WO2018228205A1 - 盐酸美呋哌瑞多晶型物及其制备方法与应用 - Google Patents

盐酸美呋哌瑞多晶型物及其制备方法与应用 Download PDF

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WO2018228205A1
WO2018228205A1 PCT/CN2018/089222 CN2018089222W WO2018228205A1 WO 2018228205 A1 WO2018228205 A1 WO 2018228205A1 CN 2018089222 W CN2018089222 W CN 2018089222W WO 2018228205 A1 WO2018228205 A1 WO 2018228205A1
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hydrochloride
polymorph
water
alcohol
group
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PCT/CN2018/089222
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English (en)
French (fr)
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杨春皓
缪泽鸿
谭村
宦霞娟
丁健
陈奕
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中国科学院上海药物研究所
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Priority to SG11201912281PA priority Critical patent/SG11201912281PA/en
Priority to CA3067336A priority patent/CA3067336C/en
Priority to KR1020207000951A priority patent/KR102458566B1/ko
Priority to AU2018286057A priority patent/AU2018286057B2/en
Priority to US16/623,297 priority patent/US11174237B2/en
Priority to JP2020519169A priority patent/JP7432503B2/ja
Priority to EP18818471.7A priority patent/EP3643708A4/en
Publication of WO2018228205A1 publication Critical patent/WO2018228205A1/zh
Priority to ZA2020/00224A priority patent/ZA202000224B/en
Priority to JP2021194722A priority patent/JP2022060192A/ja

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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
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 a polymorph of mefenopril hydrochloride, i.e., 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride, and
  • the preparation method of the crystalline form of melibexole hydrochloride and its use in preparing medicine 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 milling, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration performance, drying, Density, melting point, degradation stability, stability against phase change to other crystal forms, color, and even chemical reactivity.
  • the small crystal compound drug has different crystal forms, which may cause its dissolution, dissolution properties, pharmacokinetics and bioavailability to change, which in turn affects the efficacy and safety of the drug, so in the development of small molecule drugs It should fully consider its polymorphic problem. Therefore, crystal research and control has become one of the important research contents in the development of small molecule drugs.
  • a PARP selective inhibitor of pharmaceutical value is disclosed in WO2013117120, wherein an example of the series of inhibitors specifically described (see Example 21 on page 37) is 2-[4-(methylaminomethyl)phenyl] 5-5-fluoro-benzofuran-7-carboxamide hydrochloride (hereinafter referred to as melibeurol hydrochloride) having the structure of formula I:
  • Characterization of the compound obtained by the method disclosed in WO2013117120 is carried out by 1 HMR analysis and/or measurement of the melting point.
  • the observation of melipiper hydrochloride in different crystalline forms has not been described, nor is any description of the specific crystal form and the preparation method for obtaining a particular crystal form.
  • Different crystal forms of melibeurol hydrochloride may cause changes in its dissolution, dissolution properties, pharmacokinetics and bioavailability, which may affect the efficacy and safety of the drug.
  • the present invention discloses various crystal forms, characterization and preparation methods, and uses thereof. Therefore, the technical problem to be solved by the present invention is to provide a polycrystalline form of melibeuril hydrochloride, which provides technical support for the further development of meliberi hydrochloride.
  • a first aspect of the invention provides a polymorph of meprion hydrochloride as shown in Formula I.
  • the polymorph is meliberi hydrochloride Form A, and the powder diffraction pattern thereof comprises 3 or more 2 ⁇ values selected from the group consisting of 6.49 ⁇ 0.1° and 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 Form A also has one or more characteristics selected from the group consisting of:
  • Form A has a DSC pattern substantially as shown in Figure 1b;
  • the crystal form A has a Raman spectrum substantially as shown in Fig. 1e.
  • the polymorph is meliberi hydrochloride Form B
  • the powder diffraction pattern comprises 3 or more 2 ⁇ values selected from the group consisting of: 6.145 ⁇ 0.1°, 10.318 ⁇ 0.1°, 12.459 ⁇ 0.1°, 14.914 ⁇ 0.1°, 20.806 ⁇ 0.1°, 22.832 ⁇ 0.1°, 23.295 ⁇ 0.1°, 24.996 ⁇ 0.1°, 25.198 ⁇ 0.1°, 25.481 ⁇ 0.1°, 26.787 ⁇ 0.1°, 27.285 ⁇ 0.1°, 28.003 ⁇ 0.1° and 29.59 ⁇ 0.1°.
  • Form B also has one or more characteristics selected from the group consisting of:
  • Form B has a DSC pattern substantially as shown in Figure 2b;
  • the crystal form B has a Raman spectrum substantially as shown in Fig. 2e.
  • the polymorph is meliberi hydrochloride Form C
  • the powder diffraction pattern comprises 3 or more 2 ⁇ values selected from the group consisting of: 10.306 ⁇ 0.1°, 12.666 ⁇ 0.1°, 15.312 ⁇ 0.1°, 17.436 ⁇ 0.1°, 18.918 ⁇ 0.1°, 20.748 ⁇ 0.1°, 22.974 ⁇ 0.1°, 24.553 ⁇ 0.1°, 25.238 ⁇ 0.1°, 26.241 ⁇ 0.1°, 29.336 ⁇ 0.1°, 32.739 ⁇ 0.1°, 33.738 ⁇ 0.1°, 34.118 ⁇ 0.1°, 35.204.
