KR19990015090A - Antagonist for platelet activating factor receptor binding, containing (20S) -ginsenoside Rg₃ and / or ginsenoside Rg₃ - Google Patents
Antagonist for platelet activating factor receptor binding, containing (20S) -ginsenoside Rg₃ and / or ginsenoside Rg₃ Download PDFInfo
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Abstract
본 발명은 (20S)-진세노사이드 Rg3및/또는 진세노사이드 Rg5을 함유하는, 혈소판 활성화 인자(Platelet-Activating Factor ; PAF)에 대한 길항제에 관한 것이다.The present invention relates to antagonists for Platelet-Activating Factor (PAF), which contain (20S) -ginsenoside Rg 3 and / or ginsenoside Rg 5 .
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본 발명은 (20S)-진세노사이드 Rg3및/또는 진세노사이드 Rg5을 함유하는, 혈소판 활성화 인자 수용체 결합에 대한 길항제에 관한 것으로 더욱 상세하게는, (20S)-진세노사이드 Rg3및 진세노사이드 Rg5가 혈소판 활성화 인자 수용체 결합에 대하여 길항활성을 가진다는 사실을 새롭게 발견하고 (20S)-진세노사이드 Rg3및 진세노사이드 Rg5의 이러한 길항활성을 이용하여 혈소판 활성화 인자와 관련한 염증질환 등의 치료에 유용하게 사용할 수 있는 혈소판 활성화 인자 수용체 결합에 대한 길항제에 관한 것이다.The present invention relates to antagonists for platelet activating factor receptor binding, containing (20S) -ginsenoside Rg 3 and / or ginsenoside Rg 5, and more particularly, to (20S) -ginsenoside Rg 3 and Newly discovered that ginsenoside Rg 5 has antagonistic activity against platelet activator receptor binding and utilizing these antagonistic activities of (20S) -ginsenoside Rg 3 and ginsenoside Rg 5 in relation to platelet activating factor An antagonist to platelet activating factor receptor binding that can be usefully used in the treatment of inflammatory diseases and the like.
혈소판 활성화 인자(Platelet-Activating Factor ; PAF)는 IgE로 감작된 토끼의 호염구를 항원으로 자극하면 배양액으로 방출되어 혈소판을 활성화시키는 인자로서(Benveniste, J., P. M. Henson and C. G. Cochrane (1972) Leucocyte dependent histamine release from rabbit platelet, The role of Ig E, basophils and a platelet activating factor.J. Exp. Med.1356-1377.), 다핵형 백혈구(호중구, 호산구, 호염구), 단핵구, 대식세포, 비만세포 등 면역세포와 혈관 내피세포 및 혈소판에서 생산된다(Benveniste, J. and B. Arnoux (1983) Platelet-activating factor and structurally related ether-lipids, Elsevier, Amsterdam., Benveniste, J. and B. B. Vargaftig (1983) Platelet-activating factor, An ether lipid with biological activity in ether lipids in 'Biochemical and Biomedical Aspects' H. K. Magnold and F. Paltauf. ed. Academic Press, New York, 355-476., T. C. Lee and F. Snyder. (1984) 'Function, metabolism, and regulation of platelet-activating factor and related ether lipids, in phospholipids and cellular regulation.' J. F. Kuo ed. CRC Press, Boca Raton, F1, 1-39). 혈소판 활성화 인자의 생리적 기능은 히스타민(histamine), 루코트리엔들(leukotrienes), 프로스타글란딘들(prostaglandins) 등 염증매개 물질보다 1/1,000~1/10,000의 저농도(10-9~10-10M)에서 염증세포를 활성화하여 다른 염증 매개물질 합성 및 방출을 유도하는 급성 염증 반응의 개시인자이다(Braquet, P., T. Touqui, T. Y. Shen and B. B. Vergaftig (1987) Perspective in platelet-activating factor research,Pharmacol. Rev. 39, 97-145). 혈소판 활성화 인자의 염증 반응이 활성화되면 기관지 수축, 천식, 조직이식 거부반응, 심장 아나필락시(anaphylaxy), 내독소에 의한 쇼크, 위궤양, 급성 알러지 반응, 과민성 피부염 등 다양한 염증질환을 유발한다(Gonzalez-Crussi, F. and W. Hsueh (1983) Experimental model of ischemic bowl necrosis. The role of platelet-activating factor and endotoxin.Am. J. Pathol. 112, 127-135., Katoh, N., M. Itoh, Y. Yokoyama and T. Joh (1994) Evaluation of the mechanism of endothelin-induced rat gastric mucosal lesion formation.Nippon Shokakibyo Gakkai Zasshi, 91, 27-35., Frerichs, K. U., P. J. Lindsberg, J. M. Hallenbeck and G. Z. Feuerstein (1990) Platelet-activating factor and progressive brain damage following focal brain injury.J. Neurosurg. 