WO2024071959A1 - Procédé de préparation d'un dérivé d'ester d'alposcérate de choline et son utilisation - Google Patents

Procédé de préparation d'un dérivé d'ester d'alposcérate de choline et son utilisation Download PDF

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Publication number
WO2024071959A1
WO2024071959A1 PCT/KR2023/014766 KR2023014766W WO2024071959A1 WO 2024071959 A1 WO2024071959 A1 WO 2024071959A1 KR 2023014766 W KR2023014766 W KR 2023014766W WO 2024071959 A1 WO2024071959 A1 WO 2024071959A1
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alpha
formula
glycerylphosphorylcholine
thioctyl
group
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PCT/KR2023/014766
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English (en)
Korean (ko)
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구창휘
전호성
유재호
이규항
임송이
임영주
민창호
이혜인
신한진
박선미
김동훈
오은혜
정기문
김서연
곽승환
박지수
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하나제약 주식회사
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Publication of WO2024071959A1 publication Critical patent/WO2024071959A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a method for synthesizing a derivative obtained by esterifying choline alfoscerate.
  • the present invention also relates to preparations containing choline alposcerate ester derivatives and their uses.
  • alpha-lipoic acid choline ester a compound being developed by Novartis
  • US Patent No. It is described in 8,410,162 B2 (April 2, 2013) and is currently undergoing phase 2 clinical trials as a presbyopia improvement agent.
  • This material uses the condensing agent dicyclohexylcarbodiimide (N,N’-Dicyclohexylcarbodiimide, DCC) through an ester condensation reaction of choline and alpha-lipoic acid, but the yield was found to be low (77.4%). Additionally, the above compound was not synthesized directly, but was synthesized through methylation using additional methyliodide.
  • European patent EP 2717864 A1 introduces a method of producing the target substance by reacting lipoyl chloride prepared from lipoic acid using oxalyl chloride and choline alfoscerate using dibutyl oxide as shown in the following reaction formula.
  • liponyl chloride which is used as a reaction intermediate, is a hydrochloric acid gas generated by excessive use of oxalic chloride during production, requiring caution for worker safety, while the process using T3P does not produce harmful gases and is commercially safe. You can use it.
  • the existing reaction proceeds through liponyl chloride, so it has the disadvantage of being a two-step process. In the case of Scheme 3 ⁇ 2>, because isopropyl is present in the raw material, it is difficult to proceed with the reaction with the target compound.
  • the present inventors studied to improve the method of synthesizing triple ester in the existing choline alfoscerate synthesis method.
  • the five-step traditional synthesis method of choline alposcerate is Bull. Korean Chem. Soc. 2010, Vol. 31, No 9, 2689-2691.
  • TGPC thioctylcholinealfoscerate
  • the object of the present invention is to overcome the difficulties in the existing synthesis method by selectively using specific condensing agents, amine compounds, and organic solvents in the synthesis of ester derivatives of choline alpoicerate, alpha lipoic choline ester.
  • the goal is to provide a new manufacturing method for compounds.
  • the present invention is a method for producing (R)-alpha-mono-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula (3),
  • a condensing agent selected from the group consisting of Propylphosphonic anhydride, N,N'-Dicyclohexylcarbodiimide, Diimidazole carbonate and Oxalylchloride.
  • An amine-based compound selected from the group consisting of piperidine, dimethylaminoethanol (N,N'-dimethylethanolamine), triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA), and methylamine dimethylaminopyridine, and
  • a production method comprising reacting in the presence of an organic solvent selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and ethyl acetate.
  • an organic solvent selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and ethyl acetate.
  • the amount of thioctic acid used is preferably 0.5 to 1.5 equivalents, more preferably 0.8 to 1.2 equivalents, and most preferably 1 equivalent.
  • a condensing agent selected from the group consisting of Propylphosphonic anhydride, N,N'-Dicyclohexylcarbodiimide, Diimidazole carbonate and Oxalylchloride.
  • An amine compound selected from the group consisting of pyridine, dimethylaminoethanol (N,N'-dimethylethanolamine), triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA), and methylamine dimethylaminopyridine, and
  • a production method comprising reacting in the presence of an organic solvent selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and ethyl acetate.
  • an organic solvent selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and ethyl acetate.
  • the amount of thioctic acid used is more preferably 1.8 to 2.2 equivalents, and most preferably 2 equivalents.
  • the synthesis method according to the present invention is a method of synthesizing TPGC in one step without going through several steps, and increases the stability of the material in the form of a prodrug and promotes the synthesis of choline alposcerate (glycerylphosphocholine, GPC) and thioctic acid in vivo.
  • the effects of two drugs can be obtained simultaneously, and the antioxidant effect of a single pharmacological action can also be obtained.
  • the prodrug thioctylglycerylphosphoylcholine (TGPC, thioctylcholine alfoscerate) itself has an antioxidant effect. When decomposed in the body, it is separated into GPC and thioctic acid. In the case of GPC, it has an effect of improving brain function, and thioctic acid has an antioxidant effect and diabetes. It has a relieving effect.
  • Figure 4 shows an antioxidant test graph of thioctylcholine alfoscerate.
  • Figure 5 shows a graph of the antioxidant test of GPC (glycerylphosphocholine).
  • Figure 6 shows an antioxidant test graph of Trolox (control material).
  • L-alpha-glycerylphosphorylcholine of the formula 1 below and thioctic acid of the formula 2 below are reacted with propylphosphonic anhydride and dicyclohexylcarboimide (N,N'-Dicyclohexylcarbodiimide).
  • a condensing agent selected from the group consisting of diimidazole carbonate and oxalylchloride
  • Amine-based compounds selected from the group consisting of pyridine, dimethylaminoethanol (N,N'-dimethylethanolamine), triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA), and methylamine dimethylaminopyridine; and reacting in the presence of an organic solvent selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile, and ethyl acetate.
  • the amount of thioctic acid used is preferably 0.5 to 1.5 equivalents, more preferably 0.8 to 1.2 equivalents, and most preferably 1 equivalent.
  • a condensing agent selected from the group consisting of Propylphosphonic anhydride, N,N'-Dicyclohexylcarbodiimide, Diimidazole carbonate and Oxalylchloride.
  • Amine-based compounds selected from the group consisting of pyridine, dimethylaminoethanol (N,N'-dimethylethanolamine), triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA), and methylamine dimethylaminopyridine; And reacting in the presence of an organic solvent selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile and ethyl acetate,
  • the amount of thioctic acid used is more preferably 1.8 to 2.2 equivalents, and most preferably 2 equivalents.
  • the condensing agent may be used in a molar ratio of 1 to 3 molar to thioctic acid, and most preferably in a 2 molar ratio.
  • the manufacturing method may further include a purification process using a resin amberite inclusion resin.
  • (R)-alpha-mono-thioctyl-L-alpha-glycerylphosphorylcholine or (R)-alpha-di-thioctyl-L-alpha- prepared by the above production method A pharmaceutical composition containing glycerylphosphorylcholine for use in the treatment or prevention of dementia, mild cognitive impairment, hair loss, Alzheimer's disease, Parkinson's disease, muscle seizures and presbyopia is provided.
  • Thioctylcholine alfoscerate the final compound of the present invention, has the characteristics of a prodrug.
  • ester compounds are decomposed into fatty acid and alcohol structures when exposed to enzymes (lipase and various enzymes) in the human body, and as shown in Scheme 6 below, thioctylcholine alfoscerate is decomposed into thioctic acid and GPC by lipase enzyme, respectively.
  • the ingredients have pharmacological activity in the human body.
  • the pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable carrier, excipient, or diluent.
  • “pharmaceutically acceptable” means that the compound is commonly used in the pharmaceutical field and does not irritate the organism upon administration and does not inhibit the biological activity and properties of the administered compound.
  • the type of the carrier is not particularly limited, and any carrier commonly used in the art can be used.
  • Non-limiting examples of the carrier include saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, etc. You can. These may be used alone or in combination of two or more types.
  • the pharmaceutical composition of the present invention can be used by adding other pharmaceutically acceptable additives, such as excipients, diluents, antioxidants, buffers or bacteriostatic agents, if necessary, as well as fillers, extenders, wetting agents, disintegrants, dispersants, and surfactants. It can be used by additionally adding activators, binders, or lubricants.