  • Form C further has one or more characteristics selected from the group consisting of:
  • Form C has a DSC pattern substantially as shown in Figure 3b;
  • the crystal form C has a Raman spectrum substantially as shown in Fig. 3e.
  • a second aspect of the invention provides a process for the preparation of a polymorph of meprion hydrochloride according to the first aspect of the invention, comprising the steps of:
  • the alcohol is selected from the group consisting of methanol, ethanol, propanol, tert-butanol, butanol, octanol, pentanol, hexanol, heptanol, sunflower alcohol, or a combination thereof; From the following group: methyl ethyl ketone, methyl tert-butyl ether, isopropyl acetate, or a combination thereof;
  • the preparation method includes the steps of:
  • step a) adjusting the pH of the alcohol or aqueous alcohol solution of step a) to acidic with hydrochloric acid, stirring at room temperature, allowing to stand to precipitate crystals;
  • the alcohol-water system is selected from the group consisting of methanol-water, ethanol-water, propanol-water, tert-butanol-water, butanol-water, octanol-water, pentanol-water, hexanol - water, heptanol-water or sunflower-water.
  • the alcohol is methanol or ethanol, preferably ethanol.
  • the organic solvent is methyl ethyl ketone or methyl tert-butyl ether, preferably butanone.
  • the alcohol water system is methanol-water or ethanol-water, preferably ethanol-water.
  • the alcohol or the aqueous alcohol solution of the step a) is brought to an acidic range of from 1 to 5, preferably, the pH is from 2 to 4, more preferably, the pH is 2.
  • the precipitated crystals are dried at 25 ° C to 100 ° C.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a polymorph of meprionine hydrochloride according to the first aspect of the invention, and a pharmaceutically acceptable thereof Excipient or carrier.
  • a fourth aspect of the invention provides a use of a polymorph of meprionine hydrochloride or a composition according to the third aspect of the invention, according to the first aspect of the invention, for the preparation of a treatment and/or Or a drug that prevents diseases associated with poly ADP-ribose polymerase PARP.
  • the disease includes: tumor, inflammation, cardiovascular disease, diabetes, rheumatoid arthritis, endotoxic shock, and stroke.
  • the tumor comprises: a tumor of BRCA1 or BRCA2 deletion or mutation.
  • the tumor comprises: ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, cervical cancer, glioma, and Ewing's sarcoma.
  • the medicament comprises an antitumor drug and/or an anti-inflammatory drug.
  • Figure 1a is an X-ray powder diffraction (XRPD) pattern of meperidine hydrochloride Form A;
  • Figure 1b is a DSC spectrum of meperidine hydrochloride Form A
  • Figure 1c is an infrared (IR) spectrum of meperidine hydrochloride Form A
  • Figure 1d is a TG spectrum of meperidine hydrochloride Form A
  • Figure 1e is a Raman spectrum of meperidine hydrochloride Form A
  • Figure 2a is an X-ray powder diffraction (XRD) pattern of meperidine hydrochloride Form B;
  • Figure 2b is a DSC spectrum of meperidine hydrochloride Form B
  • Figure 2c is an infrared (IR) spectrum of meperidine hydrochloride Form B;
  • Figure 2d is a TG spectrum of meperidine hydrochloride Form B
  • Figure 2e is a Raman spectrum of meperidine hydrochloride Form B
  • Figure 3a is an X-ray powder diffraction (XRPD) pattern of meperidine hydrochloride Form C;
  • Figure 3b is a DSC spectrum of meperidine hydrochloride Form C
  • Figure 3c is an infrared (IR) spectrum of meperidine hydrochloride Form C;
  • Figure 3d is a TG spectrum of meperidine hydrochloride Form C
  • Figure 3e is a Raman spectrum of meperidine hydrochloride Form C.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term "about” means that the recited value varies by no more than 0.2, for example about X, which represents X ⁇ 0.2, preferably X ⁇ 0.1.
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “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 use in humans and/or animals without excessive adverse side effects (eg, toxicity, irritation, and allergies), ie, having a reasonable benefit/risk ratio.
  • the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or 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 that the clinician can judge.
  • the solubility limit of the compound of interest can be exceeded by operating the solution to complete production-scale crystallization. This can be done in a number of ways, for example by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. The solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • the melibele hydrochloride polymorph of the present invention comprises three crystal forms: Form A, Form B and Form C.
  • the powder X-ray diffraction pattern of the melibidine hydrochloride A crystal form of the present invention has a diffraction angle (2 ⁇ ) of about 6.49, 12.625, 15.271, 20.727, 22.933, 23.913, 25.139, 25.618, 26.082, 27.084, 27.406, 28.828. Significant characteristic absorption peaks.
  • the X-ray powder diffraction pattern of the Form A crystal form of melibeuril hydrochloride is substantially identical to that of Figure 1a; the DSC, infrared, TG and Raman spectra are substantially identical to Figures 1b, 1c, 1d and 1e .
  • the Form A has a characteristic endothermic peak in the interval of about 280-300 °C.
  • the infrared spectrum of the crystal form A is at least 3486 cm -1 , 3172 cm -1 , 2923 cm -1 , 2709 cm -1 , 2476 cm -1 , 1666 cm -1 , 1608 cm -1 , 1592 cm -1 , 1469cm -1 , 1428cm -1 , 1378cm -1 , 1338cm -1 , 1189cm -1 , 1114cm -1 , 946cm -1 , 779cm -1 and 470cm -1 have characteristic peaks with an error range of ⁇ 2cm -1 .
