KR20140092446A - A new compound and Composition comprising compounds isolated from the fruit extract of Morus alba L for immuno-stimulating activity - Google Patents
A new compound and Composition comprising compounds isolated from the fruit extract of Morus alba L for immuno-stimulating activity Download PDFInfo
- Publication number
- KR20140092446A KR20140092446A KR1020120155860A KR20120155860A KR20140092446A KR 20140092446 A KR20140092446 A KR 20140092446A KR 1020120155860 A KR1020120155860 A KR 1020120155860A KR 20120155860 A KR20120155860 A KR 20120155860A KR 20140092446 A KR20140092446 A KR 20140092446A
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- KR
- South Korea
- Prior art keywords
- compound
- pyrrole
- acid
- butanoic acid
- formyl
- Prior art date
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- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
Description
본 발명은 신규 화합물 및 상심자 추출물로부터 분리된 분리 화합물을 유효성분으로 함유하는 면역증강용 조성물에 관한 것이다.The present invention relates to a composition for immunomodulation comprising a novel compound and a separated compound isolated from a fresh heart extract as an active ingredient.
[문헌 1] Richard A. Goldsby, et al., KUBY Immunology, 2000[Patent Document 1] Richard A. Goldsby, et al., KUBY Immunology , 2000
[문헌 2] Ragupathi, G., Yeung, K.S., Leung, P.C., Lee, M., Lau, C.B.S., Vickers, A., Hood, C., Deng, G., Cheung, N.K., Cassileth, B., Livingston, P., 2008. Evaluation of widely consumed botanicals as immunological adjuvants. Vaccine 26, 4860-4865.[2] Ragupathi, G., Yeung, KS, Leung, PC, Lee, M., Lau, CBS, Vickers, A., Hood, C., Deng, G., Cheung, NK, Cassileth, B., Livingston, P., 2008. Evaluation of widely consumed botanicals as immunological adjuvants. Vaccine 26, 4860-4865.
[문헌 3] Won, D.P., Lee, J.S., Kwon, D.S., Lee, K.E., Shin, W.C., Hong, E.K., 2011. Immunostimulating activity by polysaccharides isolated from fruiting body of Inonotus obliquus. Molelular Cells 31, 165-173.[3] Won, D.P., Lee, J.S., Kwon, D. S., Lee, K.E., Shin, W.C., Hong, E.K., 2011. Immunostimulating activity by polysaccharides isolated from fruiting body of Inonotus obliquus. Molelular Cells 31, 165-173.
[문헌 4] Sun, H.X., Qin, F., Ye, Y.P., 2005. Relationship between haemolytic and adjuvant activity and structure of protopanaxadiol-type saponins from the roots of Panax notoginseng . Vaccine 23, 5533-42.[4] Sun, HX, Qin, F., Ye, YP, 2005. Relationship between haemolytic and adjuvant activity and structure of protopanaxadiol-type saponins from the roots of Panax notoginseng . Vaccine 23, 5533-42.
[문헌 5] Wolf, S.F., Sieburth. D., Sypek, J. 1994. Interleukin 12: a key modulator of immune function. Stem Cells 12, 154-168.[Literature 5] Wolf, S. F., Sieburth. D., Sypek, J. 1994. Interleukin 12: a key modulator of immune function. Stem Cells 12,154-168.
[문헌 6] Lee, J.S., Hong, E.K., 2011. Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris. International Immunopharmacology 11, 1226-1233.[Literature 6] Lee, JS, Hong, EK, 2011. Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris . International Immunopharmacology 11, 1226-1233.
[문헌 7] Murray, P.J., Wynn, T.A., 2011. Protective and pathogenic functions of macrophage subsets. Nature Reviews Immunology 11, 723-737.[Literature 7] Murray, P. J., Wynn, T. A., 2011. Protective and pathogenic functions of macrophage subsets. Nature Reviews Immunology 11, 723-737.
[문헌 8] 정보섭외, 도해 향약대사전, 영림사, p545-548, 1998)[Literature 8] Information Sourcing, Illustrated Dictionary of Contemplation, Yeonglim Publishing House, p545-548, 1998)
[문헌 9] Hiermann, A., Kedwani, S., Schramm, H.W., Seger, C., 2002. A new pyrrole alkaloids from seeds of Castanea sativa. Fitoterapia 73, 22-27.[9] Hiermann, A., Kedwani, S., Schramm, HW, Seger, C., 2002. A new pyrrole alkaloids from seeds of Castanea sativa Phytotherapy 73, 22-27.
[문헌 10] Chin, Y.W., Lim, S.W., Kim, S.H., Shin, D.Y., Suh, Y.G., Kim, Y.B., Kim, Y.C., Kim, J., 2003. Hepatoprotective pyrrole derivatives of Lycium chinensis fruits. Bioorganic & Medicinal Chemistry Letters 13, 79-81.[10] Chin, Y. W., Lim, S. W., Kim, S. H., Shin, D. Y., Suh, Y. G., Kim, Y.B., Kim, Y.C., Kim, J., 2003. Hepatoprotective pyrrole derivatives of Lycium chinensis fruits. Bioorganic & Medicinal Chemistry Letters 13, 79-81.
[문헌 11] Carmichael, J., DeGraff, W.G., Gazdar, A.F., Minna, J.D., Mitchell, J.B., Jobgen, W.S., 1987. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Research 47, 936-942.J., DeGraff, W. G., Gazdar, A. F., Minna, J. D., Mitchell, J. B., Jobgen, W. S., 1987. Evaluation of a tetrazolium-based seminomatous colorimetric assay: assessment of chemosensitivity testing. Cancer Research 47, 936-942.
[문헌 12] Jobgen, W.S., Jobgen, S.C., Li, H., Meininger, C.J., Wu, G., 2007. Analysis of nitrite and nitrate in biological samples using high-performance liquid chromatography. Journal of Chromatography B Analytical Technologies in Biomedical and Life Sciences. 851, 71-82.[Literature 12] Jobgen, W. S., Jobgen, S. C., Li, H., Meininger, C. J., Wu, G., 2007. Analysis of nitrite and nitrate in biological samples using high-performance liquid chromatography. Journal of Chromatography B Analytical Technologies in Biomedical and Life Sciences. 851, 71-82.
[문헌 13] Ledur, A., Fitting, C., David, B., Hamberger, C., Cavaillon, J.M., 1995. Variable estimates of cytokine levels produced by commercial ELISA kits: results using international cytokine standards. Journal of Immunological Methods 186, 171-179.[Literature 13] Ledur, A., Fitting, C., David, B., Hamberger, C., Cavaillon, J.M., 1995. Variable estimates of cytokine levels produced by commercial ELISA kits: results using international cytokine standards. Journal of Immunological Methods 186, 171-179.
[문헌 14] Rahim, S.S., Khan, N., Boddupalli, C.S., Hasnain, S.E., Mukhopadhyay, S. 2005. Interleukin-10 (IL-10) mediated suppression of IL-12 production in RAW 264.7 cells also involves c-rel transcription factor. Immunology 114, 313-321.(IL-10) mediated suppression of IL-12 production in RAW 264.7 cells also involved c-myc, rel transcription factor. Immunology 114, 313-321.
[문헌 15] Cheng, A.W., Wan, F.C., Wang, J.Q., Jin, Z.Y., Xu, X.M., 2008. Macrophage immunomodulatory activity of polysaccharides isolated from Glycyrrhiza uralensis Fish. International Immunopharmacology 8, 43-50.[Literature 15] Cheng, AW, Wan, FC, Wang, JQ, Jin, ZY, Xu, XM, 2008. Macrophage immunomodulatory activity of polysaccharides isolated from Glycyrrhiza uralensis Fish. International Immunopharmacology 8, 43-50.
[문헌 16] Chen W., Zhang W., Shen W., Wang K., 2010. Effects of the acid polysaccharide fraction isolated from a cultivated Cordyceps sinensis on macrophages in vitro. Cell Immunol. 262(1), 69-74. [16] Chen W., Zhang W., Shen W., Wang K., 2010. Effects of the acid polysaccharide fraction isolated from a cultivated Cordyceps sinensis on macrophages in vitro. Cell Immunol. 262 (1), 69-74.
[문헌 17] 식품의약품안전청, 의약품등의 독성시험기준, 식품의약품안전청고시 2005-60호, 2005
[Literature 17] Korea Food and Drug Administration, Toxicological Testing Standards for Drugs, etc., Korea Food & Drug Administration Notice 2005-60, 2005
면역계는 자연저항, 비특이성 면역체계 및 특이성 면역체계로 구분할 수 있다. 자연저항(1차 방어선)이란 미생물을 위시한 모든 침입자들을 그들의 종류에 관계없이 막아내는 해부생리학적 요소들을 말하며, 비특이적 면역(2차 방어선)은 자연저항을 돌파하여 체내로 들어온 침입자들을 제거하는 식세포로 구성된 방어체계를, 그리고 특이성 면역계(3차 방어선)는 림프구들로 구성된 면역체계를 말하는데, 이중 특이성 면역계는 기억능 그리고 자기와 비자기를 구분할 수 있는 능력을 지닌 고도로 발달한 면역체계이다 (Richard A. Goldsby, et al., KUBY Immunology, 2000).The immune system can be divided into natural resistance, nonspecific immune system and specific immune system. Natural resistance (first line of defense) is an anatomical physiological element that blocks all invaders, including microorganisms, regardless of their type. Nonspecific immunity (second line of defense) is a phagocyte that breaks through natural resistance and removes intruders. A specific immune system is a highly developed immune system with the ability to distinguish between memory and non-immune systems (Richard A. < RTI ID = 0.0 > A. < / RTI > Goldsby, et al., KUBY Immunology , 2000).
