KR19990015091A - Complement activity modifiers containing ginseng saponin or sapogenin - Google Patents

Complement activity modifiers containing ginseng saponin or sapogenin Download PDF

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KR19990015091A
KR19990015091A KR1019970036989A KR19970036989A KR19990015091A KR 19990015091 A KR19990015091 A KR 19990015091A KR 1019970036989 A KR1019970036989 A KR 1019970036989A KR 19970036989 A KR19970036989 A KR 19970036989A KR 19990015091 A KR19990015091 A KR 19990015091A
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glc
ginsenoside
complement activity
saponin
formula
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이형규
이임선
오세량
김동선
정근영
김정희
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박원훈
한국과학기술연구원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

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Abstract

본 발명은 화학식 1, 화학식 2 및 화학식 3으로 표시되고, 항보체활성을 갖는 사포닌 또는 사포게닌 화합물중 최소한 한 개를 함유하는 보체활성 조절제 특히, 보체활성과 관련된 질환 치료제에 관한 것이다.The present invention relates to complement activity modulators represented by formulas (1), (2) and (3) and containing at least one of a saponin or a saponenin compound having anti-complement activity, in particular, a disease therapeutic agent associated with complement activity.

본 발명의 사포닌 또는 사포게닌 화합물은 진세노사이드 Ra1, 진세노사이드 Ra2, 진세노사이드 Rb1, 진세노사이드 Rb2, 진세노사이드 Rc, 진세노사이드 Rd, 진세노사이드 Re, 진세노사이드 Rf, 진세노사이드 Rg1, 진세노사이드 Rg2, 진세노사이드 Rh1, 진세노사이드 Rh2, 진세노사이드 Rh4, 진세노사이드 Ro, 및 올레아놀 산이다.Saponins or sapongenin compounds of the present invention are ginsenosides Ra 1 , ginsenosides Ra 2 , ginsenosides Rb 1 , ginsenosides Rb 2 , ginsenosides Rc, ginsenosides Rd, ginsenosides Re, ginsenosides Side Rf, ginsenoside Rg 1 , ginsenoside Rg 2 , ginsenoside Rh 1 , ginsenoside Rh 2 , ginsenoside Rh 4 , ginsenoside Ro, and oleanolic acid.

Description

인삼 사포닌 또는 사포게닌을 함유하는 보체활성 조절제Complement activity modifiers containing ginseng saponin or sapogenin

본 발명은 인삼 또는 홍삼으로부터 추출, 분리, 정제 또는 화학적 방법으로 제조될 수 있는 인삼사포닌 또는 사포게닌 화합물 중 최소한 한 개를 함유하는 보체활성 조절제 특히, 보체활성과 관련된 질환 치료제에 관한 것이다.The present invention relates to complement activity modulators containing at least one of ginseng saponin or sapogenin compounds, which may be prepared by extraction, separation, purification or chemical methods from ginseng or red ginseng, in particular, therapeutic agents associated with complement activity.

약 20여종의 혈청 단백질로 이루어진 보체계(Complement system)는 면역 복합체에 의해 활성화되는 전통적 경로(classical pathway)와 균체성분 등에 의해 활성화되는 올터너티브 경로(alternative pathway)로 나누어진다. 이와 같은 보체계는 세균, 진균, 바이러스 등 외부 감염원에 대한 숙주 방어기전의 중요한 역할을 담당한다. 그러나 비정상적인 보체계 활성화 과정중 유리되는 C3a, C4a, C5a 등의 조각(fragment)들은 아나필라톡신(anaphylatoxin)으로서 천식, 알레르기, 아토피성 피부염 들을 비롯한 다양한 염증질환의 주요 원인이 되고 있다(Bellanti, T.A.(1985)In Immunology Ⅲ. Saunders, Philadelphia, pp. 106., Miyagawa, S., Hirose, H. Shirakura, R. Nakata, Y. Kawashima, Y. Seya, T. Matsumoto, M. Uenaka, A. and Kitamura, H. (1988)Transplantation 46, 825., Zvaifler NH (1989)Arthritis care Res. 2, S17., Sabharwal UK, Vaughan JH, Fong S, Bennett PH, Carson DA, Curd JG. (1982)Arthritis Rheum,25, 161., Murray JF, Matthay Ma, Luce Jm, Flick Mr. (1988)Am Rev Respir Dis. 138, 720)Complement system consisting of about 20 kinds of serum proteins is divided into a classical pathway activated by immune complexes and an alternative pathway activated by cell components. Such complement systems play an important role in host defense mechanisms against external infectious agents such as bacteria, fungi and viruses. However, fragments such as C3a, C4a, and C5a, which are released during abnormal complement system activation, are anaphylatoxins and are a major cause of various inflammatory diseases including asthma, allergies, and atopic dermatitis (Bellanti, TA). 1985) In Immunology III.Saunders, Philadelphia, pp. 106., Miyagawa, S., Hirose, H. Shirakura, R. Nakata, Y. Kawashima, Y. Seya, T. Matsumoto, M. Uenaka, A. and Kitamura , H. (1988) Transplantation 46 , 825., Zvaifler NH (1989) Arthritis care Res. 2 , S17., Sabharwal UK, Vaughan JH, Fong S, Bennett PH, Carson DA, Curd JG. (1982) Arthritis Rheum , 25 , 161., Murray JF, Matthay Ma, Luce Jm, Flick Mr. (1988) Am Rev Respir Dis. 138 , 720)