  • thermogravimetric analysis of the crystalline form A begins to decompose at 250 ⁇ 20 °C.
  • the powder X-ray diffraction pattern of the melibele hydrochloride B crystal form of the present invention has a diffraction angle (2 theta angle) of about 6.145, 10.318, 12.459, 14.914, 20.806, 22.832, 23.295, 24.996, 25.198, 25.481, 26.787, 27.285, There are distinct characteristic absorption peaks at 28.003 and 29.59.
  • the X-ray powder diffraction pattern of the B crystal form of melibeurole hydrochloride is substantially identical to that of Figure 2a; the DSC, infrared, TG and Raman spectra are substantially identical to Figures 2b, 2c, 2d and 2e .
  • the Form B has a characteristic endothermic peak in the interval of about 280-300 °C.
  • the infrared spectrum of the crystalline form B is at least 3469 cm -1 , 3164 cm -1 , 2923 cm -1 , 2701 cm -1 , 2470 cm -1 , 1654 cm -1 , 1606 cm -1 , 1589 cm -1 , 1428cm -1, 1469cm -1, 1428cm -1 , 1378cm -1, 1338cm -1, 1189cm -1, 1172cm -1, 1103cm -1 and 779cm -1, etc. having a characteristic peak, the error range of ⁇ 2cm -1.
  • the powder X-ray diffraction pattern of mepentazol hydrochloride C crystal form of the present invention has a diffraction angle (2 ⁇ angle) of about 10.306, 12.666, 15.312, 17.436, 18.918, 20.748, 22.974, 24.553, 25.238, 26.241, 29.336, 32.739, There are distinct characteristic absorption peaks at 33.738, 34.118, and 35.204.
  • the X-ray powder diffraction pattern of the Form C crystal form of melibeuril is substantially identical to that of Figure 3a; the DSC, IR, TG and Raman spectra are substantially identical to Figures 3b, 3c, 3d and 3e .
  • the Form C has a characteristic endothermic peak in the interval of about 270-300 °C.
  • thermogravimetric analysis of the crystalline form C begins to decompose at 250 ⁇ 20 °C.
  • the A crystal form, the B crystal form and the C crystal form of the present invention have high crystallinity and good thermal stability.
  • the invention also provides a preparation method of the above three crystals of melibeurole hydrochloride A, B and C, the specific steps are as follows.
  • the metoperiril is dissolved in an organic solvent in a free state, and an equivalent ratio of HCl/organic solvent is slowly added dropwise, and the solid is precipitated and stirred, and the solid is filtered and dried to obtain a crystalline form of mefenopril hydrochloride;
  • the organic solvent may be A combination of one or more of methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrofuran, acetone.
  • the organic solvent in which the raw material is highly insoluble in the raw material is any one or a combination of two or more of methyl ethyl ketone, methyl tert-butyl ether and isopropyl acetate, preferably, butanone or methyl tert-butyl.
  • the ether more preferably, butanone.
  • the Form A crystal form of melibeuril hydrochloride is completely dissolved in an alcohol or alcohol water system, and the pH is adjusted to be acidic with hydrochloric acid, stirred at room temperature, and filtered to obtain a white solid which is a crystal form of mefenexil hydrochloride, wherein the alcohol is methanol.
  • the alcohol-water system is methanol-water, ethanol-water, propanol-water, tert-butanol-water, butanol-water, octanol-water, pentanol-water, hexanol-water, heptanol-water Or a methanol-water or the like, preferably a methanol-water or ethanol-water system, more preferably an ethanol-water system;
  • the pH to acidic range is from 1 to 5, preferably from 2 to 4. More preferably, the pH is 2.
  • the pharmaceutical composition of the present invention comprises metoperidol hydrochloride crystal form in a safe and effective amount, ie Form A, Form B and Form C, and pharmaceutically acceptable salts thereof and pharmacologically acceptable Excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of blending with the polymorphs of the invention and with each other without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the polymorphs of the invention are typically mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example,
  • the excipient includes one or more of a filler, a disintegrant, a binder, and a lubricant.
  • the filler is a mixture of any one or more of starch, lactose, microcrystalline cellulose, dextrin, mannitol, oxidase, calcium sulfate.
  • the disintegrant comprises carboxymethylcellulose and salts thereof, croscarmellose and salts thereof, crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose. Any one or several of them.
  • the binder comprises any one or more of povidone, hydroxypropyl methylcellulose, starch syrup, pregelatinized starch.
  • the lubricant comprises any one or more of sodium stearyl fumarate, magnesium stearate, and calcium stearate.
  • the polymorph of melibeuride hydrochloride of the present invention is for use in the preparation of a medicament for preventing and/or treating a disease associated with poly ADP-ribose polymerase PARP; and can also be used for the preparation of a medicament for preventing and/or treating a tumor; It can also be used to prepare anti-inflammatory drugs.
  • the tumor is a tumor defective in homologous recombination repair, 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 and the like.
  • the present invention provides different crystalline forms of melibexole hydrochloride, which can be converted into three crystal forms A, B and C under different solvent ratios.
  • the three polymorphs are simple in preparation, and have high crystal purity, good stability and easy storage.
  • the preparation method of the three polymorphs of the invention has simple preparation process, easy operation, good process repeatability, and high purity of the obtained crystal form.
