.2°, and 24.6 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form E of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of toluene or toluene with other organic solvents, a certain temperature The crystals were stirred and the precipitated crystals were separated and dried to obtain crystal form E of the ABT-199 monohydrochloride salt.
  • the organic solvent is selected from the group consisting of an alkane, a C 4 -C 5 ester, or a mixture thereof, and the temperature is 40 to 60 °C.
  • Form A of the ABT-199 monohydrochloride characterized in that the X-ray powder diffraction pattern of Cu-K ⁇ radiation is 4.6 ⁇ 0.2°, 8.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.1. Characteristic peaks at ⁇ 0.2°, 14.7 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 23.1 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.3 ⁇ 0.2°, and 27.1 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystalline form F of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of chloroform or chloroform with other organic solvents, at a certain temperature The crystal was stirred and the precipitated crystal was separated and dried to obtain a crystal form F of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of alcohols, alkanes (including chlorinated alkanes), C 4 -C 5 esters, or mixtures thereof, at a temperature of 40 to 60 °C.
  • the crystal form G of the ABT-199 monohydrochloride is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has diffraction angles of 4.6 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.5 ⁇ 0.2°, 12.1. Characteristic peaks at ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.7 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.7 ⁇ 0.2°, and 26.5 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form G of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of isopropanol or isopropanol and other solvents; The crystal was stirred and stirred at a certain temperature, and the precipitated crystal was separated and dried to obtain a crystal form G of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of an alkane, a cyclic ether, a C 4 -C 5 ester or a mixture thereof, and the temperature is 10 to 60 °C.
  • the crystal form H of the ABT-199 monohydrochloride is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has diffraction angles of 4.6 ⁇ 0.2°, 8.3 ⁇ 0.2°, 9.5 ⁇ 0.2°, 12.1. Characteristic peaks at ⁇ 0.2°, 12.4 ⁇ 0.2°, 14.5 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.0 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.9 ⁇ 0.2°, and 23.1 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystalline form H of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of n-propanol or n-propanol with other solvents; The crystal was stirred and stirred at a certain temperature, and the precipitated crystal was separated and dried to obtain a crystal form H of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of water, cyclic ethers, alkanes, C 4 -C 5 esters or mixtures thereof, and the temperature is from 10 to 60 °C.
  • Form I of the ABT-199 monohydrochloride salt characterized by using Cu-K ⁇ radiation having an X-ray powder diffraction pattern at diffraction angles of 4.5 ⁇ 0.2°, 8.5 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.3 Characteristic peaks at ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.9 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.3 ⁇ 0.2°, and 27.1 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystalline form I of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of sec-butanol or sec-butanol with other solvents; The crystal was stirred and stirred at a certain temperature, and the precipitated crystal was separated and dried to obtain crystal form I of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of an alkane, a cyclic ether, a C 4 -C 5 ester or a mixture thereof, and the temperature is 10 to 60 °C.
  • the crystal form J of the ABT-199 monohydrochloride is characterized in that the X-ray powder diffraction pattern of the Cu-K ⁇ radiation is 4.5 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.1. Characteristic peaks at ⁇ 0.2°, 12.3 ⁇ 0.2°, 14.6 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.0 ⁇ 0.2°, 21.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.7 ⁇ 0.2°, and 26.8 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form J of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of n-butanol or n-butanol with other solvents; The crystal was stirred and stirred at a certain temperature, and the precipitated crystal was separated and dried to obtain a crystal form J of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of an alkane, a cyclic ether, a C 4 -C 5 ester or a mixture thereof, and the temperature is 10 to 60 °C.
  • the crystal form K of the ABT-199 monohydrochloride is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has diffraction angles of 4.6 ⁇ 0.2°, 8.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.5. Characteristic peaks at ⁇ 0.2°, 13.2 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.7 ⁇ 0.2°, 19.4 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.3 ⁇ 0.2°, 23.7 ⁇ 0.2°, and 26.9 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form K of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in acetone or a mixed solvent of acetone and other solvents at a certain temperature The crystal was stirred and the precipitated crystal was separated and dried to obtain a crystal form K of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of an alkane, a C 4 -C 5 ester, water or a mixture thereof, and the temperature is 10 to 50 °C.
  • the crystal form L of the ABT-199 monohydrochloride is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has diffraction angles of 4.5 ⁇ 0.2 °, 7.6 ⁇ 0.2 °, 8.3 ⁇ 0.2 °, 14.2. Characteristic peaks at ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.1 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.2 ⁇ 0.2°, and 25.7 ⁇ 0.2°.
  • the invention also provides a preparation method of crystal form L of ABT-199 monohydrochloride, comprising the steps of: solidifying ABT-199 monohydrochloride in 1,4-dioxane or 1,4-dioxane A suspension is formed in a mixed solvent with another nonaqueous solvent, and the crystal is stirred and stirred at a constant temperature, and the precipitated crystal is separated and dried to obtain a crystal form L of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of an alkane, a C 4 -C 5 ester, or a mixture thereof, and the temperature is 10 to 60 °C.
  • the crystal form M of the ABT-199 monohydrochloride is characterized in that the X-ray powder diffraction pattern of the Cu-K ⁇ radiation is 4.6 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.3. Characteristic peaks at ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.3 ⁇ 0.2°, 23.5 ⁇ 0.2°, and 27.0 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form M of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a mixed solvent of tetrahydrofuran or tetrahydrofuran with other solvents at a certain temperature The crystals were stirred and the precipitated crystals were separated and dried to obtain a crystal form M of the ABT-199 monohydrochloride.
  • the organic solvent is selected from the group consisting of an alkane, a C 4 -C 5 ester, water or a mixture thereof, and the temperature is 10 to 60 °C.
  • the crystal form N of the ABT-199 monohydrochloride is characterized in that the X-ray powder diffraction pattern of the Cu-K ⁇ radiation is 4.5 ⁇ 0.2°, 5.7 ⁇ 0.2°, 7.5 ⁇ 0.2°, 8.5. Characteristic peaks at ⁇ 0.2°, 10.5 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.4 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.5 ⁇ 0.2°, and 20.9 ⁇ 0.2°.
  • the invention also provides a preparation method of the crystal form N of ABT-199 monohydrochloride, comprising the steps of: forming a suspension of ABT-199 monohydrochloride solid in a solvent, stirring and crystallizing at a certain temperature, and crystallizing the precipitated crystal
  • the crystal form N of the ABT-199 monohydrochloride salt was obtained by separation and drying.
  • the solvent is selected from the group consisting of a mixed solvent of methanol and water, and the temperature is 10 to 60 °C.
  • Form A, Form B, Form C, Form D, Form E, Form F of ABT-199 monohydrochloride of the present invention compared to the known ABT-199 monohydrochloride crystal form.
  • Form 1 of Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N and ABT-199 dihydrochloride have the following or A variety of improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal and storage stability, better flow and better formulation Processability can be more easily prepared under room temperature conditions or high temperature conditions, which is more conducive to the industrialization of products.
  • Form A of the ABT-199 monohydrochloride of the present invention In any method of preparing Form 1 of Form K, Form L, Form M, Form N, and ABT-199 dihydrochloride:
  • room temperature means a temperature of 10 to 30 °C.
  • the "chlorinated alkane” may be dichloromethane or chloroform.
  • the "cyclic ether” may be tetrahydrofuran or 1,4-dioxane.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration under reduced pressure is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the "filtration” is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • centrifuge The specific operation of the "centrifugation" is that the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • the "drying" can be accomplished by conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying; it can be reduced or at atmospheric pressure, preferably at a pressure of less than 0.09 MPa.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; it may be carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09 MPa.
  • crystalline means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRD pattern will typically vary slightly from instrument to sample. The difference in peak angle may vary by 1°, 0.8°, 0.5°, 03°, 0.1°, etc. depending on the instrument, and the error is usually ⁇ 0.2°, so the difference in peak angle cannot be the sole criterion.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows a certain offset.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present invention is within the scope of the present invention.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • the crystalline form of the ABT-199 monohydrochloride or dihydrochloride salt of the present invention is substantially pure, unitary, and substantially free of any other crystalline or amorphous form.
  • substantially pure when used in reference to a new crystalline form means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% ( Weight), especially at least 99% by weight.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more new crystalline forms of the ABT-199 monohydrochloride and dihydrochloride of the present invention or A new crystalline form of ABT-199 monohydrochloride and dihydrochloride salt prepared by the process of the invention, and at least one pharmaceutically acceptable carrier.
  • the new crystalline form of the ABT-199 hydrochloride comprises the crystalline form A of ABT-199 monohydrochloride, the crystalline form B of ABT-199 monohydrochloride, and the crystalline form C of ABT-199 monohydrochloride Form 1 of ABT-199 dihydrochloride.
  • the pharmaceutical composition may further comprise ABT-199 hydrochloride.
  • Other pharmaceutically acceptable crystalline forms eg, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, and Crystal Type N
  • amorphous e.g, Form D
  • Excipients in the pharmaceutical compositions are well known to those skilled in the art, and the choice of species, usage, and amount is well known to those skilled in the art.
  • examples include sugars, cellulose and its derivatives, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semi-solids such as lipids or paraffins, Mixtures such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, light anhydrous silicic acid, Crystalline cellulose, talc or magnesium stearate, disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry cornstarch, lubricants such as stearin Acid, magnesium stearate, sodium stearyl fumarate, polyethylene glyco
  • the administration route of the pharmaceutical combination includes oral administration, intravenous subcutaneous injection, injection into tissue administration, transdermal administration, rectal administration, intranasal administration, and the like.
  • the pharmaceutical combination may be prepared into a certain dosage form depending on the route of administration or need, and may be solid or liquid.
  • Solid oral dosage forms including, for example, tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including, for example, solutions, syrups, suspensions, dispersions, and emulsions; injectable preparations including, for example, solutions, dispersions And lyophilizate.
  • the formulation may be suitable for immediate, sustained or controlled release of the active ingredient of the drug. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • Formulation of Form A of Form A, Form B, Form C or Dihydrochloride of ABT-199 Monohydrochloride of the present invention with one or more pharmaceutically acceptable excipients when preparing a pharmaceutical composition The agents are mixed, optionally mixed with pharmaceutically acceptable ABT-199 monohydrochloride, other crystalline forms of the dihydrochloride, amorphous, optionally with one or more other pharmaceutically active ingredients Mixed.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present invention provides one or more novel forms of the ABT-199 monohydrochloride, dihydrochloride of the present invention or a new crystal of ABT-199 hydrochloride and dihydrochloride obtained by the preparation method of the present invention.
  • Use in the manufacture of a medicament for the treatment and/or prevention of one or more disease diseases which are overexpressed by an anti-apoptotic BCL-2 family protein wherein the novel crystalline form of the ABT-199 hydrochloride comprises Form A of the ABT-199 monohydrochloride of the invention, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form 1 of Form K, Form L, Form M, Form N and ABT-199 Dihydrochloride.
  • the present invention provides a method of treating and/or preventing one or more disease diseases which are overexpressed by an anti-apoptotic BCL-2 family protein, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount A new crystalline form of ABT-199 monohydrochloride, dihydrochloride or a combination thereof, or a pharmaceutical composition thereof, wherein the novel crystalline form of ABT-199 hydrochloride comprises ABT-199 monohydrochloride Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Crystal Form 1, Form N, and Form 1 of ABT-199 Dihydrochloride.
  • Such patients include, but are not limited to, mammals.
  • Figure 1 is an X-ray powder diffraction pattern of a crystalline form II of a known hydrochloride salt prepared according to the method described in Example 14 of the patent document CN103328474A.
