WO2020119772A1 - 盐酸美呋哌瑞多晶型物及其制备方法 - Google Patents

盐酸美呋哌瑞多晶型物及其制备方法 Download PDF

Info

Publication number
WO2020119772A1
WO2020119772A1 PCT/CN2019/124968 CN2019124968W WO2020119772A1 WO 2020119772 A1 WO2020119772 A1 WO 2020119772A1 CN 2019124968 W CN2019124968 W CN 2019124968W WO 2020119772 A1 WO2020119772 A1 WO 2020119772A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrochloride
mefuroperate
crystal form
spectrum substantially
spectrum
Prior art date
Application number
PCT/CN2019/124968
Other languages
English (en)
French (fr)
Inventor
沈孝坤
杨春皓
Original Assignee
中国科学院上海药物研究所
甫康（上海）健康科技有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所, 甫康（上海）健康科技有限责任公司 filed Critical 中国科学院上海药物研究所
Publication of WO2020119772A1 publication Critical patent/WO2020119772A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention specifically relates to the polymorph of mefuroperate hydrochloride, 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride, and many
  • the preparation method of crystalline form of mefuroperate hydrochloride and its use in the preparation of medicines belong to the category of medicinal chemistry.
  • Different crystal forms of a compound may have different properties, such as solubility, dissolution rate, suspension stability, stability during grinding, vapor pressure, optical and mechanical properties, hygroscopicity, crystal form size, filtration performance, drying, Density, melting point, degradation stability, stability against phase change to other crystal forms, color, even chemical reactivity, etc. More importantly, the different crystal forms of small-molecule compounds may cause changes in their dissolution, dissolution performance, pharmacokinetics, and bioavailability, which in turn affects the efficacy and safety of the drug. China should fully consider its polymorphism. Therefore, crystal form research and control has become one of the important research contents in the development process of small molecule drugs.
  • a PARP selective inhibitor with pharmaceutical value is disclosed, wherein an example of this series of inhibitors (see Example 21 on page 37) is 2-[4-(methylaminomethyl)phenyl] -5-Fluoro-benzofuran-7-carboxamide hydrochloride (hereinafter referred to as mefuroperide hydrochloride), its structure is as shown in formula I:
  • the characterization of the compound obtained by the method disclosed in WO2013117120 is performed by 1 HMR analysis and/or measuring the melting point.
  • the observation of different crystalline forms of mefuroperate hydrochloride has not been described, nor is any characterization of the specific crystal form and the preparation method used to obtain the specific crystal form.
  • Different crystalline forms of mefuroperazone hydrochloride may cause its dissolution, dissolution performance, pharmacokinetics and bioavailability to change, which in turn affects the efficacy and safety of the drug.
  • the present invention discloses various crystal forms, characterization, preparation methods and uses of mefuroperate hydrochloride. Therefore, the technical problem to be solved by the present invention is to provide a polycrystalline form of mefuroperate hydrochloride, which provides a technical guarantee for the further in-depth development of mefuripere hydrochloride.
  • the first aspect of the present invention provides a polymorph of mefuroperate hydrochloride as shown in formula I.
  • the polymorphic form is Mefuroperate Hydrochloride Form D, which is an acetic acid compound of Mefuroperate Hydrochloride, and its X-ray powder diffraction spectrum includes 3 or more selected 2 ⁇ values from the lower group: 5.354 ⁇ 0.1°, 6.466 ⁇ 0.1°, 10.298 ⁇ 0.1°, 12.101 ⁇ 0.1°, 12.947 ⁇ 0.1°, 14.286 ⁇ 0.1°, 15.232 ⁇ 0.1°, 15.950 ⁇ 0.1°, 17.859 ⁇ 0.1 °, 19.642 ⁇ 0.1°, 20.705 ⁇ 0.1°22.209 ⁇ 0.1°, 24.379 ⁇ 0.1°, 25.097 ⁇ 0.1°, 26.059 ⁇ 0.1°, 26.982 ⁇ 0.1°, 31.999 ⁇ 0.1° and 37.248 ⁇ 0.1°.
  • the DSC spectrum of Mefuripre hydrochloride Form D has a characteristic endothermic peak in the range of about 280-300°C;
  • the infrared spectrum of the crystalline form D of mefuroperate hydrochloride is at least 3487cm -1 , 3182cm -1 , 2923cm -1 , 2706cm -1 , 2432cm -1 , 1666cm -1 , 1604cm -1 , 1468cm -1 , There are characteristic peaks at 1434cm -1 , 1273cm -1 , 1192cm -1 , 1115cm -1 , 1018cm -1 , 891cm -1 , 838cm -1 , 779cm -1 and 513cm -1 with an error range of ⁇ 2cm -1 .
  • the crystalline form D of mefuroperate hydrochloride has an X-ray powder diffraction spectrum substantially as shown in FIG. 1;
  • the crystalline form D also has one or more features selected from the group consisting of:
  • the crystal form D has a DSC spectrum substantially as shown in FIG. 2;
  • the crystal form D has an infrared spectrum substantially as shown in FIG. 3;
  • the crystal form D has a TG spectrum substantially as shown in FIG. 4;
  • the crystal form D has a Raman spectrum substantially as shown in FIG. 5.
  • the polymorphic form is Mefuroperate Hydrochloride Form E, which is 1,4-dioxane of mefuroperate hydrochloride, and its X-ray powder diffraction spectrum includes Three or more 2 ⁇ values selected from the group consisting of 6.49 ⁇ 0.1°, 12.625 ⁇ 0.1°, 15.271 ⁇ 0.1°, 20.727 ⁇ 0.1°, 22.933 ⁇ 0.1°, 23.913 ⁇ 0.1°, 25.139 ⁇ 0.1°, 25.618 ⁇ 0.1°, 26.082 ⁇ 0.1°, 27.084 ⁇ 0.1°, 27.406 ⁇ 0.1° and 28.828 ⁇ 0.1°.
  • the DSC spectrum of crystalline form E of mefuroperate hydrochloride has a characteristic endothermic peak in the range of about 280-300°C;
  • the infrared spectrum of the crystalline form E of mefuripere hydrochloride is at least 3480cm -1 , 3168cm -1 , 2957cm -1 , 2708cm -1 , 2475cm -1 , 1670cm -1 , 1613cm -1 , 1592cm -1 , There are characteristic peaks at 1467cm -1 , 1431cm -1 , 1377cm -1 , 1338cm -1 , 1199cm -1 , 1115cm -1 , 948cm -1 , 869cm -1 and 470cm -1 with an error range of ⁇ 2cm -1 .
  • the crystalline form E of mefuroperate hydrochloride has an X-ray powder diffraction spectrum substantially as shown in FIG. 6;
  • the crystalline form E also has one or more characteristics selected from the group consisting of:
  • the crystal form E has a DSC spectrum substantially as shown in FIG. 7;
  • the crystal form E has an infrared spectrum substantially as shown in FIG. 8;
  • the crystal form E has a TG spectrum substantially as shown in FIG. 9;
  • the crystal form E has a Raman spectrum substantially as shown in FIG.
  • the polymorphic form is Mefuroperate Hydrochloride Form F, a dimethyl sulfoxide compound, and its X-ray powder diffraction spectrum includes 3 or more selected from the following group 2 ⁇ values: 6.266 ⁇ 0.1°, 12.686 ⁇ 0.1°, 15.532 ⁇ 0.1°, 17.035 ⁇ 0.1°, 17.675 ⁇ 0.1°, 20.045 ⁇ 0.1°, 20.727 ⁇ 0.1°, 22.449 ⁇ 0.1°, 23.114 ⁇ 0.1°, 24.897 ⁇ 0.1°, 25.536 ⁇ 0.1°, 26.242 ⁇ 0.1°, 27.166 ⁇ 0.1°, 31.352 ⁇ 0.1° and 32.033 ⁇ 0.1°.
  • the DSC spectrum of Mefuripre hydrochloride Form F has a characteristic endothermic peak in the range of about 280-300°C;
  • the infrared spectrum of the crystalline form F of mefuripere hydrochloride is at least 3389cm -1 , 3168cm -1 , 2987cm -1 , 2741cm -1 , 2463cm -1 , 1662cm -1 , 1610cm -1 , 1596cm -1 , 1468cm -1, 1434cm -1, 1419cm -1 , 1385cm -1, 1345cm -1, 1205cm -1, 1183cm -1, 1116cm -1, 1015cm -1, 947cm -1, 833cm -1, 780cm -1 , and 558cm - One has a characteristic peak, and the error range is ⁇ 2cm -1 .
  • the crystalline form F of mefuroperate hydrochloride has an X-ray powder diffraction spectrum substantially as shown in FIG. 11;
  • the crystalline form F also has one or more features selected from the group consisting of:
  • the crystal form F has a DSC spectrum substantially as shown in FIG. 12;
  • the crystal form F has an infrared spectrum substantially as shown in FIG. 13;
  • the crystal form F has a TG spectrum substantially as shown in FIG. 14;
  • the crystal form F has a Raman spectrum substantially as shown in FIG. 15.
  • the polymorphic form is Mefuropride Hydrochloride Form G
  • its X powder diffraction spectrum includes 3 or more 2 ⁇ values selected from the group consisting of 6.428 ⁇ 0.1°, 8.374 ⁇ 0.1°, 10.281 ⁇ 0.1°, 12.566 ⁇ 0.1°, 15.231 ⁇ 0.1°, 15.794 ⁇ 0.1°, 18.043 ⁇ 0.1°, 19.405 ⁇ 0.1°, 20.667 ⁇ 0.1°, 22.912 ⁇ 0.1°, 23.874 ⁇ 0.1°25.087 ⁇ 0.1°, 26.040 ⁇ 0.1°, 29.849 ⁇ 0.1° and 232.656 ⁇ 0.1°.
  • the DSC spectrum of Mefuriperil Hydrochloride Form G has a characteristic endothermic peak in the range of about 280-300°C.