  • the relative intensities of the diffraction peaks are not characteristic for the crystals that are targeted, and it is more important to note the position of the peaks rather than their relative intensities when determining whether they are the same as the known crystal forms.
  • some of the diffraction lines are missing due to factors such as a decrease in content. At this time, it is not necessary to rely on the safety band observed in the high-purity sample, and even a band may be given.
  • the crystal is characteristic
  • the IR method was detected at room temperature using a Nicolot-Magna FT-IR750 infrared spectrometer from Nico, and the detection range was 4000-350 cm-1.
  • the suspension system was cooled to 0 ° C, and an ethyl acetate system (250 mL) of 8N hydrochloric acid was slowly added dropwise, and the system was completely dissolved. After the dropwise addition was completed, the reaction system was further stirred at 0 ° C to 10 ° C for 12 hours to precipitate a large amount of solid, which was filtered to obtain a cake.
  • the filter cake was vacuum dried at 50 ° C to 55 ° C to constant weight to obtain Form A.
  • Table 1 X-ray powder diffraction (XRPD) data for the crystalline form A of Meruparin hydrochloride
  • Example 1 Approximately 25 mg of melibexole hydrochloride in Example 1 was stirred and equilibrated with 1 ml of methanol at 25 ° C for at least 24 h. Subsequently, the solution was separately filtered, and the solid portion was dried in air for 10 min, followed by XRPD detection, X-ray powder diffraction. The data results are shown in Table 1.
  • Example 2 The difference from Example 2 was that the solvent was replaced with ethanol, and the results of X-ray powder diffraction data are shown in Table 1.
  • Example 2 The difference from Example 2 was that the solvent was replaced with isopropyl alcohol, and the results of X-ray powder diffraction data are shown in Table 1.
  • Example 2 The difference from Example 2 was that the solvent was replaced with ethyl acetate, and the results of X-ray powder diffraction data are shown in Table 1.
  • Example 2 The difference from Example 2 was that the solvent was replaced with a methanol and water system having a volume ratio of 1:1, and the results of X-ray powder diffraction data are shown in Table 1.
  • Example 2 The difference from Example 2 was that the temperature was adjusted to 50 ° C, and the results of X-ray powder diffraction data are shown in Table 1.
  • Example 2 About 25 mg of melibexole hydrochloride in Example 1 was taken, and methanol (3 mL) was added at 25 ° C until the starting material was completely dissolved, followed by dropwise addition of methyl ethyl ketone (12 mL). After the dropwise addition was completed, the mixture was stirred at this temperature for 12 hours, filtered, and the filter cake was vacuum dried at 50 ° C to 55 ° C to a constant weight to obtain Form B.
  • the obtained flurbifribine hydrochloride form B was determined by X-ray powder diffraction - the specific peak position is shown in Table 2, see Figure 2a.
  • Table 2 X-ray powder diffraction (XRPD) data for Form B crystal form of mirabir hydrochloride
  • Example 2 About 25 mg of melibexole hydrochloride in Example 1 was taken, and methanol (1.8 mL) was added at 50 ° C until the starting material was completely dissolved, followed by dropwise addition of methyl ethyl ketone (6 mL). After the dropwise addition was completed, the mixture was stirred at this temperature for 12 hours, filtered, and the filter cake was vacuum dried at 50 ° C to 55 ° C to a constant weight to obtain Form B.
  • Table 2 The results of X-ray powder diffraction data are shown in Table 2.
  • Example 1 About 100 mg of melibeurol hydrochloride in Example 1 was added to 4 ml of absolute ethanol, and the temperature was raised to 50 ° C with stirring, followed by dropwise addition of purified water until the starting material was completely dissolved. Stir at this temperature for 30 min, then add concentrated hydrochloric acid to adjust the pH to about 2, naturally cool to room temperature, stir for about 12 hours, filter, filter off white solid, filter cake with absolute ethanol rinse, drain, at 50 ° C Dry at ⁇ 55 ° C under vacuum to constant weight to obtain FormC.
  • Example 10 The difference from Example 10 was that methanol was used as the organic solvent, and X-ray powder diffraction data thereof is shown in Table 3.
  • Example 10 The difference from Example 10 was that the reaction temperature was 78 ° C, and the X-ray powder diffraction data thereof is shown in Table 3.