  • Example 2 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form A of Example 1 of the present invention.
  • Example 3 is a TGA map of ABT-199 monohydrochloride salt form A of Example 1 of the present invention.
  • Figure 5 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form B according to Example 13 of the present invention.
  • Figure 6 is an IR spectrum of ABT-199 monohydrochloride salt form B according to Example 13 of the present invention.
  • Figure 7 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form C of Example 31 of the present invention.
  • Figure 8 is a TGA map of ABT-199 monohydrochloride salt form C of Example 31 of the present invention.
  • Figure 9 is an IR spectrum of the ABT-199 monohydrochloride salt form C of Example 31 of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of ABT-199 dihydrochloride salt form 1 of Example 37 of the present invention.
  • Figure 11 is a DSC chart of ABT-199 dihydrochloride salt form 1 of Example 37 of the present invention.
  • Figure 12 is a TGA map of ABT-199 dihydrochloride salt form 1 of Example 37 of the present invention.
  • Figure 13 is an IR spectrum of Form 1 of ABT-199 dihydrochloride of the present invention
  • Figure 14 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form D of Example 43 of the present invention.
  • Figure 15 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form E of Example 44 of the present invention.
  • Figure 16 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt Form F of Example 45 of the present invention.
  • Figure 17 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form G of Example 46 of the present invention.
  • Figure 18 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form H of Example 47 of the present invention.
  • Figure 19 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form I according to Example 48 of the present invention.
  • Figure 20 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form J according to Example 49 of the present invention.
  • Figure 21 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form K of Example 50 of the present invention.
  • Figure 22 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form L according to Example 51 of the present invention.
  • Figure 23 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form M according to Example 52 of the present invention.
  • Figure 24 is an X-ray powder diffraction pattern of ABT-199 monohydrochloride salt form N of Example 53 of the present invention.
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • Differential thermal analysis data was taken from the TA Instruments Q200 MDSC.
  • the detection method is as follows: a sample of 1 to 10 mg is placed in a small-pore aluminum crucible, and the sample is raised from room temperature to 230 to 250 ° C under the protection of a drying rate of 40 mL/min dry N 2 at a heating rate of 10 ° C/min.
  • Thermogravimetric analysis data was taken from the TA Instruments Q500TGA.
  • the detection method is as follows: 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 by a stepwise high-resolution detection method at a heating rate of 10 ° C / min under the protection of 40 mL / min dry N 2 . °C.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27 using an ATR apparatus and infrared absorption spectra were acquired in the range of 600-4000 cm -1 .
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 300 MHZ NMR spectrometer. A sample of 1 to 5 mg was weighed and dissolved in a nuclear magnetic sample tube with about 0.5 mL of deuterated dimethyl sulfoxide for detection.
  • HPLC High performance liquid chromatography
  • ABT-199 can be prepared according to the method described in the synthesis of the compound 1 of the example of the patent document CN103328474A.
  • the specific preparation method is:
  • Methyl 4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate (71.84 g), 4-chlorophenylboronic acid (37.27 g), CsF (74 g And a solution of tetrakis(triphenylphosphine)palladium(0) (2.3 g) in 2:1 dimethoxyethane/methanol (700 mL) was heated to 70 ° C for 24 h. The mixture was concentrated. Diethyl ether (4 x 230 mL) was added and the mixture was filtered. Concentrate the combined ether solution to give 2-(4- Methyl chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate.
  • Methanesulfonyl chloride (8.7 mL) was added to the compound by syringe at 0 ° C to give (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol (33.9 g).
  • triethylamine 35mL
  • CH 2 Cl 2 580mL
  • N-tert-Butoxycarbonylpiperazine 25 g was added and the mixture was stirred at room temperature for 24 hours. The suspension was washed with brine, catch (Na 2 SO 4), filtered and concentrated.
  • the known hydrate crystalline form of ABT-199 hydrochloride (i.e., Form II herein) can be prepared according to the method described in the methods described in Examples 14-15 of Patent Document CN103328474A.
  • ABT-199 (free base) solid was suspended in 100 mL of acetonitrile. While stirring, 321 mg of concentrated hydrochloric acid was diluted with 1.5 mL of acetonitrile and added dropwise to the suspension. The reaction rapidly reacted to form a clear solution, followed by a pale yellow solid. Precipitate. The resulting pale yellow solid was exposed to air to give ABT-199 hydrochloride.
  • the X-ray powder diffraction pattern of the obtained ABT-199 hydrochloride sample is shown in Fig. 1, and the X-ray powder diffraction pattern of the hydrate crystal form of ABT-199 hydrochloride provided in Patent Document CN103328474A is substantially the same.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 100 mg was added, and 3 mL of ethanol was added to form a suspension. After stirring at room temperature for 3 days, it was filtered under reduced pressure, and dried under vacuum at 40 ° C for 10 hours to obtain 98 mg of ABT-199 monohydrochloride. Form A.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 50 mg was added, 0.5 mL of ethanol and 0.5 mL of water were added to form a suspension, and the mixture was stirred at room temperature for 7 days, filtered under reduced pressure, and dried under vacuum at 30 ° C for 24 hours to obtain 48 mg of ABT- 199 monohydrochloride salt form A.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.5 mL of ethanol and 0.5 mL of n-heptane were added to form a suspension, and the mixture was stirred at room temperature for 5 days, then filtered under reduced pressure, and dried under vacuum at 10 ° C for 10 hours to obtain 19 mg of ABT. -199 monohydrochloride salt form A.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 10 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.5 mL of ethanol, 0.5 mL of methyl tert-butyl ether to form a suspension, stir at room temperature for 1 day, filter under reduced pressure, and dry at 40 ° C for 16 hours under vacuum. , 9 mg of ABT-199 monohydrochloride salt form A was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 10 mg was added, 0.5 mL of ethanol and 0.5 mL of ethyl acetate were added to form a suspension, and the mixture was stirred at 60 ° C for 2 days, filtered under reduced pressure, and dried under vacuum at 25 ° C for 16 hours. 7 mg of ABT-19 monohydrochloride salt Form A was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.4 mL of ethanol and 0.6 mL of dichloromethane were added to form a suspension, and the mixture was stirred at 50 ° C for 1 day, filtered under reduced pressure, and dried at 60 ° C for 48 hours under vacuum. 15 mg of ABT-199 monohydrochloride salt form A was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 20 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.1 mL of ethanol, 0.1 mL of isopropyl acetate, 0.1 mL of n-heptane to form a suspension, stir at room temperature for 4 days, and then filter under reduced pressure, solid 55 ° C Dry in vacuum for 20 hours to get 17mg ABT-199 monohydrochloride salt form A.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 20 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.2 mL of ethanol, 0.1 mL of tetrahydrofuran, 0.2 mL of n-heptane to form a suspension, stir at room temperature for 5 days, filter under reduced pressure, and vacuum dry at 40 ° C. In an hour, 19 mg of ABT-199 monohydrochloride salt form A was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 20 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.1 mL of ethanol, 0.2 mL of acetonitrile, 0.2 mL of n-heptane to form a suspension, stir at room temperature for 2 days, filter under reduced pressure, and vacuum dry at 60 ° C. In an hour, 18 mg of ABT-199 monohydrochloride salt Form A was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 30 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.1 mL of ethanol, 0.1 mL of chloroform, 0.2 mL of methylcyclohexane to form a suspension, and stir for 3 days at 40 ° C, then filter under reduced pressure, solid 40 Drying under vacuum at °C for 36 hours gave 25 mg of ABT-199 monohydrochloride salt form A.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 60 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.2 mL of ethanol, 0.2 mL of diethyl ether, 0.2 mL of n-heptane to form a suspension, stir at 60 ° C for 1 day, filter under reduced pressure, and vacuum at 60 ° C. After drying for 16 hours, 47 mg of ABT-199 monohydrochloride salt form A was obtained.
  • the samples prepared in Examples 2 to 12 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 1, indicating that the samples of Examples 2 to 12 were identical to the samples of Example 1. Crystal form.
  • the ABT-199 monohydrochloride salt form A of the present invention was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 5 ° C / min, held at 130 ° C for 20 minutes to completely remove the solvent, and then at 20 ° C / The cooling rate of one minute was cooled to room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was heated from room temperature to a desolvation temperature of 30 ° C at a temperature increase rate of 10 ° C / min, held at 130 ° C for 10 minutes to completely remove the solvent, and then at 10 ° C / The cooling rate of one minute was cooled to room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 8 ° C / min, held at 130 ° C for 25 minutes to completely remove the solvent, and then at 15 ° C / The cooling rate of one minute was cooled to room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 20 ° C / min, held at 130 ° C for 35 minutes to completely remove the solvent, and then at 5 ° C / The cooling rate of one minute was cooled to room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 15 ° C / min, held at 130 ° C for 5 minutes to completely remove the solvent, and then at 5 ° C / The cooling rate of one minute was cooled to room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was allowed to stand in an environment of 140 ° C for 30 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was allowed to stand in an environment of 150 ° C for 20 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was allowed to stand in an environment of 145 ° C for 10 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form A of the present invention was allowed to stand in an environment of 130 ° C for 40 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form II was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 5 ° C / min, held at 130 ° C for 20 minutes to completely remove the solvent, and then cooled at 20 ° C / min. The rate was cooled to room temperature to give the crystalline form B.
  • the ABT-199 monohydrochloride salt form II was heated from room temperature to a desolvation temperature of 30 ° C at a temperature increase rate of 10 ° C / min, held at 130 ° C for 10 minutes to completely remove the solvent, and then cooled at 10 ° C / min. The rate was cooled to room temperature to give the crystalline form B.
  • the ABT-199 monohydrochloride salt form II was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 8 ° C / min, held at 130 ° C for 25 minutes to completely remove the solvent, and then cooled at 15 ° C / min. The rate was cooled to room temperature to give the crystalline form B.
  • the ABT-199 monohydrochloride salt form II was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 20 ° C / min, held at 130 ° C for 35 minutes to completely remove the solvent, and then cooled at 5 ° C / min. The rate was cooled to room temperature to give the crystalline form B.
  • the ABT-199 monohydrochloride salt form II was heated from room temperature to a desolvation temperature of 130 ° C at a temperature increase rate of 15 ° C / min, held at 130 ° C for 5 minutes to completely remove the solvent, and then cooled at 5 ° C / min. The rate was cooled to room temperature to give the crystalline form B.
  • the ABT-199 monohydrochloride salt form II was allowed to stand in an environment of 140 ° C for 30 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • the ABT-199 monohydrochloride salt form II was allowed to stand in an environment of 150 ° C for 20 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • ABT-199 monohydrochloride salt form II was allowed to stand in an environment of 145 ° C for 10 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • ABT-199 monohydrochloride salt form II was allowed to stand in an environment of 130 ° C for 40 minutes until the solvent was completely removed, and then directly placed at room temperature to obtain the crystal form B.
