KR102595126B1 - Methods for the synthesis of choline alfoscerate ester derivatives and use thereof - Google Patents
Methods for the synthesis of choline alfoscerate ester derivatives and use thereof Download PDFInfo
- Publication number
- KR102595126B1 KR102595126B1 KR1020220122303A KR20220122303A KR102595126B1 KR 102595126 B1 KR102595126 B1 KR 102595126B1 KR 1020220122303 A KR1020220122303 A KR 1020220122303A KR 20220122303 A KR20220122303 A KR 20220122303A KR 102595126 B1 KR102595126 B1 KR 102595126B1
- Authority
- KR
- South Korea
- Prior art keywords
- alpha
- formula
- glycerylphosphorylcholine
- thioctyl
- group
- Prior art date
Links
Classifications
-
- 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 System
- 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
- 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
-
- 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
Abstract
본 발명은 콜린알포세레이트를 에스테르화 한 유도체의 합성 방법에 관한 것이다. 또한 본 발명은 콜린알포세레이트 에스테르(TGPC) 유도체를 포함하는 제제 및 그 용도에 관한 것이다. 콜린알포세레이트 에스테르 화합물은 물질 독단적으로 항산화 효과를 갖고 프로드럭(prodrug, 전구의약물)으로서 생체내 효소에 의해 GPC와 티옥트산으로 분리되어 경도인지장애, 당뇨병, 근육발작 및 노안에서 선택되는 질병을 치료 또는 예방하는 효과를 갖는다. 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 (TGPC) derivatives and their uses. Choline alposcerate ester compound has an antioxidant effect on its own and is a prodrug, which is separated into GPC and thioctic acid by enzymes in vivo and is selected for mild cognitive impairment, diabetes, muscle seizures, and presbyopia. It has the effect of treating or preventing.
Description
본 발명은 콜린알포세레이트를 에스테르화 한 유도체의 합성 방법에 관한 것이다. 또한 본 발명은 콜린알포세레이트 에스테르 유도체를 포함하는 제제 및 그 용도에 관한 것이다.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.
콜린화합물에 알파-리포익산을 에스테르로서 축합시키는 기술은 3중 에스테르 반응이 필요한데, 에스테르 반응 중 상호 에스테르의 변환 분해 재결합 등 요인으로 인해 쉽게 합성되지 못하였고 수차례 세계적 제약회사가 시도하였지만 성공하지 못하고 일부 가능한 콜린 에스테르를 화합 물질을 합성하여 임상 시험을 하고 있는 실정이다.The technology for condensing alpha-lipoic acid into a choline compound as an ester requires a triple ester reaction, but it was not easily synthesized due to factors such as conversion, decomposition, and recombination of mutual esters during the ester reaction, and although global pharmaceutical companies attempted it several times, it was not successful. Some possible choline esters are being synthesized and clinically tested.
예를 들면 노바티스가 개발 중인 화합물인 알파-리포익산콜린 에스테르는 미국특허 US Patent No. 8,410,162 B2 (2013. 4. 2.)에 기술되어 있으며, 현재 노안 개선제로 임상 2상 시험 중에 있다. 상기 물질은 콜린과 알파-리포산을 에스테르 축합반응으로 축합제인 디사이클로헥실카보디이미드(N,N’-Dicyclohexylcarbodiimide , DCC)를 사용하고 있으나 수율이 적은 것으로 나타났다 (77.4%). 또한 상기 화합물은 바로 합성되지 않았으며 메틸요오드(Methyliodide)를 추가로 사용하여 메틸화를 거쳐서 합성되었다.For example, alpha-lipoic acid choline ester, a compound being developed by Novartis, is disclosed in 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.
WO 2012/168342에 기재된 바에 의하면, 리포인산염과 콜린할라이드를 반응시켰을 때 oxalic chloride를 사용하여 진행하는 합성방법은 하기 반응식 1과 같이 2개의 단계로 진행되며 수율이 26.4%로 낮은 단점이 있다.According to WO 2012/168342, the synthesis method using oxalic chloride when lipophosphate and choline halide are reacted proceeds in two steps as shown in Scheme 1 below, and has the disadvantage of having a low yield of 26.4%.
[반응식 1][Scheme 1]
[반응식 2][Scheme 2]
유럽 특허 EP 2717864 A1에는 하기 반응식과 같이 리포산으로부터 옥살릴 클로라이드를 사용하여 제조된 리포일 클로라이드와 콜린알포세레이트를 다이부틸옥사이드 사용 하에 반응시켜 목적 물질을 제조하는 방법이 소개되어 있다.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.
[반응식 3][Scheme 3]
그러나, 상기 제조 공정은 리포산에 옥살릴 클로라이드를 사용하여 클로라이드를 도입하는 반응의 합성이 어려울 뿐만 아니라 물질의 취급과 상업적으로 용이하지 않다. 더욱 자세하게 설명하자면, 반응 중간체로 사용되는 리포닐클로라이드는 제조시 oxalic chloride를 과량 사용하여 생성 되는 염산가스로 작업자의 안전에 주의가 필요한 반면 T3P를 사용하는 공정은 유해기체를 생성하지 않고 상업적으로 안전하게 사용할 수 있다. 또한 기존 반응은 리포닐클로라이드를 거쳐 진행하므로 공정이 2단계인 단점이 있으며, 반응식 3 <2>의 경우 원료물질에 아이소프로필이 존재하기 때문에, 목적화합물로 반응이 진행시키기 어렵다.However, the above manufacturing process is not only difficult to synthesize chloride using oxalyl chloride in lipoic acid, but also difficult to handle and commercialize the material. To explain in more detail, 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. In addition, 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.
본 발명자들은 기존의 콜린알포세레이트 합성 방식에서 3중 에스테르를 합성하는 방법을 개선하고자 검토하였다. 먼저 콜린알포세레이트의 5 단계 전통적인 합성 방법은 Bull. Korean Chem. Soc. 2010, Vol. 31, No 9 , 2689~ 2691에 기술되어 있다.The present inventors studied to improve the method of synthesizing triple ester in the existing choline alfoscerate synthesis method. First, the five-step traditional synthesis method of choline alposcerate is Bull. Korean Chem. Soc. 2010, Vol. 31, No 9, 2689-2691.
[반응식 4][Scheme 4]
상기 문헌에 의하면 GPC(glycerylphosphocholine) 합성반응에서 Pd/C 환원 반응을 사용함으로 인하여 벤질기만 환원되는 것이 아니라 환원에 의한 -S-S- Bond가 -SH로 분해되어 합성에 어려움이 있다.According to the above literature, due to the use of the Pd/C reduction reaction in the GPC (glycerylphosphocholine) synthesis reaction, not only the benzyl group is reduced, but the -S-S- Bond is decomposed into -SH by reduction, making synthesis difficult.
또한 본 발명자들은 국내공개특허 10-2018-0026653호 (2018. 3. 13)에 기재된 방법을 참고하여 하기와 같이 합성을 시도해보았으나 수율이 10% 미만이고 이온 반응으로 높은 온도의 반응조건이 필요할 뿐더러 -S-S- 결합이 수지상(고분자)로 중합되는 문제가 있었다.In addition, the present inventors attempted synthesis as follows with reference to the method described in Korean Patent Publication No. 10-2018-0026653 (March 13, 2018), but the yield was less than 10% and high temperature reaction conditions were required due to ionic reaction. In addition, there was a problem with the -S-S- bond polymerizing into a dendritic phase (polymer).