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Abstract

本发明公开了盐酸美呋哌瑞多晶型物及其制备方法与应用。具体地，本发明公开了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A、B、C三种晶型、三种晶型的制备方法及其这三种晶型在制备药物中的用途。 (I)

Description

盐酸美呋哌瑞多晶型物及其制备方法与应用 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 PCTCN2018089222-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 PCTCN2018089222-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A，其粉末衍射图谱包括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°。
在另一优选例中，所述晶型A还具有选自下组的一个或多个特征：
(1)所述晶型A具有基本上如图1b所示的DSC图谱；
(2)所述晶型A具有基本上如图1c所示的红外谱图；
(3)所述晶型A具有基本上如图1d所示的TG图谱；和
(4)所述晶型A具有基本上如图1e所示的拉曼图谱。
在另一优选例中，所述的多晶型物为盐酸美呋哌瑞晶型B，其粉末衍射图谱包括3个或3个以上选自下组的2θ值：6.145±0.1°、10.318±0.1°、12.459±0.1°、14.914±0.1°、20.806±0.1°、22.832±0.1°、23.295±0.1°、24.996±0.1°、25.198±0.1°、25.481±0.1°、26.787±0.1°、27.285±0.1°、28.003±0.1°和29.59±0.1°。
在另一优选例中，所述晶型B还具有选自下组的一个或多个特征：
(1)所述晶型B具有基本上如图2b所示的DSC图谱；
(2)所述晶型B具有基本上如图2c所示的红外谱图；
(3)所述晶型B具有基本上如图2d所示的TG图谱；和
(4)所述晶型B具有基本上如图2e所示的拉曼图谱。
在另一优选例中，所述的多晶型物为盐酸美呋哌瑞晶型C，其粉末衍射图谱包括3个或3个以上选自下组的2θ值：10.306±0.1°、12.666±0.1°、15.312±0.1°、17.436±0.1°、18.918±0.1°、20.748±0.1°、22.974±0.1°、24.553±0.1°、25.238±0.1°、26.241±0.1°、29.336±0.1°、32.739±0.1°、33.738±0.1°、34.118±0.1°、35.204。
在另一优选例中，所述晶型C还具有选自下组的一个或多个特征：
(1)所述晶型C具有基本上如图3b所示的DSC图谱；
(2)所述晶型C具有基本上如图3c所示的红外谱图；
(3)所述晶型C具有基本上如图3d所示的TG图谱；和
(4)所述晶型C具有基本上如图3e所示的拉曼图谱。
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0℃～80℃下，将盐酸美呋哌瑞晶型A溶于醇，从而形成含盐酸美呋哌瑞的醇溶液；
(ii)向步骤i)的醇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B；
其中，所述的醇选自下组：甲醇、乙醇、丙醇、叔丁醇、丁醇、辛醇、戊醇、己醇、庚醇、葵醇、或其组合；所述的有机溶剂选自下组：丁酮、甲基叔丁基醚、乙酸异丙酯、或其组合；
或所述的制备方法包括步骤：
(a)在0℃～80℃下，将盐酸美呋哌瑞晶型A溶于醇或醇水体系中，从而形成含盐酸美呋哌瑞的醇或醇水溶液；
(b)用盐酸将步骤a)的醇或醇水溶液调pH到酸性，室温搅拌，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C；
其中，所述的醇-水体系选自下组：甲醇-水、乙醇-水、丙醇-水、叔丁醇-水、丁醇-水、辛醇-水、戊醇-水、己醇-水、庚醇-水或葵醇-水。
在另一优选例中，所述的醇为甲醇或乙醇，较佳地，为乙醇。
在另一优选例中，所述的有机溶剂为丁酮或甲基叔丁基醚，较佳地，为丁酮。
在另一优选例中，所述的醇水体系为甲醇-水或乙醇-水，较佳地，为乙醇-水。
在另一优选例中，用盐酸将步骤a)的醇或醇水溶液到酸性的区间为1～5，较佳地，pH为2～4，更佳地，pH为2。
在另一优选例中，在25℃～100℃下干燥析出的晶体。
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
附图1a为盐酸美呋哌瑞Form A的X射线粉末衍射(XRPD)图；
附图1b为盐酸美呋哌瑞Form A的DSC谱图；
附图1c为盐酸美呋哌瑞Form A的红外(IR)光谱图；
附图1d为盐酸美呋哌瑞Form A的TG谱图；
附图1e为盐酸美呋哌瑞Form A的拉曼光(Raman)谱图；
附图2a为盐酸美呋哌瑞Form B的X射线粉末衍射(XRD)图；
附图2b为盐酸美呋哌瑞Form B的DSC谱图；
附图2c为盐酸美呋哌瑞Form B的红外(IR)光谱图；
附图2d为盐酸美呋哌瑞Form B的TG谱图；
附图2e为盐酸美呋哌瑞Form B的拉曼光(Raman)谱图；
附图3a为盐酸美呋哌瑞Form C的X射线粉末衍射(XRPD)图；
附图3b为盐酸美呋哌瑞Form C的DSC谱图；
附图3c为盐酸美呋哌瑞Form C的红外(IR)光谱图；
附图3d为盐酸美呋哌瑞Form C的TG谱图；
附图3e为盐酸美呋哌瑞Form C的拉曼光(Raman)谱图。
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三种新型多晶型物，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三种晶型：即A晶型、B晶型和C晶型。
A晶型
本发明的盐酸美呋哌瑞A晶型的粉末X射线衍射图谱在衍射角(2θ)约为6.49，12.625，15.271，20.727，22.933，23.913，25.139，25.618，26.082，27.084，27.406，28.828处有明显特征吸收峰。
所述A晶型盐酸美呋哌瑞的X射线粉末衍射图基本上与图1a一致；所述DSC图谱、红外谱图、TG图谱和拉曼图谱基本上与图1b、1c、1d和1e一致。
从图1b中可以看出，所述晶型A在约280-300℃区间内有特征吸热峰。
从图1c中可以看出，所述晶型A的红外光谱至少在3486cm -1、3172cm -1、2923cm -1、2709cm -1、2476cm -1、1666cm -1、1608cm -1、1592cm -1、1469cm -1、1428cm -1、1378cm -1、1338cm -1、1189cm -1、1114cm -1、946cm -1、779cm -1和470cm -1处具有特征峰，误差范围为±2cm -1。
从图1d中可以分析得出：所述晶型A的热失重分析在250±20℃开始分解。
B晶型
本发明的盐酸美呋哌瑞B晶型的粉末X射线衍射图谱在衍射角(2θ角)约为6.145，10.318，12.459，14.914，20.806，22.832，23.295，24.996，25.198，25.481，26.787，27.285，28.003，29.59处有明显特征吸收峰。
所述B晶型盐酸美呋哌瑞的X射线粉末衍射图基本上与图2a一致；所述DSC图谱、红外谱图、TG图谱和拉曼图谱基本上与图2b、2c、2d和2e一致。
从图2b中可以看出，所述晶型B在约280-300℃区间内有特征吸热峰。
从图2c中可以看出，所述晶型B的红外光谱至少在3469cm -1、3164cm -1、2923cm -1、2701cm -1、2470cm -1、1654cm -1、1606cm -1、1589cm -1、1428cm -1、 1469cm -1、1428cm -1、1378cm -1、1338cm -1、1189cm -1、1172cm -1、1103cm -1和779cm -1等处具有特征峰，误差范围为±2cm -1。
从图2d中可以分析得出：所述晶型B的热失重分析在250±20℃开始分解。
C晶型
本发明的盐酸美呋哌瑞C晶型的粉末X射线衍射图谱在衍射角(2θ角)约为10.306，12.666，15.312，17.436，18.918，20.748，22.974，24.553，25.238，26.241，29.336，32.739，33.738，34.118，35.204处有明显特征吸收峰。
所述C晶型盐酸美呋哌瑞的X射线粉末衍射图基本上与图3a一致；所述DSC图谱、红外谱图、TG图谱和拉曼图谱基本上与图3b、3c、3d和3e一致。
从图3b中可以看出，所述晶型C在约270-300℃区间内有特征吸热峰。
从图3c中可以看出，所述晶型C的红外光谱至少在3485cm -1、3227cm -1、3170cm -1、3047cm -1、2747cm -1、2709cm -1、2475cm -1、1665cm -1、1609cm -1、1468cm -1、1428cm -1、1377cm -1、1338cm -1、1190cm -1、1173cm -1、1114cm -1、947cm -1、838cm -1和779cm -1等处具有特征峰，误差范围为±2cm -1。
从图3d中可以分析得出：所述晶型C的热失重分析在250±20℃开始分解。
从上述实验结果可以看出，本发明的A晶型、B晶型和C晶型结晶度高且具备良好的热稳定性。
多晶型物的制备方法
本发明还提供了上述盐酸美呋哌瑞A、B和C三种晶体的制备方法，具体步骤如下。
盐酸美呋哌瑞A晶型的制备
将美呋哌瑞游离态溶于有机溶剂中，缓慢滴加当量比的HCl/有机溶剂，搅拌析出固体，固体过滤，干燥，得到A晶型盐酸美呋哌瑞；其中所述的有机溶剂可以为甲醇、乙醇、二氯甲烷、乙酸乙酯、四氢呋喃、丙酮中一种或多种的组合。
盐酸美呋哌瑞B晶型的制备
将A晶型盐酸美呋哌瑞溶于甲醇或乙醇中,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B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为丁酮、甲基叔丁基醚、乙酸异丙酯中的任意一种或两种以上的组合，较佳地，为丁酮或甲基叔丁基醚，更佳地，为丁酮。
盐酸美呋哌瑞C晶型的制备
将A晶型盐酸美呋哌瑞完全溶于醇或醇水体系中,用盐酸调PH到酸性,室温搅拌，过滤得白色固体为C晶型的盐酸美呋哌瑞，其中所述醇为甲醇、乙醇、丙醇、 叔丁醇、丁醇、辛醇、戊醇、己醇、庚醇、葵醇等，较佳地，为甲醇或乙醇，更佳地，为乙醇。
所述醇-水体系为甲醇-水、乙醇-水、丙醇-水、叔丁醇-水、丁醇-水、辛醇-水、戊醇-水、己醇-水、庚醇-水或葵醇-水等，优选甲醇-水或乙醇-水体系，更优选乙醇-水体系；
所述调pH到酸性的区间为1～5，优选pH为2～4.更优选pH为2。
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A、晶型B和晶型C、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
Figure PCTCN2018089222-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A、B、C三种晶型。这三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.本发明的三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°(2theta值)，扫描步径：0.1。需要说明的是，在粉末样品X射线衍射图谱中，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50-280℃，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 Raman Microscope；Laser power level:150.0mW，Filter:780nm,Spectrograph aperture:25slit-25，Exposure time:1.00sec,Number of exposures:10,Number of background exposures:32。
6)DVS方法仪器型号：SMS DVS Intrinsic，0～95％RH，温度：25℃
实施例1
Form A的制备方法：
将游离的盐酸美呋哌瑞(59.6g,199.9mmol,纯度大于97％)加入到甲醇/二氯甲烷(v/v＝1:1,2000mL)中剧烈搅伴，固体不完全溶解使体系成悬浮***，冷却到0℃,开始缓慢滴加8N盐酸的乙酸乙酯体系(250mL),体系完全溶解。滴加完毕，反应***在0℃～10℃下继续搅拌12小时，析出大量固体，过滤得到滤饼。滤饼在50℃～55℃真空干燥到恒重得到Form A。
经X-射线粉末衍射测定，显示得到的晶型为A的盐酸美呋哌瑞--具体峰位如表1，参见附图1a：
表1:A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％
6.49 13.6084 15.8
10.339 8.5491 9.4
12.625 7.0059 11
15.271 5.7972 100
17.395 5.094 2.8
18.121 4.8914 7.8
18.844 4.7053 6.5
19.482 4.5526 8
20.727 4.2819 34.8
21.448 4.1396 6.6
22.933 3.8748 11.4
23.133 3.8418 8.7
23.913 3.7181 21.3
24.5 3.6304 4.2
25.139 3.5395 24.3
25.618 3.4743 11.6
26.082 3.4137 26.2
27.084 3.2896 12.1
27.406 3.2517 20.8
28.828 3.0944 11.3
29.31 3.0446 3.5
29.891 2.9867 9.2
30.591 2.9199 3.3
30.789 2.9016 3.8
32.717 2.7349 5
33.681 2.6588 5.1