73, 223-233.,Tokutomi, T., M. Sigemori, T. Kikuchi and M. Hirohata (1994) Effect of platelet-activating factor antagonist on brain injury in rats.Acta. Neurochir. Suppl. Wien. 60, 508-510., Makowka, L., F. A. Chapman, D. V. Cramer, S. G. Qian, H. Sun and T. E. Starzl (1990) Platelet-activating factor antagonists, SRI 63-441, on rejection of xenografts and allografts in sensitized hosts.Transplantation 50, 359-365.).Platelet-Activating Factor (PAF) is a factor that activates platelets by stimulating basophils of IgE-sensitized rabbits with antigens and activating platelets (Benveniste, J., PM Henson and CG Cochrane (1972) Leucocyte dependent histamine release from rabbit platelet, The role of Ig E, basophils and a platelet activating factor.J.Exp. Med. 1356-1377.), multinuclear leukocytes (neutrophils, eosinophils, basophils), monocytes, macrophages, mast cells, etc. Produced in immune cells, vascular endothelial cells and platelets (Benveniste, J. and B. Arnoux (1983) Platelet-activating factor and structurally related ether-lipids, Elsevier, Amsterdam., Benveniste, J. and BB Vargaftig (1983) Platelet -activating factor, An ether lipid with biological activity in ether lipids in 'Biochemical and Biomedical Aspects' HK Magnold and F. Paltauf.ed.Academic Press, New York, 355-476., TC Lee and F. Snyder. (1984) 'Function, metabolism, and regulation of platelet-a ctivating factor and related ether lipids, in phospholipids and cellular regulation. 'JF Kuo ed.CRC Press, Boca Raton, F1, 1-39). The physiological function of platelet activators is 1 / 1,000 to 1 / 10,000 lower concentrations (10 -9 to 10 -10 M) than inflammatory mediators such as histamine, leukotrienes and prostaglandins. Is an initiator of an acute inflammatory response that activates inflammatory cells to induce the synthesis and release of other inflammatory mediators (Braquet, P., T. Touqui, TY Shen and BB Vergaftig (1987) Perspective in platelet-activating factor research, Pharmacol Rev. 39 , 97-145). When the inflammatory response of platelet activator is activated, it causes various inflammatory diseases such as bronchial contraction, asthma, tissue transplant rejection, cardiac anaphylaxy, endotoxin shock, gastric ulcer, acute allergic reaction, and irritable dermatitis (Gonzalez-Crussi). , F. and W. Hsueh (1983) Experimental model of ischemic bowl necrosis.The role of platelet-activating factor and endotoxin.Am J. Pathol. 112 , 127-135., Katoh, N., M. Itoh, Y Yokoyama and T. Joh (1994) Evaluation of the mechanism of endothelin-induced rat gastric mucosal lesion formation.Nippon Shokakibyo Gakkai Zasshi, 91 , 27-35., Frerichs, KU, PJ Lindsberg, JM Hallenbeck and GZ Feuerstein (1990). Platelet-activating factor and progressive brain damage following focal brain injury.J. Neurosurg. 73 , 223-233., Tokutomi, T., M. Sigemori, T. Kikuchi and M. Hirohata (1994) Effect of platelet-activating factor antagonist on brain injury in rats. Acta. Neurochir. suppl. Wien. 60, 508-510., Makowk a, L., FA Chapman, DV Cramer, SG Qian, H. Sun and TE Starzl (1990) Platelet-activating factor antagonists, SRI 63-441, on rejection of xenografts and allografts in sensitized hosts. Transplantation 50 , 359-365.).
그러나 혈소판 활성화 인자가 수용체에 결합되지 않으면 혈장이나 세포에서 가수분해 효소 아세틸하이드롤라제(acetylhydrolase)에 의해 리소-혈소판활성화인자(lyso-PAF)로 불활성화되는 것(Braquet, P., T. Touqui, T. Y. Shen and B. B. Vergaftig (1987) Perspective in platelet-activating factor research,Pharmacol. Rev. 39, 97-145)에 착안하여, 염증질환을 개선할 목적으로 혈소판 막 수용체에 혈소판 활성화 인자가 결합하는 것을 길항적으로 방해하는 물질 탐색이 이루어져 왔다. 혈소판 활성화 인자 유사구조 길항제로는 CV 3988(Terashita, Z. I., S. Tsushima, Y. Yoshioka, H. Nomura, Y. Inada and K. Nishikawa (1983) CV-3988, A specific antagonist of platelet activating factor(PAF).Life Sci. 32. 1975-1982), CV 6209(Terashita, Z. I., Y. Imura, M. Takatani, S. Tsushima and K. Nishikawa (1986) CV-6209, A highly potent platelet activating factor(PAF) antagonist. (abstract). Gatlingurg, Tennessee, October, p. 29), ONO 6240(Miyamoto, T., H. Ohno, T. Yano, T. Okada, N. Hamanaka and A. Kawasaki (1983) Ono-6240, A new potent antagonist of platelet activating factor,Third International Congress of Inflammation,Paris, Sept, Abstr. 513-519), SRI 계열(Lee, M. L., C. M. Winslow, C. Jaeggi, F. D'Aries, G. Frisch, C. Farley, M. K. Melden, D. A. Handly and R. N. Saunders (1985) Inhibition of platelet activating factor, Synthesis and biological activity of SRI 63-073, a new phospholipid PAF-acether antagonist in,Is there a Case for PAF-acether Antagonists?.Paris, June, Abstr. A4)이 있으며, 천연물 유래 혈소판 활성화 인자 길항제는 은행잎으로부터 진콜라이드(Ginkolide) B(Braquet, P (1985) BM52021 and related compounds, a new series of highly specific PAF-acether receptor antagonists. Prostaglandins30, 689), 후추로부터 카드수레논(Kadsurenone)(Shen, T. Y., S. B. Hwang, M. N. Chang, T. W. Doebber, M. H. Lam, M. S. Wu, X. Wang, G.Q. Han and R. Z. Li (1985) Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng(Piper futokadsura): Specific inhibition ofin vitroandin vivoplatelet-activating factor-induced effects.Proc. Natl. Acad. Sci.USA82, 672-676.), 흰꽃 바디나물로부터 쿠마린(coumarin)(Takeuchi, N., T. Kasama, K.Mayuzumi, K. Tamura, H. Fukaya, T. Ohono and S. Tobinaga (1988) The antagonist effects of compounds derived from Khellacton on platelet-activating factor.Chem. Pharm. Bull. 36, 4221-4224), 신이로부터 마그놀린(magnolin)(Pan, J. X., O. D. Hensens, D. L. Wink, M. N. Chang and S. B. Hwang (1987) Lignans with platelet activating factor antagonist activity fromMagnolia biondii. Phytochemistry 26,1377-1379) 등이 보고 되었다.However, if the platelet activator does not bind to the receptor, it is inactivated by the hydrolytic enzyme acetylhydrolase in plasma or cells to lyso-PAF (Braquet, P., T. Touqui). , TY Shen and BB Vergaftig (1987) Perspective in platelet-activating factor research, Pharmacol. Rev. 39 , 97-145), antagonizing the binding of platelet activating factors to platelet membrane receptors for the purpose of improving inflammatory diseases. The search for interfering substances has been made. Platelet activator-like structural antagonists include CV 3988 (Terashita, ZI, S. Tsushima, Y. Yoshioka, H. Nomura, Y. Inada and K. Nishikawa (1983) CV-3988, A specific antagonist of platelet activating factor (PAF) Life Sci. 32. 1975-1982), CV 6209 (Terashita, ZI, Y. Imura, M. Takatani, S. Tsushima and K. Nishikawa (1986) CV-6209, A highly potent platelet activating factor (PAF) antagonist. (abstract) .Gatlingurg, Tennessee, October, p. 29), ONO 6240 (Miyamoto, T., H. Ohno, T. Yano, T. Okada, N. Hamanaka and A. Kawasaki (1983) Ono-6240 , A new potent antagonist of platelet activating factor, Third International Congress of Inflammation, Paris, Sept, Abstr. 513-519, SRI series (Lee, ML, CM Winslow, C. Jaeggi, F. D'Aries, G. Frisch) , C. Farley, MK Melden, DA Handly and RN Saunders (1985) Inhibition of platelet activating factor, Synthesis and biological activity of SRI 63-073, a new phospholipid PAF-acether antagonist in, Is there a Case for PAF-acether Antagonists ?, Paris, June, Abstr. A4) Natural product-derived platelet activator antagonists are Ginkolide B (Braquet, P (1985) BM52021 and related compounds, a new series of highly specific PAF-acether receptor antagonists. Prostaglandins 30 , 689), Kadsurenone (Shen, TY, SB Hwang, MN Chang, TW Doebber, MH Lam, MS Wu, X. Wang, GQ Han and RZ Li (1985) Characterization of a platelet -activating factor receptor antagonist isolated from haifenteng (Piper futokadsura) : Specific inhibition of in vitro and in vivo platelet-activating factor-induced effects.Proc. Natl. Acad. Sci. USA 82 , 672-676. Coumarin (Takeuchi, N., T. Kasama, K.Mayuzumi, K. Tamura, H. Fukaya, T. Ohono and S. Tobinaga (1988) The antagonist effects of compounds derived from Khellacton on platelet-activating factor. Chem. Pharm. Bull. 36 , 4221-4224), Magnolin (Pan, JX, OD Hensens, DL Wink, MN Chang and SB Hwang (1987) Lignans with platelet activating factor antagonist activity from Magnolia biondii. Phytochemistry 26, 1377-1379).
한편, 인삼(Panax Ginseng)은 오갈피나무과(Araliaceae)에 속하는 다년생 초본류로서, 한방에서는 그 뿌리를 인삼(Ginseng Radix)이라 하며 강장(强壯), 강정(强精), 조혈(造血), 보온(保溫), 건위(健胃), 피로회복, 정신안정, 진정작용 등의 효능이 있는 것으로 알려져 있다.(고려인삼의 효능요약집, 한국인삼연구소, 대성인쇄사, p. 143(1985)., 고려인삼, 한국인삼연초연구원, 천일인쇄사, p. 89(1994).) 인삼 사포닌은 다른식물과 달리 독성이 없고 0.001% 이하에서는 용혈작용을 나타내지 않는 것으로 알려져 있으며,(田中 治, 藥用人蔘 共立出版, p. 43(1981)., 김낙두 (1978), 고려인삼, 고려인삼연구소, p. 118.)중추신경 억제작용(Tanaki, K., Saito, H. and Nabata, H. (1972)J. Pharmacol. 33, 245., Katu, Y., Miyata, T., Urano, T., Sato, I. and Kinoshita, A. (1975)Arzneim-Forsch(Drug Res.)(1975),25, 4.), 단백질합성 촉진작용(Yokozawa, T. and Oura, H. (1990),J. Nat. Prod.,53, 1514., Yamamoto, M., Takeuchi, N., Yamada, K., Hayashi, Y., Hirai, A. and Kumakai, K. (1978)Arzneim-Forsch. 27, 1169., Yamamoto, M., Masaki, M., Yamada, K., Hayashi, Y., Hirai, A. and Kumakai, K. (1978)Arzneim-Forsch. 28, 2238.), 부신피질호르몬 분비촉진작용(Pearec, P. T., Zois, I., Wynne, K. N. and Funder, J. W. (1982)Endocrinol. 29, 567., 한병훈, 장일무 (1977), 고려인삼학회지2, 17) , 혈소판 응집억제작용(田村泰 (1992),The Ginseng Review,13, 198., Nakanishi and Onishi (1992), 약용인삼연구회 강연요지집 (9회), 약용인삼연구회, p. 12.) 중성지질의 흡수촉진작용(주충노, 최임순, 이상직, 조성희, 손명희 (1973), 한국생화학회지6, 185., Joo, C. N., Cho, Y. D., Koo, J. H., Kim, C. W. and Lee, S. J. (1977)Korean Biochem. J. 13. 1.), 면역증강작용(이원영, 심우남, 김주덕, 고은희, 김병수 (1988) 대한암학회지20, 126., Kim, Y. S., Kang, K. S. and Kim, S. I. (1991)Korean J. Ginseng Sci. 15, 13., 김미정, 정노팔(1987) 고려인삼학회지11, 119) ) 등이 있는 것으로 보고되어 있다.Meanwhile, Panax Ginseng is a perennial herb belonging to the Araliaceae family, and its root is called Ginseng Radix, and the tonic, Gangjeong, hematopoiesis, and warmth ), Health, fatigue, mental stability, sedative effects, etc. (Korea Ginseng Research Institute, Ginseng Research Institute, Daesung Print Co., p. 143 (1985)., Korean ginseng, Korea Ginseng and Tobacco Research Institute, Cheonil Print Co., p. 89 (1994).) Unlike other plants, ginseng saponin is not toxic and does not show hemolytic activity below 0.001%. (田中 人, 藥用 人蔘 共 立 出版, p. 43 (1981)., Nak-Doo Kim (1978), Korean Ginseng, Korea Ginseng Research Institute, p. 118.) Central nervous inhibitory activity (Tanaki, K., Saito, H. and Nabata, H. (1972) J. Pharmacol . 33, 245., Katu, Y. , Miyata, T., Urano, T., Sato, I. and Kinoshita, A. (1975) Arzneim-Forsch (Drug Res.) (1975), 25, 4.) , Protein synthesis (Yokozawa, T. and Oura, H. (1990), J. Nat. Prod. , 53 , 1514., Yamamoto, M., Takeuchi, N., Yamada, K., Hayashi, Y., Hirai, A and Kumakai, K. (1978) Arzneim-Forsch. 27 , 1169., Yamamoto, M., Masaki, M., Yamada, K., Hayashi, Y., Hirai, A. and Kumakai, K. (1978) Arzneim-Forsch. 28 , 2238.), corticosteroid secretion promoting activity (Pearec, PT, Zois, I., Wynne, KN and Funder, JW (1982) Endocrinol. 29 , 567., Han Byung-hoon, Jang Il-mu (1977), Korean Journal of Ginseng 2 , 17), Platelet Aggregation Inhibition (田村 泰 (1992), The Ginseng Review , 13 , 198., Nakanishi and Onishi (1992), Journal of Medicinal Ginseng Research Abstracts Collection (9), Medicinal Ginseng Research Society, p . 12.) Promoting Absorption of Neutral Lipids (Cho Chung-no, Im-Soon Choi, Lee Sang-jik, Sung-Hee Cho, Myung-Hee Son (1973), Korean Journal of Biochemistry 6 , 185., Joo, CN, Cho, YD, Koo, JH, Kim, CW and Lee, SJ ( 1977) Korean Biochem.J. 13. 1.), Immune Enhancement Activity (Won Young Lee, Woo Nam Kim, Joo Deok Kim, Eun Hee Ko, Byung Soo Kim (1988) Korean Cancer Society 20 , 126., Kim, YS, Kang, KS and Kim, SI (1991) Korean J. Ginseng Sci. 15 , 13., Kim Mi-jung, Jung Nopal (1987) Korean Ginseng Society 11 , 119)
그리고 홍삼은 6년동안 재배한 인삼을 증삼, 건조 등의 과정을 거쳐 수분 함량이 12.5-13.5%가 되도록 가공한 인삼 제품으로서, 제조과정중 비효소적으로 갈색화 반응이 촉진되어 농다갈색의 색상을 가지며 매우 단단한 형태로 가공하여 원형을 유지시킨 인삼 제품이다(한국인삼연초연구원 (1993), 고려인삼, 천일인쇄사, pp. 44).Red ginseng is a ginseng product that has been processed for 6 years to produce 12.5-13.5% water content through red ginseng, drying, etc., and the browning reaction is promoted by non-enzymatic browning during the manufacturing process. It is a ginseng product processed into a very hard form and maintained in its original form (Korea Ginseng & Tobacco Research Institute (1993), Korea Ginseng, Cheonil Printed Firm, pp. 44).
이에, 본 발명자들은 홍삼에 함유되어 있는 물질을 대상으로 혈소판 활성 인자에 대한 길항활성을 연구하여 (20S)-진세노사이드 Rg3및 진세노사이드 Rg5이 혈소판 활성 인자에 대하여 길항활성이 있음을 알고 본 발명을 완성하였다.Therefore, the present inventors studied the antagonistic activity of platelet activating factor in a substance contained in red ginseng, indicating that (20S) -ginsenoside Rg 3 and ginsenoside Rg 5 have antagonistic activity against platelet activating factor. The present invention has been completed.
본 발명은 (20S)-진세노사이드 Rg3및/또는 진세노사이드 Rg5을 함유하는, 혈소판활성화인자 수용체 결합에 대한 길항제를 제공하는 것을 목적으로 한다.An object of the present invention is to provide an antagonist for platelet activator receptor binding, which contains (20S) -ginsenoside Rg 3 and / or ginsenoside Rg 5 .
본 발명은 화학식 1로 표시되는 (20S)-진세노사이드 Rg3및/또는 화학식 2로 표시되는 진세노사이드 Rg5을 함유하는, 혈소판 활성 인자에 대한 길항제를 제공한다.The present invention provides an antagonist for platelet activating factors, containing (20S) -ginsenoside Rg 3 represented by formula (1) and / or ginsenoside Rg 5 represented by formula (2).
본 발명의 혈소판 활성 인자에 대한 길항제는 생체내 또는 생체외에서 PAF 활성 조절에 사용된다. 본 발명의 혈소판 활성 인자에 대한 길항제는 염증치료제 또는 염증치료 보조제로 사용될 수 있다. 즉, 본 발명의 혈소판 활성 인자에 대한 길항제는 혈소판 활성화 인자와 관련된 염증질환 및 임신과 난자착상조절에 유용하게 사용될 수 있다. 본 발명의 혈소판 활성화 인자에 대한 길항제에 의해 치료될 수 있는 염증질환에는 천식, 알레르기, 관절염, 류마치스, 혈전증, 급성염증, 전신성과민증, 망막염, 간염, 장염, 췌장염, 신장염, 비염, 아토피성 피부염, 심장과민증, 내독소쇼크, 중추신경계 손상 또는 장기(조직) 이식 거부반응이 포함된다.Antagonists against platelet activators of the invention are used to modulate PAF activity in vivo or ex vivo. Antagonists against platelet activators of the present invention can be used as an inflammatory therapy or an inflammatory therapy adjuvant. That is, the antagonist against platelet activating factor of the present invention can be usefully used for inflammatory diseases associated with platelet activating factor and pregnancy and egg implantation control. Inflammatory diseases that can be treated by antagonists against platelet activating factors of the present invention include asthma, allergies, arthritis, rheumatoid, thrombosis, acute inflammation, systemic hypersensitivity, retinitis, hepatitis, enteritis, pancreatitis, nephritis, rhinitis, atopic dermatitis, Cardiac hypersensitivity, endotoxin shock, central nervous system damage, or organ (tissue) transplant rejection.
본 발명의 혈소판 활성화 인자에 대한 길항제는 본 발명의 (20S)-진세노사이드 Rg3및/또는 진세노사이드 Rg5과 약제학적으로 허용 가능한 담체, 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다.Antagonists for platelet activating agents of the invention may be prepared in unit dose form by formulating with (20S) -ginsenoside Rg 3 and / or ginsenoside Rg 5 of the invention and a pharmaceutically acceptable carrier, excipient or Or by incorporating into a multi-dose container.
제제 형태는 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑기스제, 분말제, 과립제, 정제, 캅셀제 형태일 수 있으며, 분산제, 현탁제 또는 안정화제를 함유할 수 있다.Formulation forms may be in the form of solutions, suspensions or emulsions in oils or aqueous media or in the form of extracts, powders, granules, tablets, capsules, and may contain dispersants, suspensions or stabilizers.
본 발명의 혈소판 활성화 인자 수용체 결합에 대하여 길항활성을 가지는 (20S)-진세노사이드 Rg3및/또는 진세노사이드 Rg5은 통상적으로 홍삼으로부터 추출공정을 통하여 분리, 제조되거나 또는 인삼의 디올계 사포닌을 초산으로 처리하여 높은 수율로 제조될 수 있다.(20S) -ginsenoside Rg 3 and / or ginsenoside Rg 5 having antagonistic activity against platelet activating factor receptor binding of the present invention is typically isolated, prepared from extraction from red ginseng or diol-based saponins of ginseng It can be prepared in high yield by treating with acetic acid.
이하에서, 실시예를 통하여 본 발명을 더욱 상세히 설명한다. 그러나 하기의 실시예는 본 발명의 예시일 뿐이므로 본 발명이 하기의 실싱예에 의하여 한정되는 것으로 간주되어서는 안된다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are only illustrative of the present invention and the present invention should not be considered as limited by the following examples.
실시예 1 홍삼으로부터 (20S)-진세노사이드 RgExample 1 (20S) -ginsenoside Rg from Red Ginseng 33 및 진세노사이드 RgAnd ginsenoside Rg 55 의 제조Manufacture
홍삼 3kg을 분쇄하여 5℃에서 95% 메탄올 10ℓ을 사용하여 2일간 3회 추출하고 여과액을 모아 감압 농축하여 540g의 추출물을 얻었다. 이 추출물을 증류수 5ℓ에 녹여 순차적으로 석유에테르 2ℓ로 3회 세척한 후, 수층을 다시 n-부탄올 2ℓ을 사용하여 3회 추출하여 부탄올 분획 320g을 얻었다.3 kg of red ginseng was ground and extracted three times for 2 days using 10 L of 95% methanol at 5 ° C. The filtrates were collected and concentrated under reduced pressure to obtain 540 g of extract. The extract was dissolved in 5 L of distilled water, washed three times sequentially with 2 L of petroleum ether, and the aqueous layer was extracted three times with 2 L of n-butanol to obtain 320 g of butanol fraction.
부탄올 분획을 메탄올 1ℓ에 가온하여 녹인 후 냉침하여 침전물을 제거한 다음, 실리카겔 칼럼 크로마토그래피(CHCl3/CH3OH/H2O, 9:3:1, v/v)하여 순수한 진세노사이드 Rg5480㎎ 및 (20R)-진세노사이드 Rg3와 (20S)-진세노사이드 Rg3라세믹 혼합물 1.5g을 얻었다. (20R)-진세노사이드 Rg3와 (20S)-진세노사이드 Rg3라세믹 혼합물 1.5g을 메탄올 30㎖에 가온 및 초음파처리로 현탁시키고 냉각하여 침전물을 제거한 후 여액을 감압 농축하였다. 감압 농축물(720㎎)을 피리딘(20㎖)에 녹이고 빙냉하에서 초산 무수물(20㎖)을 가한 후 실온에서 10시간 교반하였다. 반응생성물을 에틸아세테이트(100㎖)로 분배하여 3회 추출하고, 5% HCl(150㎖)로 3회, NaHCO3포화수용액(150㎖)으로 3회, 증류수로 3회 세척한 다음, 에틸 아세테이트 분획을 감압농축하였다. 감압농축물(940㎎)을 실리카겔 칼럼 크로마토그래피(CH2Cl2/에틸 아세테이트, 8:1, v/v)하여 분리된 (20S)-진세노사이드 Rg3퍼아세테이트(peracetate)(620mg)를 5% HCl/CH3OH(50㎖)에 녹이고 실온에서 5시간 교반하였다. 반응액에 증류수(100㎖)를 가하고 30℃에서 감압농축하여 메탄올을 제거한 후 부탄올(50㎖)로 3회 분배 추출하였다. 부탄올 분획을 감압농축하여 실리카겔 크로마토그래피(CHCl3/CH3OH/H2O, 8:3:1,v/v)하여 순수한 (20S)-진세노사이드 Rg3(390mg)을 얻었다.The butanol fraction was dissolved in 1 L of methanol, and then cooled to remove the precipitate, followed by silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 9: 3: 1, v / v) to obtain pure ginsenoside Rg 5. 480 mg and 1.5 g of (20R) -ginsenoside Rg 3 and (20S) -ginsenoside Rg 3 racemic mixture were obtained. 1.5 g of the (20R) -ginsenoside Rg 3 and (20S) -ginsenoside Rg 3 racemic mixture were suspended in 30 ml of methanol by heating and sonication, cooled to remove the precipitate, and the filtrate was concentrated under reduced pressure. The concentrate under reduced pressure (720 mg) was dissolved in pyridine (20 mL), acetic anhydride (20 mL) was added under ice cooling, followed by stirring at room temperature for 10 hours. The reaction product was partitioned into ethyl acetate (100 mL), extracted three times, washed three times with 5% HCl (150 mL), three times with saturated aqueous NaHCO 3 (150 mL), and three times with distilled water, and then ethyl acetate. Fractions were concentrated under reduced pressure. Concentration under reduced pressure (940 mg) was carried out by silica gel column chromatography (CH 2 Cl 2 / ethyl acetate, 8: 1, v / v) to give (20S) -ginsenoside Rg 3 peracetate (620 mg). It was dissolved in 5% HCl / CH 3 OH (50 mL) and stirred at room temperature for 5 hours. Distilled water (100 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 30 ° C. to remove methanol, and then partitioned and extracted three times with butanol (50 mL). The butanol fraction was concentrated under reduced pressure and purified by silica gel chromatography (CHCl 3 / CH 3 OH / H 2 O, 8: 3: 1, v / v) to obtain pure (20S) -ginsenoside Rg 3 (390 mg).
실시예 2 디올계 사포닌들로부터 (20S)-진세노사이드 RgExample 2 (20S) -ginsenoside Rg from diol-based saponins 33 및 진세노사이 드 RgAnd ginsenoside de Rg 55 의 제조Manufacture
진세노사이드 Rb1, Rb2및 Rc 혼합물(5g)을 50% 초산 (500㎖)에 녹이고 70℃에서 3시간 동안 초음파처리하였다. 반응액을 70℃에서 감압농축하여 약 1/10부피(50㎖)로 하고, 4℃ 냉장고에 하룻밤 방치한 후 침전물을 여과하여 제거하였다. 여과액을 물(500㎖)로 희석하고, n-부탄올(250㎖)로 3회 추출하였다. 부탄올 추출액을 포화 NHCO3수용액으로 2횔 세척하고 감압농축하여, 농축액을 실리카겔 칼럼크로마토그래피(CHCl3/CH3OH/H2O, 9:3:1,v/v)하여 (20S)-진세노사이드 Rg3(1.5g) 및 진세노사이드 Rg5(1.2g)을 얻었다.Ginsenosides Rb 1 , Rb 2 and Rc mixture (5 g) were dissolved in 50% acetic acid (500 mL) and sonicated at 70 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure at 70 ° C. to about 1/10 volume (50 mL), and the precipitate was left to stand in a 4 ° C. refrigerator overnight to remove the precipitate by filtration. The filtrate was diluted with water (500 mL) and extracted three times with n-butanol (250 mL). The butanol extract was washed with 2 포화 saturated aqueous NHCO 3 solution and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 9: 3: 1, v / v) to give (20S)- Cenoside Rg 3 (1.5 g) and ginsenoside Rg 5 (1.2 g) were obtained.
(20S)-진세노사이드 Rg3의 탄소 핵자기 공명스펙트럼(피리딘-d5, δ)- 15.7, 16.3, 16.3, 16.4, 17.4, 18.3, 22.4, 25.2, 26.1, 26.2, 27.5, 30.7, 31.4, 35.3, 36.3, 37.3, 38.5, 39.1, 39.4, 47.9, 49.8, 51.1, 54.2, 55.7, 62.0, 62.2, 70.4, 70.0, 72.3, 72.4, 76.5, 77.3, 77.5, 77.8, 78.2, 82.8, 88.3, 104.5, 105.4, 126.9, 130.1(20S) -Ginsenoside Rg 3 carbon nuclear magnetic resonance spectrum (pyridine-d 5 , δ)-15.7, 16.3, 16.3, 16.4, 17.4, 18.3, 22.4, 25.2, 26.1, 26.2, 27.5, 30.7, 31.4, 35.3, 36.3, 37.3, 38.5, 39.1, 39.4, 47.9, 49.8, 51.1, 54.2, 55.7, 62.0, 62.2, 70.4, 70.0, 72.3, 72.4, 76.5, 77.3, 77.5, 77.8, 78.2, 82.8, 88.3, 104.5, 105.4, 126.9, 130.1
및 진세노사이드 Rg5의 탄소 핵자기 공명스펙트럼(피리딘-d5, δ)- 13.1, 15.7, 16.3, 16.5, 16.9, 17.7, 18.3, 25.6, 26.6, 27.4, 28.0, 28.7, 32.1, 32.5, 35.2, 36.9, 39.2, 39.6, 40.1, 50.3, 50.7, 50.8, 50.9, 56.3, 62.6, 62.7, 71.5, 71.5, 72.5, 77.0, 77.8, 78.0, 78.1, 78.2, 83.3, 88.8, 105.0, 123.2, 123.5, 131.1, 140.1And carbon nuclear magnetic resonance spectra of ginsenoside Rg 5 (pyridine-d 5 , δ)-13.1, 15.7, 16.3, 16.5, 16.9, 17.7, 18.3, 25.6, 26.6, 27.4, 28.0, 28.7, 32.1, 32.5, 35.2 , 36.9, 39.2, 39.6, 40.1, 50.3, 50.7, 50.8, 50.9, 56.3, 62.6, 62.7, 71.5, 71.5, 72.5, 77.0, 77.8, 78.0, 78.1, 78.2, 83.3, 88.8, 105.0, 123.2, 123.5, 131.1 , 140.1
실험예 (20S)-진세노사이드 RgExperimental Example (20S) -ginsenoside Rg 33 및 진세노사이드 RgAnd ginsenoside Rg 55 의 혈소판 활성화 인 자 길항활성 시험Platelet Activation Factor Antagonism Test
(20S)-진세노사이드 Rg3및 진세노사이드 Rg5의 혈소판 활성화 인자 수용체 결합에 대한 길항활성 시험은 발론 등(Valone, F. H., et al)의 방법(Valone, F. H., E. Coles, V. R. Reinhold and E. J. Goetzl (1982) Specific binding of phospholipid platelet-activating factor by human platelets.J. Immunol. 129.1637-1641) 및 변형된 양 등(Yang, H. O. et al)의 방법(Yang, H. O., D. Y. Suh and B. H. Han (1995) Isolation and characterization of platelet-activating factor receptor binding antagonists from Biota orientalis.Planta Med. 61, 37-40)을 이용하여 측정하였고, 인삼의 알콜 추출물로부터 얻은 인삼 사포닌을 첨가시킴으로써 혈소판 활성화 인자의 특이적인 결합을 저해하는 현상을 시험하였다. 그리고 그 결과를 표 1에 나타내었다.Antagonistic tests for platelet activator receptor binding of (20S) -ginsenoside Rg 3 and ginsenoside Rg 5 were carried out by methods of Valone, FH, E. Coles, VR Reinhold. and EJ Goetzl (1982) Specific binding of phospholipid platelet-activating factor by human platelets.J. Immunol. 129. 1637-1641) and the method of Yang, HO et al (Yang, HO, DY Suh and BH Han (1995) Isolation and characterization of platelet-activating factor receptor binding antagonists from Biota orientalis.Planta Med. 61 , 37-40), and the addition of ginseng saponins from alcohol extracts of ginseng, The phenomenon of inhibiting specific binding was tested. The results are shown in Table 1.
본 발명은 화학식 1로 표시되는 (20S)-진세노사이드 Rg3및/또는 화학식 2로 표시되는 진세노사이드 Rg5을 함유하는, 혈소판 활성 인자에 대한 길항제를 제공하는 것으로서, 본 발명의 혈소판 활성화 인자에 대한 길항활성은 상기 표 1에서 보는 바와 같이 우수함을 알 수 있다. 따라서 본 발명의 혈소판 활성화 인자에 대한 길항제는 생체내 또는 생체외에서 혈소판 활성화 인자의 활성조절에 활용할 수 있으며, 또한, 혈소판 활성화 인자와 관련된 염증질환 예를 들어,천식, 알레르기, 관절염, 류마치스, 혈전증, 급성염증, 전신성과민증, 망막염, 간염, 장염, 췌장염, 신장염, 비염, 아토피성 피부염, 심장과민증, 내독소쇼크, 중추신경계 손상 또는 장기(조직) 이식 거부반응과 같은 염증질환 및 임신과 난자착상조절에 유용하게 사용될 수 있다.The present invention provides an antagonist to platelet activating factor, which contains (20S) -ginsenoside Rg 3 represented by Formula 1 and / or ginsenoside Rg 5 represented by Formula 2, wherein the platelet activation of the present invention is provided. It can be seen that the antagonistic activity against the factor is excellent as shown in Table 1 above. Therefore, the antagonist of the platelet activating factor of the present invention can be used for the regulation of platelet activating factor in vivo or ex vivo, and also inflammatory diseases associated with platelet activating factor, for example, asthma, allergy, arthritis, rheumatoid, thrombosis, Inflammatory diseases such as acute inflammation, systemic hypersensitivity, retinitis, hepatitis, enteritis, pancreatitis, nephritis, rhinitis, atopic dermatitis, heart hypersensitivity, endotoxin shock, central nervous system damage, or organ (tissue) rejection It can be usefully used.
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KR100815276B1 (en) * | 2005-11-29 | 2009-01-28 | 주식회사 케이티앤지 | Anti-inflammatory pharmaceutical preparation containing high percentile panaxadiol fraction isolated from Korean Red Ginseng by ultrafiltration |
CN104644656A (en) * | 2013-11-20 | 2015-05-27 | 富力 | Application of 20(R)-ginsenoside Rg3 in preparation of medicament for relieving or/and treating asthma and medicament |
WO2017217731A1 (en) * | 2016-06-15 | 2017-12-21 | 재단법인 진안홍삼연구소 | Method for preparing black ginseng without loss of active ginsenosides, and black ginseng prepared by method |
KR101988882B1 (en) * | 2017-12-29 | 2019-06-13 | 충남대학교산학협력단 | A composition comprising ginsenoside Rk1 or Rg5 for preventing or treating sepsis |
CN116120389A (en) * | 2023-03-29 | 2023-05-16 | 中国农业科学院特产研究所 | Ginsenoside Rg5 and preparation and application thereof in preparing allergic rhinitis medicine |
Families Citing this family (2)
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JP4777776B2 (en) * | 2003-08-18 | 2011-09-21 | ユーユー インコーポレイテッド | Ginseng preparation using vinegar and method for producing the same |
CN109320575B (en) * | 2018-04-22 | 2021-02-12 | 吉林大学 | Pseudo-ginsenoside 12-ketone-PF 11, extraction method and medical application thereof |
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1997
- 1997-08-01 KR KR1019970036988A patent/KR100302064B1/en not_active IP Right Cessation
Cited By (6)
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KR100497665B1 (en) * | 2002-03-28 | 2005-07-01 | 주식회사 진생사이언스 | A composition containing the extract of processed ginseng for treatment of skin disease |
KR100815276B1 (en) * | 2005-11-29 | 2009-01-28 | 주식회사 케이티앤지 | Anti-inflammatory pharmaceutical preparation containing high percentile panaxadiol fraction isolated from Korean Red Ginseng by ultrafiltration |
CN104644656A (en) * | 2013-11-20 | 2015-05-27 | 富力 | Application of 20(R)-ginsenoside Rg3 in preparation of medicament for relieving or/and treating asthma and medicament |
WO2017217731A1 (en) * | 2016-06-15 | 2017-12-21 | 재단법인 진안홍삼연구소 | Method for preparing black ginseng without loss of active ginsenosides, and black ginseng prepared by method |
KR101988882B1 (en) * | 2017-12-29 | 2019-06-13 | 충남대학교산학협력단 | A composition comprising ginsenoside Rk1 or Rg5 for preventing or treating sepsis |
CN116120389A (en) * | 2023-03-29 | 2023-05-16 | 中国农业科学院特产研究所 | Ginsenoside Rg5 and preparation and application thereof in preparing allergic rhinitis medicine |
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