  • the infrared spectrum of the memantine hydrochloride Form G furosemide piperazine Swiss at least 3486cm -1, 3171cm -1, 2923cm -1 , 2709cm -1, 2475cm -1, 1665cm -1, 1608cm -1, 1591cm -1, 1508,1468cm -1, 1429cm -1, 1377cm -1 , 1338cm -1, 1190cm -1, 1173cm -1, 1115cm -1, 1018cm -1, 947cm -1, 838cm -1, 779cm -1 and at 470cm -1 With characteristic peak, the error range is ⁇ 2cm -1 .
  • the crystalline form G of mefuroperate hydrochloride has an X-ray powder diffraction pattern substantially as shown in FIG. 16.
  • the crystalline form G also has one or more characteristics selected from the group consisting of:
  • the crystal form G has a DSC spectrum substantially as shown in FIG. 17;
  • the crystal form G has an infrared spectrum substantially as shown in FIG. 18;
  • the crystal form G has a TG spectrum substantially as shown in FIG. 19;
  • the crystal form G has a Raman spectrum substantially as shown in FIG. 20.
  • the second aspect of the present invention provides a method for preparing the polymorph of mefuroperate hydrochloride according to the first aspect of the present invention, which includes the steps of:
  • step i) The acetic acid solution containing mefuroperate hydrochloride in step i) was slowly returned to room temperature, and allowed to stand to precipitate crystals;
  • the preparation method includes the steps of:
  • the preparation method includes the steps of:
  • the organic solvent is selected from one or more of the following group of organic solvents: ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, methyl tert-butyl ether, methylene chloride, etc. ;
  • the preparation method includes the steps of:
  • step i dropwise add tetrahydrofuran to the alcohol solution containing mefuroperate hydrochloride in step i), stir, let stand, and precipitate crystals;
  • the alcohol is selected from one or more of the following group of alcohols: methanol, ethanol, propanol, tert-butanol, butanol, octanol, pentanol, hexanol, heptanol, sunflower alcohol.
  • the mass-to-volume ratio of amorphous Mefuroperat Hydrochloride to Acetic Acid is 5:1-30:1 mg/mL; more preferably 10:1-20: 1mg/mL;
  • the mass-to-volume ratio of amorphous mesopiperide hydrochloride and 1,4-dioxane is 1:1-10:1 mg/mL; more preferably 1:1 ⁇ 2:1mg/mL;
  • the mass-to-volume ratio of amorphous mefuripere hydrochloride to dimethyl sulfoxide is 10:1 to 50:1 mg/mL; more preferably 20:1 ⁇ 30:1mg/mL;
  • the mass-to-volume ratio of amorphous mesopiperide hydrochloride to the organic solvent is 1:1 to 10:1 mg/mL; more preferably 3:1 to 5 : 1mg/mL;
  • the mass-to-volume ratio of amorphous mesopiperide hydrochloride to alcohol is 10:1-50:1 mg/mL; more preferably 20:1-30: 1mg/mL;
  • the mass-to-volume ratio of amorphous mesopiperide hydrochloride to tetrahydrofuran is 1:1-10:1 mg/mL; more preferably 1:1-5: 1mg/mL.
  • the third aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically effective dose of the polymorphic form of mefuroperate hydrochloride according to the first aspect of the present invention, and a pharmaceutically acceptable Excipient or carrier.
  • the fourth aspect of the present invention provides the use of the polymorph of mefuroperate hydrochloride according to the first aspect of the present invention or the composition according to the third aspect of the present invention for the preparation of treatment and/or Or drugs to prevent diseases associated with polyadenylation ribose polymerase PARP.
  • the diseases include: tumor, inflammation, cardiovascular disease, diabetes, rheumatoid arthritis, endotoxic shock and stroke.
  • the tumors include: BRCA1 or BRCA2 deleted or mutated tumors.
  • the tumors include: ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, cervical cancer, glioma and Ewing's sarcoma.
  • the drugs include anti-tumor drugs and/or anti-inflammatory drugs.
  • FIG. 1 is an X-ray powder diffraction (XRPD) diagram of crystalline form D of mefuroperate hydrochloride
  • Figure 2 is the DSC spectrum of Mefuripre hydrochloride Form D
  • Figure 3 is an infrared (IR) spectrum of Mefuripre hydrochloride Form D;
  • Figure 4 is the TG spectrum of Mefuripre hydrochloride Form D
  • FIG. 5 is a Raman spectrum of crystal form D of mefuroperate hydrochloride
  • FIG. 6 is an X-ray powder diffraction (XRPD) diagram of crystalline form E of mefuroperate hydrochloride
  • FIG. 7 is a DSC spectrum of Mefuripre hydrochloride Form E
  • FIG. 8 is an infrared (IR) spectrum diagram of crystalline form E of mefuroperate hydrochloride
  • FIG. 9 is a TG spectrum of Mefuripre hydrochloride Form E.
  • Fig. 10 is a Raman spectrum of crystal form E of mefuroperate hydrochloride
  • FIG. 11 is an X-ray powder diffraction (XRPD) diagram of Mefuroperide Hydrochloride Form F;
  • FIG. 12 is a DSC spectrum of Mefuripre hydrochloride Form F
  • FIG. 13 is an infrared (IR) spectrum diagram of crystal form F of mefuroperate hydrochloride
  • Fig. 14 is a TG spectrum of Mefuripre hydrochloride Form F
  • FIG. 15 is a Raman spectrum of crystal form F of mefuroperate hydrochloride
  • FIG. 16 is an X-ray powder diffraction (XRPD) diagram of crystalline form G of mefuroperate hydrochloride
  • FIG. 17 is a DSC spectrum of Mefuripre hydrochloride Form G
  • FIG. 18 is an infrared (IR) spectrum of Mefuripre hydrochloride Form G
  • FIG. 19 is a TG spectrum of Mefuriperil Hydrochloride Form G
  • FIG. 20 is a Raman spectrum of Mefuripre hydrochloride Form G
  • Fig. 21 is an X-ray powder diffraction (XRPD) diagram of amorphous mefuroperate hydrochloride left at 25°C for 15 days.
  • XRPD X-ray powder diffraction
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “about” means that the enumerated value varies by no more than 0.2°, for example, about X°, it means X ⁇ 0.2°, preferably X ⁇ 0.1°.
  • the terms "containing” or “including (including)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the term "pharmaceutically acceptable” ingredient refers to a substance that is suitable for humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergies), that is, with a reasonable benefit/risk ratio.
  • the term "effective amount" refers to an amount of a therapeutic agent to treat, alleviate or prevent a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect.
  • the precise effective amount for a subject depends on the subject's body type and health condition, the nature and degree of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount, which the clinician can judge.
  • the solution can be manipulated so that the solubility limit of the compound of interest is exceeded, thereby completing production-scale crystallization. This can be accomplished by various methods, for example, dissolving the compound at a relatively high temperature, and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying or some other method to reduce the liquid volume.
  • the solubility of the compound of interest can be reduced by adding an antisolvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility.
  • crystallization please see Crystallization, Third Edition, J Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • optimization of crystallization may include seeding the crystallization medium with crystals of the desired form as seed crystals.
  • many crystallization methods use a combination of the above strategies.
  • One example is to dissolve the compound of interest in a solvent at high temperature, and then add an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this time, the seed crystal in the desired form can be added (and the integrity of the seed crystal is maintained), and the system is cooled to complete the crystallization.
  • the polymorphic form of mefuroperide hydrochloride of the present invention includes four crystal forms: namely, D form, E form, F form, and G form.
  • the powder X-ray diffraction pattern of the D crystal form of mefuroperide hydrochloride of the present invention is about 5.354, 6.466, 10.298, 12.101, 12.947, 14.286, 15.232, 15.950, 17.859, 19.642, 20.705, 22.209, There are obvious characteristic absorption peaks at 24.379, 25.097, 26.059, 26.982, 31.999 and 37.248.
  • the X-ray powder diffraction spectrum of the crystalline form D of mefuroperate hydrochloride is basically consistent with FIG. 1; the DSC spectrum, infrared spectrum, TG spectrum and Raman spectrum are basically the same as those of FIGS. 4 and 5 are the same.
  • the crystal form D has a characteristic endothermic peak in the range of about 280-300°C.
  • the infrared spectrum of the crystalline form D is at least 3487cm -1 , 3182cm -1 , 2923cm -1 , 2706cm -1 , 2432cm -1 , 1666cm -1 , 1604cm -1 , 1468cm -1 , There are characteristic peaks at 1434cm -1 , 1273cm -1 , 1192cm -1 , 1115cm -1 , 1018cm -1 , 891cm -1 , 838cm -1 , 779cm -1 and 513cm -1 with an error range of ⁇ 2cm -1 .
  • the powder X-ray diffraction spectrum of the crystalline form of mefuripre hydrochloride of the present invention is about 6.49, 12.625, 15.271, 20.727, 22.933°, 23.913, 25.139, 25.618, 26.082, 27.084, 27.406 and 28.828 . There are obvious characteristic absorption peaks.
  • the X-ray powder diffraction spectrum of the E crystalline form of mefuroperate hydrochloride is basically consistent with FIG. 6; the DSC spectrum, infrared spectrum, TG spectrum and Raman spectrum are basically the same as those of FIGS. 9 and 10 are the same.
  • the crystal form E has a characteristic endothermic peak in the range of about 280-300°C.
  • the infrared spectrum of the crystalline form E is at least 3480cm -1 , 3168cm -1 , 2957cm -1 , 2708cm -1 , 2475cm -1 , 1670cm -1 , 1613cm -1 , 1592cm -1 , There are characteristic peaks at 1467cm -1 , 1431cm -1 , 1377cm -1 , 1338cm -1 , 1199cm -1 , 1115cm -1 , 948cm -1 , 869cm -1 and 470cm -1 with an error range of ⁇ 2cm -1 .
  • the powder X-ray diffraction spectrum of the mesopiperide hydrochloride Form F of the present invention is about 6.266, 12.686, 15.532, 17.035, 17.675, 20.045, 20.727, 22.449, 23.114, 24.897, 25.536, 26.242, There are obvious characteristic absorption peaks at 27.166, 31.352 and 32.033.
  • the X-ray powder diffraction spectrum of the crystalline form of mefuroperate hydrochloride is basically consistent with FIG. 11; the DSC spectrum, infrared spectrum, TG spectrum and Raman spectrum are basically the same as those of FIGS. 14 and 15 are the same.
  • the crystal form F has a characteristic endothermic peak in the range of about 280-300°C.
  • the infrared spectrum of the crystalline form F is at least 3389cm -1 , 3168cm -1 , 2987cm -1 , 2741cm -1 , 2463cm -1 , 1662cm -1 , 1610cm -1 , 1596cm -1 , 1468cm -1, 1434cm -1, 1419cm -1 , 1385cm -1, 1345cm -1, 1205cm -1, 1183cm -1, 1116cm -1, 1015cm -1, 947cm -1, 833cm -1, 780cm -1 , and 558cm - One has a characteristic peak, and the error range is ⁇ 2cm -1 .
  • the powder X-ray diffraction spectrum of the mesopiperide hydrochloride G form of the present invention is about 6.428, 8.374, 10.281, 12.566, 15.231, 15.794, 18.043, 19.405, 20.667, 22.912, 23.874, 25.087, diffraction angle (2 ⁇ )
  • the X-ray powder diffraction spectrum of the crystalline form of mefuroperate hydrochloride is basically consistent with FIG. 16; the DSC spectrum, infrared spectrum, TG spectrum and Raman spectrum are basically the same as those of FIGS. 17, 18, 19 and 20 are the same.
  • the crystalline form G has a characteristic endothermic peak in the range of about 280-300°C.
  • the infrared spectrum of the Form G is at least 3486cm -1, 3171cm -1, 2923cm -1 , 2709cm -1, 2475cm -1, 1665cm -1, 1608cm -1, 1591cm -1, 1508,1468cm -1, 1429cm -1, 1377cm -1 , 1338cm -1, 1190cm -1, 1173cm -1, 1115cm -1, 1018cm -1, 947cm -1, 838cm -1, 779cm -1 and at 470cm -1 With characteristic peak, the error range is ⁇ 2cm -1 .
  • the invention also provides the preparation methods of the above four crystals of mefuroperate hydrochloride D, E, F and G, the specific steps are as follows.
  • the organic solvent that is highly insoluble in the raw materials is selected from ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, methyl tert-butyl ether, and dichloromethane.
  • it is ethyl acetate ester.
  • the alcohol is selected from the group consisting of methanol, ethanol, propanol, tert-butanol, butanol, octanol, amyl alcohol, hexanol, heptanol and sunflower alcohol.
  • the pharmaceutical composition of the present invention contains polymorphs of mefuroperate hydrochloride in a safe and effective amount, ie, form D, form E, form F or form G, and pharmacologically acceptable salts and pharmacology Acceptable excipients or carriers.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components of the composition can be blended with the polymorph of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the polymorph of the present invention is usually mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example,
  • the excipients include one or more of fillers, disintegrants, binders, and lubricants.
  • the filler is any one or a mixture of several types including starch, lactose, microcrystalline cellulose, dextrin, mannitol, oxidase, and calcium sulfate.
  • the disintegrant includes carboxymethyl cellulose and its salts, croscarmellose and its salts, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose in Any one or more of them.
  • the binder includes any one or more of povidone, hydroxypropyl methyl cellulose, starch slurry, and pregelatinized starch.
  • the lubricant includes any one or more of sodium stearate fumarate, magnesium stearate, and calcium stearate.
  • the polymorphic form of mefuroperate hydrochloride of the present invention is used to prepare a medicament for preventing and/or treating diseases associated with polyadenosine diphosphate ribose polymerase PARP; it can also be used for preparing a medicament for preventing and/or treating tumors; It can also be used to prepare anti-inflammatory drugs.
  • Diseases associated with polyadenylated ribose polymerase PARP include tumors, inflammation, and ischemia-reperfusion-associated diseases such as cardiovascular disease, diabetes, rheumatoid arthritis, endotoxic shock, stroke, etc.
  • the tumor is a homologous recombination repair defect tumor, that is, a tumor with BRCA1 or BRCA2 deletion or mutation, such as ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, cervical cancer, glioma, Ewing's sarcoma, etc.
  • the present invention provides different crystalline forms of mefuroperate hydrochloride, which can be converted into four crystalline forms of D, E, F, and G in different solvent ratio crystalline forms.
  • the preparation methods of these four polymorphs are simple, the product crystal form has high purity, good stability and easy storage.
  • the preparation method of the four polymorphs of the present invention has a simple preparation process, is easy to operate, and has good process repeatability, and the obtained product has high crystal form purity.
  • the Nicolot-Magna FT-IR750 infrared spectrometer of the American company Nicholi is used to detect at room temperature, and the detection range is a wave number of 4000-350 cm -1 .
  • amorphous mefuroperate hydrochloride (see WO2013117120) was added to 80°C acetic acid (2 mL) until the raw material was completely dissolved, filtered while hot, and then slowly left to cool to room temperature. After filtration, the filter cake was vacuum dried at room temperature to constant weight to obtain Form D.
  • the obtained crystal form is D of mefuroperide hydrochloride-the specific peak position is shown in Table 1, see Figure 1.
  • Example 4 The difference from Example 4 is that the slowly added solvent was replaced with acetone.
  • the X-ray powder diffraction data results are shown in Table 3.
  • Example 4 The difference from Example 4 is that the slowly added solvent was replaced with methyl tert-butyl ether.
  • the X-ray powder diffraction data results are shown in Table 3.
  • Table 4 X-ray powder diffraction (XRPD) data of crystalline form M of mepoperide hydrochloride
  • the obtained samples were subjected to other tests, and the obtained DSC spectrum, infrared spectrum, TG spectrum, and Raman spectrum were basically in accordance with Figs. 17, 18, 19, and 20.
  • Amorphous mefoperazone hydrochloride, the crystalline form D obtained in Example 1, the crystalline form E obtained in Example 2, the crystalline form F obtained in Example 3, and the crystalline form G obtained in Example 7 were each taken at 50 mg. After 15 days at °C, the solid state of each group of samples was measured. From XRPD, it can be found that the diffraction peaks of crystal forms D, E, F and G are basically unchanged, and can be stored stably. The amorphous state is unstable, and crystallization occurs. XRPD ( Figure 21) shows a distinct diffraction peak.

Abstract

提供了盐酸美呋哌瑞多晶型物及其制备方法与应用。具体地，提供了2-[4-(甲胺基甲基)苯基]-5-氟-苯并呋喃-7-甲酰胺盐酸盐(式I)的D、E、F和G四种晶型及其制备方法和在制备药物中的用途。

Description

盐酸美呋哌瑞多晶型物及其制备方法 技术领域
本发明具体地涉及盐酸美呋哌瑞即2-[4-(甲胺基甲基)苯基]-5-氟-苯并呋喃-7-甲酰胺盐酸盐的多晶型体、及多晶型体盐酸美呋哌瑞的制备方法及其在制备药物中的用途，属于药物化学范畴。
背景技术
一种化合物的不同的晶型可能具有不同的性能，例如溶解度、溶解速率、悬浮稳定性、研磨期间的稳定性、蒸汽压力、光学和机械性能、吸湿性、晶型尺寸、过滤性能、干燥、密度、熔点、降解稳定性、防止相变为其它晶型的稳定性、颜色甚至化学反应性等等。更为重要的是，小分子化合物药物的晶型不同，可能导致它的溶解、溶出性能、药物动力学和生物利用度发生改变，进而影响药物的疗效和安全性能，所以在小分子药物研发过程中应全面考虑它的多晶型问题。因此晶型研究和控制成为小分子药物研发过程中的一项重要研究内容之一。
在WO2013117120中公开了具有药学价值的PARP选择性抑制剂，其中具体描述该系列抑制剂的一个实例(参见第37页实施例21)为2-[4-(甲胺基甲基)苯基]-5-氟-苯并呋喃-7-甲酰胺盐酸盐(以下称为盐酸美呋哌瑞)，其结构如式Ⅰ：
Figure PCTCN2019124968-appb-000001
通过WO2013117120中所述公开方法获得该化合物的表征是通过 1HMR分析和/或测量熔点来进行。在现有技术中，不同结晶形式的盐酸美呋哌瑞的观察还未描述，至于特定晶型的任何表征以及用于获得特定晶型的制备方法也没有描述。不同盐酸美呋哌瑞的晶型，可能导致它的溶解、溶出性能、药物动力学和生物利用度发生改变，进而影响药物的疗效和安全性能。因此，对于大规模制备盐酸美呋哌瑞，了解是否存在此化合物的不同晶型(也经常称为多晶型物，或在溶剂包夹的情况下为假多晶型物)，如何获得它们，及其特征性能如何至关重要。
发明内容
针对以上背景，本发明公开了盐酸美呋哌瑞多种晶型、表征及制备方法及其用途。所以本发明所要解决的技术问题是提供盐酸美呋哌瑞的多晶体型，为盐酸美呋哌瑞进一步深入开发提供技术保障。
本发明的第一方面提供了一种如式I所示的盐酸美呋哌瑞的多晶型物。
Figure PCTCN2019124968-appb-000002
在另一优选例中，所述的多晶型物为盐酸美呋哌瑞晶型D，是盐酸美呋哌瑞的乙酸合物，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：5.354±0.1°、6.466±0.1°、10.298±0.1°、12.101±0.1°、12.947±0.1°、14.286±0.1°、15.232±0.1°、15.950±0.1°、17.859±0.1°、19.642±0.1°、20.705±0.1°22.209±0.1°、24.379±0.1°、25.097±0.1°、26.059±0.1°、26.982±0.1°、31.999±0.1°和37.248±0.1°。
优选地，所述盐酸美呋哌瑞晶型D的DSC谱图在约280-300℃区间内有特征吸热峰；
优选地，所述盐酸美呋哌瑞晶型D的红外光谱至少在3487cm -1、3182cm -1、2923cm -1、2706cm -1、2432cm -1、1666cm -1、1604cm -1、1468cm -1、1434cm -1、1273cm -1、1192cm -1、1115cm -1、1018cm -1、891cm -1、838cm -1、779cm -1和513cm -1处具有特征峰，误差范围为±2cm -1。
进一步优选地，所述盐酸美呋哌瑞晶型D具有基本上如图1所示的X射线粉末衍射谱图；
在另一优选例中，所述晶型D还具有选自下组的一个或多个特征：
(1)所述晶型D具有基本上如图2所示的DSC谱图；
(2)所述晶型D具有基本上如图3所示的红外谱图；
(3)所述晶型D具有基本上如图4所示的TG谱图；和
(4)所述晶型D具有基本上如图5所示的拉曼谱图。
在另一优选例中，所述的多晶型物为盐酸美呋哌瑞晶型E，是盐酸美呋哌瑞的1， 4-二氧六环合物，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：6.49±0.1°、12.625±0.1°、15.271±0.1°、20.727±0.1°、22.933±0.1°、23.913±0.1°、25.139±0.1°、25.618±0.1°、26.082±0.1°、27.084±0.1°、27.406±0.1°和28.828±0.1°。
优选地，所述盐酸美呋哌瑞晶型E的DSC谱图在约280-300℃区间内有特征吸热峰；
优选地，所述盐酸美呋哌瑞晶型E的红外光谱至少在3480cm -1、3168cm -1、2957cm -1、2708cm -1、2475cm -1、1670cm -1、1613cm -1、1592cm -1、1467cm -1、1431cm -1、1377cm -1、1338cm -1、1199cm -1、1115cm -1、948cm -1、869cm -1和470cm -1处具有特征峰，误差范围为±2cm -1。
进一步优选地，所述盐酸美呋哌瑞晶型E具有基本上如图6所示的X射线粉末衍射谱图；
在另一优选例中，所述晶型E还具有选自下组的一个或多个特征：
(1)所述晶型E具有基本上如图7所示的DSC谱图；
(2)所述晶型E具有基本上如图8所示的红外谱图；
(3)所述晶型E具有基本上如图9所示的TG谱图；和
(4)所述晶型E具有基本上如图10所示的拉曼谱图。
在另一优选例中，所述的多晶型物为盐酸美呋哌瑞晶型F，二甲基亚砜合物，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：6.266±0.1°、12.686±0.1°、15.532±0.1°、17.035±0.1°、17.675±0.1°、20.045±0.1°、20.727±0.1°、22.449±0.1°、23.114±0.1°、24.897±0.1°、25.536±0.1°、26.242±0.1°、27.166±0.1°、31.352±0.1°和32.033±0.1°。
优选地，所述盐酸美呋哌瑞晶型F的DSC谱图在约280-300℃区间内有特征吸热峰；
优选地，所述盐酸美呋哌瑞晶型F的红外光谱至少在3389cm -1、3168cm -1、2987cm -1、2741cm -1、2463cm -1、1662cm -1、1610cm -1、1596cm -1、1468cm -1、1434cm -1、1419cm -1、1385cm -1、1345cm -1、1205cm -1、1183cm -1、1116cm -1、1015cm -1、947cm -1、833cm -1、780cm -1和558cm -1处具有特征峰，误差范围为±2cm -1。
进一步优选地，所述盐酸美呋哌瑞晶型F具有基本上如图11所示的X射线粉末衍射谱图；
在另一优选例中，所述晶型F还具有选自下组的一个或多个特征：
(1)所述晶型F具有基本上如图12所示的DSC谱图；
(2)所述晶型F具有基本上如图13所示的红外谱图；
(3)所述晶型F具有基本上如图14所示的TG谱图；和
(4)所述晶型F具有基本上如图15所示的拉曼谱图。
在另一优选例中，所述的多晶型物为盐酸美呋哌瑞晶型G，其X粉末衍射谱图包括3个或3个以上选自下组的2θ值：6.428±0.1°、8.374±0.1°、10.281±0.1°、12.566±0.1°、15.231±0.1°、15.794±0.1°、18.043±0.1°、19.405±0.1°、20.667±0.1°、22.912±0.1°、23.874±0.1°25.087±0.1°、26.040±0.1°、29.849±0.1°和232.656±0.1°。
优选地，所述盐酸美呋哌瑞晶型G的DSC谱图在约280-300℃区间内有特征吸热峰。
优选地，所述盐酸美呋哌瑞晶型G的红外光谱至少在3486cm -1、3171cm -1、2923cm -1、2709cm -1、2475cm -1、1665cm -1、1608cm -1、1591cm -1、1508、1468cm -1、1429cm -1、1377cm -1、1338cm -1、1190cm -1、1173cm -1、1115cm -1、1018cm -1、947cm -1、838cm -1、779cm -1和470cm -1处具有特征峰，误差范围为±2cm -1。
进一步优选地，所述盐酸美呋哌瑞晶型G具有基本上如图16所示的X射线粉末衍射谱图。
在另一优选例中，所述晶型G还具有选自下组的一个或多个特征：
(1)所述晶型G具有基本上如图17所示的DSC谱图；
(2)所述晶型G具有基本上如图18所示的红外谱图；
(3)所述晶型G具有基本上如图19所示的TG谱图；和
(4)所述晶型G具有基本上如图20所示的拉曼谱图。
本发明的第二方面提供了一种如本发明第一方面所述的盐酸美呋哌瑞的多晶型物的制备方法，包括步骤：
(i)在80℃下，将无定形盐酸美呋哌瑞溶于乙酸中，从而形成含盐酸美呋哌瑞 的乙酸溶液；
(ii)将步骤i)的含盐酸美呋哌瑞的乙酸溶液缓慢恢复室温，静置，析出晶体；和
(iii)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型D；
或所述的制备方法包括步骤：
(a)在0℃～80℃下，将无定形盐酸美呋哌瑞溶于水体系中，从而形成含盐酸美呋哌瑞的水溶液；
(b)向步骤a)的含盐酸美呋哌瑞的水溶液缓慢的滴加1，4-二氧六环，室温搅拌，直至析出晶体；和
(c)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型E；
或所述的制备方法包括步骤：
(i)在0℃～80℃下，将无定形盐酸美呋哌瑞溶于二甲亚砜，从而形成含盐酸美呋哌瑞的二甲亚砜溶液；
(ii)向步骤i)的含盐酸美呋哌瑞的二甲亚砜溶液中滴加有机溶剂，搅拌，静置，析出晶体；和
(iii)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型F；
其中，所述的有机溶剂选自下组有机溶剂中的一种或多种：乙醇、丙酮、甲乙酮、乙腈、四氢呋喃、硝基甲烷、乙酸乙酯、甲基叔丁基醚和二氯甲烷等；
或所述的制备方法包括步骤：
(i)在0℃～80℃下，将无定形盐酸美呋哌瑞溶于醇，从而形成含盐酸美呋哌瑞的醇溶液；
(ii)向步骤i)的含盐酸美呋哌瑞的醇溶液中滴加四氢呋喃，搅拌，静置，析出晶体；和
(iii)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型G；
其中，所述的醇选自下组醇中的一种或多种：甲醇、乙醇、丙醇、叔丁醇、丁醇、辛醇、戊醇、己醇、庚醇、葵醇。
优选地，在盐酸美呋哌瑞晶型D的制备方法中，无定形盐酸美呋哌瑞与乙酸的质量体积比为5:1～30:1mg/mL；更优选为10:1～20:1mg/mL；
优选地，在盐酸美呋哌瑞晶型E的制备方法中，无定形盐酸美呋哌瑞与1，4-二氧六环的质量体积比为1:1～10:1mg/mL；更优选为1:1～2:1mg/mL；
优选地，在盐酸美呋哌瑞晶型F的制备方法中，无定形盐酸美呋哌瑞与二甲亚砜的质量体积比为10:1～50:1mg/mL；更优选为20:1～30:1mg/mL；
优选地，在盐酸美呋哌瑞晶型F的制备方法中，无定形盐酸美呋哌瑞与有机溶剂的质量体积比为1:1～10:1mg/mL；更优选为3:1～5:1mg/mL；
优选地，在盐酸美呋哌瑞晶型G的制备方法中，无定形盐酸美呋哌瑞与醇的质量体积比为10:1～50:1mg/mL；更优选为20:1～30:1mg/mL；
优选地，在盐酸美呋哌瑞晶型G的制备方法中，无定形盐酸美呋哌瑞与四氢呋喃的质量体积比为1:1～10:1mg/mL；更优选为1:1～5:1mg/mL。
本发明的第三方面提供了一种药物组合物，所述组合物包含药物有效剂量的如本发明第一方面所述的盐酸美呋哌瑞的多晶型物，及其药学上可接受的赋形剂或载体。
本发明的第四方面提供了一种如本发明第一方面所述的盐酸美呋哌瑞的多晶型物或如本发明第三方面所述的组合物的用途，用于制备治疗和/或预防与聚腺苷二磷酸核糖聚合酶PARP相关疾病的药物。
在另一优选例中，所述的疾病包括：肿瘤、炎症、心血管疾病、糖尿病、风湿性关节炎、内毒素性休克和中风。
在另一优选例中，所述的肿瘤包括：BRCA1或BRCA2缺失或突变的肿瘤。
在另一优选例中，所述的肿瘤包括：卵巢癌、乳腺癌、***癌、胃癌、胰腺癌、***、神经胶质瘤和尤文氏肉瘤。
在另一优选例中，所述的药物包括抗肿瘤药物和/或抗炎药物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为盐酸美呋哌瑞晶型D的X射线粉末衍射(XRPD)图；
图2为盐酸美呋哌瑞晶型D的DSC谱图；
图3为盐酸美呋哌瑞晶型D的红外(IR)光谱图；
图4为盐酸美呋哌瑞晶型D的TG谱图；
图5为盐酸美呋哌瑞晶型D的拉曼光(Raman)谱图；
图6为盐酸美呋哌瑞晶型E的X射线粉末衍射(XRPD)图；
图7为盐酸美呋哌瑞晶型E的DSC谱图；
图8为盐酸美呋哌瑞晶型E的红外(IR)光谱图；
图9为盐酸美呋哌瑞晶型E的TG谱图；
图10为盐酸美呋哌瑞晶型E的拉曼光(Raman)谱图；
图11为盐酸美呋哌瑞晶型F的X射线粉末衍射(XRPD)图；
图12为盐酸美呋哌瑞晶型F的DSC谱图；
图13为盐酸美呋哌瑞晶型F的红外(IR)光谱图；
图14为盐酸美呋哌瑞晶型F的TG谱图；
图15为盐酸美呋哌瑞晶型F的拉曼光(Raman)谱图；
图16为盐酸美呋哌瑞晶型G的X射线粉末衍射(XRPD)图；
图17为盐酸美呋哌瑞晶型G的DSC谱图；
图18为盐酸美呋哌瑞晶型G的红外(IR)光谱图；
图19为盐酸美呋哌瑞晶型G的TG谱图；
图20为盐酸美呋哌瑞晶型G的拉曼光(Raman)谱图；
图21为无定形盐酸美呋哌瑞25℃放置15天的X射线粉末衍射(XRPD)图。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了盐酸美呋哌瑞的四种新型多晶型物，且制备工艺简单高效，重复性好，可实现规模化工业生产。在此基础上，完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
对于用2θ角表示的特征衍射峰，术语“约”表示列举的值变动不多于0.2°， 例如约为X°，则表示X±0.2°，较佳地X±0.1°。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“室温”一般指4-30℃，较佳地指20±5℃。
如本文所用，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和***反应)，即有合理的效益/风险比的物质。
如本文所用，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断的。
结晶
可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入抗溶剂或化合物在其中具有低的溶解度的溶剂或这样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization,第三版,J W Mullens,Butterworth-Heineman Ltd.，1993,ISBN 0750611294。
假如期望盐的形成与结晶同时发生，如果盐在反应介质中比原料溶解度小，那么加入适当的酸或碱可导致所需盐的直接结晶。同样，在最终想要的形式比反应物溶解度小的介质中，合成反应的完成可使最终产物直接结晶。
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。
本发明的多晶型物
本发明的盐酸美呋哌瑞多晶型物包括四种晶型：即D晶型、E晶型、F晶型和G晶型。
D晶型
本发明的盐酸美呋哌瑞D晶型的粉末X射线衍射谱图在衍射角(2θ)约为5.354、6.466、10.298、12.101、12.947、14.286、15.232、15.950、17.859、19.642、20.705、22.209、24.379、25.097、26.059、26.982、31.999和37.248处有明显特征吸收峰。
所述D晶型盐酸美呋哌瑞的X射线粉末衍射谱图基本上与图1一致；所述DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图2、3、4和5一致。
从图2中可以看出，所述晶型D在约280-300℃区间内有特征吸热峰。
从图3中可以看出，所述晶型D的红外光谱至少在3487cm -1、3182cm -1、2923cm -1、2706cm -1、2432cm -1、1666cm -1、1604cm -1、1468cm -1、1434cm -1、1273cm -1、1192cm -1、1115cm -1、1018cm -1、891cm -1、838cm -1、779cm -1和513cm -1处具有特征峰，误差范围为±2cm -1。
从图4中可以分析得出：所述晶型D的热失重分析在280±20℃开始分解。
E晶型
本发明的盐酸美呋哌瑞E晶型的粉末X射线衍射谱图在衍射角(2θ)约为6.49、12.625、15.271、20.727、22.933°、23.913、25.139、25.618、26.082、27.084、27.406和28.828。处有明显特征吸收峰。
所述E晶型盐酸美呋哌瑞的X射线粉末衍射谱图基本上与图6一致；所述DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图7、8、9和10一致。
从图7中可以看出，所述晶型E在约280-300℃区间内有特征吸热峰。
从图8中可以看出，所述晶型E的红外光谱至少在3480cm -1、3168cm -1、2957cm -1、2708cm -1、2475cm -1、1670cm -1、1613cm -1、1592cm -1、1467cm -1、1431cm -1、1377cm -1、1338cm -1、1199cm -1、1115cm -1、948cm -1、869cm -1和470cm -1处具有特征峰，误差范围为±2cm -1。
从图9中可以分析得出：所述晶型A的热失重分析在280±20℃开始分解。
F晶型
本发明的盐酸美呋哌瑞F晶型的粉末X射线衍射谱图在衍射角(2θ)约为6.266、12.686、15.532、17.035、17.675、20.045、20.727、22.449、23.114、24.897、25.536、26.242、27.166、31.352和32.033处有明显特征吸收峰。
所述F晶型盐酸美呋哌瑞的X射线粉末衍射谱图基本上与图11一致；所述DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图12、13、14和15一致。
从图12中可以看出，所述晶型F在约280-300℃区间内有特征吸热峰。
从图13中可以看出，所述晶型F的红外光谱至少在3389cm -1、3168cm -1、2987cm -1、2741cm -1、2463cm -1、1662cm -1、1610cm -1、1596cm -1、1468cm -1、1434cm -1、1419cm -1、1385cm -1、1345cm -1、1205cm -1、1183cm -1、1116cm -1、1015cm -1、947cm -1、833cm -1、780cm -1和558cm -1处具有特征峰，误差范围为±2cm -1。
从图14中可以分析得出：所述晶型F的热失重分析在280±20℃开始分解。
G晶型
本发明的盐酸美呋哌瑞G晶型的粉末X射线衍射谱图在衍射角(2θ)约为6.428、8.374、10.281、12.566、15.231、15.794、18.043、19.405、20.667、22.912、23.874、25.087、26.040、29.849和232.656处有明显特征吸收峰。
所述G晶型盐酸美呋哌瑞的X射线粉末衍射谱图基本上与图16一致；所述DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图17、18、19和20一致。
从图17中可以看出，所述晶型G在约280-300℃区间内有特征吸热峰。
从图18中可以看出，所述晶型G的红外光谱至少在3486cm -1、3171cm -1、2923cm -1、2709cm -1、2475cm -1、1665cm -1、1608cm -1、1591cm -1、1508、1468cm -1、1429cm -1、1377cm -1、1338cm -1、1190cm -1、1173cm -1、1115cm -1、1018cm -1、947cm -1、838cm -1、779cm -1和470cm -1处具有特征峰，误差范围为±2cm -1。
从图19中可以分析得出：所述晶型G的热失重分析在250±20℃开始分解。
多晶型物的制备方法
本发明还提供了上述盐酸美呋哌瑞D、E、F和G四种晶体的制备方法，具体步骤如下。
盐酸美呋哌瑞D晶型的制备
将无定形盐酸美呋哌瑞溶于热的乙酸中，缓慢冷却至室温，静置，过滤溶液，固体部分在25℃下干燥，得到D晶型的盐酸美呋哌瑞。
盐酸美呋哌瑞E晶型的制备
将无定形盐酸美呋哌瑞溶于水中，缓慢滴加对原料高度不溶的有机溶剂1,4-二氧六环，搅拌，静置，过滤溶液，固体部分在25℃下干燥，得到E晶型的盐酸美呋哌瑞。
盐酸美呋哌瑞F晶型的制备
将无定形盐酸美呋哌瑞溶于二甲亚砜中，缓慢滴加对原料高度不溶的有机溶剂，搅拌，静置，过滤溶液，固体部分在25度下干燥，得到F晶型的盐酸美呋哌瑞。
其中所述的对原料高度不溶的有机溶剂选自乙醇、丙酮、甲乙酮、乙腈、四氢呋喃、硝基甲烷、乙酸乙酯、甲基叔丁基醚和二氯甲烷等，更佳地，为乙酸乙酯。
盐酸美呋哌瑞G晶型的制备
将无定形盐酸美呋哌瑞溶于醇中，缓慢滴加对原料高度不溶的有机溶剂四氢呋喃，搅拌，静置，过滤溶液，固体部分在25℃下干燥，得到G晶型的盐酸美呋哌瑞。
所述的醇选自下甲醇、乙醇、丙醇、叔丁醇、丁醇、辛醇、戊醇、己醇、庚醇、葵醇。
药物组合物
本发明的药物组合物包含安全有效量范围内的盐酸美呋哌瑞多晶型物，即晶型D、晶型E、晶型F或晶型G、以及其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的多晶型物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019124968-appb-000003
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的多晶型物通常与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、 明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
优选地，所述的赋形剂包括填充剂、崩解剂、粘合剂、润滑剂在内的其中一种或几种。
优选地，所述的填充剂为包括淀粉、乳糖、微晶纤维素、糊精、甘露醇、氧化酶、硫酸钙在内的任意一种或几种的混合物。
优选地，所述的崩解剂包括羧甲基纤维素及其盐、交联羧甲基纤维素及其盐、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素在内的任意一种或几种。
优选地，所述的粘合剂包括聚维酮、羟丙基甲基纤维素、淀粉浆、预胶化淀粉在内的任意一种或几种。
优选地，所述润滑剂包括硬脂富马酸钠、硬脂酸镁、硬脂酸钙在内的任意一种或几种。
应用
本发明的盐酸美呋哌瑞的多晶型物用于制备预防和/或治疗与聚腺苷二磷酸核糖聚合酶PARP相关疾病的药物；也可以用于制备预防和/或***的药物；还可以用于制备抗炎药物。
与聚腺苷二磷酸核糖聚合酶PARP相关疾病包括肿瘤、炎症以及局部缺血-再灌注并发的疾病如心血管疾病，糖尿病，风湿性关节炎，内毒素性休克，中风等。所述肿瘤为同源重组修复缺陷的肿瘤，即BRCA1或BRCA2缺失或突变的肿瘤，如卵巢癌、乳腺癌、***癌、胃癌、胰腺癌、***、神经胶质瘤、尤文氏肉瘤等。
本发明的主要优点包括：
与现有技术相比，本发明的主要优点在于：
1.本发明提供了不同晶型盐酸美呋哌瑞，在不同溶剂配比结晶形式下可以分别转为D、E、F、G四种晶型。这四种多晶型物的制法简便，产品晶型纯度 高、稳定性好、便于储存。
2.本发明的四种多晶型物的制备方法，制备工艺简单，易于操作，工艺重复性很好，得到的产品晶型纯度高。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实验条件：
1)XRPD方法
仪器型号：Bruker D8 advance，靶：Cu Kα(40kV，40mA)，样品到检测器距离为30cm，扫描范围为3°-40°(2 theta值)，扫描步径：0.1。需要说明的是，在粉末样品X射线衍射谱图中，由晶型化合物得到的衍射谱图特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径、混合物的相对含量和其它测试条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶体并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的位置而不是它们的相对强度。另外判断晶型是否一样是应注意保持整体观念，因为并不是一条衍射线代表一个物相，而是一套特定的“d-1/11”数据才代表某一物相。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的安全谱带，甚至一条谱带也可能对给定的晶体是特征性的。
2)DSC方法 仪器型号：Perkin Elmer DSC 8500，温度范围为50-320℃，扫描速率为10℃/min，氮气流速为50ml/min。
3)IR方法 采用美国尼高力公司的Nicolot-Magna FT-IR750红外光谱仪于室温检测，检测范围为4000-350厘米 -1的波数。
4)TGA方法 仪器型号：Netzsch TG 209F3，温度范围为30-400℃，扫描速率为10K/min，吹扫气流速为25mL/min，保护气流速为15mL/min。
5)Raman方法仪器型号：Thermo Scientific DXR，激光波长：780nm， 扫描范围：3500 to 50cm -1，分辨率：2cm -1。
6)DVS方法 仪器型号：SMS DVS Intrinsic，0～95％RH，温度：25℃。
实施例1
晶型D的制备方法：
取大约25mg无定形盐酸美呋哌瑞(见WO2013117120)，加入至80℃乙酸(2mL)中，直至原料完全溶解，趁热过滤，随后缓慢静置冷却至室温。过滤，滤饼在室温条件下真空干燥到恒重得到晶型D。
经X-射线粉末衍射测定，显示得到的晶型为D的盐酸美呋哌瑞--具体峰位如表1，参见图1。
表1:D晶型盐酸美呋哌瑞的X-射线粉末衍射(XRPD)数据
2θ角/° d/A 强度％
5.343 16.5262 100
6.466 13.6587 5.5
10.298 8.5832 1.4
10.661 8.2914 1
11.832 7.4734 1
12.101 7.308 1.9
12.585 7.028 1.9
12.947 6.832 2.3
14.286 6.1948 3.3
15.232 5.8119 20.7
15.95 5.5519 7.7
17.859 4.9626 3.4
18.097 4.8979 1.7
19.462 4.5574 3.1
19.722 4.4977 1.6
20.705 4.2864 4.8
21.43 4.143 1.3
22.209 3.9994 12.7
22.876 3.8842 1.7
23.855 3.727 0.9
24.379 3.6481 4.3
25.097 3.5454 3.3
25.576 3.48 1
26.059 3.4165 8.6
26.982 3.3017 2.6
27.382 3.2545 1.6
28.772 3.1003 1.1
29.465 3.0289 2.1
30.491 2.9293 1
31.701 2.8202 0.9
31.999 2.7946 5.8
33.681 2.6588 1.3
34.12 2.6256 1.2
34.601 2.5902 1.4
37.248 2.412 4
对得到的样品进行其它测试，得到的DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图2、3、4和5一致。
实施例2
晶型E的制备方法：
取大约25mg无定形盐酸美呋哌瑞，在25℃加入水(2mL)直至原料完全溶解，随后缓慢滴加1,4-二氧六环(18mL)。滴加完毕，在该温度下搅拌6h，过滤，滤饼在25℃真空干燥到恒重得到晶型E。
经X-射线粉末衍射测定，显示得到的晶型为E的盐酸美呋哌瑞--具体峰位如表2，参见图6。
表2:E晶型盐酸美呋哌瑞的X-射线粉末衍射(XRPD)数据
2θ角/° d/A 强度％
8.373 10.5518 100
13.529 6.5395 3.5
15.349 5.7679 1.5
15.854 5.5854 22.8
16.798 5.2736 14.6
17.917 4.9465 18
19.36 4.581 36.1
22.011 4.0349 2.5
22.955 3.8711 5.3
24.574 3.6195 21.1
25.065 3.5498 3
25.338 3.5121 9.5
27.705 3.2172 2.6
30.934 2.8884 2.1
32.096 2.7864 18.5
32.577 2.7463 5.8
33.161 2.6993 3.6
34.02 2.6331 9.9
34.601 2.5902 1.2
35.063 2.5571 2.4
37.213 2.4142 1.3
38.671 2.3264 1.2
39.293 2.291 1.7
对得到的样品进行其它测试，得到的DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图7、8、9和10一致。
实施例3
晶型F的制备方法：
取大约25mg无定形盐酸美呋哌瑞，在25℃加入二甲亚砜(1mL)直至原料 完全溶解，随后缓慢滴加乙酸乙酯(6mL)。滴加完毕，在该温度下搅拌12h，过滤，滤饼在50℃～55℃真空干燥到恒重得到晶型F。
经X-射线粉末衍射测定，显示得到的晶型为F的盐酸美呋哌瑞--具体峰位如表3，参见图11。
表3:F晶型盐酸美呋哌瑞的X-射线粉末衍射(XRPD)数据
2θ角/° d/A 强度％
6.266 14.0936 100
12.686 6.9721 5.9
15.532 5.7004 44.8
17.035 5.2008 12
17.675 5.0138 8.3
19.104 4.6419 4.3
20.045 4.426 16
20.727 4.2819 30.2
22.449 3.9571 21.7
23.114 3.8447 10.2
24.195 3.6753 3.5
24.897 3.5734 9.1
25.536 3.4853 6.5
26.242 3.3932 8.7
27.166 3.2798 12.7
28.405 3.1396 3.6
28.787 3.0987 6.4
29.164 3.0595 4.4
31.352 2.8508 25.2
32.033 2.7917 12.5
33.365 2.6833 2.9
34.073 2.6291 2.2
34.472 2.5996 2.4
34.903 2.5685 4.5
35.726 2.5111 3.2
38.51 2.3358 2.5
39.154 2.2989 3.1
对得到的样品进行其它测试，得到的DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图12、13、14和15一致。
实施例4