따라서 이를 예방, 치료하기 위한 물질의 탐색이 시도되어 왔다. 즉, 리포폴리사카라이드(lipopolysacharide), β(1→3)글루칸(glucan), 이눌린(inulin), 6-가지달린 β(1→3)글루칸(glucan), 아라비노갈락탄(arabinogalactan) 등 고분자의 다당류들이 곰팡이, 세균, 한약재로부터 주로 분리되었으나(Muschel, L.H., Schmoker, K. and Webb, P.M. (1964)Proc. Soc. Exp. Biol, Med. 117, 63., Okuda, T., Yoshioka, Y., Ikekawa, T., Chihara, G. and Nishioka, K. (1972)New Biol. 238, 59., Hamuro, J., Hadding, U. and Bitter-Suermann, D. (1978)Immunology 34, 695., Yamada, H., Nagai, T., Cyong, T-C., Otsuka, Y., Tomoda, M., Shimizu, N. and Shimada, K. (1985)Carbohydr. Res. 144, 101.) 보체활성이 강하지 못하였고, 저분자의 피토스테롤(phytosterol)도 항보체 활성물질로 보고되어 있다.(Tsuyoshi, E., Tomoko, K., Masanori, K., Seigo, F. and Akira, U. (1991)Yakugaku Zasshi 111(6), 299., Haruki, Y., Nasami, Y., Tsukasa, M., Takayuki, M., Horoaki, K., Jong-chol, C., Akira, N., Haruo, T. and Satoshi, O. (1987)Chem. Pharm. Bull. 35(12), 4851.)Therefore, the search for a substance for preventing and treating this has been attempted. In other words, lipopolysaccharide (lipopolysacharide), β (1 → 3) glucan, inulin, 6- branched β (1 → 3) glucan, arabinogalactan (arabinogalactan), etc. Polysaccharides were mainly isolated from fungi, bacteria and herbs (Muschel, LH, Schmoker, K. and Webb, PM (1964) Proc. Soc.Exp . Biol, Med. 117 , 63., Okuda, T., Yoshioka, Y., Ikekawa, T., Chihara, G. and Nishioka, K. (1972) New Biol. 238 , 59., Hamuro, J., Hadding, U. and Bitter-Suermann, D. (1978) Immunology 34 , 695., Yamada, H., Nagai, T., Cyong, TC., Otsuka, Y., Tomoda, M., Shimizu, N. and Shimada, K. (1985) Carbohydr. Res. 144 , 101.) Complement The activity was not strong, and low molecular weight phytosterols have also been reported as anti-complement actives (Tsuyoshi, E., Tomoko, K., Masanori, K., Seigo, F. and Akira, U. (1991)). Yakugaku Zasshi 111 (6), 299., Haruki, Y., Nasami, Y., Tsukasa, M., Takayuki, M., Horoaki, K., Jong-chol, C., Akira, N., Haruo, T and Satos hi, O. (1987) Chem. Pharm. Bull. 35 (12), 4851.)

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, sedation, etc. (Korean Ginseng Research Institute, Ginseng Research Institute, Daesung Printing Co., p. 143 (1985)., Korea Ginseng, Korea Ginseng and Tobacco Research Institute, Cheonil Printing, p. 89 (1994).). Ginseng saponin, unlike other plants, is not toxic and does not show hemolytic activity below 0.001% (Tai Chuan, 藥用 人蔘 出 立 出版, p. 43 (1981)., Kim Nak-du (1978), Korean Ginseng, Goryeo Ginseng Research Institute, p. 118.), central nervous system 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.), promoting 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.), adrenocortical Hormone secretion promoting effect (Pearec, PT, Zois, I., Wynne, KN and Funder, JW (1982) Endocrinol. 29 , 567., Han Byung-hoon, Jang Il-mu (1977), Korean Ginseng Journal 2 , 17) ( 村泰(1992), The Ginseng Review, 13, 198., Nakanishi and Onishi (1992), Medicinal Ginseng Research Lecture yojijip (9) Medicinal Ginseng Research, p. 12.), triglyceride query facilitate absorption (CN Joo, Choi Im-Soon, 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 (Won Young Lee, Woo Woo Nam, Joo Deok Kim, Eun Hee Ko, Kim Byung Soo (1988) Korean Cancer Society 20 , 126., Kim, YS, Kang, KS and Kim, SI (1991) Korean J. Ginseng Sci. 15 , 13., Mi-Jung Kim, No-Pal Chung (1987) 11 , 119).

그러나 인삼의 성분인 사포닌 화합물이 항보체 활성이 있다는 사실은 아직까지 알려지지 않았다.However, the fact that saponin compound, a component of ginseng, has anti-complement activity is not known yet.

이에 본 발명자들은 인삼 또는 홍삼으로부터 추출하여 조사포닌을 얻은 후 이 조사포닌이 강한 항보체 활성을 갖는 것을 확인하고 이들에 포함되어 있는 활성성분을 추적하여 본 발명을 완성하였다.Thus, the present inventors have obtained the irradiated ginseng or extract from ginseng or red ginseng to confirm that the irradiated with a strong anti-complementary activity and completed the present invention by tracking the active ingredient contained in them.

본 발명은 인삼 사포닌 또는 사포게닌 화합물을 함유하는 보체활성 조절제 특히 보체활성과 관련된 질환 치료제를 제공하는 것을 목적으로 한다.An object of the present invention is to provide a complement activity regulating agent containing ginseng saponin or a sapogenin compound, in particular a therapeutic agent associated with complement activity.

본 발명은 하기 화학식 1과 표1, 화학식 2와 표 2, 또는 화학식 3으로 표시되고, 항보체활성을 갖는 사포닌 또는 사포게닌 화합물중 최소한 한 개를 함유하는 보체활성 조절제 특히, 보체활성과 관련된 질환 치료제를 제공한다.The present invention is represented by the following formula (1) and (1), (1) and (2), or (3), and includes a complement activity modulator, in particular a disease associated with complement activity, containing at least one of a saponin or a saponinine compound having anticomplement activity. Provide a cure.

상기 식에서 각각의 치환기는 표 1에 기재된 바와 같다.Each substituent in the above formula is as described in Table 1.

화학식 1로 표시된 사포닌 또는 사포게닌 화합물의 치환기Substituents of saponins or sapongenin compounds represented by the formula (1) 치 환 기사포닌Substituted knightponin R1 R 1 R2 R 2 R3 R 3 진세노사이드 Ra1 Ginsenoside Ra 1 -glc2-glc-glc 2 -glc HH -glc6-ara(pyr)4-xyl-glc 6 -ara (pyr) 4 -xyl 진세노사이드 Ra2 Ginsenoside Ra 2 -glc2-glc-glc 2 -glc HH -glc6-ara(fur)2-xyl-glc 6 -ara (fur) 2 -xyl 진세노사이드 Rb1 Ginsenoside Rb 1 -glc2-glc-glc 2 -glc HH -glc6-glc-glc 6 -glc 진세노사이드 Rb2 Ginsenoside Rb 2 -glc2-glc-glc 2 -glc HH -glc6-ara(pyr)-glc 6 -ara (pyr) 진세노사이드 RcGinsenoside Rc -glc2-glc-glc 2 -glc HH -glc6-ara(fur)-glc 6 -ara (fur) 진세노사이드 RdGinsenoside Rd -glc2-glc-glc 2 -glc HH -glc-glc 진세노사이드 Rg2 Ginsenoside Rg 2 HH -O-glu-rha-O-glu-rha HH 진세노사이드 Rg3 Ginsenoside Rg 3 -glc2-glc-glc 2 -glc HH HH 진세노사이드 Rh2 Ginsenoside Rh 2 -glc-glc HH HH 진세노사이드 ReGinsenoside Re HH -O-glc-rha-O-glc-rha -glc-glc 진세노사이드 RfGinsenoside Rf HH -O-glc-glc-O-glc-glc HH 진세노사이드 Rg1 Ginsenoside Rg 1 HH -O-glc-O-glc -glc-glc 진세노사이드 Rh1 Ginsenoside Rh 1 HH -O-glc-O-glc HH

상기 식에서 각각의 치환기는 표 2에 기재된 바와 같다.Each substituent in the above formula is as described in Table 2.

화학식 2로 표시된 사포닌 또는 사포게닌 화합물의 치환기Substituents of saponin or saponenin compounds represented by the formula (2) 치환기사포닌Substituted Saponin R1 R 1 R2 R 2 올레아놀 산Oleanolic acid HH HH 진세노사이드 R0 Ginsenoside R 0 -glucuronic acid2-glc-glucuronic acid 2 -glc -glc-glc

본 발명의 인삼 사포닌 또는 사포게닌 화합물의 항보체 활성은 아직까지 알려져 있지 않으며, 본 발명자들에 의하여 비로소 밝혀지게 된 것이다.The anti-complement activity of the ginseng saponin or saponenin compound of the present invention is not yet known and will be revealed by the present inventors.

본 발명의 보체활성 조절제는 생체외(in vitro) 또는 생체내(in vivo) 모두에서 보체활성을 조절하는 능력을 갖고 있다.Complement activity modulators of the present invention have the ability to modulate complement activity both in vitro or in vivo .

또한, 본 발명의 보체활성과 관련된 질환 치료제는 천식, 알레르기, 관절염, 류마치스, 전신성 홍반성 낭창(systemic lupus erythemtosus, SLE), 망막염, 간염, 장염, 췌장염, 신장염, 비염, 아토피성 피부염을 포함하는 염증질환 치료에 사용될 수 있으며, 또한 장기 이식시 유발되는 이식거부반응을 억제하는데에도 유용하게 사용될 수 있다.In addition, the therapeutic agents associated with complement activity of the present invention include asthma, allergies, arthritis, rheumatism, systemic lupus erythemtosus (SLE), retinitis, hepatitis, enteritis, pancreatitis, nephritis, rhinitis, atopic dermatitis It can be used to treat inflammatory diseases, and can also be useful for suppressing transplant rejection reactions caused by organ transplantation.