  • the samples prepared in Examples 14 to 30 had the same or similar XRPD patterns and IR patterns (not shown) as the samples of Example 13, indicating that the samples of Examples 14 to 30 were the same crystal form as the sample of Example 13.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 100 mg was added, and 2 mL of methanol was added to form a suspension. After stirring at room temperature for 3 days, it was filtered under reduced pressure, and dried under vacuum at 40 ° C for 10 hours to obtain 98 mg of ABT-199 monohydrochloride. Crystal form.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 100 mg was added, and 1 mL of methyl ethyl ketone was added to form a suspension. After stirring at room temperature for 7 days, it was filtered under reduced pressure, and dried at 10 ° C for 24 hours under vacuum to obtain 92 mg of ABT-199 monohydrochloride. Salt crystal form C.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 80 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 2 mL of water-saturated n-heptane to form a suspension, stir at 10 ° C for 5 days, filter under reduced pressure, and dry at 30 ° C for 16 hours under vacuum to obtain 78 mg.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.4 mL of water-saturated ethyl acetate and 0.6 mL of water-saturated n-heptane were added to form a suspension, and the mixture was stirred at 60 ° C for 1 day, and then filtered under reduced pressure. The solid was dried under vacuum at 60 ° C for 48 hours to give 18 mg of ABT-199 monohydrochloride salt.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.5 mL of acetone was added to form a suspension, and the mixture was stirred at 60 ° C for 1 day, filtered under reduced pressure, and dried at 50 ° C for 36 hours under vacuum to obtain 17 mg of ABT-199. Hydrochloride crystal form C.
  • the samples prepared in Examples 32 to 36 had the same or similar XRPD patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 31, indicating that the samples of Examples 32 to 36 were identical to the samples of Example 31. Crystal form.
  • the samples prepared in Examples 38 to 42 had the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 38 to 42 and Samples of Example 37. It is the same crystal form.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 20 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.2 mL of 1,4-dioxane and 0.8 mL of water to form a suspension, stir at 60 ° C for 3 days, centrifuge, and dry at 40 ° C under vacuum 24 . In an hour, 19.75 mg of ABT-199 monohydrochloride salt Form D was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.2 mL of methanol and 0.2 mL of chloroform were added to form a suspension, and the mixture was stirred at 60 ° C for 3 days, centrifuged, and dried at 40 ° C for 24 hours under vacuum to obtain 18.68 mg of ABT. -199 monohydrochloride salt form F.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.2 mL of isopropanol, 0.2 mL of tetrahydrofuran and 0.2 mL of n-heptane were added to form a suspension, and the mixture was stirred at room temperature for 3 days, centrifuged, and dried at 40 ° C in vacuo. In an hour, 19.73 mg of ABT-199 monohydrochloride salt Form G was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 Take 20 mg of ABT-199 hydrochloride sample prepared in Preparation Example 2, add 0.2 mL of n-propanol, 0.2 mL of tetrahydrofuran, 0.2 mL of n-heptane to form a suspension, stir at room temperature for 3 days, centrifuge, and dry at 40 ° C under vacuum. In an hour, 19.73 mg of ABT-199 monohydrochloride salt Form H was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.2 mL of acetone and 0.8 mL of water were added to form a suspension, and the mixture was stirred at 50 ° C for 3 days, centrifuged, and dried at 40 ° C for 16 hours under vacuum to obtain 18.73 mg of ABT- 199 monohydrochloride salt form K.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added to 0.2 mL of water, 0.2 mL of tetrahydrofuran, and 0.2 mL of n-heptane to form a suspension. After stirring at room temperature for 3 days, it was centrifuged, and the solid was vacuum dried at 40 ° C for 16 hours. 19.65 mg of ABT-199 monohydrochloride salt Form M was obtained.
  • ABT-199 hydrochloride sample prepared in Preparation Example 2 20 mg was added, 0.6 mL of methanol and 0.6 mL of water were added to form a suspension, and the mixture was stirred at 60 ° C for 3 days, centrifuged, and dried at 40 ° C for 16 hours under vacuum to obtain 19.05 mg of ABT. -199 monohydrochloride salt form N.
  • a 300 mg potency tablet consists of 330 mg of the active ingredient ABT-199 monohydrochloride salt form A, 152 mg compressible starch, 10 mg crospovidone, 150 mg microcrystalline cellulose and 10 mg. Silica composition.
  • Preparation method First, the active ingredient, compressible starch, microcrystalline cellulose and crospovidone are mixed, then the mixture is lubricated by silica, and finally compressed into tablets.
  • ABT-199 monohydrochloride salt form A of Example 54 was replaced with Form B, Form C, Form D, Form E of ABT-199 monohydrochloride described herein, respectively.
  • Form 1 of Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N and ABT-199 Dihydrochloride The free base in the various salt forms and the free base in the ABT-199 monohydrochloride salt form A are the same molar amount, and the filler and preparation steps in the various salt forms are the same as in the example 54.
  • a 30 mg potency capsule consists of 33 mg of the active ingredient ABT-199 monohydrochloride crystal form A, 50 mg ethylcellulose, 15 mg hydroxypropylmethylcellulose, 70 mg lactose, 30 mg microcrystals. Cellulose, 10 mg magnesium stearate and 5 mg talc.
  • Preparation method firstly, the active ingredient, ethyl cellulose, hydroxypropylmethyl cellulose, lactose and microcrystalline cellulose are mixed, granulated with 75% ethanol, dried, pulverized, passed through a 80 mesh sieve, and then stearic acid is added. Mix the magnesium and talc powder and pour it into the No. 2 capsule.
  • the ABT-199 monohydrochloride salt form A of Example 69 was replaced with the crystal form B, crystal form C, crystal form D, and crystal form E of the ABT-199 monohydrochloride salt described herein.
  • the free base in the various salt forms and the free base in the ABT-199 monohydrochloride salt form A are the same molar amount, and the filler and preparation steps in the various salt forms are the same as in Example 69.
  • the ABT-199 monohydrochloride salt form A prepared by the invention and the known ABT-199 hydrochloride salt form II prepared in the preparation example 2 were subjected to a water solubility comparison experiment, and the specific operation was as follows: 10 mg of the sample was respectively taken in 50 ml of glass. In the bottle, 10 mL of deionized water was gradually added dropwise at 25 ° C to form a suspension and ultrasonicated until the solution was stirred for 24 hours. The solution was filtered for HPLC detection, and the solubility of the sample in water was calculated.
  • the ABT-199 monohydrochloride salt form A of the present invention has higher solubility than the known ABT-199 hydrochloride salt form II.