대식세포는 많은 라이소솜을 가지고 있고 이들은 산성가수분해효소와 과산화 효소를 함유하고 있다. 또한 유리면과 플라스틱 표면에 강하게 부착하는 성질이 있으며 미생물이나 종양세포 등을 활발하게 탐식한다. 상기 세포는 IFN-γ등의 사이토카인 수용체를 가지고 있다. 이들은 보체성분, 인터페론, 인터루킨-1 및 종양괴사인자 같은 사이토카인을 생산하며 T-세포로부터 생산되는 여러 가지 사이토카인에 의해 기능이 증강될 수 있다. 백혈구의 일종인 T-세포는 혈중 소림프구의 약 70%를 차지한다. T-세포는 흉선에서 분화되며 T-세포항원수용체(TCR)를 갖는다. 말초혈액 T-세포는 CD4 양성인 TH 세포(helper T-cell)와 CD8 양성인 TC 세포(cytotoxic T-cell)로 나뉘며, CD4+ TH 세포는 MHC II 급(class) 분자에 결합된 항원을 인식하여 활성화되며, B세포를 도와서 항체생성을 가능하게 하거나 다른 T 세포의 기능을 돕는다. CD4+ TH 세포는 다시 그들이 생산하는 사이토카인을 근거로 TH1 및 TH2로 분류할 수 있다. 실험용 생쥐(mouse)의 TH1세포는 인터루킨-2(IL-2), 인터페론-감마(IFN-γ) 등을 분비하는 반면에 TH2 세포는 IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 등을 분비한다. 그러나 사람에 있어서는 IL-2, IL-6, IL-10, IL-13의 생성이 엄격히 구분되지 않는다. TH1세포는 세포면역반응에 관여하며 세포독성 및 염증성 반응을 활성화한다. TH2 세포에서 생성된 사이토카인은 항체형성을 촉진시키는데, 특히 IgE의 생성을 도우며 호산구의 증식과 기능을 증강시키므로 TH2 사이토카인은 항체생성 및 알레르기 반응에서 흔히 발견된다. TH1 과 TH2 사이토카인은 서로간 억제기능을 가지고 있고, 동물의 감염증에서 항 IL-4 항체와 항 IFN-γ항체로 질환의 경과를 변화시킬 수 있음이 밝혀졌으며, 류마티스 관절염의 환자에 IFN-γ를 주사하여 증상의 호전이 관찰된 예도 있다 (Richard A. Goldsby, et al., KUBY Immunology. 2000).Macrophages contain many lysosomes, which contain acid hydrolytic enzymes and peroxidase. It is also strongly attached to the glass surface and plastic surface and actively digests microorganisms and tumor cells. The cell has a cytokine receptor such as IFN-y. They produce cytokines such as complement components, interferons, interleukin-1 and tumor necrosis factors, and can be enhanced by a variety of cytokines produced from T-cells. T-cells, a type of leukocytes, account for about 70% of the bovine lymphocytes in the blood. T-cells differentiate in the thymus and have T-cell antigen receptors (TCRs). Peripheral blood T- cells were divided into CD4-positive T H cells (helper T-cell) and CD8-positive T C cells (cytotoxic T-cell), CD4 + T H cells recognize the antigen binds to MHC II class (class) molecule And helps to stimulate B cells to enable the production of antibodies or help other T cells function. CD4 + T H cells can be further classified as
천연물은 아시아 국가즐에서 다양한 질환의 치료에 사용되어 왔다. 폭넓게 사용되어 온 식물들은 면역증강, 건강 유지 및 장수를 위한 강장제로 사용되어 왔으며, 다양한 구조의 구성성분들, 특히, 폴리사카라드(polysaccharides),β-글루칸(glucans), 사포닌(saponins) 및 쿠르쿠미노이드(curcuminoids) 등의 성분들은 임상 및 약물 적용에 있어 폭넓게 면역증강제로서 제시되어 왔다 (Ragupathi et al., 2008; Won et al., 2011; Sun et al., 2005). Natural products have been used in the treatment of various diseases in Asian countries. Plants that have been widely used have been used as tonic for immunity enhancement, health maintenance and long life, and have been found to have a variety of structural components, especially polysaccharides,? -Glucans, saponins, Curcuminoids have been proposed as a broad-spectrum immunomodulatory agent in clinical and drug applications (Ragupathi et al., 2008; Won et al., 2011; Sun et al., 2005).
면역증강(Immunostimulation)은 암 및 염증 질환 등과 같은 다양한 질환에 대한 신체 방어 기전을 보강하는 중요한 치료학적 전략중 하나이다. 대식세포들은 면역반응에서 주요한 역할을 수행한다. 대식세포에서의 주요한 역할인 식세포 작용은 미생물 및 기타 발열성 입자들을 흡수하고 또한 종양괴사인자(tumor necrosis factor; TNF)-α, 인터루킨(interleukin; IL)-1β, IL-12과 같은 다수의 시토킨(cytokin) 및 일산화 질소 (nitric oxide; NO) 및 반응성 산소종(reactive oxygen species; ROS)과 같은 세포독성 및 염증성 물질을 분비함으로서 면역 반응을 자극시킨다 (Wolf et al., 1994; Lee and Hong, 2011; Murray and Wynn, 2011). Immunostimulation is one of the important therapeutic strategies to reinforce the body defense mechanisms for various diseases such as cancer and inflammatory diseases. Macrophages play a major role in the immune response. Phagocytosis, a major role in macrophages, has been shown to absorb microbes and other exothermic particles and also to inhibit the production of many cytokines, such as tumor necrosis factor (TNF) -α, interleukin (IL) -1β, 1994, Lee and Hong (2002), stimulate the immune response by secreting cytokines and cytotoxic and inflammatory substances such as nitric oxide (NO) and reactive oxygen species (ROS) , 2011; Murray and Wynn, 2011).
상심자(桑子)는 뽕나무과(Moraceae)에 속하는 뽕나무(Morus alba ) 열매로서, 당분, 탄닌산(tannic acid), 사과산, 비타민(vitamin) B1, B2, C, 카로텐(carotene), 리놀산(linolic acid), 스테아린산(stearic acid), 올레인산(oleic acid) 등을 함유한 것으로 알려져 있으며, 소갈증 변비 등의 치료에 사용되어 왔다 (정보섭외, 도해 향약대사전, 영림사, p545-548, 1998)
Saddened chairs (桑子) is Mulberry (Morus belonging to Moraceae (Moraceae) alba ) , which contains sugars, tannic acid, malic acid, vitamins B1, B2, C, carotene, linolic acid, stearic acid and oleic acid. , And has been used for the treatment of constipation, such as dyspareunia (Information,
그러나, 상기 문헌의 어디에도 상심자 추출물로부터 분리된 화합물이 면역 증강 효과에 효과적이라는 어떠한 개시도 된 바가 없다. However, none of the above references discloses that compounds isolated from heartburn extracts are effective in enhancing the immune system.
따라서, 현대 객관적인 면역 활성 지표들을 이용하여 한약재로 사용되는 천연물 중에 면역증강효과 및 그 작용기전을 밝히고자 하였다.Therefore, we aimed to clarify the immune enhancement effect and the mechanism of action of natural products used as medicinal herbs by using modern objective immune activity indicators.
이에 본 발명자들은 상심자 추출물로부터 분리된 화합물들이 대식세포 Raw 264.7 세포내에서 NO 생성증가, TNF-α 및 IL-12 등의 면역증강인자 의 분비능 생성 증가 효과를 나타내어 면역세포 내에서 활성 증진 효과를 나타냄으로서 면역 증강 효능이 우수하여 면역저하증의 예방, 억제 및 치료에 우수함을 확인하여 면역증강 효능을 갖는 식품, 의약품 및 사료 첨가제로서 유용하게 이용될 수 있음을 확인함으로써 본 발명을 완성하였다.
Therefore, the present inventors have found that the compounds isolated from the sickle cell extract have an effect of increasing NO production in macrophage Raw 264.7 cells, and enhancing secretion ability of immunity enhancing factors such as TNF-α and IL-12, And excellent immunosuppressive effect, and it is confirmed that it is excellent in prevention, suppression and treatment of hypoimmunities, and thus it can be effectively used as food, medicine and feed additive having immunity enhancing effect.
상기한 목적을 달성하기 위하여, In order to achieve the above object,
본 발명은 상심자 추출물로부터 분리된 면역증강활성을 나타내는, 하기의 구조를 갖는 신규한 알칼로이드 화합물인 (4-(2-포르밀(formyl)-5-(((3-히드록시부탄;hydroxybutan-2-yl)옥시(oxy))메틸(methyl))-1H-피롤(pyrrol)-1-yl)부타노익 산(butanoic acid) (=모롤 A:, Morrole A), 그 이성체 또는 이의 약리학적으로 허용 가능한 염을 제공한다:The present invention relates to a novel alkaloid compound (4- (2-formyl) -5 - (((3-hydroxybutane- 2-yl) oxy) methyl) -1H-pyrrole-1-yl) butanoic acid (= morole A :, Morrole A), an isomer thereof or a pharmacologically Acceptable salts are provided:
Morrole AMorrolee
또한, 본 발명은 상심자 추출물로부터 분리된 화합물을 유효성분으로 함유하는 면역 증강용 약학조성물을 제공한다.The present invention also provides a pharmaceutical composition for enhancing immunity, which comprises a compound isolated from a topical extract as an active ingredient.
본 발명은 상심자 추출물로부터 분리된 화합물을 유효성분으로 함유하는 면역 증강용 건강기능식품을 제공한다.The present invention provides a health functional food for immunity enhancement containing as an active ingredient a compound isolated from a topical extract.
또한, 본 발명은 상심자 추출물로부터 분리된 화합물을 유효성분으로 함유하는 면역 증강용 동물사료 첨가제를 제공한다.In addition, the present invention provides an animal feed additive for immunity enhancement, which comprises a compound isolated from a root extract as an active ingredient.
본원에서 정의되는 상기 추출물은 물, 탄소수 1 내지 4의 저급알코올 또는 이들의 혼합용매, 바람직하게는 물에 가용한 추출물을 포함한다.The extracts as defined herein include water, lower alcohols having 1 to 4 carbon atoms, or a mixed solvent thereof, preferably water-soluble extracts.