[반응식 5][Scheme 5]
반응식 5의 경우 반응 온도가 40도 이상일 때 잘 진행되었으나, SH의 중합체가 형성되었다. 그 이하일 때는 반응이 잘 진행되지 않았다.In the case of Scheme 5, the reaction proceeded well when the reaction temperature was above 40 degrees, but a polymer of SH was formed. When it was lower than that, the reaction did not proceed well.
본 합성 물질인 티옥틸콜린알포세레이트 (TGPC: thioctylcholinealfoscerate)는 동시에 3개의 에스테르 형태를 가지고 있고 반응 중 상호분자 구조 재배열 이전 현상(Rearrangement Phenomenon)이 일어나기 때문에 합성이 극히 용이하지 않다. 따라서 본 발명은 이를 극복하기 위한 새로운 합성방법을 제공하는 것을 그 목적으로 한다.This synthetic material, thioctylcholinealfoscerate (TGPC), has three ester forms at the same time and is not extremely easy to synthesize because rearrangement phenomenon occurs during the reaction. Therefore, the purpose of the present invention is to provide a new synthesis method to overcome this problem.
본 발명의 목적은 콜린알포세레이트의 에스테르 유도체의 합성에 있어 특정한 축합제, 아민계 화합물 및 유기 용매를 선택적으로 사용함으로서 기존 합성방법에 있어 난점을 극복한 알파-리포익(alpha lipoic) 콜린에스테르 화합물의 새로운 제조방법을 제공하는 데 있다.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.
상기한 목적을 달성하기 위하여 본 발명은 하기 화학식 3의 (R)-알파-모노-티옥틸-L-알파-글리세릴포스포릴콜린을 제조하는 방법으로서,In order to achieve the above object, the present invention is a method for producing (R)-alpha-mono-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula (3),
화학식 1의 L-알파-글리세릴포스포릴콜린 및 화학식 2의 티옥트산을L-alpha-glycerylphosphorylcholine of Formula 1 and thioctic acid of Formula 2
프로필포스포닉산 무수물(Propylphosphonic anhydride), 디사이클로헥실카보이미드(N,N’-Dicyclohexylcarbodiimide), 디이미다졸카르보네이트(Diimidazole carbonate) 및 옥살릴클로라이드(Oxalylchloride)로 구성되는 군으로부터 선택되는 축합제,A condensing agent selected from the group consisting of Propylphosphonic anhydride, N,N'-Dicyclohexylcarbodiimide, Diimidazole carbonate and Oxalylchloride. ,
피리딘, 디메틸아미노에탄올(N,N’-dimethylethanolamine), 트리에틸아민 (TEA), N,N-Diisopropylethylamine (DIPEA), 메틸아민 및 디메틸아미노피리딘으로 구성되는 군으로부터 선택되는 아민계 화합물 및Amine-based compounds selected from the group consisting of pyridine, dimethylaminoethanol (N,N'-dimethylethanolamine), triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA), methylamine, and dimethylaminopyridine, and
메틸렌클로라이드, 클로로포름, 디메틸설폭사이드, 디메틸포름아미드, 테트라하이드로퓨란, 아세토니트릴 및 에틸아세테이트로 구성되는 군으로부터 선택되는 유기용매의 존재 하에 반응시키는 단계를 포함하는 제조방법을 제공한다.Provided is 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.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
이때, 티옥트산의 사용량은 바람직하게는 0.5 내지 1.5 당량이며, 더욱 바람직하게는 0.8 내지 1.2 당량이며, 가장 바람직하게는 1 당량이다.At this time, 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.
또한 본 발명은Additionally, the present invention
하기 화학식 4의 (R)-알파-디-티옥틸-L-알파-글리세릴포스포릴콜린을 제조하는 방법으로서,As a method for producing (R)-alpha-di-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula 4,
화학식 1의 L-알파-글리세릴포스포릴콜린 및 1.5 내지 2.5 당량의 화학식 2의 티옥트산을L-alpha-glycerylphosphorylcholine of Formula 1 and 1.5 to 2.5 equivalents of thioctic acid of Formula 2
프로필포스포닉산 무수물(Propylphosphonic anhydride), 디사이클로헥실카보이미드(N,N’-Dicyclohexylcarbodiimide), 디이미다졸카르보네이트(Diimidazole carbonate) 및 옥살릴클로라이드(Oxalylchloride)로 구성되는 군으로부터 선택되는 축합제,A condensing agent selected from the group consisting of Propylphosphonic anhydride, N,N'-Dicyclohexylcarbodiimide, Diimidazole carbonate and Oxalylchloride. ,
피리딘, 디메틸아미노에탄올(N,N’-dimethylethanolamine), 트리에틸아민 (TEA), N,N-Diisopropylethylamine (DIPEA), 메틸아민 및 디메틸아미노피리딘으로 구성되는 군으로부터 선택되는 아민계 화합물 및Amine-based compounds selected from the group consisting of pyridine, dimethylaminoethanol (N,N'-dimethylethanolamine), triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA), methylamine, and dimethylaminopyridine, and
메틸렌클로라이드, 클로로포름, 디메틸설폭사이드, 디메틸포름아미드, 테트라하이드로퓨란, 아세토니트릴 및 에틸아세테이트로 구성되는 군으로부터 선택되는 유기용매의 존재 하에 반응시키는 단계를 포함하는 제조방법을 제공한다.Provided is 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.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 4][Formula 4]
이때, 티옥트산의 사용량은 더욱 바람직하게는 1.8 내지 2.2 당량이며, 가장 바람직하게는 2 당량이다.At this time, the amount of thioctic acid used is more preferably 1.8 to 2.2 equivalents, and most preferably 2 equivalents.
본원 발명에 의한 합성법은 여러 단계를 거치지 않고 1단계(one step)로 TPGC를 합성하는 방법이며, 프로드럭 형태로 물질의 안정성을 높이고 생체 내에서 콜린알포세레이트 (glycerylphosphocholine, GPC)와 티옥트산의 두 가지 약물 작용을 동시에 얻을 수 있고 단독 약리 작용 항산화 효과도 얻을 수 있다. 프로드럭인 thioctylglycerylphosphoylcholine (TGPC, 티옥틸콜린알포세레이트) 자체만으로도 항산화 효과를 가지고 있고 체내에서 분해시 GPC와 티옥트산으로 분리되어 GPC의 경우는 뇌기능 개선 효과를 가지고, 티옥트산은 항산화 효과, 당뇨병 완화 효과를 가진다.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.
도 1은 티옥틸콜린알포세레이트 필름코팅정의 용출곡선 (pH=4)을 나타낸다.
도 2는 티옥틸콜린알포세레이트 장용코팅정의 용출곡선(pH=6.8)을 나타낸다.
도 3는 티옥틸콜린알포세레이트의 장용코팅정의 용출곡선(pH=6.8 + 판크레아틴)을 나타낸다.
도 4는 티옥틸콜린알포세레이트의 항산화 시험 그래프를 나타낸다.
도 5는 GPC(glycerylphosphocholine)의 항산화 시험 그래프를 나타낸다.
도 6는 Trolox(대조물질)의 항산화 시험 그래프를 나타낸다.Figure 1 shows the dissolution curve (pH = 4) of thioctylcholine alfoscerate film-coated tablets.
Figure 2 shows the dissolution curve (pH = 6.8) of thioctylcholine alfoscerate enteric-coated tablets.
Figure 3 shows the dissolution curve (pH = 6.8 + pancreatin) of enteric-coated tablets of thioctylcholine alfoscerate.
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).
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 측면으로서 하기 화학식 1의 L-알파-글리세릴포스포릴콜린 및 하기 화학식 2의 티옥트산을 프로필포스포닉산 무수물(Propylphosphonic anhydride), 디사이클로헥실카보이미드(N,N’-Dicyclohexylcarbodiimide), 디이미다졸카르보네이트(Diimidazole carbonate) 및 옥살릴클로라이드(Oxalylchloride)로 구성되는 군으로부터 선택되는 축합제; 피리딘, 디메틸아미노에탄올(N,N’-dimethylethanolamine), 트리에틸아민(TEA), N,N-Diisopropylethylamine (DIPEA), 메틸아민 및 디메틸아미노피리딘으로 구성되는 군으로부터 선택되는 아민계 화합물; 및 메틸렌클로라이드, 클로로포름, 디메틸설폭사이드, 디메틸포름아미드, 테트라하이드로퓨란, 아세토니트릴 및 에틸아세테이트로 구성되는 군으로부터 선택되는 유기용매의 존재 하에 반응시키는 것을 포함하는As an aspect of the present invention, 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), methylamine, and 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.
하기 화학식 3의 (R)-알파-모노-티옥틸-L-알파-글리세릴포스포릴콜린의 제조방법이 제공된다.A method for producing (R)-alpha-mono-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula (3) is provided.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
이때, 티옥트산의 사용량은 바람직하게는 0.5 내지 1.5 당량이며, 더욱 바람직하게는 0.8 내지 1.2 당량이며, 가장 바람직하게는 1 당량이다.At this time, 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.
본 발명의 또 다른 일 측면으로서As another aspect of the present invention
하기 화학식 1의 L-알파-글리세릴포스포릴콜린 및 1.5 내지 2.5 당량의 하기 화학식 2의 티옥트산을L-alpha-glycerylphosphorylcholine of the following formula (1) and 1.5 to 2.5 equivalents of thioctic acid of the formula (2)
프로필포스포닉산 무수물(Propylphosphonic anhydride), 디사이클로헥실카보이미드(N,N’-Dicyclohexylcarbodiimide), 디이미다졸카르보네이트(Diimidazole carbonate) 및 옥살릴클로라이드(Oxalylchloride)로 구성되는 군으로부터 선택되는 축합제; 피리딘, 디메틸아미노에탄올(N,N’-dimethylethanolamine), 트리에틸아민 (TEA), N,N-Diisopropylethylamine (DIPEA), 메틸아민 및 디메틸아미노피리딘으로 구성되는 군으로부터 선택되는 아민계 화합물 ; 및 메틸렌클로라이드, 클로로포름, 디메틸설폭사이드, 디메틸포름아미드, 테트라하이드로퓨란, 아세토니트릴 및 에틸아세테이트로 구성되는 군으로부터 선택되는 유기용매의 존재 하에 반응시키는 것을 포함하는,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), methylamine, and 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,
하기 화학식 4의 (R)-알파-디-티옥틸-L-알파-글리세릴포스포릴콜린의 제조방법이 제공된다.A method for producing (R)-alpha-di-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula (4) is provided.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 4][Formula 4]
이때, 티옥트산의 사용량은 더욱 바람직하게는 1.8 내지 2.2 당량이며, 가장 바람직하게는 2 당량이다.At this time, the amount of thioctic acid used is more preferably 1.8 to 2.2 equivalents, and most preferably 2 equivalents.
상기 축합제는 티옥트산에 대해 1몰 내지 3몰비로 사용되며, 가장 바람직하게는 2몰비로 사용될 수 있다.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.
일 구체예에서, 상기 제조방법은 레진 앰버라이트(resin amberite) 포접 수지를 사용하는 정제과정을 추가로 포함할 수 있다.In one embodiment, the manufacturing method may further include a purification process using a resin amberite inclusion resin.
본 발명의 또 다른 일 측면으로서 상기 제조방법으로 제조된 (R)-알파-모노-티옥틸-L-알파-글리세릴포스포릴콜린 또는 (R)-알파-디-티옥틸-L-알파-글리세릴포스포릴콜린을 포함하는, 치매, 경도인지장애, 탈모, 알츠하이머병, 파킨슨씨병, 근육발작 및 노안의 치료 또는 예방에 사용하기 위한, 약제학적 조성물이 제공된다.As another aspect of the present invention, (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.
본원발명의 최종화합물인 티옥틸콜린알포세레이트는 프로드럭의 특징을 갖는다. 일반적으로 에스테르 화합물들은 인체 내 효소(리파아제 및 다양한 효소)에 노출시 지방산과 알코올 구조로 분해되게 되고, 하기 반응식 6와 같이 티옥틸콜린알포세레이트는 리파아제 효소에 의해 티옥트산과 GPC로 분해되어 각각의 성분이 인체 내에서 약리활성을 가지게 된다.Thioctylcholine alfoscerate, the final compound of the present invention, has the characteristics of a prodrug. In general, 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.
[반응식 6][Scheme 6]
본 발명에 따른 약제학적 조성물은 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable carrier, excipient, or diluent.
본 발명에서, 상기 “약학적으로 허용 가능”하다는 것은, 이를 투여시 생물체를 자극하지 않으면서, 투여되는 화합물의 생물학적 활성 및 특성을 저해하지 않는, 약학 분야에서 통상적으로 사용되는 것을 의미한다.In the present invention, “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.
본 발명에서, 상기 담체의 종류는 특별히 제한되지 아니하며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로는, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 말토 덱스트린, 글리세롤, 에탄올 등을 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.In the present invention, 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.
또한, 본 발명의 상기 약제학적 조성물은 필요한 경우, 부형제, 희석제, 항산화제, 완충액 또는 정균제 등 기타 약학적으로 허용 가능한 첨가제들을 첨가하여 사용할 수 있으며, 충진제, 증량제, 습윤제, 붕해제, 분산제, 계면 활성제, 결합제 또는 윤활제 등을 부가적으로 첨가하여 사용할 수 있다.In addition, 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.
또한, 본 발명의 상기 약제학적 조성물은 경구 투여를 위한 적합한 다양한 제형으로 제제화되어 사용될 수 있다.Additionally, the pharmaceutical composition of the present invention can be formulated and used in various dosage forms suitable for oral administration.
상기 경구 투여용 제제의 비제한적인 예로는, 트로키제(troches), 로젠지(lozenge), 정제, 수용성 현탁액, 유성 현탁액, 조제 분말, 과립, 에멀젼, 하드 캡슐, 소프트 캡슐, 시럽 또는 엘릭시르제 등을 들 수 있다.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.
본 발명의 또 다른 일 측면으로서 상기 제조방법으로 제조된 (R)-알파-모노-티옥틸-L-알파-글리세릴포스포릴콜린 또는 (R)-알파-디-티옥틸-L-알파-글리세릴포스포릴콜린을 포함하는 정제가 제공된다.As another aspect of the present invention, (R)-alpha-mono-thioctyl-L-alpha-glycerylphosphorylcholine or (R)-alpha-di-thioctyl-L-alpha- prepared by the above production method Tablets containing glycerylphosphorylcholine are provided.
상기 정제는 장용성 정제 또는 이중정일 수 있으나 이에 국한되지는 않는다.The tablet may be an enteric-coated tablet or a double tablet, but is not limited thereto.
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1. 프로필포스포닉산 무수물(Propylphosphonic anhydride, T3P)을 활용한 합성 실시예Example 1. Synthesis Example Using Propylphosphonic Anhydride (T3P)
1 리터 반응기에 R-티옥트산 (R-thioctic acid 또는 R-lipoic acid) 8.5 g (41.11 mmol)와 콜린알포세레이트 10.56 g (41.11 mmol)을 넣고 반응용매로 DMF 80 mL를 넣고 교반한 다음 질소 조건 하에서 에스테르화 축합제로 프로필포스포닉산 무수물 용액 (50% DMF 포함용액) 52 g (82.3 mmol)을 0℃에서 천천히 가하여 교반한 뒤, 다시 축합반응 촉매로 아민계 염기인 피리딘 36 g을 0℃에서 천천히 가하여 동일 온도로 교반 반응시켰다.Add 8.5 g (41.11 mmol) of R-thioctic acid (R-thioctic acid or R-lipoic acid) and 10.56 g (41.11 mmol) of choline alfoscerate to a 1 liter reactor, add 80 mL of DMF as a reaction solvent, stir, and then add nitrogen. Under these conditions, 52 g (82.3 mmol) of propylphosphonic acid anhydride solution (50% DMF containing solution) as an esterification condensation agent was slowly added and stirred at 0°C, and then 36 g of pyridine, an amine base, as a condensation reaction catalyst was added at 0°C. It was added slowly and stirred at the same temperature.
TLC (RF 0.4)와 HPLC로 반응을 경과를 확인하고 50시간 이상 반응시킨 후 인산 완충액으로 희석시킨 다음 앰버라이트 레진 (Amberite Resin)으로 포접 흡착시킨 후 메탄올로 추출하여 용매를 회수하고 잔사를 취하였다. 고체로 티옥틸콜린알포세레이트 16 g (수율 54%)를 얻는다.The reaction progress was confirmed by TLC (RF 0.4) and HPLC, and the reaction was allowed to proceed for over 50 hours. Then, the reaction was diluted with phosphate buffer, followed by clathrate adsorption with Amberite Resin, followed by extraction with methanol, the solvent was recovered, and the residue was taken. . Obtain 16 g of thioctylcholine alfoscerate (yield 54%) as a solid.
LC-MS(m/z): 446.18[M+H]+ LC-MS(m/z): 446.18[M+H] +
1H-NMR(DMF-d 7 , 500MHz): δ1.42-1.50(2H, m), 1.58-1.67(3H, m), 1.70-1.77(1H, m), 1.89-1.97(1H, m), 2.34-2.40(2H, m), 2.46-2.52(1H, m), 3.14-3.20(1H, m), 3.23-3.27(1H, m), 3.41-3.44(9H, m), 3.52(1H, s), 3.57-3.61(1H, m), 3.62-3.68(1H, m), 3.79-3.93(4H, m), 4.06(1H, d, J=5.6Hz), 4.08-4.17(1H, m), 4.26-4.31(2H, m), 4.36-4.40(1H, m). 1 H-NMR (DMF- d 7 , 500 MHz): δ1.42-1.50 (2H, m), 1.58-1.67 (3H, m), 1.70-1.77 (1H, m), 1.89-1.97 (1H, m) , 2.34-2.40(2H, m), 2.46-2.52(1H, m), 3.14-3.20(1H, m), 3.23-3.27(1H, m), 3.41-3.44(9H, m), 3.52(1H, s), 3.57-3.61(1H, m), 3.62-3.68(1H, m), 3.79-3.93(4H, m), 4.06(1H, d, J=5.6Hz), 4.08-4.17(1H, m) , 4.26-4.31(2H, m), 4.36-4.40(1H, m).
13C-NMR(D 2 O, 126MHz): δ24.12, 28.12, 33.65, 33.92, 38.30, 40.41, 54.10, 56.64, 59.55, 65.14, 66.11, 66.48, 68.24, 74.41, 176.39 13 C-NMR ( D 2 O , 126 MHz): δ24.12, 28.12, 33.65, 33.92, 38.30, 40.41, 54.10, 56.64, 59.55, 65.14, 66.11, 66.48, 68.24, 74.41, 1 76.39
[융점(Melting Point) 측정][Melting Point Measurement]
상기 실시예 1에서 합성한 티옥틸콜린알포세레이트 2 mg을 취하여 Melting point 측정 결과 성상은 105.7℃를 시점으로 변화했고, 약 107℃로 측정되었다.As a result of measuring the melting point of 2 mg of thioctylcholine alfoscerate synthesized in Example 1, the property changed at 105.7°C and was measured at about 107°C.
[선광도 (Optical rotation) 측정][Optical rotation measurement]
상기 실시예 1에서 합성한 티옥틸콜린알포세레이트 20 mg을 취하여 20 mL (MC : MeOH : H2O = 7 : 6 : 1)에 녹여 선광도를 측정한 결과로 표 1과 같이 -0.0226 값이 측정되었다. (0.1% 농도 기준) 이를 10% 농도로 환산하면 -2.26 값이며, 이는 10% 농도 GPC(-2.4~-2.8)와 유사한 값으로 계산된다.20 mg of thioctylcholine alfoscerate synthesized in Example 1 was dissolved in 20 mL (MC: MeOH: H 2 O = 7: 6: 1) and the optical rotation was measured. The result was -0.0226 as shown in Table 1. This was measured. (Based on 0.1% concentration) When converted to 10% concentration, the value is -2.26, which is calculated as a similar value to 10% concentration GPC (-2.4 to -2.8).
[표 1][Table 1]
실시예 2Example 2
DCC(Dicyclohexylcarbodiimide)를 사용한 실시예Example using DCC (Dicyclohexylcarbodiimide)
0.25 리터 반응기에 R-티옥트산 139 mg(0.673 mmol)을 넣고 질소 조건 하에서 에스테르화 축합제로 N,N’-Dicyclohexylcarbodiimide 0.51 mL(3.25 mmol)을 가하여 0℃에서 교반한 다음 콜린알포세레이트 173 mg(0.673 mmol)을 동일온도에서 교반하고 반응 용매로 DMF 4.5 mL를 넣어 동일 온도로 교반 반응시킨다.Put 139 mg (0.673 mmol) of R-thioctic acid in a 0.25 liter reactor, add 0.51 mL (3.25 mmol) of N,N'-Dicyclohexylcarbodiimide as an esterification condensation agent under nitrogen conditions, stir at 0°C, and add 173 mg of choline alfoscerate ( 0.673 mmol) was stirred at the same temperature, and 4.5 mL of DMF was added as a reaction solvent and stirred at the same temperature.
TLC (RF 0.4)와 HPLC로 반응을 경과를 확인하고 50시간 이상 반응시킨 후 인산 완충액으로 희석시킨 다음 Amberite Resin으로 포접 흡착시킨 후 메탄올으로 추출하여 용매를 회수하고 잔사를 취한다. 고체로 티옥틸콜린알포세레이트 20 mg (수율 6.7%)를 얻는다.The reaction progress is checked by TLC (RF 0.4) and HPLC, and the reaction is allowed to proceed for more than 50 hours. Then, it is 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.
