WO2020119772A1 - Substance de chlorhydrate de mefuparib polymorphe et procédé de préparation correspondant - Google Patents

Substance de chlorhydrate de mefuparib polymorphe et procédé de préparation correspondant Download PDF

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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
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hydrochloride
mefuroperate
crystal form
spectrum substantially
spectrum
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PCT/CN2019/124968
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Chinese (zh)
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沈孝坤
杨春皓
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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
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Publication of WO2020119772A1 publication Critical patent/WO2020119772A1/fr

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    • 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.

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Abstract

L'invention concerne une substance de chlorhydrate de mefuparib polymorphe, un procédé de préparation correspondant et une utilisation associée. Plus particulièrement, l'invention concerne quatre formes cristallines, c'est-à-dire D, E, F et G, de 2-[4-(méthylaminométhyl))phényl]-5-fluor-benzofuran-7-formamide (formule I), son procédé de préparation et son utilisation dans la préparation de médicaments.
PCT/CN2019/124968 2018-12-14 2019-12-13 Substance de chlorhydrate de mefuparib polymorphe et procédé de préparation correspondant WO2020119772A1 (fr)

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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 (fr) * 2017-06-14 2018-12-20 中国科学院上海药物研究所 Polymorphe de chlorhydrate de 2-[4-(méthylaminométhyl)phényl]-5-fluoro-benzofuran-7-carboxamide, son procédé de préparation et son application

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 (fr) * 2017-06-14 2018-12-20 中国科学院上海药物研究所 Polymorphe de chlorhydrate de 2-[4-(méthylaminométhyl)phényl]-5-fluoro-benzofuran-7-carboxamide, son procédé de préparation et son application

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

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