본원에서 정의되는 상기 상심자 추출물로부터 분리된 화합물은 5-(히드록시메틸;hydroxymethyl)-1H-피롤(pyrrole)-2-카르복스알데히드(carboxaldehyde) (Compounds 1), 2-포르밀(formyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 2), 2-포르밀(formyl)-5-(히드록시메틸;hydroxymethyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 3), 2-포르밀(formyl)-5-(메톡시메틸;methoxymethyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 4) 및 신규 알칼로이드 화합물인 (4-(2-포르밀(formyl)-5-(((3-히드록시부탄;hydroxybutan-2-yl)옥시(oxy))메틸(methyl))-1H-피롤(pyrrol)-1-yl)부타노익 산(butanoic acid)로부터 선택된 화합물을 포함한다.The compounds isolated from the above extracts as defined herein may be selected from the group consisting of 5- (hydroxymethyl) -1 H -pyrrole-2-carboxaldehyde (Compounds 1), 2-formyl ) -1 H - pyrrole (pyrrole) -1- butanoate acid (butanoic acid) (Compound 2) , 2- formyl (formyl) -5- (hydroxymethyl; hydroxymethyl) -1 H - pyrrole (pyrrole) - Butanoic acid (Compound 3), 2-formyl-5- (methoxymethyl) -1 H -pyrrole-1-butanoic acid ( Compound 4) and a novel alkaloid compound (4- (2-formyl) -5 - ((hydroxybutan-2-yl) oxy) methyl) Pyrrol-1-yl) butanoic acid. ≪ / RTI >
본 발명의 화합물들은 당해 기술 분야에서 통상적인 방법에 따라 약학적으로 허용 가능한 염 및 용매화물로 제조될 수 있다.The compounds of the present invention may be prepared by pharmaceutically acceptable salts and solvates according to methods conventional in the art.
약학적으로 허용 가능한 염으로는 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 메탄올, 에탄올, 아세톤 또는 아세토니트릴과 같은 수혼화성 유기 용매를 사용하여 침전시켜서 제조한다. 동일한 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Pharmaceutically acceptable salts include acid addition salts formed by free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered by suction.
이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아 세트산, 시트르산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산 (propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르빈산, 카본산, 바닐릭산 및 히드로 아이오딕산 등을 사용할 수 있다.As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid Citric acid, lactic acid, glycollic acid, gluconic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid and hydroiodic acid can be used.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비 용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt in particular, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
본 발명의 화합물의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 본 발명의 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염이 포함되며, 아미노기의 기타 약학적으로 허용 가능한 염으로는 하이드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포 네이트(메실레이트) 및 p-톨루엔설포네이트(토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조 방법이나 제조과정을 통하여 제조될 수 있다. Pharmaceutically acceptable salts of the compounds of the present invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of the present invention. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate rate, methane sulfonate (mesylate) and p - toluene sulfonate (tosylate) and a salt, the salt manufacturing method or manufacturing process known in the art ≪ / RTI >
또한, 상기의 구조식 (5)의 구조를 갖는 신규 화합물은 비대칭 중심을 가지므로 상이한 거울상 이성질체 형태로 존재할 수 있으며, 모든 광학 이성질체 및 R 또는 S형 입체 이성질체 및 이들의 혼합물도 본 발명의 범주 내에 포함되는 것으로 한다. 본 발명은 라세미체, 하나 이상의 거울상 이성질체 형태, 하나 이상의 부분 입체 이성질체 형태 또는 이들의 혼합물의 용도를 포함하며, 당업계에서 알려진 이성질체의 분리 방법이나 제조과정을 포함한다.Further, the novel compounds having the structure of the above structural formula (5) can exist in different enantiomeric forms because they have an asymmetric center, and all optical isomers and R or S type stereoisomers and mixtures thereof are also included within the scope of the present invention . The present invention includes the use of racemates, one or more enantiomeric forms, one or more diastereoisomeric forms, or mixtures thereof, and includes methods and processes for the isolation and isomerization of isomers known in the art.
본 발명의 상심자 추출물로부터 분리된 화합물은 하기와 같은 제조공정으로 제조되거나 상용으로 구입가능하다.Compounds isolated from the extract of the present invention can be prepared by the following production process or commercially available.
건조시킨 상심자를 통상적인 추출방법에 따라 제조할 수 있으며, 건조된 상심자 건조 중량의 1 내지 20배, 바람직하게는 5 내지 15배 부피의 물, 메탄올 등과 같은 C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는 물 및 메탄올 혼합용매을 가하여 0.5 내지 10시간, 바람직하게는 2 내지 5시간씩, 70℃ 내지 100℃로, 1 내지 10회, 바람직하게는 2 내지 5회 반복하여 냉침추출, 열수추출, 초음파 추출 및 환류냉각 추출 등의 추출방법으로, 바람직하게는 열수 추출한 후, 추출액을 여지로 감압 여과한 다음, 여과액을 농축하여 동결건조한 후 본 발명의 상심자 추출물을 수득한 후에, 얻어진 메탄올 추출물에 물을 가하여 현탁시키고, 이를 연속적으로 CHCl3, EtOAc 및 n-BuOH으로 분획을 수행하고, 상기 EtOAc 분획물을 대상으로 CH2Cl2-MeOH 전개용매를 이용하여 실리카겔 ?럼 크로마토그래피법을 수행하여 6개의 분획물 (MFE1-MFE6)을 수득하고 얻어진 MFE2 분획물을 세파덱스(Sephadex) LH-20 을 충진하고 전개용매(MeOH-H2O; 1:1)를 이용한 컬럼크로마토그래피를 수행하여 6개 분획들 (MFE21-MFE26)을 수득하고, 상기 분획물 중 MFE23 분획물을 대상으로 세미프렙(semipreparative) HPLC를 수행하여 본 발명의 화합물들인 5-(히드록시메틸;hydroxymethyl)-1H-피롤(pyrrole)-2-카르복스알데히드(carboxaldehyde) (Compounds 1), 2-포르밀(formyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 2), 2-포르밀(formyl)-5-(히드록시메틸;hydroxymethyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 3), 2-포르밀(formyl)-5-(메톡시메틸;methoxymethyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 4) 및 신규 알칼로이드 화합물인 모롤 에이{Morrole A=(4-(2-포르밀(formyl)-5-(((3-히드록시부탄;hydroxybutan-2-yl)옥시(oxy))메틸(methyl))-1H-피롤(pyrrol)-1-yl)부타노익 산(butanoic acid) 에이(A),(Compound 5)}, 을 각각 분리가능하다.Dried bulkheads may be prepared according to conventional extraction methods and may be prepared from C 1 to C 4 lower alcohols, such as water, methanol, etc., in a volume from 1 to 20 times, preferably from 5 to 15 times, And the mixture is stirred for 0.5 to 10 hours, preferably 2 to 5 hours, at 70 to 100 ° C for 1 to 10 times, preferably 2 to 5 times, in a mixed solvent of these, preferably water and methanol, The extract is preferably subjected to extraction by hot water extraction such as extraction, hot water extraction, ultrasonic extraction and reflux cooling extraction. The extract is filtered under reduced pressure through a filter paper, and the filtrate is concentrated and lyophilized to obtain a fresh extract of the present invention after that, the suspended water was added to the resulting methanol extract, take advantage of this, successively performed, the fraction with CHCl 3, EtOAc and n-BuOH, and targeting the EtOAc fractions, CH 2 Cl 2 -MeOH eluant ? Silica gel performing a column chromatography of 6 fractions (MFE1-MFE6) obtained and filling the Sephadex (Sephadex) LH-20 and the resulting MFE2 fraction and a developing solvent (MeOH-H 2 O; 1 : 1) for using Column chromatography was performed to obtain six fractions (MFE21-MFE26), and semipreparative HPLC was performed on the MFE23 fraction of the fractions to obtain the compounds of the present invention, 5- (hydroxymethyl) -1 H -pyrrole-2-carboxaldehyde (Compounds 1), 2-formyl-1 H -pyrrole-1-butanoic acid (Compound 2 ), 2-formyl (formyl) -5- (hydroxymethyl; hydroxymethyl) -1 H - pyrrole (pyrrole) -1- butanoate acid (butanoic acid) (Compound 3), 2-formyl (formyl) - 5-methoxymethyl- 1H -pyrrole-1-butanoic acid (Compound 4) and the novel alkaloid compound Morro A = (4- (2- (formyl) -5 - (((3- Hydroxybutan-2-yl) oxy) methyl) -1H-pyrrole-1-yl) butanoic acid A (Compound 5) Respectively.
본 발명은 상기 제조방법 및 상기 제조방법으로 얻어진 상심자 추출물로부터 분리된 화합물을 유효성분으로 함유하는 면역 증강용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for enhancing immunity, which comprises, as an active ingredient, a compound isolated from the extract of the upper and lower heights obtained by the above production method and the above-mentioned production method.
본 발명의 면역 증강용 약학조성물은, 조성물 총 중량에 대하여 상기 추출물을 0.1 내지 50 중량%로 포함한다. The pharmaceutical composition for immunostaining according to the present invention contains the above extract in an amount of 0.1 to 50% by weight based on the total weight of the composition.
본 발명의 약학조성물은 화학요법 및 방사선요법과 같은 항암요법에 의한 면역기능의 저하 또는 골수이식 후 면역저하로 인한 질환, 면역계손상으로 인한 에이즈 및 면역기능의 저하로 인한 암질환등과 같은 면역저하증의 예방 및 치료에 사용될 수 있다.The pharmaceutical composition of the present invention can be used for the treatment of diseases caused by immunotherapy such as chemotherapy and radiotherapy such as reduction of immune function or bone marrow transplantation, immunosuppression due to immune system damage, ≪ / RTI >
본 발명의 추출물로부터 분리된 화합물을 함유하는 약학조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The pharmaceutical compositions containing the compounds isolated from the extract of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the preparation of pharmaceutical compositions.
본 발명에 따른 추출물로부터 분리된 화합물을 함유하는 약학조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 추출물로부터 분리된 화합물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물로부터 분리된 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 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.The pharmaceutical composition containing the compound isolated from the extract according to the present invention may be administered orally or parenterally in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, Examples of the carrier, excipient and diluent which can be contained in the composition including the compound isolated from the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol , Starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate And mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations may contain at least one excipient such as starch, calcium carbonate, Sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명의 추출물로부터 분리된 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 추출물로부터 분리된 화합물은 1일 0.0001 내지 100㎎/㎏으로, 바람직하게는 0.001 내지 10㎎/㎏으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The preferred dosage of the compound isolated from the extract of the present invention varies depending on the condition and body weight of the patient, the degree of disease, the drug form, the administration route and the period, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound isolated from the extract of the present invention is preferably administered at 0.0001 to 100 mg / kg per day, preferably 0.001 to 10 mg / kg per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
본 발명의 추출물로부터 분리된 화합물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다. The compound isolated from the extract of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
본 발명은 상기 상심자 추출물로부터 분리된 화합물을 함유하는 면역증강용 건강기능식품을 제공한다. The present invention provides a health functional food for immunity enhancement containing a compound isolated from the above-mentioned core extract.
본 발명의 추출물로부터 분리된 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있다.Examples of foods to which the compound isolated from the extract of the present invention can be added include various foods, beverages, gums, tea, vitamin complexes, and health functional foods.
또한, 면역력 증강 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 추출물로부터 분리된 화합물의 양은 일반적으로 본 발명의 건강 기능 식품 조성물은 전체 식품 중량의 0.01 내지 50 중량%, 바람직하게는 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.It can also be added to foods or beverages for the purpose of enhancing the immunity. In this case, the amount of the compound isolated from the extract in the food or beverage may generally be 0.01 to 50% by weight, preferably 0.01 to 15% by weight, of the total food weight of the health functional food composition of the present invention, The composition may be added at a rate of 0.02 to 5 g, preferably 0.3 to 1 g, based on 100 ml.
본 발명의 건강기능식품은 정제, 캡슐제, 환제, 액제 등의 형태를 포함한다. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquids.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물로부터 분리된 화합물을 함유하는 외에는 다른 성분에는 특별한 제한점이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health beverage composition of the present invention has no particular limitations on other ingredients other than those containing the compound isolated from the extract as an essential ingredient in the indicated ratio and contains various flavors or natural carbohydrates as an additional ingredient . Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose, polysaccharides such as maltose, sucrose and the like, such as dextrin, cyclodextrin and the like And sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 추출물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 추출물로부터 분리된 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the extract of the present invention can also be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and aging agents (cheese, chocolate, etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compounds isolated from the extract of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명은 상기 상심자 추출물로부터 분리된 화합물을 함유하는 면역증강용 동물사료 첨가제 및 이를 포함하는 사료를 제공한다. In addition, the present invention provides an animal feed additive for immunity-enhancing animal containing a compound isolated from the above-mentioned bulkhead extract and a feed comprising the animal feed additive.
상기의 동물사료 첨가제용 조성물은 20 내지 90% 고농축액 이거나 분말 또는 과립형태일 수 있다.The composition for animal feed additive may be 20 to 90% high concentrate or may be in the form of powder or granules.
본 발명의 동물사료 첨가제용 조성물은 구연산, 후말산, 아디픽산, 젖산, 사과산 등의 유기산이나 인산나트륨, 인산칼륨, 산성피로인산염, 폴리인산염(중합인산염) 등의 인산염이나 폴리페놀, 카테킨(catechin), 알파-토코페롤, 로즈마리 추출물(rosemary extract), 비타민 C, 녹차 추출물, 감초 추출물, 키토산, 탄닌산, 피틴산 등의 천연 항산화제 중 어느 하나 또는 하나 이상을 추가로 포함할 수 있다.The composition for animal feed additive of the present invention is a composition containing an organic acid such as citric acid, fumaric acid, adipic acid, lactic acid and malic acid, a phosphate such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polymerized phosphate), polyphenol, catechin ), Natural antioxidants such as alpha-tocopherol, rosemary extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid and phytic acid.
본 발명의 조성물을 함유하는 동물사료 첨가제 및 이를 포함하는 사료는 보조성분으로 아미노산, 무기염류, 비타민, 항생물질, 항균물질, 항산화, 항곰팡이 효소, 살아있는 미생물 제제 등과 같은 각종보조제가 곡물, 예를 들면 분쇄 또는 파쇄된 밀, 귀리, 보리, 옥수수 및 쌀; 식물성 단백질 사료, 예를 들면 평지, 콩 및 해바라기를 주성분으로 하는 것; 동물성 단백질 사료, 예를 들면 혈분, 육분, 골분 및 생선분; 당분 및 유제품, 예를 들면 각종 분유 및 유장 분말로 이루어지는 건조성분, 건조 첨가제를 모두 혼합한 후, 액체 성분과, 가열 후에 액체가 되는 성분, 즉, 지질, 예를 들면 가열에 의해 임의로 액화시킨 동물성 지방 및 식물성 지방 등과 같은 주성분 이외에 영양보충제, 소화 및 흡수향상제, 성장촉진제, 질병예방제 등과 같은 물질과 함께 사용될 수 있다.Animal feed additive containing the composition of the present invention and feeds containing the composition of the present invention may be supplemented with various adjuvants such as amino acids, inorganic salts, vitamins, antibiotics, antimicrobials, antioxidants, antifungal enzymes, living microbial agents, For example, crushed or shredded wheat, oats, barley, corn and rice; Vegetable protein feedstuffs, for example, based on rapeseed, soybeans and sunflower; Animal protein feeds such as blood, meat, bone meal and fish meal; It is preferable to mix all of the dry ingredients comprising the sugar and the milk product such as the various powdered milk and the whey powder and the dry additive and then mix the liquid ingredient with the ingredient to be liquid after heating, In addition to the main components such as fat and vegetable fat, can be used together with materials such as nutritional supplements, digestion and absorption enhancers, growth promoters, disease prevention agents and the like.
상기 동물사료 첨가제용 조성물은 동물에게 단독으로 식용 담체 중에서 다른 사료 첨가제와 조합되어 투여될 수 있다. The composition for the animal feed additive can be administered alone to the animal in combination with other feed additives in the edible carrier.
또한, 상기 동물사료 첨가제용 조성물은 탑 드레싱으로서 또는 이들을 동물 사료에 직접 혼합하거나 또는 사료와 별도로, 별도의 경구 제형으로, 주사 또는 경피로 또는 다른 성분과 조합하여 쉽게 투여할 수 있다. 통상적으로, 당업계에 잘 알려진 바와 같이 단독 일일 투여량 또는 분할 일일 투여량을 사용할 수 있다.In addition, the composition for animal feed additives can be easily administered as top dressing or they can be mixed directly with animal feed, or separately from feed, in separate oral formulations, by injection or percutaneously, or in combination with other ingredients. Typically, a single daily dose or a divided daily dose can be used as is well known in the art.
상기 동물사료 첨가제용 조성물은 동물 사료와 별도로 투여할 경우, 당업계에 잘 알려진 바와 같이 조성물의 투여 형태는 이들의 비-독성 제약상 허용 가능한 식용 담체와 조합하여 즉석 방출 또는 서방성 제형으로 제조할 수 있다. 이러한 식용 담체는 고체 또는 액체, 예를 들어 옥수수 전분, 락토오스, 수크로스, 콩 플레이크, 땅콩유, 올리브유, 참깨유 및 프로필렌 글리콜일 수 있다. 고체 담체가 사용될 경우, 화합물의 투여형은 정제, 캡슐제, 산제, 토로키제 또는 함당정제 또는 미분산성 형태의 탑 드레싱일 수 있다. 액체 담체가 사용될 경우, 연 젤라틴 캡슐제, 또는 시럽제 또는 액체 현탁액제, 에멀젼제 또는 용액제의 투여 형태일 수 있다. 또한, 투여 형태는 보조제, 예를 들어 보존제, 안정화제, 습윤제 또는 유화제, 용액 촉진제 등을 함유할 수 있다.When the composition for animal feed additives is administered separately from an animal feed, the dosage form of the composition, as is well known in the art, may be prepared in an immediate release or sustained release formulation in combination with their non-toxic pharmaceutically acceptable excipient . Such edible carriers may be solid or liquid, for example corn starch, lactose, sucrose, soy flakes, peanut oil, olive oil, sesame oil and propylene glycol. When a solid carrier is used, the dosage form of the compound may be a tablet, capsule, powder, troche or emulsion, or a top-dressing in finely divided form. When a liquid carrier is used, it may be in the form of a soft gelatin capsule, or a syrup or liquid suspension, emulsion or solution. In addition, the dosage form may contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution promoting agents and the like.
또한, 본 발명의 화합물이 동물사료 첨가제로 포함되는 동물사료는 동물의 식이 요구를 충족시키는데 통상적으로 사용되는 임의의 단백질-함유 유기 곡분일 수 있다. 이러한 단백질-함유 곡분은 통상적으로 옥수수, 콩 곡분 또는 옥수수/콩 곡분 믹스로 주로 구성되어 있다.In addition, the animal feed in which the compound of the present invention is included as an animal feed additive can be any protein-containing organic grain fraction commonly used to meet animal dietary needs. These protein-containing flours usually consist mainly of corn, soy flour or corn / soy flour mix.
상기의 동물사료 첨가제는 침지, 분무 또는 혼합하여 상기 동물사료에 첨가하여 이용될 수 있다.The animal feed additive may be added to the animal feed by immersion, spraying or mixing.
본 발명은 포유류, 가금 및 어류를 포함하는 다수의 동물 식이에 적용할 수 있다. 보다 상세하게, 식이는 상업상 중요한 포유류, 예를 들어 돼지, 소, 양, 염소, 실험용 설치 동물(랫트, 마우스, 햄스터 및 게르빌루스쥐), 모피 소유 동물(예, 밍크 및 여우), 및 동물원 동물(예, 원숭이 및 꼬리 없는 원숭이), 뿐만 아니라 가축 (예, 고양이 및 개)에게 사용할 수 있다. 통상적으로 상업상 중요한 가금에는 닭, 터키, 오리, 거위, 꿩 및 메추라기가 포함된다. 송어와 같은 상업적으로 사육되는 어류도 포함될 수 있다.The present invention is applicable to a number of animal diets including mammals, poultry, and fish. More specifically, the diets include, but are not limited to, commercially important mammals such as pigs, cows, sheep, goats, laboratory animals (rats, mice, hamsters and gerbils), fur- Zoo animals (eg, monkeys and tailless monkeys), as well as livestock (eg, cats and dogs). Common commercially important poultry include chicken, turkey, duck, goose, pheasant and quail. Commercial breeding fish such as trout can also be included.
본 발명에 따른 조성물을 포함한 동물용 사료 배합 방법은, 상기 조성물을 동물 사료에 건조 중량 기준으로 사료 1kg당 약 1g 내지 100g의 양으로 혼입한다.The animal feed compounding method comprising the composition according to the present invention is such that the composition is incorporated into animal feed in an amount of about 1 g to 100 g per kg of feed on a dry weight basis.
또한, 사료 혼합물은 완전히 혼합한 후, 성분들의 분쇄 정도에 따라 경점성의 조립 또는 과립 물질이 얻어진다. 이것을 매시로서 공급하거나, 또는 추가 가공 및 포장을 위해 원하는 분리된 형상으로 형성한다. 이 때, 저장 중에 분리되는 것을 방지하기 위해, 동물 사료에 물을 첨가하고, 이어서 통상의 펠릿화, 팽창화, 또는 압출 공정을 거치는 것이 바람직하다. 과잉의 물은 건조 제거될 수 있다.Also, after the feed mixture is thoroughly mixed, lightly viscous granulation or granulation material is obtained depending on the degree of crushing of the components. It is supplied as a mesh or is formed into a desired discrete shape for further processing and packaging. At this time, in order to prevent separation during storage, it is preferable to add water to the animal feed, followed by a conventional pelleting, expansion, or extrusion process. Excess water can be dried off.
본 발명의 상심자 추출물로부터 분리된 화합물은 대식세포 Raw 264.7 세포내에서 NO 생성증가, TNF-α 및 IL-12 등의 면역증강인자 의 분비능 생성 증가 효과를 나타내어 면역세포 내에서 활성 증진 효과를 나타냄으로서 면역 증강 효능이 우수하여 면역저하증의 예방, 억제 및 치료에 우수함을 확인하여 면역증강 효능을 갖는 식품, 의약품 및 사료 첨가제로서 유용하게 사용될 수 있다.Compounds isolated from the extracts of the present invention exhibit an effect of enhancing NO production in macrophage Raw 264.7 cells, and enhancing the secretion ability of immunological enhancers such as TNF-α and IL-12, thereby enhancing activity in immune cells Which is superior in immunity enhancement efficacy and is excellent in prevention, inhibition and treatment of hypoimmune, and thus can be usefully used as a food, medicine and feed additive having immunity enhancing effect.
도 1은 Raw 264.7 세포에서의 시료의 면역증강활성을 나타낸 도이다{ (A) 세포 생존능 실험 결과; (B) NO 생성, (C) TNF-α, (D) IL-12 분비 및 (E) 대식세포에서의 식균 활성을 나타내며, 각 데이터는 평균 (mean ± SD)을 나타내고 유의성은 비처치군(UN)과의 상이성으로 간주함 (*p < 0.05, **p<0.01)}. Figure 1 shows the immunomodulating activity of a sample in Raw 264.7 cells { (A) cell viability test results; (B) NO production, (C) TNF-α, (D) IL-12 secretion, and (E) phagocytic activity in macrophages. Data were mean (mean ± SD) UN) ( * p <0.05, ** p <0.01).
이하, 본 발명을 하기의 실시예 및 실험예에 의해 상세히 설명한다. Below, The present invention will be described in detail by the following examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 의해 한정되는 것은 아니다.
However, the following examples and experimental examples are illustrative of the present invention, and the content of the present invention is not limited by the following examples and experimental examples.
실시예Example 1. One. 상심자Heartbreaker 추출물로부터 화합물들의 분리 Isolation of Compounds from Extracts
1.1. 메탄올 추출물1.1. Methanol extract
상심자 (Morus alba, 구입처: 대학한약국(익산시 신용동), 충북대학교 약학대학 약초원에서 동정; 보관번호; CBNU201009-MF) 1.0 kg을 50% MeOH로 1L를 첨가하고 6시간동안 100℃에서 3회 환류 추출법으로 추출하고 감압농축하여 메탄올 추출물 (131.8 g)을 얻고, 얻어진 메탄올 추출물에 정제수 200ml를 가하여 현탁시키고, 이를 연속적으로 CHCl3, EtOAc 및 n-BuOH으로 분획을 수행하였다.1.0 kg of 50% MeOH in 1 L was added to Moru alba (purchased from the University of Korea) and 1 kg of CBNU201009-MF from the Herbal Farm of Chungbuk National University, The mixture was extracted with an extraction method and concentrated under reduced pressure to obtain a methanol extract (131.8 g). The obtained methanol extract was suspended in 200 ml of purified water and fractionated successively with CHCl 3 , EtOAc and n-BuOH.
여기에서 얻은 EtOAc 분획물 2.7 g을 대상으로 CH2Cl2-MeOH 전개용매를 이용하여 실리카겔 컬럼 크로마토그래피법을 수행하여 6개의 분획물 (MFE1-MFE6)을 수득하고 얻어진 MFE2 분획물을 세파덱스(Sephadex) LH-20 을 충진하고 전개용매(MeOH-H2O; 1:1)를 이용한 컬럼크로마토그래피를 수행하여 6개 분획들 (MFE21-MFE26)을 수득하였다.
The resulting EtOAc fraction (2.7 g) was subjected to silica gel column chromatography using CH 2 Cl 2 -MeOH developing solvent to obtain six fractions (MFE 1 -MFE 6), and the resulting
1.2. 메탄올 추출물로부터 물질 분리1.2. Separation of material from methanol extract
용리 용매 (MeOH-water with 0.1% acetic acid; 43:57, F=2 min/ml, Rt=11.4, 14.0 및 15.21 min, 각각)를 이용한 세미프렙(semipreparative) HPLC를 수행하여 MFE23 분획물로부터 피롤 알칼로이드 계열 화합물들인 (pyrrole alkaloids), 하기 물성치를 나타내는 2-포르밀(formyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 2, 4.2mg), Semipreparative HPLC using an elution solvent (MeOH-water with 0.1% acetic acid; 43:57, F = 2 min / ml, Rt = 11.4, 14.0 and 15.21 min, respectively) gave the pyrrole alkaloid based compounds which are (pyrrole alkaloids), 2- formyl (formyl) -1 H showing the following physical-pyrrole (pyrrole) -1- butanoate acid (butanoic acid) (
2-포르밀(formyl)-5-(메톡시메틸;methoxymethyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 4. 13.9mg) 및 신규 알칼로이드 화합물인 모롤A{ (4-(2-포르밀(formyl)-5-(((3-히드록시부탄;hydroxybutan-2-yl)옥시(oxy))메틸(methyl))-1H-피롤(pyrrol)-1-yl)부타노익산(butanoic acid), 3.9mg)을 각각 얻었고, Butanoic acid (
상기 n-BuOH 분획물 30.3 g을 대상으로 용매(methanol-water; 0%, 25%, 50%, 75%, 100% MeOH in water)를 이용한 XAD-2 컬럼크로마토그래피를 수행하여 5 분획물 (MFB1-MFB5)을 얻고 상기 MFB4 분획물을 대상으로 용매(MeOH-H2O; 1:1)를 이용한 세파덱스(Sephadex) LH-20 컬럼크로마토그래피법을 수행하여 3개 분획물 (MFB41-MFB43)을 수득하고 MFB43 분획물을 대상으로 용매(MeOH-water with 0.1% acetic acid; 45:55, F=2 min/ml, Rt=4.8 및 6.2 min, 각각)를 이용한 세미프렙(semipreparative) HPLC를 수행하여 하기 물성치를 나타내는 5-(히드록시메틸;hydroxymethyl)-1H-피롤(pyrrole)-2-카르복스알데히드(carboxaldehyde) (Compounds 1, 2.1 mg) 및 2-포르밀(formyl)-5-(히드록시메틸;hydroxymethyl)-1H-피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 3, 12.0mg)을 각각 분리하였고 이들의 구조를 기존문헌에 기재된 물성치와 비교하여 동정하였다. (Hiermann et al., 2002; Chin et al., 2003)
The fraction (30.3 g) of the n- BuOH fraction was subjected to XAD-2 column chromatography using a solvent (methanol-water; 0%, 25%, 50%, 75%, 100% MeOH in water) MFB4 fractions were subjected to Sephadex LH-20 column chromatography using a solvent (MeOH-H 2 O; 1: 1) to obtain three fractions (MFB41-MFB43) MFB43 fractions were subjected to semipreparative HPLC using a solvent (MeOH-water with 0.1% acetic acid; 45:55, F = 2 min / ml, Rt = 4.8 and 6.2 min, respectively) 5- (hydroxymethyl) -1 H -pyrrole-2-carboxaldehyde (
5-(5- ( 히드록시메틸Hydroxymethyl ;; hydroxymethylhidroxymethyl )-1)-One HH -피롤(- pyrrole ( pyrrolepyrrole )-2-카르복스알데히드() -2-carboxaldehyde ( carbcarb oxaldehyde) (oxaldehyde) ( CompoundsCompounds 1) One)
1H NMR (400 MHz, CD3OD): δ 4.64 (2H, s, CH2-6), δ 6.60 (1H, d, J = 3.5 Hz, CH-5), 7.40 (1H, d, J = 3.5Hz, CH-4), 9.56 (1H, s, CH-1) ppm; 1 H NMR (400 MHz, CD 3 OD): δ 4.64 (2H, s, CH 2 -6), δ 6.60 (1H, d, J = 3.5 Hz, CH-5), 7.40 (1H, d, J = 3.5 Hz, CH-4), 9.56 (1H, s, CH-1) ppm;
13C NMR (100 MHz, CD3OD): δ 56.8 (C-6), 108.5 (C-4), 125.7 (C-3), 132.6 (C-2), 142.0 (C-5), 178.1 (C-1) 13 C NMR (100 MHz, CD 3 OD): δ 56.8 (C-6), 108.5 (C-4), 125.7 (C-3), 132.6 (C-2), 142.0 (C-5), 178.1 ( C-1)
ESI-MS (positive mode) m/z : 148.15 [M+Na]+
ESI-MS (positive mode) m / z : 148.15 [M + Na] < + &
2-2- 포르밀Formyl (( formylformyl )-1)-One HH -피롤(- pyrrole ( pyrrolepyrrole )-1-)-One- 부타노익산Butanoic acid (( butanoicbutanoic acidacid ) () ( CompoundCompound 2) 2)
1H NMR (400 MHz, CD3OD): δ 2.04 (2H, p, J = 7.2 Hz, CH2-H2´), 2.26 (2H, t, J = 7.2 Hz, CH2-H3´), 4.39 (2H, t, J = 7.2 Hz, CH2-H1´), 6.27 (1H, dd, J = 2.4, 4.0, CH-H4), 7.05 (1H, dd, J = 1.6, 4.0, CH-H3), 7.18 (1H, s, CH-5), 9.47 (1H, d, J = 0.8, CH-1) ppm; 1 H NMR (400 MHz, CD 3 OD): δ 2.04 (2H, p, J = 7.2 Hz, CH 2 -H2'), 2.26 (2H, t, J = 7.2 Hz, CH2-H3'), 4.39 ( 2H, t, J = 7.2 Hz , CH 2 -H1'), 6.27 (1H, dd, J = 2.4, 4.0, CH-H4), 7.05 (1H, dd, J = 1.6, 4.0, CH-H3), 7.18 (1H, s, CH-5), 9.47 (1H, d, J = 0.8, CH-1) ppm;
13C NMR (100 MHz, CD3OD): δ 26.3 (C-2´), 30.1 (C-3´), 45.6 (C-1´), 108.7 (C-4), 125.3 (C-3), 128.1 (C-5), 132.3 (C-2), 175.1 (COOH), 179.4 (CHO) 13 C NMR (100 MHz, CD 3 OD): δ 26.3 (C-2'), 30.1 (C-3'), 45.6 (C-1'), 108.7 (C-4), 125.3 (C-3) , 128.1 (C-5), 132.3 (C-2), 175.1 (COOH), 179.4 (CHO)
ESI-MS (positive mode) m/z : 261.01 [2M-H]-
ESI-MS (positive mode) m / z : 261.01 [2M-H] -
2-포르밀(formyl)-5-(히드록시메틸;hydroxymethyl)-12-formyl-5- (hydroxymethyl) -1 HH -피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 3)Pyrrole-1-butanoic acid (Compound 3)
1H NMR (400 MHz, CD3OD): δ 2.04 (2H, m, H-2´), 2.33 (2H, m, H-3´), 4.42 (2H, m, H-1´), 4.66 (2H, s, H-6), 6.28 (1H, d, J = 4.0 Hz, H-4), 7.01 (1H, d, J = 4.0 Hz), 9.44 (1H, s, H-1) ppm; 1 H NMR (400 MHz, CD 3 OD): δ 2.04 (2H, m, H-2'), 2.33 (2H, m, H-3'), 4.42 (2H, m, H-1'), 4.66 (2H, s, H-6), 6.28 (1H, d, J = 4.0 Hz, H-4), 7.01 (1H, d, J = 4.0 Hz), 9.44 (1H, s, H-1) ppm;
13C NMR (100 MHz, CD3OD): δ 26.2 (C-2´), 30.4 (C-3´), 44.4 (C-1´), 55.0 (C-5), 110.8 (C-4), 125.9 (C-3), 132.1 (C-2), 143.2 (C-5), 175.3 (COOH), 179.5 (CHO) 13 C NMR (100 MHz, CD 3 OD): δ 26.2 (C-2'), 30.4 (C-3'), 44.4 (C-1'), 55.0 (C-5), 110.8 (C-4) , 125.9 (C-3), 132.1 (C-2), 143.2 (C-5), 175.3 (COOH), 179.5
ESI-MS (positive mode) m/z : 234.19 [M+Na]+
ESI-MS (positive mode) m / z : 234.19 [M + Na] < + &
2-포르밀(formyl)-5-(메톡시메틸;methoxymethyl)-12-formyl-5- (methoxymethyl) -1 HH -피롤(pyrrole)-1-부타노익산(butanoic acid) (Compound 4)Pyrrole-1-butanoic acid (Compound 4)
1H NMR (400 MHz, CD3OD): δ 2.01 (2H, m, H-2´), δ 2.34 (2H, t, J = 7.6, H-3´), 3.38 (3H, s, H-OCH3), 4.39 (2H, m, H-1´), 4.51 (2H, s, H-6), 6.30 (1H, d, J = 4.0 Hz, H-4), 7.00 (1H, d, J = 4.0 Hz, H-3), 9.47 (1H, s, H-1) ppm; 1 H NMR (400 MHz, CD 3 OD): δ 2.01 (2H, m, H-2'), δ 2.34 (2H, t, J = 7.6, H-3'), 3.38 (3H, s, H- OCH 3), 4.39 (2H, m, H-1'), 4.51 (2H, s, H-6), 6.30 (1H, d, J = 4.0 Hz, H-4), 7.00 (1H, d, J = 4.0 Hz, H-3), 9.47 (1H, s, H-1) ppm;
13C NMR (100 MHz, CD3OD): δ 26.2 (C-2´), 30.3 (C-3´), 44.4 (C-1´), 56.8 (OCH3), 64.9 (C-6), 111.4 (C-4), 124.4 (C-3), 132.4 (C-2), 139.6 (C-5), 175.1 (COOH), 179.7 (CHO) 13 C NMR (100 MHz, CD 3 OD): δ 26.2 (C-2'), 30.3 (C-3'), 44.4 (C-1'), 56.8 (OCH 3), 64.9 (C-6), (C-2), 139.6 (C-5), 175.1 (COOH), 179.7 (CHO)
ESI-MS (positive mode) m/z : 248.21 [M+Na]+
ESI-MS (positive mode) m / z : 248.21 [M + Na] < + &
4-(2-4- (2- 포르밀Formyl (( formylformyl )-5-(((3-) -5 - (((3- 히드록시부탄Hydroxybutane ;; hydroxybutanhydroxybutane -2--2- ylyl )) 옥시Oxy ;; oxyoxy )) 메틸methyl ;; methylmethyl )-1H-피롤() -1H-pyrrole ( pyrrolpyrrol )-1-)-One- ylyl )) 부타노익Butanowic 산( mountain( butanoicbutanoic acidacid ) () ( CompoundCompound 5) 5)
pale yellowish gum; pale yellowish gum;
UV (MeOH) λmax (log ε): 293 (3.85); IRmax 3407, 2938, 1703, 1408 cm-1 UV (MeOH)? Max (log?): 293 (3.85); IR max 3407, 2938, 1703, 1408 cm < -1 >
1H NMR (400 MHz, CD3OD): δ 1.15 (3H, d, J = 6.4 Hz, CH3-4″), 1.18 (3H, d, J = 6.4 Hz, CH3-3″, 2.03 (2H, m, H-3′), 2.36 (2H, t, J = 7.2 Hz, H-2′), 3.47 (1H, m, H-1″, 3.75 (1H, m, H-2″, 4.43 (2H, t, J = 7.6 Hz, H-1′), 4.62 (1H, d, J= 12.4 Hz, H-6a), 4.67 (1H, d, J = 12.4 Hz, H-6b), 6.31 (1H, d, J = 4.0 Hz, H-4), 7.01 (1H, d, J= 4.0 Hz, H-3), 9.46 (1H, s, CHO) ppm; 1 H NMR (400 MHz, CD 3 OD): δ 1.15 (3H, d, J = 6.4 Hz, CH 3 -4 "), 1.18 (3H, d, J = 6.4 Hz, CH 3 -3", 2.03 ( M, H-3 '), 2.36 (2H, t, J = 7.2 Hz, H-2'), 3.47 (2H, t, J = 7.6 Hz, H-1 '), 4.62 (1H, d, J = 12.4 Hz, H-6a), 4.67 (1H, d, J = 12.4 Hz, H-6b), 6.31 ( 1H, d, J = 4.0 Hz, H-4), 7.01 (1H, d, J = 4.0 Hz, H-3), 9.46 (1H, s, CHO) ppm;
13C NMR (100 MHz, CD3OD): δ 15.0 (C-3″, 18.6 (C-4″, 27.6 (C-2′, 31.8 (C-3′, 45.9 (C-1′, 63.1 (C-6), 70.9 (C-2″, 80.6 (C-1″, 112.6 (C-4), 126.0 (C-3), 133.7 (C-2), 141.8 (C-5), 176.6 (COOH), 181.0 (CHO) ESI-MS (positive mode) m/z : 306 [M+Na]+ 13 C (100 MHz, CD 3 OD):? 15.0 (C-3 ", 18.6 (C-4", 27.6 C-6), 70.9 (C-2), 80.6 (C-1), 112.6 (C-4), 126.0 ), 181.0 (CHO) ESI- MS (positive mode) m / z: 306 [M + Na] +
HRESIMS (positive mode) m/z: 306.1312 [M+Na]+ (Calc. for [C14H21NO5 + Na]+ 306.1317).
HRESIMS (positive mode) m / z :. 306.1312 [M + Na] + (Calc for [C 14 H 21
실험예Experimental Example 1. 세포 1. Cells 생존능에On survival 대한 효과 Effect on
상기 실시예 화합물들의 새포 생존능에 대한 효과를 확인하기 위하여 문헌에 기재된 방법을 이용하여 하기와 같이 MTT 어세이법(assay)을 수행하였다 (Carmichael et al., 1987). In order to confirm the effect of the compounds of the above examples on the viability of the cells, MTT assays were performed as follows (Carmichael et al., 1987) using the method described in the literature.
RAW 264.7 세포 (ATCC, USA)를 10% 열처리-불활성 우태아 혈청(heat-inactivated fetal bovine serum) 및 항생제(penicillin-streptomycin)를 첨가한 DMEM 배지(Gibco, USA)로 37℃ 5% CO2 및 95% 대기 함유한 가습화 조건하에서 배양하였다. RAW 264.7 세포들을 3, 10, 30 및 100 mM 농도의 시료들로 24시간 동안 처리하고 배양하였다. RAW 264.7 cells (ATCC, USA) were cultured in DMEM medium (Gibco, USA) supplemented with 10% heat-inactivated fetal bovine serum and penicillin-streptomycin at 37 ° C in 5% CO2 and 95% % Air in the humidified condition. RAW 264.7 cells were treated with 3, 10, 30 and 100 mM concentrations for 24 hours and cultured.
실험결과, 도 1-A에서 나타난 바와 같이 본 발명 화합물들은 음성대조군(화합물을 처리하지 않은 군)과 비교하여 유의적인 세포독성을 나타내지 않음을 확인하였다.
As a result of the experiment, it was confirmed that the compounds of the present invention did not show significant cytotoxicity as compared with the negative control group (the group not treated with the compound) as shown in Fig. 1-A.
실험예Experimental Example 2. 면역증강효과 실험. 2. Experiment of immune enhancement.
2.1. 2.1. NONO , , TNFTNF -α 및-α and ILIL -12 -12 분비의 증가 효과Increased effect of secretion
상기 실시예 화합물들의 NO, TNF-α 및 IL-12 분비에 대한 증가효과를 확인하기 위하여 문헌에 기재된 방법을 이용하여 하기와 같이 문헌에 기재된 방법을 응용하여 측정하였다.(Jobgen, W.S., Jobgen, S.C., Li, H., Meininger, C.J., Wu, G., 2007. Analysis of nitrite and nitrate in biological samples using high-performance liquid chromatography. Journal of Chromatography B Analytical Technologies in Biomedical and Life Sciences. 851, 71-82). In order to confirm the increasing effect of the compounds of the above examples on the secretion of NO, TNF-α and IL-12, the method described in the literature was applied using the method described in the literature (Jobgen, WS, Jobgen, SC, Li, H., Meininger, CJ, Wu, G., 2007. Analysis of nitrite and nitrate in biological samples using high-performance liquid chromatography. Journal of Chromatography B Analytical Technologies in Biomedical and Life Sciences 851, 71-82 ).
RAW 264.7 세포 (ATCC, USA)를 96웰 마이크로플레이트에 웰 당 1×105 씩 분주하고, 3, 10, 30 및 100 mM의 농도로 본 발명 화합물을 처리한 후, 37℃, 5% CO2 조건에서 24시간 배양한 후, 상층액을 취하여, 50㎕의 세포 배양 상층액에 동량의 그리스 시약(Griess reagent, 0.1% (w/v)N-(1-naphthyl)ethylenediamine dihydrochloride + 1% (w/v) sulfanilamide in 5%(v/v)phosphoric acid)을 넣고 혼합한 다음, 상온에서 10분 두었으며, 그 후 인피니트 200 스펙트로포토메터 (Tecan사, Switzerland)를 사용하여 540nm에서 흡광도를 측정하였다. 리포폴리사카리드(Lipopolysaccharide; LPS, 100 ng/ml)를 양성 대조군으로 사용하였다.
RAW 264.7 cells (ATCC, USA) and then by 1 × 10 per well in a 96-well microplate 5 frequency divider, and the process of the invention compounds with a 3, 10, 30 and a concentration of 100 mM, 37 ℃, 5% CO 2 (Griess reagent, 0.1% w / v N- (1-naphthyl) ethylenediamine dihydrochloride + 1% (w / v)) was added to 50 μl of the cell culture supernatant. / v) sulfanilamide in 5% (v / v) phosphoric acid) was added and mixed at room temperature for 10 minutes. Absorbance was then measured at 540 nm using an Infinite 200 spectrophotometer (Tecan, Switzerland) . Lipopolysaccharide (LPS, 100 ng / ml) was used as a positive control.
또한, 같은 조건에서 50㎕의 세포 배양 상층액을 취하여 염증 매개물질(inflammatory mediator)인 TNF-α(tumor necrosis factor-α)와 IL-12 (Interlukin 12)의 ELISA 검사를 실시하였다 (R&D Systems Quantikine Mouse TNF-α/IL-12 kit; Ledur et al., 1995; Rahim et al., 2005).
In addition, 50 [mu] l of the cell culture supernatant was subjected to ELISA test for inflammatory mediators TNF-alpha (tumor necrosis factor-alpha) and IL-12 (Interlukin 12) under the same conditions (R & D Systems Quantikine Mouse TNF-α / IL-12 kit; Ledur et al., 1995; Rahim et al., 2005).
실험결과, 도 1 B에 나타난 바와 같이 RAW 264.7세포에서 화합물 3,4의 아질산 이온(NO2 -)의 농도가 대조군 대비 각각 1.8, 1.5배 증가하였고, 양성대조군으로 사용한 LPS 단독 처리군과 유사한 증가를 나타내어, 이를 통해 갈근 추출물이 NO 분비를 증가시킴을 확인할 수 있었으며, RAW 264.7세포에서 TNF-α가 대조군 대비 2.37, 2.31배 증가, 양성대조군으로 사용한 LPS 단독 처리군과 유사한 증가효과를 나타내었고, IL-12분비 역시 대조군 대비 유의적인 증가 효과를 나타냄에 따라, 화합물 3,4는 측정된 TNF-α,IL-12 와 NO 분비를 모두 증가시킴을 확인할 수 있었다(도 1C, 1D , 참조).
As a result, as shown in FIG. 1B, the concentration of nitrite ions (NO 2 - ) in
2.2. 2.2. RAWRAW 264.7에서의 In 264.7 식균작용에On phagocytosis 대한 활성 효과 Active effect on
상기 실시예 화합물들의 RAW 264.7에서의 식균작용에 대한 활성을 확인하기 위하여 문헌에 기재된 Neutral Red Uptake법을 이용하여 이용하여 분석을 수행하였다 (Cheng, W.X. et al., Cellular Immunology, 262, pp69-74 2010.).Analysis was carried out using the Neutral Red Uptake method described in the literature (Cheng, WX et al., Cellular Immunology, 262, pp69-74 2010.).
RAW 264.7 세포 (ATCC, USA)를 96웰 마이크로플레이트에 웰 당 1×105 씩 분주하고, 3, 10, 30 및 100 mM의 농도로 본 발명 화합물을 37℃, 5% CO2 조건에서 24시간 배양하고, 100㎕의 0.075% Neutral Red를 넣고 37℃ 배양기에서 1시간 배양후, 0.01% acetic acid와 100% 에탄올을 동량으로 혼합한 용액 200㎕를 실온에서 2시간 처리후, 인피니트 200 스펙트로포토메터 (Tecan사, Switzerland)를 사용하여 570nm에서 흡광도를 측정하였다. 리포폴리사카리드(Lipopolysaccharide; LPS, 100 ng/ml)를 양성 대조군으로 사용하였다.RAW 264.7 cells (ATCC, USA) were dispensed into 96-well microplates at a rate of 1 × 10 5 cells per well, and the compounds of the present invention were added at 37 ° C., 5% CO 2 , And 100 μl of 0.075% Neutral Red was added. After culturing in an incubator at 37 ° C for 1 hour, 200 μl of a solution containing 0.01% acetic acid and 100% ethanol in an equal volume was treated at room temperature for 2 hours, Absorbance was measured at 570 nm using a 200 spectrophotometer (Tecan, Switzerland). Lipopolysaccharide (LPS, 100 ng / ml) was used as a positive control.
실험결과, 도 1E 에 나타난 바와 같이 화합물 3 처리에 따른 RAW 264.7세포의 탐식능은 대조군 대비 30mM 처리군에서 최대 2.29배 증가하였고, 4번 화합물 역시 모든 농도에서 탐식능을 유의적으로 증가시켰다. 이를 통해 화합물 3,4는 대식세포의 탐식능을 향상시키는 것을 확인할 수 있었다(도 1B 참조).
As a result, as shown in FIG. 1E, the sowing ability of RAW 264.7 cells according to the treatment with
2.3. 실험 결과2.3. Experiment result
본 실험 결과, 화합물 3 및 4는 100 mM까지 유의적인 세포독성이 없이 NO 생성을 증가시켰다 (표 1 및 2, 도 1 A 및 B). TNF-α 및 IL-12 생성에 대한 효과에서도 유사한 양상을 나타냈다 (표 3 및 4, 도 1 C 및 D). As a result, compounds 3 and 4 increased NO production without significant cytotoxicity up to 100 mM (Tables 1 and 2, FIGS. 1A and B). The effects on TNF-a and IL-12 production were similar (Tables 3 and 4, Figs. 1C and D).
추가적으로 100mM 화합물 3으로 처치한 RAW 264.7 세포에서의 식균 활성은 비처치군보다 약 1.93배 정도 높은 활성을 나타냈다 (표 4, 도 1 E). 화합물 4 역시, 유의적으로 식균 작용을 증강시키는 활성을 나타냈다.In addition, phagocyte activity in RAW 264.7 cells treated with 100
통계학적 검정Statistical test
통계학적 유의성은 스튜던트 시험법(Student’s t-test) 상에서 p<0.05 이하 수치를 통계학적으로 유의성이 있는 것으로 간주하였다.
Statistical significance was considered to be statistically significant at p <0.05 on the Student's t- test.
실험예Experimental Example 3. 경구투여 독성실험 3. Oral dose toxicity test
본 실험에서는 7주령의 ICR 마우스 (오리엔트바이오, Japan)를 사용하여 본 발명의 화합물들 투여 전 4시간 동안 마우스를 절식하고, 체중을 측정한 후, 식품의약품안전청의 독성시험기준(식품의약품안전청, 의약품등의 독성시험기준, 식품의약품안전청고시 2005-60호, 2005)에 따라 2,000 mg/kg을 최고 용량으로 정하고, 정제 증류수로 희석하여 5 mg/kg, 50 mg/kg 및 500 mg/kg의 시험물질을 제조하였다. 투여는 임상에서의 주요 적용경로인 경구투여로 하였으며, 투여방법은 동물을 경배부 피부 고정법으로 고정한 후 금속제 경구투여용 존대를 이용하여 위내에 직접주입 하였다. 1일 1회 당일 체중을 기준으로 체중 kg당 10 ml을 투여액량으로 하여 투여하였고, 시험동물에 시험물질투여 후 2시간동안은 사료를 제한하였으며, 이후 시험기간 동안 사료와 물은 계속 공급하였다.In this experiment, the mice were fasted for 4 hours before the administration of the compounds of the present invention using ICR mice (Orient Bio, Japan) at 7 weeks of age, and their weights were measured. The test results were evaluated by the Food and Drug Administration Kg, 50 mg / kg and 500 mg / kg, respectively) were diluted with purified distilled water to a maximum dose of 2,000 mg / kg according to the Korea Food and Drug Administration Notice 2005-60 A test substance was prepared. The administration was made by oral administration, which is the main route of application in the clinic. The method of administration was as follows: The animal was fixed by the adriamycin fixation method and then injected directly into the stomach using a metal oral administration unit. 10 ml per kg of body weight was administered once a day on the basis of body weight on the day of feeding. Feed was restricted for 2 hours after administration of the test substance to the test animal, and then feed and water were continuously supplied during the test period.