본 발명의 인삼 사포닌 또는 사포게닌 화합물을 함유하는 보체활성 조절제 또는 보체활성과 관련된 질환 치료제는 본 발명의 인삼 사포닌 또는 사포게닌 화합물과 약제학적으로 허용 가능한 담체, 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조하거나 또는 다용량 용기 내에 내입 시켜 제조할 수 있다.Complement activity modifiers or ginseng treatment agents containing the ginseng saponin or saponenin compound of the present invention or a therapeutic agent associated with complement activity in a unit dose form by formulating the ginseng saponin or saponenin compound of the present invention with a pharmaceutically acceptable carrier, excipient It can be prepared or prepared in 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 안정제를 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 명세서에서 주종 사포닌 또는 사포게닌 화합물이라 함은 진세노사이드(ginsenoside) R0, Ra1, Ra2, Rb1, Rb2, Rc, Rd, Re, Rf, Rg1을 말하며,In the present specification, the predominantly saponin or sapongenin compound refers to ginsenosides R 0 , Ra 1 , Ra 2 , Rb 1 , Rb 2 , Rc, Rd, Re, Rf, Rg 1 ,

미량 사포닌 또는 사포게닌 화합물이라 함은 (20R)-진세노사이드 Rg2, (20S)-진세노사이드 Rg2, (20S)-진세노사이드 Rh1, (20R)-진세노사이드 Rh2, 진세노사이드 Rh4및 올레아놀 산 (oleanolic acid)를 말한다.Trace saponins or sapongenin compounds refer to (20R) -ginsenosides Rg 2 , (20S) -ginsenosides Rg 2 , (20S) -ginsenosides Rh 1 , (20R) -ginsenosides Rh 2 , Senoside Rh 4 and oleanolic acid.

인삼 또는 홍삼으로부터 알코올을 추출 용매로 사용하여 추출한 추출물을 분리하는 통상적인 방법을 사용함으로써 주종 사포닌 또는 사포게닌 화합물을 제조할 수 있다. 즉,Main species saponins or sapongenin compounds can be prepared by using a conventional method of separating the extracted extract using alcohol as an extraction solvent from ginseng or red ginseng. In other words,

분쇄된 인삼 또는 홍삼을 알코올 특히 메탈올을 추출용매로 사용하여 추출하여 추출물을 얻고, 상기 추출물을 물에 용해시킨 다음에 알코올 이외의 용매 특히 석유에테르를 사용하여 불순물을 세척하여 제거한다. 그런 후에 다시 알코올 특히 n-부탄올을 추출용매로 사용하여 추출함으로써 조사포닌 분획을 얻는다. 다음에 상기 부탄올 분획을 분리수단 특히 실리카겔 칼럼 크로마토그래피를 사용하여 분리함으로써 주종 사포닌 또는 사포게닌 화합물을 얻는다. 또한, 주종 사포닌 화합물의 라세믹 혼합물을 아세틸화 및 탈아세틸화하여 분리할 수도 있다.The pulverized ginseng or red ginseng is extracted using an alcohol, in particular a metalol, as an extraction solvent to obtain an extract. The extract is dissolved in water and then removed by washing impurities using a solvent other than alcohol, in particular petroleum ether. Thereafter, alcohol-particularly n-butanol is used as the extraction solvent to extract the irradiated saponinine fraction. The butanol fraction is then separated using separation means, in particular silica gel column chromatography, to obtain a predominantly saponin or saponenin compound. It is also possible to separate racemic mixtures of the dominant saponin compounds by acetylation and deacetylation.

또한, 통상적인 방법을 사용하여 주종 사포닌 또는 사포게닌 화합물로부터 미량 사포닌 또는 사포게닌 화합물을 제조할 수 있다. 즉,In addition, conventional methods can be used to prepare trace saponins or sapongenin compounds from predominantly saponin or saponenin compounds. In other words,

화학식 1 또는 화학식 2에 표시되어 있는, 에테르 결합을 하고 있는 치환기 R1, R2및 R3를 가지는 주종 사포닌을 산 수용액 또는 염기성 수용액으로 가수분해함으로써 상기 치환기들을 선택적으로 제거하거나 디하이드레이션하고, 알콜 특히 부탄올을 사용하여 이들을 추출한 후, 분리하여 제조한다. 또한, 라세믹 혼합물의 경우 아세틸화하여 아세틸화된 물질을 분리한 후 탈아세틸화하여 미량 사포닌 화합물을 제조할 수 있다.Selectively removing or dehydrating the substituents by hydrolyzing the main species saponin represented by the formula (1) or (2) with the substituents R 1 , R 2 and R 3 having an ether bond with an aqueous solution of an acid or a basic solution, They are prepared by extracting them with alcohol, in particular butanol, and then separating them. In addition, the racemic mixture may be prepared by acetylation to separate the acetylated material and then deacetylated to prepare a trace saponin compound.

이하 실시예에서 본 발명을 더욱 상세히 설명한다. 다만, 하기 실시예는 본 발명의 예시일 뿐이며, 하기 실시예에 의하여 본 발명이 한정되는 것으로 간주하여서는 안된다.In the following Examples the present invention will be described in more detail. However, the following examples are only examples of the present invention, and the present invention should not be considered to be limited by the following examples.

실시예 1 주종 사포닌 또는 사포게닌 화합물의 제조Example 1 Preparation of Main Saccharin Saponin or Sapogenin Compound

홍삼 3kg을 분쇄하여 실온에서 메탄올 10ℓ을 사용하여 2일간 3회 추출하고 여과액을 모아 감압 농축하여 490g의 추출물을 얻었다. 이 추출물을 증류수 5ℓ에 녹여 순차적으로 석유에테르 2ℓ로 3회 세척한 후, n-부탄올 2ℓ을 사용하여 2회 분배추출하고 감압 농축하여 조사포닌 분획 270g을 얻었다.3 kg of red ginseng was ground and extracted three times for 2 days using 10 liters of methanol at room temperature. The filtrates were collected and concentrated under reduced pressure to obtain 490 g of extract. The extract was dissolved in 5 L of distilled water, washed three times sequentially with 2 L of petroleum ether, and then partitioned and extracted twice using 2 L of n-butanol, and concentrated under reduced pressure to obtain 270 g of irradiated phony.

상기에서 얻은 부탄올 분획 250g을 실리카겔 칼럼 크로마토그래피(CHCl3/CH3OH/H2O, 7:3:1, 하층 → 6:4:1)하여 각각 진세노사이드 Rg1, Rf, Re, Rd, Rb2와 Rc, Rb1, Ra1과 Ra2, Ro를 함유하는 8개의 분획을 얻었다. 상기 8개의 분획 각각을 실리카겔 칼럼 크로마토그래피(BuOH/EtOAc/H2O, 15:1:4 및 4:1:2, 상층)에 의하여 진세노사이드 Ro(1.2g), Ra1(140mg), Ra2(75mg), Rb1(5.3g), Rb2(3.8g), Rc(2.5g), Rd(1.7g), Re(6.3g) 및 Rg1(5.8g)을 얻었다.250 g of the butanol fraction obtained above was subjected to silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 7: 3: 1, lower layer → 6: 4: 1) to obtain ginsenosides Rg 1 , Rf, Re, and Rd, respectively. Eight fractions containing Rb 2 and Rc, Rb 1 , Ra 1 and Ra 2 , Ro were obtained. Each of the eight fractions was subjected to silica gel column chromatography (BuOH / EtOAc / H 2 O, 15: 1: 4 and 4: 1: 2, upper layer) to ginsenosides Ro (1.2 g), Ra 1 (140 mg), Ra 2 (75 mg), Rb 1 (5.3 g), Rb 2 (3.8 g), Rc (2.5 g), Rd (1.7 g), Re (6.3 g) and Rg 1 (5.8 g) were obtained.

실시예 2 미량 사포닌 또는 사포게닌의 제조Example 2 Preparation of Trace Saponins or Sapongenins

1) △1) △ 2020 -진세노사이드 RgGinsenoside Rg 22 , (20R)-진세노사이드 Rg, (20R) -ginsenoside Rg 22 및 (20S)-진세노사이드 RgAnd (20S) -ginsenoside Rg 22 의 제조Manufacture

진세노사이드 Re 4g을 50% 초산(500㎖)에 녹이고 70℃에서 2시간 동안 초음파 처리한 후 냉각하였다. 반응 혼합물을 증류수(500㎖)로 희석하여 n-부탄올(500㎖)로 3회 추출하고, 상기 부탄올 추출액을 합하여 NaHCO3포화 수용액(500㎖)으로 2회, 증류수로 3회 세척한 다음, 감압농축하고 실리카겔 칼럼 크로마토그래피(CHCl3/CH3OH/H2O, 8:3:1, 하층)하여 △20-진세노사이드 Rg2(550mg) 및 (20R)-진세노사이드 Rg2와 (20S)-진세노사이드 Rg2입체이성체 혼합물(1.7g)을 얻었다.4 g of ginsenoside Re was dissolved in 50% acetic acid (500 mL), sonicated at 70 ° C. for 2 hours, and cooled. The reaction mixture was diluted with distilled water (500 mL), extracted three times with n-butanol (500 mL), the combined butanol extracts were washed twice with saturated NaHCO 3 aqueous solution (500 mL) and three times with distilled water, and then concentrated and purified by silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 8: 3: 1, lower layer) to △ 20 - ginsenoside Rg 2 (550mg) and (20R) - ginsenoside Rg 2 and ( 20S) -ginsenoside Rg 2 stereoisomeric mixture (1.7 g) was obtained.