  • the crystal form stability comparison experiment was carried out by taking ABT-199 monohydrochloride salt form B prepared by the present invention and known ABT-199 hydrochloride salt form II prepared in Preparation 2.
  • the specific operation was as follows: 30 mg of the sample was placed at 130 ° C for one day, and XRPD was detected to examine the crystal form stability.
  • the ABT-199 monohydrochloride salt form B of the present invention has better high temperature stability than the known ABT-199 hydrochloride salt form II.
  • the crystal form stability competition experiment was carried out by taking the ABT-199 monohydrochloride salt form C prepared by the present invention and the known ABT-199 hydrochloride salt form II prepared in Preparation 2.
  • the specific operation is as follows: 20 mg of ABT-199 hydrochloride salt form II and ABT-199 monohydrochloride salt form C sample were respectively added to the same water-saturated ethyl acetate to form a slurry, and stirred at room temperature and 40 ° C for 3 days. XRPD detection was carried out to examine the crystal form stability.
  • Crystal form C was stirred for 3 days at room temperature and water-saturated ethyl acetate at 40 ° C, and the crystal form remained unchanged.
  • Form II was in water-saturated ethyl acetate at room temperature and 40 ° C. After stirring for 3 days, the crystal form was converted to Form C, indicating that the ABT-199 monohydrochloride salt form C of the present invention is more than the known ABT-199 hydrochloride salt form II in an aqueous solvent such as water-saturated ethyl acetate. Has better crystal form stability.
  • the ABT-199 dihydrochloride salt form 1 prepared by the invention and the known ABT-199 hydrochloride salt form II prepared in the preparation example 2 were subjected to a water solubility comparison experiment, and the specific operation was as follows: 10 mg of the sample was respectively taken in 20 ml of glass. In the bottle, 10 mL of deionized water was added to form a suspension at 25 ° C and stirred for 24 hours. The solution was filtered for HPLC detection, and the solubility of the sample in water was calculated.
  • the ABT-199 dihydrochloride salt form 1 of the present invention has higher solubility than the known ABT-199 hydrochloride salt form II.

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Abstract

ABT-199单盐酸盐及其二盐酸盐的晶型、其制备方法、其药物组合物被公开，与已知的ABT-199相比，它们具有一种或多种改进的特性。它们可用于制备治疗和／或预防一种或多种抗细胞凋亡BCL-2家族蛋白过度表达的疾病的药物。

Description

ABT-199加成盐及其晶型、其制备方法和药物组合物 技术领域
本申请涉及药物化学结晶技术领域。具体而言，本申请涉及ABT-199盐酸盐的晶型及其制备方法和用途，以及包含所述晶型的药物组合物。
背景技术
ABT-199是由艾伯维公司开发的一种新型的治疗慢性淋巴细胞白血病的药物，该药物是一种B细胞淋巴瘤因子-2(BCL-2)抑制剂。
ABT-199又名GDC-0199或GDC-199，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，英文名称为Venetoclax，分子式为C45H50ClN7O7S，分子量为868.44，其化学结构式如下所示：
Figure PCTCN2016099139-appb-000001
专利CN103328474A描述了ABT-199化合物的制备方法和ABT-199化合物游离态的多种晶型、ABT-199单盐酸盐晶型(本发明中，为了便于区分，将此晶型命名为ABT-199盐酸盐晶型Ⅰ)、ABT-199单盐酸盐的水合物(本发明中，为了便于区分，将此晶型命名为ABT-199盐酸盐的晶型Ⅱ)、ABT-199硫酸盐的制备方法及其PXRD表征图谱，并描述了他们的药物组合物。
专利CN103328474A中公开的ABT-199盐酸盐晶型Ⅰ具有稳定性差的缺点，暴露在空气中易转为ABT-199盐酸盐晶型Ⅱ；本发明人在研究过程中发现ABT-199盐酸盐晶型Ⅱ存在水中溶解度低且高温下稳定性差的缺陷。
鉴于现有技术尚存不足，本领域仍需要开发具有更多优势性能的ABT-199盐酸盐的新的固体形态。
发明内容
针对现有技术的不足，本发明的目的是提供ABT-199盐酸盐的晶型及其制备方法和用途，以及包含所述ABT-199盐酸盐晶型的药物组合物。与已知的ABT-199盐酸盐晶型Ⅰ和晶型Ⅱ相比，本发明的晶型具有一种或多种改进的特性，特别是表现在具备良好的溶解性和稳定性。
与已知的ABT-199单盐酸盐固体形态相比，本发明的ABT-199盐、其晶型或无定型的固体形态具有至少一种或多种更优越的性能。具体的改进性能例如，具有较高的溶解度、较高的溶解速度、较好的稳定性、较好的流动性和有利的加工与处理特性等。尤其是，本发明的新的固体形态具有较高的溶解度和较好的稳定性。
根据本发明的目的，本发明提供ABT-199单盐酸盐的晶型A(在本发明中简称为“晶型A”)。
所述晶型A为ABT-199单盐酸盐的乙醇溶剂化物，其结构式如下式(I)所示：
Figure PCTCN2016099139-appb-000002
使用Cu-Kα辐射，所述晶型A以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.5±0.2°、8.3±0.2°、12.1±0.2°、17.2±0.2°、18.0±0.2°和19.0±0.2°。
更优选地，所述晶型A以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.5±0.2°、8.3±0.2°、9.4±0.2°、12.1±0.2°、17.2±0.2°、18.0±0.2°、19.0±0.2°、19.5±0.2°、20.8±0.2°、23.0±0.2°、24.7±0.2°和27.0±0.2°。
进一步优选地，所述的晶型A，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099139-appb-000003
非限制性地，所述晶型A的一个典型实例具有如图2所示的X-射线粉末衍射(XRPD)图谱。
所述晶型A的傅里叶红外光谱在波数为1669、1522、1431、1418、1269、1173、1105、985、756和660cm-1处具有特征峰。
根据本发明的目的，本发明提供晶型A的制备方法，其包括以下步骤：将ABT-199单盐酸盐固体在乙醇或乙醇与其他有机溶剂的混合溶剂中形成悬浮液，所述其它溶剂选自水、烷烃(包括氯代烷烃)、C4～C5酯、C4～C6醚(包括环醚)、乙腈、四氢呋喃或其混合物，搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型A。
优选地，所述其它溶剂选自水、正庚烷、甲基叔丁基醚、四氢呋喃或其混合物。
优选地，所述制备方法的操作温度为10～60℃，更优选为室温；所述搅拌的时间为1～7天，更优选为3～7天。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中ABT-199单盐酸盐的用量与溶剂用量的质量体积比为10mg/mL～100mg/mL，更优选为20mg/mL～50mg/mL。
所述晶型A具有以下有益效果：
①本发明的ABT-199单盐酸盐的晶型A在25℃下水中溶解度较已知ABT-199盐酸盐晶型Ⅱ的溶解度高，说明本发明的ABT-199单盐酸盐的晶型A具有更好的溶解度，因而具有更好的生物利用度。
②本发明的ABT-199单盐酸盐的晶型A在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的ABT-199单盐酸盐的晶型A具有好的贮存稳定性，能够更好地保证药物活性成分自身和含有ABT-199单盐酸盐的制剂剂型避免或减少药物 制造和/或存储等过程中质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
根据本发明的目的，本发明提供ABT-199单盐酸盐的晶型B(在本发明中简称为“晶型B”)。
所述晶型B为ABT-199单盐酸盐的无水物，其结构式如下式(II)所示：
Figure PCTCN2016099139-appb-000004
使用Cu-Kα辐射，所述晶型B以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、9.9±0.2°、12.2±0.2°、13.3±0.2°、18.0±0.2°和20.8±0.2°。
更优选地，所述晶型B以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.6±0.2°、7.2±0.2°、9.1±0.2°、9.9±0.2°、12.2±0.2°、13.3±0.2°、18.0±0.2°、18.8±0.2°、19.1±0.2°、20.8±0.2°、22.0±0.2°和27.0±0.2°。
进一步优选地，所述的晶型B，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099139-appb-000005
非限制性地，所述晶型B的一个典型实例具有如图5所示的X-射线粉末衍射(XRPD)图谱。
优选地，所述晶型B的傅里叶红外光谱在波数为1669、1573、1431、1367、1229、1205、1143、985、866和811cm-1处具有特征峰。
优选地，所述晶型B具有以下的单晶结构信息：
Figure PCTCN2016099139-appb-000006
Figure PCTCN2016099139-appb-000007
根据本发明的目的，本发明提供晶型B的制备方法，所述制备方法采用下述方法中的任意一种：
(1)将ABT-199单盐酸盐晶型A或ABT-199盐酸盐的晶型Ⅱ以5～20℃/分钟的升温速率从室温升温至130℃，在此温度下保持5～35分钟至完全脱去溶剂，然后以5～20℃/分钟的冷却速率冷却至室温，得到所述晶型B。
所述ABT-199盐酸盐晶型Ⅱ具有如图1所示的X-射线粉末衍射图谱。
优选地，所述保持的时间为20～35分钟，更优选为20～30分钟；
优选地，所述升温速率为5～10℃/分钟。
优选地，所述冷却速率为10～20℃/分钟。
(2)将ABT-199单盐酸盐晶型A或ABT-199盐酸盐的晶型Ⅱ在130～150℃的环境中放置20～40分钟至完全脱去溶剂，再置于室温下，得到所述晶型B。
所述ABT-199盐酸盐晶型Ⅱ具有如图1所示的X-射线粉末衍射图谱。
优选地，所述环境的温度为140～150℃。
优选地，所述放置的时间为20～30分钟。
所述晶型B具有以下有益效果：
①已知的ABT-199单盐酸盐晶型Ⅱ在130℃下条件下放置1天晶型发生了转变，而本发明的ABT-199单盐酸盐晶型B的晶型没有发生变化，说明本发明的ABT-199单盐酸盐的晶型B具有更好的晶型稳定性。
②本发明的ABT-199单盐酸盐的晶型B在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的ABT-199单盐酸盐的晶型B具有好的贮存稳定性，能够更好地保证药物活性成分自身和含有ABT-199单盐酸盐的制剂剂型避免或减少药物制造和/或存储等过程中质量、安全性和稳定性的问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
根据本发明的目的，本发明提供ABT-199单盐酸盐的晶型C(在本发明中简称为“晶型C”)。
所述晶型C为ABT-199单盐酸盐的二水合物，其结构式如下式(III)所示：
Figure PCTCN2016099139-appb-000008
使用Cu-Kα辐射，所述晶型C以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、8.3±0.2°、11.9±0.2°、17.2±0.2°和17.8±0.2°。
更优选地，所述晶型C以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.6±0.2°、8.3±0.2°、11.9±0.2°、17.2±0.2°、17.8±0.2°、18.5±0.2°、19.3±0.2°、21.2±0.2°、23.6±0.2°和27.0±0.2°。
进一步优选地，所述的晶型C，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099139-appb-000009
非限制性地，所述晶型C的一个典型实例具有如图7所示的X-射线粉末衍射(XRPD)图谱。
所述晶型C的傅里叶红外光谱在波数为1669、1605、1522、1418、1367、1346、1250、1173、904和842cm-1处具有特征峰。
根据本发明的目的，本发明提供晶型C的制备方法，其包括以下步骤：将ABT-199单盐酸盐固体在二氯甲烷、甲醇、水饱和的酯/烷烃、C3～C4酮或其混合物中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型C。
优选地，所述溶剂选自二氯甲烷、甲醇、水饱和的乙酸乙酯、水饱和的正庚烷、丁酮或其混合物。
优选地，所述制备方法的操作温度为10～60℃，更优选为室温。
优选地，所述搅拌的时间为1～7天，更优选为3～7天。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中ABT-199单盐酸盐与溶剂的质量体积比为10mg/mL～100mg/m，更优选为20mg/mL～50mg/mL。
所述晶型C具有以下有益效果：
①通过在溶剂中晶浆的稳定性竞争实验对比，已知的ABT-199单盐酸盐晶型Ⅱ不能维持原有的结晶形态，转变成本发明的ABT-199单盐酸盐的晶型C，而本发明的ABT-199单盐酸盐的晶型C在同样实验条件下保持晶型不变。
②本发明的ABT-199单盐酸盐的晶型C在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的ABT-199单盐酸盐的晶型C具有好的贮存稳定性，能够更好地保证药物活性成分自身和含有ABT-199单盐酸盐的制剂剂型避免或减少药物制造和/或存储等过程中质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
根据本发明的目的，本发明提供ABT-199二盐酸盐的晶型1(在本发明中简称为“晶型1”)，其结构式如下式(IV)所示：
Figure PCTCN2016099139-appb-000010
所述晶型1为ABT-199二盐酸盐的无水物。
使用Cu-Kα辐射，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.5±0.2°、9.9±0.2°、12.4±0.2°、16.5±0.2°、19.0±0.2°和20.7±0.2°。
更优选地，所述晶型1以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.5±0.2°、9.9±0.2°、12.4±0.2°、15.5±0.2°、16.5±0.2°、16.7±0.2°、17.2±0.2°、19.0±0.2°、19.6±0.2°、20.7±0.2°、22.9±0.2°和25.2±0.2°。
进一步优选地，所述的晶型1，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099139-appb-000011
非限制性地，所述晶型1的一个典型实例具有如图10所示的X-射线粉末衍射(XRPD)图谱。
所述晶型1的傅里叶红外光谱在波数为1687、1618、1569、1447、1351、1312、1275、1238、1172、1091、831、790和659cm-1处具有特征峰。
根据本发明的目的，本发明提供晶型1的制备方法，其包括以下步骤：在选自C1～C4醇、C3～C4酮、乙腈或其混合物的溶剂中，将摩尔比为1:2～1:2.5的ABT-199和37％的盐酸溶液混合并搅拌，分离固体，得到所述ABT-199二盐酸盐的晶型1。
优选地，所述溶剂选自异丙醇、丙酮、乙腈或其混合物。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述搅拌的时间为1～7天，更优选为3～7天。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中ABT-199游离碱与溶剂的质量体积比为40mg/mL～100mg/mL，更优选为40mg/mL～80mg/mL。
起始原料ABT-199可参照专利文献04-CN103328474A实施例化合物1的合成所描述的方法制备得到，该文献通过引用其全文的方式并入到本申请中；亦可由市售购买得到，可为无定型或晶态。
所述晶型1具有以下有益效果：
①本发明的ABT-199二盐酸盐的晶型1在25℃下水中溶解度较ABT-199盐酸盐晶型Ⅱ的溶解度高，说明本发明的ABT-199二盐酸盐的晶型1具有更好的溶解度，因而具有更好的生物利用度。
②本发明的ABT-199二盐酸盐的晶型1在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的ABT-199二盐酸盐晶型1具有好的贮存稳定性，能够更好地保证药物活性成分自身和含有ABT-199单盐酸盐的制剂剂型避免或减少药物制造和/或存储等过程中质量、安全性和稳定性的问题，例如活性成分含量不均匀、杂质。避免特殊和昂贵的包装。
本发明人在研究中还开发了ABT-199单盐酸盐的晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N以及它们的制备方法。
与已知的ABT-199单盐酸盐的固体形态相比，上述ABT-199单盐酸盐的晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N具有一种或多种改进的特性，例如：更高的结晶度、更好的溶解度、溶解速度、较佳的结晶形态、较好的热稳定性和贮存稳定性、较低的吸湿性、较好的可流动性和有利的加工与处理特性。
所述ABT-199单盐酸盐的晶型D，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角2θ为5.8±0.2°、7.3±0.2°、11.4±0.2°、11.8±0.2°、16.0±0.2°、17.4±0.2°、17.8±0.2°、18.0±0.2°、19.6±0.2°、20.1±0.2°、21.7±0.2°和24.8±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型D的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型D。优选地，所述溶剂选自1,4-二氧六环和水的混合溶剂，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型E，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.6±0.2°、8.3±0.2°、12.1±0.2°、17.3±0.2°、17.9±0.2°、18.2±0.2°、18.9±0.2°、19.5±0.2°、20.8±0.2°、22.9±0.2°、23.5±0.2°和24.6±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型E的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在甲苯或甲苯与其他有机溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型E。优选地，所述有机溶剂选自烷烃、C4～C5酯或其混合物，所述温度为40～60℃。
所述ABT-199单盐酸盐的晶型F，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.6±0.2°、8.4±0.2°、12.0±0.2°、13.1±0.2°、14.7±0.2°、17.8±0.2°、19.2±0.2°、20.9±0.2°、23.1±0.2°、24.7±0.2°、26.3±0.2°和27.1±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型F的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在氯仿或氯仿与其他有机溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型F。优选地，所述有机溶剂选自醇、烷烃(包括氯代烷烃)、C4～C5酯或其混合物，所述温度为40～60℃。
所述ABT-199单盐酸盐的晶型G，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.6±0.2°、8.2±0.2°、9.5±0.2°、12.1±0.2°、17.1±0.2°、18.0±0.2°、18.8±0.2°、19.5±0.2°、20.7±0.2°、23.0±0.2°、24.7±0.2°和26.5±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型G的制备方法，包括以下步骤：将ABT-199单盐酸盐 固体在异丙醇或异丙醇与其他溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型G。优选地，所述有机溶剂选自烷烃、环醚、C4～C5酯或其混合物，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型H，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.6±0.2°、8.3±0.2°、9.5±0.2°、12.1±0.2°、12.4±0.2°、14.5±0.2°、17.1±0.2°、18.0±0.2°、19.0±0.2°、19.4±0.2°、20.9±0.2°和23.1±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型H的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在正丙醇或正丙醇与其他溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型H。优选地，所述有机溶剂选自水、环醚、烷烃、C4～C5酯或其混合物，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型I，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.5±0.2°、8.5±0.2°、12.1±0.2°、17.3±0.2°、18.0±0.2°、18.3±0.2°、19.1±0.2°、19.5±0.2°、20.9±0.2°、23.0±0.2°、26.3±0.2°和27.1±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型I的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在仲丁醇或仲丁醇与其他溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型I。优选地，所述有机溶剂选自烷烃、环醚、C4～C5酯或其混合物，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型J，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.5±0.2°、8.1±0.2°、11.8±0.2°、12.1±0.2°、12.3±0.2°、14.6±0.2°、17.8±0.2°、19.0±0.2°、21.1±0.2°、23.0±0.2°、24.7±0.2°和26.8±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型J的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在正丁醇或正丁醇与其他溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型J。优选地，所述有机溶剂选自烷烃、环醚、C4～C5酯或其混合物，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型K，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.6±0.2°、8.5±0.2°、11.8±0.2°、12.5±0.2°、13.2±0.2°、17.4±0.2°、17.7±0.2°、19.4±0.2°、21.4±0.2°、22.3±0.2°、23.7±0.2°和26.9±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型K的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在丙酮或丙酮与其他溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型K。优选地，所述有机溶剂选自烷烃、C4～C5酯、水或其混合物，所述温度为10～50℃。
所述ABT-199单盐酸盐的晶型L，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.5±0.2°、7.6±0.2°、8.3±0.2°、14.2±0.2°、15.7±0.2°、16.8±0.2°、17.9±0.2°、18.7±0.2°、19.1±0.2°、21.2±0.2°、22.2±0.2°和25.7±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型L的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在1,4-二氧六环或1,4-二氧六环与其他非水溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型L。优选地，所述有机溶剂选自烷烃、C4～C5酯或其混合物，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型M，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.6±0.2°、8.3±0.2°、11.9±0.2°、12.3±0.2°、17.2±0.2°、17.8±0.2°、18.3±0.2°、19.1±0.2°、21.0±0.2°、22.3±0.2°、23.5±0.2°和27.0±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型M的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在四氢呋喃或四氢呋喃与其他溶剂的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型M。优选地，所述有机溶剂选自烷烃、C4～C5酯、水或其混合物，所述温度为10～60℃。
所述ABT-199单盐酸盐的晶型N，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图谱在衍射角为4.5±0.2°、5.7±0.2°、7.5±0.2°、8.5±0.2°、10.5±0.2°、12.1±0.2°、17.4±0.2°、18.0±0.2°、18.3±0.2°、19.2±0.2°、19.5±0.2°和20.9±0.2°处具有特征峰。
本发明还提供ABT-199单盐酸盐的晶型N的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型N。优选地，所述溶剂选自甲醇和水的混合溶剂，所述温度为10～60℃。
与已知的ABT-199单盐酸盐晶型相比，本发明的ABT-199单盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N和ABT-199二盐酸盐的晶型1都具有以下一种或多种的改进性能，例如：具有更高的结晶度、较好的溶解度、溶解速度、较佳的结晶形态、较好的热稳定性和贮存稳定性、更好的流动性和更好的制剂可加工性，可在室温条件或高温条件下更简便地制备，更有利于产品的工业化。
本发明的ABT-199单盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N和ABT-199二盐酸盐的晶型1的任何制备方法中：
除非特殊注明，“室温”是指10～30℃的温度。
所述“氯代烷烃”可以是二氯甲烷、氯仿。
所述“环醚”可以是四氢呋喃、1,4-二氧六环。
所述“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。
所述“分离”可以采用本领域的常规方法，例如离心或过滤。优选减压过滤，一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。
所述“过滤”一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。