35.163 2.5501 3
35.441 2.5307 2.1
35.964 2.4951 2.9
36.688 2.4475 3.5
37.048 2.4245 5
38.132 2.3581 1.3
39.375 2.2865 3.6
40.075 2.2481 1.8
40.68 2.216 2.7
43.606 2.0739 1.4
43.926 2.0596 1.4
对得到的样品进行其它测试，得到的DSC图谱、红外谱图、TG图谱和拉曼图谱基本上与附图1b、1c、1d和1e一致。
实施例2
Form A的制备方法：
取大约25mg实施例1中的盐酸美呋哌瑞，在25℃与1ml甲醇搅拌平衡至少24h，随后，分别过滤溶液，固体部分在空气中干燥10min，随后做XRPD检测，其X-射线粉末衍射数据结果如表1所示。
实施例3
Form A的制备方法：
与实施例2不同之处在于将溶剂置换成为乙醇，其X-射线粉末衍射数据结果如表1所示。
实施例4
Form A的制备方法：
与实施例2不同之处在于将溶剂置换成为异丙醇，其X-射线粉末衍射数据结果如表1所示。
实施例5
Form A的制备方法：
与实施例2不同之处在于将溶剂置换成为乙酸乙酯，其X-射线粉末衍射数据结果如表1所示。
实施例6
Form A的制备方法：
与实施例2不同之处在于将溶剂置换成为体积比为1:1的甲醇与水体系，其X-射线粉末衍射数据结果如表1所示。
实施例7
Form A的制备方法
与实施例2不同之处在于将温度调整到50℃，其X-射线粉末衍射数据结果如表1所示。
实施例9
Form B的制备方法：
取大约25mg实施例1中的盐酸美呋哌瑞,在25℃加入甲醇(3mL)直至原料完全溶解,随后缓慢滴加丁酮(12mL)。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Form B。
经X-射线粉末衍射测定，显示得到的晶型为B的盐酸美呋哌瑞--具体峰位如表2，参见附图2a。
表2:B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％
6.145 14.37 18.6
10.318 8.566 16.5
12.459 7.0985 12.8
14.914 5.9353 100
15.154 5.8418 8.5
17.204 5.15 3.5
17.6 5.0349 5.4
18.643 4.7557 6.3
19.082 4.6472 6.6
19.965 4.4436 3.6
20.806 4.2659 51.1
22.832 3.8917 10.7
23.295 3.8153 10.9
23.933 3.7151 4.6
24.996 3.5595 30.1
25.198 3.5313 42.1
25.481 3.4928 11
25.778 3.4532 2.5
26.787 3.3254 10.8
27.285 3.2658 10.4
28.003 3.1836 19.8
29.59 3.0165 18.2
31.374 2.8488 2.7
32.012 2.7935 2.1
32.536 2.7497 2.4
32.9 2.7202 6.3
33.519 2.6713 3.2
33.722 2.6556 3.6
35.065 2.557 2.6
35.724 2.5113 9.8
36.046 2.4896 5.4
36.767 2.4424 3.5
39.012 2.3069 6
39.426 2.2836 1.7
对得到的样品进行其它测试，得到的DSC图谱、红外谱图、TG图谱和拉曼图谱基本上与附图2b、2c、2d和2e一致。
实施例10
Form B的制备方法：
取大约25mg实施例1中的盐酸美呋哌瑞,在50℃加入甲醇(1.8mL)直至原料完全溶解,随后缓慢滴加丁酮(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Form B。其X-射线粉末衍射数据结果如表2所示。
实施例11
Form C的制备方法：
取大约100mg实施例1中的盐酸美呋哌瑞加入到4ml无水乙醇中，搅拌下升温到50℃,随后滴加纯净水搅拌直到原料完全溶解。在此温度下搅拌30min，随后滴加浓盐酸调pH到2左右，自然冷却到室温，搅拌12小时左右，过滤，滤出白色固体，滤饼用无水乙醇淋洗，抽干，在50℃～55℃真空干燥到恒重得到FormC。
经X-射线粉末衍射测定，显示得到的晶型为C的盐酸美呋哌瑞--具体峰位如表3，参见附图3a。
表3:C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％
10.306 8.5765 19.2
12.666 6.9831 17.9
15.312 5.7817 100.0
17.436 5.0820 23.3
18.918 4.6870 33.8
20.748 4.2776 90.0
22.974 3.8679 37.1
24.553 3.6226 27.1
25.238 3.5259 16.7
26.241 3.3934 52.1
29.336 3.0419 27.1
32.739 2.7331 45.0
33.738 2.6544 20.4
34.118 2.6257 18.8
35.204 2.5472 26.7
对得到的样品进行其它测试，得到的DSC图谱、红外谱图、TG图谱和拉曼图谱基本上与附图3b、3c、3d和3e一致。
实施例12
Form C的制备方法：
与实施例10不同之处在于有机溶剂采用甲醇，其X-射线粉末衍射数据如表3所示。
实施例13
Form C的制备方法：
与实施例10不同之处在于其反应温度为78℃，其X-射线粉末衍射数据如表3所示。
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 (10)

  1. 一种如式I所示的盐酸美呋哌瑞的多晶型物。
    Figure PCTCN2018089222-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A，其粉末衍射图谱包括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°。
  3. 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，所述晶型A还具有选自下组的一个或多个特征：
    (1)所述晶型A具有基本上如图1b所示的DSC图谱；
    (2)所述晶型A具有基本上如图1c所示的红外谱图；
    (3)所述晶型A具有基本上如图1d所示的TG图谱；和
    (4)所述晶型A具有基本上如图1e所示的拉曼图谱。
  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B，其粉末衍射图谱包括3个或3个以上选自下组的2θ值：6.145±0.1°、10.318±0.1°、12.459±0.1°、14.914±0.1°、20.806±0.1°、22.832±0.1°、23.295±0.1°、24.996±0.1°、25.198±0.1°、25.481±0.1°、26.787±0.1°、27.285±0.1°、28.003±0.1°和29.59±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B还具有选自下组的一个或多个特征：