(20R)-진세노사이드 Rg2와 (20S)-진세노사이드 Rg2입체이성체 혼합물을 피리딘 50㎖에 녹이고, 빙냉하에서 초산 무수물(50㎖)을 한방울씩 가한 후 실온에서 10시간 교반하였다. 반응 생성물을 에틸 아세테이트(50㎖)로 분배하여 3회 추출하고, 5% HCl(150㎖)로 3회, NaHCO3포화수용액(150㎖)으로 3회 세척한 다음, 에틸 아세테이트 분획을 감압농축하였다. 반응 혼합물을 실리카겔 칼럼 크로마토그래피(CH2Cl2/에틸 아세테이트, 8:1)하여 (20R)-진세노사이드 Rg2퍼아세테이트(peracetate)(870mg)과 (20S)-진세노사이드 Rg2퍼아세테이트(640mg)를 얻었다.The (20R) -ginsenoside Rg 2 and (20S) -ginsenoside Rg 2 stereoisomer mixture was dissolved in 50 ml of pyridine, acetic anhydride (50 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 10 hours. The reaction product was partitioned into ethyl acetate (50 mL), extracted three times, washed three times with 5% HCl (150 mL), three times with saturated aqueous NaHCO 3 (150 mL), and the ethyl acetate fractions were concentrated under reduced pressure. . Silica gel and the reaction mixture was purified by column chromatography (CH 2 Cl 2 / ethyl acetate, 8: 1) to give (20R) - ginsenoside Rg 2 flops acetate (peracetate) (870mg) and (20S) - ginsenoside Rg 2 flops acetate (640 mg) was obtained.

이들 각각 400mg을 5% NaOH/n-부탄올(100㎖)에 용해시키고 실온에서 3시간 교반하였다. 반응혼합물을 증류수로 세척한 후 부탄올 분획을 감압농축하고 실리카겔 칼럼 크로마토그래피(CHCl3/CH3OH/H2O, 8:3:1)하여 (20R)-진세노사이드 Rg2(250mg)과 (20S)-진세노사이드 Rg2(270mg)을 얻었다.Each of these 400 mg was dissolved in 5% NaOH / n-butanol (100 mL) and stirred at room temperature for 3 hours. The reaction mixture was washed with distilled water, and the butanol fraction was concentrated under reduced pressure, followed by silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 8: 3: 1) and (20R) -ginsenoside Rg 2 (250 mg). (20S) -ginsenoside Rg 2 (270 mg) was obtained.

2) (20R)-진세노사이드 Rh2) (20R) -ginsenoside Rh 1One , (20S)-진세노사이드 Rh, (20S) -ginsenoside Rh 1One 및 진세노사이드 RhAnd ginsenosides Rh 44 의 제조Manufacture

(20R)-진세노사이드 Rg2퍼아세테이트, (20S)-진세노사이드 Rg2퍼아세테이트 및 진세노사이드 Rg5각각 400mg을 5% NaOH 부탄올 용액(100㎖)에 용해시키고 80℃에서 6시간 교반하였다. 각각의 반응혼합물을 상온까지 식힌 후 5% HCl로 중화하고, 증류수로 3회 세척한 후, 부탄올 분획을 감압농축하였다. 반응혼합물 각각을 실리카겔 칼럼 크로마토그래피(CHCl3/CH3OH/H2O, 12:3:1, 하층)하여 (20R)-진세노사이드 Rh1(107mg), (20S)-진세노사이드 Rh1(95mg) 및 진세노사이드 Rh4(73mg)를 얻었다.400 mg each of (20R) -ginsenoside Rg 2 peracetate, (20S) -ginsenoside Rg 2 peracetate and ginsenoside Rg 5 were dissolved in 5% NaOH butanol solution (100 mL) and stirred at 80 ° C. for 6 hours. It was. Each reaction mixture was cooled to room temperature, neutralized with 5% HCl, washed three times with distilled water, and the butanol fraction was concentrated under reduced pressure. Each reaction mixture was subjected to silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 12: 3: 1, lower layer) to give (20R) -ginsenoside Rh 1 (107 mg), (20S) -ginsenoside Rh. 1 (95 mg) and ginsenoside Rh 4 (73 mg) were obtained.

3) (20R)-진세노사이드 Rg3) (20R) -ginsenoside Rg 33 의 제조Manufacture

진세노사이드 Rb(4g)을 50% 초산(500㎖)에 녹이고 70℃에서 3시간 동안 초음파 처리하였다. 반응액을 70℃에서 감압농축하여 약 1/10부피(50㎖)로 하고, 4℃ 냉장고에 하룻밤 방치한 후 침전물을 여과하였다. 침전물을 4℃에서 증류수와 에탄올로 세척하고 건조하여 (20R)-진세노사이드 Rg3(650mg)을 얻었다.Ginsenoside Rb (4 g) was 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 filtered after being allowed to stand overnight in a 4 ° C. refrigerator. The precipitate was washed with distilled water and ethanol at 4 ° C. and dried to give (20R) -ginsenoside Rg 3 (650 mg).