所述“离心”的具体操作为：将欲分离的样品置于离心管中，以6000转/分的速率进行离心，直至固体全部沉至离心管底部。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥；可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。
本发明中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。XRD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°，03°，0.1°等，通常允许误差±0.2°，所以峰角度的差别不能作为唯一标准。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本发明所述ABT-199单盐酸盐或二盐酸盐的晶型是基本纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本纯的”当用来指新晶型时，指这个新晶型占所存在的化合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。
进一步地，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的一种或多种本发明ABT-199单盐酸盐及二盐酸盐的新晶型或者由本发明方法制备得到的ABT-199单盐酸盐及二盐酸盐的新晶型，以及至少一种药学上可接受的载体。其中，所述ABT-199盐酸盐的新晶型包括ABT-199单盐酸盐的晶型A、ABT-199单盐酸盐的晶型B、ABT-199单盐酸盐的晶型C和ABT-199二盐酸盐的晶型1。此外，所述药物组合物还可以包含ABT-199盐酸盐的 其它可药用的晶型(例如晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M和晶型N)或无定型。
所述药物组合物中的赋形剂，是本领域技术人员公知的，其种类、用法、用量的选择也是本领域技术人员公知的。例如包括糖类，纤维素及其衍生物，淀粉或改性淀粉，固体无机物如磷酸钙、磷酸氢二钙、羟基磷灰石、硫酸钙、碳酸钙，半固体如脂质或石蜡，粘合剂如微晶纤维素、乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素，助流剂如胶态二氧化硅、轻质无水硅酸、结晶纤维素、滑石粉或硬脂酸镁，崩解剂如乙醇酸淀粉钠、交聚维酮、交联羧甲基纤维素、羧甲基纤维素钠、干玉米淀粉，润滑剂如硬脂酸、硬脂酸镁、硬脂酰富马酸钠、聚乙二醇。
所述药物组合的给药途径包括口服、静脉皮下注射、注射入组织给药、透皮给药、直肠给药、滴鼻给药等。所述药物组合可以根据给药途径或需要，制备成一定的剂型，可为固态或液态。固体口服剂型，例如包括片剂、颗粒剂、散剂、丸剂和胶囊剂；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，例如包括溶液剂、分散剂和冻干剂。配方可适于药物活性成分的速释、缓释或可控释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，将本发明的ABT-199单盐酸盐的晶型A、晶型B、晶型C或二盐酸盐的晶型1与一种或多种药学上可接受的赋形剂相混合，任选地与可药用的ABT-199单盐酸盐、二盐酸盐的其它晶型、无定型物相混合，任选地与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
进一步地，本发明提供一种或多种本发明ABT-199单盐酸盐、二盐酸盐的新晶型或者由本发明制备方法得到的ABT-199盐酸盐、二盐酸盐的新晶型在制备用于治疗和/或预防一种或多种抗细胞凋亡BCL-2家族蛋白过度表达的疾病疾病的药物中的用途，其中所述ABT-199盐酸盐的新晶型包括本发明的ABT-199单盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N以及ABT-199二盐酸盐的晶型1。
进一步地，本发明提供一种治疗和/或预防一种或多种抗细胞凋亡BCL-2家族蛋白过度表达的疾病疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的本发明的ABT-199单盐酸盐、二盐酸盐的新晶型或其组合或其药物组合物，其中所述ABT-199盐酸盐的新晶型包括ABT-199单盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N以及ABT-199二盐酸盐的晶型1。所述患者包括但不限于哺乳动物。
附图说明
图1为按照专利文献CN103328474A中实施例14所描述的方法制备的已知盐酸盐的晶型Ⅱ的X射线粉末衍射图
图2为本发明实施例1的ABT-199单盐酸盐晶型A的X射线粉末衍射图
图3为本发明实施例1的ABT-199单盐酸盐晶型A的TGA图谱
图4为本发明实施例1的ABT-199单盐酸盐晶型A的IR谱图
图5为本发明实施例13的ABT-199单盐酸盐晶型B的X射线粉末衍射图
图6为本发明实施例13的ABT-199单盐酸盐晶型B的IR谱图
图7为本发明实施例31的ABT-199单盐酸盐晶型C的X射线粉末衍射图
图8为本发明实施例31的ABT-199单盐酸盐晶型C的TGA图谱
图9为本发明实施例31的ABT-199单盐酸盐晶型C的IR谱图
图10为本发明实施例37的ABT-199二盐酸盐晶型1的X射线粉末衍射图
图11为本发明实施例37的ABT-199二盐酸盐晶型1的DSC图谱
图12为本发明实施例37的ABT-199二盐酸盐晶型1的TGA图谱
图13为本发明ABT-199二盐酸盐的晶型1的IR谱图
图14为本发明实施例43的ABT-199单盐酸盐晶型D的X射线粉末衍射图
图15为本发明实施例44的ABT-199单盐酸盐晶型E的X射线粉末衍射图
图16为本发明实施例45的ABT-199单盐酸盐晶型F的X射线粉末衍射图
图17为本发明实施例46的ABT-199单盐酸盐晶型G的X射线粉末衍射图
图18为本发明实施例47的ABT-199单盐酸盐晶型H的X射线粉末衍射图
图19为本发明实施例48的ABT-199单盐酸盐晶型I的X射线粉末衍射图
图20为本发明实施例49的ABT-199单盐酸盐晶型J的X射线粉末衍射图
图21为本发明实施例50的ABT-199单盐酸盐晶型K的X射线粉末衍射图
图22为本发明实施例51的ABT-199单盐酸盐晶型L的X射线粉末衍射图
图23为本发明实施例52的ABT-199单盐酸盐晶型M的X射线粉末衍射图
图24为本发明实施例53的ABT-199单盐酸盐晶型N的X射线粉末衍射图
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
差热分析数据采自于TA Instruments Q200MDSC。检测方法为：取1～10毫克的样品放置于小孔铝坩埚内，以10℃/分钟的升温速度在40mL/分钟干燥N2的保护下将样品从室温升至230～250℃。
热重分析数据采自于TA Instruments Q500TGA。检测方法为：取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/分钟的升温速度在40mL/分钟干燥N2的保护下将样品从室温升至300℃。
红外光谱分析(IR)数据采自于Bruker Tensor 27，采用ATR设备，在600-4000cm-1范围内，采集红外吸收光谱。
核磁氢谱数据(1HNMR)采自于Bruker Avance II DMX 300MHZ核磁共振波谱仪。称量1～5mg样品，用约0.5mL氘代二甲亚砜溶解到核磁样品管中进行检测。
高效液相色谱仪(HPLC)数据采自于Ultimate 3000，采用外标法进行浓度测试。
除非特殊注明，实施例均在室温下操作。
实施例中所用的各种试剂如无特别说明均为市售购买。
制备例1
ABT-199可根据专利文献CN103328474A实施例化合物1的合成所描述的方法制备得到。
具体制备方法为：
将4-氟-3-硝基苯磺酰胺(2.52g)、1-(四氢吡喃-4-基)甲胺(1.32g)和三乙胺(1.16g)在四氢呋喃(35mL)中的混合物搅拌过夜，用浓HCl中和并浓缩。将残余物悬浮于乙酸乙酯中并收集沉淀，用水洗涤并干燥得到3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰胺。
在0℃下向经己烷洗涤的NaH(20g)的二氯甲烷(809mL)悬浮液逐滴加入5,5-二甲基-2-甲氧基羰基环己酮(44.5g)。搅拌30分钟后，将化合物冷却至-78℃并加入三氟乙酸酐(46mL)。将反应混合物升至室温并搅拌24小时。用盐水洗涤有机层，干燥(Na2SO4)，过滤，并浓缩得到4,4-二甲基-2-(三氟甲基磺酰基氧基)环己-1-烯甲酸甲酯。
将化合物4,4-二甲基-2-(三氟甲基磺酰基氧基)环己-1-烯甲酸甲酯(71.84g)、4-氯苯基硼酸(37.27g)、CsF(74g)和四(三苯基膦)钯(0)(2.3g)的2:1二甲氧基乙烷/甲醇(700mL)溶液加热至70℃，保持24小时。浓缩混合物。加入乙醚(4×230mL)并过滤混合物。浓缩合并的乙醚溶液以得到2-(4- 氯苯基)-4,4-二甲基环己-1-烯甲酸甲酯。
通过注射器向LiBH4(15g)、化合物2-(4-氯苯基)-4,4-二甲基环己-1-烯甲酸甲酯(62.2)和乙醚(460mL)的混合物中缓慢加入甲醇(30mL)。在室温下将混合物搅拌24小时。用1N HCl淬灭反应，同时用冰冷却。用水稀释混合物并用乙醚(3×116mL)萃取。干燥(Na2SO4)萃取物，过滤并浓缩。在硅胶上使用0-30％乙酸乙酯/己烷层析粗产物。得到(2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲醇。
在0℃下通过注射器将甲磺酰氯(8.7mL)加入到化合物得到(2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲醇(33.9g)和三乙胺(35mL)的CH2Cl2(580mL)溶液中，并将混合物搅拌1分钟。加入N-叔丁氧基羰基哌嗪(25g)并在室温下将混合物搅拌24小时。用盐水洗涤悬浮液，赶在(Na2SO4)，过滤并浓缩。在硅胶上使用10-20％乙酸乙酯/己烷层析粗产物。得到4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-甲酸叔丁酯。
在二氯甲烷(17mL)和三氟乙酸(17mL)中将化合物4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-甲酸叔丁酯(231mg)和三乙基硅烷(1.2mL)搅拌1小时。浓缩混合物，吸收于乙酸乙酯中，用NaH2PO4和盐水洗涤两次，并干燥(Na2SO4)，过滤和浓缩。得到1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪。
向5-溴-1H-吡咯并[2,3-b]吡啶(15.4g)在四氢呋喃(290mL)中的混合物加入1M六甲基二硅烷胺化锂的四氢呋喃(100mL)溶液，并在10分钟后加入TIPS-Cl(三异丙基氯硅烷)(21mL)。在室温下将混合物搅拌24小时。用乙醚稀释反应，并将所得溶液用水洗涤两次。干燥(Na2SO4)萃取物，过滤并浓缩。在硅胶上使用10％乙酸乙酯/己烷层析处产物。得到5-溴-1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶。
在-78℃下向化合物5-溴-1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶(28g)在四氢呋喃(580mL)中的混合物加入2.5M BuLi(35mL)。2分钟后，加入硼酸三甲酯(13mL)，并经1小时使混合物升至室温，将反应物倒入水中，用乙酸乙酯萃取三次，并用盐水洗涤合并的萃取物并浓缩。在0℃下将粗产物吸收于四氢呋喃(230mL)中，并加入1M NaOH(80mL)，随后加入30％H2O2(9.7mL)，并将溶液搅拌1小时。加入Na2S2O3(11.6g),并用浓HCl和固体NaH2PO4将PH调节至4-5。将溶液用乙酸乙酯萃取两次，并用盐水洗涤合并的萃取物，干燥(Na2SO4)，过滤并浓缩。在硅胶上使用5-25％乙酸乙酯/己烷层析粗产物，得到1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-醇。
在115℃下将1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-醇(9.8g)、2,4-二氟苯甲酸甲酯(8.1g)和K3PO4(10.77g)在二乙二醇二甲醚(46mL)中的混合物搅拌24小时。冷却反应，用乙醚(600mL)稀释，并用水和盐水洗涤两次，并浓缩。在硅胶上使用2-50％乙酸乙酯/己烷层次粗产物。得到2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-氟苯甲酸甲酯。
在135℃下将化合物2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-氟苯甲酸甲酯(1.79g)、化合物1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪(2.80g)和HK2PO4(1.64g)在二甲亚砜(23mL)中的混合物搅拌24小时。冷却反应，用乙醚(460mL)稀释，并用3×1M NaOH和盐水洗涤，并浓缩。在硅胶上使用10-50％乙酸乙酯/己烷层析粗产物。得到2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯。
在50℃下将化合物2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯(231mg)的二噁烷(11.6mL)和1M NaOH(6.9mL)溶液搅拌24小时。冷却反应，加入到NaH2PO4溶液中，并用乙酸乙酯萃取三次。用盐水洗涤合并的萃取物，并浓缩以得到纯净产物2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸。
将化合物2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸(3.92g)、化合物3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰胺(2.16g)、1-乙基-3-[3-(二甲基氨基)丙基]-碳二亚胺盐(2.76g)和4-二甲基氨基吡啶(1.26g)在CH2Cl2(46mL) 中搅拌24小时。冷却反应并在硅胶上使用25-100％乙酸乙酯/己烷，、然后使用具有1％乙酸的10％甲醇/乙酸乙酯层析，得到呈固体形式的产物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(1.81g)。
1HNMR°(300MHz,DMSO～d6)：11.65(brs,1H),8.55(brs,1H),8.04(d,1H),7.89(dd,1H),7.51(m,3H),7.33(d,2H),7.08(m,1H),7.04(d,2H),6.68(dd,1H),6.39(d,1H)，6.19(d,4H)，3.84(m,1H)，3.30(m,4H)，3.07(m,4H)，2.73(m,2H)，2.18(m,6H)，1.95(m,2H)，1.61(dd,2H)，1.38(m,2H)，1.24(m,4H)，0.92(s,6H)，显示为已知的ABT-199。
制备例2
已知的ABT-199盐酸盐的水合物晶型(即本文的晶型Ⅱ)可根据专利文献CN103328474A中实施例14～15所描述的方法描述的方法制备得到。
将ABT-199(游离碱)固体2.5g悬浮于100mL乙腈中，搅拌的同时将浓盐酸321mg用1.5mL乙腈稀释后滴加至悬浮液中，反应物迅速反应并形成透明溶液，随后淡黄色固体析出。将得到的淡黄色固体暴露于空气中，得到ABT-199盐酸盐。
所得ABT-199盐酸盐样品的X-射线粉末衍射图谱如图1所示，与专利文献CN103328474A中提供的ABT-199盐酸盐的水合物晶型的X射线粉末衍射图谱基本相同。
实施例1
取制备例2制备的ABT-199盐酸盐样品100mg，加入3mL乙醇形成混悬液，室温下搅拌3天后，减压过滤，固体40℃真空干燥10小时，得到98mg ABT-199单盐酸盐晶型A。
其X-射线粉末衍射图谱如图2所示。
其TGA图谱如图3所示。
其IR图谱如图4所示。
实施例2
取制备例2制备的ABT-199盐酸盐样品50mg，加入0.5mL乙醇、0.5mL水形成混悬液，室温下搅拌7天后，减压过滤，固体30℃真空干燥24小时，得到48mg ABT-199单盐酸盐晶型A。
实施例3
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.5mL乙醇、0.5mL正庚烷形成混悬液，室温下搅拌5天后，减压过滤，固体10℃真空干燥10小时，得到19mgABT-199单盐酸盐晶型A。
实施例4
取制备例2制备的ABT-199盐酸盐样品10mg，加入0.5mL乙醇、0.5mL甲基叔丁基醚形成混悬液，室温下搅拌1天后，减压过滤，固体40℃真空干燥16小时，得到9mg ABT-199单盐酸盐晶型A。
实施例5
取制备例2制备的ABT-199盐酸盐样品10mg，加入0.5mL乙醇、0.5mL乙酸乙酯形成混悬液，60℃环境下搅拌2天后，减压过滤，固体25℃真空干燥16小时，得到7mg ABT-19单盐酸盐晶型A。
实施例6
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.4mL乙醇、0.6mL二氯甲烷形成混悬液，50℃环境下搅拌1天后，减压过滤，固体60℃真空干燥48小时，得到15mg ABT-199单盐酸盐晶型A。
实施例7
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.1mL乙醇、0.1mL乙酸异丙酯、0.1mL正庚烷形成混悬液，室温下搅拌4天后，减压过滤，固体55℃真空干燥20小时，得到17mg  ABT-199单盐酸盐晶型A。
实施例8
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL乙醇、0.1mL四氢呋喃、0.2mL正庚烷形成混悬液，室温下搅拌5天后，减压过滤，固体40℃真空干燥24小时，得到19mg ABT-199单盐酸盐晶型A。
实施例9
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.1mL乙醇、0.2mL乙腈、0.2mL正庚烷形成混悬液，室温下搅拌2天后，减压过滤，固体60℃真空干燥16小时，得到18mg ABT-199单盐酸盐晶型A。
实施例10
取制备例2制备的ABT-199盐酸盐样品30mg，加入0.1mL乙醇、0.1mL氯仿、0.2mL甲基环己烷形成混悬液，40℃环境下搅拌3天后，减压过滤，固体40℃真空干燥36小时，得到25mg ABT-199单盐酸盐晶型A。
实施例11
取制备例2制备的ABT-199盐酸盐样品60mg，加入0.2mL乙醇、0.2mL乙醚、0.2mL正庚烷形成混悬液，60℃环境下搅拌1天后，减压过滤，固体60℃真空干燥16小时，得到47mg ABT-199单盐酸盐晶型A。
实施例12
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL乙醇、0.2mL1,4-二氧六环、0.2mL正庚烷形成混悬液，40℃环境下搅拌5天后，减压过滤，固体40℃真空干燥24小时，得到17mg ABT-199单盐酸盐晶型A。
实施例2～12制备得到的样品与实施例1的样品具有相同或相似的XRPD图谱、TGA图谱、IR图谱(未示出)，说明实施例2～12样品与实施例1的样品是相同的晶型。
实施例13
将本发明的ABT-199单盐酸盐晶型A以5℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持20分钟至完全脱去溶剂，然后以20℃/分钟的冷却速率冷却至室温，得到所述晶型B。
其X-射线粉末衍射图谱如图5所示。
其IR图谱如图6所示。
实施例14
将本发明的ABT-199单盐酸盐晶型A以10℃/分钟的升温速率从室温升温至脱溶剂温度30℃，在130℃下保持10分钟至完全脱去溶剂，然后以10℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例15
将本发明的ABT-199单盐酸盐晶型A以8℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持25分钟至完全脱去溶剂，然后以15℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例16
将本发明的ABT-199单盐酸盐晶型A以20℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持35分钟至完全脱去溶剂，然后以5℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例17
将本发明的ABT-199单盐酸盐晶型A以15℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持5分钟至完全脱去溶剂，然后以5℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例18
将本发明的ABT-199单盐酸盐晶型A在140℃的环境中放置30分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例19
将本发明的ABT-199单盐酸盐晶型A在150℃的环境中放置20分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例20
将本发明的ABT-199单盐酸盐晶型A在145℃的环境中放置10分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例21
将本发明的ABT-199单盐酸盐晶型A在130℃的环境中放置40分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例22
将ABT-199单盐酸盐晶型Ⅱ以5℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持20分钟至完全脱去溶剂，然后以20℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例23
将ABT-199单盐酸盐晶型Ⅱ以10℃/分钟的升温速率从室温升温至脱溶剂温度30℃，在130℃下保持10分钟至完全脱去溶剂，然后以10℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例24
将ABT-199单盐酸盐晶型Ⅱ以8℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持25分钟至完全脱去溶剂，然后以15℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例25 ABT-199
将ABT-199单盐酸盐晶型Ⅱ以20℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持35分钟至完全脱去溶剂，然后以5℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例26 ABT-199
将ABT-199单盐酸盐晶型Ⅱ以15℃/分钟的升温速率从室温升温至脱溶剂温度130℃，在130℃下保持5分钟至完全脱去溶剂，然后以5℃/分钟的冷却速率冷却至室温，得到所述晶型B。
实施例27
将ABT-199单盐酸盐晶型Ⅱ在140℃的环境中放置30分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例28
将ABT-199单盐酸盐晶型Ⅱ在150℃的环境中放置20分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例29
将ABT-199单盐酸盐晶型Ⅱ在145℃的环境中放置10分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例30
将ABT-199单盐酸盐晶型Ⅱ在130℃的环境中放置40分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型B。
实施例14～30制备得到的样品与实施例13的样品具有相同或相似的XRPD图谱、IR图谱(未示出)，说明实施例14～30样品与实施例13的样品是相同的晶型。
实施例31
取制备例2制备的ABT-199盐酸盐样品100mg，加入2mL甲醇形成混悬液，室温下搅拌3天后，减压过滤，固体40℃真空干燥10小时，得到98mg ABT-199单盐酸盐晶型。
其X射线粉末衍射图谱如图7所示。
其TGA图谱如图8所示。
其IR图谱如图9所示。
实施例32
取制备例2制备的ABT-199盐酸盐样品100mg，加入1mL丁酮形成混悬液，室温下搅拌7天后，减压过滤，固体10℃真空干燥24小时，得到92mg ABT-199单盐酸盐晶型C。
实施例33
取制备例2制备的ABT-199盐酸盐样品80mg，加入2mL水饱和的正庚烷形成混悬液，10℃环境下搅拌5天后，减压过滤，固体30℃真空干燥16小时，得到78mg ABT-199单盐酸盐晶型C。
实施例34
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.4mL水饱和的乙酸乙酯、0.6mL水饱和的正庚烷形成混悬液，60℃环境下搅拌1天后，减压过滤，固体60℃真空干燥48小时，得到18mg ABT-199单盐酸盐晶型C。
实施例35
取制备例2制备的ABT-199盐酸盐样品20mg，加入2mL二氯甲烷形成混悬液，40℃环境下搅拌7天后，减压过滤，固体40℃真空干燥10小时，得到15mg ABT-199单盐酸盐晶型C。
实施例36
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.5mL丙酮形成混悬液，60℃环境下搅拌1天后，减压过滤，固体50℃真空干燥36小时，得到17mg ABT-199单盐酸盐晶型C。
实施例32～36制备得到的样品与实施例31的样品具有相同或相似的XRPD图谱、TGA图谱、IR图谱(未示出)，说明实施例32～36样品与实施例31的样品是相同的晶型。
实施例37
取40mg(0.046mmol)制备例1制备的ABT-199游离碱，加入1.0mL异丙醇形成悬浮液。取37％的浓盐酸9.1mg(0.092mmol),加入0.5mL异丙醇稀释。搅拌条件下，将盐酸的异丙醇溶液滴加至ABT-199游离碱中，室温下搅拌反应3天，减压过滤，30℃真空干燥24小时，得到41mg ABT-199二盐酸盐晶型1。
其X射线粉末衍射图谱如图10所示。
其DSC图谱如图11所示。
其TGA图谱如图12所示。
其IR图谱如图13所示。
实施例38
取40mg(0.046mmol)制备例1制备的ABT-199游离碱，加入0.8mL乙醇形成悬浮液。取15％的浓盐酸23.6mg(0.097mmol)，加入0.5mL乙醇稀释。搅拌条件下，将盐酸的乙醇溶液滴加至ABT-199游离碱中，40℃搅拌反应5天，减压过滤，40℃真空干燥10小时，得到36mg ABT-199二盐酸盐晶型1。
实施例39
取50mg(0.058mmol)制备例1制备的ABT-199游离碱，加入0.5mL丙酮形成悬浮液。取20％的浓盐酸26.3mg(0.144mmol)，加入0.5mL丙酮稀释。搅拌条件下，将盐酸的丙酮溶液滴加至ABT-199游离碱中，50℃环境下搅拌反应1天，减压过滤，60℃真空干燥48小时，得到47mg ABT-199二盐酸盐晶型1。
实施例40
取40mg(0.046mmol)制备例1制备的ABT-199游离碱，加入0.5mL乙腈形成悬浮液。取25％的浓盐酸15.2mg(0.104mmol)，加入0.5mL乙腈稀释。搅拌条件下，将盐酸的乙腈溶液滴加至ABT-199游离碱中，室温下搅拌反应4天，减压过滤，30℃真空干燥18小时，得到40mg ABT-199二盐酸盐晶型1。
实施例41
取40mg(0.046mmol)制备例1制备的ABT-199游离碱，加入0.6mL甲醇形成悬浮液。取30％的浓盐酸14.0mg(0.115mmol)，加入0.5mL甲醇稀释。搅拌条件下，将盐酸的甲醇溶液滴加至ABT-199游离碱中，60℃搅拌反应2天，减压过滤，50℃真空干燥30小时，得到30mg ABT-199二盐酸盐晶型1。
实施例42
取40mg(0.046mmol)制备例1制备的ABT-199游离碱，加入0.5mL丁酮形成悬浮液。取37％的浓盐酸10.3mg(0.127mmol)，加入0.5mL丁酮稀释。搅拌条件下，将盐酸的丁酮溶液滴加至ABT-199游离碱中，室温下搅拌反应4天，减压过滤，40℃真空干燥24小时，得到35mg ABT-199二盐酸盐晶型1。
实施例38～42制备得到的样品与实施例37的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例38～42样品与实施例37的样品是相同的晶型。
实施例43
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL1,4-二氧六环、0.8mL水形成混悬液，60℃环境下搅拌3天后，离心，固体40℃真空干燥24小时，得到19.75mg ABT-199单盐酸盐晶型D。
其X射线粉末衍射图谱如图14所示。
实施例44
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.4mL甲苯、0.6mL正庚烷形成混悬液，60℃环境下搅拌3天后，离心，固体40℃真空干燥24小时，得到18.73mgABT-199单盐酸盐晶型E。
其X射线粉末衍射图谱如图15所示。
实施例45
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL甲醇、0.2mL氯仿形成混悬液，60℃环境下搅拌3天后，离心，固体40℃真空干燥24小时，得到18.68mg ABT-199单盐酸盐晶型F。
其X射线粉末衍射图谱如图16所示。
实施例46
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL异丙醇、0.2mL四氢呋喃、0.2mL正庚烷形成混悬液，室温下搅拌3天后，离心，固体40℃真空干燥16小时，得到19.73mgABT-199单盐酸盐晶型G。
其X射线粉末衍射图谱如图17所示。
实施例47
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL正丙醇、0.2mL四氢呋喃、0.2mL正庚烷形成混悬液，室温下搅拌3天后，离心，固体40℃真空干燥16小时，得到19.73mg ABT-199单盐酸盐晶型H。
其X射线粉末衍射图谱如图18所示。
实施例48
取制备例2制备的ABT-199盐酸盐的样品20mg，加入0.2mL仲丁醇、0.2mL四氢呋喃、0.2mL正庚烷形成混悬液，室温下搅拌3天后，离心，固体40℃真空干燥16小时，得到20.01mg ABT-199单盐酸盐晶型I。
其X射线粉末衍射图谱如图19所示。
实施例49
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL正丁醇、0.2mL四氢呋喃、0.2mL正庚烷形成混悬液，室温下搅拌3天后，离心，固体40℃真空干燥16小时，得到20.01mgABT-199 盐酸盐晶型J。
其X射线粉末衍射图谱如图20所示。
实施例50
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL丙酮、0.8mL水形成混悬液，50℃环境下搅拌3天后，离心，固体40℃真空干燥16小时，得到18.73mgABT-199单盐酸盐晶型K。
其X射线粉末衍射图谱如图21所示。
实施例51
取制备例2制备的ABT-199盐酸盐样品100mg，加入3mL1,4-二氧六环、3mL正庚烷形成混悬液，室温下搅拌3天后，离心，固体40℃真空干燥16小时，得到97.67mg单盐酸盐晶型L。
其X射线粉末衍射图谱如图22所示ABT-199。
实施例52
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.2mL水、0.2mL四氢呋喃、0.2mL正庚烷形成混悬液，室温下搅拌3天后，离心，固体40℃真空干燥16小时，得到19.65mg ABT-199单盐酸盐晶型M。
其X射线粉末衍射图谱如图23所示。
实施例53
取制备例2制备的ABT-199盐酸盐样品20mg，加入0.6mL甲醇、0.6mL水形成混悬液，60℃环境下搅拌3天后，离心，固体40℃真空干燥16小时，得到19.05mg ABT-199单盐酸盐晶型N。
其X射线粉末衍射图谱如图24所示。
实施例54
作为口服药物组合物的一个具体实施方案，300mg效能片剂由330mg的活性成分ABT-199单盐酸盐晶型A、152mg可压淀粉、10mg交联聚维酮、150mg微晶纤维素和10mg二氧化硅组成。
制备方法：首先将活性成分、可压淀粉、微晶纤维素和交联聚维酮混合，然后通过二氧化硅润滑混合物，最后将其压制成片剂。
实施例55-68
片剂：将实施例54的ABT-199单盐酸盐晶型A分别替换为将本申请所述的ABT-199单盐酸盐的晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N和ABT-199二盐酸盐的晶型1，配方中各种盐型中的游离碱和ABT-199单盐酸盐晶型A中游离碱的摩尔用量相同，各种盐型中的填充剂和制备步骤同实施例54。
实施例69
作为口服药物组合物的一个具体实施方案，30mg效能胶囊由33mg的活性成分ABT-199单盐酸盐晶型A、50mg乙基纤维素、15mg羟丙甲基纤维素、70mg乳糖、30mg微晶纤维素、10mg硬脂酸镁和5mg滑石粉组成。
制备方法：首先将活性成分、乙基纤维素、羟丙甲基纤维素、乳糖和微晶纤维素混合，用75％乙醇制粒，烘干，粉碎，过80目筛，然后加入硬脂酸镁和滑石粉混匀，最后将其灌入2号胶囊。
实施例70-83
胶囊剂：将实施例69的ABT-199单盐酸盐晶型A分别替换为将本申请所述的ABT-199单盐酸盐的晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I、晶型J、晶型K、晶型L、晶型M、晶型N和ABT-199二盐酸盐的晶型1，配方中各种盐型中的游离碱和ABT-199单盐酸盐晶型A中游离碱的摩尔用量相同，各种盐型中的填充剂和制备步骤同实施例69。
对比例1
取本发明制备的ABT-199单盐酸盐晶型A与制备例2制备的已知的ABT-199盐酸盐晶型Ⅱ进行水中溶解度对比实验，具体操作如下：分别取10mg样品于50ml玻璃瓶内，25℃条件下逐步滴加10mL去离子水形成悬浮液并超声直至溶清搅拌24小时，取溶液过滤进行HPLC检测，计算样品在水中的溶解度。
表1：对比例1对比实验数据统计
Figure PCTCN2016099139-appb-000012
由表1可知，本发明的ABT-199单盐酸盐晶型A与已知的ABT-199盐酸盐晶型Ⅱ相比，具有更高的溶解度。
对比例2
取本发明制备的ABT-199单盐酸盐晶型B与制备例2制备的已知的ABT-199盐酸盐晶型Ⅱ进行晶型稳定性对比实验。具体操作如下：分别取30mg样品放置于130℃条件下一天，进行XRPD检测，考察其晶型稳定性。
表2：对比例2对比实验数据统计
Figure PCTCN2016099139-appb-000013
由表2可知，本发明的ABT-199单盐酸盐晶型B与已知的ABT-199盐酸盐晶型Ⅱ相比，具有更好的高温稳定性。
对比例3
取本发明制备的ABT-199单盐酸盐晶型C与制备例2制备的已知的ABT-199盐酸盐晶型Ⅱ进行晶型稳定性竞争实验。具体操作如下：分别取20mg的ABT-199盐酸盐晶型Ⅱ和ABT-199单盐酸盐晶型C样品加入同一水饱和的乙酸乙酯形成浆液，在室温和40℃环境下搅拌3天，进行XRPD检测，考察其晶型稳定性。
表3：对比例3竞争实验数据统计
Figure PCTCN2016099139-appb-000014
由表3可知，通过竞争实验，晶型C在室温和40℃下水饱和的乙酸乙酯中搅拌3天，晶型均保持不变，晶型Ⅱ在室温和40℃下水饱和的乙酸乙酯中搅拌3天，晶型均转为晶型C，说明本发明的ABT-199单盐酸盐晶型C比已知的ABT-199盐酸盐晶型Ⅱ在含水溶剂，如水饱和乙酸乙酯中具有更好的晶型稳定性。
对比例4
取本发明制备的ABT-199二盐酸盐晶型1与制备例2制备的已知的ABT-199盐酸盐晶型Ⅱ进行水中溶解度对比实验，具体操作如下：分别取10mg样品于20ml玻璃瓶内，25℃条件下加10mL去离子水形成悬浮液并搅拌24小时，取溶液过滤进行HPLC检测，计算样品在水中的溶解度。
表4：对比例4对比实验数据统计
Figure PCTCN2016099139-appb-000015
由表4可知，本发明的ABT-199二盐酸盐晶型1与已知的ABT-199盐酸盐晶型Ⅱ相比，具有更高的溶解度。
本说明书中所引用的所有专利、专利申请公开、专利申请及非专利出版物，均通过引用以其全文并入本文中。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (24)

  1. 结构式如式(I)所示的ABT-199化合物的单盐酸盐的晶型A，
    Figure PCTCN2016099139-appb-100001
    其特征在于，所述晶型A以2θ角度表示的X-射线粉末衍射图具有以下特征峰:4.5±0.2°、8.3±0.2°、12.1±0.2°、17.2±0.2°、18.0±0.2°和19.0±0.2°。
  2. 根据权利要求1所述的ABT-199单盐酸盐晶型A，其特征在于，所述晶型A以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.5±0.2°、8.3±0.2°、9.4±0.2°、12.1±0.2°、17.2±0.2°、18.0±0.2°、19.0±0.2°、19.5±0.2°、20.8±0.2°、23.0±0.2°、24.7±0.2°和27.0±0.2°。
  3. 根据权利要求2所述的ABT-199单盐酸盐晶型A，其特征在于，所述晶型A以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016099139-appb-100002
  4. 根据权利要求1～3中任一项所述ABT-199单盐酸盐晶型A，其特征在于，所述晶型A的傅里叶红外光谱在波数为1669、1522、1431、1418、1269、1173、1105、985、756和660cm-1处具有特征峰。
  5. 根据权利要求1～4中任一项所述的ABT-199单盐酸盐晶型A的制备方法，包括以下步骤：将ABT-199单盐酸盐在乙醇或乙醇与其它溶剂的混合溶剂中形成悬浮液，所述其它溶剂选自水、烷烃、C4～C5酯、C4～C6醚、乙腈、四氢呋喃或其混合物，搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐晶型A；
    优选地，所述其它溶剂选自水、正庚烷、甲基叔丁基醚、四氢呋喃或其混合物；
    优选地，所述制备方法的操作温度为10～60℃，更优选为室温；
    优选地，所述搅拌的时间为1～7天，更优选为3～7天；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中ABT-199单盐酸盐与溶剂的质量体积比为10mg/mL～100mg/mL，更优选为20mg/mL～50mg/mL。
  6. 结构式如式(II)所示的ABT-199单盐酸盐晶型B，
    Figure PCTCN2016099139-appb-100003
    其特征在于，所述晶型B以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、9.9±0.2°、12.2±0.2°、13.3±0.2°、18.0±0.2°和20.8±0.2°。
  7. 根据权利要求6所述的ABT-199单盐酸盐的晶型B，其特征在于，所述晶型B以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、7.2±0.2°、9.1±0.2°、9.9±0.2°、12.2±0.2°、13.3±0.2°、18.0±0.2°、18.8±0.2°、19.1±0.2°、20.8±0.2°、22.0±0.2°和27.0±0.2°。
  8. 根据权利要求7所述的ABT-199单盐酸盐晶型B，其特征在于，所述晶型B以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2016099139-appb-100004
  9. 根据权利要求6～8中任一项所述ABT-199单盐酸盐晶型B，其特征在于，所述晶型B的傅里叶红外光谱在波数为1669、1573、1431、1367、1229、1205、1143、985、866和811cm-1处具有特征峰。
  10. 根据权利要求6～9中任一项所述ABT-199单盐酸盐的晶型B，其特征在于，所述晶型B具有以下的单晶结构信息：
    Figure PCTCN2016099139-appb-100005
  11. 根据权利要求6～10所述的ABT-199单盐酸盐的晶型B的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)将ABT-199单盐酸盐晶型A或ABT-199盐酸盐的晶型Ⅱ以5～20℃/分钟的升温速率从室温升温至130℃，在此温度下保持5～35分钟至完全脱去溶剂，然后以5～20℃/分钟的冷却速率冷却至室温，得到所述晶型B；所述ABT-199盐酸盐晶型Ⅱ具有如图1所示的X-射线粉末衍射图谱；
    优选地，所述保持的时间为20～35分钟，更优选为20～30分钟；
    优选地，所述升温速率为5～10℃/分钟；
    优选地，所述冷却速率为10～20℃/分钟；
    (2)将ABT-199单盐酸盐的晶型A或ABT-199盐酸盐的晶型Ⅱ在130～150℃的环境中放置20～40分钟至完全脱去溶剂，再置于室温下，得到所述晶型B；所述ABT-199盐酸盐晶型Ⅱ具有如图1所示的X-射线粉末衍射图谱；
    优选地，所述环境的温度为140～150℃；
    优选地，所述放置的时间为20～30分钟。
  12. 结构式如式(III)所示的ABT-199单盐酸盐的晶型C，
    Figure PCTCN2016099139-appb-100006
    其特征在于，所述晶型C以2θ角度表示的X-射线粉末衍射图具有以下特征峰:4.6±0.2°、8.3±0.2°、11.9±0.2°、17.2±0.2°和17.8±0.2°。
  13. 根据权利要求12所述的ABT-199单盐酸盐的晶型C，其特征在于，所述晶型C以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、8.3±0.2°、11.9±0.2°、17.2±0.2°、17.8±0.2°、18.5±0.2°、19.3±0.2°、21.2±0.2°、23.6±0.2°和27.0±0.2°。
  14. 根据权利要求13所述的ABT-199单盐酸盐的晶型C，其特征在于，所述晶型C以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016099139-appb-100007
    Figure PCTCN2016099139-appb-100008
  15. 根据权利要求12～14中任一项所述ABT-199单盐酸盐的晶型C，其特征在于，所述晶型C的傅里叶红外光谱在波数为1669、1605、1522、1418、1367、1346、1250、1173、904和842cm-1处具有特征峰。
  16. 根据权利要求12～15中任一项所述ABT-199单盐酸盐的晶型C的制备方法，包括以下步骤：将ABT-199单盐酸盐固体在二氯甲烷、甲醇、水饱和的酯/烷烃、C3～C4酮或其混合物中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述ABT-199单盐酸盐的晶型C；
    优选地，所述溶剂选自二氯甲烷、甲醇、水饱和的乙酸乙酯、水饱和的正庚烷、丁酮或其混合物；
    优选地，所述制备方法的操作温度为10～60℃，更优选为室温；
    优选地，所述搅拌的时间为1～7天，更优选为3～7天；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中ABT-199单盐酸盐与溶剂的质量体积比为10mg/mL～100mg/mL，更优选为20mg/mL～50mg/mL。
  17. 结构式如式(IV)所示的ABT-199二盐酸盐的晶型1，
    Figure PCTCN2016099139-appb-100009
    其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰:4.5±0.2°、9.9±0.2°、12.4±0.2°、16.5±0.2°、19.0±0.2°和20.7±0.2°。
  18. 根据权利要求17所述的ABT-199二盐酸盐的晶型1，其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.5±0.2°、9.9±0.2°、12.4±0.2°、15.5±0.2°、16.5±0.2°、16.7±0.2°、17.2±0.2°、19.0±0.2°、19.6±0.2°、20.7±0.2°、22.9±0.2°和25.2±0.2°。
  19. 根据权利要求18所述的ABT-199二盐酸盐的晶型1，其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016099139-appb-100010
    Figure PCTCN2016099139-appb-100011
  20. 根据权利要求17～19中任一项所述ABT-199二盐酸盐的晶型1，其特征在于，所述晶型1的傅里叶红外光谱在波数为1687、1618、1569、1447、1351、1312、1275、1238、1172、1091、831、790和659cm-1处具有特征峰。
  21. 根据权利要求17～20中任一项所述ABT-199二盐酸盐的晶型1的制备方法，包括以下步骤：在选自C1～C4醇、C3～C4酮、乙腈或其混合物的溶剂中，将摩尔比为1:2～1:2.5的ABT-199游离碱和盐酸溶液混合并搅拌，分离固体，得到所述ABT-199二盐酸盐的晶型1；
    优选地，所述溶剂选自异丙醇、丙酮、乙腈或其混合物；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述搅拌的时间为1～7天，更优选为3～7天；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中ABT-199游离碱与溶剂的质量体积比为40mg/mL～100mg/mL，更优选为40mg/mL～80mg/mL。
  22. 一种药物组合物，其包含治疗和/或预防有效量的一种或多种的选自权利要求1～5中任一项所述的ABT-199单盐酸盐的晶型A、权利要求6～11中任一项所述的ABT-199单盐酸盐的晶型B、权利要求12～16中任一项所述的ABT-199单盐酸盐的晶型C、权利要求17～21中任一项所述的ABT-199二盐酸盐的晶型1，以及至少一种药学上可接受的载体。
  23. 权利要求1～5中任一项所述的ABT-199单盐酸盐的晶型A、权利要求6～11中任一项所述的ABT-199单盐酸盐的晶型B、权利要求12～16中任一项所述的ABT-199单盐酸盐的晶型C、权利要求17～21中任一项所述的ABT-199二盐酸盐的晶型1或权利要求22所述药物组合物在制备用于治疗和/或预防一种或多种抗细胞凋亡BCL-2家族蛋白过度表达的疾病的药物中的用途。
  24. 一种治疗和/或预防一种或多种抗细胞凋亡BCL-2家族蛋白过度表达的疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的一种或多种的选自权利要求1～5中任一项所述的ABT-199单盐酸盐的晶型A、权利要求6～11中任一项所述的ABT-199单盐酸盐的晶型B、权利要求12～16中任一项所述的ABT-199单盐酸盐的晶型C、根据权利要求17～21所述制备方法得到的ABT-199二盐酸盐的晶型1。
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