식품의약품안전청의 독성시험기준 및 국제경제협력기구의 급성독성시험 가이드라인 (OECD Guideline for the Testing Chemicals revised draft guideline 420, Organization for Economic Cooperation and Development (OECD), 2001)에 독성시험기준에 따라 투여 후 처음 6시간 동안을 특별한 주의를 가지고 시험동물의 피부, 털, 눈, 점막, 호흡기, 순환기, 자율신경계, 중추신경계, 신체 운동 활동성, 행동형태 및 시험동물의 진전(tremors), 경련(convulsions), 유연(salivation), 설사(diarrhoea), 기면(lethargy), 수면(sleep), 혼수(coma) 등의 유무를 관찰하였다. 투여 후 14 일 동안 1일 1회씩 일반 임상증상을 관찰하고 시험동물의 개별 체중은 시험물질을 투여하기 전과 후, 시험기간 동안 1일 1회씩 측정하였다.In accordance with the Toxicological Testing Standards of the Korea Food and Drug Administration and the guidelines of the International Organization for Economic Cooperation and Development (OECD) Guidelines for the Testing Chemicals revised draft guideline 420 (OECD, 2001) During the first 6 hours, with special attention, the test animal's skin, hair, eyes, mucous membrane, respiratory system, circulatory system, autonomic nervous system, central nervous system, physical activity, behavioral form and tremors of test animals, convulsions, We observed the presence of salivation, diarrhea, lethargy, sleep, and coma. The general clinical symptoms were observed once a day for 14 days after the administration and the individual body weight of the test animals was measured once a day before and after administration of the test substance and during the test period.
투여 후 14일째에 ICR 마우스를 에틸 에테르(ethyl ether)로 마취하고, 방혈 치사시킨 후 모든 장기를 적출하여, 개체 시험동물의 육안적 병변 관찰하고 장기의 무게를 측정하였다.ICR mice were anesthetized with ethyl ether on the 14th day after the injection, and all the organs were removed by bled lethal injection to observe gross lesions of individual test animals and weigh the organs.
면역증강에 효과를 나타내는 본 발명의 화합물들의 단회 경구투여에 의한 급성독성시험결과, 본 연구에 사용된 시험동물 및 조건에서 투여된 최고 용량인 2,000 mg/kg에서 사망하는 개체가 관찰되지 않았으며, 사용한 어떠한 용량에서도 식품의약품안전청의 독성시험기준에 따라 관찰된 모든 지표에서 본 발명의 화합물들의 투여에 의한 독성은 유발되지 않았다. 결론적으로 본 발명의 화합물들은 급성독성시험 권고 최대용량인 2,000 mg/kg에서도 독성이 없이 안전함을 확인하였다.
As a result of the acute toxicity test by single oral administration of the compounds of the present invention showing the effect on the immune enhancement, no mortality was observed at the highest dose of 2,000 mg / kg administered in the test animals and conditions used in the present study, No toxicity by administration of the compounds of the present invention was observed in any of the indicators observed according to the Food and Drug Administration's toxicity test standards at any dose used. In conclusion, the compounds of the present invention were found to be safe without toxicity at the maximum recommended dose of 2,000 mg / kg of acute toxicity test.
본 발명의 화합물들을 포함하는 약학조성물의 제제 예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Formulation examples of the pharmaceutical compositions containing the compounds of the present invention are illustrated, but the present invention is not intended to be limited thereto but is specifically described.
제제예Formulation example 1. One. 산제의Sanje 제조 Produce
Compound 1 ---------------------------------------- 20 ㎎
유당 ---------------------------------------------- 100 ㎎Lactose ---------------------------------------------- 100 mg
탈크 ---------------------------------------------- 10 ㎎Talc ---------------------------------------------- 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above components are mixed and filled in airtight bags to prepare powders.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
Compound 2 ---------------------------------------- 10 ㎎
옥수수전분 ---------------------------------------- 100 ㎎Corn starch ---------------------------------------- 100 mg
유당 ---------------------------------------------- 100 ㎎Lactose ---------------------------------------------- 100 mg
스테아린산 마그네슘 ------------------------------- 2 ㎎Magnesium stearate ------------------------------- 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
제제예 3. 캅셀제의 제조Formulation Example 3. Preparation of capsules
Compound 3 ---------------------------------------- 10 ㎎
결정성 셀룰로오스 --------------------------------- 3 ㎎Crystalline cellulose - 3 mg
락토오스 ------------------------------------------ 14.8 ㎎Lactose ------------------------------------------ 14.8 mg
마그네슘 스테아레이트 ----------------------------- 0.2 ㎎Magnesium stearate 0.2 mg < RTI ID = 0.0 >
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4. Preparation of injection
Compound 4 ---------------------------------------- 10 ㎎
만니톨 -------------------------------------------- 180 ㎎Mannitol -------------------------------------------- 180 mg
주사용 멸균 증류수 -------------------------------- 2974 ㎎Sterile sterilized distilled water for injection - 297 mg
Na2HPO4·12H2O ------------------------------------- 26 ㎎Na 2 HPO 4 .12H 2 O ------------------------------------- 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.
(2 ml) per ampoule in accordance with the usual injection method.
제제예 5. 액제의 제조Formulation Example 5. Preparation of a liquid preparation
Compound 5 ---------------------------------------- 20 ㎎
이성화당 ------------------------------------------ 10 gIsomerization Party ------------------------------------------ 10 g
만니톨 -------------------------------------------- 5 gMannitol -------------------------------------------- 5 g
정제수 -------------------------------------------- 적량Purified water --------------------------------------------
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.
Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, And sterilized to prepare a liquid preparation.
제제예 6. 건강 식품의 제조 Formulation Example 6. Preparation of Healthy Foods
Compound 4 ---------------------------------------- 1000 ㎎
비타민 혼합물 ------------------------------------- 적량Vitamin mixture -------------------------------------
비타민 A 아세테이트 ------------------------------- 70 ㎍Vitamin A Acetate ------------------------------- 70 μg
비타민 E ------------------------------------------ 1.0 ㎎Vitamin E ------------------------------------------ 1.0 mg
비타민 B1 ------------------------------------------ 0.13 ㎎Vitamin B 1 ------------------------------------------ 0.13 mg
비타민 B2 ------------------------------------------ 0.15 ㎎Vitamin B 2 ------------------------------------------ 0.15 mg
비타민 B6 ------------------------------------------ 0.5 ㎎Vitamin B 6 ------------------------------------------ 0.5 mg
비타민 B12 ----------------------------------------- 0.2 ㎍Vitamin B 12 ----------------------------------------- 0.2 g
비타민 C ------------------------------------------ 10 ㎎Vitamin C ------------------------------------------ 10 mg
비오틴 -------------------------------------------- 10 ㎍Biotin -------------------------------------------- 10 μg
니코틴산아미드 ------------------------------------ 1.7 ㎎Nicotinic acid amide 1.7 mg
엽산 ---------------------------------------------- 50 ㎍Folic acid ---------------------------------------------- 50 g
판토텐산 칼슘 ------------------------------------- 0.5 ㎎Calcium pantothenate ------------------------------------- 0.5 mg
무기질 혼합물 ------------------------------------- 적량Inorganic mixture -------------------------------------
황산제1철 ----------------------------------------- 1.75 ㎎Ferrous sulfate - 1.75 mg < RTI ID = 0.0 >
산화아연 ------------------------------------------ 0.82 ㎎Zinc oxide ------------------------------------------ 0.82 mg
탄산마그네슘 -------------------------------------- 25.3 ㎎Magnesium carbonate -------------------------------------- 25.3 mg
제1인산칼륨 --------------------------------------- 15 ㎎Potassium phosphate monohydrate 15 mg
제2인산칼슘 --------------------------------------- 55 ㎎Secondary calcium phosphate --------------------------------------- 55 mg
구연산칼륨 ---------------------------------------- 90 ㎎Potassium citrate ---------------------------------------- 90 mg
탄산칼슘 ------------------------------------------ 100 ㎎Calcium carbonate ------------------------------------------ 100 mg
염화마그네슘 -------------------------------------- 24.8 ㎎Magnesium chloride -------------------------------------- 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.
Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
제제예Formulation example 7. 건강 음료의 제조 7. Manufacture of health drinks
Compound 1 ---------------------------------------- 100 ㎎
비타민 C ------------------------------------------ 15 gVitamin C ------------------------------------------ 15 g
비타민 E(분말) ------------------------------------ 100 gVitamin E (powder) ------------------------------------ 100 g
젖산철 -------------------------------------------- 19.75 gLactic Acid Iron -------------------------------------------- 19.75 g
산화아연 ------------------------------------------ 3.5 gZinc oxide ------------------------------------------ 3.5 g
니코틴산아미드 ------------------------------------ 3.5 gNicotinic acid amide 3.5 g
비타민 A ------------------------------------------ 0.2 gVitamin A ------------------------------------------ 0.2 g
비타민 B1 ------------------------------------------ 0.25 gVitamin B 1 ------------------------------------------ 0.25 g
비타민 B2 ------------------------------------------ 0.3gVitamin B 2 ------------------------------------------ 0.3g
물 ------------------------------------------------ 정량Water ------------------------------------------------ Quantitative
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 ° C for about 1 hour. The resulting solution was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, It is used in the production of the health beverage composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다. Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
Claims (7)
Morrole A (5): (4- (2-formyl) -5 - (((3-hydroxybutane; hydroxybutane), which is a novel alkaloid compound having a structure of the following formula (5) -2-yl) oxy) methyl) -1H-pyrrole-1-yl) butanoic acid, an isomer thereof or a pharmacologically acceptable salt thereof,
Morrolee ( 5) :
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CN104844497A (en) * | 2015-05-05 | 2015-08-19 | 竺叶洪 | Method for extracting active acid from Japanese ardisia root |
CN105753761A (en) * | 2015-04-01 | 2016-07-13 | 司红康 | Method for extracting pharmacodynamically active ingredients efficiently from root of Brassica rapa |
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CN105753761A (en) * | 2015-04-01 | 2016-07-13 | 司红康 | Method for extracting pharmacodynamically active ingredients efficiently from root of Brassica rapa |
CN104844497A (en) * | 2015-05-05 | 2015-08-19 | 竺叶洪 | Method for extracting active acid from Japanese ardisia root |
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