4) (20R)-진세노사이드 Rh4) (20R) -ginsenoside Rh 22 의 제조Manufacture

(20R)-진세노사이드 Rg3(400mg)을 5% NaOH n-부탄올/메탄올(4:1)(200㎖)에 용해시키고 80℃에서 6시간 교반하면서 반응시켰다. 반응혼합물을 35℃에서 감압농축하여 메탄올을 제거하고, 5% HCl(150㎖)로 1회, 증류수(150㎖)로 3회 세척한 후, 부탄올 분획을 감압농축하였다. 농축물을 실리카겔 칼럼 크로마토그래피(CHCl3/CH3OH/H2O, 15:3:1)하여 (20R)-진세노사이드 Rh2(157mg)을 얻었다.(20R) -Ginsenoside Rg 3 (400 mg) was dissolved in 5% NaOH n-butanol / methanol (4: 1) (200 mL) and reacted with stirring at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure at 35 ° C. to remove methanol, washed once with 5% HCl (150 mL) and three times with distilled water (150 mL), and the butanol fraction was concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (CHCl 3 / CH 3 OH / H 2 O, 15: 3: 1) to give (20R) -ginsenoside Rh 2 (157 mg).

5)올레아놀 산의 제조5) Preparation of Oleanol Acid

진세노사이드 R0(1.0g)을 10% HCl/50% 메탄올 용액에 녹이고 80℃에서 5시간 환류하였다. 40℃에서 감압증류하여 메탄올을 제거한 후 에틸 에테르로 분배하고 얻은 에틸 에테르 분획을 실리카겔 칼럼 크로마토그래피(헥산/아세톤, 2:1)하여 올레아놀 산(240mg)을 얻었다.Ginsenoside R 0 (1.0 g) was dissolved in 10% HCl / 50% methanol solution and refluxed at 80 ° C. for 5 hours. Distillation under reduced pressure at 40 ℃ to remove methanol, and then partitioned with ethyl ether, and the obtained ethyl ether fractions were purified by silica gel column chromatography (hexane / acetone, 2: 1) to obtain oleanolic acid (240 mg).

실험예 인삼 사포닌의 항보체 활성 시험Experimental Example Anti-complement Activity Test of Ginseng Saponin

인삼 조사포닌 및 사포닌 성분들 각각의 항보체 활성 시험은 통상의 방법에 의하여 실시하였다. 즉, 전통적 경로(classical pathway)에 대한 항보체 활성은 메이어(Mayer)법(Kabat, E. A. and Mayer, M. M. (1961)In 'Experimental Immunochemistry'2nd ed. Charles and Thomas, U. S. A.) 및 변형된 클럭스(Klerx)의 보체반응(Klerx, J. P. A. M., Beukelman, C. J., Dijk, H. V. and Willers, J. M. N. (1983)J. Immunol. Methods 63, 215.)을 이용하여 측정하였고, 인삼의 알콜 추출물로부터 얻은 인삼 사포닌을 첨가시킴으로써 감작된 양의 적혈구에 대한 보체의 용혈 저해 현상을 시험하였다. 이하 그 결과를 표 3에 제시하였다.Anti-complement activity test of each of ginseng irradiated saponin and saponin components was conducted by conventional methods. That is, anti-complementary activity against the classical pathway was determined by the Mayer method (Kabat, EA and Mayer, MM (1961) In 'Experimental Immunochemistry' 2nd ed. Charles and Thomas, USA) and modified klox ( Klerx) was measured using the complement reaction (Klerx, JPAM, Beukelman, CJ, Dijk, HV and Willers, JMN (1983) J. Immunol. Methods 63 , 215.) and added ginseng saponin from the alcoholic extract of ginseng. Hemolysis inhibition of the complement to the sensitized amount of red blood cells was tested. The results are shown in Table 3 below.

홍삼 사포닌의 항보체 활성Anti-complement Activity of Red Ginseng Saponin 인삼 사포닌 또는 사포게닌Ginseng saponin or sapongenin IC50(μM)IC50 (μM) 진세노사이드 Ra1 Ginsenoside Ra 1 107107 진세노사이드 Ra2 Ginsenoside Ra 2 104104 진세노사이드 Rb1 Ginsenoside Rb 1 289289 진세노사이드 Rb2 Ginsenoside Rb 2 113113 진세노사이드 RcGinsenoside Rc 115115 진세노사이드 RdGinsenoside Rd 109109 진세노사이드 ReGinsenoside Re 580580 진세노사이드 RfGinsenoside Rf 9797 진세노사이드 Rg1 Ginsenoside Rg 1 180180 (20R)-진세노사이드 Rg2 (20R) -Ginsenoside Rg 2 109109 (20S)-진세노사이드 Rg2 (20S) -ginsenoside Rg 2 230230 (20S)-진세노사이드 Rh1 (20S) -Ginsenoside Rh 1 105105 (20R)-진세노사이드 Rh2 (20R) -Ginsenoside Rh 2 230230 진세노사이드 Rh4 Ginsenoside Rh 4 112112 진세노사이드 R0 Ginsenoside R 0 5858 올레아놀 산Oleanolic acid 6969 전체 사포닌 분획Whole saponin fraction 154(㎍/㎖)154 (μg / ml)

본 발명의 화학식 1과 표 1, 화학식 2와 표 2 및 화학식 3으로 표시되는 사포닌 또는 사포게닌 화합물 또는 이들을 함유하는 조사포닌은 상기 표 3에서 보는 바와 같이 강한 항보체 활성을 갖는다. 따라서 본 발명의 사포닌 또는 사포게닌 화합물을 함유하는 보체활성 조절제는 항보체활성을 발휘하여 보체활성을 원할하게 조절할 수 있으며, 특히, 보체활성과 관련된 질환 즉, 천식, 알레르기, 아토피성 피부염 등 다양한 염증질환 치료에 유용하게 사용할 수 있다.The saponin or sapongenin compounds represented by the formulas (1) and (1), (1) and (2) and (3) of the present invention or irradiated saponin containing them have a strong anti-complementary activity as shown in Table 3 above. Therefore, the complement activity modulator containing the saponin or saponenin compound of the present invention can exert anti complement activity to smoothly regulate the complement activity, in particular, diseases associated with complement activity, that is, various inflammations such as asthma, allergy, atopic dermatitis It can be usefully used to treat diseases.

Claims (3)

하기 화학식 1, 화학식 2 및 화학식 3으로 표시되고 항보체 활성을 가지는 사포닌 또는 사포게닌 화합물중 최소한 한 개를 함유하는 보체활성 조절제.Complement activity regulators represented by the following formula (1), (2) and (3) and containing at least one of saponin or saponenin compounds having anti-complement activity. 화학식 1Formula 1 상기 식에서 각각의 치환기는 표 1에 기재된 바와 같다.Each substituent in the above formula is as described in Table 1. 표 1Table 1 화학식 1로 표시된 사포닌 또는 사포게닌 화합물의 치환기Substituents of saponins or sapongenin compounds represented by the formula (1) 치 환 기사포닌Substituted knightponin R1 R 1 R2 R 2 R3 R 3 진세노사이드 Ra1 Ginsenoside Ra 1 -glc2-glc-glc 2 -glc HH -glc6-ara(pyr)4-xyl-glc 6 -ara (pyr) 4 -xyl 진세노사이드 Ra2 Ginsenoside Ra 2 -glc2-glc-glc 2 -glc HH -glc6-ara(fur)2-xyl-glc 6 -ara (fur) 2 -xyl 진세노사이드 Rb1 Ginsenoside Rb 1 -glc2-glc-glc 2 -glc HH -glc6-glc-glc 6 -glc 진세노사이드 Rb2 Ginsenoside Rb 2 -glc2-glc-glc 2 -glc HH -glc6-ara(pyr)-glc 6 -ara (pyr) 진세노사이드 RcGinsenoside Rc -glc2-glc-glc 2 -glc HH -glc6-ara(fur)-glc 6 -ara (fur) 진세노사이드 RdGinsenoside Rd -glc2-glc-glc 2 -glc HH -glc-glc 진세노사이드 Rg2 Ginsenoside Rg 2 HH -O-glu-rha-O-glu-rha HH 진세노사이드 Rg3 Ginsenoside Rg 3 -glc2-glc-glc 2 -glc HH HH 진세노사이드 Rh2 Ginsenoside Rh 2 -glc-glc HH HH 진세노사이드 ReGinsenoside Re HH -O-glc-rha-O-glc-rha -glc-glc 진세노사이드 RfGinsenoside Rf HH -O-glc-glc-O-glc-glc HH 진세노사이드 Rg1 Ginsenoside Rg 1 HH -O-glc-O-glc -glc-glc 진세노사이드 Rh1 Ginsenoside Rh 1 HH -O-glc-O-glc HH
화학식 2Formula 2 상기 식에서 각각의 치환기는 표 2에 기재된 바와 같다.Each substituent in the above formula is as described in Table 2. 표 2TABLE 2 화학식 2로 표시된 사포닌 또는 사포게닌 화합물의 치환기Substituents of saponin or saponenin compounds represented by the formula (2) 치환기사포닌Substituted Saponin R1 R 1 R2 R 2 올레아놀 산Oleanolic acid HH HH 진세노사이드 R0 Ginsenoside R 0 -glucuronic acid2-glc-glucuronic acid 2 -glc -glc-glc
화학식 3Formula 3 제1항에 있어서, 보체활성 조절제는 보체활성과 관련된 질환의 치료에 유용한 치료제인 것을 특징으로 하는 보체활성 조절제.The complement activity modulator of claim 1, wherein the complement activity modulator is a therapeutic agent useful for the treatment of a disease associated with the complement activity. 제2항에 있어서, 보체활성과 관련된 질환은 천식, 알레르기, 관절염, 류마치스, 전신성 홍반성 낭창(systemic lupus erythemtosus, SLE), 망막염, 간염, 장염, 췌장염, 신장염, 비염, 아토피성 피부염 및 장기 이식거부반응으로 구성되는 염증질환인 것을 특징으로 하는 보체활성 조절제.The disease according to claim 2, wherein the disease associated with complement activity is asthma, allergy, arthritis, rheumatism, systemic lupus erythemtosus (SLE), retinitis, hepatitis, enteritis, pancreatitis, nephritis, rhinitis, atopic dermatitis and organ transplantation Complement activity modulator, characterized in that the inflammatory disease consisting of rejection.
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