  • pharmaceutically acceptable additives such as excipients, diluents, antioxidants, buffers or bacteriostatic agents, if necessary, as well as fillers, extenders, wetting agents, disintegrants, dispersants, and surfactants. It can be used by additionally adding activators, binders, or lubricants.
  • composition of the present invention can be formulated and used in various dosage forms suitable for oral administration.
  • Non-limiting examples of the preparation for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, etc. can be mentioned.
  • the tablet may be an enteric-coated tablet or a double tablet, but is not limited thereto.
  • reaction progress is checked by TLC (RF 0.4) and HPLC, and the reaction is allowed to proceed for more than 50 hours, then diluted with phosphate buffer, adsorbed by inclusion with Amberite Resin, extracted with methanol, the solvent is recovered, and the residue is taken. Obtain 20 mg (yield 6.7%) of thioctylcholine alfoscerate as a solid.
  • reaction progress is checked by TLC (RF 0.4) and HPLC, and the reaction is allowed to proceed for more than 50 hours. Then, the reaction is diluted with a phosphate buffer solution, followed by clathrate adsorption with Amberite Resin, followed by extraction with methanol, the solvent is recovered, and the residue is taken. Obtain 13 mg (yield 4.3%) of thioctylcholine alfoscerate as a solid. Compared to the reaction using T3P (n-propanephosphonic acid anhydride) condensing agent, the yield was very low at 4.3%.
  • T3P n-propanephosphonic acid anhydride
  • TGPC The antioxidant effect of the synthesized TGPC was measured using DPPH radical (DPPH Antioxidant Assay kit, BIOMAX).
  • TGPC and GPC were diluted using distilled water to 300 mg/mL, 150 mg/mL, 75 mg/mL, 37.5 mg/mL, 18.8 mg/mL, 9.4 mg/mL, and 4.7 mg/mL.
  • Trolox used as a positive control was diluted with 95% ethanol to 80 ⁇ g/mL, 60 ⁇ g/mL, 40 ⁇ g/mL, 20 ⁇ g/mL, and 10 ⁇ g/mL.
  • DPPH radical scavenging ability was not observed in GPC in the concentration range of 4.7 to 300 mg/mL ( Figure 5).
  • Trolox used as a positive control, was observed to have a concentration-dependent DPPH radical scavenging ability in the concentration range of 10 to 80 ⁇ g/mL, and the IC 50 value was calculated to be 74.4 ⁇ g/mL.
  • TGPC was observed to have a DPPH radical scavenging effect (IC 50 : 262.6 mg/mL) at a level similar to that of lipoic acid, which has a DPPH radical scavenging effect (IC 50 : 250 mg/mL a ). Since the DPPH radical scavenging effect was observed in a concentration-dependent manner, it has an antioxidant effect. It was judged that there was.
  • Example 7 - Formulation experiment regular tablet, enteric-coated tablet
  • Example 10 A tablet was manufactured using 225 mg of TGPC as the main ingredient and auxiliary ingredients such as magnesium aluminometasilicate, microcrystalline cellulose, crospovidone, and magnesium stearate, and then coated with a film coating base such as Opadry to produce a film-coated tablet.
  • the dissolution curve was as shown in Figure 1, and it was confirmed that most of the thioctylcholine alfoscerate was eluted during the tablets and that thioctylcholine alfoscerate was stable at pH 4.0.
  • TGPC and magnesium aluminometasilicate were added to the high-speed coalescing machine and mixed, and TGPC was adsorbed onto the magnesium aluminometasilicate.
  • Microcrystalline cellulose was added here, purified water was added, and kneaded.
  • Example 7-3 was prepared in the same manner as Example 7-2.
  • the main ingredient is 225 mg of thioctylcholine alposcerate
  • the secondary ingredients are magnesium aluminometasilicate, microcrystalline cellulose, crospovidone, magnesium stearate, etc. to manufacture tablets and coated with an enteric coating base such as Acryliz, Eudragit, etc. to produce enteric coated tablets.
  • the dissolution curve was as shown in Figure 2, and it was confirmed that most of the thioctylcholine alfoscerate in the tablet was eluted and that thioctylcholine alfoscerate was stable at pH 6.8.
