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

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
hydrochloride
polymorph
water
alcohol
group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2018/089222
Other languages
English (en)
French (fr)
Chinese (zh)
Inventor
杨春皓
缪泽鸿
谭村
宦霞娟
丁健
陈奕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
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
Priority to US16/623,297 priority Critical patent/US11174237B2/en
Priority to JP2020519169A priority patent/JP7432503B2/ja
Priority to SG11201912281PA priority patent/SG11201912281PA/en
Priority to KR1020207000951A priority patent/KR102458566B1/ko
Priority to CA3067336A priority patent/CA3067336C/en
Priority to EP18818471.7A priority patent/EP3643708B1/en
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to AU2018286057A priority patent/AU2018286057B2/en
Publication of WO2018228205A1 publication Critical patent/WO2018228205A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2020/00224A priority patent/ZA202000224B/en
Priority to JP2021194722A priority patent/JP2022060192A/ja
Ceased legal-status Critical Current

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
    • C07D307/82—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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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 Ceased WO2018228205A1 (zh)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2020519169A JP7432503B2 (ja) 2017-06-14 2018-05-31 塩酸メフパリブの多形体およびその製造方法と使用
SG11201912281PA SG11201912281PA (en) 2017-06-14 2018-05-31 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof
KR1020207000951A KR102458566B1 (ko) 2017-06-14 2018-05-31 메푸파리브 히드로클로라이드 다결정형 물질 및 이의 제조방법과 응용
CA3067336A CA3067336C (en) 2017-06-14 2018-05-31 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof
EP18818471.7A EP3643708B1 (en) 2017-06-14 2018-05-31 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof
US16/623,297 US11174237B2 (en) 2017-06-14 2018-05-31 2-[4-(meihylaminomethyl)phenyl]-5-fluoro- benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof
AU2018286057A AU2018286057B2 (en) 2017-06-14 2018-05-31 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof
ZA2020/00224A ZA202000224B (en) 2017-06-14 2020-01-13 2-[4-(methylaminomethyl)phenyl]-5-fluoro-benzofuran-7-carboxamide hydrochloride polymorph, preparation method therefor and application thereof
JP2021194722A JP2022060192A (ja) 2017-06-14 2021-11-30 塩酸メフパリブの多形体およびその製造方法と使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710449281.2A CN109134409B (zh) 2017-06-14 2017-06-14 盐酸美呋哌瑞多晶型物及其制备方法与应用
CN201710449281.2 2017-06-14

Publications (1)

Publication Number Publication Date
WO2018228205A1 true WO2018228205A1 (zh) 2018-12-20

Family

ID=64660851

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/089222 Ceased WO2018228205A1 (zh) 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

Country Status (11)

Country Link
US (1) US11174237B2 (enExample)
EP (1) EP3643708B1 (enExample)
JP (2) JP7432503B2 (enExample)
KR (1) KR102458566B1 (enExample)
CN (1) CN109134409B (enExample)
AU (1) AU2018286057B2 (enExample)
CA (1) CA3067336C (enExample)
SG (1) SG11201912281PA (enExample)
TW (1) TWI675027B (enExample)
WO (1) WO2018228205A1 (enExample)
ZA (1) ZA202000224B (enExample)

Cited By (2)

* 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
JP2023514794A (ja) * 2020-02-24 2023-04-10 フーカン（シャンハイ） ヘルス テクノロジー カンパニー、 リミテッド ポリａｄｐリボースポリメラーゼ阻害剤の抗コロナウイルス応用

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
CN105246875A (zh) * 2013-09-03 2016-01-13 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
CN111320596B (zh) * 2018-12-14 2024-07-05 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 (2)

* 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
JP2023514794A (ja) * 2020-02-24 2023-04-10 フーカン（シャンハイ） ヘルス テクノロジー カンパニー、 リミテッド ポリａｄｐリボースポリメラーゼ阻害剤の抗コロナウイルス応用

Also Published As

Publication number Publication date
US20200172502A1 (en) 2020-06-04
TW201904952A (zh) 2019-02-01
US11174237B2 (en) 2021-11-16
AU2018286057A1 (en) 2020-01-30
TWI675027B (zh) 2019-10-21
EP3643708C0 (en) 2025-09-24
ZA202000224B (en) 2021-08-25
EP3643708A4 (en) 2021-02-24
KR102458566B1 (ko) 2022-10-24
JP2022060192A (ja) 2022-04-14
CN109134409B (zh) 2023-09-29
EP3643708A1 (en) 2020-04-29
CA3067336A1 (en) 2018-12-20
EP3643708B1 (en) 2025-09-24
JP2020524707A (ja) 2020-08-20
CA3067336C (en) 2022-11-15
SG11201912281PA (en) 2020-01-30
JP7432503B2 (ja) 2024-02-16
AU2018286057B2 (en) 2021-03-18
KR20200014924A (ko) 2020-02-11
CN109134409A (zh) 2019-01-04

Similar Documents

Publication Publication Date Title
CN101970425B (zh) 4-氨基-5-氟-3-[5-(4-甲基哌嗪-1-基)-1h-苯并咪唑-2-基]喹啉-2(1h)-酮乳酸盐的结晶形式和两种溶剂化形式
US20040010151A1 (en) Lansoprazole polymorphs and processes for preparation thereof
AU2023223327A1 (en) POLYMORPHIC FORM OF REDUCED β-NICOTINAMIDE MONONUCLEOTIDE DISODIUM SALT, AND PREPARATION METHOD THEREFOR AND USE 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
EP1507531A2 (en) Stable pharmaceutical compositions of desloratadine
CN107709304B (zh) 苯基氨基嘧啶化合物或其盐的多晶型物
WO2020119772A1 (zh) 盐酸美呋哌瑞多晶型物及其制备方法
WO2025002355A9 (zh) 一种jak2抑制剂的晶型及制备方法
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
CN111732586A (zh) 含炔基化合物盐的晶型、制备方法及应用
US20240279167A1 (en) Crystalline polymorphs of rigosertib sodium
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
WO2025094081A2 (en) Solid state forms of deutivacaftor and process thereof
WO2006098834A2 (en) Crystalline forms of ziprasidone mesylate
WO2025257758A1 (en) Solid state forms of navacaprant
US20220009893A1 (en) Solid state forms of reproxalap
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
WO2018049634A1 (zh) Abt-199加成盐及其晶型、其制备方法和药物组合物
WO2018054359A1 (zh) 一种喹唑啉衍生物的盐、其制备方法及应用

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: 18818471

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3067336

Country of ref document: CA

Ref document number: 2020519169

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20207000951

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2018286057

Country of ref document: AU

Date of ref document: 20180531

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2018818471

Country of ref document: EP

Effective date: 20200114

WWG Wipo information: grant in national office

Ref document number: 2018818471

Country of ref document: EP