    (1)所述晶型B具有基本上如图2b所示的DSC图谱；
    (2)所述晶型B具有基本上如图2c所示的红外谱图；
    (3)所述晶型B具有基本上如图2d所示的TG图谱；和
    (4)所述晶型B具有基本上如图2e所示的拉曼图谱。
  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C，其粉末衍射图谱包括3个或3个以上选自下组的2θ值： 10.306±0.1°、12.666±0.1°、15.312±0.1°、17.436±0.1°、18.918±0.1°、20.748±0.1°、22.974±0.1°、24.553±0.1°、25.238±0.1°、26.241±0.1°、29.336±0.1°、32.739±0.1°、33.738±0.1°、34.118±0.1°、35.204。
  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C还具有选自下组的一个或多个特征：
    (1)所述晶型C具有基本上如图3b所示的DSC图谱；
    (2)所述晶型C具有基本上如图3c所示的红外谱图；
    (3)所述晶型C具有基本上如图3d所示的TG图谱；和
    (4)所述晶型C具有基本上如图3e所示的拉曼图谱。
  8. 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，将盐酸美呋哌瑞晶型A溶于醇，从而形成含盐酸美呋哌瑞的醇溶液；
    (ii)向步骤i)的醇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B；
    其中，所述的醇选自下组：甲醇、乙醇、丙醇、叔丁醇、丁醇、辛醇、戊醇、己醇、庚醇、葵醇、或其组合；所述的有机溶剂选自下组：丁酮、甲基叔丁基醚、乙酸异丙酯、或其组合；
    或所述的制备方法包括步骤：
    (a)在0℃～80℃下，将盐酸美呋哌瑞晶型A溶于醇或醇水体系中，从而形成含盐酸美呋哌瑞的醇或醇水溶液；
    (b)用盐酸将步骤a)的醇或醇水溶液调pH到酸性，室温搅拌，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C；
    其中，所述的醇-水体系选自下组：甲醇-水、乙醇-水、丙醇-水、叔丁醇-水、丁醇-水、辛醇-水、戊醇-水、己醇-水、庚醇-水或葵醇-水。
  9. 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1～7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。
  10. 一种如权利要求1～7中任一项所述的盐酸美呋哌瑞的多晶型物或如权利要 求9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/CN2018/089222 2017-06-14 2018-05-31 盐酸美呋哌瑞多晶型物及其制备方法与应用 WO2018228205A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020119772A1 (zh) * 2018-12-14 2020-06-18 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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109134409B (zh) * 2017-06-14 2023-09-29 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

Citations (2)

* 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
WO2013117120A1 (zh) 2012-02-09 2013-08-15 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

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104003979B (zh) * 2013-02-21 2016-08-17 上海汇伦生命科技有限公司 苯并咪唑-2-哌嗪类化合物、其药物组合物及其制备方法和用途
WO2015032328A1 (zh) * 2013-09-03 2015-03-12 四川海思科制药有限公司 茚满衍生物及其制备方法和在医药上的应用
CN104003940B (zh) * 2014-06-16 2017-02-15 华东理工大学 2,4‑二氟‑5‑(酞嗪酮‑1‑甲基)‑苯甲酰哌嗪类化合物及其用途
CN109134409B (zh) * 2017-06-14 2023-09-29 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
CN111320596A (zh) * 2018-12-14 2020-06-23 甫康（上海）健康科技有限责任公司 盐酸美呋哌瑞多晶型物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013117120A1 (zh) 2012-02-09 2013-08-15 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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J W MULLENS: "Crystallization", 1993, BUTTERWORTH-HEINEMAN LTD.
JIN, QIU ET AL.: "Design, synthesis and activity of benzofuran-7-carboxarmide poly(ADP-ribode) polymerase inhibitors", CHINESE JOURNAL OF ORGANIC CHEMISTRY, vol. 33, no. 3, 31 March 2013 (2013-03-31), pages 590 - 595, XP055642654, ISSN: 0253-2786, DOI: 10.6023/cjoc201211019 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020119772A1 (zh) * 2018-12-14 2020-06-18 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

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