WO2019200502A1 - 玻玛西尼甲磺酸盐晶型及其制备方法和药物组合物 - Google Patents

玻玛西尼甲磺酸盐晶型及其制备方法和药物组合物 Download PDF

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WO2019200502A1
WO2019200502A1 PCT/CN2018/083152 CN2018083152W WO2019200502A1 WO 2019200502 A1 WO2019200502 A1 WO 2019200502A1 CN 2018083152 W CN2018083152 W CN 2018083152W WO 2019200502 A1 WO2019200502 A1 WO 2019200502A1
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crystalline
mesylate
pomsini
crystal form
ray powder
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PCT/CN2018/083152
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English (en)
French (fr)
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盛晓红
盛晓霞
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杭州领业医药科技有限公司
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Priority to CN201880090731.6A priority Critical patent/CN111801323A/zh
Priority to PCT/CN2018/083152 priority patent/WO2019200502A1/zh
Priority to US17/048,384 priority patent/US20210179585A1/en
Publication of WO2019200502A1 publication Critical patent/WO2019200502A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 novel crystal forms of pomaxini mesylate salt, a process for the preparation thereof, a pharmaceutical composition and use.
  • Pomaxini mesylate is a special inhibitor of CDK4 and CDK6 and can be used to treat colorectal cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia. And drugs for cancer diseases such as acute myeloid leukemia.
  • the chemical name is N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2- Methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-amine methanesulfonate, the chemical structural formula of which is as follows:
  • the patent document CN102264725B discloses a synthetic preparation method of a pomesinismethanesulfonate, but so far no report of the crystal form of the pomsini mesylate has been reported.
  • the inventors have found that, according to the preparation method of Example 16 in CN102264725B, the oil of the pomsini mesylate salt is obtained after vacuum removal of the solvent, and the obtained glassy solution is solidified by grinding with methyl tert-butyl ether.
  • the mesylate salt is amorphous.
  • the appearance of the oil and the manner of grinding and solidification make the preparation method industrially less likely, and the obtained amorphous state has the disadvantages of being difficult to purify, having poor chemical stability, high dissolving, and poor processability of the preparation.
  • the present invention provides crystalline forms of pomaxinismethanesulfonate and methods for their preparation, pharmaceutical compositions comprising the crystalline forms and uses.
  • the crystalline form is a stable crystalline solid which should have one or more improved properties, particularly in terms of good crystallinity and stability, good flowability, and advantageous processing and handling characteristics.
  • the invention relates to a process for the preparation of said crystalline form, to a pharmaceutical composition comprising said crystalline form and to the use thereof.
  • crystal form 1 of pomaxini mesylate, hereinafter referred to as "crystal form 1".
  • the crystal form 1 provided by the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angle has the following characteristic peaks: 4.0 ° ⁇ 0.2 °, 8.2 ° ⁇ 0.2 ° 23.6 ° ⁇ 0.2 ° and 26.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 1 represented by the 2 ⁇ angle further has one or more of the following characteristic peaks: 15.9 ° ⁇ 0.2 °, 16.6 ° ⁇ 0.2 ° , 17.0 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 ° and 20.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 1 represented by the 2 ⁇ angle further has one or more characteristic peaks of: 4.7° ⁇ 0.2°, 9.5° ⁇ 0.2°, 11.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 19.3° ⁇ 0.2°, 22.5° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form 1 represented by the 2 ⁇ angle further has one or more of the following characteristic peaks: 10.5° ⁇ 0.2°, 14.3° ⁇ 0.2°. 15.3° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.2° ⁇ 0.2°, 29.7° ⁇ 0.2°, and 30.5° ⁇ 0.2°.
  • a typical example of the Form 1 has an XRPD pattern as shown in FIG.
  • Form 1 of the present invention has the following beneficial properties as compared to existing amorphous forms:
  • the crystalline form 1 of the present invention is an anhydrous crystalline solid having a better physical form.
  • the crystalline form 1 of the present invention is left to stand in a dry state at room temperature and placed in a 60 ° C environment for one month; the amorphous form exhibits a weak crystalline state and discoloration.
  • the crystalline form 1 of the present invention has a relatively high melting point.
  • the crystalline form 1 of the present invention is a crystalline solid, has better fluidity and better subsequent processing (such as filtration, drying, weighing in the pharmaceutical manufacturing process) than the prior art amorphous material.
  • the characteristics of the amount, sieving, etc., are beneficial to improve the uniformity of the preparation.
  • Form 1 has good stability and higher melting point, which can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation form containing Form 1 against the manufacture and/or storage of drugs. To avoid problems such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the second technical problem to be solved by the present invention is to provide crystal form 2 of pomaxini mesylate, hereinafter referred to as "crystal form 2".
  • the crystal form 2 provided by the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle has the following characteristic peaks: 6.1 ° ⁇ 0.2 °, 12.0 ° ⁇ 0.2 ° , 14.3 ° ⁇ 0.2 ° and 21.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 2 represented by the 2 ⁇ angle further has one or more characteristic peaks at the following points: 11.4° ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.0 ⁇ 0.2 °, 14.7 ⁇ 0.2 °, 15.6 ⁇ 0.2 °, 17.5 ° ⁇ 0.2 °, 22.8 ° ⁇ 0.2 °, 23.4 ° ⁇ 0.2 °, 24.6 ° ⁇ 0.2 ° and 26.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 2 represented by the 2 ⁇ angle further has one or more characteristic peaks at the following points: 11.2 ⁇ 0.2°, 15.1 ⁇ 0.2°, 18.0 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, 23.1 ° ⁇ 0.2 °, 24.4 ° ⁇ 0.2 °, 25.7 ⁇ 0.2 °, 27.5 ⁇ 0.2 °, 28.6 ⁇ 0.2 °, 29.6 ⁇ 0.2 °, 30.2 ⁇ 0.2 ° and 32.6 ° ⁇ 0.2°.
  • a typical example of the crystal form 2 has an XRPD pattern as shown in FIG.
  • Form 2 of the present invention has the following beneficial properties as compared to existing amorphous forms:
  • the crystalline form 2 of the present invention is an anhydrate crystalline solid having a better physical form.
  • the crystalline form 2 of the present invention is left to stand at room temperature and placed in a 60 ° C environment for one month; the amorphous form exhibits a weak crystalline state and discoloration.
  • the crystalline form 2 of the present invention is a crystalline solid, has better fluidity and better subsequent processing (such as filtration, drying, weighing in the pharmaceutical manufacturing process) than the prior art amorphous material.
  • the characteristics of the amount, sieving, etc., are beneficial to improve the uniformity of the preparation.
  • Form 2 has good stability, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation form containing Form 2 in the process of drug manufacture and/or storage, and avoid, for example, the content of the active ingredient. Uneven, impurities and other issues. Avoid special and expensive packaging.
  • the third technical problem to be solved by the present invention is to provide crystal form 3, crystal form 4 and form 7 of pomaxini mesylate, hereinafter referred to as “crystal form 3" and “crystal form 4". , "Form 7".
  • the crystal form 3 is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern expressed in 2 ⁇ angle has characteristic peaks of at least 3 or more of the following: 8.1° ⁇ 0.2°, 9.0° ⁇ 0.2 °, 11.7 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 ° and 21.7 ° ⁇ 0.2 °.
  • the crystal form 4 using Cu-K ⁇ radiation has an X-ray powder diffraction pattern represented by 2 ⁇ angles having the following three or more characteristic peaks: 5.7° ⁇ 0.2°, 6.4° ⁇ 0.2°, 8.6 ⁇ 0.2° 11.2° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.2 ⁇ 0.2°, 22.3 ⁇ 0.2°, 26.3° ⁇ 0.2° and 27.1° ⁇ 0.2 °.
  • the crystal form 7, using Cu-K ⁇ radiation has an X-ray powder diffraction pattern represented by 2 ⁇ angles having characteristic peaks at three or more of the following: 4.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 25.3° ⁇ 0.2°, and 27.7° ⁇ 0.2°.
  • the pomesinismethane salt form 3, the crystal form 4 and the crystal form 7 of the present invention have one or more improved properties, for example, higher crystallinity, Good crystal morphology, good thermal stability and storage stability, low hygroscopicity, good flowability and favorable processing and handling characteristics.
  • the fourth technical problem to be solved by the present invention is to provide crystal form 5 of pomaxini mesylate, hereinafter referred to as "crystal form 5".
  • the crystal form 5 provided by the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angle has the following characteristic peaks: 4.4 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 ° , 18.1 ⁇ 0.2 ° and 23.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 5 expressed by the 2 ⁇ angle further has one or more characteristic peaks at the following points: 11.8° ⁇ 0.2°, 13.2 ⁇ 0.2°, 13.5 ° ⁇ 0.2 °, 16.3 ⁇ 0.2 °, 20.6 ⁇ 0.2 °, 21.7 ° ⁇ 0.2 °, 26.7 ° ⁇ 0.2 ° and 30.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 2 represented by the 2 ⁇ angle further has one or more of the following characteristic peaks: 14.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.4 ⁇ 0.2 °, 17.1 ⁇ 0.2 °, 18.2 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 ° and 22.1 ° ⁇ 0.2 °.
  • a typical example of the crystal form 5 has an XRPD pattern as shown in FIG.
  • Form 5 of the present invention has the following beneficial properties as compared to existing amorphous forms:
  • the crystalline form 5 of the present invention is an anhydrate crystalline solid having a better physical form.
  • the crystalline form 5 of the present invention is left to stand at room temperature and placed in a 60 ° C environment for one month; the amorphous form exhibits a weak crystalline state and discoloration.
  • the crystalline form 5 of the present invention is a crystalline solid compared to the prior art amorphous, has better fluidity and better subsequent processing (such as filtration, drying, weighing in the pharmaceutical manufacturing process).
  • the characteristics of the amount, sieving, etc., are beneficial to improve the uniformity of the preparation.
  • Form 5 has good stability, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation form containing Form 5 in the process of drug manufacture and/or storage, and avoid, for example, the content of the active ingredient. Uneven, impurities and other issues. Avoid special and expensive packaging.
  • the fifth technical problem to be solved by the present invention is to provide crystal form 6 of pomaxini mesylate, hereinafter referred to as "crystal form 6".
  • the crystal form 6 provided by the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angle has the following characteristic peaks: 3.8 ° ⁇ 0.2 °, 7.5 ° ⁇ 0.2 ° , 15.0 ° ⁇ 0.2 ° and 18.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 6 expressed by the angle of 2 ⁇ also has one or more of the following characteristic peaks: 4.3° ⁇ 0.2°, 8.6° ⁇ 0.2° 9.9 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 11.2 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 22.6 ° ⁇ 0.2 °, 25.8 ° ⁇ 0.2 ° and 28.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 6 expressed by the angle of 2 ⁇ further has one or more characteristic peaks at the following points: 12.9 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.2° ⁇ 0.2°, 23.6° ⁇ 0.2°, 24.5° ⁇ 0.2°, 26.3° ⁇ 0.2°, 27.2° ⁇ 0.2°, 27.9° ⁇ 0.2°, 34.2° ⁇ 0.2 ° and 35.8 ° ⁇ 0.2 °.
  • crystal form 6 has an XRPD pattern as shown in FIG.
  • Form 6 of the present invention has the following beneficial properties as compared to existing amorphous forms:
  • Form 6 of the present invention is a hemihydrate crystalline solid having a better physical form.
  • the crystalline form 6 of the present invention is left to stand at room temperature and placed in a 60 ° C environment for one month; the amorphous form exhibits a weak crystalline state and discoloration.
  • the crystalline form 6 of the present invention is a crystalline solid, has better fluidity and better subsequent processing (such as filtration, drying, weighing in the pharmaceutical manufacturing process) than the prior art amorphous material.
  • the characteristics of the amount, sieving, etc. are beneficial to improve the uniformity of the preparation.
  • Form 6 has good stability, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation form containing Form 6 in the process of drug manufacture and/or storage, and avoid, for example, the content of the active ingredient. Uneven, impurities and other issues. Avoid special and expensive packaging.
  • the sixth technical problem to be solved by the present invention is to provide a crystal form 8 of a pomaxin mesylate salt, hereinafter referred to as "crystal form 8".
  • the crystal form 8 provided by the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angle has the following characteristic peaks: 4.8 ° ⁇ 0.2 °, 9.5 ° ⁇ 0.2 ° , 14.2 ° ⁇ 0.2 ° and 22.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 8 represented by the 2 ⁇ angle further has one or more of the following characteristic peaks: 11.9° ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.6 ⁇ 0.2 °, 23.7 ⁇ 0.2 °, 24.8 ° ⁇ 0.2 ° and 26.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 8 expressed by the angle of 2 ⁇ further has one or more characteristic peaks of: 10.1 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.9 ⁇ 0.2 °, 19.8 ⁇ 0.2 °, 20.3 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, 24.3 ° ⁇ 0.2 °, 28.2 ° ⁇ 0.2 °, 29.7 ° ⁇ 0.2 ° and 30.3 ° ⁇ 0.2 °.
  • crystal form 8 has an XRPD pattern as shown in FIG.
  • the crystalline form 8 of the present invention has the following beneficial properties as compared to existing amorphous materials:
  • the crystalline form 8 of the present invention is an anhydrate crystalline solid having a better physical form.
  • the crystalline form 8 of the present invention is left to stand in a dry state at room temperature and in a 60 ° C environment for one month; the amorphous form exhibits a weak crystalline state and discoloration.
  • the crystalline form 8 of the present invention is a crystalline solid, has better fluidity and better subsequent processing (such as filtration, drying, weighing in the pharmaceutical manufacturing process) than the prior art amorphous material.
  • the characteristics of the amount, sieving, etc., are beneficial to improve the uniformity of the preparation.
  • Form 8 has good stability, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation form containing Form 8 in the process of drug manufacture and/or storage, and avoid, for example, the content of the active ingredient. Uneven, impurities and other issues. Avoid special and expensive packaging.
  • the seventh technical problem to be solved by the present invention is to provide a method for preparing the crystal form 1, the crystal form 2, the form 5, the form 6 and the form 8.
  • the preparation method of the crystal form 1 may adopt any one of the following methods:
  • the halogenated alkane solvent is dichloromethane
  • the molar ratio of the pomaxini to methanesulfonic acid is 1:1 to 1:1.5;
  • the anti-solvent is isopropyl ether in an amount of 2 to 4 times that of dichloromethane;
  • the mass to volume ratio of the pomaxini to the solvent is 20 to 170 mg: 1 mL, more preferably 40 to 170 mg: 1 mL;
  • the reaction is carried out at room temperature;
  • the stirring and crystallization time is 3 to 5 days;
  • the drying temperature is 25 to 60 ° C;
  • the drying time is 16 to 48 hours;
  • the halogenated alkane solvent is dichloromethane
  • the molar ratio of the pomaxini to methanesulfonic acid is 1:1 to 1:1.5;
  • the mass to volume ratio of the pomaxini to the solvent is 50 to 250 mg: 1 mL, more preferably 60 to 250 mg: 1 mL;
  • the reaction is carried out at room temperature;
  • the stirring and crystallization time is 3 to 7 days;
  • the drying temperature is 25 to 60 ° C;
  • the drying time is from 16 to 48 hours.
  • the preparation method of the crystal form 2 is as follows:
  • the pomesin is dissolved in a ketone solvent to form a suspension, the methanesulfonic acid is added dropwise with stirring, and the crystallized is stirred, and the obtained solid is filtered and dried to obtain the crystal form of the pomaxini mesylate salt 2;
  • the ketone solvent is acetone
  • the molar ratio of the pomaxini to methanesulfonic acid is 1:1 to 1:1.5;
  • the mass to volume ratio of the pomaxini to the solvent is 5 to 25 mg: 1 mL, more preferably 10 to 25 mg: 1 mL;
  • the reaction is carried out at room temperature;
  • the stirring time is 3 to 7 days;
  • the drying temperature is 25 to 60 ° C;
  • the drying time is from 16 to 48 hours.
  • the preparation method of the crystal form 5 may adopt any one of the following methods:
  • the mass to volume ratio of the pomaxini mesylate to the solvent is 15 to 100 mg: 1 mL, more preferably 20 to 50 mg: 1 mL;
  • the reaction temperature is 4 to 40 ° C;
  • the stirring time is 3 to 7 days;
  • the drying temperature is 25 to 60 ° C;
  • the drying time is from 16 to 48 hours.
  • the mass to volume ratio of the vimazin mesylate solid to the C 1 -C 4 alcohol is 10 to 35 mg: 1 mL, more preferably 10 to 20 mg: 1 mL;
  • the anti-solvent is C 3 -C 6 ether, C 6 -C 7 alkane, and the amount is 2 to 4 times of the C 1 -C 4 alcohol;
  • the reaction is carried out at room temperature;
  • the drying temperature is 25 to 60 ° C;
  • the drying time is from 16 to 48 hours.
  • the preparation method of the crystal form 6 can adopt any one of the following methods:
  • the pomsini mesylate solid is placed under conditions of 58% to 85% humidity to obtain the form of the pomesinismethanesulfonate 6;
  • the placement environment is 20 to 40 °C.
  • the mass ratio of the pomsini mesylate solid to ethanol is 20-25 mg: 1 mL;
  • the low temperature is -10 to 5 ° C;
  • the drying temperature is 25 to 60 ° C;
  • the drying time is from 16 to 48 hours.
  • the preparation method of the crystal form 8 is as follows:
  • the pomesinis methanesulfonate crystal form 1, the crystal form 2, the crystal form 5 and the form 6 are placed at 200 to 210 ° C for a period of time to obtain the pomsini mesylate crystal Type 8.
  • the starting material of the carbamacilene can be prepared by the method described in the embodiment 16 of the patent document CN102264725 (B), or can be purchased from the market. This document is incorporated herein by reference in its entirety.
  • the "room temperature” means 10 to 30 °C.
  • 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 "drying" can be accomplished using conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying.
  • 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; the pressure may be reduced or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying temperature is 10 to 40 ° C, and the drying time is 10 to 72 hours, preferably 2 to 24 hours, more preferably 2 to 8 hours.
  • 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 of peak angles may vary by 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc. depending on the instrument. Different angles are usually allowed to be ⁇ 0.2°, so the difference in peak angle cannot be used as 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 bomasin mesylate 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.
  • a seventh aspect of the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically effective amount of a pharmaceutically active ingredient selected from the crystalline form of the invention or a crystalline form prepared by the process of the invention, and at least one pharmaceutically acceptable carrier or adjuvant.
  • the crystal forms of the present invention are crystalline form 1, crystalline form 2, crystalline form 3, crystalline form 4, crystalline form 5, crystalline form 6, crystalline form 7 and crystalline form 8.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms or amorphous forms.
  • the dosage form of the compound used in the method of the present invention can be determined by the solid form of the particular compound selected, the route of administration, and the state of the patient.
  • the crystalline form of the compound of the present invention can be prepared according to the accepted methods in the pharmaceutical field and is suitable for administration by one or more of the following routes: oral, sublingual, parenteral (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technique). a composition by inhalation, intranasal or rectal, and the preparation contains at least one active compound.
  • the pharmaceutical compositions of the present invention are preferably provided in unit dosage form, each containing from about 5 to 1000 mg, more usually from about 100 to 500 mg of the pomsinismethane salt of the present invention and crystalline forms thereof.
  • patient refers to an animal, preferably a mammal, more preferably a human, as a therapeutic, observation or experimental target.
  • treatment refers to one or more of the following: (1) prevention of diseases and symptoms; for example, lesions or symptoms that may be prone to disease or symptoms but have not yet suffered or manifested the disease. (2) inhibiting the disease or symptom; (2) inhibiting the disease and symptoms, for example, in a patient who is suffering from or showing the disease or condition; and (3) improving the disease; for example, suffering or Ameliorating the disease or condition (ie, reversing the disease and/or symptoms) in a patient showing the disease or condition, such as reducing the severity of the disease.
  • phrases “effective amount” means an amount sufficient to exert a therapeutic or prophylactic effect.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition are compatible with each other and are suitable for the recipient thereof.
  • compositions is intended to include a bulk composition and/or individual doses consisting of one or more pharmaceutically active ingredients comprising a crystalline form of the invention together with any non-pharmaceutically active excipient. unit.
  • Bulk compositions and individual dosage units may contain a fixed amount of one or more of the pharmaceutically active ingredients described above.
  • Bulk compositions refer to materials that have not yet formed individual dosage units. Examples of non-limiting dosage units are oral dosage units such as tablets, pills, and the like.
  • the pharmaceutical compositions of the present invention are also intended to include the aforementioned bulk compositions and individual dosage units by administering to a subject in need thereof.
  • compositions of the present invention comprise the active ingredient and are usually mixed with the excipient, diluted with the excipient or enclosed in a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as an excipient, carrier or medium for the active ingredient.
  • the preparation may be in the form of tablets, pills, troches, powders, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or in liquid medium), ointments, soft and Hard capsules, gels, suppositories, sterile injectable solutions and sterile encapsulated powders.
  • excipients for some solid preparations suitable for oral administration include sugars such as lactose, glucose, sucrose, sorbitol, mannose, starch, gum arabic, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline fibers. , polyvinylpyrrolidone, kaolin, cellulose, methyl cellulose, binders, disintegrants, and the like.
  • Some liquid preparations suitable for oral administration may employ a medium such as water, glycol, oil, or alcohol.
  • Parenteral compositions typically employ sterile water as a vehicle and optionally other ingredients such as a dissolution aid.
  • the injectable solution can be prepared, for example, using a carrier comprising a saline solution, a glucose solution or a solution containing a mixture of saline and glucose.
  • Formulations may also include: lubricants such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as propyl hydroxybenzoate, sweeteners and flavoring agents.
  • lubricants such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as propyl hydroxybenzoate, sweeteners and flavoring agents.
  • the compounds of the invention may be formulated by methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.
  • the sixth aspect of the present invention provides a crystal form of the present invention or a crystal form obtained by the preparation method of the present invention for preparing and treating colorectal cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, and mantle cells.
  • Use in drugs for cancer diseases such as lymphoma, chronic myeloid leukemia, and acute myeloid leukemia.
  • a method of treating a cancer disease or symptom such as colorectal cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia, and acute myeloid leukemia, the method comprising Providing to a patient in need thereof a prophylactically effective amount of the aforementioned pharmaceutical composition selected from the group consisting of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and Form 8 of the present invention;
  • the disease is the same as the foregoing of the present specification.
  • the active compounds are usually effective over a wide range of dosages.
  • the daily dose of the active compound (which may be a single dose or divided dose) will generally be from about 1 [mu]g/kg to 1 g/kg body weight per day.
  • the preferred dose is from about 0.01 mg to 100 mg/kg body weight per day.
  • the amount of compound actually administered and the frequency of administration in any particular patient may vary and depend on a variety of factors, including the activity of the compound employed, the metabolism and duration of action of the compound, and the actual dosage to be administered.
  • the various dosages, the conditions and severity of the treatment, the route of administration, the age, weight, excretion rate, and overall response of the particular patient are adjusted, and thus, the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the above dosage range may be more appropriate, while in other cases higher doses that do not produce any side effects may be employed, provided that the larger dose is first divided into several A smaller dose is administered throughout the day.
  • Figure 2 is a DSC pattern of Form 1 of the present invention
  • Figure 3 is a TGA map of Form 1 of the present invention
  • Figure 4 is an XRPD pattern of Form 2 of the present invention
  • Figure 5 is a DSC pattern of Form 2 of the present invention
  • Figure 6 is a TGA map of Form 2 of the present invention
  • Figure 7 is an XRPD pattern of Form 3 of the present invention
  • Figure 8 is an XRPD pattern of Form 4 of the present invention
  • Figure 10 is a DSC map of Form 5 of the present invention
  • Figure 13 is a DSC map of Form 6 of the present invention
  • Figure 14 is a TGA map of Form 6 of the present invention.
  • Figure 17 is a DSC map of Form 8 of the present invention
  • Figure 18 is a TGA map of Form 8 of the present invention.
  • X-ray powder diffraction (XRPD): The instrument was Bruker D8 Advance. 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.
  • DSC Differential Thermal Analysis Data
  • Thermogravimetric analysis data was taken from the TA Instruments Q500 TGA.
  • 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 a temperature of 10 ° C/min under the protection of 40 mL/min dry N 2 by means of segmented high-resolution detection. 350 ° C.
  • Nuclear magnetic resonance spectroscopy ( 1 H-NMR): Data were taken from Bruker Ascend Tm 500. Using full-frequency excitation, spectral width 30ppm, single pulse, 30° angle excitation, 16 scans, digital orthogonal detection, temperature control 298K.
  • the preparation of the pomesinismethanesulfonate was carried out by referring to the preparation method of the example 16 of the patent document CN102264725 (B), and the solvent was removed under reduced pressure to obtain an oily substance, which was triturated with methyl tert-butyl ether to obtain an amorphous substance.
  • the TGA map is shown in Figure 3.
  • the samples prepared in Examples 2 to 6 have the same or similar XRPD patterns (not shown), DSC patterns (not shown), TGA patterns (not shown), and Examples 2 to 6
  • the sample was the same crystalline form as the sample of Example 1.
  • the DSC spectrum is shown in Figure 5.
  • the TGA map is shown in Figure 6.
  • the samples prepared in Examples 8 to 9 had the same or similar XRPD patterns (not shown) and TGA patterns (not shown) as those of the samples of Example 7, indicating that the samples of Examples 8-9 and Example 7 were The same crystal form.
  • the DSC spectrum is shown in Figure 10.
  • the TGA map is shown in Figure 11.
  • the samples prepared in Examples 11 to 23 had the same or similar XRPD patterns (not shown) and TGA patterns (not shown) as those of the samples of Example 10, indicating that the samples of Examples 11 to 23 and the sample of Example 10 were The same crystal form.
  • the TGA map is shown in Figure 14.
  • the samples prepared in Examples 25 to 28 had the same or similar XRPD patterns (not shown) and TGA patterns (not shown) as the samples of Examples 24, indicating that the samples of Examples 25-28 and Example 24 were The same crystal form.
  • the DSC spectrum is shown in Figure 17.
  • the TGA map is shown in Figure 18.
  • the samples prepared in Examples 30 to 32 had the same or similar XRPD patterns (not shown) and TGA patterns (not shown) as the samples of Examples 29, indicating that the samples of Examples 30 to 33 and Example 29 were The same crystal form.
  • the pomesin mesylate form 1 or mixed with starch, hydroxypropylcellulose, magnesium stearate and talc is filled into capsules.
  • aqueous solution of hydroxypropylcellulose and the pomesin mesylate salt form 1, starch are wet granulated, dried, mixed with magnesium stearate and talc, and compressed into tablets.
  • the pomesinismethanesulfonate crystal form 1 in Examples 33 and 34 was replaced with the Bomasini mesylate salt form 2, Form 3, Form 4, and crystal form, respectively, as described herein. 5.
  • Form 6, Form 7 and Form 8 the free base in the formulation and the molar amount of the free base in Form 1 of the pomsini mesylate salt are the same, and the other components in each formulation are also the same as in the examples.
  • the preparation steps of the respective formulations were also the same as in Examples 33 and 34.
  • Crystal form stability placement experiment 20 mg of the preparation of the pomaxini mesylate of Preparation Example 1, the form of the pomsini mesylate salt of the present invention 1, the crystal form 2, the crystal form 5, the crystal form 6, The crystal form 8 was placed under different conditions such as high temperature at 60 ° C and drying at room temperature, and XRD crystal form was detected after 30 days.

Abstract

一种玻玛西尼甲磺酸盐的晶型，其与已知的玻玛西尼甲磺酸盐相比具有一种或多种改进的特性。还涉及该玻玛西尼甲磺酸盐晶型的制备方法，药物组合物及其在制备用于治疗结肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病等癌症疾病的药物中的用途。

Description

玻玛西尼甲磺酸盐晶型及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，本申请涉及新型的玻玛西尼甲磺酸盐晶型及其制备方法、药物组合物和用途。
背景技术
玻玛西尼甲磺酸盐是一种CDK4和CDK6的特别的抑制剂，可用于治疗结肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病等癌症疾病的药物。化学名称为N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-胺甲磺酸盐，其化学结构式如下所示：
Figure PCTCN2018083152-appb-000001
专利文献CN102264725B公开玻玛西尼甲磺酸盐的合成制备方法，但到目前为止暂未有玻玛西尼甲磺酸盐晶型的报导。本发明人研究发现，按照CN102264725B中实施例16的制备方法，在真空去除溶剂后得到玻玛西尼甲磺酸盐的油状物，用甲基叔丁基醚研磨后固化得到的玻玛西尼甲磺酸盐无定型态。油状物的出现和研磨固化的方式使得该制备方法工业化的可能性很低，并且所获得的无定型态存在难以纯化、化学稳定性差、溶残高、制剂可加工性差的缺点。
因此，本领域仍需要开发具有改进性能的玻玛西尼甲磺酸盐晶型，以满足药物制剂对于活性成分的严格要求。
发明内容
针对现有技术的不足，本发明的目的是提供玻玛西尼甲磺酸盐的晶型以及它们的制备方法、包含所述晶型的药物组合物和用途。所述晶型为稳定的结晶态固体，应具有一种或多种改进的特性，特别是表现在具备良好结晶度和稳定性、较好的流动性和有利的加工与处理特性等方面。此外，本发明还 涉及所述晶型的制备方法、包含所述晶型的药物组合物及其用途。
根据本发明目的，本发明解决的技术问题之一是提供玻玛西尼甲磺酸盐的晶型1，以下简称为“晶型1”。
本发明提供的晶型1，在本发明的一个实施方案中，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.0°±0.2°、8.2°±0.2°、23.6°±0.2°和26.9°±0.2°。
在本发明优选的一个实施方案中，所述的晶型1以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：15.9°±0.2°、16.6°±0.2°、17.0°±0.2°、18.5°±0.2°和20.7°±0.2°。
在本发明优选的一个实施方案中，所述的晶型1以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处特征峰：4.7°±0.2°、9.5°±0.2°、11.4°±0.2°、12.7°±0.2°、19.3°±0.2°、22.5°±0.2°和26.3°±0.2°。
在本发明进一步优选的一个实施方案中，所述的晶型1以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处特征峰：10.5°±0.2°、14.3°±0.2°、15.3°±0.2°、17.9°±0.2°、18.3°±0.2°、19.9°±0.2°、20.2°±0.2°、29.7°±0.2°和30.5°±0.2°。
非限制性地，所述晶型1的一个典型实例具有如图1所示的XRPD图谱。
非限制性地，所述晶型1的DSC图谱如图2所示。
非限制性地，所述晶型1的TGA图谱如图3所示。
与现有的无定型物相比，本发明的晶型1具有以下有益性质：
1)本发明的晶型1为无水物结晶态固体，具有更好的物理形态。
2)本发明的晶型1在室温干燥和60℃环境中放置一月晶型不变；无定型物则出现弱晶态和变色。
3)本发明的晶型1具有较高的熔点。
上述有益性质表明：与现有技术无定型物相比，本发明的晶型1为结晶态固体，具有更好的流动性和更优良的后续加工(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高制剂均一性。晶型1具有良好的稳定性和更高的熔点，能够更好地保证药物活性成分自身和含有晶型1的制剂剂型对抗在药物制造和/或存储等过程中的质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质等问题。避免特殊和昂贵的包装。
根据本发明目的，本发明解决的技术问题之二是提供玻玛西尼甲磺酸盐 的晶型2，以下简称为“晶型2”。
本发明提供的晶型2，在本发明的一个实施方案中，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.1°±0.2°、12.0°±0.2°、14.3°±0.2°和21.6°±0.2°。
在本发明优选的一个实施方案中，所述的晶型2以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.4°±0.2°、12.7±0.2°、13.0±0.2°、14.7±0.2°、15.6±0.2°、17.5°±0.2°、22.8°±0.2°、23.4°±0.2°、24.6°±0.2°和26.9°±0.2°。
在本发明进一步优选的一个实施方案中，所述的晶型2以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.2±0.2°、15.1±0.2°、18.0±0.2°、20.0±0.2°、23.1°±0.2°、24.4°±0.2°、25.7±0.2°、27.5±0.2°、28.6±0.2°、29.6±0.2°、30.2±0.2°和32.6°±0.2°。
非限制性地，所述晶型2的一个典型实例具有如图4所示的XRPD图谱。
非限制性地，所述晶型2的DSC图谱如图5所示。
非限制性地，所述晶型2的TGA图谱如图6所示。
与现有的无定型物相比，本发明的晶型2具有以下有益性质：
1)本发明的晶型2为无水物结晶态固体，具有更好的物理形态。
2)本发明的晶型2在室温干燥和60℃环境中放置一月晶型不变；无定型物则出现弱晶态和变色。
上述有益性质表明：与现有技术无定型物相比，本发明的晶型2为结晶态固体，具有更好的流动性和更优良的后续加工(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高制剂均一性。晶型2具有良好的稳定性，能够更好地保证药物活性成分自身和含有晶型2的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质等问题。避免特殊和昂贵的包装。
根据本发明目的，本发明解决的技术问题之三是提供玻玛西尼甲磺酸盐的晶型3、晶型4和晶型7，以下简称为“晶型3”、“晶型4”、“晶型7”。
所述晶型3，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下至少3处或更多处的特征峰：8.1°±0.2°、9.0°±0.2°、11.7°±0.2°、17.1°±0.2°、17.9°±0.2°、18.1°±0.2°和21.7°±0.2°。
所述晶型4，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下三处或更多处特征峰：5.7°±0.2°、6.4°±0.2°、8.6±0.2°、11.2°±0.2°、14.3°±0.2°、 15.4°±0.2°、16.7°±0.2°、17.4±0.2°、17.2±0.2°、22.3±0.2°、26.3°±0.2°和27.1°±0.2°。
所述晶型7，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下三处或更多处的特征峰：4.0°±0.2°、14.5°±0.2°、17.6°±0.2°、18.0°±0.2°、25.3°±0.2°和27.7°±0.2°。
与现有的无定型相比，本发明的玻玛西尼甲磺酸盐晶型3、晶型4和晶型7具有一种或多种改进的特性，例如：更高的结晶度、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。
根据本发明目的，本发明解决的技术问题之四是提供玻玛西尼甲磺酸盐的晶型5，以下简称为“晶型5”。
本发明提供的晶型5，在本发明的一个实施方案中，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.4°±0.2°、9.0°±0.2°、18.1±0.2°和23.0°±0.2°。
在本发明优选的一个实施方案中，所述的晶型5以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.8°±0.2°、13.2±0.2°、13.5°±0.2°、16.3±0.2°、20.6±0.2°、21.7°±0.2°、26.7°±0.2°和30.7°±0.2°。
在本发明进一步优选的一个实施方案中，所述的晶型2以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：14.2±0.2°、14.5±0.2°、15.4±0.2°、17.1±0.2°、18.2°±0.2°、19.2°±0.2°和22.1°±0.2°。
非限制性地，所述晶型5的一个典型实例具有如图9所示的XRPD图谱。
非限制性地，所述晶型5的DSC图谱如图10所示。
非限制性地，所述晶型5的TGA图谱如图11所示。
与现有的无定型物相比，本发明的晶型5具有以下有益性质：
1)本发明的晶型5为无水物结晶态固体，具有更好的物理形态。
2)本发明的晶型5在室温干燥和60℃环境中放置一月晶型不变；无定型物则出现弱晶态和变色。
上述有益性质表明：与现有技术无定型物相比，本发明的晶型5为结晶态固体，具有更好的流动性和更优良的后续加工(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高制剂均一性。晶型5具有良好的稳定性，能够更好地保证药物活性成分自身和含有晶型5的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性，避免例如活性成分含量不均匀、 杂质等问题。避免特殊和昂贵的包装。
根据本发明目的，本发明解决的技术问题之五是提供玻玛西尼甲磺酸盐的晶型6，以下简称为“晶型6”。
本发明提供的晶型6，在本发明的一个实施方案中，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：3.8°±0.2°、7.5°±0.2°、15.0°±0.2°和18.8°±0.2°。
在本发明优选的一个实施方案中，所述的晶型6以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：4.3°±0.2°、8.6°±0.2°、9.9±0.2°、10.8±0.2°、11.2±0.2°、19.9±0.2°、21.8°±0.2°、22.6°±0.2°、25.8°±0.2°和28.8°±0.2°。
在本发明进一步优选的一个实施方案中，所述的晶型6以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：12.9±0.2°、16.4±0.2°、17.2±0.2°、18.3±0.2°、19.2°±0.2°、23.6°±0.2°、24.5°±0.2°、26.3°±0.2°、27.2°±0.2°、27.9°±0.2°、34.2°±0.2°和35.8°±0.2°。
非限制性地，所述晶型6的一个典型实例具有如图12所示的XRPD图谱。
非限制性地，所述晶型6的DSC图谱如图13所示。
非限制性地，所述晶型6的TGA图谱如图14所示。
与现有的无定型物相比，本发明的晶型6具有以下有益性质：
1)本发明的晶型6为半水合物结晶态固体，具有更好的物理形态。
2)本发明的晶型6在室温干燥和60℃环境中放置一月晶型不变；无定型物则出现弱晶态和变色。
上述有益性质表明：与现有技术无定型物相比，本发明的晶型6为结晶态固体，具有更好的流动性和更优良的后续加工(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高制剂均一性。晶型6具有良好的稳定性，能够更好地保证药物活性成分自身和含有晶型6的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质等问题。避免特殊和昂贵的包装。
根据本发明目的，本发明解决的技术问题之六是提供玻玛西尼甲磺酸盐的晶型8，以下简称为“晶型8”。
本发明提供的晶型8，在本发明的一个实施方案中，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.8°±0.2°、9.5°±0.2°、14.2°±0.2°和22.5±0.2°。
在本发明优选的一个实施方案中，所述的晶型8以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.9°±0.2°、16.8±0.2°、18.6±0.2°、23.7±0.2°、24.8°±0.2°和26.2°±0.2°。
在本发明进一步优选的一个实施方案中，所述的晶型8以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：10.1±0.2°、17.1±0.2°、18.9±0.2°、19.8±0.2°、20.3°±0.2°、20.8°±0.2°、24.3°±0.2°、28.2°±0.2°、29.7°±0.2°和30.3°±0.2°。
非限制性地，所述晶型8的一个典型实例具有如图16所示的XRPD图谱。
非限制性地，所述晶型8的DSC图谱如图17所示。
非限制性地，所述晶型8的TGA图谱如图18所示。
与现有的无定型物相比，本发明的晶型8具有以下有益性质：
1)本发明的晶型8为无水物结晶态固体，具有更好的物理形态。
2)本发明的晶型8在室温干燥和60℃环境中放置一月晶型不变；无定型物则出现弱晶态和变色。
上述有益性质表明：与现有技术无定型物相比，本发明的晶型8为结晶态固体，具有更好的流动性和更优良的后续加工(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高制剂均一性。晶型8具有良好的稳定性，能够更好地保证药物活性成分自身和含有晶型8的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质等问题。避免特殊和昂贵的包装。
根据本发明目的，本发明解决的技术问题之七是提供晶型1、晶型2、晶型5、晶型6和晶型8的制备方法。
所述晶型1的制备方法可采用下述方法中的任意一种：
(1)、将玻玛西尼溶解在卤代烷烃类溶剂中形成清液，搅拌下滴加甲磺酸，搅拌过程中加入抗溶剂析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型1；
优选地，所述卤代烷烃类溶剂为二氯甲烷；
优选地，所述玻玛西尼与甲磺酸的摩尔比为1:1～1:1.5；
优选地，所述的抗溶剂为异丙醚，用量为二氯甲烷的2～4倍；
优选地，所述玻玛西尼与溶剂的质量体积比为20～170mg:1mL，更优选为40～170mg:1mL；
优选地，所述反应在室温下进行；
优选地，所述搅拌析晶时间为3～5天；
优选地，所述干燥温度为25～60℃；
优选地，所述干燥时间为16～48小时；
(2)、将玻玛西尼溶解在卤代烷烃类溶剂中形成清液，搅拌下滴加甲磺酸，搅拌析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型1；
优选地，所述卤代烷烃类溶剂为二氯甲烷；
优选地，所述玻玛西尼与甲磺酸的摩尔比为1:1～1:1.5；
优选地，所述玻玛西尼与溶剂的质量体积比为50～250mg:1mL，更优选为60～250mg:1mL；
优选地，所述反应在室温下进行；
优选地，所述搅拌析晶时间为3～7天；
优选地，所述干燥温度为25～60℃；
优选地，所述干燥时间为16～48小时。
所述晶型2的制备方法如下：
将玻玛西尼溶解在酮类溶剂中形成悬浊液，搅拌下滴加甲磺酸，搅拌析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型2；
优选地，所述酮类溶剂为丙酮；
优选地，所述玻玛西尼与甲磺酸的摩尔比为1:1～1:1.5；
优选地，所述玻玛西尼与溶剂的质量体积比为5～25mg:1mL，更优选为10～25mg:1mL；
优选地，所述反应在室温下进行；
优选地，所述搅拌时间为3～7天；
优选地，所述干燥温度为25～60℃；
优选地，所述干燥时间为16～48小时。
所述的晶型5的制备方法可采用下述方法中的任意一种：
(1)、将玻玛西尼甲磺酸盐固体在C 1～C 4醇、C 3～C 6醚、C 4～C 5酯、C 3～C 4酮、环醚、腈类、水、烷烃、硝基甲烷或其混合溶剂中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述玻玛西尼甲磺酸盐晶型5；
优选地，所述玻玛西尼甲磺酸盐与溶剂的质量体积比为15～100mg:1mL，更优选为20～50mg:1mL；
优选地，所述反应温度为4～40℃；
优选地，所述搅拌时间为3～7天；
优选地，所述干燥温度为25～60℃；
优选地，所述干燥时间为16～48小时。
(2)、将玻玛西尼甲磺酸盐固体溶解在C 1～C 4醇中形成清液，搅拌过程中加入抗溶剂析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型5；
优选地，所述玻玛西尼甲磺酸盐固体与C 1～C 4醇的质量体积比为10～35mg:1mL，更优选为10～20mg:1mL；
优选地，所述的抗溶剂为C 3～C 6醚、C 6～C 7烷烃，用量为C 1～C 4醇的2～4倍；
优选地，所述反应在室温下进行；
优选地，所述干燥温度为25～60℃；
优选地，所述干燥时间为16～48小时。
所述的晶型6的制备方法可采用下述方法中的任意一种：
(1)、将玻玛西尼甲磺酸盐固体放置在58％～85％湿度条件下，得到所述玻玛西尼甲磺酸盐晶型6；
优选地，所述放置环境为20～40℃。
(2)、将玻玛西尼甲磺酸盐固体溶解在乙醇中，加热溶清形成清液，将反应液放置低温下搅拌析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型6；
优选地，所述玻玛西尼甲磺酸盐固体与乙醇的质量体积比为20～25mg:1mL；
优选地，所述低温为-10～5℃；
优选地，所述干燥温度为25～60℃；
优选地，所述干燥时间为16～48小时。
所述的晶型8的制备方法如下：
将玻玛西尼甲磺酸盐晶型1、晶型2、晶型5和晶型6放置在200～210℃条件下，保持一段时间后，得到所述玻玛西尼甲磺酸盐晶型8。
本发明的玻玛西尼甲磺酸盐的晶型的制备方法中：起始原料玻玛西尼可参照专利文献CN102264725(B)中实施例16所描述的方法制备得到，亦可由市售购买得到，该文献通过引用其全文的方式并入到本申请中。
本发明中使用的术语有：
所述“室温”，是指10～30℃。
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，优选300～900转/分。
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“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。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；可以减压或常压，优选压力小于0.09MPa。干燥温度为10～40℃，干燥时间为10～72小时，优选为2～24小时，更优选为2～8小时。
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°，0.3°，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。
本发明所述玻玛西尼甲磺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)。
根据本发明目的，本发明的内容之七是提供一种药物组合物。所述药物组合物含有治疗有效量的药物活性成分选自本发明的晶型或者由本发明制备方法制备得到的晶型，以及至少一种药学上可接受的载体或助剂。其中所述本发明的晶型为晶型1、晶型2、晶型3、晶型4、晶型5、晶型6、晶型7和晶型8。此外，所述药物组合物还可以包含其它可药用晶型或无定型物。本发明 方法中使用的化合物的给药剂型可以通过所选择的特定化合物固体形态、给药途径及患者的状态来确定。本发明的化合物晶型可按制药领域的公认方法制备适合于一种或多种下列途径给药：口服、舌下、肠胃外(包括皮下注射、静脉内、肌肉内、胸骨内注射或输液技术)、通过吸入、鼻内或直肠的组合物，并且所述制剂含有至少一种活性化合物。优选以单位剂型的形式提供本发明的药物组合物，每剂大约可含有5～1000mg，更经常的是含有约100-500mg本发明的玻玛西尼甲磺酸盐及其晶型。
本文所用的术语“患者”是指作为治疗、观察或实验目标的动物，优选哺乳动物，更优选人。
本发明中所用的术语“治疗”是指下列中的一种或多种：(1)预防疾病和症状；例如在可能倾向于罹患疾病或症状、但还没有遭受或显示该疾病的病变或症状的患者中预防该疾病或症状；(2)抑制该疾病和症状；例如在正遭受或显示该疾病或症状的患者中抑制该疾病和症状；以及(3)改善该疾病；例如，在遭受或显示该疾病或症状的患者中改善该疾病或症状(即逆转病变和/或症状)，例如降低疾病的严重程度。
本发明说用的术语“或”是指备选项，如果适当，它们可以组合。因此术语“或”包含分开的各个所列的备选项以及它们的组合，只要该组合不是相互排斥。
术语“有效量”是指足以发挥治疗或预防作用的量。所述“药学上可接受”是指该药物组合物的成分彼此相容并适合其接受者。
所述“药物组合物”或“组合物”意在包括由包含本发明的晶型的一种或多种药物活性成分与任何非医药活性赋形剂一起组成的散装组合物和/或个别剂量单位。散装组合物和个别剂量单位可以含有固定量的上述一种或多种医药活性成分。散装组合物是指还未形成个别剂量单位的物质。非限制性的剂量单位例子如片剂、丸剂和及其类似物的口服剂量单位。相似地，通过给予有需要的个体本发明的药物组合物还意在包括前述所说的散装组合物和单个剂量单位。
一般而言，本发明的组合物包括活性组分，并通常与赋型剂混合、被赋型剂稀释或包封在可呈胶囊、小药囊、纸或其他容器状的载体中。当赋型剂用作稀释剂时，其可以是固体、半固体或液体物料，对活性组分起赋型剂、载体或介质的作用。因此，制剂可以是片剂、丸剂、锭剂、粉剂、香囊、扁 囊剂、酏剂、悬浮剂、乳剂、溶液、糖浆、气溶胶(为固体或在液体介质中)、软膏、软和硬胶囊、凝胶、栓剂、无菌注射液和无菌封装粉剂。
一些合适口服给药的固体制剂的赋型剂实例包括糖例如乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、高岭土、纤维素、甲基纤维素、粘合剂、崩解剂等。一些适合口服给药的液体制剂(例如悬浮剂、糖浆、酏剂等)可使用如水、二醇、油、醇之类的介质。肠胃外组合物通常使用无菌水作为载体和任选使用其它成分，例如溶解助剂。可注射溶液可例如使用包含盐溶液、葡萄糖溶液或含盐水和葡萄糖的混合物的溶液的载体制备。制剂还可包括：诸如滑石粉、硬脂酸镁和矿物油的润滑剂，润湿剂，乳化剂和悬浮剂，诸如羟基苯甲酸丙酯的防腐剂，甜味剂和矫味剂。可以采用本领域的已知方法来配制本发明化合物，以便患者给药后能快速、持续或延缓放出活性组份。
根据本发明目的，本发明的内容之六是提供本发明的晶型或者由本发明制备方法得到的晶型在制备治疗结肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病等癌症疾病的药物中的用途。
根据本发明目的，治疗肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病等癌症疾病或症状的方法，所述方法包括给予需要的患者预防有效量的选自本发明的晶型1、晶型2、晶型3、晶型4、晶型5、晶型6、晶型7和晶型8的前述药物组合物；所述疾病同本说明书的前述内容。
活性化合物通常在很大剂量范围内有效。例如，活性化合物每天的剂量(可为单剂量或分计剂量)一般为约1μg/kg-1g/kg体重/日。对于人类患者的成人治疗，优选的剂量(单剂量或分剂量)为约0.01mg-100mg/kg体重/日。然而，应当理解，任何特定患者的实际给药的化合物量和给药频率可变，并取决于多种因素，包括所用的化合物的活性、该化合物的代谢和作用时长、实际要服用的一种或多种化合物、所治疗的疾病及其严重性、给药途径、具体患者的年龄、体重、排泄速率和整体响应而调整，因此，以上剂量范围不应以任何方式限制本发明范围。在某些情况下，低于上述剂量范围的剂量水平可能更为合适，而在其它情况下，可采用不产生任何副作用的更高剂量，其前提条件是，首先将这种较大剂量分成数个较小剂量供全天给药。
附图说明
图1本发明晶型1的XRPD图谱
图2本发明晶型1的DSC图谱
图3本发明晶型1的TGA图谱
图4本发明晶型2的XRPD图谱
图5本发明晶型2的DSC图谱
图6本发明晶型2的TGA图谱
图7本发明晶型3的XRPD图谱
图8本发明晶型4的XRPD图谱
图9本发明晶型5的XRPD图谱
图10本发明晶型5的DSC图谱
图11本发明晶型5的TGA图谱
图12本发明晶型6的XRPD图谱
图13本发明晶型6的DSC图谱
图14本发明晶型6的TGA图谱
图15本发明晶型7的XRPD图谱
图16本发明晶型8的XRPD图谱
图17本发明晶型8的DSC图谱
图18本发明晶型8的TGA图谱
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 D8 Advance。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(DSC)采自于TA Instruments Q200 DSC。检测方法为：取0.1～10毫克的样品放置于密闭小孔铝坩埚内，以10℃/min的升温速度在40mL/min干燥N 2的保护下将样品从室温升至250℃。
热重分析数据(TGA)采自于TA Instruments Q500 TGA。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℃/min的升温速度在40mL/min干燥N 2的保护下将样品从室温升至350℃。
核磁共振氢谱分析( 1H-NMR)：数据采自于Bruker Ascend Tm 500。使用全频激发，谱宽30ppm，单脉冲，30°角激发，扫描16次，数字化正交检测，控温298K。
实施例中所用的各种试剂如无特别说明均为市售购买。
实施例中如无特别说明均为室温操作。
制备例1
参照专利文献CN102264725(B)中实例1的制备方法得到的玻玛西尼。
制备例2
参照专利文献CN102264725(B)中实例16的制备方法进行玻玛西尼甲磺酸盐制备，减压去除溶剂后得到油状物，添加甲基叔丁基醚研磨后得到无定型物。
实施例1
取500mg玻玛西尼游离态，加入2mL二氯甲烷，形成清液，室温搅拌下滴加1mL含96.2mg甲磺酸的二氯甲烷溶液，再加入5mL异丙醚，析出白色固体，搅拌反应3天后，将所得固体过滤，40℃真空干燥，得到所述玻玛西尼甲磺酸盐晶型1。
XRPD图谱如图1所示。
DSC图谱如图2所示。
TGA图谱如图3所示。
产物的 1H-NMR(DMSO)数据如下：
1H-NMR(500MHz,DMSO-d6):δ10.18(s,1H),8.71(d,J＝3.7Hz,1H),8.28(s,1H),8.27–8.20(m,2H),7.71(t,J＝10.3Hz,2H),4.85(hept,J＝6.9Hz,1H),3.59(s,2H),3.13(s,2H),3.04–2.89(m,4H),2.65(s,3H),2.33(s,3H),1.63(d,J＝6.9Hz,6H),1.21(t,J＝7.3Hz,3H)。显示为化合物玻玛西尼甲磺酸盐。
实施例2
取500mg玻玛西尼游离态，加入2mL二氯甲烷，形成清液，室温搅拌下滴加1mL含96.2mg甲磺酸的二氯甲烷溶液，搅拌反应5分钟后析出白色固体，继续搅拌反应7天后，将所得固体过滤，25℃真空干燥48h，得到所述玻玛西尼甲磺酸盐晶型1。
实施例3
取250mg玻玛西尼游离态，加入6.25mL二氯甲烷，形成清液，室温搅拌 下滴加1mL含71mg甲磺酸的二氯甲烷溶液，再加入12.5mL异丙醚，析出白色固体，搅拌反应3天后，将所得固体过滤，60℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型1。
实施例4
取250mg玻玛西尼游离态，加入12.5mL二氯甲烷，形成清液，室温搅拌下滴加1mL含47mg甲磺酸的二氯甲烷溶液，再加入30mL异丙醚，析出白色固体，搅拌反应5天后，将所得固体过滤，25℃真空干燥48h，得到所述玻玛西尼甲磺酸盐晶型1。
实施例5
取250mg玻玛西尼游离态，加入5mL二氯甲烷，形成清液，室温搅拌下滴加1mL含47.4mg甲磺酸的二氯甲烷溶液，搅拌反应5分钟后析出白色固体，搅拌反应3天后，将所得固体过滤，60℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型1。
实施例6
取250mg玻玛西尼游离态，加入4.2mL二氯甲烷，形成清液，室温搅拌下滴加1mL含96.2mg甲磺酸的二氯甲烷溶液，搅拌反应5分钟后析出白色固体，搅拌反应5天后，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型1。
实施例2～6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(未示出)、DSC图谱(未示出)、TGA图谱(未示出)，说明实施例2～6样品与实施例1的样品是相同的晶型。
实施例7
取250mg玻玛西尼游离态，加入10mL丙酮，室温搅拌下滴加3mL含47.4mg甲磺酸的丙酮溶液，搅拌反应7天后，将所得固体过滤，60℃真空干燥48h，得到所述玻玛西尼甲磺酸盐晶型2。
XRPD图谱如图4所示。
DSC图谱如图5所示。
TGA图谱如图6所示。
产物的 1H-NMR(DMSO)数据如下：
1H-NMR(500MHz,DMSO-d6):δ9.17(s,1H),8.71(d,J＝3.7Hz,1H),8.37–8.11(m,3H),7.71(t,J＝11.4Hz,2H),4.84(h,J＝7.0Hz,1H),3.59(s,2H),3.12(d,J＝8.4Hz,2 H),2.97(s,4H),2.65(s,3H),2.33(s,4H),1.63(d,J＝6.9Hz,6H),1.21(t,J＝7.3Hz,3H).显示为化合物玻玛西尼甲磺酸盐。
实施例8
取50mg玻玛西尼游离态，加入10mL丙酮，室温搅拌下滴加2mL含10mg甲磺酸的丙酮溶液，搅拌反应3天后，将所得固体过滤，25℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型2。
实施例9
取50mg玻玛西尼游离态，加入5mL丙酮，室温搅拌下滴加2mL含14.2mg甲磺酸的丙酮溶液，搅拌反应5天后，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型2。
实施例8～9制备得到的样品与实施例7的样品具有相同或相似的XRPD图谱(未示出)、TGA图谱(未示出)，说明实施例8～9样品与实施例7的样品是相同的晶型。
实施例10
取100mg制备例2的玻玛西尼甲磺酸盐，加入1mL乙醇，形成悬浮液，4℃搅拌7天，将所得固体过滤，60℃真空干燥48h，得到所述玻玛西尼甲磺酸盐晶型5。
XRPD图谱如图9所示。
DSC图谱如图10所示。
TGA图谱如图11所示。
产物的1H-NMR(DMSO)数据如下：
1HNMR(500MHz,DMSO-d6)δ10.12(s,1H),8.68(d,J＝3.6Hz,1H),8.46–8.00(m,3H),7.68(d,J＝12.5Hz,2H),4.83(p,J＝7.0Hz,1H),3.56(s,2H),3.11(d,J＝8.2Hz,2H),2.94(d,J＝13.2Hz,4H),2.63(s,3H),2.31(d,J＝2.7Hz,5H),1.61(d,J＝6.8Hz,6H),1.19(t,J＝7.3Hz,3H).显示为化合物玻玛西尼甲磺酸盐。
实施例11
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.2mL甲醇和0.8mL乙酸异丙酯，形成悬浮液，25℃搅拌5天，将所得固体过滤，40℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例12
取15mg制备例2的玻玛西尼甲磺酸盐，加入1mL甲基叔丁基醚，形成悬浮 液，25℃搅拌7天，将所得固体过滤，60℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例13
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.4mL丙酮，形成悬浮液，4℃搅拌3天，将所得固体过滤，60℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例14
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.6mL四氢呋喃，形成悬浮液，25℃搅拌7天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例15
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.8mL 1,4-二氧六环，形成悬浮液，25℃搅拌7天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例16
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.4mL乙腈和0.01mL水，形成悬浮液，4℃搅拌7天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例17
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.2mL硝基甲烷、0.2mL丁酮和0.2mL 1,4-二氧六环，形成悬浮液，25℃搅拌7天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例18
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.2mL仲丁醇、0.2mL乙酸乙酯和0.2mL氯仿，形成悬浮液，25℃搅拌7天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例19
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.6mL丁酮和0.6mL正庚烷，形成悬浮液，40℃搅拌3天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例20
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.2mL正丁醇、0.6mL异丙醚和0.2mL乙酸乙酯，形成悬浮液，25℃搅拌7天，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例21
取20mg制备例2的玻玛西尼甲磺酸盐，加入0.6mL甲醇形成清液，搅拌下加入2.4mL异丙醚，析出白色浑浊，将所得固体过滤，25℃真空干燥48h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例22
取20mg制备例2的玻玛西尼甲磺酸盐，加入1.0mL乙醇形成清液，搅拌下加入3mL正庚烷，析出白色浑浊，将所得固体过滤，60℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例23
取20mg制备例2的玻玛西尼甲磺酸盐，加入2mL仲丁醇形成清液，搅拌下加入4mL甲基叔丁基醚，析出白色浑浊，将所得固体过滤，40℃真空干燥24h，得到所述玻玛西尼甲磺酸盐晶型5。
实施例11～23制备得到的样品与实施例10的样品具有相同或相似的XRPD图谱(未示出)、TGA图谱(未示出)，说明实施例11～23样品与实施例10的样品是相同的晶型。
实施例24
取100mg制备例2的玻玛西尼甲磺酸盐，加入4mL乙醇，60℃加热溶清形成清液，将溶液放置5℃环境下搅拌析晶，析出白色浑浊，将所得固体过滤，60℃真空干燥16h，得到所述玻玛西尼甲磺酸盐晶型6。
XRPD图谱如图12所示。
DSC图谱如图13所示。
TGA图谱如图14所示。
实施例25
取20mg制备例2的玻玛西尼甲磺酸盐，加入1.0mL乙醇，60℃加热溶清形成清液，将溶液放置-10℃环境下搅拌析晶，析出白色浑浊，将所得固体过滤，25℃真空干燥48h，得到所述玻玛西尼甲磺酸盐晶型6。
实施例26
取20mg制备例2的玻玛西尼甲磺酸盐，在20℃、58％RH环境下放置7天， 得到所述玻玛西尼甲磺酸盐晶型6。
实施例27
取20mg制备例2的玻玛西尼甲磺酸盐，在20℃、85％RH环境下放置1天，得到所述玻玛西尼甲磺酸盐晶型6。
实施例28
取20mg制备例2的玻玛西尼甲磺酸盐，在40℃、75％RH环境下放置1天，得到所述玻玛西尼甲磺酸盐晶型6。
实施例25～28制备得到的样品与实施例24的样品具有相同或相似的XRPD图谱(未示出)、TGA图谱(未示出)，说明实施例25～28样品与实施例24的样品是相同的晶型。
实施例29
取50mg实施例1的玻玛西尼甲磺酸盐晶型1，在210℃环境下放置5min，得到所述玻玛西尼甲磺酸盐晶型8。
XRPD图谱如图16所示。
DSC图谱如图17所示。
TGA图谱如图18所示。
实施例30
取50mg实施例7的玻玛西尼甲磺酸盐晶型2，在200℃环境下放置8min，得到所述玻玛西尼甲磺酸盐晶型8。
实施例31
取50mg实施例10的玻玛西尼甲磺酸盐晶型5，在210℃环境下放置5min，得到所述玻玛西尼甲磺酸盐晶型8。
实施例32
取50mg实施例24的玻玛西尼甲磺酸盐晶型6，在200℃环境下放置10min，得到所述玻玛西尼甲磺酸盐晶型8。
实施例30～32制备得到的样品与实施例29的样品具有相同或相似的XRPD图谱(未示出)、TGA图谱(未示出)，说明实施例30～33样品与实施例29的样品是相同的晶型。
实施例33
Figure PCTCN2018083152-appb-000002
将玻玛西尼甲磺酸盐晶型1或和淀粉、羟丙基纤维素、硬脂酸镁和滑石粉进行混合后填充到胶囊中。
实施例34
Figure PCTCN2018083152-appb-000003
将羟丙基纤维素的水溶液和玻玛西尼甲磺酸盐晶型1、淀粉湿法制粒，干燥后，与硬脂酸镁和滑石粉进行混合后压制成片剂。
实施例35～41
将实施例33和34中的玻玛西尼甲磺酸盐晶型1分别替换为将本申请所述的玻玛西尼甲磺酸盐晶型2、晶型3、晶型4、晶型5、晶型6、晶型7和晶型8，配方中的游离碱和玻玛西尼甲磺酸盐晶型1中游离碱的摩尔用量相同，各配方中的其他组分也与实施例33和34中的相同，各制剂的制备步骤也同实施例33和34。
对比例1
晶型稳定性放置实验：分别取20mg制备例1的玻玛西尼甲磺酸盐、本发明的玻玛西尼甲磺酸盐晶型1、晶型2、晶型5、晶型6、晶型8分别在60℃高温、室温干燥等不同条件下进行放置，于30天后进行XRD晶型检测。
Figure PCTCN2018083152-appb-000004
结果显示：本发明的玻玛西尼甲磺酸盐晶型1、晶型2、晶型5、晶型6和晶型8在60℃高温、室温干燥等不同条件下放置30天后，仍保持原有晶型，具有较好的晶型稳定性。
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 (26)

  1. 结构式如下所示的结晶态玻玛西尼甲磺酸盐，
    Figure PCTCN2018083152-appb-100001
    其特征在于，所述结晶态玻玛西尼甲磺酸盐为无水物、水合物或者非溶剂化物。
  2. 根据权利要求1所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述结晶态玻玛西尼甲磺酸盐为晶型1，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.0°±0.2°、8.2°±0.2°、23.6°±0.2°和26.9°±0.2°。
  3. 根据权利要求2所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述结晶态玻玛西尼甲磺酸盐为晶型1，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下一处或多处的特征峰：15.9°±0.2°、16.6°±0.2°、17.0°±0.2°、18.5°±0.2°和20.7°±0.2°。
  4. 根据权利要求2或3所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：4.7°±0.2°、9.5°±0.2°、11.4°±0.2°、12.7°±0.2°、19.3°±0.2°、22.5°±0.2°和26.3°±0.2°。
  5. 根据权利要求2或3或4所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：10.5°±0.2°、14.3°±0.2°、15.3°±0.2°、17.9°±0.2°、18.3°±0.2°、19.9°±0.2°、20.2°±0.2°、29.7°±0.2°和30.5°±0.2°。
  6. 权利要求2～5中任一项所述的结晶态玻玛西尼甲磺酸盐的晶型1的制备方法，所述制备方法可采用下述方法中的任意一种：
    (1)将玻玛西尼溶解在卤代烷烃类溶剂中形成清液，搅拌下滴加甲磺酸，搅拌过程中加入抗溶剂析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型1；
    优选地，所述卤代烷烃类溶剂为二氯甲烷；
    优选地，所述玻玛西尼与甲磺酸的摩尔比为1:1～1:1.5；
    优选地，所述的抗溶剂为异丙醚，用量为二氯甲烷的2～4倍；
    优选地，所述玻玛西尼与溶剂的质量体积比为20～170 mg:1mL，更优选为40～170 mg:1mL；
    优选地，所述反应在室温下进行；
    优选地，所述搅拌析晶时间为3～5天；
    优选地，所述干燥温度为25～60℃；
    优选地，所述干燥时间为16～48小时；
    (2)将玻玛西尼溶解在卤代烷烃类溶剂中形成清液，搅拌下滴加甲磺酸，搅拌析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型1；
    优选地，所述卤代烷烃类溶剂为二氯甲烷；
    优选地，所述玻玛西尼与甲磺酸的摩尔比为1:1～1:1.5；
    优选地，所述玻玛西尼与溶剂的质量体积比为50～250 mg:1mL，更优选为60～250 mg:1mL；
    优选地，所述反应在室温下进行；
    优选地，所述搅拌析晶时间为3～7天；
    优选地，所述干燥温度为25～60℃；
    优选地，所述干燥时间为16～48小时。
  7. 根据权利要求1所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述结晶态玻玛西尼甲磺酸盐为晶型2，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.1°±0.2°、12.0°±0.2°、14.3°±0.2°和21.6°±0.2°。
  8. 根据权利要求7所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型2以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.4°±0.2°、12.7±0.2°、13.0±0.2°、14.7±0.2°、15.6±0.2°、17.5°±0.2°、22.8°±0.2°、23.4°±0.2°、24.6°±0.2°和26.9°±0.2°。
  9. 根据权利要求7或8所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型2以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.2±0.2°、15.1±0.2°、18.0±0.2°、20.0±0.2°、23.1°±0.2°、24.4°±0.2°、25.7±0.2°、27.5±0.2°、28.6±0.2°、29.6±0.2°、30.2±0.2°和32.6°±0.2°。
  10. 权利要求7～9中任一项所述的结晶态玻玛西尼甲磺酸盐的晶型2的制备方法，所述制备方法如下：
    将玻玛西尼溶解在酮类溶剂中形成悬浊液，搅拌下滴加甲磺酸，搅拌析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型2；
    优选地，所述酮类溶剂为丙酮；
    优选地，所述玻玛西尼与甲磺酸的摩尔比为1:1～1:1.5；
    优选地，所述玻玛西尼与溶剂的质量体积比为5～25 mg:1mL，更优选为10～25 mg:1mL；
    优选地，所述反应在室温下进行；
    优选地，所述搅拌时间为3～7天；
    优选地，所述干燥温度为25～60℃；
    优选地，所述干燥时间为16～48小时。
  11. 根据权利要求1所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述结晶态玻玛西尼甲磺酸盐为晶型5，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.4°±0.2°、9.0°±0.2°、18.1±0.2°和23.0°±0.2°。
  12. 根据权利要求11所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型5以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.8°±0.2°、13.2±0.2°、13.5°±0.2°、16.3±0.2°、20.6±0.2°、21.7°±0.2°、26.7°±0.2°和30.7°±0.2°。
  13. 根据权利要求11或12所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型5以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：14.2±0.2°、14.5±0.2°、15.4±0.2°、17.1±0.2°、18.2°±0.2°、19.2°±0.2°和22.1°±0.2°。
  14. 权利要求11～13中任一项所述的结晶态玻玛西尼甲磺酸盐的晶型5的制备方法，所述制备方法可采用下述方法中的任意一种：
    (1)将玻玛西尼甲磺酸盐固体在C 1～C 4醇、C 3～C 6醚、C 4～C 5酯、C3～C4酮、环醚、腈类、水、烷烃、硝基甲烷或其混合溶剂中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述玻玛西尼甲磺酸盐晶型5；
    优选地，所述玻玛西尼甲磺酸盐与溶剂的质量体积比为15～100 mg:1mL， 更优选为20～50 mg:1mL；
    优选地，所述反应温度为4～40℃；
    优选地，所述搅拌时间为3～7天；
    优选地，所述干燥温度为25～60℃；
    优选地，所述干燥时间为16～48小时；
    (2)将玻玛西尼甲磺酸盐固体溶解在C 1～C 4醇中形成清液，搅拌过程中加入抗溶剂析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型5；
    优选地，所述玻玛西尼甲磺酸盐固体与C 1～C 4醇的质量体积比为10～35mg:1mL，更优选为10～20 mg:1mL；
    优选地，所述的抗溶剂为C 3～C 6醚、C 6～C 7烷烃，用量为C 1～C 4醇的2～4倍；
    优选地，所述反应在室温下进行；
    优选地，所述干燥温度为25～60℃；
    优选地，所述干燥时间为16～48小时。
  15. 根据权利要求1所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述结晶态玻玛西尼甲磺酸盐为晶型6，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：3.8°±0.2°、7.5°±0.2°、15.0°±0.2°和18.8°±0.2°。
  16. 根据权利要求15所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型6以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：4.3°±0.2°、8.6°±0.2°、9.9±0.2°、10.8±0.2°、11.2±0.2°、19.9±0.2°、21.8°±0.2°、22.6°±0.2°、25.8°±0.2°和28.8°±0.2°。
  17. 根据权利要求15或16所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型6以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：12.9±0.2°、16.4±0.2°、17.2±0.2°、18.3±0.2°、19.2°±0.2°、23.6°±0.2°、24.5°±0.2°、26.3°±0.2°、27.2°±0.2°、27.9°±0.2°、34.2°±0.2°和35.8°±0.2°。
  18. 权利要求15～17中任一项所述的结晶态玻玛西尼甲磺酸盐的晶型6的制备方法，所述制备方法可采用下述方法中的任意一种：
    (1)、将玻玛西尼甲磺酸盐固体放置在58％～85％湿度条件下，得到所述玻玛西尼甲磺酸盐晶型6；
    优选地，所述放置环境为20～40℃；
    (2)、将玻玛西尼甲磺酸盐固体溶解在乙醇中，加热溶清形成清液，将反应液放置低温下搅拌析晶，将所得固体过滤，干燥，得到所述玻玛西尼甲磺酸盐晶型6；
    优选地，所述玻玛西尼甲磺酸盐固体与乙醇的质量体积比为20～25mg:1mL；
    优选地，所述低温为-10～5℃；
    优选地，所述干燥温度为25～60℃；
    优选地，所述干燥时间为16～48小时。
  19. 根据权利要求1所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述结晶态玻玛西尼甲磺酸盐为晶型8，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.8°±0.2°、9.5°±0.2°、14.2°±0.2°和22.5±0.2°。
  20. 根据权利要求19所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型8以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：11.9°±0.2°、16.8±0.2°、18.6±0.2°、23.7±0.2°、24.8°±0.2°和26.2°±0.2°。
  21. 根据权利要求19或20所述的结晶态玻玛西尼甲磺酸盐，其特征在于，所述晶型8以2θ角度表示的X-射线粉末衍射图还具有以下一处或多处的特征峰：10.1±0.2°、17.1±0.2°、18.9±0.2°、19.8±0.2°、20.3°±0.2°、20.8°±0.2°、24.3°±0.2°、28.2°±0.2°、29.7°±0.2°和30.3°±0.2°。
  22. 权利要求19～21中任一项所述的结晶态玻玛西尼甲磺酸盐的晶型8的制备方法，所述制备方法如下：
    将玻玛西尼甲磺酸盐晶型1、晶型2、晶型5和晶型6放置在200～210℃条件下，保持5～15分钟后，得到所述玻玛西尼甲磺酸盐晶型8。
  23. 一种药物组合物，其包含治疗有效量的权利要求2～6中任一项所述的玻玛西尼甲磺酸盐的晶型1，权利要求7～10中任一项所述的玻玛西尼甲磺酸盐的晶型2，权利要求11～14中任一项所述的玻玛西尼甲磺酸盐的晶型5，权利要求15～18中任一项所述的玻玛西尼甲磺酸盐的晶型6，权利要求19～22中任一项所述的玻玛西尼甲磺酸盐的晶型8，以及至少一种药学上可接受的载体或助剂。
  24. 根据权利要求23所述的药物组合物，其特征在于，所述药物组合物为口服施用的药物制剂形式，具体为片剂、胶囊、粒剂、栓剂、乳剂、混悬剂或溶液剂。
  25. 权利要求2～6中任一项所述的玻玛西尼甲磺酸盐的晶型1、权利要求7～10中任一项所述的玻玛西尼甲磺酸盐的晶型2、权利要求11～14中任一项所述的玻玛西尼甲磺酸盐的晶型5、权利要求15～18中任一项所述的玻玛西尼甲磺酸盐的晶型6、权利要求19～22中任一项所述的玻玛西尼甲磺酸盐的晶型8，在制备用于治疗结肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病的药物中的用途。
  26. 一种治疗结肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病的方法，所述方法包括给予需要的患者治疗有效量的选自权利要求2～6中任一项所述的玻玛西尼甲磺酸盐的晶型1、权利要求7～10中任一项所述的玻玛西尼甲磺酸盐的晶型2、权利要求11～14中任一项所述的玻玛西尼甲磺酸盐的晶型5、权利要求15～18中任一项所述的玻玛西尼甲磺酸盐的晶型6、权利要求19～22中任一项所述的玻玛西尼甲磺酸盐的晶型8，或权利要求23～25中任一项所述的药物组合物；所述癌症疾病包括结肠直肠癌、乳腺癌、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病。
PCT/CN2018/083152 2018-04-16 2018-04-16 玻玛西尼甲磺酸盐晶型及其制备方法和药物组合物 WO2019200502A1 (zh)

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