실시예 3Example 3
DIC(N,N'-Diisopropylcarbodiimide)를 사용한 실시예Example using DIC (N,N'-Diisopropylcarbodiimide)
0.25 리터 반응기에 R-티옥트산 139 mg(0.673 mmol)을 넣고 질소 조건 하에서 에스테르화 축합제로 N,N'-Diisopropylcarbodiimide 410 mg(3.25 mmol)을 가하여 0℃에서 교반한 다음 콜린 알포세레이트 173 mg(0.673 mmol)을 첨가하고 반응용매로 DMF 4.5 mL를 넣어 동일 온도로 교반 반응시킨다.Put 139 mg (0.673 mmol) of R-thioctic acid in a 0.25 liter reactor, add 410 mg (3.25 mmol) of N,N'-Diisopropylcarbodiimide as an esterification condensation agent under nitrogen conditions, stir at 0°C, and add 173 mg (173 mg (0.673 mmol) of choline alfoscerate). 0.673 mmol), add 4.5 mL of DMF as a reaction solvent, and stir to react at the same temperature.
TLC (RF 0.4)와 HPLC로 반응을 경과를 확인하고 50시간 이상 반응 시킨 후 인산 완충액으로 희석시킨 다음 Amberite Resin으로 포접 흡착시킨 후 메탄올으로 추출하여 용매를 회수하고 잔사를 취한다. 고체로 티옥틸콜린알포세레이트 13 mg (수율 4.3%)를 얻는다. T3P(n-propanephosphonic acid anhydride) 축합제를 사용한 반응에 비해 수율이 4.3%로 매우 저조하였다.The 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%.
실시예 4Example 4
OXC를 사용한 합성 실시예Synthesis Example Using OXC
0.25 리터 반응기에 R-thioctic acid 139 mg(0.673 mmol)을 넣고 질소 조건 하에서 에스테르화 축합제로 oxalyl chloride 0.28 mL(3.25 mmol)을 가하여 0℃에서 교반한 다음 콜린 알포세레이트 173 mg(0.673 mmol)을 첨가하고 반응용매로 DMF 4.5 mL를 넣어 동일 온도로 교반 overnight 반응시킨다. TLC와 HPLC로 반응을 경과를 확인하는 과정에서 HPLC 상에서 티옥틸콜린알포세레이트가 확인되지 않았다. Put 139 mg (0.673 mmol) of R-thioctic acid in a 0.25 liter reactor, add 0.28 mL (3.25 mmol) of oxalyl chloride as an esterification condensation agent under nitrogen conditions, stir at 0°C, and then add 173 mg (0.673 mmol) of choline alfoscerate. Add 4.5 mL of DMF as a reaction solvent, stir at the same temperature, and react overnight. In the process of checking the reaction progress with TLC and HPLC, thioctylcholine alfoscerate was not confirmed on HPLC.
실시예 5Example 5
R-알파-디리포익산 콜린알포세레이트 에스테르(R-alpha-dilipoic acid choline alfoscerate ester)의 합성 실시예Example of synthesis of R-alpha-dilipoic acid choline alfoscerate ester
0.5 리터 반응기에 R-티옥트산 4.25 g(20.6 mmol)와 콜린알포세레이트 10.5g (40.8 mmol)을 넣고 반응용매로 DMF 82 mL를 넣고 교반한 다음 질소 조건 하에서 에스테르화 축합제로 T3P 용액(50% DMF 포함용액) 104 g(163.2 mmol)을 0℃에서 천천히 가하여 교반한 뒤, 다시 축합반응 촉매로 아민계 염기인 피리딘 35.5 g을 0℃에서 천천히 가하여 동일 온도로 교반 반응시킨다. 표 2는 반응액의 HPLC Area %를 나타낸다. HPLC로 반응을 경과를 확인하고 반응액에서 목적 물질의 분자량[634.22[M+H]+]을 확인하였다.Put 4.25 g (20.6 mmol) of R-thioctic acid and 10.5 g (40.8 mmol) of choline alfoscerate in a 0.5 liter reactor, add 82 mL of DMF as a reaction solvent, stir, and then add T3P solution (50% T3P solution) as an esterification condensation agent under nitrogen conditions. 104 g (163.2 mmol) of DMF-containing solution) was slowly added at 0°C and stirred, and then 35.5 g of pyridine, an amine base as a condensation reaction catalyst, was slowly added at 0°C and stirred at the same temperature. Table 2 shows the HPLC Area % of the reaction solution. The progress of the reaction was confirmed by HPLC, and the molecular weight of the target substance [634.22[M+H] + ] was confirmed in the reaction solution.
[표 2][Table 2]
실시예 6 - 약리 실험 Example 6 - Pharmacological experiments
리포익산과 콜린알포세레이트를 단독으로 각각 신경아교세포(Astroglial Cell)에 처리할 경우 세포의 증식과 분화에 효과를 보이지만 두 물질을 동시에 함께 처리한 경우에는 이에 대한 효과가 보이지 않았다 (Journal of Neuroscience Research 92 : 86~94 (2014) S. Grasso et al.).When lipoic acid and choline alposcerate were treated individually on glial cells (Astroglial Cells), they showed an effect on cell proliferation and differentiation, but when both substances were treated together at the same time, no effect was seen (Journal of Neuroscience Research 92:86~94 (2014) S. Grasso et al.).
아스피린의 경우 살리실산(salicyclic acid)과 초산 또는 빙초산 (acetic acid)이 단순 혼합되어 있을 때는 항혈전효과가 나타나지 않지만 두 물질을 에스테르화시키면 이에 대한 효과가 나타나는 것으로 알려져있다. 이에 아스피린의 경우를 참고하여 알파-리포익산과 콜린알포세레이트를 에스테르화 시켜 어떻게 약효가 다르게 나타나는지에 대해 시험하여 보았다. 리포익산의 대표적인 효력으로 알려진 항산화 작용에 대한 시험을 한 후 마침내 발명을 완수하게 되었다.In the case of aspirin, it is known that the anti-thrombotic effect does not appear when salicylic acid and acetic acid or glacial acetic acid are simply mixed, but the effect appears when the two substances are esterified. Accordingly, referring to the case of aspirin, we esterified alpha-lipoic acid and choline alposcerate and tested how the drug effects differed. After testing the antioxidant effect, which is known to be a representative effect of lipoic acid, the invention was finally completed.
DPPH(1,1-diphenyl-2-picrylhydrazyl) assayDPPH (1,1-diphenyl-2-picrylhydrazyl) assay
상기의 합성한 TGPC의 항산화 효과는 DPPH radical을 이용하여 측정(DPPH Antioxidant Assay kit, BIOMAX)하였다. TGPC와 GPC를 300 mg/mL, 150 mg/mL, 75 mg/mL, 37.5 mg/mL, 18.8 mg/mL, 9.4 mg/mL, 4.7 mg/mL이 되도록 증류수(Deionized Water)를 이용하여 희석하였고, 양성대조물질로 사용한 Trolox는 80 μg/mL, 60 μg/mL, 40 μg/mL, 20 μg/mL, 10 μg/mL 이 되도록 95% 에탄올을 이용하여 희석하였다. 각각 희석한 TGPC와 GPC, Trolox 시료 20 μL에 Assay buffer 80 uL, DPPH solution 100 μL를 가한 후 실온에서 30분 동안 반응 시켰다. 그 후 Microplate reader(GloMax®, Promega)를 이용하여 517 nm에서 흡광도를 측정하였다. 그 결과를 표 3에 나타냈다. 모든 실험은 3회 반복 실험 하였으며, TGPC와 GPC의 DPPH radical inhibition ratio(%)는 수학식 1을 통해 계산되었고, Trolox의 DPPH radical inhibition ratio(%)는 수학식 2를 통해 계산되었다.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 μg/mL, 60 μg/mL, 40 μg/mL, 20 μg/mL, and 10 μg/mL. 80 μL of Assay buffer and 100 μL of DPPH solution were added to 20 μL of each diluted TGPC, GPC, and Trolox sample, and then reacted at room temperature for 30 minutes. Afterwards, the absorbance was measured at 517 nm using a microplate reader (GloMax®, Promega). The results are shown in Table 3. All experiments were repeated three times, and the DPPH radical inhibition ratio (%) of TGPC and GPC was calculated using Equation 1, and the DPPH radical inhibition ratio (%) of Trolox was calculated using Equation 2.
수학식 1.Equation 1.
Inhibition ratio of sample (%) : {(Acs - As)/ Acs} * 100Inhibition ratio of sample (%): {(Acs - As)/ Acs} * 100
Acs : Blank 1 - Blank 2Acs: Blank 1 - Blank 2
As : Abs Sample - Blank 2As: Abs Sample - Blank 2
수학식 2.Equation 2.
Inhibition ratio of Trolox (%) : {(A0 - AT)/ A0} * 100Inhibition ratio of Trolox (%) : {(A 0 - A T )/ A 0 } * 100
A0 : Abs 0 μg/mL Trolox Standard Solution - Blank 3A 0 : Abs 0 μg/mL Trolox Standard Solution - Blank 3
AT : Abs 40 ~ 100 μg/mL Trolox Standard Solution - Blank 3A T : Abs 40 ~ 100 μg/mL Trolox Standard Solution - Blank 3
실험 결과의 통계 처리는 SigmaPlot 14.0 프로그램을 이용하여 평균±표준편차로 표시하였고, 농도간의 유의차는 분산분석(ANOVA)과 다중범위검정(Duncan’s multiple range test)으로 평균치 간의 유의적 차이를 검증하였다{(***) p<0.001}. TGPC, GPC, Trolox 각각 시료의 농도에 따른 inhibition ratio(%) 결과를 도면 4, 도면 5, 도면 6 에 나타냈다. TGPC는 4.7 ~ 300 mg/mL 농도 범위에서 농도 의존적으로 DPPH radical 소거능이 관찰되었으며(도면 4), IC50값은 262.6 mg/mL이 산출되었다. 반면 GPC는 4.7~300 mg/mL 농도 범위에서 DPPH radical 소거능이 관찰되지 않았다 (도면 5). 양성대조물질로 사용한 Trolox는 10 ~ 80 μg/mL 농도 범위에서 농도 의존적인 DPPH radical 소거능이 관찰되었고, IC50 값은 74.4 μg/mL로 산출되었다. TGPC는 DPPH radical 소거능 IC50 250mg/mLa)을 갖는 lipoic acid 와 유사한 수준으로 DPPH radical 소거 효과(IC50 : 262.6 mg/mL)가 관찰되었고, 농도의존적으로 DPPH Radical 소거 효과가 관찰되었기 때문에 항산화 효과가 있다고 판단되었다.Statistical processing of the experimental results was expressed as mean ± standard deviation using the SigmaPlot 14.0 program, and significant differences between concentrations were verified using analysis of variance (ANOVA) and multiple range tests (Duncan's multiple range test) {( ***)p<0.001}. The inhibition ratio (%) results according to sample concentration for TGPC, GPC, and Trolox are shown in Figures 4, 5, and 6, respectively. The DPPH radical scavenging ability of TGPC was observed in a concentration-dependent manner in the concentration range of 4.7 to 300 mg/mL (Figure 4), and the IC 50 value was calculated to be 262.6 mg/mL. On the other hand, 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 μg/mL, and the IC 50 value was calculated to be 74.4 μg/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.
[표 3][Table 3]
실시예 7 - 제제 실험: 일반정, 장용정 Example 7 - Formulation experiment: regular tablet, enteric-coated tablet
실시예 7-1Example 7-1
필름코팅정제 제조 및 용출시험 자료 표Film coated tablet manufacturing and dissolution test data table
예) 주성분 TGPC 225 mg를 가지고 부원료는 메타규산알루민산마그네슘, 미결정셀룰로오스, 크로스포비돈, 스테아르산마그네슘 등으로 정제를 제조하고 오파드라이등 필름코팅기제로 코팅을 하여서 필름코팅정제를 제조하였다. 용출곡선은 도 1과 같았으며, 정제 중 대부분의 티옥틸콜린알포세레이트가 용출되었고 티옥틸콜린알포세레이트가 PH 4.0에서 안정함을 확인할 수 있었다.Example) 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.
실시예 7-2Example 7-2
고속연합기에 TGPC와 메타규산알루민산마그네슘을 넣고 혼합하여 TGPC를 메타규산알루민산마그네슘에 흡착시켰다. 여기에 미결정셀룰로오스를 넣고 정제수를 투입하여 연합하였다.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.
위의 연합물을 건조하고 20 메쉬체로 정립하였다. 그 후 콜로이드성이산화규소,크로스포비돈, 저치환도히드록시프로필셀룰로오스를 넣고 후혼합을 진행하였다. 이 혼합물에 스테아르산 마그네슘을 넣고 활택을 진행 후 타정하고 필름코팅을 진행하여 TGPC 필름코팅정을 제조하였다. 각 성분의 처방은 하기 표 4와 같았다.The above combined product was dried and sieved through a 20 mesh sieve. Afterwards, colloidal silicon oxide, crospovidone, and low-substituted hydroxypropyl cellulose were added and post-mixed. Magnesium stearate was added to this mixture, lubrication was performed, tableting was performed, and film coating was performed to prepare TGPC film-coated tablets. The prescription for each ingredient was as shown in Table 4 below.
[표 4][Table 4]
실시예 7-3Example 7-3
각 성분의 처방을 하기 표 5와 같이 한 것을 제외하고는. 실시예 7-2와 모두 동일한 방법으로 실시예 7-3을 제조하였다.Except that the prescription of each ingredient is as shown in Table 5 below. Example 7-3 was prepared in the same manner as Example 7-2.
[표 5][Table 5]
실시예 7-4Example 7-4
장용코팅정제제 제조 및 용출시험 자료 표Enteric coated tablet manufacturing and dissolution test data table
주성분 티옥틸콜린알포세레이트 225 mg를 가지고 부원료는 메타규산알루민산마그네슘, 미결정셀룰로오스, 크로스포비돈, 스테아르산마그네슘 등으로 정제를 제조하고 아크릴이즈, 유드라짓 등 장용코팅기제로 코팅을 하여서 장용코팅정제를 제조하였다. 용출곡선은 도 2와 같았으며, 정제의 티옥틸콜린알포세레이트가 대부분이 용출 되었고 티옥틸콜린알포세레이트가 PH 6.8에서 안정함을 확인할 수 있었다.The main ingredient is 225 mg of thioctylcholine alposcerate, and 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. was manufactured. 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.
실시예 7-5Example 7-5
주성분인 티옥틸콜린알포세레이트 225 mg를 가지고 부원료는 메타규산알루민산마그네슘, 미결정셀룰로오스, 크로스포비돈, 스테아르산마그네슘 등으로 정제를 제조하고 아크릴이즈, 유드라짓등 장용코팅 기제로 코팅을 하여서 장용코팅정제를 제조하였다. 용출곡선은 도 3과 같았으며, pancreatin 과 같은 효소 존재시 티옥틸콜린알포세레이트가 프로드럭으로서 티옥트산 및 GPC로 분해되어 각각 약리활성을 지닌 물질로 전환되는 결과를 확인할 수 있었다.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.
실시예 8 - 분석실시예 Example 8 - Analytical Example
[TGPC 원료시험조건 및 사용기기][TGPC raw material test conditions and equipment used]
- 사용기기 : Waters ACQUITY UPLC- Device used: Waters ACQUITY UPLC
- Mobile phase : ACN(0.1% Formic acid) , Water(0.1% Formic acid)- Mobile phase: ACN (0.1% Formic acid), Water (0.1% Formic acid)
- Detector : UV 194 nm, 254 nm QDA- Detector: UV 194 nm, 254 nm QDA
- Column : ACQUITY UPLC BEH C18 (1.7 μM , 2.1 x 50mm)- Column: ACQUITY UPLC BEH C18 (1.7 μM, 2.1 x 50mm)
- Temp : 25℃- Temp: 25℃
- Mass range : 50 Da - 1250Da- Mass range: 50 Da - 1250Da
- Flow : 0.5 mL/min- Flow: 0.5 mL/min
- Run time : 20 min- Run time: 20 min
[HPLC 용출시험 분석 조건 및 사용기기][HPLC dissolution test analysis conditions and equipment used]
- 사용기기 : Agilent 1260 infinity II- Equipment used: Agilent 1260 infinity II
- Mobile phase : ACN : KH2PO4 Solution : MeOH = 8 : 41 : 51- Mobile phase: ACN: KH 2 PO 4 Solution: MeOH = 8:41:51
- Method : Isocratic 100% Mobile phase- Method: Isocratic 100% Mobile phase
- Detector : UV 215 nm- Detector: UV 215 nm
- Colunm : Aegispak C18-L (5 μM , 100Å , 4.6 × 250mm)- Colunm: Aegispak C18-L (5 μM, 100Å, 4.6 × 250mm)
- Temp : 35℃- Temp: 35℃
- Flow : 1.2 mL/min- Flow: 1.2 mL/min
- Run time : 10 min- Run time: 10 min
[TGPC MPLC 정제 조건 및 사용기기][TGPC MPLC purification conditions and equipment used]
- 사용기기 : Biotage (Selekt UV Spektra system SEL-2SV)- Device used: Biotage (Selekt UV Spektra system SEL-2SV)
- Detector : UV 200 nm- Detector: UV 200 nm
- Column : Biotage sfar silica 100g - Column: Biotage sfar silica 100g
- Flow rate : 120 mL/min- Flow rate: 120 mL/min
- Solvent : MC : MeOH : H2O = 7 : 6 : 1- Solvent : MC : MeOH : H 2 O = 7 : 6 : 1
- Method : Solvent (MC : MeOH : H2O = 7 : 6 : 1) 100% , 30 CV- Method: Solvent (MC: MeOH: H2O = 7: 6: 1) 100%, 30 CV
[융점(Melting Point) 측정 및 사용기기][Measurement of melting point and equipment used]
- 사용기기 : MP50 Melting point system (METTLER TOLEDO)- Device used: MP50 Melting point system (METTLER TOLEDO)
- Start Temp : 90.0℃- Start Temp: 90.0℃
- End Temp : 130.0℃-End Temp: 130.0℃
- Rate : 2.0℃/min- Rate: 2.0℃/min
[선광도 (Optical rotation) 측정 및 사용기기][Optical rotation measurement and equipment used]
- 사용기기 : Automatic polarimeter(p-2000)- Device used: Automatic polarimeter (p-2000)
- Blank : MC : MeOH : H20 = 7 : 6 : 1- Blank : MC : MeOH : H 2 0 = 7 : 6 : 1
- Temp : 20℃- Temp: 20℃
- Light source : Na- Light source: Na
- Monitor wavelength : 589nm- Monitor wavelength: 589nm
- Cycle : 3- Cycle: 3
- Mode : Optical rotation- Mode: Optical rotation
[TLC 분석][TLC analysis]
TLC solvents ; MC : H2O : MeOH : AcOH = 40 : 22 : 5 : 5 TLC solvents; MC: H2O :MeOH:AcOH = 40:22:5:5
발색제 : PMAColoring agent: PMA
약효 분석Drug efficacy analysis
도 4와 같이 티옥틸콜린알포세레이트는 4.7 mg/mL 내지 300 mg/mL 농도에서 농도 의존적인 DPPH(2,2-Diphenyl-1-picrylhydrazyl) 라디컬 소거능이 관찰되었으며, IC50 값은 262.6 mg/mL로 산출되었다. 도 5와 같이 GPC는 4.7 mg/mL ~ 300 mg/mL 농도에서 DPPH radical 소거능이 관찰되지 않았다. 도 6과 같이 양성대조물질인 Trolox는 10 내지 80 μg/mL 농도에서 DPPH radical 소거능이 관찰되었으며, IC50 값은 74.4 μg/mL로 산출되었다.As shown in Figure 4, a concentration-dependent DPPH (2,2-Diphenyl-1-picrylhydrazyl) 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. As shown in Figure 5, DPPH radical scavenging activity was not observed in GPC at concentrations of 4.7 mg/mL to 300 mg/mL. As shown in Figure 6, Trolox, a positive control material, was observed to have DPPH radical scavenging ability at a concentration of 10 to 80 μg/mL, and the IC 50 value was calculated to be 74.4 μg/mL.
티옥틸콜린알포세레이트는 글리세릴포스포릴콜린과 lipoic acid 가 에스테르화 결합으로 연결된 프로드럭으로 lipoic acid (IC50 250 mg/mL)와 유사한 수준의 항산화효과가 관찰되었다.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.
Claims (9)
프로필포스포닉산 무수물(Propylphosphonic anhydride), 디사이클로헥실카보이미드(N,N’-Dicyclohexylcarbodiimide), 디이미다졸카르보네이트(Diimidazole carbonate) 및 옥살릴클로라이드(Oxalylchloride)로 구성되는 군으로부터 선택되는 축합제; 피리딘, 디메틸아미노에탄올(N,N’-dimethylethanolamine), 트리에틸아민 (TEA), N,N-Diisopropylethylamine (DIPEA), 메틸아민 및 디메틸아미노피리딘으로 구성되는 군으로부터 선택되는 아민계 화합물; 및 메틸렌클로라이드, 클로로포름, 디메틸설폭사이드, 디메틸포름아미드, 테트라하이드로퓨란, 아세토니트릴 및 에틸아세테이트로 구성되는 군으로부터 선택되는 유기용매의 존재 하에 반응시키는 것을 포함하며,
상기 축합제가 티옥트산에 대해 1몰 내지 3몰비로 사용되는 것인,
하기 화학식 3의 (R)-알파-모노-티옥틸-L-알파-글리세릴포스포릴콜린의 제조방법:
[화학식 1]
[화학식 2]
[화학식 3]
L-alpha-glycerylphosphorylcholine of the following formula (1) and 0.5 to 1.5 equivalents of thioctic acid of the formula (2)
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), methylamine, and 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,
wherein the condensing agent is used in a molar ratio of 1 to 3 molar to thioctic acid,
Method for producing (R)-alpha-mono-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula (3):
[Formula 1]
[Formula 2]
[Formula 3]
프로필포스포닉산 무수물(Propylphosphonic anhydride), 디사이클로헥실카보이미드(N,N’-Dicyclohexylcarbodiimide), 디이미다졸카르보네이트(Diimidazole carbonate) 및 옥살릴클로라이드(Oxalylchloride)로 구성되는 군으로부터 선택되는 축합제; 피리딘, 디메틸아미노에탄올(N,N’-dimethylethanolamine), 트리에틸아민 (TEA), N,N-Diisopropylethylamine (DIPEA), 메틸아민 및 디메틸아미노피리딘으로 구성되는 군으로부터 선택되는 아민계 화합물; 및 메틸렌클로라이드, 클로로포름, 디메틸설폭사이드, 디메틸포름아미드, 테트라하이드로퓨란, 아세토니트릴 및 에틸아세테이트로 구성되는 군으로부터 선택되는 유기용매의 존재 하에 반응시키는 것을 포함하며,
상기 축합제가 티옥트산에 대해 1몰 내지 3몰비로 사용되는 것인,
하기 화학식 4의 (R)-알파-디-티옥틸-L-알파-글리세릴포스포릴콜린의 제조방법:
[화학식 1]
[화학식 2]
[화학식 4]
L-alpha-glycerylphosphorylcholine of the following formula (1) and 1.5 to 2.5 equivalents of thioctic acid of the formula (2)
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), methylamine, and 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,
wherein the condensing agent is used in a molar ratio of 1 to 3 molar to thioctic acid,
Method for producing (R)-alpha-di-thioctyl-L-alpha-glycerylphosphorylcholine of the following formula 4:
[Formula 1]
[Formula 2]
[Formula 4]
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220122303A KR102595126B1 (en) | 2022-09-27 | 2022-09-27 | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof |
| PCT/KR2023/014766 WO2024071959A1 (en) | 2022-09-27 | 2023-09-26 | Method for preparing choline alposcerate ester derivative and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220122303A KR102595126B1 (en) | 2022-09-27 | 2022-09-27 | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20220139825A KR20220139825A (en) | 2022-10-17 |
| KR102595126B1 true KR102595126B1 (en) | 2023-10-30 |
Family
ID=83809959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020220122303A KR102595126B1 (en) | 2022-09-27 | 2022-09-27 | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR102595126B1 (en) |
| WO (1) | WO2024071959A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106967044A (en) * | 2017-05-12 | 2017-07-21 | 苏州富士莱医药股份有限公司 | The method for preparing R lipoic acid cholinester halide |
| CN110385427A (en) * | 2019-07-31 | 2019-10-29 | 东南大学 | A kind of water soluble nanometer particles and its preparation method and application |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2546289B2 (en) * | 1987-09-02 | 1996-10-23 | 日本油脂株式会社 | Method for producing synthetic lecithin |
| KR100966627B1 (en) | 2006-06-14 | 2010-06-29 | 주식회사 대웅제약 | A process for preparation of L?glycerophosphoryl choline |
| PT2821405E (en) | 2009-06-15 | 2016-06-14 | Encore Health Llc | Choline esters for treating presbyopia and cataract |
| DE102011103948A1 (en) | 2011-06-06 | 2012-12-06 | B. Braun Melsungen Ag | Biopassivating coating of vascular prostheses with phospholipids containing nitrocarboxylic acids |
| KR101601685B1 (en) | 2015-08-24 | 2016-03-09 | 여명바이오켐 주식회사 | Taxifolin derivative with high anti-oxidant effect and cosmetic composition therefrom |
| KR20180026653A (en) | 2016-09-02 | 2018-03-13 | (주) 파마젠 | Method for Preparation of Choline alfoscerate |
| KR20200033751A (en) * | 2018-09-20 | 2020-03-30 | 주식회사 셀트리온제약 | Pharmaceutical Composition comprising Choline alfoscerate |
-
2022
- 2022-09-27 KR KR1020220122303A patent/KR102595126B1/en active IP Right Grant
-
2023
- 2023-09-26 WO PCT/KR2023/014766 patent/WO2024071959A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106967044A (en) * | 2017-05-12 | 2017-07-21 | 苏州富士莱医药股份有限公司 | The method for preparing R lipoic acid cholinester halide |
| CN110385427A (en) * | 2019-07-31 | 2019-10-29 | 东南大学 | A kind of water soluble nanometer particles and its preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024071959A1 (en) | 2024-04-04 |
| KR20220139825A (en) | 2022-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101500766B1 (en) | Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2Ｈ-pyrido[2,1-a]isoquinolin-2-ol Compounds and Methods Relating Thereto | |
| Saari et al. | Cyclization-activated prodrugs. Basic carbamates of 4-hydroxyanisole | |
| US6239169B1 (en) | Non-steroidal polycyclic ring sulphamate derivatives, their preparation and their use as oestrone sulphatase inhibitors | |
| NO325689B1 (en) | Condensed pyrrolocarbazoles, as well as uses and pharmaceutical preparations | |
| JP2020500931A (en) | Sepipterin polymorphism | |
| EP3838901B1 (en) | Compound for treatment of rabies and method for treatment of rabies | |
| CA2939012C (en) | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising the same and use thereof | |
| WO2012148550A1 (en) | Prodrugs of therapeutic compounds | |
| EP3424913B1 (en) | 2,3-epoxy succinyl derivative, preparation method therefor, and uses thereof | |
| JPH03181483A (en) | Physostigmine-related aminocarbonylcarbamate | |
| WO2010075287A2 (en) | Compounds and methods for the treatment of pain and other diseases | |
| KR102595126B1 (en) | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof | |
| KR20170087497A (en) | Tripeptide compound, preparation method therefor, and application thereof | |
| EP0861842B1 (en) | Novel water-soluble fluoroethylcamptothecin derivative and process for production thereof | |
| EP3617211A1 (en) | Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredient | |
| US8378112B2 (en) | Glycyrrhetinic acid derivative and use thereof | |
| KR100796637B1 (en) | Geldanamycin derivatives, pharmaceutically acceptable salt thereof, preparation method thereof and agent for the prevention and treatment of tumor containing the same as an active ingredient | |
| CN114716441A (en) | Impurity compound A in new crown treatment medicine palofurtide, preparation method and application thereof | |
| WO2005108400A1 (en) | Pyridoquinazoline derivatives having heterobicyclic substituents | |
| CN114591346B (en) | Camptothecin prodrug, preparation method, application and salt thereof | |
| CN112358469A (en) | Angiogenesis inhibitor, preparation method and application thereof | |
| KR100907475B1 (en) | 2-methyl-2'-hydroxymethyl-6-amido benzopyrans derivatives or pharmaceutically acceptable salt thereof and pharmaceutical composition for treating dementia and brain stroke | |
| CN111499619B (en) | Medicine for treating hepatic fibrosis and preparation method thereof | |
| CN110382468A (en) | Dihydro pyrido benzodiazine ketone compound and application thereof with poly- (ADP- ribose) polymerase (PARP) inhibitory activity | |
| KR101451401B1 (en) | Conjugate of vitamin C with vitamin E and antioxidant comprising the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A302 | Request for accelerated examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |