WO2022199707A1 - Pharmaceutically acceptable salt of pimavanserin, and preparation method therefor, pharmaceutical composition containing same, and use thereof - Google Patents

Pharmaceutically acceptable salt of pimavanserin, and preparation method therefor, pharmaceutical composition containing same, and use thereof Download PDF

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WO2022199707A1
WO2022199707A1 PCT/CN2022/083287 CN2022083287W WO2022199707A1 WO 2022199707 A1 WO2022199707 A1 WO 2022199707A1 CN 2022083287 W CN2022083287 W CN 2022083287W WO 2022199707 A1 WO2022199707 A1 WO 2022199707A1
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pimaserin
solvent
acid
hydroxy
preparation
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PCT/CN2022/083287
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French (fr)
Chinese (zh)
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陈志祥
朱涛
刘爽
施晓红
王婷婷
应述欢
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上海博志研新药物技术有限公司
上海博志研新药物研究有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • 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 invention belongs to the technical field of medicine, and in particular relates to a medicinal salt of pimaserin and a preparation method and application thereof.
  • Pimavanserin is an atypical antipsychotic that is an inverse agonist and antagonist of the serotonin 5-HT2A receptor.
  • Pemaserin is available in the United States as form of sales. Contains pemaserin hemitartrate, indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (also known as PDP), and is widely used clinically.
  • Pimaserin N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenyl Methyl)urea
  • the molecular formula is C 25 H 34 FN 3 O 2
  • the molecular weight is 427.55
  • the CAS number is 706779-91-1
  • the chemical structural formula is shown in the following formula.
  • pimaserin tablets and capsules the raw material of which is pimaserin hemi-tartrate crystal form C, which are oral preparations that require daily administration and can only reach effective plasma levels within a limited time range . Due to the need for frequent dosing, the patient's medication compliance is poor.
  • Patent document CN 101031548 A discloses various salt forms of pimaserin (including phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, clavulanate, isothiosulfate, borate, halide, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate , oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannin, tosylate, valerate, ethanesulfonate , benzenesulfonate, p-toluenesulfonate, 2-ethanedisulfonate and naphthoate) and compositions comprising these salts; and further discloses citrate, fumarate, maleate, Crystal form, preparation method and solubility in water of malate, phosphate, succinate,
  • Patent document CN 1816524A discloses pimaserin L-tartrate.
  • Patent document CN 101035759 A discloses pimaserin hemitartrate crystal form A to crystal form F, and discloses that crystal form C is highly water-soluble, with a solubility of about 50 to 100 mg/mL, and crystal forms A, B, D, E and F has a high water solubility higher than 200 mg/mL, and Form C has higher thermodynamic and chemical stability than Form A or Form B.
  • Patent document CN 106916098 A discloses pimaserin monotartrate hemihydrate.
  • Patent document CZ 2015702 A discloses pimaserin dibenzoyl L-tartrate, hydrochloride, p-toluenesulfonate, benzenesulfonate, 4-hydroxybenzoate, benzoate, Hydrobromide, mesylate and their crystalline or amorphous forms.
  • Patent document WO 2018007842 A1 discloses pimaserin besylate, cyclamate, p-toluenesulfonate, benzoate and mandelate.
  • pimaserin salts and their crystalline forms that can prolong the efficacy of the drug and are suitable for long-acting preparations, so as to ensure that the drug can play a long-term role in the patient's body. Reduce the frequency of medication and improve the clinical efficacy of patients.
  • sustained-release dosage form of pemaserin and a pimaserin salt and its crystalline form suitable for the application of the sustained-release dosage form are very useful for maintaining treatment and improving patient compliance.
  • the present invention provides a medicinal salt of pimaserin, which is a salt formed by pimaserin free base and an organic acid having more than six carbons, wherein the structure of pimaserin free base is as formula I shown:
  • the organic acids with more than six carbons in the present invention are C6 - C30 organic acids, including but not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, sebacic acid, tenacic acid Monodecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, eicosanoic acid Pentadecanoic acid, behenic acid, heptacosanoic acid, octaco
  • the medicinal salt of pimaserin is pimaserin hemipamoate or pimaserin 1-hydroxy-2-naphthoate.
  • the pharmaceutical salt of pimaserin is in the form of crystal, polymorph or amorphous.
  • the pharmaceutically acceptable salt of pimaserin includes its solvate formed with a solvent.
  • the "solvate” includes a hydrate of a pharmaceutically acceptable salt of pimaserin or a solvate formed by a pharmaceutically acceptable salt of pimaserin and an organic solvent.
  • the organic solvent can be one, two or more of methanol, ethanol, dimethyl sulfoxide and N,N-dimethylformamide, preferably methanol and/or N,N-dimethylformamide formamide.
  • the pimaserin hemipamoic acid salt is a salt formed by compounding pimaserin and pamoic acid in a molar ratio of 1:0.5.
  • the pimaserin hemi-pamoate salt may be a pimaserin hemi-pamoate crystal form A, a pimaserin hemi-pamoate crystal form B or an amorphous form.
  • the X-ray powder diffraction pattern of the crystalline form A of pimaserin hemipramogenate has 2 ⁇ values of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, and 7.5° ⁇ 0.2°. Diffraction peaks.
  • the X-ray powder diffractogram of the crystalline form A of pemaserin hemipamoate has 2 ⁇ values of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.5° ⁇ 0.2°, 12.2° ⁇ 0.2° , 13.7° ⁇ 0.2°, and 17.0° ⁇ 0.2° have diffraction peaks.
  • the X-ray powder diffraction pattern of the crystalline form A of pemaserin hemipamoate has 2 ⁇ values of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.5° ⁇ 0.2°, 12.2° ⁇ 0.2 There are diffraction peaks at °, 13.7° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the pimaserine hemipamoate crystal form A is basically as shown in FIG. 6 .
  • the differential scanning calorimetry analysis diagram of the crystalline form A of pimaserin hemipamoate is substantially as shown in FIG. 4 , and FIG. 4 shows that its melting point is about 180° C., and the peak value is about 186° C. °C.
  • thermogravimetric analysis diagram of the crystalline form A of the pimaserin hemipamoate salt is substantially as shown in FIG. 5 , and FIG. 5 shows that the weight loss at 100° C. is about 0.2%.
  • the X-ray powder diffraction pattern of the crystalline form B of pimaserin hemipamoate has 2 ⁇ values of 6.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, and 19.9° ⁇ 0.2°. Diffraction peaks.
  • the X-ray powder diffractogram of the crystalline form B of pemaserin hemipamoate has 2 ⁇ values of 6.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 19.9° ⁇ 0.2°, 9.6° ⁇ 0.2° , 13.0° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.9° ⁇ 0.2° have diffraction peaks.
  • the X-ray powder diffraction pattern of the crystalline form B of pemaserin hemipamoate has 2 ⁇ values of 6.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 9.6° ⁇ 0.2°, 13.0° ⁇ 0.2 °, 13.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.9° ⁇ 0.2°, There are absorption peaks at 20.2° ⁇ 0.2° and 20.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the pemaserin hemipamoate crystal form B is basically as shown in FIG. 8 .
  • the 1-hydroxy-2-naphthoic acid salt of pimaserin is a salt formed by compounding pimaserin and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, which can be It is the crystalline form A of pimaserin 1-hydroxy-2-naphthoate or the crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 13.2° ⁇ 0.2°, 18.6° There are diffraction peaks at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 8.8° ⁇ 0.2°, 13.2° ⁇ 0.2°, There are characteristic peaks at 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, and 20.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.8° ⁇ 0.2° , 13.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.2° ⁇ 0.2° have absorption peaks.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.8° ⁇ 0.2° , 11.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.6 There are absorption peaks at ° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 25.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pemaserin is basically as shown in FIG. 11 .
  • the differential scanning calorimetry analysis diagram of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin is substantially as shown in FIG. 9 , and FIG. 9 shows that its melting point is about 166° C. , the peak value is about 169°C.
  • thermogravimetric analysis diagram of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is substantially as shown in FIG. 10 , and FIG. 10 shows that its weight loss at 100° C. is about 0.05% .
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2° , There are diffraction peaks at 14.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.2° ⁇ There are diffraction peaks at 0.2°, 15.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 20.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.7° There are diffraction peaks at ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, 21.3° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.0° ⁇ 0.2°, 25.3° ⁇ 0.2°, 26.8° ⁇ 0.2 There is an absorption peak at °.
  • the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 14 .
  • the differential scanning calorimetry analysis diagram of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 12 , and FIG. 12 shows that it is in There is an endothermic peak between 100°C and 150°C, which is caused by the removal of crystal water, the melting point is about 168°C, and the peak is about 169°C.
  • thermogravimetric analysis diagram of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 13 , and FIG. 13 shows that it is before 110° C. There is a period of about 2.6% weight loss, which is about one molecule of crystal water, which is the crystalline form of Pimaserin 1-hydroxy-2-naphthoate monohydrate.
  • the NMR data of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin shows that pimaserin and 1-hydroxy-2-naphthoic acid have a molar ratio of 1 :1 into salt.
  • the present invention also provides the above-mentioned preparation method of the pharmaceutical salt of pimaserin, which comprises the following steps: reacting the free base of pimaserin with the organic acid with more than six carbons.
  • the reaction may be referred to as a "salt formation reaction” or a “neutralization reaction”.
  • the preparation method of the pharmaceutical salt of pimaserin is carried out in a solvent selected from the group consisting of water, methanol, ethyl acetate, tetrahydrofuran, isopropanol, dichloromethane, N, One, two or more of N-dimethylformamide, acetone, methyl tert-butyl ether and isopropyl ether solvents.
  • the mass-volume ratio of pimaserin to the organic solvent is (1:10) g/mL ⁇ (1:50) g/mL Or 20 ⁇ 600mg/mL, preferably (1:10)g/mL ⁇ (1:30)g/mL or 40 ⁇ 550mg/mL; for example 50mg/mL, 214mg/mL, 42.8mg/mL, 416.7mg/mL , 400 mg/mL, 501 mg/mL, 90.8 mg/mL, 166.7 mg/mL or 142.7 mg/mL.
  • the molar ratio of pimaserin to the organic acid is preferably (1:0.5) ⁇ (1:3), more preferably (1:0.5) ) ⁇ (1:1), for example (2 ⁇ 0.33):1, preferably (2 ⁇ 0.5):1; for example 1.9:1, 1.8:1, 1.55:1, 1.33:1, 1.40:1, 0.88: 1 or 0.83:1.
  • the reaction temperature may be 0-80°C, preferably 25°C-65°C, for example 20°C-35°C.
  • the reaction time in the preparation method of the pharmaceutically acceptable salt of pimaserin, can be monitored by a conventional detection method in the art (such as TLC, HPLC or NMR), generally with pimaserin
  • a conventional detection method in the art such as TLC, HPLC or NMR
  • the end of the reaction is when the free base disappears, and the reaction time is 0.5 hours to 10 days, preferably 1 hour to 7 days.
  • the preparation method of the pharmaceutical salt of pimaserin comprises the following steps:
  • Method 1 Mix the solution formed by pimasholine and a good solvent with an organic acid, and then add a poor solvent to crystallize; or,
  • Method 2 Add the solution formed by pimazoline, good solvent and organic acid into poor solvent, and crystallize; or,
  • Method 3 removing the solvent from the solution formed by the pimachromoline, the solvent and the organic acid for crystallization; the solvent is a good solvent or a mixed solvent of a good solvent and a poor solvent.
  • the preparation method of the Pimaserin Hemipamoate Crystal Form A is selected from one of the following methods:
  • Method (a3) adding pimaserine and pamoic acid to a good solvent for stirring reaction, filtering, adding the filtrate to a poor solvent, optionally, adding a crystalline form of pimaserine hemipamoate to the poor solvent A seed crystal, stirring and crystallization.
  • the good solvent is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent (eg ethyl acetate) ), acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, one, two or more of N,N-dimethylformamide and N,N-dimethylacetamide .
  • alcohol solvent eg methanol
  • a ketone solvent eg acetone
  • an ester solvent eg ethyl acetate
  • the poor solvent is an alkane-based solvent, an ether-based solvent (such as isopropyl ether or methyl tert-butyl ether) and a solvent in water One, two or more.
  • the molar ratio of pimaserin to pamoic acid in the methods (a1), (a2) and (a3) is (0.5-2):1, for example 0.88:1, 1.8:1 or 1.9:1;
  • the mass-volume ratio of the pimaserin to the good solvent is 40-214 mg/mL, for example, 50 mg/mL or 214 mg/mL; when the method (a3) is adopted , the mass-volume ratio of the pimaserin to the good solvent is 416-501 mg/mL, for example, 416.7 mg/mL, 400 mg/mL or 501 mg/mL.
  • the volume ratio of the poor solvent to the good solvent is (5-9):1, such as 8:1 or 9:1; when the method (3) is adopted, the The volume ratio of the poor solvent to the good solvent is (4-21):1, for example, 20.8:1, 4:1 or 20:1.
  • the temperature for stirring and crystallization is room temperature.
  • the stirring and crystallization time is 18 hours to 7 days.
  • the stirring and crystallization time is 18-24 hours.
  • the preparation method of the pimaserin hemipamoate crystal form B includes the following steps: dispersing pamoic acid in a solvent to obtain a suspension, dissolving pimaserine in a solvent to obtain a free base solution, the free base solution is added dropwise to the suspension and the reaction is stirred; optionally, in the process of stirring the reaction, the crystal form A of the pimaserin hemipamoate as described above is added as a seed crystal.
  • the solvent in the method for preparing the crystalline form B of pimaserin hemipamoate is selected from ester solvents, such as ethyl acetate.
  • the method for preparing the amorphous form of pimaserin hemipamoate comprises the following steps: dissolving pemaserin hemipamoate in a solvent, and volatilizing the solvent until the solvent is dry to obtain pemaserin Linsemipamoate amorphous.
  • the solvent in the amorphous preparation method is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent, an ether solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran), One, two or more of alkane-based solvents, acetonitrile, dichloromethane, chloroform, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and water.
  • an alcohol solvent eg methanol
  • a ketone solvent eg acetone
  • an ester solvent eg tetrahydrofuran, 2-methyltetrahydrofuran
  • an ether solvent eg tetrahydrofuran, 2-methyltetrahydrofuran
  • the mass-to-volume ratio of the pimaserin hemipamoate to the solvent may be 1-500 mg/mL, preferably 10-125 mg/mL, such as 90.8 mg/mL, 20.8 mg/mL, 10mg/mL or 125mg/mL.
  • the volatilization mode may be normal pressure volatilization or reduced pressure volatilization.
  • the volatilization temperature may be 0-60°C, preferably 20-40°C.
  • the preparation method of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is selected from one of the following methods:
  • Method (b1) separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, stir to react, add a poor solvent, and stir to crystallize; or,
  • Method (b2) separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, and crystallize by stirring.
  • the good solvent is selected from one, two or three kinds of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably N,N-dimethylformamide. amide;
  • the mass ratio of described pimaserin and 1-hydroxy-2-naphthoic acid is 2:1;
  • the poor solvent is selected from one, two or three kinds of alkane solvents, ether solvents and water, preferably water;
  • the volume ratio of the poor solvent to the good solvent is (1-20):1, for example, 8:1.
  • the temperature of the stirring and crystallization can be room temperature, and the time of stirring and crystallization can be 1-12 hours.
  • the good solvent is an alcohol solvent and/or an ester solvent, and the alcohol solvent is preferably isopropanol; the ester solvent is preferably ethyl acetate.
  • the volume-to-mass ratio of the good solvent to pemaserin is 1 mL/g to 25 mL/g, for example, 6 mL/g, 15 mL/g or 23.4 mL/g.
  • the molar ratio of the described pimaserin and 1-hydroxy-2-naphthoic acid is preferably (0.5 ⁇ 1.5):1, for example 0.83:1;
  • the temperature of the stirring and crystallization is room temperature, and the time of stirring and crystallization is 18-24 hours.
  • the preparation method of the Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is selected from one of the following methods:
  • the good solvent is a ketone solvent, preferably acetone.
  • the molar ratio of the pimaserin to the 1-hydroxy-2-naphthoic acid is (0.5-1.5):1, for example, 0.88:1.
  • the temperature of the stirring reaction is room temperature, and the time of the stirring reaction is 1-12 hours.
  • the poor solvent is one, two or three kinds of alkane solvents, ether solvents and water, preferably water.
  • the volume ratio of the poor solvent to the good solvent is (1-20):1, for example, 8:1.
  • the temperature of the stirring and crystallization is room temperature, and the time of the stirring and crystallization is 1-12 hours.
  • the solvent is one, two or more of alcohol-based solvent, ketone-based solvent, ester-based solvent, ether-based solvent, alkane-based solvent, dichloromethane, chloroform, dimethyl sulfoxide and water.
  • the alcohol solvent is preferably methanol.
  • the ester solvent is preferably ethyl acetate.
  • the ether solvent is preferably tetrahydrofuran.
  • the volatilization temperature is room temperature.
  • Described solvent is selected from the mixed solvent that water or water and organic solvent form;
  • Described organic solvent is selected from one in alcohol solvent, ester solvent, ketone solvent, ether solvent, nitrile solvent and amide solvent.
  • the alcohol solvent is preferably one, two or more of methanol, ethanol, n-propanol and isopropanol.
  • the ester solvent is preferably ethyl acetate and isopropyl acetate.
  • the ketone solvent is preferably acetone.
  • the nitrile solvent is preferably acetonitrile.
  • the ether solvent is preferably tetrahydrofuran.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the volume ratio of the water to the organic solvent is preferably (1-5):1, such as 4:1, 5:1, 3.5:1, 2.5:1 or 2:1.
  • the solvent is further preferably a mixed solvent of ethanol and water, a mixed solvent of methanol and water, a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, a mixed solvent of n-propanol and water, a mixed solvent of acetonitrile and water, N , Mixed solvent of N-dimethylformamide and water, isopropanol or ethyl acetate.
  • the volume-to-mass ratio of the solvent to pimazoline is preferably 10 mg/mL to 50 mg/mL, for example, 30 mg/mL or 35 mg/mL.
  • Described stirring temperature is 10 °C ⁇ 60 °C;
  • the stirring time is 3 to 10 days.
  • the good solvent is alcohol solvent, ketone solvent, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane One, two or more of hexacyclic, dichloromethane and chloroform;
  • the poor solvent is one, two or three kinds of alkane solvents, ether solvents and water.
  • the high temperature is 60°C ⁇ 80°C;
  • the solvent is selected from alcohol solvents, ketone solvents, ether solvents, ester solvents, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, dimethyl sulfoxide and water. One, two or more.
  • the present invention also provides the use of the pharmaceutical salt of pemaserin as described above in the preparation of a medicament for preventing, treating or ameliorating the frequency and/or severity of hallucinations, delusions, and/or delusions associated with Parkinson's psychosis.
  • the present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of pimaserin as described above.
  • the pharmaceutical composition may further include pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to a patient in need thereof, such as a human or other mammalian organism.
  • the pharmaceutically acceptable adjuvants include one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
  • the present invention also provides a pimaserin pharmaceutical preparation, which comprises the pimaserin pharmaceutical salt or the pimaserin pharmaceutical composition.
  • the dosage forms of the pharmaceutical preparations of pimaserin include but are not limited to tablets, capsules, solutions, suspensions and semi-solid preparations.
  • the pharmaceutical preparation of pimaserin is a pharmaceutically acceptable salt suspension of pimaserin.
  • the pimaserin pharmaceutical salt suspension may further include auxiliary materials, and the auxiliary materials may be selected from suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and One, two or more of the surfactants.
  • the concentration of the solid particles of pemaserin in the pimaserin pharmaceutical salt suspension is 62 mg/mL to 124 mg/mL.
  • the pimaserin solid particles are pimaserin, pimaserin pharmaceutically acceptable salts, and the pimaserin pharmaceutically acceptable salts include but are not limited to pimaserin hemipamoic acid salt and pimaserin 1-hydroxy-2-naphthoate.
  • the concentration of the wetting agent ranges from 1 mg/mL to 10 mg/mL, preferably from 1 mg/mL to 5 mg/mL, such as 1 mg/mL, 1.5 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL or 5.0 mg/mL.
  • the wetting agent is selected from one, two or three of Tween 20, Tween 80 and Poloxamer 188, preferably Poloxamer 188.
  • the buffering agent is selected from one, two or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
  • the preparation method of the pharmaceutical salt suspension of pimaserin comprises the following steps:
  • step (e3) add the solution prepared by step (e2) to the sieved pimaserin medicinal salt solid particles, fully wet and disperse;
  • the present invention also provides a method for preventing, treating or ameliorating the frequency and/or severity of hallucinations, delusions, and/or delusions associated with Parkinson's psychosis, comprising adding a pharmaceutically acceptable salt of pimaserin as described above, or a pharmaceutical composition thereof, Or a pharmaceutical formulation of pimaserin is administered to a patient in need thereof.
  • the "crystal” described in the present invention is a structure in which a large number of microscopic material units (atoms, ions, molecules, etc.) are arranged in an orderly manner according to certain rules.
  • polymorphism refers to different crystalline forms and other solid-state molecular forms of the same compound, for example, including two or more crystalline forms and/or amorphous forms of the pharmaceutically acceptable salt of pimaserin form of solid.
  • Amorphous refers to the constitution of an amorphous solid (amorphous).
  • the "carrier”, “diluent”, “vehicle” or “excipient” refers to a substance (or substances) that can be included with a specific agent to form a drug composition, and can be solid or liquid.
  • the solid carriers include but are not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • the liquid carrier includes, but is not limited to, syrup, peanut oil, olive oil, saline solution, water, and the like.
  • the carrier or diluent may include delayed or timed release materials known in the art, such as monostearic acid alone or in combination with waxes, ethyl cellulose, hypromellose, methyl methacrylate, and the like Glycerides or Glyceryl Distearate.
  • the "pharmaceutically acceptable excipients” refer to the following substances, which are suitable for contact with the patient's tissue without inappropriate toxicity, irritation, allergic reaction within the scope of normal medical judgment etc., have a reasonable ratio of pros and cons, and can be effectively used for their intended purpose.
  • the "solvate” refers to a molecular complex comprising a drug (eg, pimaserin) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg, water).
  • a drug eg, pimaserin
  • solvent molecules eg, water
  • the complex formed has a well-defined stoichiometry independent of humidity.
  • the solvent is weakly binding (as in channel solvates and hygroscopic compounds)
  • the solvent content is dependent on humidity and drying conditions.
  • the complex is generally non-stoichiometric.
  • the "hydrate” refers to a solvate containing a drug (eg, pimaserin) and stoichiometric or non-stoichiometric water.
  • the “overnight” means that the time is 12 to 24 hours.
  • the "patient” includes organisms such as humans or other mammals.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to the ambient temperature, which is generally 0°C to 35°C.
  • the technical problem to be solved by the present invention is to provide a medicinal salt of pimaserin, a preparation method, The pharmaceutical composition containing it and the application of the pharmaceutical composition.
  • the medicinal salt of pimaserin provided by the invention has no pH dependence, has low solubility in water (compared with the existing salt form, its solubility is significantly reduced), good stability, simple and convenient preparation method, and is suitable for industrialization Production.
  • the NMR test was carried out on Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400Mz/600Mz, and the solvent was deuterated DMSO.
  • the TGA measurement was carried out in a TA Instruments model Q2000 device, and the sample (about 2-5 mg) was weighed in a platinum pan and transferred to the instrument for measurement.
  • the test parameters are as follows: the instrument is heated to 350°C at a rate of 10°C/min, and the experimental atmosphere is nitrogen.
  • XRPD measurements were performed in a Bruker model D8 Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage.
  • the scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3°-45°, scanning step size 0.02°, and scanning mode is continuous scanning.
  • the X-ray powder diffraction pattern of pimaserin free base at 2 ⁇ is approximately 6.790°, 8.093°, 12.945°, 13.655°, 14.364°, 14.901°, 17.012°, 17.687°, 19.045°, 19.697°, 20.839°, There are diffraction peaks at 21.036°, 22.219°, 24.531°, 25.219°, 25.733°, 27.133°, 27.922°, 28.971°, 30.669° and 32.935°, with an error range of ⁇ 0.2°.
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • DSC Differential scanning calorimetry curve
  • Thermogravimetric analysis showed that the weight loss of pemaserin hemipamoic acid was 0.2270% at 100°C, see Figure 5 for details.
  • PLM Polarized light microscopy
  • X-ray powder diffractogram shows that pimaserin hemipamoate has diffraction peaks, and it is judged to be a crystalline form based on PLM, and it is named as pimaserin hemipamoate crystal form A, as shown in the figure for details. 6.
  • Embodiment 10 Preparation of amorphous form of pemaserin hemipamoate
  • Example 3 Take 25 mg of the Pimaserin crystal form A sample prepared in Example 3, add 2 mL of acetone to dissolve it, and volatilize it to dryness at room temperature and pressure. The obtained sample is characterized by PLM, and it is a non-polarized solid.
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • Pimaserin 1-hydroxy-2-naphthoate The X-ray powder diffraction pattern of Pimaserin 1-hydroxy-2-naphthoate is shown in Figure 14, which has a diffraction peak different from that of Pimaserin 1-hydroxy-2-naphthoate crystal form A, which is a This new crystal form can be determined to be a monohydrate with reference to Figure 13, so it is named Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.
  • Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16 Take 30 mg of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 1 mL of water and 1 mL of ethanol, stir to dissolve at 60°C, and keep it at room temperature for about 2 minutes and stir for 24 hours. , centrifugation, and drying to obtain the crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate.
  • Example 1 in Patent Document CN105924381A also refer to Example 1 in Patent Document CN106008323A
  • the crystalline form C of Pimaserin hemitartrate was prepared.
  • the crystalline form A of pimaserin hemipamoate, the crystalline form A of pimaserin 1-hydroxy-2-naphthoate salt and the crystalline form A of pimaserin 1-hydroxy-2 -Naphthoate monohydrate crystal form B has lower solubility than pimaserin under both acidic and neutral conditions, and the lower the pH, the greater the difference.
  • the crystalline form A of Pimaserin hemipamoate, the crystalline form A of Pimaserin 1-hydroxy-2-naphthoate and the 1-hydroxy-2-naphthalene of Pimaserin of the present invention are shown in Table 2.
  • the formate monohydrate crystal form B is relatively stable under various conditions and is suitable for the development of pharmaceutical preparations.
  • Example Dv10( ⁇ m) Dv50( ⁇ m) Dv90( ⁇ m) Example 49 1.357 6.219 14.334
  • Example 50 0.898 3.294 8.917
  • Example 51 0.848 3.292 8.945
  • Embodiment 56 Prescription stability investigation
  • results are shown in the following table.
  • the results show that the prescription samples of pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B are relatively stable under various conditions, and the pimaserine hemipamoate crystal form A is stable.
  • the formulation samples were stable except for slight degradation under long-term light conditions.

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Abstract

Provided are a pharmaceutically acceptable salt of pimavanserin, and a preparation method therefor, a pharmaceutical composition containing same, and the use thereof. The pharmaceutically acceptable salt of pimavanserin is a salt formed from a pimavanserin free base and an organic acid having no less than six carbon atoms. The prepared pharmaceutically acceptable salt of pimavanserin has good solubility and stability, is convenient to prepare, and is suitable for large-scale industrial production.

Description

哌马色林药用盐、制备方法、含其的药物组合物及应用Medicinal salt of pimaserin, preparation method, pharmaceutical composition containing same and application
本申请要求享有如下在先申请的优先权权益：2021年3月26日向中国国家知识产权局提交的申请号为202110330687.5，发明名称为“哌马色林药用盐、制备方法、含其的药物组合物及应用”的中国发明专利申请。上述在先申请的全文以引用的方式结合至本申请。This application claims to enjoy the priority rights of the following prior applications: the application number submitted to the State Intellectual Property Office of China on March 26, 2021 is 202110330687.5, and the name of the invention is "Piemaserin medicinal salt, preparation method, medicine containing it" Chinese Invention Patent Application for "Composition and Application". The entire contents of the aforementioned prior applications are incorporated by reference into the present application.
技术领域technical field
本发明属于医药技术领域，具体涉及哌马色林药用盐及其制备方法和应用。The invention belongs to the technical field of medicine, and in particular relates to a medicinal salt of pimaserin and a preparation method and application thereof.
背景技术Background technique
哌马色林(Pimavanserin)是一种非典型的抗精神病药，它是5-羟色胺5-HT2A受体的反向激动剂和拮抗剂。哌马色林在美国以
Figure PCTCN2022083287-appb-000001
的形式销售。
Figure PCTCN2022083287-appb-000002
含有哌马色林半酒石酸盐，被指定用于治疗与帕金森氏病精神病(也称为PDP)相关的幻觉和妄想，在临床中应用广泛。 Pimavanserin is an atypical antipsychotic that is an inverse agonist and antagonist of the serotonin 5-HT2A receptor. Pemaserin is available in the United States as
Figure PCTCN2022083287-appb-000001
form of sales.
Figure PCTCN2022083287-appb-000002
Contains pemaserin hemitartrate, indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (also known as PDP), and is widely used clinically.
哌马色林化学名称为N-(4-氟苄基)-N-(1-甲基哌啶-4-基)-N’-(4-(2-甲基丙氧基)-苯基甲基)脲，分子式为C 25H 34FN 3O 2，分子量427.55，CAS号706779-91-1，化学结构式如下式所示。 The chemical name for Pimaserin is N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenyl Methyl)urea, the molecular formula is C 25 H 34 FN 3 O 2 , the molecular weight is 427.55, the CAS number is 706779-91-1, and the chemical structural formula is shown in the following formula.
Figure PCTCN2022083287-appb-000003
Figure PCTCN2022083287-appb-000003
目前上市的是哌马色林片剂和胶囊，其原料为哌马色林半酒石酸盐晶型C，均为口服制剂，需要每日给药，只能在有限的时间范围内达到有效血浆水平。由于需要频繁给药，使得患者的用药依从性差。Currently on the market are pimaserin tablets and capsules, the raw material of which is pimaserin hemi-tartrate crystal form C, which are oral preparations that require daily administration and can only reach effective plasma levels within a limited time range . Due to the need for frequent dosing, the patient's medication compliance is poor.
专利文献CN 101031548 A公开了哌马色林的多种盐型(包括磷酸盐、硫酸盐、硝酸盐、二磷酸盐、碳酸氢盐、碳酸盐、克拉维酸盐、异硫代硫酸盐、硼酸盐、卤化物、醋酸盐、琥珀酸盐、乳酸盐、乳糖酸盐、月桂酸盐、扁桃酸盐、苹果酸盐、柠檬酸盐、延胡索酸盐、马来酸盐、油酸盐、草酸盐、抗坏血酸盐、烟酸盐、苯甲酸盐、甲磺酸盐、水杨酸盐、硬脂酸盐、单宁酸盐、甲苯磺酸盐、戊酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、 2-乙烷二磺酸盐和萘甲酸盐)及包含这些盐的组合物；并进一步公开了柠檬酸盐、延胡索酸盐、马来酸盐、苹果酸盐、磷酸盐、琥珀酸盐、硫酸盐、乙二磺酸盐的晶型、制备方法及在水中的溶解度。Patent document CN 101031548 A discloses various salt forms of pimaserin (including phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, clavulanate, isothiosulfate, borate, halide, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate , oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannin, tosylate, valerate, ethanesulfonate , benzenesulfonate, p-toluenesulfonate, 2-ethanedisulfonate and naphthoate) and compositions comprising these salts; and further discloses citrate, fumarate, maleate, Crystal form, preparation method and solubility in water of malate, phosphate, succinate, sulfate and ethanedisulfonate.
专利文献CN 1816524A公开了哌马色林L-酒石酸盐。Patent document CN 1816524A discloses pimaserin L-tartrate.
专利文献CN 101035759 A公开了哌马色林半酒石酸盐晶型A至晶型F，并公开了晶型C水溶性高，溶解度约50～100mg/mL，晶型A、B、D、E和F具有高于200mg/mL的高水溶性，且晶型C与晶型A或晶型B相比，热力学和化学稳定性更高。Patent document CN 101035759 A discloses pimaserin hemitartrate crystal form A to crystal form F, and discloses that crystal form C is highly water-soluble, with a solubility of about 50 to 100 mg/mL, and crystal forms A, B, D, E and F has a high water solubility higher than 200 mg/mL, and Form C has higher thermodynamic and chemical stability than Form A or Form B.
专利文献CN 106916098 A公开了哌马色林单酒石酸盐半水合物。Patent document CN 106916098 A discloses pimaserin monotartrate hemihydrate.
专利文献CZ 2015702 A公开了哌马色林二苯甲酰L-酒石酸盐、盐酸盐、对甲基苯磺酸盐、苯磺酸盐、4-羟基苯甲酸盐、苯甲酸盐、氢溴酸盐、甲磺酸盐及其晶型或无定型。Patent document CZ 2015702 A discloses pimaserin dibenzoyl L-tartrate, hydrochloride, p-toluenesulfonate, benzenesulfonate, 4-hydroxybenzoate, benzoate, Hydrobromide, mesylate and their crystalline or amorphous forms.
专利文献WO 2018007842 A1公开了哌马色林苯磺酸盐、环己氨基磺酸盐、对甲苯磺酸盐、苯甲酸盐和扁桃酸盐。Patent document WO 2018007842 A1 discloses pimaserin besylate, cyclamate, p-toluenesulfonate, benzoate and mandelate.
已报道的哌马色林药用盐溶解度均较大，不适用于长效制剂应用，且目前无哌马色林长效注射剂的相关专利或文献报道。The reported pharmaceutical salts of pimaserin have high solubility and are not suitable for long-acting preparations, and there is no relevant patent or literature report on pimaserin long-acting injections at present.
为了满足药物制剂对于活性物质形态的严格要求，仍需要开发能延长药效且适于长效制剂应用的哌马色林盐及其晶型，以保证该药在患者体内能够长时间发挥作用，减少用药次数和提高患者的临床疗效。In order to meet the strict requirements of pharmaceutical preparations for the form of active substances, it is still necessary to develop pimaserin salts and their crystalline forms that can prolong the efficacy of the drug and are suitable for long-acting preparations, so as to ensure that the drug can play a long-term role in the patient's body. Reduce the frequency of medication and improve the clinical efficacy of patients.
因此，开发哌马色林缓释剂型和适用于缓释剂型应用的哌马色林盐及其晶型，对于维持治疗及提高病人的依从性是非常有用的。Therefore, the development of a sustained-release dosage form of pemaserin and a pimaserin salt and its crystalline form suitable for the application of the sustained-release dosage form are very useful for maintaining treatment and improving patient compliance.
发明内容SUMMARY OF THE INVENTION
为改善上述技术问题，本发明提供了哌马色林药用盐，其为哌马色林游离碱与六个碳以上的有机酸形成的盐，其中哌马色林游离碱的结构如式I所示：In order to improve the above-mentioned technical problems, the present invention provides a medicinal salt of pimaserin, which is a salt formed by pimaserin free base and an organic acid having more than six carbons, wherein the structure of pimaserin free base is as formula I shown:
Figure PCTCN2022083287-appb-000004
Figure PCTCN2022083287-appb-000004
本发明中所述六个碳以上的有机酸为C 6～C 30的有机酸，包括但不限于：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、癸二酸、十一烷酸、月桂酸(十二烷酸)、十三烷酸、肉豆蔻酸(十四烷酸)、十五烷酸、棕榈酸(十六烷酸)、十七烷酸、硬脂酸(十八烷酸)、十 九烷酸、二十烷酸(花生酸)、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸(蜂花酸)、甘油三乙酸、木质酸、双羟萘酸(棕榈酸酯)、1-羟基-2萘甲酸、帕莫酸和萘酸衍生物。所述的“萘酸衍生物”包括但不限于萘酸酯，例如包含羧基和额外的酯基官能团的萘酸。 The organic acids with more than six carbons in the present invention are C6 - C30 organic acids, including but not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, sebacic acid, tenacic acid Monodecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, eicosanoic acid Pentadecanoic acid, behenic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid (mellitic acid), triglyceride, lignin, pamoic acid (palmitate), 1-hydroxy-2 naphthoic acid, pamoic acid and naphthoic acid derivatives. The "naphthoic acid derivatives" include, but are not limited to, naphthoic acid esters, such as naphthoic acid containing a carboxyl group and an additional ester functional group.
本发明中所述哌马色林药用盐为哌马色林半帕莫酸盐或哌马色林1-羟基-2-萘甲酸盐。In the present invention, the medicinal salt of pimaserin is pimaserin hemipamoate or pimaserin 1-hydroxy-2-naphthoate.
本发明中，所述的哌马色林药用盐为晶体、多晶或无定型的形式。In the present invention, the pharmaceutical salt of pimaserin is in the form of crystal, polymorph or amorphous.
本发明中，所述的哌马色林药用盐包括其与溶剂形成的溶剂合物。所述的“溶剂合物”包括哌马色林药用盐的水合物或哌马色林药用盐与有机溶剂形成的溶剂合物。所述的有机溶剂可以为甲醇、乙醇、二甲基亚砜和N,N-二甲基甲酰胺中的一种，两种或更多种，优选甲醇和/或N,N-二甲基甲酰胺。In the present invention, the pharmaceutically acceptable salt of pimaserin includes its solvate formed with a solvent. The "solvate" includes a hydrate of a pharmaceutically acceptable salt of pimaserin or a solvate formed by a pharmaceutically acceptable salt of pimaserin and an organic solvent. The organic solvent can be one, two or more of methanol, ethanol, dimethyl sulfoxide and N,N-dimethylformamide, preferably methanol and/or N,N-dimethylformamide formamide.
根据本发明的实施方案，所述的哌马色林半帕莫酸盐为哌马色林与帕莫酸以摩尔比为1:0.5复合形成的盐。According to an embodiment of the present invention, the pimaserin hemipamoic acid salt is a salt formed by compounding pimaserin and pamoic acid in a molar ratio of 1:0.5.
根据本发明的实施方案，所述的哌马色林半帕莫酸盐可以为哌马色林半帕莫酸盐晶型A、哌马色啉半帕莫酸晶型B或无定型。According to an embodiment of the present invention, the pimaserin hemi-pamoate salt may be a pimaserin hemi-pamoate crystal form A, a pimaserin hemi-pamoate crystal form B or an amorphous form.
根据本发明的实施方案，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.5°±0.2°处有衍射峰。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form A of pimaserin hemipramogenate has 2θ values of 3.3°±0.2°, 6.7°±0.2°, and 7.5°±0.2°. Diffraction peaks.
进一步地，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.5°±0.2°、12.2°±0.2°、13.7°±0.2°、17.0°±0.2°处有衍射峰。Further, the X-ray powder diffractogram of the crystalline form A of pemaserin hemipamoate has 2θ values of 3.3°±0.2°, 6.7°±0.2°, 7.5°±0.2°, 12.2°±0.2° , 13.7°±0.2°, and 17.0°±0.2° have diffraction peaks.
更进一步地，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.5°±0.2°、12.2°±0.2°、13.7°±0.2°、17.0°±0.2°、19.5°±0.2°、20.4°±0.2°、21.1°±0.2°处有衍射峰。Further, the X-ray powder diffraction pattern of the crystalline form A of pemaserin hemipamoate has 2θ values of 3.3°±0.2°, 6.7°±0.2°, 7.5°±0.2°, 12.2°±0.2 There are diffraction peaks at °, 13.7°±0.2°, 17.0°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 21.1°±0.2°.
更进一步地，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图基本如图6所示。Further, the X-ray powder diffraction pattern of the pimaserine hemipamoate crystal form A is basically as shown in FIG. 6 .
根据本发明的实施方案，所述哌马色林半帕莫酸盐晶型A的差式扫描量热分析图基本如图4所示，图4显示其熔点约为180℃，峰值约为186℃。According to an embodiment of the present invention, the differential scanning calorimetry analysis diagram of the crystalline form A of pimaserin hemipamoate is substantially as shown in FIG. 4 , and FIG. 4 shows that its melting point is about 180° C., and the peak value is about 186° C. °C.
根据本发明的实施方案，所述哌马色林半帕莫酸盐晶型A的热重分析图基本如图5所示，图5显示其在100℃时失重约为0.2％。According to an embodiment of the present invention, the thermogravimetric analysis diagram of the crystalline form A of the pimaserin hemipamoate salt is substantially as shown in FIG. 5 , and FIG. 5 shows that the weight loss at 100° C. is about 0.2%.
根据本发明的实施方案，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图在2θ值为6.1°±0.2°、8.6°±0.2°、19.9°±0.2°处有衍射峰。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B of pimaserin hemipamoate has 2θ values of 6.1°±0.2°, 8.6°±0.2°, and 19.9°±0.2°. Diffraction peaks.
进一步地，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图在2θ值为6.1°±0.2°、 8.6°±0.2°、19.9°±0.2°、9.6°±0.2°、13.0°±0.2°、17.9°±0.2°、19.9°±0.2°处有衍射峰。Further, the X-ray powder diffractogram of the crystalline form B of pemaserin hemipamoate has 2θ values of 6.1°±0.2°, 8.6°±0.2°, 19.9°±0.2°, 9.6°±0.2° , 13.0°±0.2°, 17.9°±0.2°, 19.9°±0.2° have diffraction peaks.
更进一步地，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图在2θ值为6.1°±0.2°、8.6°±0.2°、9.6°±0.2°、13.0°±0.2°、13.3°±0.2°、15.6°±0.2°、17.0°±0.2°、17.3°±0.2°、17.9°±0.2°、18.9°±0.2°、19.1°±0.2°、19.9°±0.2°、20.2°±0.2°、20.7°±0.2°处有吸收峰。Further, the X-ray powder diffraction pattern of the crystalline form B of pemaserin hemipamoate has 2θ values of 6.1°±0.2°, 8.6°±0.2°, 9.6°±0.2°, 13.0°±0.2 °, 13.3°±0.2°, 15.6°±0.2°, 17.0°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.9°±0.2°, There are absorption peaks at 20.2°±0.2° and 20.7°±0.2°.
更进一步地，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图基本如图8所示。Further, the X-ray powder diffraction pattern of the pemaserin hemipamoate crystal form B is basically as shown in FIG. 8 .
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐为哌马色林与1-羟基-2-萘甲酸以摩尔比1:1复合形成的盐，其可以为哌马色林1-羟基-2-萘甲酸盐晶型A或哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。According to an embodiment of the present invention, the 1-hydroxy-2-naphthoic acid salt of pimaserin is a salt formed by compounding pimaserin and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, which can be It is the crystalline form A of pimaserin 1-hydroxy-2-naphthoate or the crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate.
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图在2θ值为4.3°±0.2°、13.2°±0.2°、18.6°±0.2°处有衍射峰。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2θ values of 4.3°±0.2°, 13.2°±0.2°, 18.6° There are diffraction peaks at ±0.2°.
进一步地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图在2θ值为4.3°±0.2°、8.8°±0.2°、13.2°±0.2°、17.7°±0.2°、18.6°±0.2°、20.2°±0.2°处有特征峰。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2θ values of 4.3°±0.2°, 8.8°±0.2°, 13.2°±0.2°, There are characteristic peaks at 17.7°±0.2°, 18.6°±0.2°, and 20.2°±0.2°.
更进一步地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图在2θ值为4.3°±0.2°、7.7°±0.2°、8.8°±0.2°、13.2°±0.2°、17.0°±0.2°、17.7°±0.2°、18.6°±0.2°、19.0°±0.2°、20.2°±0.2°处有吸收峰。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2θ values of 4.3°±0.2°, 7.7°±0.2°, 8.8°±0.2° , 13.2°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 20.2°±0.2° have absorption peaks.
更进一步地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图在2θ值为4.3°±0.2°、7.7°±0.2°、8.8°±0.2°、11.4°±0.2°、13.2°±0.2°、15.1°±0.2°、17.0°±0.2°、17.7°±0.2°、18.6°±0.2°、19.0°±0.2°、20.2°±0.2°、20.6°±0.2°、21.3°±0.2°、21.6°±0.2°、22.7°±0.2°、25.8°±0.2°处有吸收峰。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2θ values of 4.3°±0.2°, 7.7°±0.2°, 8.8°±0.2° , 11.4°±0.2°, 13.2°±0.2°, 15.1°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 20.6 There are absorption peaks at °±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.7°±0.2°, and 25.8°±0.2°.
更进一步地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图基本如图11所示。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pemaserin is basically as shown in FIG. 11 .
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐晶型A的差式扫描量热分析图基本如图9所示，图9显示其熔点约为166℃，峰值约为169℃。According to an embodiment of the present invention, the differential scanning calorimetry analysis diagram of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin is substantially as shown in FIG. 9 , and FIG. 9 shows that its melting point is about 166° C. , the peak value is about 169°C.
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐晶型A的热重分析图基本如图10所示，图10显示其在100℃失重约为0.05％。According to an embodiment of the present invention, the thermogravimetric analysis diagram of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is substantially as shown in FIG. 10 , and FIG. 10 shows that its weight loss at 100° C. is about 0.05% .
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图在2θ值为3.8°±0.2°、7.8°±0.2°、14.2°±0.2°处有衍射峰。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2θ values of 3.8°±0.2°, 7.8°±0.2° , There are diffraction peaks at 14.2°±0.2°.
进一步地，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图在2θ值为3.8°±0.2°、7.8°±0.2°、14.2°±0.2°、15.7°±0.2°、17.7°±0.2°、20.2°±0.2°处有衍射峰。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2θ values of 3.8°±0.2°, 7.8°±0.2°, 14.2°± There are diffraction peaks at 0.2°, 15.7°±0.2°, 17.7°±0.2°, and 20.2°±0.2°.
更进一步地，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图在2θ值为3.8°±0.2°、7.8°±0.2°、11.7°±0.2°、14.2°±0.2°、15.7°±0.2°、17.7°±0.2°、21.3°±0.2°、22.4°±0.2°处有衍射峰。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2θ values of 3.8°±0.2°, 7.8°±0.2°, 11.7° There are diffraction peaks at ±0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.7°±0.2°, 21.3°±0.2°, and 22.4°±0.2°.
更进一步地，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图在2θ值为3.8°±0.2°、7.8°±0.2°、11.7°±0.2°、14.2°±0.2°、15.7°±0.2°、17.7°±0.2°、21.3°±0.2°、22.4°±0.2°、23.0°±0.2°、25.3°±0.2°、26.8°±0.2°处有吸收峰。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2θ values of 3.8°±0.2°, 7.8°±0.2°, 11.7° ±0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.7°±0.2°, 21.3°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 25.3°±0.2°, 26.8°±0.2 There is an absorption peak at °.
更进一步地，所述的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图基本如图14所示。Further, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 14 .
根据本发明的实施方案，所述的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的差式扫描量热分析图基本如图12所示，图12显示其在100℃～150℃之间有一个吸热峰，为脱去结晶水所致，其熔点约为168℃，峰值约为169℃。According to an embodiment of the present invention, the differential scanning calorimetry analysis diagram of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 12 , and FIG. 12 shows that it is in There is an endothermic peak between 100°C and 150°C, which is caused by the removal of crystal water, the melting point is about 168°C, and the peak is about 169°C.
根据本发明的实施方案，所述的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的热重分析图基本如图13所示，图13显示其在110℃之前有一段约为2.6％的失重，约合一分子结晶水，其为哌马色林1-羟基-2-萘甲酸盐一水合物晶型。According to an embodiment of the present invention, the thermogravimetric analysis diagram of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 13 , and FIG. 13 shows that it is before 110° C. There is a period of about 2.6% weight loss, which is about one molecule of crystal water, which is the crystalline form of Pimaserin 1-hydroxy-2-naphthoate monohydrate.
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的核磁数据显示哌马色林与1-羟基-2-萘甲酸以摩尔比1:1成盐。According to an embodiment of the present invention, the NMR data of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin shows that pimaserin and 1-hydroxy-2-naphthoic acid have a molar ratio of 1 :1 into salt.
本发明还提供如上所述哌马色林药用盐的制备方法，包括以下步骤：将哌马色林游离碱与所述的六个碳以上的有机酸进行反应。The present invention also provides the above-mentioned preparation method of the pharmaceutical salt of pimaserin, which comprises the following steps: reacting the free base of pimaserin with the organic acid with more than six carbons.
优选地，所述反应可称为“成盐反应”或“中和反应”。Preferably, the reaction may be referred to as a "salt formation reaction" or a "neutralization reaction".
根据本发明的实施方案，所述哌马色林药用盐的制备方法在溶剂中进行，所述的溶剂选自水、甲醇、乙酸乙酯、四氢呋喃、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、丙酮、甲基叔丁基醚和异丙醚溶剂中的一种，两种或更多种。According to an embodiment of the present invention, the preparation method of the pharmaceutical salt of pimaserin is carried out in a solvent selected from the group consisting of water, methanol, ethyl acetate, tetrahydrofuran, isopropanol, dichloromethane, N, One, two or more of N-dimethylformamide, acetone, methyl tert-butyl ether and isopropyl ether solvents.
根据本发明的实施方案，所述哌马色林药用盐的制备方法中，哌马色林与有机溶剂的质量体积比为(1：10)g/mL～(1：50)g/mL或20～600mg/mL，优选(1：10)g/mL～(1：30)g/mL或40～550mg/mL；例如50mg/mL、214mg/mL、42.8mg/mL、416.7mg/mL、400mg/mL、501mg/mL、90.8mg/mL、166.7mg/mL或142.7mg/mL。According to an embodiment of the present invention, in the preparation method of the medicinal salt of pimaserin, the mass-volume ratio of pimaserin to the organic solvent is (1:10) g/mL～(1:50) g/mL Or 20～600mg/mL, preferably (1:10)g/mL～(1:30)g/mL or 40～550mg/mL; for example 50mg/mL, 214mg/mL, 42.8mg/mL, 416.7mg/mL , 400 mg/mL, 501 mg/mL, 90.8 mg/mL, 166.7 mg/mL or 142.7 mg/mL.
根据本发明的实施方案，所述哌马色林药用盐的制备方法中，哌马色林与有机酸的摩尔比优选(1：0.5)～(1：3)，进一步优选(1：0.5)～(1：1)，例如为(2～0.33):1，优选(2～0.5):1；例如1.9:1、1.8:1、1.55:1、1.33:1、1.40:1、0.88:1或0.83:1。According to an embodiment of the present invention, in the preparation method of the pharmaceutically acceptable salt of pimaserin, the molar ratio of pimaserin to the organic acid is preferably (1:0.5)～(1:3), more preferably (1:0.5) )～(1:1), for example (2～0.33):1, preferably (2～0.5):1; for example 1.9:1, 1.8:1, 1.55:1, 1.33:1, 1.40:1, 0.88: 1 or 0.83:1.
根据本发明的实施方案，所述哌马色林药用盐的制备方法中，反应温度可以为0～80℃，优选25℃～65℃，例如20℃～35℃。According to an embodiment of the present invention, in the preparation method of the pharmaceutically acceptable salt of pimaserin, the reaction temperature may be 0-80°C, preferably 25°C-65°C, for example 20°C-35°C.
根据本发明的实施方案，所述哌马色林药用盐的制备方法中，反应的时间可以采用本领域中的常规检测方法(例如TLC、HPLC或NMR)进行监测，一般以哌马色林游离碱消失时为反应的终点，所述反应的时间为0.5小时～10天，优选为1小时～7天。According to an embodiment of the present invention, in the preparation method of the pharmaceutically acceptable salt of pimaserin, the reaction time can be monitored by a conventional detection method in the art (such as TLC, HPLC or NMR), generally with pimaserin The end of the reaction is when the free base disappears, and the reaction time is 0.5 hours to 10 days, preferably 1 hour to 7 days.
根据本发明的实施方案，所述哌马色林药用盐的制备方法，包括以下步骤：According to an embodiment of the present invention, the preparation method of the pharmaceutical salt of pimaserin comprises the following steps:
方法1：将哌马色啉与良溶剂形成的溶液与有机酸混合，然后加入不良溶剂析晶；或者，Method 1: Mix the solution formed by pimasholine and a good solvent with an organic acid, and then add a poor solvent to crystallize; or,
方法2：将哌马色啉、良溶剂、有机酸形成的溶液加入到不良溶剂中，析晶；或者，Method 2: Add the solution formed by pimazoline, good solvent and organic acid into poor solvent, and crystallize; or,
方法3：将哌马色啉、溶剂和有机酸形成的溶液除去溶剂析晶；所述的溶剂为良溶剂或良溶剂与不良溶剂的混合溶剂。Method 3: removing the solvent from the solution formed by the pimachromoline, the solvent and the organic acid for crystallization; the solvent is a good solvent or a mixed solvent of a good solvent and a poor solvent.
根据本发明的实施方案，所述哌马色林半帕莫酸盐晶型A的制备方法选自下列方法中的一种：According to an embodiment of the present invention, the preparation method of the Pimaserin Hemipamoate Crystal Form A is selected from one of the following methods:
方法(a1)：将哌马色林在良溶剂中形成溶液，加入帕莫酸，搅拌反应，加入不良溶剂搅拌析晶；或者，Method (a1): forming a solution of pimaserin in a good solvent, adding pamoic acid, stirring the reaction, adding a poor solvent and stirring for crystallization; or,
方法(a2)：取哌马色林和帕莫酸加入良溶剂搅拌反应，过滤，往滤液中加入不良溶剂搅拌析晶；或者，Method (a2): take pimaserin and pamoic acid, add a good solvent to stir and react, filter, add a poor solvent to the filtrate and stir for crystallization; or,
方法(a3)：取哌马色林和帕莫酸加入良溶剂搅拌反应，过滤，将滤液加入到不良溶剂中，可选地，在不良溶剂中加入哌马色林半帕莫酸盐晶型A的晶种，搅拌析晶。Method (a3): adding pimaserine and pamoic acid to a good solvent for stirring reaction, filtering, adding the filtrate to a poor solvent, optionally, adding a crystalline form of pimaserine hemipamoate to the poor solvent A seed crystal, stirring and crystallization.
根据本发明的实施方案，方法(a1)、(a2)和(a3)中，所述良溶剂为醇类溶剂(例如甲醇)、酮类溶剂(例如丙酮)、酯类溶剂(例如乙酸乙酯)、乙腈、二氯甲烷、氯仿、甲苯、四氢呋喃、2-甲基四氢呋喃，N,N-二甲基甲酰胺和N,N-二甲基乙酰胺中的一种，两种或更多种。According to an embodiment of the present invention, in the methods (a1), (a2) and (a3), the good solvent is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent (eg ethyl acetate) ), acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, one, two or more of N,N-dimethylformamide and N,N-dimethylacetamide .
根据本发明的实施方案，方法(a1)、(a2)和(a3)中，所述的不良溶剂为烷烃类溶剂、醚类溶剂(例如异丙醚或甲基叔丁基醚)和水中的一种，两种或更多种。According to an embodiment of the present invention, in the methods (a1), (a2) and (a3), the poor solvent is an alkane-based solvent, an ether-based solvent (such as isopropyl ether or methyl tert-butyl ether) and a solvent in water One, two or more.
根据本发明的实施方案，方法(a1)、(a2)和(a3)中所述哌马色林与帕莫酸的摩尔比值为(0.5～2):1，例如0.88:1、1.8:1或1.9:1；According to an embodiment of the present invention, the molar ratio of pimaserin to pamoic acid in the methods (a1), (a2) and (a3) is (0.5-2):1, for example 0.88:1, 1.8:1 or 1.9:1;
根据本发明的实施方案，当采用方法(a2)时，所述哌马色林与良溶剂的质量体积比值为40～214mg/mL，例如50mg/mL或214mg/mL；当采用方法(a3)时，所述哌马色林与良溶剂的质量体积比值为416～501mg/mL，例如416.7mg/mL、400mg/mL或501mg/mL。According to an embodiment of the present invention, when the method (a2) is adopted, the mass-volume ratio of the pimaserin to the good solvent is 40-214 mg/mL, for example, 50 mg/mL or 214 mg/mL; when the method (a3) is adopted , the mass-volume ratio of the pimaserin to the good solvent is 416-501 mg/mL, for example, 416.7 mg/mL, 400 mg/mL or 501 mg/mL.
根据本发明的实施方案，当采用方法(a2)时，不良溶剂与良溶剂的体积比值为(5～9):1，例如8:1或9:1；当采用方法(3)时，所述的不良溶剂与所述的良溶剂的体积比值为(4～21):1，例如20.8:1、4:1或20:1。According to an embodiment of the present invention, when the method (a2) is adopted, the volume ratio of the poor solvent to the good solvent is (5-9):1, such as 8:1 or 9:1; when the method (3) is adopted, the The volume ratio of the poor solvent to the good solvent is (4-21):1, for example, 20.8:1, 4:1 or 20:1.
根据本发明的实施方案，方法(a1)、(a2)和(a3)中，搅拌析晶的温度为室温。According to an embodiment of the present invention, in the methods (a1), (a2) and (a3), the temperature for stirring and crystallization is room temperature.
根据本发明的实施方案，当采用方法(a1)时，搅拌析晶的时间为18小时～7天。According to an embodiment of the present invention, when the method (a1) is adopted, the stirring and crystallization time is 18 hours to 7 days.
根据本发明的实施方案，当采用方法(a2)和(a3)时，搅拌析晶的时间为18～24小时。According to an embodiment of the present invention, when the methods (a2) and (a3) are adopted, the stirring and crystallization time is 18-24 hours.
根据本发明的实施方案，所述哌马色林半帕莫酸盐晶型B的制备方法包括如下步骤：将帕莫酸用溶剂分散得到悬浮液，将哌马色林用溶剂溶解得到游离碱溶液，将游离碱溶液滴加到悬浮液中搅拌反应；可选地，在搅拌反应过程中加入如上所述哌马色林半帕莫酸盐晶型A作为晶种。According to an embodiment of the present invention, the preparation method of the pimaserin hemipamoate crystal form B includes the following steps: dispersing pamoic acid in a solvent to obtain a suspension, dissolving pimaserine in a solvent to obtain a free base solution, the free base solution is added dropwise to the suspension and the reaction is stirred; optionally, in the process of stirring the reaction, the crystal form A of the pimaserin hemipamoate as described above is added as a seed crystal.
根据本发明的实施方案，哌马色林半帕莫酸盐晶型B制备方法中溶剂选自酯类溶剂，例如乙酸乙酯。According to an embodiment of the present invention, the solvent in the method for preparing the crystalline form B of pimaserin hemipamoate is selected from ester solvents, such as ethyl acetate.
根据本发明的实施方案，所述哌马色林半帕莫酸盐无定型的制备方法包括如下步骤：将哌马色林半帕莫酸盐用溶剂溶解，挥发至溶剂干，得到哌马色林半帕莫酸盐无定型。According to an embodiment of the present invention, the method for preparing the amorphous form of pimaserin hemipamoate comprises the following steps: dissolving pemaserin hemipamoate in a solvent, and volatilizing the solvent until the solvent is dry to obtain pemaserin Linsemipamoate amorphous.
根据本发明的实施方案，无定型制备方法中所述溶剂为醇类溶剂(例如甲醇)、酮类溶剂(例如丙酮)、酯类溶剂、醚类溶剂(例如四氢呋喃、2-甲基四氢呋喃)、烷烃类溶剂、乙腈、二氯甲烷、氯仿、甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和水中的一种，两种或更多种。According to an embodiment of the present invention, the solvent in the amorphous preparation method is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent, an ether solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran), One, two or more of alkane-based solvents, acetonitrile, dichloromethane, chloroform, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and water.
根据本发明的实施方案，所述哌马色林半帕莫酸盐与溶剂的质量体积比可以为1～500mg/mL，优选10～125mg/mL，例如90.8mg/mL、20.8mg/mL、10mg/mL或125mg/mL。According to an embodiment of the present invention, the mass-to-volume ratio of the pimaserin hemipamoate to the solvent may be 1-500 mg/mL, preferably 10-125 mg/mL, such as 90.8 mg/mL, 20.8 mg/mL, 10mg/mL or 125mg/mL.
根据本发明的实施方案，所述挥发方式可以为常压挥发或减压挥发。According to an embodiment of the present invention, the volatilization mode may be normal pressure volatilization or reduced pressure volatilization.
根据本发明的实施方案，所述挥发温度可以为0～60℃，优选20～40℃。According to an embodiment of the present invention, the volatilization temperature may be 0-60°C, preferably 20-40°C.
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐晶型A的制备方法选自下列方法中的一种：According to an embodiment of the present invention, the preparation method of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is selected from one of the following methods:
方法(b1)：分别将哌马色林和1-羟基-2-萘甲酸在良溶剂中形成溶液，搅拌下将酸溶液滴加到碱溶液中，搅拌反应，添加不良溶剂，搅拌析晶；或者，Method (b1): separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, stir to react, add a poor solvent, and stir to crystallize; or,
方法(b2)：分别将哌马色林和1-羟基-2-萘甲酸在良溶剂中形成溶液，搅拌下将酸溶液滴加到碱溶液中，搅拌析晶。Method (b2): separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, and crystallize by stirring.
根据本发明的实施方案，方法(b1)中：According to an embodiment of the present invention, in method (b1):
所述良溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲亚砜中的一种，两种或三种，优选N,N-二甲基甲酰胺；The good solvent is selected from one, two or three kinds of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably N,N-dimethylformamide. amide;
所述哌马色林与1-羟基-2-萘甲酸的质量比值为2:1；The mass ratio of described pimaserin and 1-hydroxy-2-naphthoic acid is 2:1;
所述不良溶剂选自烷烃类溶剂、醚类溶剂和水中的一种，两种或三种，优选为水；The poor solvent is selected from one, two or three kinds of alkane solvents, ether solvents and water, preferably water;
所述不良溶剂与所述良溶剂的体积比值为(1～20):1，例如8:1。The volume ratio of the poor solvent to the good solvent is (1-20):1, for example, 8:1.
所述搅拌析晶的温度可以为室温，搅拌析晶的时间可以为1～12小时。The temperature of the stirring and crystallization can be room temperature, and the time of stirring and crystallization can be 1-12 hours.
根据本发明的实施方案，方法(b2)中：According to an embodiment of the present invention, in method (b2):
所述的良溶剂为醇类溶剂和/或酯类溶剂，所述的醇类溶剂优选异丙醇；所述的酯类溶剂优选乙酸乙酯。The good solvent is an alcohol solvent and/or an ester solvent, and the alcohol solvent is preferably isopropanol; the ester solvent is preferably ethyl acetate.
所述良溶剂与哌马色林的体积质量比为1mL/g～25mL/g，例如6mL/g、15mL/g或23.4mL/g。The volume-to-mass ratio of the good solvent to pemaserin is 1 mL/g to 25 mL/g, for example, 6 mL/g, 15 mL/g or 23.4 mL/g.
所述的哌马色林与1-羟基-2-萘甲酸的摩尔比值优选(0.5～1.5):1，例如0.83:1；The molar ratio of the described pimaserin and 1-hydroxy-2-naphthoic acid is preferably (0.5～1.5):1, for example 0.83:1;
所述搅拌析晶的温度为室温，搅拌析晶的时间为18～24小时。The temperature of the stirring and crystallization is room temperature, and the time of stirring and crystallization is 18-24 hours.
根据本发明的实施方案，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备方法选自下列方法中的一种：According to an embodiment of the present invention, the preparation method of the Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is selected from one of the following methods:
(c1)分别将哌马色林和1-羟基-2-萘甲酸溶解在良溶剂中形成溶液，搅拌下将酸溶液滴加到碱溶液中，搅拌反应，添加不良溶剂，搅拌析晶；或者，(c1) respectively dissolving pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent to form a solution, adding the acid solution dropwise to the alkali solution under stirring, stirring the reaction, adding a poor solvent, and stirring for crystallization; or ,
(c2)将哌马色林1-羟基-2-萘甲酸晶型A溶解在溶剂中形成溶液，挥发至溶剂干；或者，(c2) Dissolving the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin in a solvent to form a solution, and volatilizing it to dryness of the solvent; or,
(c3)将哌马色林1-羟基-2-萘甲酸晶型A溶解在溶剂中形成悬浮液，搅拌析晶；或者，(c3) Dissolving the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin in a solvent to form a suspension, stirring for crystallization; or,
(c4)将哌马色林1-羟基-2-萘甲酸晶型A溶解在良溶剂中形成溶液，加入抗溶剂，搅拌析晶；或者，(c4) Dissolving the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin in a good solvent to form a solution, adding an antisolvent, and stirring for crystallization; or,
(c5)在高温下将哌马色林1-羟基-2-萘甲酸晶型A溶解在溶剂中形成溶液，室温搅拌析晶。(c5) Dissolving the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin in a solvent at high temperature to form a solution, and stirring at room temperature for crystallization.
根据本发明的实施方案，方法(c1)中：According to an embodiment of the present invention, in method (c1):
所述的良溶剂为酮类溶剂，优选丙酮。The good solvent is a ketone solvent, preferably acetone.
所述哌马色林与所述1-羟基-2-萘甲酸的摩尔比值为(0.5～1.5):1，例如0.88:1。The molar ratio of the pimaserin to the 1-hydroxy-2-naphthoic acid is (0.5-1.5):1, for example, 0.88:1.
所述搅拌反应的温度为室温，搅拌反应的时间为1～12小时。The temperature of the stirring reaction is room temperature, and the time of the stirring reaction is 1-12 hours.
所述不良溶剂为烷烃类溶剂、醚类溶剂和水中的一种，两种或三种，优选水。The poor solvent is one, two or three kinds of alkane solvents, ether solvents and water, preferably water.
所述不良溶剂与所述良溶剂的体积比值为(1～20):1，例如8:1。The volume ratio of the poor solvent to the good solvent is (1-20):1, for example, 8:1.
所述搅拌析晶的温度为室温，所述搅拌析晶的时间为1～12小时。The temperature of the stirring and crystallization is room temperature, and the time of the stirring and crystallization is 1-12 hours.
根据本发明的实施方案，方法(c2)中：According to an embodiment of the present invention, in method (c2):
所述的溶剂为醇类溶剂、酮类溶剂、酯类溶剂、醚类溶剂、烷烃类溶剂、二氯甲烷、氯仿、二甲亚砜和水中的一种，两种或更多种。所述的醇类溶剂优选甲醇。所述的酯类溶剂优选乙酸乙酯。所述的醚类溶剂优选四氢呋喃。The solvent is one, two or more of alcohol-based solvent, ketone-based solvent, ester-based solvent, ether-based solvent, alkane-based solvent, dichloromethane, chloroform, dimethyl sulfoxide and water. The alcohol solvent is preferably methanol. The ester solvent is preferably ethyl acetate. The ether solvent is preferably tetrahydrofuran.
所述挥发温度为室温。The volatilization temperature is room temperature.
根据本发明的实施方案，方法(c3)中：According to an embodiment of the present invention, in method (c3):
所述的溶剂选自水或水和有机溶剂构成的混合溶剂；所述的有机溶剂选自醇类溶剂、酯类溶剂、酮类溶剂、醚类溶剂、腈类溶剂和酰胺类溶剂中的一种，两种或更多种；所述的醇类溶剂优选甲醇、乙醇、正丙醇和异丙醇中的一种，两种或更多种。所述的酯类溶剂优选乙酸乙酯、乙酸异丙酯。所述的酮类溶剂优选丙酮。所述的腈类溶剂优选乙腈。所述的醚类溶剂优选四氢呋喃。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的水与有机溶剂的体积比值优选(1～5):1，例如4:1、5:1、3.5:1、2.5:1或2:1。Described solvent is selected from the mixed solvent that water or water and organic solvent form; Described organic solvent is selected from one in alcohol solvent, ester solvent, ketone solvent, ether solvent, nitrile solvent and amide solvent. one, two or more; the alcohol solvent is preferably one, two or more of methanol, ethanol, n-propanol and isopropanol. The ester solvent is preferably ethyl acetate and isopropyl acetate. The ketone solvent is preferably acetone. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran. The amide solvent is preferably N,N-dimethylformamide. The volume ratio of the water to the organic solvent is preferably (1-5):1, such as 4:1, 5:1, 3.5:1, 2.5:1 or 2:1.
所述溶剂进一步优选乙醇与水的混合溶剂、甲醇与水的混合溶剂、丙酮与水的混合溶剂、四氢呋喃与水的混合溶剂、正丙醇与水的混合溶剂、乙腈与水的混合溶剂、N,N-二甲基甲酰胺与水的混合溶剂、异丙醇或乙酸乙酯。The solvent is further preferably a mixed solvent of ethanol and water, a mixed solvent of methanol and water, a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, a mixed solvent of n-propanol and water, a mixed solvent of acetonitrile and water, N , Mixed solvent of N-dimethylformamide and water, isopropanol or ethyl acetate.
所述溶剂与哌马色啉的体积质量比值优选10mg/mL～50mg/mL，例如30mg/mL或35mg/mL。The volume-to-mass ratio of the solvent to pimazoline is preferably 10 mg/mL to 50 mg/mL, for example, 30 mg/mL or 35 mg/mL.
所述的搅拌温度为10℃～60℃；Described stirring temperature is 10 ℃～60 ℃;
所述的搅拌时间为3天～10天。The stirring time is 3 to 10 days.
根据本发明的实施方案，方法(c4)中：According to an embodiment of the present invention, in method (c4):
所述良溶剂为醇类溶剂、酮类溶剂、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、四氢呋喃、乙腈、1,4-二氧六环、二氯甲烷和氯仿中的一种，两种或更多种；The good solvent is alcohol solvent, ketone solvent, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane One, two or more of hexacyclic, dichloromethane and chloroform;
所述不良溶剂为烷烃类溶剂、醚类溶剂和水中的一种，两种或三种。The poor solvent is one, two or three kinds of alkane solvents, ether solvents and water.
根据本发明的实施方案，方法(c5)中：According to an embodiment of the present invention, in method (c5):
所述的高温为60℃～80℃；The high temperature is 60℃～80℃;
所述的溶剂选自醇类溶剂、酮类溶剂、醚类溶剂、酯类溶剂、二氯甲烷、氯仿、四氢呋喃、1,4-二氧六环、乙腈、甲苯、二甲亚砜和水中的一种，两种或更多种。The solvent is selected from alcohol solvents, ketone solvents, ether solvents, ester solvents, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, dimethyl sulfoxide and water. One, two or more.
本发明还提供如上所述的哌马色林药用盐在制备预防、治疗或改善与帕金森氏精神病相关的幻觉、妄想的频率和/或严重程度的药物中的应用。The present invention also provides the use of the pharmaceutical salt of pemaserin as described above in the preparation of a medicament for preventing, treating or ameliorating the frequency and/or severity of hallucinations, delusions, and/or delusions associated with Parkinson's psychosis.
本发明还提供了一种药物组合物，其包括如上所述的哌马色林药用盐。The present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of pimaserin as described above.
根据本发明的实施方案，所述的药物组合物还可以包括药学上可接受的辅料。According to an embodiment of the present invention, the pharmaceutical composition may further include pharmaceutically acceptable excipients.
根据本发明的实施方案，所述的药物组合物的目的是促进化合物向有需要的患者，如人或其他哺乳动物的生物体的给药。According to an embodiment of the present invention, the purpose of the pharmaceutical composition is to facilitate the administration of the compound to a patient in need thereof, such as a human or other mammalian organism.
根据本发明的实施方案，所述的药学上可接受的辅料包括生理或药学上可接受的载体、稀释剂、媒介物和/或赋形剂中的一种，两种或更多种。According to an embodiment of the present invention, the pharmaceutically acceptable adjuvants include one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
本发明还提供了一种哌马色林药物制剂，其包括所述的哌马色林药用盐或所述的哌马色林药物组合物。The present invention also provides a pimaserin pharmaceutical preparation, which comprises the pimaserin pharmaceutical salt or the pimaserin pharmaceutical composition.
根据本发明的实施方案，所述的哌马色林药物制剂的剂型包括但不限于片剂、胶囊、溶液剂、混悬剂和半固体制剂。According to the embodiments of the present invention, the dosage forms of the pharmaceutical preparations of pimaserin include but are not limited to tablets, capsules, solutions, suspensions and semi-solid preparations.
根据本发明的实施方案，所述的哌马色林药物制剂为哌马色林药用盐混悬剂。According to an embodiment of the present invention, the pharmaceutical preparation of pimaserin is a pharmaceutically acceptable salt suspension of pimaserin.
根据本发明的实施方案，所述哌马色林药用盐混悬剂还可以包括辅料，所述辅料可以选自助悬剂、润湿剂、渗透压调节剂、溶剂、稳定剂、缓冲剂和表面活性剂中的一种，两种或更多种。According to an embodiment of the present invention, the pimaserin pharmaceutical salt suspension may further include auxiliary materials, and the auxiliary materials may be selected from suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and One, two or more of the surfactants.
根据本发明的实施方案，所述哌马色林药用盐混悬剂中哌马色林固体粒子的浓度为62mg/mL～124mg/mL。According to an embodiment of the present invention, the concentration of the solid particles of pemaserin in the pimaserin pharmaceutical salt suspension is 62 mg/mL to 124 mg/mL.
根据本发明的实施方案，所述哌马色林固体粒子为哌马色林、哌马色林药用盐，所述哌马色林药用盐包括但不限于哌马色林半帕莫酸盐和哌马色林1-羟基-2-萘甲酸盐。According to an embodiment of the present invention, the pimaserin solid particles are pimaserin, pimaserin pharmaceutically acceptable salts, and the pimaserin pharmaceutically acceptable salts include but are not limited to pimaserin hemipamoic acid salt and pimaserin 1-hydroxy-2-naphthoate.
根据本发明的实施方案，所述的润湿剂的浓度范围为1mg/mL～10mg/mL，优选为1mg/mL～5mg/mL，如1mg/mL、1.5mg/mL、2.0mg/mL、2.5mg/mL、3.0mg/mL、3.5mg/mL、4.0mg/mL、4.5mg/mL或5.0mg/mL。According to an embodiment of the present invention, the concentration of the wetting agent ranges from 1 mg/mL to 10 mg/mL, preferably from 1 mg/mL to 5 mg/mL, such as 1 mg/mL, 1.5 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL or 5.0 mg/mL.
根据本发明的实施方案，所述的润湿剂选自吐温20、吐温80、泊洛沙姆188中的一种，两种或三种，优选为泊洛沙姆188。According to an embodiment of the present invention, the wetting agent is selected from one, two or three of Tween 20, Tween 80 and Poloxamer 188, preferably Poloxamer 188.
根据本发明的实施方案，所述的缓冲剂选自磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸和氢氧化钠中的一种，两种或更多种。According to an embodiment of the present invention, the buffering agent is selected from one, two or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
根据本发明的实施方案，所述哌马色林药用盐混悬剂的制备方法包括下列步骤：According to an embodiment of the present invention, the preparation method of the pharmaceutical salt suspension of pimaserin comprises the following steps:
(d1)将润湿剂和缓冲剂溶解于溶剂中；(d1) dissolving the wetting agent and the buffer in the solvent;
(d2)加入如上所述哌马色林药用盐，得到粗颗粒的混悬水溶液；(d2) adding the above-mentioned pimaserin medicinal salt to obtain the aqueous suspension of coarse particles;
(d3)将上述粗颗粒的混悬水溶液使用球磨机研磨，得到混悬液；或者，(d3) grinding the above-mentioned coarse particle suspension solution using a ball mill to obtain a suspension; or,
(e1)将如上所述哌马色林药用盐的固体粒子过筛；(e1) sieving the solid particles of the pharmaceutical salt of pimaserin as described above;
(e2)将润湿剂和缓冲剂溶解于溶剂中；(e2) dissolving the wetting agent and buffer in the solvent;
(e3)向过筛后的哌马色林药用盐固体粒子中加入步骤(e2)制备的溶液，充分润湿，分散；(e3) add the solution prepared by step (e2) to the sieved pimaserin medicinal salt solid particles, fully wet and disperse;
(e4)用溶剂定容至目标体积，得到混悬液。(e4) Make up to a target volume with a solvent to obtain a suspension.
本发明还提供一种预防、治疗或改善与帕金森氏精神病相关的幻觉、妄想的频率和/或严重程度的方法，包括将如上所述哌马色林药用盐，或其药物组合物，或哌马色林药物制剂施用于有此需要的患者。The present invention also provides a method for preventing, treating or ameliorating the frequency and/or severity of hallucinations, delusions, and/or delusions associated with Parkinson's psychosis, comprising adding a pharmaceutically acceptable salt of pimaserin as described above, or a pharmaceutical composition thereof, Or a pharmaceutical formulation of pimaserin is administered to a patient in need thereof.
术语定义和解释Definition and Explanation of Terms
本发明中“更多种”表示三种或三种以上。In the present invention, "more" means three or more.
本发明中所述的“晶体”是由大量微观物质单位(原子、离子、分子等)按一定规则有序排列的结构。The "crystal" described in the present invention is a structure in which a large number of microscopic material units (atoms, ions, molecules, etc.) are arranged in an orderly manner according to certain rules.
本发明中所述的“多晶”是指同一化合物的不同晶体形式和其他固态分子形式，例如包含所述的哌马色林药用盐的两种或两种以上晶型和/或无定型形式的固体。In the present invention, "polymorphism" refers to different crystalline forms and other solid-state molecular forms of the same compound, for example, including two or more crystalline forms and/or amorphous forms of the pharmaceutically acceptable salt of pimaserin form of solid.
本发明中所述的“无定型”是指无定形固体(非晶体)的构成方式。"Amorphous" as used in the present invention refers to the constitution of an amorphous solid (amorphous).
本发明中，所述的“载体”、“稀释剂”、“媒介物”或“赋形剂”指这样的一种物质(或多种物质)，其可与特定药剂一起被包含从而形成药物组合物，并且可以是固体或液体。所述的固体载体包括但不限于淀粉、硫酸钙二水合物、石膏粉、滑石粉、乳糖、蔗糖、云母、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。所述的液体载体包括但不限于糖浆、花生油、橄榄油、盐水溶液和水等。所述的载体或稀释剂可包括本领域已知的延时或定时释放材料，如单独或与蜡、乙基纤维素、羟丙甲纤维素、甲基丙烯酸甲酯等一起的单硬脂酸甘油酯或二硬脂酸甘油酯。In the present invention, the "carrier", "diluent", "vehicle" or "excipient" refers to a substance (or substances) that can be included with a specific agent to form a drug composition, and can be solid or liquid. The solid carriers include but are not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. The liquid carrier includes, but is not limited to, syrup, peanut oil, olive oil, saline solution, water, and the like. The carrier or diluent may include delayed or timed release materials known in the art, such as monostearic acid alone or in combination with waxes, ethyl cellulose, hypromellose, methyl methacrylate, and the like Glycerides or Glyceryl Distearate.
本发明中，所述的“药学上可接受的的辅料”，是指如下物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。In the present invention, the "pharmaceutically acceptable excipients" refer to the following substances, which are suitable for contact with the patient's tissue without inappropriate toxicity, irritation, allergic reaction within the scope of normal medical judgment etc., have a reasonable ratio of pros and cons, and can be effectively used for their intended purpose.
所述的“溶剂合物”是指含药物(例如哌马色林)和化学计量或非化学计量的一种或多种药学上可接受溶剂分子(例如水)的分子配合物。当溶剂与药物紧密结合时，所形成配合物具有明确的化学计量，而不依赖于湿度。然而，当该溶剂具弱结合性(如在通道溶剂化物和吸湿性化合物中)时，溶剂含量依赖于湿度和干燥条件。在该情况下，配合物通常具非化学计量性。The "solvate" refers to a molecular complex comprising a drug (eg, pimaserin) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg, water). When the solvent is intimately bound to the drug, the complex formed has a well-defined stoichiometry independent of humidity. However, when the solvent is weakly binding (as in channel solvates and hygroscopic compounds), the solvent content is dependent on humidity and drying conditions. In this case, the complex is generally non-stoichiometric.
所述的“水合物”表示含药物(例如哌马色林)和化学计量或非化学计量的水的溶剂化物。The "hydrate" refers to a solvate containing a drug (eg, pimaserin) and stoichiometric or non-stoichiometric water.
所述的“过夜”表示时间为12～24小时。The "overnight" means that the time is 12 to 24 hours.
所述的“患者”包括诸如人或其他哺乳动物的生物体。The "patient" includes organisms such as humans or other mammals.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明中，所述的室温是指环境温度，一般为0℃～35℃。In the present invention, the room temperature refers to the ambient temperature, which is generally 0°C to 35°C.
本发明的积极进步效果在于：The positive progressive effect of the present invention is:
本发明所要解决的技术问题是为了克服现有技术中哌马色林药用盐溶解度较大、患者用药频繁无长效注射剂等缺陷而提供了一种哌马色林药用盐、制备方法、含其的药物组合物及药物组合物的应用。本发明提供的哌马色林药用盐无pH依赖性、在水中具有低溶解特性(与现有的盐型相比，其溶解性显著降低)、稳定性好、制备方法简单方便，适合工业化生产。The technical problem to be solved by the present invention is to provide a medicinal salt of pimaserin, a preparation method, The pharmaceutical composition containing it and the application of the pharmaceutical composition. The medicinal salt of pimaserin provided by the invention has no pH dependence, has low solubility in water (compared with the existing salt form, its solubility is significantly reduced), good stability, simple and convenient preparation method, and is suitable for industrialization Production.
附图说明Description of drawings
图1.哌马色林游离碱的XRPD图谱；Figure 1. XRPD pattern of pemaserin free base;
图2.哌马色林游离碱的DSC图谱；Figure 2. The DSC spectrum of pemaserin free base;
图3.哌马色林游离碱的TGA图谱；Figure 3. TGA profile of pemaserin free base;
图4.实施例2获得的哌马色林半帕莫酸盐晶型A的DSC图谱；Fig. 4. the DSC spectrum of the Pimaserin hemipamoate crystal form A obtained in Example 2;
图5.实施例2获得的哌马色林半帕莫酸盐晶型A的TGA图谱；Figure 5. The TGA spectrum of the pimaserin hemipamoate crystal form A obtained in Example 2;
图6.实施例2获得的哌马色林半帕莫酸盐晶型A的XRPD图谱；Fig. 6. The XRPD spectrum of the pimaserin hemipamoate crystal form A obtained in Example 2;
图7.实施例7获得的哌马色林半帕莫酸盐晶型A的XRPD图谱；Fig. 7. The XRPD pattern of the pemaserin hemipamoate crystal form A obtained in Example 7;
图8.实施例8获得的哌马色林半帕莫酸盐晶型B的XRPD图谱；Fig. 8. The XRPD pattern of the crystalline form B of pemaserin hemipamoate obtained in Example 8;
图9.实施例13获得的哌马色林1-羟基-2萘甲酸盐晶型A的DSC图谱；Figure 9. The DSC spectrum of the 1-hydroxy-2 naphthoate crystal form A of Pimaserin obtained in Example 13;
图10.实施例13获得的哌马色林1-羟基-2-萘甲酸盐晶型A的TGA图谱；Figure 10. The TGA spectrum of Pimaserin 1-hydroxy-2-naphthoate crystal form A obtained in Example 13;
图11.实施例13获得的哌马色林1-羟基-2-萘甲酸盐晶型A的XRPD图谱；Figure 11. The XRPD pattern of the 1-hydroxy-2-naphthoate crystal form A of Pimaserin obtained in Example 13;
图12.实施例18获得的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的DSC图谱；Figure 12. The DSC spectrum of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B obtained in Example 18;
图13.实施例18获得的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的TGA图谱；Figure 13. TGA spectrum of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B obtained in Example 18;
图14.实施例18获得的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的XRPD图谱；Figure 14. The XRPD pattern of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B obtained in Example 18;
图15.对比例1获得的哌马色林半酒石酸盐晶型C的XRPD图谱；Figure 15. The XRPD pattern of Pimaserin hemitartrate crystal form C obtained in Comparative Example 1;
图16.对比例1获得的哌马色林半酒石酸盐晶型C的DSC图谱。Figure 16. The DSC pattern of the crystalline form C of Pimaserin hemitartrate obtained in Comparative Example 1.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
分别采用核磁共振( 1H-NMR)、差示扫描量热法(DSC)、热重分析(TGA)、偏光显微镜(PLM)、X-射线粉末衍射(XRPD)，对实施例和对比例的化合物进行测试，测试参数如下： Using nuclear magnetic resonance ( 1 H-NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), X-ray powder diffraction (XRPD), respectively, for the examples and comparative examples Compounds were tested with the following parameters:
(1)NMR测试在布鲁克型号为Bruker Advance III 500M核磁共振谱仪上进行，测量频率为400Mz/600Mz，使用溶剂为氘代DMSO。(1) The NMR test was carried out on Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400Mz/600Mz, and the solvent was deuterated DMSO.
(2)DSC测量在TA Instruments型号为Q2000的密封盘装置进行，将样品(约1～2mg)在铝盘中称量，转移至仪器中进行测量。测试参数如下：仪器在30℃平衡，以10℃/min的速率升温至300℃，实验气氛为氮气。(2) DSC measurement was carried out in a sealed pan device of TA Instruments model Q2000, the sample (about 1-2 mg) was weighed in an aluminum pan, and transferred to the instrument for measurement. The test parameters are as follows: the instrument is equilibrated at 30°C, heated to 300°C at a rate of 10°C/min, and the experimental atmosphere is nitrogen.
(3)TGA测量在TA Instruments型号为Q2000装置中进行，将样品(约2～5mg)在铂金盘中称量，转移至仪器中进行测量。测试参数如下：仪器以10℃/min的速率升温至350℃，实验气氛为氮气。(3) The TGA measurement was carried out in a TA Instruments model Q2000 device, and the sample (about 2-5 mg) was weighed in a platinum pan and transferred to the instrument for measurement. The test parameters are as follows: the instrument is heated to 350°C at a rate of 10°C/min, and the experimental atmosphere is nitrogen.
(4)XRPD测量是在布鲁克型号为D8 Advance X-射线粉末衍射仪中进行，并使用圆形零背景的单晶硅样品台。扫描参数如下：电压40kv，电流40mA，扫描范围3°～45°，扫描步长0.02°，扫描模式为连续扫描。(4) XRPD measurements were performed in a Bruker model D8 Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage. The scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3°-45°, scanning step size 0.02°, and scanning mode is continuous scanning.
实施例1哌马色林游离碱固相表征检测Example 1 Solid-phase characterization and detection of pemaserin free base
将哌马色林游离碱进行固相表征检测，XRPD图谱见图1，DSC图谱见图2，TGA图谱见图3， 1H-NMR结果如下。 The free base of pemaserin was detected by solid phase characterization, the XRPD spectrum was shown in Figure 1, the DSC spectrum was shown in Figure 2, the TGA spectrum was shown in Figure 3, and the 1 H-NMR results were as follows.
1H-NMR(400MHz,DMSO-d 6)：δ7.25-7.22(m,2H)，7.12-7.08(m,4H)，6.87-6.82(m,3H)，4.41(s,2H)，4.18(d,2H)，3.93-3.87(m,1H)，3.70(d,2H)，2.70(d,2H)，2.09(s,3H)，2.04-1.94(m,1H)，1.87(t,2H)，1.59-1.49(m,2H)，1.42(d,2H)，0.96(d,6H)。 1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.25-7.22 (m, 2H), 7.12-7.08 (m, 4H), 6.87-6.82 (m, 3H), 4.41 (s, 2H), 4.18 (d,2H), 3.93-3.87(m,1H), 3.70(d,2H), 2.70(d,2H), 2.09(s,3H), 2.04-1.94(m,1H), 1.87(t,2H) ), 1.59-1.49 (m, 2H), 1.42 (d, 2H), 0.96 (d, 6H).
哌马色林游离碱的X射线粉末衍射图中在2θ大约为6.790°，8.093°，12.945°，13.655°，14.364°，14.901°，17.012°，17.687°，19.045°，19.697°，20.839°，21.036°，22.219°，24.531°，25.219°，25.733°，27.133°，27.922°，28.971°，30.669°和32.935°处有衍射峰，误差范围 ±0.2°。The X-ray powder diffraction pattern of pimaserin free base at 2θ is approximately 6.790°, 8.093°, 12.945°, 13.655°, 14.364°, 14.901°, 17.012°, 17.687°, 19.045°, 19.697°, 20.839°, There are diffraction peaks at 21.036°, 22.219°, 24.531°, 25.219°, 25.733°, 27.133°, 27.922°, 28.971°, 30.669° and 32.935°, with an error range of ±0.2°.
差式扫描量热曲线(DSC)显示哌马色林游离碱吸热峰峰顶值为122.07℃，具体见图2。热重分析(TGA)显示哌马色林游离碱在100℃时失重为0.2206％，具体见图3。Differential scanning calorimetry (DSC) showed that the peak value of the endothermic peak of pimaserin free base was 122.07°C, as shown in Figure 2 for details. Thermogravimetric analysis (TGA) showed that the weight loss of pimaserin free base at 100° C. was 0.2206%, as shown in FIG. 3 .
实施例2哌马色林半帕莫酸盐晶型A的制备Example 2 Preparation of Pimaserin Hemipamoate Crystal Form A
将哌马色林200mg(0.88eq)溶于4mL甲醇中，加入206mg帕莫酸(1.0eq)到含游离碱的甲醇溶液中，置于磁力搅拌器上，于室温下搅拌反应7天；反应结束后将反应液离心，上清液加8倍体积的反溶剂异丙醚，得到黄色粘稠析出物，离心，置于40℃真空干燥12小时，得白色至微黄色粉末。将上述样品进行固相表征检测( 1H-NMR，DSC，TGA，PLM，XRPD)。 Dissolve 200 mg (0.88 eq) of pimaserin in 4 mL of methanol, add 206 mg of pamoic acid (1.0 eq) to the methanol solution containing the free base, place it on a magnetic stirrer, and stir the reaction at room temperature for 7 days; After the end, the reaction solution was centrifuged, and 8 times the volume of anti-solvent isopropyl ether was added to the supernatant to obtain a yellow viscous precipitate, which was centrifuged and vacuum-dried at 40°C for 12 hours to obtain a white to slightly yellow powder. The above samples were subjected to solid phase characterization ( 1 H-NMR, DSC, TGA, PLM, XRPD).
哌马色林半帕莫酸固相DSC，TGA和XRPD表征结果具体见图4～6。The solid-phase DSC, TGA and XRPD characterization results of pemaserin hemipamoic acid are shown in Figures 4-6.
1H-NMR(400MHz,DMSO-d 6)：δ8.20(t,2H)，7.65(d,1H)，7.25-7.21(m,2H)，7.15-7.08(m,5H)，7.04-6.96(m,2H)，6.83(d,2H)，4.70(s,1H)，4.43(s,1H)，4.19(d,3H)，3.70(d,2H)，2.69(s,3H)，2.04-1.83(m,3H)，1.67(d,2H)，0.96(d,6H)。 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.20 (t, 2H), 7.65 (d, 1H), 7.25-7.21 (m, 2H), 7.15-7.08 (m, 5H), 7.04-6.96 (m,2H), 6.83(d,2H), 4.70(s,1H), 4.43(s,1H), 4.19(d,3H), 3.70(d,2H), 2.69(s,3H), 2.04- 1.83 (m, 3H), 1.67 (d, 2H), 0.96 (d, 6H).
核磁结果显示哌马色林半帕莫酸的酸碱摩尔比为0.5:1。NMR results showed that the acid-base molar ratio of pemaserin hemipamoic acid was 0.5:1.
差式扫描量热曲线(DSC)显示哌马色林半帕莫酸熔点约为180℃，峰值约为186℃，具体见图4。Differential scanning calorimetry curve (DSC) showed that the melting point of pemaserin hemipamoic acid was about 180°C, and the peak value was about 186°C, see Figure 4 for details.
热重分析(TGA)显示100℃时哌马色林半帕莫酸失重为0.2270％，具体见图5。Thermogravimetric analysis (TGA) showed that the weight loss of pemaserin hemipamoic acid was 0.2270% at 100°C, see Figure 5 for details.
偏光显微镜(PLM)显示哌马色林半帕莫酸有偏振光，为晶体形式。Polarized light microscopy (PLM) showed that pimaserin hemipamoic acid had polarized light and was in crystalline form.
X射线粉末衍射图(XRPD)显示哌马色林半帕莫酸盐有衍射峰，结合PLM判断其为晶型，将其命名为哌马色林半帕莫酸盐晶型A，具体见图6。X-ray powder diffractogram (XRPD) shows that pimaserin hemipamoate has diffraction peaks, and it is judged to be a crystalline form based on PLM, and it is named as pimaserin hemipamoate crystal form A, as shown in the figure for details. 6.
实施例3哌马色林半帕莫酸盐晶型A的制备Example 3 Preparation of Pimaserin Hemipamoate Crystal Form A
取428mg哌马色林(1.8eq)和214mg帕莫酸(1.0eq)，加入2mL甲醇，室温搅拌过夜，过滤，往滤液中缓慢滴加18mL异丙醚，继续搅拌过夜，过滤，35℃真空干燥4小时，得到569mg哌马色林半帕莫酸盐晶型A样品，收率约为91％。Take 428mg pimaserin (1.8eq) and 214mg pamoic acid (1.0eq), add 2mL methanol, stir at room temperature overnight, filter, slowly add 18mL isopropyl ether dropwise to the filtrate, continue stirring overnight, filter, vacuum at 35°C After drying for 4 hours, a sample of 569 mg of the crystalline form A of pemaserin hemipamoate was obtained, and the yield was about 91%.
实施例4哌马色林半帕莫酸盐晶型A的制备Example 4 Preparation of Pimaserin Hemipamoate Crystal Form A
取42.8mg哌马色林(1.9eq)和20.4mg帕莫酸(1.0eq)，加入1mL甲醇，室温搅拌过夜，过滤，往滤液中加入5mL异丙醚，继续搅拌过夜，过滤，35℃真空干燥3小时，得到54mg哌马色林半帕莫酸盐晶型A样品，收率约为87％。Take 42.8 mg of pimaserin (1.9 eq) and 20.4 mg of pamoic acid (1.0 eq), add 1 mL of methanol, stir at room temperature overnight, filter, add 5 mL of isopropyl ether to the filtrate, continue to stir overnight, filter, vacuum at 35°C After drying for 3 hours, a 54 mg sample of the crystalline form A of pemaserin hemipamoate was obtained, and the yield was about 87%.
实施例5哌马色林半帕莫酸盐晶型A的制备Example 5 Preparation of Pimaserin Hemipamoate Crystal Form A
取5g哌马色林(1.8eq)和2.5g帕莫酸(1.0eq)，加入12mL甲醇，室温搅拌过夜，过滤，将滤液滴加到含有50mg实施例3制备的哌马色林半帕莫酸盐晶型A样品的250mL甲基叔丁基醚中，搅拌过夜，过滤，用50mL甲基叔丁基醚洗涤滤饼，60℃真空干燥4小时，得到5.57g哌马色林半帕莫酸盐晶型A样品，收率约为90％。Take 5 g of pemaserin (1.8 eq) and 2.5 g of pamoic acid (1.0 eq), add 12 mL of methanol, stir at room temperature overnight, filter, and add the filtrate dropwise to 50 mg of pemaserin half-pamoic acid prepared in Example 3 In 250 mL of methyl tert-butyl ether of the salt crystal form A sample, stirred overnight, filtered, washed the filter cake with 50 mL of methyl tert-butyl ether, and vacuum-dried at 60 °C for 4 hours to obtain 5.57 g of pemaserin hemipamol A sample of salt crystal form A, the yield is about 90%.
实施例6哌马色林半帕莫酸盐晶型A的制备Example 6 Preparation of Pimaserin Hemipamoate Crystal Form A
取40g哌马色林(1.8eq)和20g帕莫酸(1.0eq)，加入100mL甲醇，室温搅拌过夜，过滤，将滤液滴加到含有100mg实施例3制备的哌马色林半帕莫酸盐晶型A样品的400mL甲基叔丁基醚中，搅拌过夜，过滤，用100mL甲基叔丁基醚洗涤滤饼，60℃真空干燥5小时，得到52.1g哌马色林半帕莫酸盐晶型A样品，收率约为90％。Take 40g of pemaserin (1.8eq) and 20g of pamoic acid (1.0eq), add 100mL of methanol, stir at room temperature overnight, filter, and add the filtrate dropwise to the filtrate containing 100mg of pemaserin half-pamoic acid prepared in Example 3 The salt crystal form A sample was placed in 400 mL of methyl tert-butyl ether, stirred overnight, filtered, and the filter cake was washed with 100 mL of methyl tertiary butyl ether, and dried under vacuum at 60 °C for 5 hours to obtain 52.1 g of pemaserin hemipamoic acid. A sample of salt crystal form A, the yield is about 90%.
实施例7哌马色林半帕莫酸盐晶型A的制备Example 7 Preparation of Pimaserin Hemipamoate Crystal Form A
取3006mg哌马色林(1.8eq)和1503mg帕莫酸(1.0eq)，加入6mL甲醇，室温搅拌过夜，过滤，将滤液滴加到含有20mg实施例3制备的哌马色林半帕莫酸盐晶型A样品的120mL甲基叔丁基醚中，搅拌过夜，过滤，用100mL甲基叔丁基醚洗涤滤饼，35℃真空干燥3天，得到4.1g哌马色林半帕莫酸盐晶型A样品，收率约为97％。Take 3006 mg of pemaserin (1.8 eq) and 1503 mg of pamoic acid (1.0 eq), add 6 mL of methanol, stir at room temperature overnight, filter, and add the filtrate dropwise to the filtrate containing 20 mg of pemaserin hemi-pamoic acid prepared in Example 3 The salt crystal form A sample was placed in 120 mL of methyl tert-butyl ether, stirred overnight, filtered, and the filter cake was washed with 100 mL of methyl tertiary butyl ether, and dried at 35 °C for 3 days under vacuum to obtain 4.1 g of pemaserin hemipamoic acid. A sample of salt crystal form A, the yield is about 97%.
其XRPD图如图7，为哌马色林半帕莫酸盐晶型A。Its XRPD pattern is shown in Figure 7, which is the crystalline form A of pimaserin hemipamoate.
实施例8哌马色林半帕莫酸盐晶型B的制备Example 8 Preparation of Pimaserin Hemipamoate Crystal Form B
取90.8mg帕莫酸，加入1mL乙酸乙酯，室温搅拌分散，得到悬浮液；取220mg哌马色林，加入5mL乙酸乙酯溶解，得到游离碱溶液；搅拌下将游离碱溶液滴加到悬浮液中，搅拌反应，加入5mg实施例7制备的哌马色林半帕莫酸盐晶型A和2mL乙酸乙酯，继续搅拌8天，离心，洗涤，干燥，得到231mg哌马色林半帕莫酸盐晶型B。Take 90.8 mg of pamoic acid, add 1 mL of ethyl acetate, stir and disperse at room temperature to obtain a suspension; take 220 mg of pemaserin, add 5 mL of ethyl acetate to dissolve to obtain a free base solution; add the free base solution dropwise to the suspension with stirring In the liquid, the reaction was stirred, and 5 mg of the crystalline form A of pimaserin hemipamoate prepared in Example 7 and 2 mL of ethyl acetate were added, and the stirring was continued for 8 days. Moulinate crystal form B.
其XRPD图如图8，其为哌马色林半帕莫酸盐晶型B。Its XRPD pattern is shown in Figure 8, which is the crystalline form B of pimaserin hemipamoate.
实施例9哌马色林半帕莫酸盐无定型的制备Example 9 Preparation of the amorphous form of pemaserin hemipamoate
取25mg实施例3制备的哌马色林晶型A样品，加入0.2mL N,N-二甲基乙酰胺溶解，40℃常压挥发至溶剂干，将得到的样品进行PLM表征，为无偏光固体。Take 25 mg of the sample of Pimaserin crystal form A prepared in Example 3, add 0.2 mL of N,N-dimethylacetamide to dissolve it, volatilize it to dryness at 40°C under normal pressure, and perform PLM characterization on the obtained sample, which is no polarized light. solid.
实施例10哌马色林半帕莫酸盐无定型的制备 Embodiment 10 Preparation of amorphous form of pemaserin hemipamoate
取25mg实施例3制备的哌马色林晶型A样品，加入2mL丙酮溶解，室温常压挥发至溶剂干，将得到的样品进行PLM表征，为无偏光固体。Take 25 mg of the Pimaserin crystal form A sample prepared in Example 3, add 2 mL of acetone to dissolve it, and volatilize it to dryness at room temperature and pressure. The obtained sample is characterized by PLM, and it is a non-polarized solid.
实施例11哌马色林半帕莫酸盐无定型的制备Example 11 Preparation of the amorphous form of pemaserin hemipamoate
取25mg实施例3制备的哌马色林晶型A样品，加入1mL甲醇和0.2mL水溶解，室温常压挥发至溶剂干，将得到的样品进行PLM表征，为无偏光固体。Take 25 mg of the pimaserin crystal form A sample prepared in Example 3, add 1 mL of methanol and 0.2 mL of water to dissolve, volatilize at room temperature and pressure to dry the solvent, and perform PLM characterization on the obtained sample, which is a non-polarized solid.
实施例12哌马色林半帕莫酸盐无定型的制备Example 12 Preparation of the amorphous form of pemaserin hemipamoate
取100mg实施例3制备的哌马色林晶型A样品，加入10mL四氢呋喃溶解，室温减压浓缩至溶剂干，将得到的样品进行PLM表征，为无偏光固体。Take 100 mg of the sample of Pimaserin crystal form A prepared in Example 3, add 10 mL of tetrahydrofuran to dissolve, and concentrate under reduced pressure at room temperature until the solvent is dry. The obtained sample is characterized by PLM and is a non-polarized solid.
实施例13哌马色林1-羟基-2-萘甲酸盐晶型A的制备Example 13 Preparation of Pimaserin 1-hydroxy-2-naphthoate crystal form A
精密称定哌马色林50mg(0.88eq)，添加适量N,N-二甲基甲酰胺，超声使之完全溶解；样品置于磁力搅拌器上搅拌，缓慢滴加含25mg1-羟基-2-萘甲酸(1.0eq)N,N-二甲基甲酰胺溶液，滴毕，室温搅拌反应12小时；反应结束后，无固体物质析出，加入8倍体积的反溶剂水，得到白色絮状析出物，室温下搅拌12小时；对其进行离心，沉淀物真空干燥40℃真空干燥12小时，得白色粉末。对上述样品进行固相表征检测( 1H-NMR，DSC，TGA，PLM，XRPD)。 Precisely weigh 50mg (0.88eq) of pemaserin, add an appropriate amount of N,N-dimethylformamide, and ultrasonically dissolve it completely; stir the sample on a magnetic stirrer, and slowly dropwise add 25mg of 1-hydroxy-2- Naphthoic acid (1.0eq) N,N-dimethylformamide solution, after dripping was completed, the reaction was stirred at room temperature for 12 hours; after the reaction, no solid matter was precipitated, 8 times the volume of anti-solvent water was added to obtain white flocculent precipitates , stirred at room temperature for 12 hours; centrifuged, and the precipitate was vacuum-dried at 40°C for 12 hours to obtain a white powder. The above samples were subjected to solid phase characterization ( 1 H-NMR, DSC, TGA, PLM, XRPD).
哌马色林1-羟基-2-萘甲酸盐晶型A固相DSC，TGA和XRPD表征结果具体见图9～11。The solid-phase DSC, TGA and XRPD characterization results of pimaserin 1-hydroxy-2-naphthoate crystal form A are shown in Figures 9-11.
核磁结果显示哌马色林1-羟基-2-萘甲酸盐中酸碱摩尔比为1:1。The NMR results showed that the molar ratio of acid to base in pimaserin 1-hydroxy-2-naphthoate was 1:1.
1H-NMR(400MHz,DMSO-d 6)：δ8.21(d,1H)，7.76-7.73(m,2H)，7.51-7.47(m,1H)，7.42-7.38(m,1H)，7.23-7.20(m,2H)，7.12-7.06(m,5H)，6.97(t,1H)，6.83(d,2H)，4.41(s,2H)，4.19-4.18(m,3H)，3.70(d,2H)，2.69(s,3H)，2.04-1.84(m,3H)，1.66(d,2H)，0.96(d,6H)。 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.21 (d, 1H), 7.76-7.73 (m, 2H), 7.51-7.47 (m, 1H), 7.42-7.38 (m, 1H), 7.23 -7.20(m, 2H), 7.12-7.06(m, 5H), 6.97(t, 1H), 6.83(d, 2H), 4.41(s, 2H), 4.19-4.18(m, 3H), 3.70(d , 2H), 2.69 (s, 3H), 2.04-1.84 (m, 3H), 1.66 (d, 2H), 0.96 (d, 6H).
差式扫描量热曲线(DSC)显示哌马色林1-羟基-2-萘甲酸盐吸热峰峰值为169℃，具体见图9。热重分析(TGA)显示100℃时哌马色林1-羟基-2-萘甲酸盐失重约为0.05074％，具体见图10。Differential scanning calorimetry (DSC) showed that the peak endothermic peak of pimaserin 1-hydroxy-2-naphthoate salt was 169°C, see Figure 9 for details. Thermogravimetric analysis (TGA) showed that the weight loss of pimaserin 1-hydroxy-2-naphthoate was about 0.05074% at 100°C, see Figure 10 for details.
其X射线粉末衍射图见图11，图11显示哌马色林1-羟基-2-萘甲酸盐有衍射峰，判断哌马色林1-羟基-2-萘甲酸盐为晶型，将其命名为哌马色林1-羟基-2-萘甲酸盐晶型A。Its X-ray powder diffraction pattern is shown in Figure 11, and Figure 11 shows that pimaserin 1-hydroxy-2-naphthoate has diffraction peaks, and it is judged that pimaserin 1-hydroxy-2-naphthoate is a crystalline form, It was named as Pimaserin 1-hydroxy-2-naphthoate crystalline form A.
实施例14哌马色林1-羟基-2-萘甲酸盐晶型A的制备Example 14 Preparation of Pimaserin 1-hydroxy-2-naphthoate crystal form A
取30g哌马色林(0.83eq)，加入180mL异丙醇，搅拌溶清，得到游离碱溶液；取15.84g1-羟基-2-萘甲酸(1.0eq)，加入250mL异丙醇，搅拌溶清，得到酸溶液；搅拌下将酸溶液滴加到游离碱溶液中，搅拌反应过夜，过滤，用100mL异丙醇洗涤滤饼，60℃真空干燥过夜，得到42g哌马色林1-羟基-2-萘甲酸盐晶型A，收率约为97％。Take 30g pimaserin (0.83eq), add 180mL isopropanol, stir to dissolve to obtain a free base solution; take 15.84g 1-hydroxy-2-naphthoic acid (1.0eq), add 250mL isopropanol, stir to dissolve , to obtain an acid solution; add the acid solution dropwise to the free base solution under stirring, stir and react overnight, filter, wash the filter cake with 100 mL of isopropanol, and vacuum dry at 60 °C overnight to obtain 42 g of pimaserin 1-hydroxy-2 - Naphthoate crystal form A, the yield is about 97%.
实施例15哌马色林1-羟基-2-萘甲酸盐晶型A的制备Example 15 Preparation of Pimaserin 1-hydroxy-2-naphthoate crystal form A
取42.8mg哌马色林(0.83eq)和22.6mg1-羟基-2-萘甲酸(1.0eq)，加入1mL乙酸乙酯，搅拌反应3小时，过滤，得到约53mg哌马色林1-羟基-2-萘甲酸盐晶型A， 收率约为86％。Take 42.8mg pimaserin (0.83eq) and 22.6mg 1-hydroxy-2-naphthoic acid (1.0eq), add 1mL ethyl acetate, stir the reaction for 3 hours, filter to obtain about 53mg pimaserin 1-hydroxy- 2-Naphthoate crystal form A, the yield is about 86%.
实施例16哌马色林1-羟基-2-萘甲酸盐晶型A的制备Example 16 Preparation of Pimaserin 1-hydroxy-2-naphthoate crystal form A
取2996mg哌马色林(0.83eq)，加入21mL异丙醇，搅拌溶清，得到游离碱溶液；取1582mg1-羟基-2-萘甲酸(1.0eq)，加入45mL异丙醇，搅拌溶清，过滤，得到酸溶液；搅拌下将酸溶液滴加到游离碱溶液中，搅拌反应过夜，过滤，用20mL异丙醇洗涤滤饼，35℃真空干燥3天，得到3.9g哌马色林1-羟基-2-萘甲酸盐晶型A，收率约为90.4％。Take 2996mg of pimaserin (0.83eq), add 21mL of isopropanol, stir to dissolve to obtain a free base solution; take 1582mg of 1-hydroxy-2-naphthoic acid (1.0eq), add 45mL of isopropanol, stir to dissolve, Filter to obtain an acid solution; add the acid solution dropwise to the free base solution with stirring, stir and react overnight, filter, wash the filter cake with 20 mL of isopropanol, and dry at 35°C for 3 days under vacuum to obtain 3.9 g of pemaserin 1- Hydroxy-2-naphthoate crystal form A, the yield is about 90.4%.
实施例17哌马色林1-羟基-2-萘甲酸盐晶型A的制备Example 17 Preparation of Pimaserin 1-hydroxy-2-naphthoate crystal form A
取5g哌马色林(0.83eq)，加入30mL异丙醇，搅拌溶清，得到游离碱溶液；取2.64g1-羟基-2-萘甲酸(1.0eq)，加入60mL异丙醇，搅拌溶清，过滤，得到酸溶液；搅拌下将酸溶液滴加到游离碱溶液中，搅拌反应过夜，过滤，用20mL异丙醇洗涤滤饼，60℃真空干燥3小时，得到6.7g哌马色林1-羟基-2-萘甲酸盐晶型A，收率约为93％。Take 5g of pimaserin (0.83eq), add 30mL of isopropanol, stir to dissolve to obtain a free base solution; take 2.64g of 1-hydroxy-2-naphthoic acid (1.0eq), add 60mL of isopropanol, stir to dissolve , filtered to obtain an acid solution; the acid solution was added dropwise to the free base solution under stirring, and the reaction was stirred overnight, filtered, washed with 20 mL of isopropanol, and dried under vacuum at 60 °C for 3 hours to obtain 6.7 g of pemaserin 1 -Hydroxy-2-naphthoate crystal form A, the yield is about 93%.
实施例18哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 18 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
精密称定哌马色林50mg(0.88eq)，添加适量丙酮，超声使之完全溶解；样品置于磁力搅拌器上搅拌，缓慢滴加含25mg1-羟基-2-萘甲酸(1.0eq)丙酮溶液，滴毕，室温搅拌反应12小时；反应结束后，无固体物质析出，加入丙酮8倍体积的反溶剂水，得到白色析出物，室温下搅拌12小时；对其进行离心，沉淀物真空干燥40℃真空干燥12小时，得白色粉末。上述样品进行固相表征检测DSC，TGA，XRPD。Precisely weigh 50mg (0.88eq) of pemaserin, add an appropriate amount of acetone, and ultrasonically dissolve it completely; the sample is placed on a magnetic stirrer and stirred, and 25mg 1-hydroxy-2-naphthoic acid (1.0eq) acetone solution is slowly added dropwise. , the dropping was completed, and the reaction was stirred at room temperature for 12 hours; after the reaction was completed, no solid matter was precipitated, and 8 times the volume of acetone was added to the anti-solvent water to obtain a white precipitate, which was stirred at room temperature for 12 hours; it was centrifuged, and the precipitate was vacuum-dried for 40 ℃ and vacuum drying for 12 hours to obtain white powder. The above samples were subjected to solid-phase characterization to detect DSC, TGA, and XRPD.
哌马色林萘甲酸盐固相表征结果具体见图12～14。The solid-phase characterization results of pimaserin naphthoate are shown in Figures 12-14.
差式扫描量热曲线(DSC)显示哌马色林1-羟基-2-萘甲酸盐在100℃～150℃之间有一个吸热峰，为脱去结晶水所致，熔点约为168℃，峰值约为170.15℃，具体见图12。Differential scanning calorimetry (DSC) showed that pimaserin 1-hydroxy-2-naphthoate had an endothermic peak between 100 ℃ and 150 ℃, which was caused by the removal of crystal water, and the melting point was about 168 °C, the peak value is about 170.15 °C, see Figure 12 for details.
热重分析(TGA)显示哌马色林1-羟基-2-萘甲酸盐在110℃之前有一段约为2.619％的失重，约合一分子结晶水，具体见图13。Thermogravimetric analysis (TGA) showed that pimaserin 1-hydroxy-2-naphthoate had a period of weight loss of about 2.619% before 110°C, which was about one molecule of crystal water, as shown in Figure 13.
哌马色林1-羟基-2-萘甲酸盐X射线粉末衍射图见图14，其有不同于哌马色林1-羟基-2-萘甲酸盐晶型A的衍射峰，为一种新晶型，结合图13可以判定其为一水合物，故命名为哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。The X-ray powder diffraction pattern of Pimaserin 1-hydroxy-2-naphthoate is shown in Figure 14, which has a diffraction peak different from that of Pimaserin 1-hydroxy-2-naphthoate crystal form A, which is a This new crystal form can be determined to be a monohydrate with reference to Figure 13, so it is named Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.
实施例19哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 19 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
取15mg实施例16制备的哌马色林1-羟基-2-萘甲酸盐晶型A，加入0.5mL甲醇和2mL水，超声溶清，室温挥发至溶剂干，得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。Take 15 mg of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin prepared in Example 16, add 0.5 mL of methanol and 2 mL of water, dissolve by ultrasonic, and evaporate at room temperature until the solvent is dry to obtain pimaserin 1- Hydroxy-2-naphthoate monohydrate Form B.
实施例20和实施例21哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 20 and Example 21 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
将实施例19中的溶剂替换成以下溶剂，也可得到哌马色林1-羟基-2-萘甲酸盐一水 合物晶型B。By replacing the solvent in Example 19 with the following solvent, the crystalline form B of Pimaserin 1-hydroxy-2-naphthoate monohydrate can also be obtained.
Figure PCTCN2022083287-appb-000005
Figure PCTCN2022083287-appb-000005
实施例22哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 22 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
取42g实施例14制备的哌马色林1-羟基-2-萘甲酸盐晶型A，加入400mL乙醇和800mL水，室温搅拌2天，过滤，60℃真空干燥4小时，得到41.2g哌马色林1-羟基-2-萘甲酸盐一水合物晶型B，收率约为98％。Take 42 g of Pimaserin 1-hydroxy-2-naphthoate crystalline form A prepared in Example 14, add 400 mL of ethanol and 800 mL of water, stir at room temperature for 2 days, filter, and vacuum dry at 60 °C for 4 hours to obtain 41.2 g of piperine Maserin 1-hydroxy-2-naphthoate monohydrate crystal form B, the yield is about 98%.
实施例23哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 23 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
取30mg实施例16制备的哌马色林1-羟基-2-萘甲酸盐晶型A，加入1mL水，室温搅拌10天，离心，干燥，得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。Take 30 mg of the 1-hydroxy-2-naphthoate crystalline form A prepared in Example 16, add 1 mL of water, stir at room temperature for 10 days, centrifuge, and dry to obtain 1-hydroxy-2-naphthalene pimaserin Form B formate monohydrate.
实施例24～实施例31哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 24-Example 31 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
将实施例23中的溶剂替换为以下溶剂，也可得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。By replacing the solvent in Example 23 with the following solvent, the crystalline form B of Pimaserin 1-hydroxy-2-naphthoate monohydrate can also be obtained.
Figure PCTCN2022083287-appb-000006
Figure PCTCN2022083287-appb-000006
实施例32哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 32 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
取30mg实施例16制备的哌马色林1-羟基-2-萘甲酸盐晶型A，加入1mL甲醇，室温搅拌溶清，快速加入4mL水，搅拌析晶24小时，离心，干燥，得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。Take 30 mg of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin prepared in Example 16, add 1 mL of methanol, stir to dissolve at room temperature, quickly add 4 mL of water, stir and crystallize for 24 hours, centrifuge, and dry to obtain Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.
实施例33～实施例43哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 33-Example 43 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
将实施例32中的溶剂替换为以下溶剂，也可得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。By replacing the solvent in Example 32 with the following solvent, the crystalline form B of Pimaserin 1-hydroxy-2-naphthoate monohydrate can also be obtained.
Figure PCTCN2022083287-appb-000007
Figure PCTCN2022083287-appb-000007
Figure PCTCN2022083287-appb-000008
Figure PCTCN2022083287-appb-000008
实施例44哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 44 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
取30mg实施例16制备的哌马色林1-羟基-2-萘甲酸盐晶型A，加入1mL水和1mL乙醇，60℃搅拌溶清，保温约2分钟后直接置于室温搅拌24小时，离心，干燥，得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。Take 30 mg of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 1 mL of water and 1 mL of ethanol, stir to dissolve at 60°C, and keep it at room temperature for about 2 minutes and stir for 24 hours. , centrifugation, and drying to obtain the crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate.
实施例45和实施例46哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备Example 45 and Example 46 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B
将实施例44中的溶剂替换为以下溶剂，也可得到哌马色林1-羟基-2-萘甲酸盐一水合物晶型B。By replacing the solvent in Example 44 with the following solvent, the crystalline form B of Pimaserin 1-hydroxy-2-naphthoate monohydrate can also be obtained.
Figure PCTCN2022083287-appb-000009
Figure PCTCN2022083287-appb-000009
对比例1哌马色林半酒石酸盐晶型C的制备Comparative Example 1 Preparation of Pimaserin Hemitartrate Crystal Form C
根据专利文献CN105924381A中实施例1(也可参考专利文献CN106008323A中实施例1)的方法制备哌马色林半酒石酸盐晶型C。According to the method of Example 1 in Patent Document CN105924381A (also refer to Example 1 in Patent Document CN106008323A), the crystalline form C of Pimaserin hemitartrate was prepared.
其XRPD图如图15所示，DSC图如图16所示。Its XRPD pattern is shown in Figure 15, and its DSC pattern is shown in Figure 16.
实施例47溶解度比较Example 47 Solubility Comparison
分别取哌马色林游离碱、实施例2制备的哌马色林半帕莫酸盐晶型A、实施例13制备的哌马色林1-羟基-2-萘甲酸盐晶型A、实施例22制备的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B和对比例1制备的哌马色林半酒石酸盐晶型C，分别加入到纯水、pH3.0醋酸盐缓冲溶液、pH5.0醋酸盐缓冲溶液、pH7.0磷酸盐缓冲溶液、pH9.0磷酸盐缓冲溶液中，使其成为饱和溶液，在37℃振摇24小时，用0.45μm微孔滤膜过滤，收集滤液，采用高效液相色谱进行溶解度测定。测试结果见表1。由于哌马色林半酒石酸盐晶型C溶解度过高，未进行高效液相色谱检测，根据称样量和介质添加量计算其溶解度。Take the free base of Pimaserin, the crystalline form A of the pimaserin hemipamoate prepared in Example 2, the crystalline form A of the 1-hydroxy-2-naphthoate salt of Pimaserin prepared in Example 13, The pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B prepared in Example 22 and the pimaserin hemi-tartrate crystal form C prepared in Comparative Example 1 were added to pure water, pH3. 0 acetate buffer solution, pH 5.0 acetate buffer solution, pH 7.0 phosphate buffer solution, pH 9.0 phosphate buffer solution to make a saturated solution, shake at 37°C for 24 hours, use 0.45 μm The filtrate was collected by microporous membrane filtration, and the solubility was determined by high performance liquid chromatography. The test results are shown in Table 1. Due to the high solubility of pimaserin hemitartrate crystal form C, high performance liquid chromatography was not carried out.
表1溶解度检测结果Table 1 Solubility test results
Figure PCTCN2022083287-appb-000010
Figure PCTCN2022083287-appb-000010
由表1可知，本发明制得的哌马色林半帕莫酸盐晶型A、哌马色林1-羟基-2-萘甲酸盐晶型A和哌马色林1-羟基-2-萘甲酸盐一水合物晶型B在酸性和中性条件下溶解度均较哌马色林低，且pH越低差异越大。上述结果表明相对于哌马色林游离碱和哌马色林半酒石酸盐晶型C，本发明哌马色林半帕莫酸盐晶型A、哌马色林1-羟基-2-萘甲酸盐晶型A和哌马色林1-羟基-2-萘甲酸盐一水合物晶型B更适用于缓释制剂的研究与开发。As can be seen from Table 1, the crystalline form A of pimaserin hemipamoate, the crystalline form A of pimaserin 1-hydroxy-2-naphthoate salt and the crystalline form A of pimaserin 1-hydroxy-2 -Naphthoate monohydrate crystal form B has lower solubility than pimaserin under both acidic and neutral conditions, and the lower the pH, the greater the difference. The above results show that, relative to the free base of pimaserin and the crystalline form C of pimaserin hemi-tartrate, the crystalline form A of pimaserin hemi-pamoate of the present invention, the 1-hydroxy-2-naphthoyl of pimaserin Salt crystal form A and pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B are more suitable for the research and development of sustained-release preparations.
实施例48稳定性比较Example 48 Stability Comparison
分别取哌马色林游离碱、实施例2制备的哌马色林半帕莫酸盐晶型A、实施例13制备的哌马色林1-羟基-2-萘甲酸盐晶型A、实施例22制备的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B和对比例1制备的哌马色林半酒石酸盐晶型C于高温(60℃)，高湿(25℃/90％RH)，常规(环境温湿度)，加速(40℃/75％RH)和长期(20℃/60％RH)条件下放置，分别于0天、5天、10天取样进行HPLC检测，结果如表2所示。Take the free base of Pimaserin, the crystalline form A of the pimaserin hemipamoate prepared in Example 2, the crystalline form A of the 1-hydroxy-2-naphthoate salt of Pimaserin prepared in Example 13, The crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate prepared in Example 22 and the crystalline form C of pimaserin hemi-tartrate prepared in (25°C/90%RH), normal (ambient temperature and humidity), accelerated (40°C/75%RH) and long-term (20°C/60%RH) conditions, sampling at 0 days, 5 days and 10 days respectively HPLC detection was performed, and the results are shown in Table 2.
由表2可知，本发明的哌马色林半帕莫酸盐晶型A、哌马色林1-羟基-2-萘甲酸盐晶型A和哌马色林1-羟基-2-萘甲酸盐一水合物晶型B在各条件下均较稳定，适用于药物制剂的开发。As can be seen from Table 2, the crystalline form A of Pimaserin hemipamoate, the crystalline form A of Pimaserin 1-hydroxy-2-naphthoate and the 1-hydroxy-2-naphthalene of Pimaserin of the present invention are shown in Table 2. The formate monohydrate crystal form B is relatively stable under various conditions and is suitable for the development of pharmaceutical preparations.
表2稳定性检测结果Table 2 Stability test results
Figure PCTCN2022083287-appb-000011
Figure PCTCN2022083287-appb-000011
Figure PCTCN2022083287-appb-000012
Figure PCTCN2022083287-appb-000012
实施例49～实施例51哌马色林半帕莫酸盐晶型A处方制备Example 49-Example 51 Preparation of Pimaserin Hemipamoate Crystal Form A Recipe
Figure PCTCN2022083287-appb-000013
Figure PCTCN2022083287-appb-000013
Figure PCTCN2022083287-appb-000014
Figure PCTCN2022083287-appb-000014
制备过程：making process:
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠与约60％(体积分数)配制总量的注射用水中，搅拌溶解分散；(1) take by weighing the water for injection of recipe quantity Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate and about 60% (volume fraction) preparation total amount, stir, dissolve and disperse;
(2)加入处方量的哌马色林半帕莫酸盐晶型A，得到粗颗粒的混悬水溶液；(2) add the pimaserin hemipamoate crystal form A of recipe quantity, obtain the suspension aqueous solution of coarse particle;
(3)将上述所得粗颗粒混悬水溶液使用球磨机研磨分散；(3) the above-mentioned obtained coarse particle suspension aqueous solution is ground and dispersed using a ball mill;
(4)用注射用水定容至10mL，即得哌马色林半帕莫酸盐晶型A混悬液；(4) Dilute the volume to 10 mL with water for injection to obtain the suspension of Pimaserin Hemipamoate crystal form A;
(5)采用OMEC LS-909粒度测定仪测定研磨后实施例样品粒度分布，结果见下表：(5) adopt OMEC LS-909 particle size analyzer to measure the particle size distribution of embodiment sample after grinding, the results are shown in the following table:
实施例Example Dv10(μm)Dv10(μm) Dv50(μm)Dv50(μm) Dv90(μm)Dv90(μm)
实施例49Example 49 1.3571.357 6.2196.219 14.33414.334
实施例50Example 50 0.8980.898 3.2943.294 8.9178.917
实施例51Example 51 0.8480.848 3.2923.292 8.9458.945
(6)取实施例49～51所得的处方样品，进行通针性和沉降比考察，发现上述样品通针性和沉降比良好。(6) The prescription samples obtained in Examples 49 to 51 were taken, and the needle penetration and sedimentation ratio were investigated, and it was found that the needle penetration and sedimentation ratio of the above-mentioned samples were good.
实施例52和实施例53哌马色林半帕莫酸盐晶型A处方制备Example 52 and Example 53 Preparation of Pimaserin Hemipamoate Crystal Form A Recipe
Figure PCTCN2022083287-appb-000015
Figure PCTCN2022083287-appb-000015
制备过程：making process:
(1)称取处方量吐温20、泊洛沙姆、188磷酸氢二钠、磷酸二氢钠与约60％(体积分数)配制总量的注射用水中，搅拌溶解分散；(1) take by weighing recipe quantity Tween 20, poloxamer, 188 disodium hydrogen phosphate, sodium dihydrogen phosphate and about 60% (volume fraction) preparation total water for injection, stir, dissolve and disperse;
(2)加入处方量的过300目筛的哌马色林半帕莫酸盐晶型A，充分润湿、分散；(2) adding the Pimaserin hemipamoate crystal form A of the recipe quantity that crosses 300 mesh sieves, fully wets and disperses;
(3)用注射用水定容至10mL，摇匀，即得哌马色林半帕莫酸盐晶型A混悬液；(3) Dilute the volume to 10 mL with water for injection, and shake well to obtain the suspension of Pimaserin Hemipamoate crystal form A;
(4)取实施例52和53所得的处方样品，进行通针性和沉降比考察，发现上述样品通针性和沉降比良好。(4) The prescription samples obtained in Examples 52 and 53 were taken, and the needle penetration and sedimentation ratio were investigated, and it was found that the needle penetration and sedimentation ratio of the above-mentioned samples were good.
实施例54和实施例55哌马色林1-羟基-2-萘甲酸盐一水合物晶型B处方制备Example 54 and Example 55 Preparation of Pimaserin 1-Hydroxy-2-Naphthoate Monohydrate Crystal Form B
Figure PCTCN2022083287-appb-000016
Figure PCTCN2022083287-appb-000016
制备过程：making process:
(1)称取处方量吐温20、泊洛沙姆188、磷酸氢二钠、磷酸二氢钠与约60％(体积分数)配制总量的注射用水中，搅拌溶解分散；(1) take by weighing the water for injection of recipe quantity Tween 20, Poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate and about 60% (volume fraction) preparation total amount, stir, dissolve and disperse;
(2)加入处方量的过300目筛的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B，充分润湿、分散；(2) adding the Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B that passes through a 300-mesh sieve of the recipe quantity, fully wets and disperses;
(3)用注射用水定容至10mL，摇匀，即得哌马色林1-羟基-2-萘甲酸盐一水合物晶型B混悬液；(3) Dilute to 10 mL with water for injection, shake well, and obtain the suspension of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B;
(4)取实施例54和55所得的处方样品，进行通针性和沉降比考察，发现上述样品通针性和沉降比良好。(4) The prescription samples obtained in Examples 54 and 55 were taken, and the needle penetration and sedimentation ratio were investigated, and it was found that the needle penetration and sedimentation ratio of the above-mentioned samples were good.
实施例56处方稳定性考察Embodiment 56 Prescription stability investigation
取实施例53制备的哌马色林半帕莫酸盐处方和实施例55制备的1-羟基-2-萘甲酸盐处方样品分别置于高温(60℃)，加速(40℃/75％RH)、光照(25℃/5000Lux)和长期(20℃/60％RH)条件下放置，于0天、5天、10天取样进行HPLC检测。Take the pimaserin hemipramoxate recipe prepared in Example 53 and the 1-hydroxy-2-naphthoate recipe sample prepared in Example 55 and place them at high temperature (60° C.) respectively, and accelerate (40° C./75% RH), light (25°C/5000Lux) and long-term (20°C/60%RH) conditions, samples were taken at 0 days, 5 days and 10 days for HPLC detection.
结果见下表，结果显示哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的处方样品在各条件下均较稳定，哌马色林半帕莫酸盐晶型A的处方样品除长期光照条件下略有降解外，其余条件均稳定。The results are shown in the following table. The results show that the prescription samples of pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B are relatively stable under various conditions, and the pimaserine hemipamoate crystal form A is stable. The formulation samples were stable except for slight degradation under long-term light conditions.
处方稳定性检测结果Formulation Stability Test Results
Figure PCTCN2022083287-appb-000017
Figure PCTCN2022083287-appb-000017
Figure PCTCN2022083287-appb-000018
Figure PCTCN2022083287-appb-000018
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (10)

  1. 一种哌马色林药用盐，其特征在于，其为哌马色林游离碱与六个碳以上的有机酸形成的盐；哌马色林游离碱的结构如式I所示：A medicinal salt of Pimaserin, it is characterized in that, it is the salt that Pimaserin free base and organic acid more than six carbons form; The structure of Pimaserin free base is as shown in formula I:
    Figure PCTCN2022083287-appb-100001
    Figure PCTCN2022083287-appb-100001
    优选地，所述的“六个碳以上的有机酸”为C 6～C 30的有机酸；所述的“C 6～C 30的有机酸”优选己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、癸二酸、十一烷酸、月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、十七烷酸、硬脂酸、十九烷酸、二十烷酸、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸、甘油三乙酸、木质酸、双羟萘酸、1-羟基-2萘甲酸、帕莫酸和萘酸衍生物中的一种或多种； Preferably, the "organic acid with more than six carbons" is a C6 - C30 organic acid; the " C6 - C30 organic acid" is preferably hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, Azelaic acid, capric acid, sebacic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, Eicosanic acid, oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, hexadecanoic acid, heptacosanoic acid, one of octacosanoic acid, nonacosanoic acid, triaconoic acid, triglyceride, lignin, pamoic acid, 1-hydroxy-2 naphthoic acid, pamoic acid and naphthoic acid derivatives or more;
    还优选地，所述的哌马色林药用盐为哌马色林半帕莫酸盐或哌马色林1-羟基-2-萘甲酸盐。Also preferably, the pharmaceutically acceptable salt of pimaserin is pimaserin hemipamoate or pimaserin 1-hydroxy-2-naphthoate.
  2. 根据权利要求1所述的哌马色林药用盐，其特征在于：所述的哌马色林半帕莫酸盐为哌马色林与帕莫酸以摩尔比为1:0.5复合形成的盐；The medicinal salt of pimaserin according to claim 1, is characterized in that: described pemaserin hemipamoate is a compound formed of pimaserin and pamoic acid in a mol ratio of 1:0.5 Salt;
    优选地，所述的哌马色林半帕莫酸盐为哌马色林半帕莫酸盐晶型A、哌马色啉半帕莫酸晶型B或无定型；Preferably, the pimaserin hemi-pamoate salt is a pemaserin hemi-pamoate crystal form A, a pemaserin hemi-pamoate crystal form B or an amorphous form;
    优选地，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.5°±0.2°处有衍射峰；Preferably, the X-ray powder diffraction pattern of the pimaserin hemipamoxate crystal form A has diffraction peaks at 2θ values of 3.3°±0.2°, 6.7°±0.2°, and 7.5°±0.2°;
    优选地，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.5°±0.2°、12.2°±0.2°、13.7°±0.2°、17.0°±0.2°、19.5°±0.2°、20.4°±0.2°、21.1°±0.2°处有衍射峰；Preferably, the X-ray powder diffraction pattern of the crystalline form A of pimaserin hemipamoate has 2θ values of 3.3°±0.2°, 6.7°±0.2°, 7.5°±0.2°, 12.2°±0.2° , 13.7°±0.2°, 17.0°±0.2°, 19.5°±0.2°, 20.4°±0.2°, 21.1°±0.2° have diffraction peaks;
    还优选地，所述哌马色林半帕莫酸盐晶型A的X射线粉末衍射图基本如图6所示。Also preferably, the X-ray powder diffractogram of the crystalline form A of pemaserin hemipamoate is substantially as shown in FIG. 6 .
    优选地，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图在2θ值为6.1°±0.2°、8.6°±0.2°、19.9°±0.2°处有衍射峰；Preferably, the X-ray powder diffraction pattern of the pimaserin hemipamoxate crystal form B has diffraction peaks at 2θ values of 6.1°±0.2°, 8.6°±0.2°, and 19.9°±0.2°;
    优选地，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图在2θ值为6.1°±0.2°、8.6°±0.2°、9.6°±0.2°、13.0°±0.2°、13.3°±0.2°、15.6°±0.2°、17.0°±0.2°、17.3°±0.2°、17.9°±0.2°、18.9°±0.2°、19.1°±0.2°、19.9°±0.2°、20.2°±0.2°、20.7°±0.2°处有吸收峰；Preferably, the X-ray powder diffraction pattern of the crystalline form B of pimaserin hemipamoate has 2θ values of 6.1°±0.2°, 8.6°±0.2°, 9.6°±0.2°, 13.0°±0.2° , 13.3°±0.2°, 15.6°±0.2°, 17.0°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.2 There are absorption peaks at °±0.2° and 20.7°±0.2°;
    还优选地，所述哌马色林半帕莫酸盐晶型B的X射线粉末衍射图基本如图8所示。Also preferably, the X-ray powder diffraction pattern of the crystalline form B of pemaserin hemipamoate is substantially as shown in FIG. 8 .
  3. 根据权利要求1所述的哌马色林药用盐，其特征在于：所述哌马色林1-羟基-2-萘甲酸盐为哌马色林与1-羟基-2-萘甲酸以摩尔比1:1复合形成的盐，其可以为哌马色林1-羟基-2-萘甲酸盐晶型A或哌马色林1-羟基-2-萘甲酸盐一水合物晶型B；The medicinal salt of pimaserin according to claim 1, wherein the 1-hydroxy-2-naphthoic acid salt of pimaserin is a combination of pimaserin and 1-hydroxy-2-naphthoic acid. The salt formed by compounding in a molar ratio of 1:1, which can be the crystalline form A of Pimaserin 1-hydroxy-2-naphthoate or the crystalline form of Pimaserin 1-hydroxy-2-naphthoate monohydrate B;
    优选地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图在2θ值为4.3°±0.2°、13.2°±0.2°、18.6°±0.2°处有衍射峰；Preferably, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin is at 2θ values of 4.3°±0.2°, 13.2°±0.2°, 18.6°±0.2° There are diffraction peaks;
    优选地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图在2θ值为4.3°±0.2°、7.7°±0.2°、8.8°±0.2°、11.4°±0.2°、13.2°±0.2°、15.1°±0.2°、17.0°±0.2°、17.7°±0.2°、18.6°±0.2°、19.0°±0.2°、20.2°±0.2°、20.6°±0.2°、21.3°±0.2°、21.6°±0.2°、22.7°±0.2°、25.8°±0.2°处有吸收峰；Preferably, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pemaserin has 2θ values of 4.3°±0.2°, 7.7°±0.2°, 8.8°±0.2°, 11.4°±0.2°, 13.2°±0.2°, 15.1°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 20.6° There are absorption peaks at ±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.7°±0.2°, 25.8°±0.2°;
    更优选地，所述哌马色林1-羟基-2-萘甲酸盐晶型A的X射线粉末衍射图基本如图11所示；More preferably, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is substantially as shown in Figure 11;
    优选地，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图在2θ值为3.8°±0.2°、7.8°±0.2°、14.2°±0.2°处有衍射峰；Preferably, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin has 2θ values of 3.8°±0.2°, 7.8°±0.2°, 14.2°± There is a diffraction peak at 0.2°;
    优选地，所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图在2θ值为3.8°±0.2°、7.8°±0.2°、11.7°±0.2°、14.2°±0.2°、15.7°±0.2°、17.7°±0.2°、21.3°±0.2°、22.4°±0.2°、23.0°±0.2°、25.3°±0.2°、26.8°±0.2°处有吸收峰；Preferably, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2θ values of 3.8°±0.2°, 7.8°±0.2°, 11.7°± 0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.7°±0.2°, 21.3°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 25.3°±0.2°, 26.8°±0.2° There is an absorption peak;
    更优选地，所述的哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的X射线粉末衍射图基本如图14所示。More preferably, the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 14 .
  4. 权利要求1-3任一项所述哌马色林药用盐的制备方法，包括以下步骤：将哌马色林游离碱与所述的六个碳以上的有机酸进行反应；The preparation method of the described pimaserin medicinal salt of any one of claim 1-3, comprises the following steps: reacting pimaserin free base and described organic acid more than six carbons;
    优选地，所述哌马色林药用盐的制备方法在溶剂中进行，所述的溶剂选自水、甲醇、乙酸乙酯、四氢呋喃、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、丙酮、甲基叔丁基醚和异丙醚溶剂中的一种，两种或更多种。Preferably, the preparation method of the pharmaceutical salt of pimaserin is carried out in a solvent selected from the group consisting of water, methanol, ethyl acetate, tetrahydrofuran, isopropanol, dichloromethane, N,N-dimethylformaldehyde One, two or more of the solvents of methyl amide, acetone, methyl tert-butyl ether and isopropyl ether.
  5. 根据权利要求4所述的制备方法，其中：The preparation method according to claim 4, wherein:
    所述哌马色林半帕莫酸盐晶型A的制备方法选自下列方法中的一种：The preparation method of described Pimaserin Hemipamoate crystal form A is selected from one of the following methods:
    方法(a1)：将哌马色林在良溶剂中形成溶液，加入帕莫酸，搅拌反应，加入不良溶剂搅拌析晶；或者，Method (a1): forming a solution of pimaserin in a good solvent, adding pamoic acid, stirring the reaction, adding a poor solvent and stirring for crystallization; or,
    方法(a2)：取哌马色林和帕莫酸加入良溶剂搅拌反应，过滤，往滤液中加入不良溶剂搅拌析晶；或者，Method (a2): take pimaserin and pamoic acid, add a good solvent to stir and react, filter, add a poor solvent to the filtrate and stir for crystallization; or,
    方法(a3)：取哌马色林和帕莫酸加入良溶剂搅拌反应，过滤，将滤液加入到不良溶剂中，可选地，在不良溶剂中加入哌马色林半帕莫酸盐晶型A的晶种，搅拌析晶；Method (a3): adding pimaserine and pamoic acid to a good solvent for stirring reaction, filtering, adding the filtrate to a poor solvent, optionally, adding a crystalline form of pimaserine hemipamoate to the poor solvent A seed crystal, stirring and crystallization;
    其中，方法(a1)、(a2)和(a3)中，所述良溶剂为醇类溶剂(例如甲醇)、酮类溶剂(例如丙酮)、酯类溶剂(例如乙酸乙酯)、乙腈、二氯甲烷、氯仿、甲苯、四氢呋喃、2-甲基四氢呋喃，N,N-二甲基甲酰胺和N,N-二甲基乙酰胺中的一种，两种或更多种；所述的不良溶剂为烷烃类溶剂、醚类溶剂(例如异丙醚或甲基叔丁基醚)和水中的一种，两种或更多种；Wherein, in the methods (a1), (a2) and (a3), the good solvent is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent (eg ethyl acetate), acetonitrile, diethyl ether One, two or more of chloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide and N,N-dimethylacetamide; said poor The solvent is one, two or more of alkane solvents, ether solvents (such as isopropyl ether or methyl tert-butyl ether) and water;
    所述哌马色林半帕莫酸盐晶型B的制备方法包括如下步骤：将帕莫酸用溶剂分散得到悬浮液，将哌马色林用溶剂溶解得到游离碱溶液，将游离碱溶液滴加到悬浮液中搅拌反应；可选地，在搅拌反应过程中加入如上所述哌马色林半帕莫酸盐晶型A作为晶种；The preparation method of the pimaserine hemipamoate crystal form B comprises the following steps: dispersing pamoic acid with a solvent to obtain a suspension, dissolving pimaserine with a solvent to obtain a free base solution, and adding dropwise the free base solution Adding to the suspension and stirring the reaction; optionally, adding the above-mentioned Pimaserin Hemipamoate crystal form A as a seed crystal during the stirring reaction;
    所述哌马色林半帕莫酸盐无定型的制备方法包括如下步骤：将哌马色林半帕莫酸盐用溶剂溶解，挥发至溶剂干，得到哌马色林半帕莫酸盐无定型；优选地，所述无定型的制备方法中，所述溶剂为醇类溶剂(例如甲醇)、酮类溶剂(例如丙酮)、酯类溶剂、醚类溶剂(例如四氢呋喃、2-甲基四氢呋喃)、烷烃类溶剂、乙腈、二氯甲烷、氯仿、甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和水中的一种，两种或更多种。The amorphous preparation method of the pimaserin hemipamoate comprises the following steps: dissolving the pemaserin hemipamoate in a solvent, and volatilizing the solvent until the solvent is dry, to obtain the pemaserin hemipamoate without the Preferably, in the amorphous preparation method, the solvent is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent, an ether solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran) ), one, two or more of alkane-based solvents, acetonitrile, dichloromethane, chloroform, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and water.
  6. 根据权利要求4所述的制备方法，其中：The preparation method according to claim 4, wherein:
    所述哌马色林1-羟基-2-萘甲酸盐晶型A的制备方法选自下列方法中的一种：The preparation method of described Pimaserin 1-hydroxy-2-naphthoate crystal form A is selected from one of the following methods:
    方法(b1)：分别将哌马色林和1-羟基-2-萘甲酸在良溶剂中形成溶液，搅拌下将酸溶液滴加到碱溶液中，搅拌反应，添加不良溶剂，搅拌析晶；Method (b1): separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, stir to react, add a poor solvent, and stir to crystallize;
    其中，所述良溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲亚砜中的一种，两种或三种，优选N,N-二甲基甲酰胺；Wherein, the good solvent is selected from one, two or three kinds of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably N,N-dimethyl sulfoxide carboxamide;
    所述不良溶剂选自烷烃类溶剂、醚类溶剂和水中的一种，两种或三种；The poor solvent is selected from one, two or three kinds of alkane solvents, ether solvents and water;
    或者，or,
    方法(b2)：分别将哌马色林和1-羟基-2-萘甲酸在良溶剂中形成溶液，搅拌下将 酸溶液滴加到碱溶液中，搅拌析晶；Method (b2): pimaserin and 1-hydroxy-2-naphthoic acid are respectively formed into solutions in good solvent, the acid solution is added dropwise to the alkaline solution under stirring, and the crystallization is stirred;
    其中，所述的良溶剂为醇类溶剂和/或酯类溶剂，所述的醇类溶剂优选异丙醇；所述的酯类溶剂优选乙酸乙酯；Wherein, the good solvent is an alcohol solvent and/or an ester solvent, and the alcohol solvent is preferably isopropanol; the ester solvent is preferably ethyl acetate;
    所述哌马色林1-羟基-2-萘甲酸盐一水合物晶型B的制备方法选自下列方法中的一种：The preparation method of described Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is selected from one of the following methods:
    (c1)分别将哌马色林和1-羟基-2-萘甲酸溶解在良溶剂中形成溶液，搅拌下将酸溶液滴加到碱溶液中，搅拌反应，添加不良溶剂，搅拌析晶；(c1) respectively dissolving pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent to form a solution, adding the acid solution dropwise to the alkaline solution under stirring, stirring the reaction, adding a poor solvent, stirring and crystallization;
    其中，所述的良溶剂为酮类溶剂，优选丙酮；所述不良溶剂为烷烃类溶剂、醚类溶剂和水中的一种，两种或三种，优选水；Wherein, the good solvent is a ketone solvent, preferably acetone; the poor solvent is one, two or three of an alkane solvent, an ether solvent and water, preferably water;
    或者，or,
    (c2)将哌马色林1-羟基-2-萘甲酸晶型A溶解在溶剂中形成溶液，挥发至溶剂干；(c2) dissolving the 1-hydroxy-2-naphthoic acid crystal form A of pimaserin in a solvent to form a solution, and volatilizing it to dryness of the solvent;
    其中，所述的溶剂为醇类溶剂、酮类溶剂、酯类溶剂、醚类溶剂、烷烃类溶剂、二氯甲烷、氯仿、二甲亚砜和水中的一种，两种或更多种；所述的醇类溶剂优选甲醇。所述的酯类溶剂优选乙酸乙酯。所述的醚类溶剂优选四氢呋喃；Wherein, the solvent is one, two or more of alcohol-based solvent, ketone-based solvent, ester-based solvent, ether-based solvent, alkane-based solvent, dichloromethane, chloroform, dimethyl sulfoxide and water; The alcohol solvent is preferably methanol. The ester solvent is preferably ethyl acetate. Described ether solvent is preferably tetrahydrofuran;
    或者，or,
    (c3)将哌马色林1-羟基-2-萘甲酸晶型A溶解在溶剂中形成悬浮液，搅拌析晶；(c3) dissolving the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin in a solvent to form a suspension, stirring for crystallization;
    其中，所述的溶剂选自水或水和有机溶剂构成的混合溶剂；所述的有机溶剂选自醇类溶剂、酯类溶剂、酮类溶剂、醚类溶剂、腈类溶剂和酰胺类溶剂中的一种，两种或更多种；所述的醇类溶剂优选甲醇、乙醇、正丙醇和异丙醇中的一种，两种或更多种；所述的酯类溶剂优选乙酸乙酯、乙酸异丙酯；所述的酮类溶剂优选丙酮；所述的腈类溶剂优选乙腈；所述的醚类溶剂优选四氢呋喃；所述的酰胺类溶剂优选N,N-二甲基甲酰胺；Wherein, the solvent is selected from water or a mixed solvent composed of water and an organic solvent; the organic solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents and amide solvents one, two or more; the alcohol solvent is preferably one, two or more in methanol, ethanol, n-propanol and isopropanol; the ester solvent is preferably ethyl acetate , isopropyl acetate; the ketone solvent is preferably acetone; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran; the amide solvent is preferably N,N-dimethylformamide;
    或者，or,
    (c4)将哌马色林1-羟基-2-萘甲酸晶型A溶解在良溶剂中形成溶液，加入抗溶剂，搅拌析晶；(c4) Dissolving the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin in a good solvent to form a solution, adding an antisolvent, and stirring for crystallization;
    其中，所述良溶剂为醇类溶剂、酮类溶剂、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、四氢呋喃、乙腈、1,4-二氧六环、二氯甲烷和氯仿中的一种，两种或更多种；所述不良溶剂为烷烃类溶剂、醚类溶剂和水中的一种，两种或三种；Wherein, the good solvent is alcohol solvent, ketone solvent, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4- One, two or more of dioxane, dichloromethane and chloroform; the poor solvent is one, two or three of alkane solvents, ether solvents and water;
    或者，or,
    (c5)在高温下将哌马色林1-羟基-2-萘甲酸晶型A溶解在溶剂中形成溶液，室温搅拌析晶；(c5) at high temperature, the 1-hydroxy-2-naphthoic acid crystal form A of Pimaserin is dissolved in a solvent to form a solution, and the crystallization is stirred at room temperature;
    其中，所述的溶剂选自醇类溶剂、酮类溶剂、醚类溶剂、酯类溶剂、二氯甲烷、氯仿、 四氢呋喃、1,4-二氧六环、乙腈、甲苯、二甲亚砜和水中的一种，两种或更多种。Wherein, the solvent is selected from alcohol solvents, ketone solvents, ether solvents, ester solvents, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, dimethyl sulfoxide and One, two or more in water.
  7. 权利要求1-3任一项所述哌马色林药用盐在制备预防、治疗或改善与帕金森氏精神病相关的幻觉、妄想的频率和/或严重程度的药物中的应用。The use of the pharmaceutical salt of pimaserin according to any one of claims 1-3 in the preparation of a medicament for preventing, treating or improving the frequency and/or severity of hallucinations and delusions associated with Parkinson's psychosis.
  8. 一种药物组合物，其包括权利要求1-3任一项所述的哌马色林药用盐；A pharmaceutical composition comprising the pharmaceutically acceptable salt of pimaserin according to any one of claims 1-3;
    优选地，所述的药物组合物还包括药学上可接受的辅料；Preferably, the pharmaceutical composition further includes pharmaceutically acceptable excipients;
    优选地，所述的药学上可接受的辅料包括生理或药学上可接受的载体、稀释剂、媒介物和/或赋形剂中的一种，两种或更多种。Preferably, the pharmaceutically acceptable adjuvants include one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
  9. 一种哌马色林药物制剂，其包括权利要求1-3任一项所述的哌马色林药用盐或权利要求8所述的药物组合物；A pimaserin pharmaceutical preparation, comprising the pimaserin pharmaceutical salt according to any one of claims 1-3 or the pharmaceutical composition according to claim 8;
    优选地，所述的哌马色林药物制剂的剂型选自片剂、胶囊、溶液剂、混悬剂和半固体制剂；Preferably, the dosage form of the described pimaserin pharmaceutical preparation is selected from tablets, capsules, solutions, suspensions and semi-solid preparations;
    优选地，所述混悬剂还包括辅料，所述辅料可以选自助悬剂、润湿剂、渗透压调节剂、溶剂、稳定剂、缓冲剂和表面活性剂中的一种，两种或更多种。Preferably, the suspension further comprises auxiliary materials, and the auxiliary materials can be selected from one, two or more of suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and surfactants. variety.
  10. 权利要求9中的混悬剂的制备方法，其中所述制备方法包括下列步骤：The preparation method of the suspension in claim 9, wherein said preparation method comprises the following steps:
    (d1)将润湿剂和缓冲剂溶解于溶剂中；(d1) dissolving the wetting agent and the buffer in the solvent;
    (d2)加入所述哌马色林药用盐，得到粗颗粒的混悬水溶液；(d2) adding described pimaserin medicinal salt, obtains the suspension aqueous solution of coarse particle;
    (d3)将上述粗颗粒的混悬水溶液使用球磨机研磨，得到混悬液；(d3) using a ball mill to grind the aqueous suspension of the above-mentioned coarse particles to obtain a suspension;
    或者，or,
    所述制备方法包括下列步骤：The preparation method comprises the following steps:
    (e1)将所述哌马色林药用盐的固体粒子过筛；(e1) sieving the solid particles of the pharmaceutically acceptable salt of pemaserin;
    (e2)将润湿剂和缓冲剂溶解于溶剂中；(e2) dissolving the wetting agent and buffer in the solvent;
    (e3)向过筛后的哌马色林药用盐的固体粒子中加入步骤(e2)制备的溶液，充分润湿，分散；(e3) add the solution prepared by step (e2) to the solid particles of the sieved pimaserin medicinal salt, fully wet and disperse;
    (e4)用溶剂定容至目标体积，得到混悬液。(e4) Make up to a target volume with a solvent to obtain a suspension.
PCT/CN2022/083287 2021-03-26 2022-03-28 Pharmaceutically acceptable salt of pimavanserin, and preparation method therefor, pharmaceutical composition containing same, and use thereof WO2022199707A1 (en)

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