晶型F的制备方法：
取大约25mg无定形盐酸美呋哌瑞，在25℃加入二甲亚砜(1mL)直至原料完全溶解，随后缓慢滴加乙醇(6mL)。滴加完毕，在该温度下搅拌12h，过滤，滤饼在50℃～55℃真空干燥到恒重得到晶型F。其X-射线粉末衍射数据结果如表3所示。
实施例5
晶型F的制备方法：
与实施例4不同的是缓慢滴加的溶剂置换成丙酮。其X-射线粉末衍射数据结果如表3所示。
实施例6
晶型F的制备方法：
与实施例4不同的是缓慢滴加的溶剂置换成甲基叔丁基醚。其X-射线粉末衍射数据结果如表3所示。
实施例7
晶型G的制备方法：
取大约25mg无定形盐酸美呋哌瑞，在25℃加入甲醇(1mL)直至原料完全 溶解，随后缓慢滴加四氢呋喃(10mL)。滴加完毕，在该温度下搅拌12h，过滤，滤饼在25℃真空干燥到恒重得到晶型G。
经X-射线粉末衍射测定，显示得到的晶型为G的盐酸美呋哌瑞--具体峰位如表4，参见图16。
表4:G晶型盐酸美呋哌瑞的X-射线粉末衍射(XRPD)数据
2θ角/° d/A 强度％
6.428 13.7389 24.2
8.374 10.55 9.2
10.281 8.5973 6.4
12.566 7.0385 6.7
13.485 6.5607 2.4
15.231 5.8124 100
15.794 5.6065 23.6
17.241 5.1391 3.3
18.043 4.9124 10.1
18.802 4.7157 3.9
19.405 4.5706 11
20.088 4.4165 2.3
20.667 4.2943 20.3
21.408 4.1471 3
22.912 3.8782 7.5
23.874 3.7242 8.5
25.078 3.548 11.3
25.562 3.4819 4.6
26.04 3.419 26.5
27.024 3.2967 4.9
27.363 3.2567 8.4
27.797 3.2068 1.8
28.769 3.1006 4.6
29.266 3.049 2.7
29.849 2.9908 4.3
30.723 2.9077 2.9
32.656 2.7399 7.8
33.659 2.6605 4.7
36.592 2.4537 4.5
37.01 2.427 4.5
对得到的样品进行其它测试，得到的DSC谱图、红外谱图、TG谱图和拉曼谱图基本上与图17、18、19和20一致。
测试例 稳定性试验
将无定形盐酸美呋哌瑞、实施例1得到的晶型D、实施例2得到的晶型E、实施例3得到的晶型F、实施例7得到的晶型G分别取50mg，于25℃放置15天，测各组样品的固体状态，从XRPD可发现晶型D、E、F和G的衍射峰基本没有变化，能够稳定保存。而无定形则固态状态不稳定，发生了结晶的现象，XRPD(图21)显示具有明显的衍射峰。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种如式I所示的盐酸美呋哌瑞的多晶型物。
    Figure PCTCN2019124968-appb-100001
  2. 如权利要求1所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述的多晶型物为盐酸美呋哌瑞晶型D，是盐酸美呋哌瑞的乙酸合物，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：5.354±0.1°、6.466±0.1°、10.298±0.1°、12.101±0.1°、12.947±0.1°、14.286±0.1°、15.232±0.1°、15.950±0.1°、17.859±0.1°、19.642±0.1°、20.705±0.1°22.209±0.1°、24.379±0.1°、25.097±0.1°、26.059±0.1°、26.982±0.1°、31.999±0.1°和37.248±0.1°。
  3. 如权利要求2所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述晶型D还具有选自下组的一个或多个特征：
    (1)所述晶型D具有基本上如图2所示的DSC谱图；
    (2)所述晶型D具有基本上如图3所示的红外谱图；
    (3)所述晶型D具有基本上如图4所示的TG谱图；和
    (4)所述晶型D具有基本上如图5所示的拉曼谱图。
  4. 如权利要求1所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述的多晶型物为盐酸美呋哌瑞晶型E，是盐酸美呋哌瑞的1.4-二氧六环合物，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：6.49±0.1°、12.625±0.1°、15.271±0.1°、20.727±0.1°、22.933±0.1°、23.913±0.1°、25.139±0.1°、25.618±0.1°、26.082±0.1°、27.084±0.1°、27.406±0.1°和28.828±0.1°。
  5. 如权利要求4所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述晶型E还具有选自下组的一个或多个特征：
    (1)所述晶型E具有基本上如图7所示的DSC谱图；
    (2)所述晶型E具有基本上如图8所示的红外谱图；
    (3)所述晶型E具有基本上如图9所示的TG谱图；和
    (4)所述晶型E具有基本上如图10所示的拉曼谱图。
  6. 如权利要求1所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述的多晶 型物为盐酸美呋哌瑞晶型F，二甲基亚砜合物，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：6.266±0.1°、12.686±0.1°、15.532±0.1°、17.035±0.1°、17.675±0.1°、20.045±0.1°、20.727±0.1°、22.449±0.1°、23.114±0.1°、24.897±0.1°、25.536±0.1°、26.242±0.1°、27.166±0.1°、31.352±0.1°和32.033±0.1°。
  7. 如权利要求6所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述晶型F还具有选自下组的一个或多个特征：
    (1)所述晶型F具有基本上如图12所示的DSC谱图；
    (2)所述晶型F具有基本上如图13所示的红外谱图；
    (3)所述晶型F具有基本上如图14所示的TG谱图；和
    (4)所述晶型F具有基本上如图15所示的拉曼谱图。
  8. 如权利要求1所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述的多晶型物为盐酸美呋哌瑞晶型G，其X射线粉末衍射谱图包括3个或3个以上选自下组的2θ值：6.428±0.1°、8.374±0.1°、10.281±0.1°、12.566±0.1°、15.231±0.1°、15.794±0.1°、18.043±0.1°、19.405±0.1°、20.667±0.1°、22.912±0.1°、23.874±0.1°25.087±0.1°、26.040±0.1°、29.849±0.1°和232.656±0.1°。
  9. 如权利要求8所述的盐酸美呋哌瑞的多晶型物，其特征在于，所述晶型G还具有选自下组的一个或多个特征：
    (1)所述晶型G具有基本上如图17所示的DSC谱图；
    (2)所述晶型G具有基本上如图18所示的红外谱图；
    (3)所述晶型G具有基本上如图19所示的TG谱图；和
    (4)所述晶型G具有基本上如图20所示的拉曼谱图。
  10. 一种如权利要求1中所述的盐酸美呋哌瑞的多晶型物的制备方法，其特征在于，包括步骤：
    (i)在0～80℃下，将无定形盐酸美呋哌瑞溶于乙酸中，从而形成含盐酸美呋哌瑞的乙酸溶液；
    (ii)将步骤i)的含盐酸美呋哌瑞的乙酸溶液缓慢恢复室温，静置，析出晶体；和
    (iii)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型D；
    或所述的制备方法包括步骤：
    (a)在0℃～80℃下，将无定形盐酸美呋哌瑞溶于水体系中，从而形成含盐酸美 呋哌瑞的水溶液；
    (b)向步骤a)的含盐酸美呋哌瑞的水溶液缓慢的滴加1，4-二氧六环，室温搅拌，直至析出晶体；和
    (c)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型E；
    或所述的制备方法包括步骤：
    (i)在0℃～80℃下，将无定形盐酸美呋哌瑞溶于二甲亚砜，从而形成含盐酸美呋哌瑞的二甲亚砜溶液；
    (ii)向步骤i)的含盐酸美呋哌瑞的二甲亚砜溶液中滴加有机溶剂，搅拌，静置，析出晶体；和
    (iii)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型F；
    其中，所述的有机溶剂选自下组有机溶剂中的一种或多种：乙醇、丙酮、甲乙酮、乙腈、四氢呋喃、硝基甲烷、乙酸乙酯、甲基叔丁基醚和二氯甲烷；
    或所述的制备方法包括步骤：
    (a)在0℃～80℃下，将无定形盐酸美呋哌瑞溶于醇，从而形成含盐酸美呋哌瑞的醇溶液；
    (b)向步骤a)的含盐酸美呋哌瑞的醇溶液中滴加四氢呋喃，搅拌，静置，析出晶体；和
    (c)分离并干燥析出的晶体，从而得到盐酸美呋哌瑞晶型G；
    其中，所述的醇选自下组醇中的一种或多种：甲醇、乙醇、丙醇、叔丁醇、丁醇、辛醇、戊醇、己醇、庚醇、葵醇。
  11. 一种药物组合物，其特征在于，所述组合物包含药物有效剂量的如权利要求1～9中任意一项所述的盐酸美呋哌瑞的多晶型物，及其药学上可接受的赋形剂或载体。
  12. 一种如权利要求1～9中任一项所述的盐酸美呋哌瑞的多晶型物或如权利要求11中所述的组合物的用途，其特征在于，用于制备治疗和/或预防与聚腺苷二磷酸核糖聚合酶PARP相关疾病的药物。
PCT/CN2019/124968 2018-12-14 2019-12-13 盐酸美呋哌瑞多晶型物及其制备方法 WO2020119772A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811536377.3 2018-12-14
CN201811536377.3A CN111320596A (zh) 2018-12-14 2018-12-14 盐酸美呋哌瑞多晶型物及其制备方法

Publications (1)

Publication Number Publication Date
WO2020119772A1 true WO2020119772A1 (zh) 2020-06-18

Family

ID=71076257

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/124968 WO2020119772A1 (zh) 2018-12-14 2019-12-13 盐酸美呋哌瑞多晶型物及其制备方法

Country Status (2)

Country Link
CN (1) CN111320596A (zh)
WO (1) WO2020119772A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174237B2 (en) * 2017-06-14 2021-11-16 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 2-[4-(meihylaminomethyl)phenyl]-5-fluoro- benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627620A (zh) * 2012-04-10 2012-08-08 江苏先声药物研究有限公司 一类苯并呋喃衍生物及其医药应用
CN103242273A (zh) * 2012-02-09 2013-08-14 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
WO2018228205A1 (zh) * 2017-06-14 2018-12-20 中国科学院上海药物研究所 盐酸美呋哌瑞多晶型物及其制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103242273A (zh) * 2012-02-09 2013-08-14 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
CN102627620A (zh) * 2012-04-10 2012-08-08 江苏先声药物研究有限公司 一类苯并呋喃衍生物及其医药应用
WO2018228205A1 (zh) * 2017-06-14 2018-12-20 中国科学院上海药物研究所 盐酸美呋哌瑞多晶型物及其制备方法与应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174237B2 (en) * 2017-06-14 2021-11-16 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 2-[4-(meihylaminomethyl)phenyl]-5-fluoro- benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof

Also Published As

Publication number Publication date
CN111320596A (zh) 2020-06-23

Similar Documents

Publication Publication Date Title
US20230183235A1 (en) Solid state forms of amg-510 and process for preparation thereof
EP1908756A1 (en) Processes for preparation of crystalline mycophenolate sodium
WO2011095059A1 (zh) 达沙替尼多晶型物及其制备方法和药物组合物
US7759481B2 (en) Solid state forms of 5-azacytidine and processes for preparation thereof
JP2022060192A (ja) 塩酸メフパリブの多形体およびその製造方法と使用
TW201638090A (zh) 一種週期素依賴性蛋白激酶抑制劑的結晶形式及其製備方法
WO2011023146A1 (en) Imatinib mesylate polymorphs generated by crystallization in aqueous inorganic salt solutions
WO2020119772A1 (zh) 盐酸美呋哌瑞多晶型物及其制备方法
US20040235904A1 (en) Crystalline and amorphous solids of pantoprazole and processes for their preparation
WO2023064519A1 (en) Solid state forms of elacestrant and processes for preparation thereof
WO2015037010A1 (en) Preparation of vilazodone hydrochloride crystalline form iv
US20060270684A1 (en) Crystalline forms of ziprasidone mesylate
AU2020240301A1 (en) Crystalline and amorphous forms of N-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof
RU2783418C1 (ru) Способ получения полиморфа гидрохлорида 2-[4-(метиламинометил)фенил]-5-фтор-бензофуран-7-карбоксамида
RU2783418C9 (ru) Способ получения полиморфа гидрохлорида 2-[4-(метиламинометил)фенил]-5-фтор-бензофуран-7-карбоксамида
EP1907379A1 (en) Crystalline forms of (2r-trans)-6-chloro-5ýý4-ý(4-fluorophenyl)methyl¨-2,5-dimethyl-1-piperazinyl¨carbonyl¨-n,n, 1-trimethyl-alpha-oxo-1h-indole-3-acetamide monohydrochloride
JP2015522591A (ja) 重水素化ω―ジメチル尿素又はその塩の多形物
CN110964017A (zh) 瑞博西尼单琥珀酸盐的多晶型物及其制备方法和用途
WO2022253261A1 (zh) Lazertinib甲磺酸盐的水合物晶型及其制备方法和用途
JP2018518515A (ja) フェニルアミノピリミジン化合物またはその塩の多形物
WO2024069574A1 (en) Solid state forms of denifanstat
EP1768969B1 (en) Crystalline mycophenolate sodium
TW202321215A (zh) Aurora a 選擇性抑制劑的多晶型及其用途
WO2022197884A1 (en) Solid state forms of zandelisib and salts thereof
CN115974878A (zh) 抗肿瘤药物的盐及其晶型

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19896083

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19896083

Country of ref document: EP

Kind code of ref document: A1