  • Tablets are manufactured using 225 mg of thioctylcholine alfoscerate as the main ingredient and auxiliary ingredients such as magnesium aluminometasilicate, microcrystalline cellulose, crospovidone, magnesium stearate, etc. and coated with an enteric coating base such as Acryliz, Eudragit, etc. for enteric use. Coated tablets were prepared. The dissolution curve was as shown in Figure 3, and it was confirmed that in the presence of an enzyme such as pancreatin, thioctylcholine alfoscerate was decomposed into thioctic acid and GPC as a prodrug and converted into substances with pharmacological activity, respectively.
  • an enzyme such as pancreatin
  • thioctylcholine alfoscerate was decomposed into thioctic acid and GPC as a prodrug and converted into substances with pharmacological activity, respectively.
  • DPPH radical scavenging ability was observed for thioctylcholine alfoscerate at a concentration of 4.7 mg/mL to 300 mg/mL, and the IC 50 value was 262.6 mg. It was calculated as /mL.
  • DPPH radical scavenging activity was not observed in GPC at concentrations of 4.7 mg/mL to 300 mg/mL.
  • Trolox a positive control material, was observed to have DPPH radical scavenging ability at a concentration of 10 to 80 ⁇ g/mL, and the IC 50 value was calculated to be 74.4 ⁇ g/mL.
  • Thioctylcholine alfoscerate is a prodrug in which glycerylphosphorylcholine and lipoic acid are linked by an esterification bond, and an antioxidant effect similar to that of lipoic acid (IC 50 250 mg/mL) was observed.

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Abstract

La présente invention concerne un procédé de synthèse d'un dérivé obtenu par estérification d'alfoscérate de choline. La présente invention concerne également une préparation comprenant un dérivé d'ester d'alfoscérate de choline (TGPC) et son utilisation. Un composé ester d'alfoscérate de choline a un effet antioxydant indépendamment, et en tant que promédicament, le composé est séparé en GPC et en acide thioctique au moyen d'enzymes in vivo pour traiter ou prévenir des maladies choisies parmi un trouble cognitif léger, le diabète, les crises musculaires et la presbytie.
PCT/KR2023/014766 2022-09-27 2023-09-26 Procédé de préparation d'un dérivé d'ester d'alposcérate de choline et son utilisation WO2024071959A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2546289B2 (ja) * 1987-09-02 1996-10-23 日本油脂株式会社 合成レシチンの製造法
US20100317725A1 (en) * 2009-06-15 2010-12-16 Encore Health Llc Choline Esters
CN106967044A (zh) * 2017-05-12 2017-07-21 苏州富士莱医药股份有限公司 制备r‑硫辛酸胆碱酯卤化物的方法
CN110385427A (zh) * 2019-07-31 2019-10-29 东南大学 一种水溶性纳米粒子及其制备方法和应用
KR20200033751A (ko) * 2018-09-20 2020-03-30 주식회사 셀트리온제약 콜린 알포세레이트를 포함하는 약학 조성물

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100966627B1 (ko) 2006-06-14 2010-06-29 주식회사 대웅제약 Ｌ-α-글리세로포스포릴 콜린의 제조방법
DE102011103948A1 (de) 2011-06-06 2012-12-06 B. Braun Melsungen Ag Biopassivierende Beschichtung von Gefäßprothesen mit Nitrocarbonsäuren enthaltenden Phospholipiden
KR101601685B1 (ko) 2015-08-24 2016-03-09 여명바이오켐 주식회사 항산화 효과가 우수한 택시폴린 유도체 및 이를 함유하는 화장료 조성물
KR20180026653A (ko) 2016-09-02 2018-03-13 (주) 파마젠 콜린 알포세레이트의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2546289B2 (ja) * 1987-09-02 1996-10-23 日本油脂株式会社 合成レシチンの製造法
US20100317725A1 (en) * 2009-06-15 2010-12-16 Encore Health Llc Choline Esters
CN106967044A (zh) * 2017-05-12 2017-07-21 苏州富士莱医药股份有限公司 制备r‑硫辛酸胆碱酯卤化物的方法
KR20200033751A (ko) * 2018-09-20 2020-03-30 주식회사 셀트리온제약 콜린 알포세레이트를 포함하는 약학 조성물
CN110385427A (zh) * 2019-07-31 2019-10-29 东南大学 一种水溶性纳米粒子及其制备方法和应用

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