KR102544543B1 - Individual co-crystal of l, d-erdosteine - Google Patents
Individual co-crystal of l, d-erdosteine Download PDFInfo
- Publication number
- KR102544543B1 KR102544543B1 KR1020210055923A KR20210055923A KR102544543B1 KR 102544543 B1 KR102544543 B1 KR 102544543B1 KR 1020210055923 A KR1020210055923 A KR 1020210055923A KR 20210055923 A KR20210055923 A KR 20210055923A KR 102544543 B1 KR102544543 B1 KR 102544543B1
- Authority
- KR
- South Korea
- Prior art keywords
- eldostain
- crystal
- crystal compound
- polyethylene glycol
- present
- Prior art date
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
본 발명은, L,D-엘도스테인의 개별적 공결정화합물에 관한 것으로서, L형 또는 D형 엘도스테인과 약제학적으로 허용 가능한 공형성체가 공결정상으로 이루어진 것을 특징으로 한다. 본 발명의 D-엘도스테인, 및 L-엘도스테인 공결정 화합물은, 용해도, 생체이용률, 및 안정성이 높을 뿐 아니라, 약제 조성물의 활성성분으로서 요구되는 사항을 모두 만족하여 유용하게 사용될 수 있다.The present invention relates to an individual co-crystal compound of L,D-eldostein, and is characterized in that a pharmaceutically acceptable co-former with L-type or D-type eldosteine is formed in a co-crystal phase. The D-eldostain and L-eldostain co-crystal compounds of the present invention have high solubility, bioavailability, and stability, and can be usefully used by satisfying all requirements as an active ingredient of a pharmaceutical composition.
Description
본 발명은, L,D-엘도스테인의 개별적 공결정화합물에 관한 것이다.The present invention relates to individual co-crystal compounds of L,D-eldosteine.
엘도스테인은 프리 라디칼 제거활성을 갖는 물질로서, 급성 및 만성 기관지염의 치료제로 널리 사용되고 있으며, 흡연으로 유발된 α1-안티트립신의 산화를 억제하여 기관지 폐포의 파괴를 방지하고, 호흡기 면역물질인 면역글로블린 A, 리소자임 등의 인체 내 생리적 항균물질을 증가시켜 세균에 대한 저항력을 강화시키는 것으로 알려져 있으며, 현재 통상적으로 엘도스테인은 D-form 과 L-form이 섞인 라세미 화합물로 거울상 이성질체들이 가지는 독성이 없어 라세미 화합물의 분리 없이 약제로 사용되고 있다.Ldosteine is a substance with free radical scavenging activity, and is widely used as a treatment for acute and chronic bronchitis. It inhibits the oxidation of α1-antitrypsin caused by smoking to prevent destruction of bronchoalveoli, and immunoglobulin, a respiratory immune substance. It is known to strengthen resistance to bacteria by increasing physiological antibacterial substances in the human body such as A and lysozyme. Currently, eldostain is a racemic compound mixed with D-form and L-form, and does not have the toxicity of enantiomers. It is used as a drug without separation of racemic compounds.
그러나, 엘도스테인은 비교적 수 용해도가 낮은 편이고, 이에 따라 인체 내의 생체 이용률 또한 낮은 편이다.However, eldosteine has relatively low solubility in water, and accordingly, its bioavailability in the human body is also low.
이에 따라, 엘도스테인의 용해도 및 생체 이용률을 개선하고자 하고자 하는 시도가 있어왔다.Accordingly, attempts have been made to improve the solubility and bioavailability of eldosteine.
예를 들어, CN101606931 B(특허문헌 1)에서는, 수중에서 신속하고 균일하게 분산되는 분산성 정제를 제조함으로써, 엘도스테인의 낮은 용해도로 인한 문제를 개선한다.For example, in CN101606931 B (Patent Document 1), the problem caused by the low solubility of eldostain is improved by preparing a dispersible tablet that is rapidly and uniformly dispersed in water.
그러나, 이와 같은 방법은, 정제 등의 고형 제제의 붕해 등의 속도를 높히는 방법일 뿐이므로, 엘도스테인과 같이 수 용해도가 비교적 낮은 약물의 경우, 약물의 용해 속도 이상의 개선을 이루기 어렵다는 한계가 있다.However, since this method is only a method of increasing the rate of disintegration of solid preparations such as tablets, in the case of drugs having relatively low water solubility, such as eldostain, it is difficult to improve the dissolution rate or higher of the drug. .
결국, 근본적으로 엘도스테인 자체의 용해도를 개선해야 할 필요성이 있으며, 나아가, 원료 의약품으로서 안정성도 높아야할 필요성이 있다.After all, there is a need to fundamentally improve the solubility of eldostein itself, and furthermore, there is a need to increase the stability as a drug substance.
이에 본 발명은 용해도, 생체이용률, 및 안정성이 높을 뿐 아니라, 약제 조성물의 활성성분으로서 요구되는 사항을 모두 만족하여 유용하게 사용될 수 있는 엘도스테인 공결정화합물을 제공하고 한다.Accordingly, the present invention provides an eldostain co-crystal compound that can be usefully used by satisfying all requirements as an active ingredient of a pharmaceutical composition as well as having high solubility, bioavailability, and stability.
본 발명은 상술한 종래기술의 문제점을 해결하고 위해 안출된 것으로서,The present invention has been made to solve the problems of the prior art described above,
L형 또는 D형 엘도스테인과 약제학적으로 허용 가능한 공형성체가 공결정상으로 이루어진 것을 특징으로 하는 엘도스테인 공결정화합물을 제공한다.Provided is an eldostain co-crystal compound characterized in that a pharmaceutically acceptable co-former with L-type or D-type eldostain is formed in a co-crystal phase.
본 발명에 있어서, 상기 공형성체가 폴리에틸렌글리콜, 니코틴아마이드, 말론산, 사카린, 푸마르산, 및 카페인산에서 선택되는 1종 이상인 것을 특징으로 하는 엘도스테인 공결정화합물을 제공한다.In the present invention, an eldostane co-crystal compound is provided, wherein the co-former is at least one selected from polyethylene glycol, nicotinamide, malonic acid, saccharin, fumaric acid, and caffeic acid.
본 발명에 있어서, 상기 폴리에틸렌글리콜은 폴리에틸렌글리콜-6000인 것을 특징르로 하는 엘도스테인 공결정화합물을 제공한다.In the present invention, the polyethylene glycol provides an eldostain co-crystal compound characterized in that polyethylene glycol-6000.
본 발명에 있어서, L-엘도스테인 및 공형성체인 폴리에틸렌글리콜-6000으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이, 18.1, 19.1, 19.9, 21.1, 22.9, 23.2, 23.5, 28.3, 31.2, 32.7인 것을 특징으로 하는 엘도스테인 공결정화합물을 제공한다.In the present invention, it is composed of L-eldostain and polyethylene glycol-6000 as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 18.1, 19.1, 19.9, 21.1, 22.9, 23.2, 23.5, 28.3, 31.2, It provides an eldostain co-crystal compound, characterized in that 32.7.
본 발명에 있어서, 시차주사 열량계 (DSC)로 분석한 스펙트럼상에서의 최대 흡열피크가 134.9℃ 인 것을 특징으로 하는 엘도스테인 공결정화합물을 제공한다.In the present invention, an eldostain co-crystal compound characterized in that the maximum endothermic peak on the spectrum analyzed by differential scanning calorimetry (DSC) is 134.9° C. is provided.
본 발명에 있어서, D-엘도스테인 및 공형성체인 폴리에틸렌글리콜-6000으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이, 18.1, 19.1, 19.9, 21.1, 22.9, 23.2, 23.5, 28.3, 31.4, 32.7인 것을 특징으로 하는 엘도스테인 공결정화합물을 제공한다.In the present invention, it is composed of D-eldostain and polyethylene glycol-6000 as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 18.1, 19.1, 19.9, 21.1, 22.9, 23.2, 23.5, 28.3, 31.4, It provides an eldostain co-crystal compound, characterized in that 32.7.
본 발명에 있어서, 시차주사 열량계 (DSC)로 분석한 스펙트럼상에서의 최대 흡열피크가 135.8℃ 인 것을 특징으로 하는 엘도스테인 공결정화합물을 제공한다.In the present invention, an eldostain co-crystal compound characterized in that the maximum endothermic peak on the spectrum analyzed by differential scanning calorimetry (DSC) is 135.8° C. is provided.
본 발명의 엘도스테인 공결정화합물을 유효성분으로 포함하는 급성 또는 만성 호흡기질환 예방 또는 치료용 약학 조성물을 제공한다.Provided is a pharmaceutical composition for preventing or treating acute or chronic respiratory diseases comprising the eldosteine co-crystal compound of the present invention as an active ingredient.
본 발명의 D-엘도스테인, 및 L-엘도스테인 공결정 화합물은, 용해도, 생체이용률, 및 안정성이 높을 뿐 아니라, 약제 조성물의 활성성분으로서 요구되는 사항을 모두 만족하여 유용하게 사용될 수 있다.The D-eldostain and L-eldostain co-crystal compounds of the present invention have high solubility, bioavailability, and stability, and can be usefully used by satisfying all requirements as an active ingredient of a pharmaceutical composition.
도 1은, L-엘도스테인 폴리에틸렌글리콜 공결정 NMR 데이터이다.
도 2는, L-엘도스테인 폴리에틸렌글리콜 공결정 XRD 데이터이다.
도 3은, L-엘도스테인 폴리에틸렌글리콜 공결정 DSC 데이터이다.
도 4는, D-엘도스테인 폴리에틸렌글리콜 공결정 NMR 데이터이다.
도 5는, D-엘도스테인 폴리에틸렌글리콜 공결정 XRD 데이터이다.
도 6은, D-엘도스테인 폴리에틸렌글리콜 공결정 DSC 데이터이다.1 is L-eldostain polyethylene glycol co-crystal NMR data.
Fig. 2 shows XRD data of L-eldostain polyethylene glycol co-crystal.
3 is L-eldostain polyethylene glycol co-crystal DSC data.
4 is D-eldostain polyethylene glycol co-crystal NMR data.
Fig. 5 is XRD data of D-eldostain polyethylene glycol co-crystal.
6 is DSC data of D-eldostain polyethylene glycol co-crystal.
이하, 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일측면은, One aspect of the present invention,
L형 또는 D형 엘도스테인과 약제학적으로 허용 가능한 공형성체가 공결정상으로 이루어진 것을 특징으로 하는 엘도스테인 공결정화합물이다.An eldostain co-crystal compound characterized in that a pharmaceutically acceptable co-former with L-type or D-type eldostain is formed in a co-crystal phase.
상기 공결정이란, 하나의 결정격자 안에 일정한 화학양론 비율(stoichiometric ratio)로 두 개 이상의 다른 분자가 결정 구조를 형성하고 있는 형태를 의미하며, 공결정 내 분자간 결합 형태는 염, 혼합물과 구별된다.The co-crystal means a form in which two or more different molecules form a crystal structure at a constant stoichiometric ratio in one crystal lattice, and the form of intermolecular bonds in the co-crystal is distinguished from salts and mixtures.
또한, 상기 공형성체(coformer)란, 공결정 의약품의 결정을 구성하는 분자 중 활성이 없는 분자를 지칭한다.In addition, the coformer (coformer) refers to molecules that are not active among the molecules constituting the crystal of the co-crystal drug.
공결정화합물에 대해서는 이미 알려진 내용이지만, 알반적인 유기화합물의 1%에도 미치지 못할 정도로 전체적인 연구가 미흡한 실정이며, 특히, D-엘도스테인, L-엘도스테인에 대한 공결정화물에 대한 연구는 전무한 실정이다.Co-crystal compounds are already known, but overall research is insufficient to the extent that they account for less than 1% of general organic compounds. In particular, there is no research on co-crystals of D-Eldostain and L-Eldostain. am.
이에, 본 발명자들은, D-엘도스테인, L-엘도스테인의 공결정은, 활성성분으로서 요구되는 물성은 만족하면서도, 안정한 새로운 결정형을 합성할 수 있었기 때문에 본 발명을 완성하기에 이르렀다.Accordingly, the present inventors have completed the present invention because they were able to synthesize a stable new crystal form of the co-crystal of D-eldostain and L-eldostain while satisfying the physical properties required as an active ingredient.
상기 공형성체가 폴리에틸렌글리콜, 니코틴아마이드, 말론산, 사카린, 푸마르산, 및 카페인산에서 선택되는 1종 이상인 것을 사용할 수 있고, 바람직하게는, 폴리에틸렌글리콜인 것이다.The coformer may be one or more selected from polyethylene glycol, nicotinamide, malonic acid, saccharin, fumaric acid, and caffeic acid, and preferably polyethylene glycol.
본 발명의 다른 측면은,Another aspect of the present invention is
상기 본 발명의 D형 또는 L형 엘도스테인 공결정화합물을 유효성분으로 포함하는 급성 또는 만성 호흡기질환 예방 또는 치료용 약학 조성물이다.A pharmaceutical composition for preventing or treating acute or chronic respiratory diseases comprising the D-type or L-type eldosteine co-crystal compound of the present invention as an active ingredient.
여기서, 급성 또는 만성 호흡기질환은, 담배 연기나 가스 등의 유해 입자, 세균, 바이러스 등의 생물학적 항원 등에 의해 폐 또는 기도에 비정상적 염증반응을 일으키는 모든 질환을 의미한다.Here, the acute or chronic respiratory disease refers to any disease that causes an abnormal inflammatory response in the lungs or airways due to harmful particles such as cigarette smoke or gas, biological antigens such as bacteria and viruses, and the like.
구체적인 예시로, 급성 기관지염(acute bronchitis), 만성 기관지염(chronic bronchitis), 만성 폐쇄성 폐질환(Chronic Obstructive Pulmonary Disease: COPD), 또는 폐섬유화증(pulmonary fibrosis) 등이 포함된다.Specific examples include acute bronchitis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), or pulmonary fibrosis.
이하, 본 발명에 대하여 실시예를 들어 보다 더 상세히 설명한다. 다만, 이하의 실시예는 발명의 상세한 설명을 위한 것일 뿐이며, 이에 의해 권리범위를 제한하려는 의도가 아님을 분명히 해둔다.Hereinafter, examples of the present invention will be described in more detail. However, it is made clear that the following examples are only for detailed description of the invention, and are not intended to limit the scope of rights thereby.
실시예Example
실시예Example 1: (R)-2- 1: (R)-2- methoxymethoxy -N-((R)-2--N-((R)-2- oxotetrahydrothiophenoxotetrahydrothiophene -3--3- ylyl )-2-phenylacetamide 제조 )-2-phenylacetamide manufacturing
D,L-호모시스테인싸이오락톤염산염 36g, 클로로포름 3.4L 투입후 5℃로 냉각한다. 트리에틸아민 33.2g 5℃유지하며 반응기에 투입한다. 1-하이드록시벤조트리아졸 38g, S-(+)-(2)-메톡시페닐아세트산 43.3g, 1-(3-다이메틸아미노피로필)-3-에틸카보다이이미드 염삼염 54g을 5℃ 유지하며 반응기에 투입한다. 0~5℃ 유지하며 7시간 30분 교반후 증류수를 투입하여 반응을 종결한다. 5% 중탄산나트륨용액과 2M 염산용액, 포화 염화나트륨 용액으로 세척하고, 황산마그네슘 상에서 건조시키고, 감압하여 농축시켰다. 상기 조 생성물을 컬럼크로마토그래피(실리카, 에틸아세테이트/헥산)로 정제하였다.After adding 36 g of D,L-homocysteine thiolactone hydrochloride and 3.4 L of chloroform, the mixture was cooled to 5°C. 33.2 g of triethylamine was added to the reactor while maintaining 5°C. 38g of 1-hydroxybenzotriazole, 43.3g of S-(+)-(2)-methoxyphenylacetic acid, and 54g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt salt were mixed at 5℃. maintained and put into the reactor. Maintaining 0 ~ 5 ℃ and after stirring for 7 hours and 30 minutes, distilled water is added to terminate the reaction. Washed with 5% sodium bicarbonate solution, 2M hydrochloric acid solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, ethyl acetate/hexane).
실시예Example 2: (R)-3- 2: (R)-3- aminodihydrothiophenaminodihydrothiophene -2(3H)-one 제조Manufacture of -2(3H)-one
(R)-2-메톡시-N-((R)-2-옥소테트라하이로싸이오펜-3-yl)-2-페닐아세트아마이드 20g, 에탈올:4M HCl = 2:1 용액 1.2L 상온에서 투입한다. 온도를 승온하여 25시간 환류 교반후 상온으로 냉각한다. 증류수와 톨루엔을 가하여 유기층으로 불순물 제거를 한다. 수층 감압 농축하였다. 상기 조 생성물을 아이소프로필알코올을 사용하여 재결정하여 (R)-3-아미노다이하이드로싸이오펜-2(3H)-one 7.24g (55.6%) 얻었다.(R)-2-methoxy-N-((R)-2-oxotetrahydrothiophen-3-yl)-2-phenylacetamide 20g, ethanol:4M HCl = 2:1 solution 1.2L at room temperature put in After raising the temperature and stirring under reflux for 25 hours, the mixture is cooled to room temperature. Distilled water and toluene were added to remove impurities with the organic layer. The aqueous layer was concentrated under reduced pressure. The crude product was recrystallized from isopropyl alcohol to obtain 7.24 g (55.6%) of (R)-3-aminodihydrothiophene-2(3H)-one.
실시예Example 3: (S)-3- 3: (S)-3- aminodihydrothiophenaminodihydrothiophene -2(3H)-one 제조Manufacture of -2(3H)-one
(S)-2-메톡시-N-((S)-2-옥소테트라하이로싸이오펜-3-yl)-2-페닐아세트아마이드 20g, 에탈올:4M HCl = 2:1 용액 1.2L 상온에서 투입한다. 온도를 승온하여 25시간 환류 교반후 상온으로 냉각한다. 증류수와 톨루엔을 가하여 유기층으로 불순물 제거를 한다. 수층 감압 농축하였다. 상기 조 생성물을 아이소프로필알코올을 사용하여 재결정하여 (S)-3-아미노다이하이드로싸이오펜-2(3H)-one 7.98g (61.1%) 얻었다.(S)-2-methoxy-N-((S)-2-oxotetrahydrothiophen-3-yl)-2-phenylacetamide 20g, ethanol:4M HCl = 2:1 solution 1.2L at room temperature put in After raising the temperature and stirring under reflux for 25 hours, the mixture is cooled to room temperature. Distilled water and toluene were added to remove impurities with the organic layer. The aqueous layer was concentrated under reduced pressure. The crude product was recrystallized from isopropyl alcohol to obtain 7.98 g (61.1%) of (S)-3-aminodihydrothiophene-2(3H)-one.
실시예Example 4: L- 4: L- ErdosteineErdosteine 제조 manufacturing
(R)-3-아미노다이하이드로싸이오펜-2(3H)-one 9g, 증류수 21.6ml, 아세톤 18ml 상온에서 투입한다.9g of (R)-3-aminodihydrothiophene-2(3H)-one, 21.6ml of distilled water, and 18ml of acetone were added at room temperature.
0~10℃ 냉각하여 중탄산나트륨 4.92g 투입후 온도 유지하며 30분 교반한다. 싸이오다이글리콜릭산 9.29g 0~10℃ 유지하며 반응기에 투입한다. 0~10℃ 에서 3시간 교반후 여과하여 L-Erdosteine을 얻는다(수율 82%).Cool to 0~10℃, add 4.92g of sodium bicarbonate, and stir for 30 minutes while maintaining the temperature. 9.29 g of thiodiglycolic acid is added to the reactor while maintaining 0 to 10 ° C. After stirring at 0~10℃ for 3 hours, filter to obtain L-Erdosteine (yield: 82%).
실시예Example 5: D- 5: D- ErdosteineErdosteine 제조 manufacturing
(S)-3-아미노다이하이드로싸이오펜-2(3H)-one 9g, 증류수 21.6ml, 아세톤 18ml 상온에서 투입한다.Add 9g of (S)-3-aminodihydrothiophene-2(3H)-one, 21.6ml of distilled water, and 18ml of acetone at room temperature.
0~10℃ 냉각하여 중탄산나트륨 4.92g 투입후 온도 유지하며 30분 교반한다. 싸이오다이글리콜릭산 9.29g 0~10℃ 유지하며 반응기에 투입한다. 0~10℃ 에서 3시간 교반후 여과하여 D-Erdosteine을 얻는다(수율 65%).Cool to 0~10℃, add 4.92g of sodium bicarbonate, and stir for 30 minutes while maintaining the temperature. 9.29 g of thiodiglycolic acid is added to the reactor while maintaining 0 to 10 ° C. After stirring at 0~10℃ for 3 hours, filter to obtain D-Erdosteine (yield: 65%).
실시예Example 6: L- 6: L- ErdosteineErdosteine 공결정co-crystal 제조 manufacturing
플라스크에 L-엘도스테인 50mg, 폴리에틸렌글리콜-6000 50mg, 용매(acetone: methanol=1:1) 10ml 투입후 상온에서 30분 교반한다. 교반액을 감압 농축하여 용매를 제거한 후, 진공건조하여 L-엘도스테인/폴리에틸렌글리콜-6000 공결정을 얻는다. 얻어진 결정은 핵자기공명법과 시차주사열계량법으로 분석하였다.After adding 50 mg of L-Eldostain, 50 mg of polyethylene glycol-6000, and 10 ml of solvent (acetone: methanol = 1:1) to the flask, stir at room temperature for 30 minutes. After concentrating the stirred solution under reduced pressure to remove the solvent, vacuum drying is performed to obtain L-Eldostain/polyethylene glycol-6000 co-crystal. The crystals obtained were analyzed by nuclear magnetic resonance and differential scanning calorimetry.
실시예Example 7: D- 7: D- ErdosteineErdosteine 공결정co-crystal 제조 manufacturing
플라스크에 D-엘도스테인 50mg, 폴리에틸렌글리콜-6000 50mg, 용매(acetone: methanol=1:1) 10ml 투입후 상온에서 30분 교반한다. 교반액을 감압 농축하여 용매를 제거한 후, 진공건조하여 D-엘도스테인/폴리에틸렌글리콜-6000 공결정을 얻는다. 얻어진 결정은 핵자기공명법과 시차주사열계량법으로 분석하였다.After adding 50 mg of D-Eldostain, 50 mg of polyethylene glycol-6000, and 10 ml of solvent (acetone: methanol = 1:1) to the flask, stir at room temperature for 30 minutes. The stirred solution is concentrated under reduced pressure to remove the solvent, and vacuum dried to obtain D-Eldostain/polyethylene glycol-6000 co-crystal. The crystals obtained were analyzed by nuclear magnetic resonance and differential scanning calorimetry.
실험예Experimental example
* 용해도 테스트* Solubility test
상기 실시예 4 내지 7에서 제조된 엘도스테인 또는 이의 공결정화합물에 대해서, 하기 표 1에 나타난 바와 같은 다양한 용매 하에서 용해도 비교 실험을 진행하였다.For eldostain or its co-crystal compound prepared in Examples 4 to 7, solubility comparison experiments were conducted under various solvents as shown in Table 1 below.
* EA: Ethyl Acetate; MC: Methyl Chloride; ACN: Acetonitrile; IPA: Isopropyl alcohol* ○: well recorded ~ recorded; △: slightly soluble to very difficult to soluble; ×: substantially insoluble to insoluble
*EA: Ethyl Acetate; MC: Methyl Chloride; ACN: Acetonitrile; IPA: Isopropyl alcohol
상기 표에서 확인되듯이, 공결정화합물의 수용해도 개선효과가 뚜렷하였으며, 유기용매 중에서도 ACN에서의 용해도 개선효과가 나타났다.As confirmed in the table above, the water solubility improvement effect of the co-crystal compound was evident, and the solubility improvement effect in ACN was also shown among organic solvents.
아울러, 수용해도가 개선되었다는 점은 흡수 과정에서 체내 생체 이용률에 있어서 좀더 유리한 쪽으로 개선되었다는 것을 말해주는 것으로 볼 수 있다.In addition, the fact that the water solubility is improved can be seen as saying that the bioavailability in the body has been improved to a more favorable side during the absorption process.
* 안정성 테스트* Stability test
기존 L-엘도스테인, D-엘도스테인 각각의 공결정에 대한 온도에 대한 안정성을 확인하기 위하여, 하기의 실험방법을 실시하여 L-엘도스테인, D-엘도스테인 온도에 대한 안정성을 비교하였다.In order to confirm the temperature stability of the existing co-crystals of L-Eldostein and D-Eldosteine, the following experimental method was performed to compare the stability of L-Eldosteine and D-Eldosteine in temperature.
*실험방법*Test method
실온과 65℃오븐에서, L-엘도스테인, D-엘도스테인 결정형 실시예 4,5와 실시예 6,7을 각각 1일, 3일, 7일동안 고체상태로 방치한 후에, 고성능 액체크로마토그래피(HPLC)로 분석하여 순도를 측정하였다.At room temperature and 65 ° C. in an oven, L-Eldostain, D-Eldostain crystalline Examples 4 and 5 and Examples 6 and 7 were allowed to stand in a solid state for 1 day, 3 days, and 7 days, respectively, followed by high-performance liquid chromatography. (HPLC) to determine the purity.
상기 표 2에서 확인할 수 있듯이, 본 발명이 특징으로 하는 L-엘도스테인, D-엘도스테인 각각의 공결정은 L-엘도스테인, D-엘도스테인과 비교해볼 때, 온도에 있어서 더 안정함을 알 수 있다.As can be seen from Table 2, the co-crystals of L-eldostain and D-eldostain, which are characterized by the present invention, are more stable in temperature compared to L-eldostain and D-eldostain. can
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210055923A KR102544543B1 (en) | 2021-04-29 | 2021-04-29 | Individual co-crystal of l, d-erdosteine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210055923A KR102544543B1 (en) | 2021-04-29 | 2021-04-29 | Individual co-crystal of l, d-erdosteine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20220148616A KR20220148616A (en) | 2022-11-07 |
| KR102544543B1 true KR102544543B1 (en) | 2023-06-16 |
Family
ID=84043457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210055923A KR102544543B1 (en) | 2021-04-29 | 2021-04-29 | Individual co-crystal of l, d-erdosteine |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR102544543B1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100554108B1 (en) * | 2003-10-02 | 2006-02-22 | 주식회사 한서켐 | A process for preparing erdosteine |
| CN101606931B (en) | 2009-08-06 | 2011-06-15 | 山东罗欣药业股份有限公司 | Erdosteine composition and preparation method thereof |
| CN108601791A (en) * | 2015-09-18 | 2018-09-28 | 格兰泰有限公司 | Method for crystallising and bioavilability |
-
2021
- 2021-04-29 KR KR1020210055923A patent/KR102544543B1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| KR20220148616A (en) | 2022-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2728541C (en) | Crystalline forms of thiazolidinedione compound and its manufacturing method | |
| KR20120016277A (en) | Improved method for synthesizing pirfenidone | |
| RU2603138C1 (en) | Crystalline form of hidamide, method of its production and use | |
| EP0579681B1 (en) | Crystalline tiagabine hydrochloride monohydrate, its preparation and use | |
| KR101710740B1 (en) | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof | |
| JP2019529504A (en) | Non-solvate crystals, method for producing the same, and application | |
| CN114026085A (en) | (E) Solid forms of (E) -3- [2- (2-thienyl) vinyl ] -1H-pyrazole | |
| KR102544543B1 (en) | Individual co-crystal of l, d-erdosteine | |
| CN106963766B (en) | Azaspiroanone pharmaceutical composition and preparation method thereof | |
| JP6908657B2 (en) | Polymorphs of 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl4-methylbenzoate hydrochloride, methods of making them and their use | |
| WO2020244148A1 (en) | Doramectin crystal form a, crystal form b, and preparation method thereof | |
| US8791269B2 (en) | Complex of amorphous tomoxiprole and cyclodextrin with fast dissolution rate and process for the preparation thereof | |
| CN106478616B (en) | Crystalline form of GPR40 agonist and preparation method thereof | |
| BG108065A (en) | Novel benzoylguanidine salt | |
| WO2001068587A1 (en) | Novel crystal of stilbene derivative and process for producing the same | |
| KR20180023419A (en) | Novel salt of (r)-(1-methylpyrrolidin -3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and crystalline forms thereof | |
| KR102026337B1 (en) | Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same | |
| WO2020198939A1 (en) | Crystalline form a of 2,2-bis(4-fluorophenyl)-2-phenylacetamide and preparation method therefor and application thereof | |
| KR20200127480A (en) | Crystalline Forms of Teneligliptin Edisylate and Process of Preparing the Same | |
| JPH10316677A (en) | Crystal | |
| KR20110095545A (en) | (s)-rivastigmine orotate and pharmaceutical composition including the same | |
| KR20110103711A (en) | Novel crystalline zanamivir hydrate and process for preparation thereof | |
| WO2013103004A1 (en) | Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |