WO2020032365A1 - Composition, comprising ginsenoside compound, for preventing or treating inflammasome-mediated inflammatory disease - Google Patents
Composition, comprising ginsenoside compound, for preventing or treating inflammasome-mediated inflammatory disease Download PDFInfo
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- WO2020032365A1 WO2020032365A1 PCT/KR2019/006677 KR2019006677W WO2020032365A1 WO 2020032365 A1 WO2020032365 A1 WO 2020032365A1 KR 2019006677 W KR2019006677 W KR 2019006677W WO 2020032365 A1 WO2020032365 A1 WO 2020032365A1
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
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- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
Definitions
- the present invention relates to a composition for preventing, ameliorating or treating an inflammasome-mediated inflammatory disease containing a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
- Inflammasomes are caspase-1-activated complex protein complexes that include: 1) the sensory protein, NLRP3 (NOD-like receptor family, pyrin domain-containing 3), and 2) the adapter protein.
- ASC adaptor protein apoptosis-associated spec-like protein containing a caspase-recruitment domain
- effector protein procaspase-1 The above inflamasome components are assembled when microbial infection or tissue injury occurs. Inflamasomes activated by assembly in the cytosol activate caspase-1, thereby interleukin (IL) -1 ⁇ .
- IL interleukin
- Ginseng contains a variety of ginsenosides, meaning saponins.
- Ginsenosides are protopanaxadiol-type (PPD type) ginsenosides, Protopanaxatriol-type (PPT type) ginsenosides and oleanolinic acids depending on the structure of aglycone.
- PPD type protopanaxadiol-type
- PPT type Protopanaxatriol-type
- ginsenosides oleanolinic acids depending on the structure of aglycone.
- Olelic acid type can be classified into three types of ginsenosides. These three groups, in turn, depend on the location of the sugar, the number of sugars, and the type of sugars attached by the glycosidic bonds to the carbon 3, 6 and 20 positions of the aglycone ring in the compound structure. Are classified.
- Gifenoside LXXV is a ginsenoside compound belonging to the PPD type, and ginsenoside Rf is the PPT type.
- the ginsenoside compound can be used for the prevention, amelioration or treatment of inflammasome-mediated diseases by inhibiting inflammasome activity.
- an object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammasome-mediated inflammatory disease, which contains a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
- Still another object of the present invention is to provide a food composition for preventing or ameliorating inflammasome mediated inflammatory disease, which contains a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
- Another object of the present invention is to administer a therapeutically effective amount of a ginsenoside compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof to prevent or prevent inflammasome mediated inflammatory disease. It is to provide a method of treatment.
- the inventors of the present invention while searching for various types of ginsenosides, have found the effect of inhibiting the inflammasome activity of Gypenoside LXXV and Ginsenoside Rf to complete the present invention.
- the present invention provides a pharmaceutical composition for the prevention or treatment of inflammasome-mediated inflammatory disease, comprising a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
- Ginsenoside compound represented by General formula (1) of this invention is Gypenoside LXXV which has the following structure.
- Gypenoside LXXV has a molecular formula of C 42 H 72 O 13 , referred to as ( ⁇ , 12 ⁇ ) -3,12-dihydroxydammar-24-en-20-yl 6-O- ⁇ -D-glucopyranosyl- ⁇ -D-glucopyranoside do.
- Ginsenoside compound represented by the formula (2) of the present invention is Ginsenoside Rf having the following structure.
- the molecular formula of Ginsenoside Rf is C 42 H 72 O 14 , (3 ⁇ , 6 ⁇ , 12 ⁇ ) -3,12,20-Trihydroxydammar-24-en-6-yl 2-O- ⁇ -D-glucopyranosyl- ⁇ -D- It is called glucopyranoside.
- the ginsenoside compound represented by Formula 1 or Formula 2 may be extracted from a plant, and hydrolyzed using an acid, hydrolyzed using heat, hydrolyzed using ultrasonic waves, or enzymes according to methods known in the art. It may be used by hydrolysis or synthesis, or may be commercially available.
- the compound may be obtained from ginseng extract.
- the type of ginseng used is not particularly limited, and ginseng, red ginseng, white ginseng, taeguksam, misam and the like can be used.
- extracts from all parts of ginseng such as stems, roots, leaves, flowers, fruits, etc. can be used and are not limited to extracts of any particular part.
- a method for extracting the ginsenoside compound represented by Formula 1 or Formula 2 from ginseng extract may use a known method.
- active ingredient refers to a substance or a group of substances (including herbal medicines for which pharmacologically active ingredients and the like are not known) which are expected to express the efficacy effect of the composition directly or indirectly by inherent pharmacological action. It means to include the main component.
- the pharmaceutical composition of the present invention may contain the ginsenoside compound represented by Formula 1 or Formula 2 in an amount of 0.001 to 50% by weight based on the total weight of the composition.
- a pharmaceutical composition containing the compound represented by Formula 1 or Formula 2 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient effectively inhibits the production of IL-1 ⁇ according to the activation of inflammasomes, thereby causing an inflammasome-mediated inflammatory disease.
- the prophylactic or therapeutic effect is excellent.
- the activity of inflamasome induced by Nigericin or ATP and IL-1 ⁇ production in mice and human macrophages was effectively inhibited by the pharmaceutical composition of the present invention. (FIGS. 1-8).
- the term “inflammasome” is present in the cytoplasm of myeloid cells and is a protein complex consisting of innate immune receptors (NOD-like receptor), ASC protein and caspase-1. It is involved in the conversion of pro-IL-1 ⁇ , a precursor of inflammatory cytokines associated with innate immune defenses, to mature IL-1 ⁇ . Inflamasomes composed of NLRP1, NLRP3, NLRC4, AIM4, etc., of which NLRP3 inflamasomes have been reported to be associated with the development of various autoimmune diseases.
- IL-1 ⁇ is associated with human or acquired disease in humans, and it has been found that antagonists or receptors of IL-1 ⁇ may help in successful treatment of some diseases. Therefore, the relationship between inadequate inflamasome action and congenital and acquired inflammatory diseases is important in the immune response control mechanism.
- the composition of the present invention can effectively regulate the amount of inflammatory cytokine IL-1 ⁇ secreted by inhibiting the activity of the inflamasome, has an excellent effect in the prevention and treatment of inflammatory diseases.
- the pharmaceutical composition containing the compound represented by Formula 1 or Formula 2 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be usefully used for the prevention or treatment of inflammasome mediated inflammatory diseases.
- inflammasome-mediated inflammatory disease refers to a condition or disease in which a prophylactic, ameliorating, or therapeutic effect can be expected by inhibiting the activity of an inflamasome (eg, NLRP3 inflamasome). Specific kinds of are well known in the art.
- NLRP3 inflamasome is a metabolic disease, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic syndrome (CAPS), and other autoimmune diseases. And the initiation and progression of autoinflammatory diseases and the like.
- NLRP3 inflammasome inhibitors such as MCC950 (diacylsulfonylurea-containing compound), ⁇ -hydroxybutyrate (BHB), type I interferon and IFN- ⁇ may be used to treat related diseases through inhibition of IL-1 ⁇ secretion. Suggests that it can be used.
- an NLRP3 inhibitor specifically inhibits the activity of NLRP3 but not AIM2, NLRC4 or NLRP1 activity, blocks canonical and non-canonical NLRP3 activity, and inhibits IL-1 ⁇ production, thereby autoimmune encephalomyelitis, a disease model of multiple sclerosis ( relieving symptoms of encephalomyelitis (EAE), restoring the postmortal lethality of the CAPS mouse model, and having an activity on ex vivo samples of individuals with Muckel-Wells syndrome, including autoinflammatory and autoimmune diseases Suggests that it is a therapeutic agent for NLRP3-related diseases.
- EAE encephalomyelitis
- NLRP3 inflamasomes are associated with Alzheimer's disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration (AMD).
- AMD age-related macular degeneration
- gouty arthritis is caused by the deposition of uric acid crystals that induce the activity of NLRP3 inflamasomes and is closely associated with the development of various metabolic diseases, including gouty arthritis. do.
- the pharmaceutical composition containing the ginsenoside compound represented by Formula 1 or Formula 2 inhibits inflammasome activity.
- the inflammasome is NLRP3 (NOD-like receptor family, pyrin domain-containing 3).
- Inflamasome mediated inflammatory diseases in the present invention include at least one disease selected from the group consisting of autoinflammatory diseases, neuroinflammatory diseases and metabolic diseases.
- auto-inflammatory disease refers to a group of diseases in which systemic inflammation is frequently repeated in the state where autoantibodies or antigen-specific T cells are not found, unlike autoimmune diseases.
- Welles-Wells syndrome MMS
- LADA adult delayed autoimmune diabetes
- FCAS familial cold autoimmune syndrome
- CAS cryopyrin-related periodic syndromes
- NOMID neonatal-onset multicenter inflammatory syndrome
- CINCA Chronic infant nerve skin joint
- FMF familial Mediterranean fever
- SJIA systemic onset childhood idiopathic arthritis
- juvenile rheumatoid arthritis juvenile rheumatoid arthritis, adult rheumatoid arthritis, age-related macular degeneration, atopic dermatitis and psoriasis
- It may be any one or more selected from, but includes, but is not limited to, other autoinflammatory diseases known in the art.
- Formulations for parenteral administration may be formulated in the form of sterile aqueous solutions, liquids, non-aqueous solutions, suspensions, emulsions, eye drops, ophthalmic ointments, syrups, suppositories, aerosols, etc., and sterile injectables, respectively, according to conventional methods. It can be used to prepare a pharmaceutical composition of creams, gels, patches, sprays, ointments, warnings, lotions, linings, eye ointments, eye drops, pasta or cataplasma However, the present invention is not limited thereto. Compositions of topical administration may be anhydrous or aqueous, depending on the clinical prescription.
- non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
- base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
- the term “therapeutically effective amount” refers to the amount of the compound represented by Formula 1 or Formula 2 effective for the prevention or treatment of inflammasome mediated inflammatory diseases, which is the disease or disorder being treated. Includes amounts that induce symptomatic relief.
- the method for preventing or treating inflamasome-mediated inflammatory diseases of the present invention may be performed by administering a therapeutically effective amount of an additional active agent to help treat the disease together with the ginsenoside compound represented by Formula 1 or Formula 2. It may further include, an additional active agent may exhibit a synergistic or auxiliary effect with the ginsenoside compound represented by Formula 1 or Formula 2.
- the present invention also provides a food composition for preventing or ameliorating an inflamasome-mediated inflammatory disease containing a ginsenoside compound represented by Formula 1 or Formula 2 or a salt thereof.
- the food composition may be a nutraceutical or dietary supplement.
- Figure 3 shows the effect of inhibiting the production of Nigericin-induced IL-1 ⁇ according to the concentration of the compound of the present invention.
- LPS purified from E. coli was obtained from List Biological Laboratory Inc (Hornby, Canada) and dissolved in a non-toxic solution.
- the ginsenosides used in the experiment used high purity materials of more than 98%.
- ATP and Nigericin were purchased from Invivogen (San Diego, USA) and IL-1 ⁇ was purchased from R & D Systems (Minneapolis, MN, USA).
- IL-1 ⁇ For ELISA experiments, the methods described in the known levels of IL-1 ⁇ in cell culture supernatants were determined with an ELISA kit (IL-1 ⁇ : R & D Systems) according to the manufacturer's instructions were used. IL-1 ⁇ levels in cell culture supernatants were determined according to the manufacturer's instructions using an ELISA kit (IL-1 ⁇ : R & D Systems).
- the compound of Formula 1 or Formula 2 was treated with mouse macrophages at a concentration of 100 ⁇ g / ml, and then treated with 10 ⁇ M of Nigericin, and then measured at a concentration of IL-1 ⁇ 16 hours, induced by Nigericin, an NLRP3 agonist. The effect on the production of mature IL-1 ⁇ was investigated.
- the compounds of Formula 1 and Formula 2 according to the present invention have an effect of inhibiting the production of IL-1 ⁇ by 50% or more compared to the vehicle induced with IL-1 ⁇ (200 pg / ml) by Nigericin treatment. (FIG. 1).
- composition of the present invention can be used as a prophylactic, ameliorating or treating agent of NLRP3 inflamasome-related diseases by showing an excellent NLRP3 inflamasome inhibitory activity.
- the compound of Formula 1 or Formula 2 of the present invention did not significantly affect the cell viability at the treatment concentration of 100 ⁇ g / ml did not have cytotoxicity (Fig. 2).
- composition of the present invention can be used as a prophylactic, ameliorating, or treating agent of excellent NLRP3 inflamasome-related diseases.
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Abstract
The present invention relates to a composition comprising a ginsenoside compound represented by chemical formula 1 or 2 as an effective ingredient for preventing, alleviating, or treating an inflammasome-mediated inflammatory disease.
Description
본 발명은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는 인플라마좀 매개 염증성 질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, ameliorating or treating an inflammasome-mediated inflammatory disease containing a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
인플라마좀(inflammasomes)은 카스파제-1-활성화 복합 단백질 복합체로, 1) 감각 단백질(sensor protein)인 NLRP3(NOD-like receptor family, pyrin domain-containing 3), 2) 연결 단백질(adaptor protein)인 ASC(adaptor protein apoptosis-associated spec-like protein containing a caspase-recruitment domain) 및 3) 이펙터 단백질인 프로카스파제-1으로 구성된다. 상기한 인플라마좀 구성 성분들은 미생물의 감염이나 조직의 상해가 발생한 경우에 조립되는데, 시토졸에서 조립에 의해 활성화된 인플라마좀은 카스파제-1을 활성화시켜 인터루킨(interleukin 이하, IL)-1β 또는 IL-18을 분비하여 숙주의 선천면역 방어기능을 수행한다(Schroder K, Tschopp J, Cell 140:821-832(2010); Franchi L, Munoz-Planillo R, Nunex, Nat Immunol 13:325-332(2012)).Inflammasomes are caspase-1-activated complex protein complexes that include: 1) the sensory protein, NLRP3 (NOD-like receptor family, pyrin domain-containing 3), and 2) the adapter protein. ASC (adaptor protein apoptosis-associated spec-like protein containing a caspase-recruitment domain) and 3) effector protein procaspase-1. The above inflamasome components are assembled when microbial infection or tissue injury occurs. Inflamasomes activated by assembly in the cytosol activate caspase-1, thereby interleukin (IL) -1β. Or secrete IL-18 to perform innate immune defense of the host (Schroder K, Tschopp J, Cell 140: 821-832 (2010); Franchi L, Munoz-Planillo R, Nunex, Nat Immunol 13: 325-332 (2012)).
상기 메카니즘에 기초하여, NLRs(Nucleotide-binding Oligomerization Domain (NOD)-Like Receptors) 또는 ASC 및 인플라마좀 복합체의 형성 억제가 이들 단백질에 의해 매개되는 질환을 치료할 수 있는 잠재적인 방법으로 고려되었다(문헌[Ozaki et al., Journal of Inflammation Research 2015, 8:15-27]).Based on this mechanism, inhibition of the formation of Nucleotide-binding Oligomerization Domain (NOD) -Like Receptors (NLRs) or ASC and inflammasome complexes has been considered as a potential way to treat diseases mediated by these proteins (see literature). Ozaki et al., Journal of Inflammation Research 2015, 8: 15-27).
인삼에는 사포닌을 의미하는 다양한 종류의 진세노사이드가 함유되어 있다. 진세노사이드는 아글리콘(aglycone)의 구조에 따라 프로토파낙사이다이올계(Protopanaxadiol-type, PPD 타입) 진세노사이드, 프로토파낙사트라이올계(Protopanaxatriol-type, PPT 타입) 진세노사이드 및 올레아놀린산계(Oleanolic acid 타입) 진세노사이드의 세 가지로 분류될 수 있다. 이러한 세 그룹은 다시, 화합물 구조 중 아글리콘(aglycone) 고리의 3번 탄소, 6번 탄소 및 20번 탄소 위치에 글리코시드 결합(glycosidic bond)에 의해 부착되는 당의 위치, 당의 수 및 당의 종류에 따라 분류된다. Ginseng contains a variety of ginsenosides, meaning saponins. Ginsenosides are protopanaxadiol-type (PPD type) ginsenosides, Protopanaxatriol-type (PPT type) ginsenosides and oleanolinic acids depending on the structure of aglycone. (Oleanolic acid type) can be classified into three types of ginsenosides. These three groups, in turn, depend on the location of the sugar, the number of sugars, and the type of sugars attached by the glycosidic bonds to the carbon 3, 6 and 20 positions of the aglycone ring in the compound structure. Are classified.
지페노사이드(gypenoside) LXXV는 PPD 타입, 진세노사이드(ginsenoside) Rf는 PPT 타입에 속하는 진세노사이드 화합물이다. 그러나, 상기 진세노사이드 화합물이 인플라마좀 활성을 억제하여 인플라마좀 매개 질환의 예방, 개선 또는 치료에 사용될 수 있는지는 전혀 알려진 바가 없다.Gifenoside LXXV is a ginsenoside compound belonging to the PPD type, and ginsenoside Rf is the PPT type. However, it is not known at all whether the ginsenoside compound can be used for the prevention, amelioration or treatment of inflammasome-mediated diseases by inhibiting inflammasome activity.
본 발명자들은 인삼에 함유된 다양한 진세노사이드 화합물들 중 화학식 1로 표시되는 PPD 계열의 진세노사이드 화합물 1종과 화학식 2로 표시되는 PPT 계열의 진세노사이드 화합물 1종이 현저히 우수한 인플라마좀 억제 효능이 있음을 확인하였으며, 상기 화합물은 세포독성이 없을 뿐만 아니라 니제리신(Nigericin)-유도 인플라마좀 및 ATP-유도 인플라마좀 제어 효능이 뛰어나 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용할 수 있음을 확인하여 본 발명을 완성하였다.Among the various ginsenoside compounds contained in ginseng, the present inventors found that one of the ginsenoside compounds of the PPD series and the one of the ginsenoside compounds of the PPT series represented by the formula (2) is significantly superior to inflamasome inhibitory effect. In addition, the compound is not cytotoxic and has excellent control effects of nigerin-induced inflamasomes and ATP-induced inflamasomes as a prophylactic, amelioration, or therapeutic agent for inflamesome-related diseases. It was confirmed that it can be used to complete the present invention.
따라서, 본 발명의 목적은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammasome-mediated inflammatory disease, which contains a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
본 발명의 또 다른 목적은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Still another object of the present invention is to provide a food composition for preventing or ameliorating inflammasome mediated inflammatory disease, which contains a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
본 발명의 또 다른 목적은 치료학적으로 유효한 양의 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 이의 약학적으로 허용되는 염을 치료가 필요한 대상체에게 투여 하여 인플라마좀 매개 염증성 질환을 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to administer a therapeutically effective amount of a ginsenoside compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof to prevent or prevent inflammasome mediated inflammatory disease. It is to provide a method of treatment.
본 발명의 또 다른 목적은 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약제의 제조를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공하는 것이다.Still another object of the present invention is to provide a use of the compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of inflamasome mediated inflammatory diseases.
본 발명의 또 다른 목적은 인플라마좀 매개 염증성 질환의 예방 또는 치료를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공하는 것이다.Still another object of the present invention is to provide a use of the compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the prevention or treatment of inflammasome mediated inflammatory diseases.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각에 대한 다른 설명 및 실시형태에도 적용될 수 있다. 즉, 본 발명에 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.This will be described in detail below. On the other hand, each of the descriptions and embodiments disclosed in the present invention can be applied to other descriptions and embodiments of each. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention is not to be limited by the specific description described below.
인플라마좀Inflamasome
매개 염증성 질환의 예방 또는 치료용 약학 조성물 Pharmaceutical composition for the prevention or treatment of mediated inflammatory diseases
본 발명의 발명자들은 염증반응에 있어서 인플라마좀 활성 억제 필요성을 인지하고 인플라마좀 매개 염증질환을 예방 또는 치료할 수 있는 물질을 탐색하고자 하였다.The inventors of the present invention have recognized the necessity of inhibiting inflammasome activity in the inflammatory response, and have searched for a substance capable of preventing or treating inflamesome-mediated inflammatory diseases.
구체적으로, 본 발명의 발명자들은 다양한 종류의 진세노사이드를 탐색하던 중, Gypenoside LXXV 및 Ginsenoside Rf의 인플라마좀 활성 억제 효과를 발견하여 본 발명을 완성하게 되었다.Specifically, the inventors of the present invention, while searching for various types of ginsenosides, have found the effect of inhibiting the inflammasome activity of Gypenoside LXXV and Ginsenoside Rf to complete the present invention.
본 발명에 따른 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약학 조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제함으로써 인플라마좀 매개 염증성 질환의 예방 또는 치료 효과가 우수함을 확인하였다.The pharmaceutical composition for preventing or treating inflammasome-mediated inflammatory diseases according to the present invention has been found to have an excellent effect of preventing or treating inflammasome-mediated inflammatory diseases by effectively inhibiting IL-1β production according to activation of inflammasomes.
이하, 본 발명을 구체적으로 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of inflammasome-mediated inflammatory disease, comprising a ginsenoside compound represented by Formula 1 or Formula 2 as an active ingredient.
본 발명에서 용어 “진세노사이드(ginsenoside)”는 천연 스테로이드 글리코사이드이자 트라이터펜 사포닌의 일종으로, 인삼 속에 속하는 식물 속에서 많이 발견되며 인삼 화합물에 대해 약리학적 연구를 한 전통의학에서 오랫동안 사용해 온 물질이다.In the present invention, the term “ginsenoside” is a natural steroid glycoside and a kind of triterpene saponin, which is widely found in plants belonging to the ginseng and has been used for a long time in traditional medicine for pharmacological research on ginseng compounds. It is a substance.
본 발명의 화학식 1로 표시되는 진세노사이드 화합물은 하기 구조를 갖는 Gypenoside LXXV이다. Gypenoside LXXV는 C
42H
72O
13의 분자식을 가지며, (β,12β)-3,12-dihydroxydammar-24-en-20-yl 6-O-β-D-glucopyranosyl-β-D-glucopyranoside로 지칭된다.Ginsenoside compound represented by General formula (1) of this invention is Gypenoside LXXV which has the following structure. Gypenoside LXXV has a molecular formula of C 42 H 72 O 13 , referred to as (β, 12β) -3,12-dihydroxydammar-24-en-20-yl 6-O-β-D-glucopyranosyl-β-D-glucopyranoside do.
<화학식 1><Formula 1>
본 발명의 화학식 2로 표시되는 진세노사이드 화합물은 하기 구조를 갖는 Ginsenoside Rf이다. Ginsenoside Rf의 분자식은 C
42H
72O
14이고, (3β,6α,12β)-3,12,20-Trihydroxydammar-24-en-6-yl 2-O-β-D-glucopyranosyl-β-D-glucopyranoside로 지칭된다.Ginsenoside compound represented by the formula (2) of the present invention is Ginsenoside Rf having the following structure. The molecular formula of Ginsenoside Rf is C 42 H 72 O 14 , (3β, 6α, 12β) -3,12,20-Trihydroxydammar-24-en-6-yl 2-O-β-D-glucopyranosyl-β-D- It is called glucopyranoside.
<화학식 2><Formula 2>
상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물은 식물에서 추출될 수 있고, 당업계에 공지된 방법에 따라 산을 이용한 가수분해, 열을 이용한 가수분해, 초음파를 이용한 가수분해, 효소를 이용한 가수분해 또는 합성하여 사용할 수도 있으며, 상업적으로 시판되는 것을 사용할 수도 있다. 예컨대, 상기 화합물은 인삼 추출물에서 수득할 수 있다. 이때 사용되는 인삼의 종류는 특별히 제한되지 않고, 수삼, 홍삼, 백삼, 태극삼, 미삼 등을 사용할 수 있다. 또한, 줄기, 뿌리, 잎, 꽃, 열매 등 인삼의 모든 부분으로부터의 추출물이 사용가능하고 어느 특정 부분의 추출물로 한정되지 않는다. 또한, 인삼 추출물로부터 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 추출하는 방법은 공지의 방법을 사용할 수 있다.The ginsenoside compound represented by Formula 1 or Formula 2 may be extracted from a plant, and hydrolyzed using an acid, hydrolyzed using heat, hydrolyzed using ultrasonic waves, or enzymes according to methods known in the art. It may be used by hydrolysis or synthesis, or may be commercially available. For example, the compound may be obtained from ginseng extract. At this time, the type of ginseng used is not particularly limited, and ginseng, red ginseng, white ginseng, taeguksam, misam and the like can be used. In addition, extracts from all parts of ginseng such as stems, roots, leaves, flowers, fruits, etc. can be used and are not limited to extracts of any particular part. In addition, a method for extracting the ginsenoside compound represented by Formula 1 or Formula 2 from ginseng extract may use a known method.
본 발명에서 용어 “유효성분”은 내재된 약리작용에 의해 그 조성물의 효능 효과를 직접 또는 간접적으로 발현한다고 기대되는 물질 또는 물질군(약리학적 활성성분 등이 밝혀지지 않은 생약 등을 포함한다)으로서 주성분을 포함하는 것을 의미한다.As used herein, the term “active ingredient” refers to a substance or a group of substances (including herbal medicines for which pharmacologically active ingredients and the like are not known) which are expected to express the efficacy effect of the composition directly or indirectly by inherent pharmacological action. It means to include the main component.
본 발명의 약학 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 조성물 총 중량에 대하여 0.001 내지 50 중량%의 양으로 함유할 수 있다.The pharmaceutical composition of the present invention may contain the ginsenoside compound represented by Formula 1 or Formula 2 in an amount of 0.001 to 50% by weight based on the total weight of the composition.
본 발명에서, 약학적으로 허용되는 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 주석산 및 황산 등으로 제조된 무기산염, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트리메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 본 발명에 있어서 바람직한 염은 염산, 트라이플루오로아세트산, 시트르산, 브롬산, 말레산, 인산, 황산, 타르타르산을 포함한다.In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ionic salts, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, prepared with calcium, potassium, sodium and magnesium, Inorganic acid salts made with iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluc Organic acid salts, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, which are made of cornic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. amino acid salts made with sulfonates, glycine, arginine, lysine, etc., made of p-toluenesulfonic acid and naphthalenesulfonic acid, and trimethylamine, triethylamine, ammo Although there are amine salts made of nia, pyridine, picoline and the like, the salts used in the present invention are not limited by these salts. Preferred salts in the present invention include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid.
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 약학 조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제함으로써 인플라마좀 매개 염증성 질환의 예방 또는 치료 효과가 탁월하다. 구체적으로, 본 발명의 실험예에서는 마우스 및 사람의 대식 세포를 대상으로 Nigericin 또는 ATP에 의해 유도된 인플라마좀의 활성과 그에 따른 IL-1β 생성이 본 발명의 약학 조성물에 의해 효과적으로 억제됨을 확인하였다(도 1 내지 도 8).A pharmaceutical composition containing the compound represented by Formula 1 or Formula 2 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient effectively inhibits the production of IL-1β according to the activation of inflammasomes, thereby causing an inflammasome-mediated inflammatory disease. The prophylactic or therapeutic effect is excellent. Specifically, in the experimental example of the present invention, it was confirmed that the activity of inflamasome induced by Nigericin or ATP and IL-1β production in mice and human macrophages was effectively inhibited by the pharmaceutical composition of the present invention. (FIGS. 1-8).
본 발명에서 용어 “인플라마좀(inflammasome)”은 골수성세포(myeoloid cell)의 세포질에 존재하며 선천적 면역 수용체(NOD-like receptor), ASC 단백질 및 caspase-1으로 이루어진 단백질 복합체로써 세포의 감염이나 스트레스 등 선천성 면역 방어체계와 관련된 염증성 사이토카인의 전구체인 pro-IL-1β를 성숙한 IL-1β으로 전화시키는 데에 관여한다. NLRP1, NLRP3, NLRC4, AIM4 등으로 구성된 인플라마좀이 있으며 이중 NLRP3 인플라마좀은 다양한 자가면역질환의 발병과 연관되어있음이 보고되었다.In the present invention, the term “inflammasome” is present in the cytoplasm of myeloid cells and is a protein complex consisting of innate immune receptors (NOD-like receptor), ASC protein and caspase-1. It is involved in the conversion of pro-IL-1β, a precursor of inflammatory cytokines associated with innate immune defenses, to mature IL-1β. Inflamasomes composed of NLRP1, NLRP3, NLRC4, AIM4, etc., of which NLRP3 inflamasomes have been reported to be associated with the development of various autoimmune diseases.
또한, 증가된 IL-1β는 인간의 선천적 또는 후천적 질병과 관계 있으며, IL-1β의 길항제나 수용체가 일부 질병의 성공적인 치료에 도움이 된다는 사실이 밝혀졌다. 따라서, 부적절한 인플라마좀의 작용과 선천적 및 후천적 염증성 질환의 관련성이 면역반응 조절기작에서 중요하게 부각되고 있다. 본 발명의 조성물은 이러한 인플라마좀의 활성을 억제함으로써, 염증성 사이토카인 IL-1β의 분비 양을 효과적으로 조절할 수 있어 염증성 질환의 예방 및 치료에 탁월한 효과를 갖는다.In addition, increased IL-1β is associated with human or acquired disease in humans, and it has been found that antagonists or receptors of IL-1β may help in successful treatment of some diseases. Therefore, the relationship between inadequate inflamasome action and congenital and acquired inflammatory diseases is important in the immune response control mechanism. The composition of the present invention can effectively regulate the amount of inflammatory cytokine IL-1β secreted by inhibiting the activity of the inflamasome, has an excellent effect in the prevention and treatment of inflammatory diseases.
그러므로, 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 약학 조성물은 인플라마좀 매개 염증성 질환의 예방 또는 치료에 유용하게 사용될 수 있다.Therefore, the pharmaceutical composition containing the compound represented by Formula 1 or Formula 2 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be usefully used for the prevention or treatment of inflammasome mediated inflammatory diseases.
본 발명에서 용어 “인플라마좀 매개 염증성 질환”은 인플라마좀 (예컨대, NLRP3 인플라마좀)의 활성을 억제함으로써 예방, 개선 또는 치료 효과를 기대할 수 있는 상태 또는 질환으로, 인플라마좀 매개 염증성 질환의 구체적 종류는 당업계에 널리 공지되어 있다.As used herein, the term “inflammasome-mediated inflammatory disease” refers to a condition or disease in which a prophylactic, ameliorating, or therapeutic effect can be expected by inhibiting the activity of an inflamasome (eg, NLRP3 inflamasome). Specific kinds of are well known in the art.
예컨대, 문헌[Shao, Bo-Zong, et al. Frontiers in pharmacology 6 (2015): 262.]은 NLRP3 인플라마좀이 대사성 질환, 다발성 경화증(multiple sclerosis), 염증성 장질환, 크리오피린 관련 주기적 증후군(cryopyrin-associated periodic syndrome; CAPS), 기타 자가면역질환 및 자가염증성 질환 등의 개시 및 진행과 관련되어 있음을 개시한다. 상기 문헌은 MCC950(디아실술포닐우레아-함유 화합물), β-하이드록시부티레이트(BHB), type I 인터페론 및 IFN-β와 같은 NLRP3 인플라마좀 억제제가 IL-1β 분비 억제를 통해 관련 질환의 치료에 사용될 수 있음을 시사한다.See, eg, Shao, Bo-Zong, et al. Frontiers in pharmacology 6 (2015): 262.] indicate that the NLRP3 inflamasome is a metabolic disease, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic syndrome (CAPS), and other autoimmune diseases. And the initiation and progression of autoinflammatory diseases and the like. This document suggests that NLRP3 inflammasome inhibitors such as MCC950 (diacylsulfonylurea-containing compound), β-hydroxybutyrate (BHB), type I interferon and IFN-β may be used to treat related diseases through inhibition of IL-1β secretion. Suggests that it can be used.
문헌[Coll, Rebecca C., et al. Nature medicine 21.3 (2015): 248.]은 NLRP 인플라마좀의 비정상적 활성화가 CAPS와 같은 유전 질환 및 다발성 경화증, 제2형 당뇨병 및 죽상동맥경화증(atherosclerosis) 같은 복합 질환과 연관되어 있음을 개시한다. NLRP3 억제제인 MCC950은 AIM2, NLRC4 또는 NLRP1 활성이 아닌 NLRP3의 활성을 특이적으로 억제하여 canonical 및 non-canonical NLRP3 활성을 차단하고, IL-1β 생성을 억제하여 다발성 경화증의 질환 모델인 자가면역성 뇌척수염(encephalomyelitis; EAE)의 증상을 완화하고, CAPS 마우스 모델의 사후 치사율을 회복시키며, 머켈-웰스(Muckel-Wells) 증후군을 앓는 개체의 ex vivo 샘플에 활성을 갖는 등 자가염증 및 자가면역성 질환을 포함하는 NLRP3-관련 질환의 치료제임을 시사한다.See Coll, Rebecca C., et al. Nature medicine 21.3 (2015): 248. discloses that abnormal activation of NLRP inflamasomes is associated with genetic diseases such as CAPS and complex diseases such as multiple sclerosis, type 2 diabetes and atherosclerosis. MCC950, an NLRP3 inhibitor, specifically inhibits the activity of NLRP3 but not AIM2, NLRC4 or NLRP1 activity, blocks canonical and non-canonical NLRP3 activity, and inhibits IL-1β production, thereby autoimmune encephalomyelitis, a disease model of multiple sclerosis ( relieving symptoms of encephalomyelitis (EAE), restoring the postmortal lethality of the CAPS mouse model, and having an activity on ex vivo samples of individuals with Muckel-Wells syndrome, including autoinflammatory and autoimmune diseases Suggests that it is a therapeutic agent for NLRP3-related diseases.
문헌[Ozaki, Ema, Matthew Campbell, and Sarah L. Doyle. Journal of inflammation research 8 (2015): 15.]은 NLRP3 인플라마좀이 알츠하이머병, 죽상동맥경화증, 대사 증후군, 및 연령관련 황반변성(age-related macular degeneration; AMD) 등과 연관되어 있으며, 인플라마좀의 최종 산물인 성숙한 IL-1β의 억제(예컨대, IL-1β에 대한 항체)가 NLRP3 인플라마좀 관련 질환에 대한 치료적 전략임을 개시한다.Ozaki, Ema, Matthew Campbell, and Sarah L. Doyle. Journal of inflammation research 8 (2015): 15.] shows that NLRP3 inflamasomes are associated with Alzheimer's disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration (AMD). Inhibition of mature IL-1β (eg, antibodies against IL-1β), which is the end product, is a therapeutic strategy for NLRP3 inflamasome related diseases.
문헌[Yang, Gabsik, Hye Eun Lee, and Joo Young Lee. Scientific reports 6 (2016): 24399.]은 NLRP3 인플라마좀의 약리학적 억제가 고지방 식단으로부터 유도된 비알코올성 지방간 질환을 억제할 수 있음을 시사한다.Yang, Gabsik, Hye Eun Lee, and Joo Young Lee. Scientific reports 6 (2016): 24399.] suggest that pharmacological inhibition of NLRP3 inflamasomes can inhibit nonalcoholic fatty liver disease induced from a high fat diet.
문헌[Mao, Zhijuan, et al. Neurochemical research 42.4 (2017): 1104-1115.]은 NLRP3 인플라마좀이 파킨슨병의 발병과 연관되어 있고, NLRP3/caspase-1/IL-1β 다운스트림 경로의 억제가 파킨슨병의 발병을 완화할 수 있음을 개시한다.See Mao, Zhijuan, et al. Neurochemical research 42.4 (2017): 1104-1115.] Has shown that NLRP3 inflammasomes are associated with the development of Parkinson's disease, and that inhibition of the NLRP3 / caspase-1 / IL-1β downstream pathway may mitigate the development of Parkinson's disease. It is started.
문헌[Lee, Hye Eun, et al. Scientific reports 6 (2016): 38622.]은 통풍성 관절염이 NLRP3 인플라마좀의 활성을 유도하는 요산 결정의 침착에 의해 발생하며, 통풍성 관절염을 포함하는 다양한 대사성 질환의 발병과 밀접하게 연관되어 있음을 개시한다.Lee, Hye Eun, et al. Scientific reports 6 (2016): 38622.] disclose that gouty arthritis is caused by the deposition of uric acid crystals that induce the activity of NLRP3 inflamasomes and is closely associated with the development of various metabolic diseases, including gouty arthritis. do.
상기 문헌들에서 확인할 수 있듯이, 인플라마좀의 활성을 억제하여 IL-1β 생성을 억제하는 인플라마좀 억제 활성을 갖는 물질이 다양한 질환을 치료할 수 있는 방법이라는 점이 당업계에 공지되어 있다.As can be seen in the above documents, it is known in the art that a substance having an inflamasome inhibitory activity that inhibits the activity of the inflamasome to inhibit IL-1β production is a method for treating various diseases.
본 발명에서 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 함유하는 약학적 조성물은 인플라마좀 활성을 억제한다. 본 발명의 일 실시양태에서, 상기 인플라마좀은 NLRP3(NOD-like receptor family, pyrin domain-containing 3)이다.In the present invention, the pharmaceutical composition containing the ginsenoside compound represented by Formula 1 or Formula 2 inhibits inflammasome activity. In one embodiment of the invention, the inflammasome is NLRP3 (NOD-like receptor family, pyrin domain-containing 3).
본 발명에서 인플라마좀 매개 염증성 질환은 자가 염증성 질환, 신경 염증성 질환 및 대사성 질환으로 구성된 군으로부터 선택되는 1종 이상의 질환을 포함한다. Inflamasome mediated inflammatory diseases in the present invention include at least one disease selected from the group consisting of autoinflammatory diseases, neuroinflammatory diseases and metabolic diseases.
본 발명에서 “자가 염증성 질환”이란 자가면역 질환과는 달리 자가항체나 항원특이 T세포가 발견되지 않는 상태에서 전신 염증이 자주 반복되는 양상을 보이는 질환 군을 의미하며, 상기 자가 염증성 질환은 머클-웰스 증후군(Muckle-Wells syndrome; MWS), 성인성 지연성 자가면역 당뇨병(LADA), 가족성 한랭 자가면역성 증후군(FCAS), 크리오피린-관련 주기성 증후군(CAPS), 신생아-발병 다기관 염증성 증후군(NOMID), 만성 영아 신경 피부 관절(CINCA) 증후군, 가족성 지중해열(FMF), 전신 발병 소아 특발성 관절염(SJIA), 소아 류마티스 관절염, 성인 류마티스 관절염, 연령관련 황반변성, 아토피성 피부염 및 건선으로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않으며 당업계에 공지된 기타의 자가 염증성 질환을 포함한다.In the present invention, "auto-inflammatory disease" refers to a group of diseases in which systemic inflammation is frequently repeated in the state where autoantibodies or antigen-specific T cells are not found, unlike autoimmune diseases. Welles-Wells syndrome (MWS), adult delayed autoimmune diabetes (LADA), familial cold autoimmune syndrome (FCAS), cryopyrin-related periodic syndromes (CAPS), neonatal-onset multicenter inflammatory syndrome (NOMID) ), Chronic infant nerve skin joint (CINCA) syndrome, familial Mediterranean fever (FMF), systemic onset childhood idiopathic arthritis (SJIA), juvenile rheumatoid arthritis, adult rheumatoid arthritis, age-related macular degeneration, atopic dermatitis and psoriasis It may be any one or more selected from, but includes, but is not limited to, other autoinflammatory diseases known in the art.
본 발명에서 “신경 염증성 질환”이란 신경계의 염증에 의하여 발생하는 질환이라면 제한 없이 포함할 수 있으며, 상기 신경 염증성 질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 크로이츠펠트야콥병, 다발성 경화증, 근위축성 측삭 증후군, 미만성루이소체병, 백색질뇌염, 측두엽간질, 및 염증성 척추손상으로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않으며 당업계에 공지된 기타의 신경 염증성 질환을 포함한다.In the present invention, "neuro-inflammatory disease" may include without limitation any disease caused by inflammation of the nervous system, the neuro-inflammatory disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfeldt-Jakob disease, multiple sclerosis, muscular dystrophy And may be one or more selected from the group consisting of lateral syndrome, diffuse leukopathy, white encephalitis, temporal lobe epilepsy, and inflammatory spinal injury, including but not limited to other neuro-inflammatory diseases known in the art.
본 발명에서 “대사성 질환”이란 생체 내 물질대사 장애에 의해서 발생하는 질환을 총칭하는 것으로, 상기 대사성 질환은 비만, 제2형 당뇨병, 고지혈증, 고콜레스테롤증, 죽상동맥경화증, 비알코올성지방간(NAFLD) 및 비알코올성지방간염(NASH)으로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않으며 당업계에 공지된 기타의 대사성 질환을 포함한다.In the present invention, "metabolic disease" refers to diseases caused by metabolic disorders in vivo, the metabolic disease is obesity, type 2 diabetes, hyperlipidemia, hypercholesterolosis, atherosclerosis, nonalcoholic fatty liver (NAFLD) And non-alcoholic steatohepatitis (NASH), but may be any one or more selected from the group consisting of, and other metabolic diseases known in the art.
본 발명에서 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 인플라마좀(inflammasome) 매개 염증 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.The term "prevention" in the present invention means any action that inhibits or delays the development of inflammasome mediated inflammatory disease by administration of the pharmaceutical composition according to the present invention.
본 발명에서 용어 “치료”란 본 발명에 따른 약학적 조성물의 투여에 의해 인플라마좀(inflammasome) 매개 염증 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" refers to any action in which symptoms for inflammasome-mediated inflammatory diseases improve or benefit altered by administration of the pharmaceutical composition according to the invention.
본 발명의 약학 조성물은 투여를 위해서 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염 외에 추가로 약학적으로 허용되는 담체를 1 종 이상 더 포함할 수 있다. 약학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA 에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, if necessary. And other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Thus, the compositions of the present invention may be patches, solutions, pills, capsules, granules, tablets, suppositories, and the like. These formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA and formulated into various formulations depending on the individual disease or component. Can be.
본 발명의 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있다.The pharmaceutical compositions of the invention may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method.
본 명세서에 있어서, 용어 “경구 투여”는 병리학적 증상을 호전하기 위한 약제를 입으로 주입하는 방법이며, 본 명세서에 있어서, 용어 “비경구투여”는 입으로 투여하는 것을 제외한 피하, 근육내, 정맥, 튜브를 이용한 복강내로 투여하는 방법을 의미한다.As used herein, the term “oral administration” refers to a method of injecting a medicament for improving pathological symptoms. In this specification, the term “parenteral administration” refers to subcutaneous, intramuscular, Means to administer intraperitoneally by intravenous, tube.
경구 투여를 위한 고형제제에는 산제, 과립제, 정제, 캡슐제, 연질캡슐제, 환제 등이 포함된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액상제, 유제, 시럽제, 에어로졸 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid form preparations for oral administration include powders, granules, tablets, capsules, soft capsules, pills and the like. Liquid preparations for oral administration include suspensions, solvents, emulsions, syrups, aerosols, and other excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. This may be included.
비경구 투여를 위한 제제로는 각각 통상의 방법에 따라 멸균된 수용액, 액상제, 비수성용제, 현탁제, 에멀젼, 점안제, 안연고제, 시럽, 좌제, 에어로졸 등의 외용제 및 멸균 주사제제의 형태로 제형화하여 사용될 수 있으며, 바람직하게는 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 안연고제, 점안제, 파스타제 또는 카타플 라스마제의 약제학적 조성물을 제조하여 사용할 수 있으나, 이에 한정되는 것은 아니다. 국소 투여의 조성물은 임상적 처방에 따라 무수형 또는 수성형일 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration may be formulated in the form of sterile aqueous solutions, liquids, non-aqueous solutions, suspensions, emulsions, eye drops, ophthalmic ointments, syrups, suppositories, aerosols, etc., and sterile injectables, respectively, according to conventional methods. It can be used to prepare a pharmaceutical composition of creams, gels, patches, sprays, ointments, warnings, lotions, linings, eye ointments, eye drops, pasta or cataplasma However, the present invention is not limited thereto. Compositions of topical administration may be anhydrous or aqueous, depending on the clinical prescription. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 약학 조성물의 바람직한 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하며, 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물의 일일 투여량은 약 1 내지 1000 ㎎/㎏ 이고, 바람직하게는 5 내지 100 ㎎/㎏이며, 하루 일회 내지 수회에 나누어 투여할 수 있다.Preferred dosages of the pharmaceutical compositions of the present invention vary in the range depending on the weight, age, sex, health condition, diet, time of administration, administration method, excretion rate and severity of the disease, etc., and may be appropriately selected by those skilled in the art. Can be. The daily dosage of the compound represented by Formula 1 or Formula 2 of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and may be administered once to several times a day.
본 발명의 약학 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 각각 함유하거나, 또는 상기 화학식 1로 표시되는 진세노사이드 화합물과 화학식 2로 표시되는 진세노사이드 화합물을 모두 함유할 수 있다. 본 발명의 약학 조성물이 상기 화학식 1 및 화학식 2로 표시되는 화합물을 모두 함유할 경우, 화학식 1로 표시되는 화합물과 화학식 2로 표시되는 화합물을 1:10 내지 10:1의 중량비로 함유할 수 있다.The pharmaceutical composition of the present invention may each contain a ginsenoside compound represented by Formula 1 or Formula 2, or may contain both a ginsenoside compound represented by Formula 1 and a ginsenoside compound represented by Formula 2. have. When the pharmaceutical composition of the present invention contains both the compounds represented by Formula 1 and Formula 2, the compound represented by Formula 1 and the compound represented by Formula 2 may contain 1:10 to 10: 1 by weight. .
본 발명의 상기 약학적 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 이의 약학적으로 허용되는 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상 더 포함할 수 있다. The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicaments in addition to the ginsenoside compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof.
인플라마좀Inflamasome
매개 염증성 질환의 예방 또는 치료방법 How to prevent or treat mediated inflammatory diseases
본 발명은 치료학적으로 유효한 양의 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 이의 약학적으로 허용되는 염을 치료가 필요한 대상체에게 투여하여 인플라마좀 매개 염증성 질환을 예방 또는 치료하는 방법을 제공한다. The present invention provides a method for preventing or treating inflammasome-mediated inflammatory diseases by administering to a subject in need thereof a therapeutically effective amount of a ginsenoside compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof. to provide.
본 발명에서 용어 “치료가 필요한 대상체”는, 인간을 포함한 포유동물을 의미하고, 용어 “투여”는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미한다.As used herein, the term “subject in need” refers to a mammal, including a human, and the term “administration” means providing a patient with a substance in any suitable manner.
본 발명에서 사용되는 “치료학적으로 유효한 양”이라는 용어는 인플라마좀 매개 염증성 질환의 예방 또는 치료에 유효한 상기 화학식 1 또는 화학식 2로 표시되는 화합물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상 완화를 유도하는 양을 포함한다.As used herein, the term “therapeutically effective amount” refers to the amount of the compound represented by Formula 1 or Formula 2 effective for the prevention or treatment of inflammasome mediated inflammatory diseases, which is the disease or disorder being treated. Includes amounts that induce symptomatic relief.
또한, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염을 인간을 포함하는 포유류에 투여하여 인플라마좀을 억제하는 방법을 제공한다.The present invention also provides a method for inhibiting inflamasomes by administering a compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof to a mammal including a human.
본 발명의 인플라마좀 매개 염증성 질환의 예방 또는 치료 방법은 상기 화학식 1 또는 화학식 2로 표시되는 화합물을 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서, 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성(nature)과 심각도, 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령, 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한, 본 발명의 인플라마좀 매개 염증성 질환의 예방 또는 치료 방법은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물과 함께 시너지 효과 또는 보조적 효과를 나타낼 수 있다.A method for preventing or treating an inflamasome mediated inflammatory disease of the present invention, by administering a compound represented by the formula (1) or (2), not only treats the disease itself before the onset of the indication, but also includes inhibiting or avoiding the indication thereof. do. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dose will vary depending on the age, weight and response of the individual patient. Appropriate dosage regimens can be readily selected by those of ordinary skill in the art that naturally take these factors into account. In addition, the method for preventing or treating inflamasome-mediated inflammatory diseases of the present invention may be performed by administering a therapeutically effective amount of an additional active agent to help treat the disease together with the ginsenoside compound represented by Formula 1 or Formula 2. It may further include, an additional active agent may exhibit a synergistic or auxiliary effect with the ginsenoside compound represented by Formula 1 or Formula 2.
인플라마좀Inflamasome
매개 염증성 질환의 치료용 약제의 제조를 위한 용도 Use for the manufacture of a medicament for the treatment of mediated inflammatory diseases
본 발명은 또한 인플라마좀 매개 염증성 질환의 치료용 약제의 제조를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공한다. 약제의 제조를 위한 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. The present invention also provides the use of a compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of inflamasome mediated inflammatory disease. The ginsenoside compound represented by Formula 1 or Formula 2 for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier, and the like, and may be prepared as a complex formulation with other active agents to have a synergistic effect of the active ingredients. Can be.
인플라마좀Inflamasome
매개 염증성 질환의 치료를 위한 용도 Use for the treatment of mediated inflammatory diseases
본 발명은 또한 인플라마좀 매개 염증성 질환의 예방 또는 치료를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공한다. 인플라마좀 매개 염증성 질환의 예방 또는 치료 용도로 사용하기 위한 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.The invention also provides the use of a compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the prevention or treatment of inflammasome mediated inflammatory diseases. The ginsenoside compound represented by Formula 1 or Formula 2 for use in the prophylaxis or treatment of inflamasome-mediated inflammatory diseases may be mixed with an acceptable adjuvant, diluent, carrier, etc. It can be prepared with a synergistic action of the active ingredients.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.The matters mentioned in the uses, compositions and methods of treatment of the invention apply equally unless they contradict each other.
인플라마좀Inflamasome
매개 염증성 질환의 예방 또는 개선용 식품 조성물 Food composition for the prevention or improvement of mediated inflammatory diseases
본 발명은 또한, 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 그의 염을 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or ameliorating an inflamasome-mediated inflammatory disease containing a ginsenoside compound represented by Formula 1 or Formula 2 or a salt thereof.
본 발명에 따른 인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제함으로써 인플라마좀 매개 염증성 질환의 예방 또는 개선 효과가 탁월하다.Food composition for the prevention or improvement of inflammasome-mediated inflammatory diseases according to the present invention is excellent in preventing or improving the effect of inflamasome-mediated inflammatory diseases by effectively inhibiting IL-1β production according to the activation of the inflamasome.
상기 화학식 1 또는 화학식 2는 위에서 정의한 바와 같다. Formula 1 or Formula 2 is as defined above.
본 발명에서 사용되는 용어 “개선”은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term "improvement" refers to any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
본 발명의 일 실시양태에서, 식품 조성물은 건강기능식품 또는 건강보조식품일 수 있다.In one embodiment of the invention, the food composition may be a nutraceutical or dietary supplement.
본 발명에서 사용되는 용어, "건강식품 (health food)"은 일반 식품에 비해 적극적인 건강 유지나 증진 효과를 가지는 식품을 의미하고, "건강보조식품 (health supplement food)"은 건강 보조 목적의 식품을 의미한다. 경우에 따라, 기능성 식품, 건강식품, 건강보조식품의 용어는 호용된다. 상 기 식품은 유용한 효과를 얻기 위하여 정제, 캅셀, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다.As used herein, the term "health food" means a food having an active health maintenance or promotion effect as compared to general food, and "health supplement food" means a food for health supplement purposes. do. In some cases, the terms functional food, health food, and dietary supplement are used. The food may be prepared in various forms such as tablets, capsules, powders, granules, liquids, and pills to obtain useful effects.
본 발명에서 사용되는 용어, "기능식품 (functional food)"은 특정보건용 식품 (food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다.The term "functional food" used in the present invention is the same term as a food for special health use (FOSHU), and the medicine, medical processing to be processed efficiently appear in addition to the nutritional control function Means foods that are highly effective.
본 발명의 건강기능식품의 구체적인 예로, 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 이용하여 농산물의 특성을 살려 변형시키는 동시에 저장성을 좋게 한 가공식품을 제조할 수 있다.As a specific example of the health functional food of the present invention, by using the ginsenoside compound represented by the formula (1) or formula (2), it is possible to produce a processed food with improved storage characteristics while modifying the characteristics of agricultural products.
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제할 뿐만 아니라, 세포독성이 없으며 Nigericin-유도 인플라마좀 및 ATP-유도 인플라마좀 제어 효능이 뛰어나 인플라마좀 매개 염증성 질환의 예방 또는 치료 효과가 탁월하다. 따라서, 본 발명의 조성물은 다양한 NLRP3 인플라마좀 매개 염증성 질환의 예방, 개선 또는 치료제로 유용하게 사용될 수 있다.The composition containing the compound represented by Formula 1 or Formula 2 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient not only effectively inhibits IL-1β production due to activation of inflammasomes, but also has no cytotoxicity. It is excellent in controlling Nigericin-induced inflamasomes and ATP-induced inflamasomes, and is excellent in preventing or treating inflamesome-mediated inflammatory diseases. Therefore, the composition of the present invention can be usefully used as a prophylactic, ameliorating or treating agent for various NLRP3 inflamasome mediated inflammatory diseases.
도 1은 본 발명의 화합물이 인플라마좀 활성화에 미치는 영향을 나타낸다.1 shows the effect of the compounds of the present invention on inflammasome activation.
도 2는 본 발명의 화합물의 세포 독성 측정 결과를 나타낸다.2 shows the cytotoxicity measurement results of the compounds of the present invention.
도 3은 본 발명의 화합물의 농도별 Nigericin유도 IL-1β 생성 억제 효과를 나타낸다.Figure 3 shows the effect of inhibiting the production of Nigericin-induced IL-1β according to the concentration of the compound of the present invention.
도 4는 본 발명의 화합물의 농도별 ATP-유도 IL-1β 생성 억제 효과를 나타낸다.Figure 4 shows the inhibitory effect of ATP-induced IL-1β production by concentration of the compound of the present invention.
도 5는 인간 대식세포주에서 본 발명의 화합물에 의한 Nigericin유도 IL-1β 생성 억제 효과를 나타낸다.Figure 5 shows the inhibitory effect of Nigericin-induced IL-1β production by the compounds of the present invention in human macrophage lines.
도 6은 본 발명의 화합물에 의한 Nigericin유도 IL-1β 생성 억제 IC
50을 나타낸다.6 shows a Nigericin induced IL-1β inhibition IC 50 generated by the compounds of the present invention.
도 7은 인간 대식세포주에서 본 발명의 화합물에 의한 ATP유도 IL-1β 생성 억제 효과를 나타낸다.Figure 7 shows the effect of inhibiting ATP-induced IL-1β production by a compound of the present invention in human macrophage lines.
도 8은 본 발명의 화합물에 의한 ATP유도 IL-1β 생성 억제 IC
50를 나타낸다.Figure 8 shows the ATP induced IL-1β IC 50 generates inhibition by compounds of the invention.
이하, 본 발명을 하기 실시예를 통하여 보다 상세하게 설명한다. 그러나 실시예는 본 발명을 설명하기 위해 예시적으로 제공되었을 뿐, 본 발명의 범위가 실시예의 기재에 한정되지 않는다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the examples are provided by way of example only to illustrate the invention, the scope of the invention is not limited to the description of the examples.
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실시예Example
> 실험 재료 및 방법> Experimental Materials and Methods
1. 진세노사이드 화합물의 준비1. Preparation of Ginsenoside Compound
실험에 사용한 화학식 1 또는 화학식 2로 표시되는 화합물은 에이스엠자임으로부터 순도 98% 이상의 표준물질을 구입하여 사용하였다.The compound represented by the formula (1) or formula (2) used in the experiment was used by purchasing a standard material with a purity of 98% or more from AceMzyme.
2. 세포 배양2. Cell Culture
문헌[Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1. J Immunol, 186(1): 499-507.] 등에 공지된 방법에 따라, C57BL/6 생쥐로부터 골수 및 골수 유래 초대 마이크로파지(bone marrow-derived primary macrophages; BMDMs)를 분리하였다. THP-1세포는 ATCC(Manassas, US)로부터 구입하였다. Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1. J Immunol, 186 (1): 499-507.], Bone marrow and bone marrow from C57BL / 6 mice Derived primary microphages (bone marrow-derived primary macrophages (BMDMs)) were isolated. THP-1 cells were purchased from ATCC (Manassas, US).
3. 시약3. Reagent
대장균으로부터 정제된 LPS는 List Biological Laboratory Inc (Hornby, Canada)로부터 얻어 무독소 용액에 용해시켜 사용하였다. 실험에 사용된 진세노사이드는 98%이상의 고순도 물질을 사용하였다.LPS purified from E. coli was obtained from List Biological Laboratory Inc (Hornby, Canada) and dissolved in a non-toxic solution. The ginsenosides used in the experiment used high purity materials of more than 98%.
ATP 및 Nigericin은 Invivogen (San Diego, USA)에서 구입하였으며, IL-1β는 R&D Systems (Minneapolis, MN, USA)에서 구입하였다.ATP and Nigericin were purchased from Invivogen (San Diego, USA) and IL-1β was purchased from R & D Systems (Minneapolis, MN, USA).
4. 실험방법4. Experimental method
ELISA 실험을 위해, 공지 문헌[Levels of IL-1β in cell culture supernatants were determined with an ELISA kit (IL-1β: R&D Systems) according to the manufacturer's instructions]에 기재된 방법을 사용하였다. 세포 배양 상층액 중 IL-1β 수준은 ELISA 키트 (IL-1β : R & D Systems)를 사용하여 제조자의 지시에 따라 결정 하였다.For ELISA experiments, the methods described in the known levels of IL-1β in cell culture supernatants were determined with an ELISA kit (IL-1β: R & D Systems) according to the manufacturer's instructions were used. IL-1β levels in cell culture supernatants were determined according to the manufacturer's instructions using an ELISA kit (IL-1β: R & D Systems).
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실험예Experimental Example
1> 세포 시스템에서 1> in cell system
인플라마좀Inflamasome
제어 효능을 가진 인삼의 진세노사이드 물질 발굴 Discovery of ginsenosides from ginseng with controlled efficacy
인삼의 진세노사이드 물질이 인플라마좀 활성화에 미치는 영향을 분석하고자, 다양한 진세노사이드 화합물을 마우스 대식세포에 처리하고, 인플라마좀 활성화제인 Nigericin을 처리하였다. Nigericin은 세포 K
+ 이온의 방출을 유도하여 NLRP3 인플라마좀의 활성을 유도하며, NLRP3 인플라마좀의 활성화는 pro-caspase-1을 caspase-1으로 활성화시켜, pro-IL-1β를 성숙한(mature) IL-1β로 절단한다는 것이 공지되어 있다. 본 실험예에서는 세포 배양액 내 성숙한 IL-1β의 양을 ELISA로 측정함으로써 NLRP3 인플라마좀의 활성화 정도를 확인하였다.To analyze the effects of ginsenosides of ginseng on inflamasome activation, various ginsenoside compounds were treated in mouse macrophages and treated with nigericin, an inflamasome activator. Nigericin induces the release of cellular K + ions to induce the activity of NLRP3 inflammasomes. Activation of NLRP3 inflamasomes activates pro-caspase-1 to caspase-1, which leads to the proliferation of pro-IL-1β. Is known to cleave with IL-1β. In this experimental example, the degree of activation of NLRP3 inflamasome was confirmed by measuring the amount of mature IL-1β in cell culture by ELISA.
구체적으로, 화학식 1 또는 화학식 2의 화합물을 100 μg/ml 농도로 마우스 대식 세포에 처리한 다음, Nigericin 10 μM을 처리하고 16시간 뒤 IL-1β의 농도를 측정하여, NLRP3 작용제인 Nigericin에 의하여 유도되는 성숙한 IL-1β 생성에 미치는 영향을 조사하였다.Specifically, the compound of Formula 1 or Formula 2 was treated with mouse macrophages at a concentration of 100 μg / ml, and then treated with 10 μM of Nigericin, and then measured at a concentration of IL-1β 16 hours, induced by Nigericin, an NLRP3 agonist. The effect on the production of mature IL-1β was investigated.
그 결과, 본 발명에 따른 화학식 1 및 화학식 2의 화합물은 Nigericin 처리에 의해 IL-1β가 유도된 비히클 대비(200 pg/ml), IL-1β 생성을 50% 이상 억제하는 효과가 있음을 확인하였다 (도 1).As a result, it was confirmed that the compounds of Formula 1 and Formula 2 according to the present invention have an effect of inhibiting the production of IL-1β by 50% or more compared to the vehicle induced with IL-1β (200 pg / ml) by Nigericin treatment. (FIG. 1).
상기 실험예를 통해, 본 발명의 조성물은 우수한 NLRP3 인플라마좀 억제 활성을 나타냄으로써 NLRP3 인플라마좀 관련 질환의 예방, 개선 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, it was confirmed that the composition of the present invention can be used as a prophylactic, ameliorating or treating agent of NLRP3 inflamasome-related diseases by showing an excellent NLRP3 inflamasome inhibitory activity.
<실험예 2> 화학식 1 또는 화학식 2 화합물의 세포 독성 측정Experimental Example 2 Cytotoxicity of Chemical Formula 1 or Chemical Formula 2
실험예 1에서 확인한 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물의 IL-1β 생성 억제 효과가 세포 사멸에 의한 IL-1β 생성 억제 효과인지 확인하기 위하여 대식 세포에 25 μg/ml, 50 μg/ml, 100 μg/ml 농도의 상기 화합물을 16시간 처리한 후 MTT 분석을 통해 세포 생존율을 측정하였다.25 μg / ml, 50 μg / in macrophages to determine whether the inhibitory effect of the IL-1β production of the compound represented by the formula (1) or formula (2) of the present invention confirmed in Experiment 1 Cell viability was measured by MTT assay after 16 hours treatment of the compound at 100 ml / ml concentration.
그 결과, 본 발명의 화학식 1 또는 화학식 2 화합물은 처리농도 100 ㎍/ml에서 세포 생존율에 유의미한 영향을 미치지 않아 세포독성이 없는 것을 확인하였다 (도 2).As a result, the compound of Formula 1 or Formula 2 of the present invention did not significantly affect the cell viability at the treatment concentration of 100 ㎍ / ml did not have cytotoxicity (Fig. 2).
상기 실험예를 통해, 본 발명의 조성물은 부작용을 갖지 않는 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, it was confirmed that the composition of the present invention can be used as a prophylactic, ameliorating, or treating agent of an excellent NLRP3 inflamasome-related disease having no side effects.
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실험예Experimental Example
3> 화학식 1 또는 화학식 2 화합물의 3> of the compound of formula 1 or formula 2
NigericinNigericin
-유도 -Judo
인플라마좀Inflamasome
제어 효능을 농도별 확인 Check control efficacy by concentration
Nigericin에 노출된 단핵 세포는 IL-1β 활성화가 유도되고 활성화된 IL-1β는 NLRP3 염증조절복합체(인플라마좀)의 생성을 유도하는 것이 보고되었다. 이에 따라, Nigericin에 의해 유도되는 NLRP3 인플라마좀에 대한 화학식 1 또는 화학식 2의 화합물의 효과를 규명하기 위해 도 3에 나타난 것과 같은 과정으로 골수 유래 대식세포인 BMDM에서 실험을 수행하였다.Mononuclear cells exposed to nigericin induced IL-1β activation and activated IL-1β induced the production of NLRP3 inflammatory regulatory complexes (inflammasomes). Accordingly, experiments were performed on BMDM, a bone marrow-derived macrophage, in the same process as shown in FIG. 3 to identify the effect of the compound of Formula 1 or Formula 2 on NLRP3 inflamasome induced by Nigericin.
먼저, LPS에 의한 TLR-4의 자극은 pro IL-1β및 NLRP3 전사를 유도하기 때문에, LPS의 가능성을 제외하기 위해 PBS로 세척하고 LPS가 사전에 처리된 BMDM 세포를 25, 50, 100 ㎍/ml 농도의 화학식 1 또는 화학식 2의 화합물이 포함된 조건에서 1시간 동안 사전 배양한 후 10 μM Nigericin으로 자극하고 16시간 후 BMDM 세포를 수확하여 ELISA 분석을 수행하였다.First, since stimulation of TLR-4 by LPS induces pro IL-1β and NLRP3 transcription, BMDM cells washed with PBS and pretreated with LPS were treated with 25, 50, 100 μg / L to exclude the possibility of LPS. ELISA analysis was performed by stimulating with 10 μM Nigericin and harvesting BMDM cells after 16 hours after pre-incubation for 1 hour in a condition containing the compound of Formula 1 or Formula 2 in ml concentration.
그 결과, Nigericin에 의해 활성화된 IL-1β는 화학식 1의 화합물에서는 100㎍/ml 농도에서 대조군에 비해 분비가 억제되었고, 화학식 2의 화합물은 50㎍/ml 및 100㎍/ml 에서 대조군에 비해 분비가 억제된 것을 확인할 수 있었다 (도 3).As a result, IL-1β activated by Nigericin was inhibited in the compound of Formula 1 at a concentration of 100 μg / ml compared to the control, and the compound of Formula 2 was secreted at 50 μg / ml and 100 μg / ml compared to the control. It was confirmed that was suppressed (FIG. 3).
상기 실험예를 통해, 화학식 1의 화합물은 100 ㎍/ml 농도로 처리시 현저한 IL-1β 분비 억제 효과가 있고 화학식 2의 화합물은 농도 의존적으로 IL-1β 분비 억제 효과가 있음을 알 수 있는바 본 발명의 조성물은 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, the compound of formula 1 has a significant inhibitory effect of IL-1β secretion when treated at a concentration of 100 ㎍ / ml and the compound of formula 2 has a concentration-dependent IL-1β secretion inhibitory effect The compositions of the invention were found to be used as a prophylactic, ameliorating, or therapeutic agent for NLRP3 inflamasome related diseases.
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실험예Experimental Example
4> 화학식 1의 화합물의 ATP-유도 4> ATP-induced compound of formula 1
인플라마좀Inflamasome
제어 효능을 농도별 확인 Check control efficacy by concentration
인플라마좀 제어 효능을 가진 활성성분을 도출하기 위하여 화학식 1 또는 화학식 2의 화합물이 NLRP3의 다른 작용제인 ATP-유도 인플라마좀 활성을 억제하는지 조사하였다. In order to derive the active ingredient with inflammasome control efficacy, it was investigated whether the compound of Formula 1 or Formula 2 inhibits ATP-induced inflammasome activity, another agent of NLRP3.
ATP에 노출된 단핵 세포는 IL-1β 활성화가 유도되고 활성화된 IL-1β는 NLRP3 염증조절복합체(인플라마좀)의 생성을 유도하는 것이 보고되었다. 이에 따라, ATP에 의해 유도되는 NLRP3 인플라마좀에 대한 화학식 1 및 화학식 2 화합물의 효과를 규명하기 위해, 도 4와 같은 과정으로 골수 유래 대식세포인 BMDM에서 실험을 수행하였다.Mononuclear cells exposed to ATP induce IL-1β activation and activated IL-1β induces the production of NLRP3 inflammatory regulatory complexes (inflammasomes). Accordingly, in order to identify the effects of the compounds of Formula 1 and Formula 2 on the NLRP3 inflamasome induced by ATP, experiments were performed on BMDM, a bone marrow-derived macrophage, in the same manner as in FIG. 4.
먼저, LPS에 의한 TLR-4의 자극은 pro IL-1β및 NLRP3 전사를 유도하기 때문에, LPS의 가능성을 제외하기 위해 PBS로 세척하고 LPS가 사전에 처리된 BMDM 세포를 25, 50, 100 ㎍/ml 농도의 화학식 1 또는 화학식 2의 화합물이 포함된 조건에서 1시간 동안 사전 배양한 후 ATP 5mM로 자극하고 2시간 뒤 BMDM 세포를 수확하여 ELISA 분석을 수행하였다.First, since stimulation of TLR-4 by LPS induces pro IL-1β and NLRP3 transcription, BMDM cells washed with PBS and pretreated with LPS were treated with 25, 50, 100 μg / L to exclude the possibility of LPS. ELISA analysis was performed by pre-incubation for 1 hour in a condition containing the compound of Formula 1 or Formula 2 in ml concentration, stimulated with ATP 5 mM, and harvesting BMDM cells 2 hours later.
그 결과, 도 4에 나타난 것처럼 ATP에 의해 활성화된 IL-1β는 실험한 모든 농도의 화학식 1 또는 화학식 2의 화합물 처리군에서 분비가 억제된 것을 확인할 수 있었다.As a result, as shown in FIG. 4, it was confirmed that IL-1β activated by ATP was suppressed in the compound treated group of the formula (1) or the formula (2) at all concentrations tested.
상기 실험예를 통해, 본 발명의 조성물은 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, it was confirmed that the composition of the present invention can be used as a prophylactic, ameliorating, or treating agent of excellent NLRP3 inflamasome-related diseases.
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실험예Experimental Example
5> 5>
화학식 1의 화합물의 인간 대식세포주인 Human macrophage line of the compound of formula 1
THPTHP
-1 세포주에서 Nigericin-유도 인플라마좀 제어 효능 확인Efficacy of Nigericin-induced Inflamasomes in the A-1 Cell Line
상기 마우스 대식세포를 이용한 실험을 통해 Nigericin-유도 인플라마좀 활성 억제 효과가 확인된 화학식 1의 화합물이 인간 대식세포주인 THP-1 세포주에서도 Nigericin-유도 인플라마좀 활성을 억제하는지를 조사하였다.Experiments using the mouse macrophages to investigate whether the compound of formula (1) confirmed that the inhibitory effect of Nigericin-induced inflammasome activity inhibits Nigericin-induced inflamasome activity in THP-1 cell line, a human macrophage line.
그 결과, 화학식 1의 화합물이 Nigericin-유도 IL-1β 분비를 25μg/ml 내지 100 μg/ml 범위에서 농도 의존적으로 억제하는 것을 확인하였다 (도 5). 또한, Nigericin-유도 IL-1β를 억제하는 화학식 1의 화합물의 IC
50 값은 31.92 ㎍/ml임을 확인하였다 (도 6).As a result, it was confirmed that the compound of Formula 1 inhibits Nigericin-induced IL-1β secretion in a concentration-dependent manner in the range of 25 μg / ml to 100 μg / ml (FIG. 5). In addition, the IC 50 value of the compound of formula 1 that inhibits Nigericin-induced IL-1β was found to be 31.92 μg / ml (FIG. 6).
상기 실험예를 통해, 본 발명의 조성물은 농도 의존적으로 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, it was confirmed that the composition of the present invention can be used as a prophylactic, ameliorating, or treating agent of a concentration-dependent excellent NLRP3 inflamasome-related disease.
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실험예Experimental Example
6> 화학식 1 또는 화학식 2의 화합물의 인간 6> human of the compound of formula 1 or formula 2
대식세포주(THP-1)에서In macrophage (THP-1)
ATP-유도 인플라마좀 제어 효능 확인 Confirmation of ATP-induced Inflamasome Control Efficacy
본 발명의 화학식 1 또는 화학식 2 화합물이 인간 대식세포주인 THP-1 세포주에서 ATP-유도 인플라마좀 활성을 억제하는지를 조사하였다. 구체적으로, IL-1β 유도를 위해 5mM의 ATP를 이용하였고, 화학식 1 및 화학식 2의 화합물은 25 μg/ml, 50 μg/ml 및 100 μg/ml 농도로 처리하였다.It was investigated whether the compound of Formula 1 or Formula 2 of the present invention inhibits ATP-induced inflammasome activity in THP-1 cell line, which is a human macrophage line. Specifically, 5 mM ATP was used for IL-1β induction, and the compounds of Formulas 1 and 2 were treated at 25 μg / ml, 50 μg / ml and 100 μg / ml concentrations.
그 결과, 화학식 1 및 화학식 2의 화합물은 모두 대조군에 비해 ATP-유도 IL-1β 분비를 효과적으로 억제하는 것을 확인하였다. 구체적으로, 화학식 1의 화합물은 농도 의존적으로 IL-1β 분비를 억제하였으나 화학식 2의 화합물은 IL-1β 분비 억제효과는 보이되 농도 의존성은 확인할 수 없었다(도 7). 또한, ATP-유도 IL-1β를 억제하는 화학식 1의 화합물의 IC
50 값은 15.38 ㎍/ml임을 확인하였다 (도 8).As a result, it was confirmed that the compounds of Formula 1 and Formula 2 both effectively inhibit ATP-induced IL-1β secretion compared to the control. Specifically, the compound of Formula 1 inhibited IL-1β secretion in a concentration-dependent manner, but the compound of Formula 2 showed IL-1β secretion inhibitory effect but could not confirm the concentration dependence (FIG. 7). In addition, the IC 50 value of the compound of Formula 1 that inhibits ATP-induced IL-1β was found to be 15.38 μg / ml (FIG. 8).
상기 실험예를 통해, 본 발명의 조성물은 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, it was confirmed that the composition of the present invention can be used as a prophylactic, ameliorating, or treating agent of excellent NLRP3 inflamasome-related diseases.
상기 실험예 1 내지 실험예 6의 결과로부터 화학식 1 또는 화학식 2의 화합물은 in-vitro에서 ATP 및 Nigericin에 의해 유도되는 IL-1β의 분비를 억제하는 효과를 나타내었으며, 이를통해 화학식 1 또는 화학식 2의 화합물이 NLRP3 인플라마좀에 의해 유도되는 IL-1β의 활성 억제를 통하여 염증반응을 억제하는 기능이 있음을 확인할 수 있으며, NLRP3 인플라마좀의 활성으로 인한 질환을 억제하는 치료제의 개발을 할 수 있다고 제안할 수 있다.From the results of Experimental Examples 1 to 6, the compound of Formula 1 or Formula 2 showed an effect of inhibiting the secretion of IL-1β induced by ATP and Nigericin in-vitro, and through this, Formula 1 or Formula 2 It can be confirmed that the compound of the NLRP3 inflammasomes induced by the inhibition of the activity of the IL-1β induced by the inflammatory response, and can be developed a therapeutic agent that suppresses the disease caused by the activity of the NLRP3 inflammasomes It can be suggested that.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 관련 기술 분야의 통상의 지식을 가진 자에게 있어 이러한 구체적인 기술은 단지 바람직한 구현예 일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구범위와 그의 등가물에 의하여 정의될 것이다.As described above in detail a specific part of the present invention, it is apparent to those skilled in the art that such a specific technology is only a preferred embodiment, which is not intended to limit the scope of the present invention. . Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제함으로써 인플라마좀 매개 염증성 질환의 예방 또는 치료 효과가 탁월하다. 따라서, 본 발명의 조성물은 다양한 NLRP3 인플라마좀 매개 염증성 질환의 예방, 개선 또는 치료제로 유용하게 사용될 수 있으므로 관련된 의약 및 식품 산업 분야에서 유용하게 이용될 것으로 기대된다.A composition containing the compound represented by Formula 1 or Formula 2 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient effectively inhibits the production of IL-1β by activation of inflammasomes, Excellent prophylactic or therapeutic effect. Therefore, the composition of the present invention can be usefully used as a prophylactic, ameliorating, or treating agent for various NLRP3 inflamasome mediated inflammatory diseases, and thus, it is expected to be useful in the related medicine and food industries.
Claims (17)
- 하기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는, 인플라마좀(inflammasome) 매개 염증 질환의 예방 또는 치료용 약학 조성물:A pharmaceutical composition for preventing or treating inflammasome-mediated inflammatory diseases, comprising a ginsenoside compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient:<화학식 1><Formula 1>
<화학식 2><Formula 2>
- 제1항에 있어서, 인플라마좀 활성을 억제하는 것인 약학 조성물.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition inhibits inflammasome activity.
- 제2항에 있어서, 인플라마좀은 NLRP3(NOD-like receptor family, pyrin domain-containing 3)인 약학 조성물.The pharmaceutical composition of claim 2, wherein the inflammasome is NLRP3 (NOD-like receptor family, pyrin domain-containing 3).
- 제1항에 있어서, 인플라마좀 매개 염증성 질환은 자가 염증성 질환, 신경 염증성 질환 및 대사성 질환으로 구성된 군으로부터 선택되는 1종 이상의 질환인 약학 조성물.The pharmaceutical composition of claim 1, wherein the inflammasome mediated inflammatory disease is one or more diseases selected from the group consisting of autoinflammatory diseases, neuroinflammatory diseases, and metabolic diseases.
- 제4항에 있어서, 자가 염증성 질환은 머클-웰스 증후군(Muckle-Wells syndrome; MWS), 성인성 지연성 자가면역 당뇨병(LADA), 가족성 한랭 자가면역성 증후군(FCAS), 크리오피린-관련 주기성 증후군(CAPS), 신생아-발병 다기관 염증성 증후군(NOMID), 만성 영아 신경 피부 관절(CINCA) 증후군, 가족성 지중해열(FMF), 전신 발병 소아 특발성 관절염(SJIA), 소아 류마티스 관절염, 성인 류마티스 관절염, 연령관련 황반변성, 아토피성 피부염 및 건선으로 구성된 군으로부터 선택되는 어느 하나 이상인 약학 조성물.The method of claim 4, wherein the autoinflammatory disease is Muckle-Wells syndrome (MWS), adult delayed autoimmune diabetes (LADA), familial cold autoimmune syndrome (FCAS), cryopyrin-associated periodic syndromes. (CAPS), neonatal-onset manifold inflammatory syndrome (NOMID), chronic infant nerve skin joint (CINCA) syndrome, familial Mediterranean fever (FMF), systemic onset pediatric idiopathic arthritis (SJIA), juvenile rheumatoid arthritis, adult rheumatoid arthritis, age At least one pharmaceutical composition selected from the group consisting of related macular degeneration, atopic dermatitis and psoriasis.
- 제4항에 있어서, 신경 염증성 질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 크로이츠펠트야콥병, 다발성 경화증, 근위축성 측삭 증후군, 미만성루이소체병, 백색질뇌염, 측두엽간질, 및 염증성 척추손상으로 구성된 군으로부터 선택되는 어느 하나 이상인 약학 조성물.The method of claim 4, wherein the neuro-inflammatory disease consists of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfeldt-Jakob disease, Multiple sclerosis, Amyotrophic lateral syndrome, Diffuse Lewy body disease, White encephalitis, Temporal lobe epilepsy, and Inflammatory spinal cord injury. At least one pharmaceutical composition selected from the group.
- 제4항에 있어서, 대사성 질환은 비만, 제2형 당뇨병, 고지혈증, 고콜레스테롤증, 죽상동맥경화증, 비알코올성지방간(NAFLD) 및 비알코올성지방간염(NASH)으로 구성된 군으로부터 선택되는 어느 하나 이상인 약학 조성물.The pharmaceutical composition of claim 4, wherein the metabolic disease is at least one selected from the group consisting of obesity, type 2 diabetes, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic fatty liver (NAFLD) and nonalcoholic steatohepatitis (NASH). Composition.
- 제1항에 있어서, 약학적으로 허용되는 1종 이상의 담체를 포함하는 약학 조성물.The pharmaceutical composition of claim 1, comprising one or more pharmaceutically acceptable carriers.
- 제1항에 있어서, 전염증성 사이토카인 IL-1β의 생성 억제제인 약학 조성물.The pharmaceutical composition of claim 1, which is an inhibitor of the production of proinflammatory cytokine IL-1β.
- 제1항에 있어서, 세포 독성을 나타내지 않는 약학 조성물.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition does not exhibit cytotoxicity.
- 제1항에 있어서, 진세노사이드 화합물은 화학식 1로 표시되는 화합물인 약학 조성물.The pharmaceutical composition of claim 1, wherein the ginsenoside compound is a compound represented by Formula 1.
- 제 1 항에 있어서, 진세노사이드 화합물은 화학식 2로 표시되는 화합물인 약학 조성물.The pharmaceutical composition of claim 1, wherein the ginsenoside compound is a compound represented by Formula 2.
- 하기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 그의 염을 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물:A food composition for preventing or ameliorating an inflammasome-mediated inflammatory disease, comprising a ginsenoside compound represented by the following Formula 1 or Formula 2 or a salt thereof:<화학식 1><Formula 1>
<화학식 2><Formula 2>
- 제 13 항에 있어서, 인플라마좀 매개 염증성 질환은 자가 염증성 질환, 신경 염증성 질환 및 대사성 질환으로 구성된 군으로부터 선택되는 1종 이상의 질환인 식품 조성물.The food composition of claim 13, wherein the inflammasome mediated inflammatory disease is one or more diseases selected from the group consisting of autoinflammatory diseases, neuroinflammatory diseases, and metabolic diseases.
- 치료학적으로 유효한 양의 하기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 이의 약학적으로 허용되는 염을 치료가 필요한 대상체에게 투여 하는 인플라마좀 매개 염증성 질환의 예방 또는 치료방법:A method for preventing or treating inflammasome-mediated inflammatory disease in which a therapeutically effective amount of a ginsenoside compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof:<화학식 1><Formula 1>
<화학식 2><Formula 2>
- 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약제의 제조를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도:Use of a compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of inflamasome mediated inflammatory diseases:<화학식 1><Formula 1>
<화학식 2><Formula 2>
- 인플라마좀 매개 염증성 질환의 예방 또는 치료를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도:Use of a compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the prevention or treatment of inflammasome mediated inflammatory diseases:<화학식 1><Formula 1>
<화학식 2><Formula 2>
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20080003931A (en) * | 2005-04-27 | 2008-01-08 | 주식회사 티지 바이오텍 | Treatment of insulin resistance syndrome |
| KR20130069430A (en) * | 2011-12-14 | 2013-06-26 | (주)셀트리온 | Composition for treating or preventing diabetes type ii, obesity, or hyperlipidemia comprising gypenoside extract of gynostemma pentaphyllum |
| WO2016070795A1 (en) * | 2014-11-03 | 2016-05-12 | Sheau-Long Lee | Use of ginsenoside m1 for treating iga nephropathy |
| KR101660834B1 (en) * | 2015-04-28 | 2016-10-11 | 재단법인 지능형 바이오 시스템 설계 및 합성 연구단 | Anti-diabetic effects of Gypenoside 75 |
| KR101928553B1 (en) * | 2018-08-07 | 2018-12-12 | 주식회사 모든바이오 | A Composition for Preventing or Treating Inflammasome Mediated Inflammatory Disease Containing Ginsenoside Compounds |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20080003931A (en) * | 2005-04-27 | 2008-01-08 | 주식회사 티지 바이오텍 | Treatment of insulin resistance syndrome |
| KR20130069430A (en) * | 2011-12-14 | 2013-06-26 | (주)셀트리온 | Composition for treating or preventing diabetes type ii, obesity, or hyperlipidemia comprising gypenoside extract of gynostemma pentaphyllum |
| WO2016070795A1 (en) * | 2014-11-03 | 2016-05-12 | Sheau-Long Lee | Use of ginsenoside m1 for treating iga nephropathy |
| KR101660834B1 (en) * | 2015-04-28 | 2016-10-11 | 재단법인 지능형 바이오 시스템 설계 및 합성 연구단 | Anti-diabetic effects of Gypenoside 75 |
| KR101928553B1 (en) * | 2018-08-07 | 2018-12-12 | 주식회사 모든바이오 | A Composition for Preventing or Treating Inflammasome Mediated Inflammatory Disease Containing Ginsenoside Compounds |
Non-Patent Citations (1)
| Title |
|---|
| YI, Y.-S.: "Roles of ginsenosides in inflammasome activation", JOURNAL OF GINSENG RESEARCH, vol. 43, no. 2, 1 April 2019 (2019-04-01), pages 172 - 178, XP055686162, ISSN: 1226-8453, DOI: 10.1016/j.jgr.2017.11.005 * |
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