WO2015043404A1 - Sel d'(-)-huperzine-a - Google Patents

Sel d'(-)-huperzine-a Download PDF

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Publication number
WO2015043404A1
WO2015043404A1 PCT/CN2014/086721 CN2014086721W WO2015043404A1 WO 2015043404 A1 WO2015043404 A1 WO 2015043404A1 CN 2014086721 W CN2014086721 W CN 2014086721W WO 2015043404 A1 WO2015043404 A1 WO 2015043404A1
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Prior art keywords
huperzine
crystal
diffraction pattern
methyl
salt
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PCT/CN2014/086721
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English (en)
Chinese (zh)
Inventor
赵守明
江月华
陈安
庄银枪
丁跃庭
谢金生
谢蔚华
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万邦德制药集团股份有限公司
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Publication of WO2015043404A1 publication Critical patent/WO2015043404A1/fr

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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems

Definitions

  • the invention belongs to the field of medicinal chemistry, in particular to a salt of huperzine A, which is prepared by reacting (-)-huperzine A with a corresponding acid.
  • Huperzine A is a highly active alkaloid isolated from Huperzia serrata (Thunb) Thev., and (-)-huperzine A is a pharmaceutically active ingredient.
  • Huperzine A The preparation process of Huperzine A has pure natural plant extracts obtained by extraction and isolation from plants, and also compounds obtained by chemical synthesis. Natural (-)-huperzine A is only about one-tenth of a million in the kelp plant of the genus Huperaceae. Because the growth cycle of the galaxies is as long as 8-10 years, plant extraction alone is far from satisfying the market. Demand, chemical synthesis (-) - Huperzine A has a long-term market prospects.
  • (-)-Huperzine A is a highly effective and highly selective reversible acetylcholinesterase inhibitor, which has the functions of improving learning and memory effects, and can be used for the treatment of benign memory disorders and various neuropsychiatric diseases.
  • the patient's ability to point to memory, association learning, image recall, meaningless graphics recognition and portrait recall also improves memory impairment caused by dementia patients and brain organic diseases.
  • Huperzine A is China's first drug.
  • USP 33
  • EP 7.0
  • Both BP (2010) and the Japanese Pharmacopoeia (XV) are not included.
  • (-)-Huperzine A injection was launched in China in 1985, clinically used for myasthenia gravis.
  • (-)-Huperzine A tablet was launched in 1995, clinically used for Alzheimer's disease (AD) and memory.
  • AD Alzheimer's disease
  • Huperzine A is widely used as a food additive and functional beverage active ingredient, mainly used to improve the memory function of the elderly and improve the brain reaction speed of athletes.
  • (-)-Huperzine A preparation has the functions of improving learning and memory efficiency and repairing neuronal damage. It is mainly used for the treatment of myasthenia gravis, schizophrenia, senile dementia, benign memory impairment and other symptoms, especially for senile forgetfulness. Symptoms and Alzheimer's disease are effective and effective in improving children's memory.
  • (-)-Huperzine A is highly toxic, and acute toxicity test showed that the LD50 of mice injected intraperitoneally was 1.8 mg/kg, and that of rats was 5 mg/kg. Excessive dose can cause dizziness, nausea, gastrointestinal discomfort, fatigue and other reactions.
  • the existing (-)-huperzine tablets and capsules and injections are marketed, and the specifications are: 0.05 mg/tablet or granules, and the injection is 0.2 mg/ampule.
  • (-)-Huperzine A oral absorption is good, the dosage is: oral, 0.1mg ⁇ 0.2mg (2 ⁇ 4 tablets), 2 times a day, but the maximum amount of no more than 9 tablets a day.
  • (-)-Huperzine A has a darker color, and under certain conditions of acid, alkali and oxidation forced destruction test, it shows a certain degree of degradation. Accelerated stability test and long-term stability test results show that the related substances are on the rise.
  • huperzine A and its derivatives or their salts. Release the nanoparticles. Its particle size is between 20 and 500 nm. The drug can be slowly released in the body. The blood concentration is stable and long-lasting, which can improve bioavailability and reduce the number of administrations.
  • huperzine A and its derivatives or salts thereof may be mentioned, and may be a salt combined with hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid, citric acid or maleic acid.
  • Huperzine A and its derivatives or salts thereof which may be with hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid, citric acid or malay The acid is combined into a salt.
  • the base a compound may be in the form of a free base or an acid addition salt, and examples of the acid forming the acid addition salt include hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid or citric acid.
  • Cipheral Patent 200310108852.4 describes a salt of Huperzine A, which is a compound of the formula (I), the formula (II), the formula (III), the formula (IV) and the formula (IV) with hydrochloric acid, acetic acid, phosphoric acid, a salt of sulfuric acid, lactic acid, citric acid or maleic acid combined.
  • 01119952.0 describes a sustained release microsphere of Huperzine A and derivatives thereof or a salt thereof according to the general formula (1), characterized in that it is 0.2 to 50% of the weight of the microspheres of Huperzine A and The derivative or its salt and the weight of the microspheres are 50-99.8% of a biodegradable medicinal polymer excipient having a molecular weight ranging from 5,000 to 1,000,000, wherein the acid forming the salt is hydrochloric acid, acetic acid, phosphoric acid, Sulfuric acid, lactic acid, citric acid.
  • the (-)-huperzine A is prepared as a sulfadipine methyl salt having better quality stability than huperzine A, in order to improve (-)-huperzine A.
  • the quality and quality stability of its preparation products are described in detail below.
  • the invention also studies the physicochemical properties of the Huperzine M salt, and finds that it has good crystal stability, good water solubility, and is particularly suitable for preparing liquid preparations or soluble preparations.
  • the present inventors have found that the quality stability of (-)-huperzine methyl salt is superior to (-)-huperzine methyl free base.
  • the acid-to-salt process step becomes an important step in the preparation of the preparation.
  • the present invention provides a pharmaceutically acceptable huperzine methyl salt, which is selected from the group consisting of the hydrochloride salt of huperzine A, a hydrobromide salt, a nitrate salt, a citrate salt, an acetate salt, Trifluoroacetate, lactate, phosphate, sulfate, oxalate, maleate, succinate, tartrate, fumarate, mandelate, methanesulfonate, besylate , gluconate, ascorbate, pyruvate, alaninate, aspartate An acid salt, a lysine salt or an arginine salt.
  • a preferred huperzine methyl salt is selected from the group consisting of the hydrochloride salt of huperzine A, hydrobromide, citrate, acetate, lactate, phosphate, sulfate, fumarate.
  • the invention also includes a method for preparing a huperzine methyl salt, the method comprising the steps of:
  • the solvent in the step (1) is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetone, tetrahydrofuran, water; and the molar ratio of (-)-huperzine A to acid is 1:1 to 1: 2.
  • the solvent is selected from the group consisting of water, acetone and water or a mixed solvent of ethanol and water, the ratio of acetone to water is 1:1 to 5:1, and the ratio of ethanol to water is 1:1 to 5:1; (-)- The weight ratio of Huperzine A to the solvent is 1:1 to 10.
  • the acid in the step (1) is hydrochloric acid or hydrobromic acid
  • the molar ratio of (-)-huperzine to the acid is 1:1 to 1:1.05
  • the pH of the reaction liquid is 3.5 to 5.5.
  • the recrystallization solvent in the step (2) is selected from the group consisting of methanol, absolute ethanol, isopropanol and ethyl acetate; and the amount thereof is 3 to 20 times the weight of (-)-huperzine A, and the amount of acetone is ( -) - 10 to 50 by weight of Huperzine A.
  • a preferred method of preparation of the invention comprises the steps of:
  • (-)-Huperzine A is reacted with hydrochloric acid or hydrobromic acid in a solvent to obtain a solution of huperzine methyl salt; wherein the solvent is selected from the group consisting of water, acetone and water or a mixed solvent of ethanol and water.
  • the ratio of acetone to water is 1:1-5:1, the ratio of ethanol to water is 1:1-5:1;
  • the weight ratio of (-)-huperzine A to solvent is 1:1-10,
  • ( -) - the molar ratio of Huperzine A to hydrobromic acid is 1:1 to 1:1.05, and the pH of the reaction solution is 3.5 to 5.5;
  • the present invention has been studied in the form of a polymorphic form, in particular, some specific crystal forms have excellent physical and chemical properties. To this end, the present invention also provides a solid of (-)-huperzine methyl salt. crystallization.
  • the solid crystal of the (-)-huperzine methyl salt of the present invention includes the following crystal forms:
  • Huperzine methyl hydrochloride an amorphous crystalline form.
  • Huperzine hydrobromide crystal form Huperzine hydrobromide crystal form, X-ray diffraction pattern of the crystal, expressed as degrees 2 ⁇ of 8.720, 10.560, 11.957, 13.381, 14.506, 15.253, 16.109, 17.074, 17.488, 18.102, 18.932, 19.339 , 20.249, 20.863, 21.218, 21.968, 22.677, 23.074, 23.944, 24.437, 24.851, 25.343, 25.713, 25.974, 26.350, 26.943, 27.204, 28.028, 28.945, 30.318, 31.087, etc. have obvious characteristic absorption peaks, as shown in the figure 1b.
  • the DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 1c, 1d, and 1e.
  • Huperzine methyl sulfate crystal form respectively named huperzine methyl sulfate crystal form I, huperzine methyl sulfate form II.
  • Huperzine methyl phosphate crystal form, X-ray diffraction pattern of the crystal, the 2 ⁇ angle expressed in degrees is 4.677, 6.613, 7.363, 8.033, 9.869, 11.338, 11.924, 13.112, 13.519, 14.843, 16.955, 17.862, 19.048 , 19.934, 21.297, 22.346, 23.567, 24.198, 25.049, 25.957, 27.674, 28.661, 31.582, etc. have obvious characteristic absorption peaks, see Figure 4b.
  • the DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 4c, 4d, 4e.
  • Huperzine mesylate The three crystal forms of Huperzine mesylate are named as Huperzine Methionate Form I, Huperzine Formate Form II, and Huperzine Formate Form III.
  • Huperzine form of fumarate the X-ray diffraction pattern of the crystal, expressed as degrees 2 ⁇ of 7.837, 11.033, 12.221, 12.611, 13.185, 14.785, 15.711, 17.134, 19.068, 19.778, 20.765, 21.416
  • the DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 8c, 8d, and 8e.
  • Huperzine form of the huperzine the X-ray diffraction pattern of the crystal, expressed as degrees 2 ⁇ at 5.980, 9.316, 10.934, 12.356, 13.895, 14.880, 15.733, 16.185, 17.646, 18.260, 18.949, 21.456, There are obvious characteristic absorption peaks at 22.344, 22.937, 23.905, 24.656, 25.956, as shown in Figure 9b.
  • the DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 9c, 9d, and 9e.
  • Huperzine formamidine crystal form respectively named as Huperzine Methionate Form I, Huperzine Formate Form II.
  • Huperzine methyl hydrochloride crystals which are amorphous powders.
  • the invention additionally provides a method for preparing polymorphs of four huperzine methyl salts, specifically:
  • Method 4 Add the huperzine methyl salt to dimethyl sulfoxide or N, N-dimethylformamide, stir to dissolve, slowly add organic solvent, precipitate crystals and stir for 12 hours; filter, collect The solid was dried under reduced pressure for 24 hours.
  • the organic solvent includes all organic solvents, as long as it has a certain solubility to the huperzine methyl salt and does not deteriorate.
  • the organic solvent used in this patent uses acetone, ethanol, ethyl acetate, acetonitrile, and aqueous acetone.
  • the present invention also encompasses a pharmaceutical preparation comprising the huperzine methyl salt of the present invention or a polymorph thereof, which is selected from any of the pharmaceutical dosage forms suitable for administration, such as tablets, capsules, pills, granules. , powders, suppositories, films, oral solutions, sprays and injections.
  • the pharmaceutical preparation of the present invention is particularly suitable for preparation into a liquid preparation or a soluble preparation such as an oral solution, a large-volume injection, a small-volume injection, a dry powder injection, a freeze-dried injection or the like.
  • the invention is particularly suitable for the preparation of oral orally soluble preparations, such as dropping pills, orally disintegrating tablets, buccal tablets, granules, dispersible tablets and the like.
  • the salt-refining process further improves the product quality of the Huperzine methyl salt, and the content can be More than 99.9%, the total impurity content is less than 0.1%, and its quality stability is better than Huperzine A, which is beneficial to the quality stability of the product storage period and preparation production, improve the quality of the final preparation product, and is beneficial to patients. Medication safety Sexuality, effectiveness.
  • huperzine A refers to (-)-huperzine A.
  • Very soluble means that 1g of solute can be dissolved in less than 1ml
  • Soluble means that 1 g of solute can be dissolved in 1 to less than 10 ml;
  • Slightly soluble means that 1 g of solute can be dissolved in 30 to less than 100 ml;
  • Microsolute means that 1g of solute can be dissolved in 100 ⁇ less than 1000ml;
  • Very slightly soluble means that 1g of solute can be dissolved in 1000 ⁇ less than 10000ml;
  • huperzine methyl salt has an improved taste and is particularly suitable for the preparation of instant oral preparations such as dropping pills, orally disintegrating tablets, buccal tablets, oral liquids, dispersible tablets and the like.
  • the following crystal forms of huperzine methyl salt, hydrobromide crystal, sulfate crystal form I, sulfate crystal form II, phosphate crystal, acetate crystal form I, B were found.
  • the above crystal form has good stability, and stability test is carried out for this purpose.
  • the test conditions are: temperature 40 ⁇ 2° C., RH 75 ⁇ 5%; test basis: “Chinese Pharmacopoeia” 2010 edition 2; number of tests: 0 months, 1 month, 2 months, 3 months, 6 months.
  • the test results are as follows:
  • Figure 1e shows the Raman spectrum of the Huperzine hydrobromide salt of the present invention
  • Figure 2e shows the Raman spectrum of the Huperzine Methanesulfate Form I of the present invention
  • Figure 3e shows the Raman spectrum of the Huperzine Methanesulfate Form II of the present invention
  • Figure 4e shows the Raman spectrum of the Huperzine Methyl Phosphate of the present invention
  • Figure 5e is a Raman spectrum of the crystalline form I of Huperzine meacetate of the present invention
  • Figure 6e shows the Raman spectrum of the Huperzine meacetate crystal form II of the present invention
  • Figure 7e shows the Raman spectrum of the crystalline form III of Huperzine meacetate of the present invention
  • Figure 8e shows the Raman spectrum of the Huperzine Methyl Fumarate of the present invention
  • Figure 9e shows the Raman spectrum of the Huperzine Lactate of the present invention
  • Figure 11e shows the Raman spectrum of the huperzine formamidine crystal form II of the present invention
  • XRPD In the present invention, the XRPD spectrum was detected by a Bruker Advance X-ray diffractometer, and the 2 ⁇ angle scan was from 5 to 45 degrees, Cu-Ka radiation.
  • the DSC spectrum in the present invention was detected by a DSC8500 differential scanning calorimeter from a US PE company, the atmosphere was nitrogen, and the heating rate was 10 ° C / min.
  • IR The infrared spectrum of the present invention is detected by a Bruker Tenso 227 infrared absorption spectrometer with a detection range of 4000-350 wave numbers.
  • Raman In the present invention, the Raman spectrum is detected by a DXR micro-Raman spectrometer with a detection range of 3500-50 cm -1 Raman shift.
  • huperzine formate was added to 10 mL of ethanol, heated to reflux for 1 hour, slowly cooled to room temperature with stirring, stirring was continued for 2 hours, filtered, and the filter cake was rinsed with ethanol, and the solid was vacuumed at 45 ° C. After drying for 4 hours, 0.27 g of a crystalline powder was obtained, and the obtained crystalline powder was determined by X-ray powder diffraction to be a huperzine formamidine crystal form I. The specific spectrum is shown in Fig. 10b.
  • huperzine formate 0.3 g was added to 10 mL of acetonitrile, heated to reflux for 1 hour, slowly cooled to room temperature with stirring, stirring was continued for 2 hours, filtered, and the filter cake was rinsed once with acetonitrile, and the solid was vacuumed at 45 ° C. After drying for 4 hours, 0.28 g of a crystalline powder was obtained, which was measured by X-ray powder diffraction, and the obtained crystalline powder was huperzine formate crystal form II, and the specific spectrum is shown in Fig. 11b.
  • the above ingredients were uniformly mixed, granulated by 20 mesh, sieved and sized, dried, and compressed into 1000 pieces.
  • the preparation method of the Huperzine hydrochloride mouth-containing tablet is as follows:
  • sucrose, citric acid, sodium citrate were crushed through a 100 mesh sieve and used.
  • the oxalipine hydrochloride A is sufficiently dissolved in dilute ethanol to prepare a dispersion of Huperzine Hydrochloride.
  • sucrose powder, citric acid and citric acid are mixed and granulated by high-efficiency wet method.
  • the oxalipine hydrochloride and the solvent are dissolved into a solution, and the above components are added and stirred uniformly. After granulation by a wet granulation method, the granules are sieved, dried, microcrystalline cellulose is added, and 1000 capsules are obtained by capsule filling.
  • the oxalipine hydrochloride and the solvent are dissolved into a solution, and the above components are added and stirred uniformly. After granulation by a wet granulation method, the granules are sieved, dried, microcrystalline cellulose is added, and 1000 capsules are obtained by capsule filling.
  • the preparation method of the Huperzine Hydrochloride A Drop Pill is as follows:
  • the oxalipine hydrochloride and the solvent are dissolved into a solution, and the above components are added, melted and mixed uniformly, and dropped into 5-10C liquid paraffin or dimethyl silicone oil to form a pellet, rubbed with oil, and dried to prepare 1000 pellets.
  • the preparation method of the Huperzine Hydrochloride A Drop Pill is as follows:
  • the huperzine hydrochloride A is dissolved uniformly with an appropriate amount of solvent, and mixed with the already melted polyethylene glycol 6000, the temperature is 60-90 ° C, melted and stirred uniformly, and then transferred into the drip irrigation of the dropping machine (insulation 70-90) °C), dripping into liquid paraffin or methyl silicone oil at 5-17 ° C, taking out the dropping pills, removing liquid paraffin or methyl silicone oil, washing the pellets, and drying, to obtain 1000 pills (pill weight 50-60 mg).
  • the preparation method of the lyophilized injection is as follows:
  • Each unit contains -(-) Huperzine A 30-100 ⁇ g)
  • the preparation method of small volume injection is as follows:
  • the preparation method of large-volume injection is as follows:
  • the rest is water for injection (30-100 ⁇ g per unit cell/bag containing -(-) Huperzine A)

Abstract

L'invention concerne un sel d'(-)-huperzine-a, préparé à partir de la réaction de l'huperzine-a avec un acide correspondant. Le sel d'huperzine-a est sélectionné dans le groupe comprenant chlorhydrate, bromhydrate, sulfate, phosphate, nitrate, acétate, trifluoroacétate, lactate, citrate, oxalate, maléate, succinate, tartrate, fumarate, mandélate, mésylate, sulfonate de benzène, gluconate, ascorbate, acétonate, sel d'alanine, aspartate, lysinate et sel d'arginine de l'huperzine-a.
PCT/CN2014/086721 2013-09-24 2014-09-17 Sel d'(-)-huperzine-a WO2015043404A1 (fr)

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CN201310436992 2013-09-24
CN201310436992.8 2013-09-24

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1393220A (zh) * 2001-07-03 2003-01-29 山东绿叶制药股份有限公司 石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法
CN1621039A (zh) * 2003-11-25 2005-06-01 上海医药工业研究院 石杉碱甲及其衍生物或其盐的经鼻脑靶向制剂
CN1682719A (zh) * 2005-03-01 2005-10-19 沈阳药科大学 一种含有石杉碱甲的肠溶包衣缓释片剂及制备方法
CN1751683A (zh) * 2004-09-21 2006-03-29 山东绿叶制药有限公司 石杉碱甲及其衍生物或其盐的骨架型缓释片及其制备工艺
CN103224467A (zh) * 2013-05-17 2013-07-31 浙江万邦药业股份有限公司 一种(-)-石杉碱甲的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1393220A (zh) * 2001-07-03 2003-01-29 山东绿叶制药股份有限公司 石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法
CN1621039A (zh) * 2003-11-25 2005-06-01 上海医药工业研究院 石杉碱甲及其衍生物或其盐的经鼻脑靶向制剂
CN1751683A (zh) * 2004-09-21 2006-03-29 山东绿叶制药有限公司 石杉碱甲及其衍生物或其盐的骨架型缓释片及其制备工艺
CN1682719A (zh) * 2005-03-01 2005-10-19 沈阳药科大学 一种含有石杉碱甲的肠溶包衣缓释片剂及制备方法
CN103224467A (zh) * 2013-05-17 2013-07-31 浙江万邦药业股份有限公司 一种(-)-石杉碱甲的制备方法

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