KR100316567B1 - Anti-cancer ginseng saponin, method for producing the same, and anticancer composition containing the same as an active ingredient - Google Patents
Anti-cancer ginseng saponin, method for producing the same, and anticancer composition containing the same as an active ingredient Download PDFInfo
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- KR100316567B1 KR100316567B1 KR1019980033462A KR19980033462A KR100316567B1 KR 100316567 B1 KR100316567 B1 KR 100316567B1 KR 1019980033462 A KR1019980033462 A KR 1019980033462A KR 19980033462 A KR19980033462 A KR 19980033462A KR 100316567 B1 KR100316567 B1 KR 100316567B1
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Abstract
본 발명은 화학식 1로 표시되는 신규한 인삼 사포닌, 그 제조방법 및 그를 활성 성분으로 함유하는 항암제 조성물에 관한 것으로서, 탁월한 항암 효과를 가짐으로써 다양한 암 질환에 대한 치료제 또는 예방제로 사용될 수 있다.The present invention relates to a novel ginseng saponin represented by the general formula (1), a process for producing the same, and an anticancer composition comprising the same as an active ingredient. The ginseng saponin has excellent anticancer effect and can be used as a therapeutic or preventive agent for various cancer diseases.
상기 식에서, R1은 수소, β-D-글루코피라노실(1→2)-β-D-글루코피라노실, β-D-글루코피라노실, 및 β-D-(6"-O-아세틸)-글루코피라노실(1→2)-β-D-글루코피라노실로 이루어진 군으로부터 선택되는 것이며, R2는 수소 또는 OR3로서, R3는 β-D-글루코피라노실 또는 β-D-(6'-O-아세틸)-글루코피라노실이다.Wherein R 1 is selected from the group consisting of hydrogen, β-D-glucopyranosyl (1 → 2) - β-D-glucopyranosyl, β-D-glucopyranosyl, and β-D- (6 " - glucopyranosyl (1 → 2) - β-D-glucopyranosyl, R 2 is hydrogen or OR 3 , R 3 is selected from the group consisting of β-D-glucopyranosyl or β- 6'-O-acetyl) -glycopyranosyl.
Description
[산업상 이용분야][Industrial Applications]
본 발명은 항암 효과를 갖는 신규한 인삼 사포닌에 관한 것으로서, 더욱 상세하게는 화학식 1로 표시되는 인삼 사포닌, 그 제조방법 및 그를 활성 성분으로 함유하는 항암제 조성물에 관한 것이다.The present invention relates to a novel ginseng saponin having an anticancer effect, and more particularly, to a ginseng saponin represented by the general formula (1), a preparation method thereof, and an anticancer composition containing the same as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 식에서, R1은 수소, β-D-글루코피라노실(1→2)-β-D-글루코피라노실(β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl), β-D-글루코피라노실(β-D-glucopyranosyl) 및 β-D-(6"-O-아세틸)-글루코피라노실(1→2)-β-D-글루코피라노실(β-D-(6"-O-acetyl)-glucopyranosyl(1→2)-β-D-glucopyranosyl)로 이루어진 군으로부터 선택되는 것이며, R2는 수소 또는 OR3로서, R3는 β-D-글루코피라노실 또는 β-D-(6'-O-아세틸)-글루코피라노실이다.Wherein R 1 is selected from the group consisting of hydrogen,? -D-glucopyranosyl (1? 2) -? - D-glucopyranosyl (? - D- -? - D-glucopyranosyl and? -D- (6 "-O-acetyl) -glucopyranosyl (1 → 2) D-glucopyranosyl), R 2 is hydrogen or OR 3 , R 3 is selected from the group consisting of? (6'-O-acetyl) -glycopyranosyl.
[종래기술]BACKGROUND ART [0002]
인삼은 예로부터 대표적인 자양강장제로 널리 사용되어 온 식물로서, 일반적으로 재배하여 채취한 그대로의 수삼, 수삼을 상온에서 건조시킨 백삼 또는 수삼을 98∼100℃에서 가열처리하여 제조되는 홍삼의 형태로 사용된다. 인삼의 성분과 약효에 관한 많은 연구결과가 보고되어 있는데, 현재까지 알려진 인삼의 약효로는 노화억제, 항동맥경화 및 고지혈증 개선, 간기능항진, 방사선장애 제거, 면역증강, 항혈전, 뇌기능항진, 항스트레스, 혈당강하, 혈압강하 또는 항암 효과 등이 있다. 인삼이 갖는 여러 가지 약리학적 작용중 항암 효과에 관한 연구는 비교적 최근에 와서야 이루어졌다. 그 연구 결과의 하나로 생쥐의 백혈병 임파모세포 P388, 인체 결장암세포 HT-29 및 직장암세포 HRT-18을 대상으로 홍삼의 석유에테르, 클로로포름, 메탄올 및 아세톤 추출물의 세포증식억제 효과를 측정한 결과 모든 분획이 항암 효과를 가지며, 특히 아세톤 분획이 가장 큰 효과를 갖는 것으로 보고되었다(고려인삼학회지, 제17권, 제3호, pp196-202 (1993)). 또한 B16 세포주를 주입하여 암을 유발시킨 마우스에게 홍삼을 투여하여 형태학적 및 면역학적 연구를 수행한 결과 홍삼의 항암 작용은 T 림프구에 의한 매개성 면역반응 및 자연살해세포의 활성도 증가에 의한 것으로 보고되었다(고려인삼학회지, 제18권, 제3호, pp151-159 (1994)). 또한 분화연구의 대표적인 모델인 F9 기형종을 이용하여 진세노사이드Rh1이 라미닌과 피브로렉틴의 생성 및 암유전자의 발현에 미치는 영향을 관찰하고, 그 형태학적 관찰의 결과, 진세노사이드 Rh1은 F9 세포의 정상배아세포로의 분화를 유도하며, 이와 같은 진세노사이드에 의한 분화 유도는 스테로이드 호르몬과 유사한 분화기전에 의해 일어나는 것으로 보고되었다. 또한 멜라닌 합성 촉진 작용에 의해 진세노사이드 Rh1과 Rh2가 미분화된 암세포를 정상세포로 분화시키는 것으로 보고되었다(캔서 리서치, 47, p3868 (1987)).Ginseng is a plant widely used as a typical nourishing tonic for a long time. It is generally used in the form of red ginseng prepared by heat-treating white ginseng or ginseng dried at room temperature at a temperature of 98 to 100 ° C do. There have been many reports on the composition and effects of ginseng. The known effects of ginseng to date include suppression of aging, improvement of atherosclerosis and hyperlipidemia, enhancement of liver function, elimination of radiation damage, immunity enhancement, , Anti-stress, hypoglycemic, hypotensive or anticancer effects. Studies on the anticancer effects of various pharmacological actions of ginseng have been made relatively recently. As a result of the study, the inhibitory effect of the petroleum ether, chloroform, methanol and acetone extracts of red ginseng on the cell proliferation inhibition of mouse leukemia lymphocyte P388, human colon cancer cell HT-29 and rectal cancer cell HRT- (Korean Ginseng Journal, Vol. 17, No. 3, pp. 196-202 (1993)). As a result of morphological and immunological studies, red ginseng was injected into mice induced by B16 cell line, and the anti-cancer effect of red ginseng was attributed to the increase of T lymphocyte-mediated immune response and natural killer cell activity (Journal of Korean Ginseng, Vol. 18, No. 3, pp151-159 (1994)). In addition, the effect of ginsenoside Rh 1 on the production of laminin and fibrin reductin and on the expression of cancer gene was observed using F9 teratoma, which is a representative model of differentiation study. As a result of morphological observation, ginsenoside Rh 1 Induces the differentiation of F9 cells into normal cells, and induction of differentiation by ginsenosides has been reported to be caused by a mechanism of differentiation similar to that of steroid hormones. In addition, it has been reported that ginsenosides Rh 1 and Rh 2 are differentiated into cancer cells by normal melanin synthesis promoting action (Kanser Research, 47, p3868 (1987)).
본 발명자들은 인삼의 특이 성분들을 증가시켜 인삼의 약효를 강화시킬 수 있는 수단을 강구하기 위하여, 인삼의 가공방법과 그에 따른 생리활성 및 생리활성물질의 변화에 관한 연구를 수행하여 왔다. 그 결과 인삼을 110∼180℃의 고온에서 0.5∼20시간 동안 가열처리하면 기존의 수삼, 백삼 및 홍삼보다 약효가 훨씬 증강된 가공인삼이 제조되는 것을 확인하였다. 나아가 이 가공인삼에 존재하는 각종 성분들을 분리하여 약효를 검증하는 과정에서 원래의 인삼에는 존재하지 않는 신규한 구조를 갖는 사포닌 성분을 발견하였다. 즉 현재까지 알려진 대부분의 인삼 사포닌들은 곁가지의 24번 및 25번 탄소간에 하나의 이중결합만이 존재하는데 비하여(화학식 2; 예를 들면, 진세노사이드 Ra, Rb1, Rb2, Rc, Rd, Rg1, Rg2, Rg3, Re 등), 최근 20번 및 22번 탄소간에 하나의 이중결합을 추가로 갖는 인삼 사포닌(화학식 4; 예를 들면, 진세노사이드 Rg5, Rh3, Rh4등)을 분리한 바 있다(대한민국 특허출원 1996년 제 19281 호).The present inventors have conducted studies on the processing method of ginseng, the physiological activity thereof and the change of physiologically active substances in order to increase the specific components of ginseng to enhance the medicinal effect of ginseng. As a result, it was confirmed that the processed ginseng having a much enhanced effect than that of the existing ginseng, white ginseng and red ginseng was prepared by heating the ginseng at a high temperature of 110 to 180 ° C for 0.5 to 20 hours. Furthermore, in the process of isolating various components present in the processed ginseng and verifying its efficacy, a saponin component having a novel structure which does not exist in the original ginseng was found. That is, most of the ginseng saponins known so far have only one double bond between the 24th and 25th carbons of the side chain (Formula 2; for example, ginsenosides Ra, Rb 1 , Rb 2 , Rc, Rd, Rg 1 , Rg 2 , Rg 3 , Re, etc.), recently ginsenoside having one double bond between carbons 20 and 22 (formula 4; for example, ginsenoside Rg 5 , Rh 3 , Rh 4 Etc.) (Korean Patent Application No. 199628191).
상기 화학식에서, R1및 R2는 상기에서 정의한 바와 동일하다.In the above formula, R 1 and R 2 are the same as defined above.
본 발명의 목적은 상기한 바 있는 공지의 인삼 사포닌과 상이한 구조를 가질 뿐 아니라, 탁월한 항암 효과를 갖는 신규한 인삼 사포닌, 그 제조방법 및 그를 활성 성분으로 함유하는 항암제 조성물을 제공하기 위한 것이다.It is an object of the present invention to provide a novel ginseng saponin having an excellent anticancer effect as well as having a structure different from that of the known ginseng saponin as described above, a process for producing the same, and an anticancer composition containing the same as an active ingredient.
상기한 본 발명의 목적을 달성하기 위하여, 첫째 본 발명은 화학식 1의 화합물을 제공한다.In order to accomplish the above object of the present invention, first, the present invention provides a compound of Chemical Formula 1.
[화학식 1][Chemical Formula 1]
상기 화학식 1에서, R1은 수소, β-D-글루코피라노실(1→2)-β-D-글루코피라노실, β-D-글루코피라노실 및 β-D-(6"-O-아세틸)-글루코피라노실(1→2)-β-D-글루코피라노실로 이루어진 군으로부터 선택되는 것이며, R2는 수소 또는 OR3로서, R3는 β-D-글루코피라노실 또는 β-D-(6'-O-아세틸)-글루코피라노실이다. 상기 화합물은 3β,12β-디하이드록시-다마르-20(21),24-디엔-3-O-β-D-글루코피라노실-(1→2)-β-D-글루코피라노사이드(3β,12β-dihydroxy-dammar-20(21),24-diene-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside; Rk1이라 명명함), 3β,12β-디하이드록시-다마르-20(21),24-디엔-3-O-β-D-글루코피라노사이드(3β,12β- dihydroxy-dammar-20(21),24-diene-3-O-β-D-glucopyranoside; Rk2라 명명함), 3β,6α,12β-트리하이드록시-다마르-20(21),24-디엔-6-O-β-D-글루코피라노사이드(3β,6α,12β-trihydroxy-dammar-20(21),24-diene-6-O-β-D-glucopyranoside; Rk3라 명명함), 3β,12β-디하이드록시-다마르-20(21),24-디엔-3-O-β-D-글루코피라노실(1→2)-β-D-6"-O-아세틸글루코피라노사이드(3β,12β-dihydroxy-dammar-20(21),24-diene-3-O-β-D-glucopyranosyl(1→2)-β-D-6"-O-acetylglucopyranoside; Rs5라 명명함) 및 3β,6α,12β-트리하이드록시-다마르-20(21),24-디엔-6-O-β-D-6'-O-아세틸글루코피라노사이드(3β,6α,12β-trihydroxy-dammar-20(21),24-diene-6-O-β-D-6'-O-acetylglucopyranoside; Rs7이라 명명함)로 이루어진 군으로부터 선택되는 것이 바람직하다.Wherein R 1 is selected from the group consisting of hydrogen, β-D-glucopyranosyl (1 → 2) - β-D-glucopyranosyl, β-D-glucopyranosyl and β-D- (6 " ) -Glucopyranosyl (1 → 2) - β-D-glucopyranosyl, R 2 is hydrogen or OR 3 , R 3 is selected from the group consisting of β-D-glucopyranosyl or β- (6'-O-acetyl) -glycopyranosyl. The above compounds were prepared from 3?, 12? -Dihydroxy-damar-20 (21), 24- D-glucopyranoside (3?, 12? -Dihydroxy-dammar-20 (21), 24-diene-3-0-? -D-glucopyranosyl- -glucopyranoside; Rk 1 as name card), 3β, 12β- dihydroxy-the-Mar-20 (21), 24-diene-O-β-D- gluconic -3 nose Llano side (3β, 12β- dihydroxy-dammar 20 (21), 24-diene-6 (18), 24-diene-3-O- beta -D- glucopyranoside; Rk 2 ), 3 ?, 6 ?, 12? -Trihydroxy- -Β-D-glucopyranoside (3β, 6α, 12β-trihydroxy-dammar-20 (21), 24-diene- -glucopyranoside (Rk 3 ), 3?, 12? -dihydroxy-damar-20 (21), 24-diene-3-O-? -D-glucopyranosyl 6-O-acetylglucopyranoside (3?, 12? -Dihydroxy-dammar-20 (21), 24-diene-3-0-? -D- glucopyranosyl -O-acetylglucopyranoside (hereinafter referred to as Rs 5 ) and 3?, 6 ?, 12? -Trihydroxy-damar-20 (21), 24-diene-6-0-? -D-6'- Llano side; is selected from the group consisting of (3β, 6α, 12β-trihydroxy -dammar-20 (21), 24-diene-6-O-β-D-6'-O-acetylglucopyranoside as Rs 7 myeong card) desirable.
둘째, 본 발명은 상기 화합물을 활성 성분으로 함유하는 항암제 조성물을 제공한다. 상기 항암제 조성물은 상기 화합물이 5∼500mg/일로 투여되도록 하는 것이 바람직하다.Second, the present invention provides an anticancer composition comprising the compound as an active ingredient. Preferably, the anticancer composition is administered at a dose of 5 to 500 mg / day.
셋째, 본 발명은 화학식 2의 화합물을 아세틸화(acetylation)하여 화학식 3의 화합물을 수득하고, 화학식 3의 화합물을 탈수(dehydration) 및 탈아세틸화(deacetylation)하여 화학식 1의 화합물을 수득하는 단계를 포함하는 화학식 1의 화합물의 제조방법을 제공한다.Third, the present invention provides a process for producing a compound represented by the formula (1) by acetylating the compound of the formula (2) to obtain a compound of the formula (3), dehydration and deacetylation of the compound of the formula Wherein R < 1 >
[화학식 2](2)
상기 화학식에서, R1및 R2는 상기에서 정의한 바와 동일하며, R4는 CH3CO 또는 (CH3CO)nR1이고, R5는 수소 또는 (CH3CO)nR2O이며, n은 1~4의 정수이다.Wherein R 1 and R 2 are the same as defined above, R 4 is CH 3 CO or (CH 3 CO) n R 1 , R 5 is hydrogen or (CH 3 CO) n R 2 O, n is an integer of 1 to 4;
이하 본 발명을 상세히 설명하면 하기와 같다.Hereinafter, the present invention will be described in detail.
본 발명에 따른 인삼 사포닌은 이미 공지된 인삼 사포닌에 비하여 20번 및 21번 탄소간에 이중결합을 추가로 갖는 신규한 구조인 화학식 1로 표시되는 화합물이다. 바람직하게는, 상기 화합물은 표 1에 나타낸 화합물, Rk1, Rk2, Rk3, Rs5또는 Rs7이다.The ginseng saponin according to the present invention is a compound represented by the formula (1), which is a novel structure having a double bond between carbons 20 and 21 as compared with the already known ginseng saponin. Preferably, the compound is the compound shown in Table 1, Rk 1 , Rk 2 , Rk 3 , Rs 5 or Rs 7 .
상기 화합물은 하기와 같이 인삼속 식물을 가공처리하여 추출·분리함으로써 제조할 수 있다. 즉, 파낙스속 식물, 예를 들면, 파낙스 진셍(Panax ginseng), 파낙스 노토진셍(Panax notoginseng), 파낙스 퀸크폴리움(Panax quinquefolium), 파낙스 자포니쿰(Panax japonicum), 파낙스 슈도진셍(Panax pseudoginseng), 파낙스 트리폴리움(Panax trifolium) 등의 잎, 줄기, 또는 뿌리 또는 이들의 조직배양물을 110∼180℃에서 0.5∼20시간 가열처리하여 수득한 가공물을 물, 저급 알코올, 또는 그 혼합용매로 1차 추출한다. 그런 다음 유기용매를 날려보내고 남은 잔사를 물에 현탁시키고 헥산, 에테르, 디클로로메탄 또는 클로르포름 등의 비극성 유기용매로 2차 추출한다. 그런 다음 유기용매층을 버리고 남은 수층을 수포화 부탄올 또는 에틸아세테이트로 3차 추출하고 유기용매를 날려보내어 비극성 사포닌 분획을 얻는다. 이렇게 하여 얻은 유기용매층에는 화학식 1의 화합물이 사용원료, 가공방법 및 추출방법에 따라 약 5-20% 함유되어 있다. 이 분획을 실리카겔 컬럼 크로마토그래피, 실리카겔 박층크로마토그래피, 분취용 HPLC(High Performance Liquid Chromatography) 등을 이용하여 정제하여 화학식 1의 화합물을 얻는다.The compound can be produced by processing and extracting and isolating a plant of the genus Ginseng as described below. Namely, plants belonging to the genus Panax, for example, Panax ginseng , Panax notoginseng , Panax quinquefolium , Panax japonicum , Panax pseudoginseng , Stem, or root or a tissue culture thereof such as Panax trifolium at a temperature of 110 to 180 캜 for 0.5 to 20 hours to obtain a processed product obtained by treating the obtained product with water, a lower alcohol, or a mixed solvent thereof Extract tea. The organic solvent is then blown off and the residue is suspended in water and extracted with a nonpolar organic solvent such as hexane, ether, dichloromethane or chloroform. Then, the organic solvent layer is discarded and the remaining water layer is subjected to tertiary extraction with water saturated butanol or ethyl acetate and the organic solvent is blown off to obtain the non-polar saponin fraction. The organic solvent layer thus obtained contains about 5-20% of the compound of formula (1) according to the raw materials used, the processing method and the extraction method. This fraction is purified by silica gel column chromatography, silica gel thin layer chromatography, preparative HPLC (High Performance Liquid Chromatography) or the like to obtain a compound of formula (1).
본 발명에 의한 화학식 1의 화합물을 제조하는 또 다른 방법은 인삼 또는 홍삼에 원래 함유되어 있는 인삼 사포닌을 탈수반응을 통하여 20번 탄소 위치에 이중결합을 형성시키는 것이다. 즉 화학식 2의 화합물을 피리딘을 용매로 하여 무수 아세트산(acetic anhydride)과 반응시키는 것과 같은 통상적인 아세틸화 방법을 이용하여 아세틸화시킴으로써, 20번 위치의 -OH기를 제외한 나머지 -OH기들이 모두 아세틸화된 화학식 3의 화합물을 얻는다. 상기 화학식 3의 화합물을 톨루엔설폰산과 같은 시약을 사용하여 탈수시키고, 탄산칼륨(K2CO3)과 같은 알칼리로 아세틸기를 제거하여 화학식 1의 화합물을 얻게 된다(반응식 1).Another method for preparing the compound of Chemical Formula 1 according to the present invention is to form a double bond at the carbon position 20 through dehydration reaction of ginseng saponin originally contained in ginseng or red ginseng. That is, the compound of formula (2) is reacted with acetic anhydride using pyridine as a solvent, acetylation of all remaining -OH groups other than the -OH group at the 20- To obtain the compound of formula (3). The compound of Formula 3 is dehydrated using a reagent such as toluenesulfonic acid and the acetyl group is removed with an alkali such as potassium carbonate (K 2 CO 3 ) to obtain a compound of Formula 1 (Scheme 1).
상기 반응식에서, R1∼R5는 상기에서 정의한 바와 동일하다.In the above reaction formulas, R 1 to R 5 are the same as defined above.
활성 성분으로 본 발명에 따른 화학식 1로 표시되는 화합물을 함유하는 조성물은 강력한 항암 효과를 가지므로 간암, 위암, 또는 백혈병 등의 다양한 암에 대한 예방 및 치료제로서 유용하게 사용될 수 있다. 상기 목적을 위하여 본 발명의 조성물은 약제학적 분야에서 통상적으로 허용되는 담체와 함께 배합하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로치제, 액제, 현탁제 등의 경구투여용 제제, 주사용 용액 또는 현탁액, 또는 주사시 주사용 증류수로 재조제하여 사용할 수 있는 즉시 사용형 주사용 건조분말 등의 형태의 주사용 제제, 연고제, 크림제, 액제 등의 국소적용형 제제 등, 다양한 제제로 제형화시킬 수 있다. 본 발명의 조성물에서 사용될 수 있는 담체로는 약제학적 분야에서 통상적인 것으로, 예를 들면 경구투여용 제제의 경우, 결합제, 활택제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소 또는 향료 등이 있으며, 주사제의 경우 보존제, 무통화제, 가용화제 또는 안정화제 등이 있고, 국소투여용 제제의 경우 기제, 부형제, 윤활제 또는 보존제 등이 있다. 이렇게 제조된 약제학적 제제는 경구적으로 투여되거나, 비경구적으로, 예를 들면 정맥내, 피하, 복강내 투여 또는 국소적용될 수 있다. 또한 경구투여시에 약제가 위산에 의해 분해되는 것을 방지하기 위하여 제산제를 병용하거나, 정제 등의 경구투여용 고형 제제를 장용피로 피복된 제제로 제형화하여 투여할 수 있다.Since the composition containing the compound represented by the formula (1) according to the present invention as an active ingredient has a strong anti-cancer effect, it can be effectively used as a preventive and therapeutic agent for various cancers such as liver cancer, stomach cancer, or leukemia. For the above-mentioned purpose, the composition of the present invention may be formulated together with a carrier generally accepted in the pharmaceutical field and used for oral administration such as tablets, capsules, troches, liquids and suspensions, , Injectable solutions or suspensions, or topically applied preparations such as injectable preparations, ointments, creams, and liquid preparations in the form of ready-to-use injectable dry powders that can be reconstituted with distilled water for injection for injection Formulation can be formulated. Carriers which can be used in the composition of the present invention include those conventionally used in the pharmaceutical field such as binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, A coloring agent or a flavoring agent. In the case of injections, preservatives, analgesics, solubilizing agents or stabilizers can be used. In the case of formulations for topical administration, there are bases, excipients, lubricants or preservatives. The pharmaceutical preparations thus prepared may be administered orally or parenterally, for example intravenously, subcutaneously, intraperitoneally, or topically. In addition, in order to prevent the drug from being degraded by gastric acid during oral administration, antacids may be used in combination, or a solid preparation for oral administration such as tablets may be formulated into a fatigue-covered preparation for enteral use.
본 발명에 따른 화학식 1로 표시되는 화합물의 인체에 대한 투여량은 체내에서의 활성 성분의 흡수도, 불활성화율 및 배설속도, 환자의 연령, 성별 및 상태, 치료할 질병의 중증도 등에 따라 적절히 선택되나, 일반적으로 성인에게 1일에 5∼500㎎, 바람직하게는 10∼200㎎의 양이 투여되도록 한다. 따라서, 본 발명의 조성물을 단위투여형으로 제조할 시에 각각의 단위투여형은 상기 유효용량 범위를 고려하여 화학식 1의 화합물을 5∼500㎎, 바람직하게는 10∼200㎎씩 함유하도록 제형화시킬 수 있다. 이렇게 제형화된 단위투여형은 필요에 따라 약제의 투여를 감시하거나 관찰하는 전문가의 판단과 개인의 요구에 따라 전문화된 투약법을 사용하거나, 일정 시간 간격으로 수회, 바람직하게는 2∼6회 분할 투여할 수 있다.The dose of the compound of formula (I) according to the present invention is appropriately selected according to the degree of absorption, inactivation rate and excretion rate of the active ingredient in the body, age, sex and condition of the patient, severity of the disease to be treated, Generally, an amount of 5 to 500 mg, preferably 10 to 200 mg per day is administered to an adult. Accordingly, when preparing the composition of the present invention in a unit dosage form, each unit dosage form is formulated so as to contain 5 to 500 mg, preferably 10 to 200 mg, of the compound of formula (1) . The unit dosage form thus formulated may be divided into a plurality of dosage forms, each of which is divided into several times, preferably two to six times, at a predetermined time interval, using a specialist dosage regimen according to the judgment of a specialist, Lt; / RTI >
[실시예][Example]
본 발명은 이하의 실시예 및 실험예에 의해 더욱 상세히 설명되나 본 발명이 이들에 의해 어떤 식으로든 제한되는 것은 아니다.The present invention is explained in more detail by the following examples and experimental examples, but the present invention is not limited thereto in any way.
[실시예 1] 화학식 1의 화합물을 함유하는 인삼 추출물 분획의 제조Example 1 Preparation of a Ginseng Extract Fraction Containing the Compound of Chemical Formula 1
가압멸균기에 인삼 100g을 넣고 130℃에서 2시간 동안 가열하여 가공인삼을 얻었다. 이 가공인삼을 메탄올 500㎖로 환류추출하여 메탄올 추출물을 얻었다. 그런 다음 메탄올을 증발시켜 제거한 후에 남은 잔사를 물 500㎖에 현탁시켜 에테르 300㎖로 3회 추출하였다. 그런 다음, 남은 수층을 에틸아세테이트 300㎖로 3 회 추출하여 합한 후 감압하에서 용매를 날려보내 에틸아세테이트 분획 3.5g을 얻었다. 이 분획에는 화합물 Rk15.6%, Rk22.9%, Rk32.6%, Rs52.5%, Rs72.1%가 함유되어 있으며, 그 밖에도 진세노사이드 Rg317.9%, Rg56.6%, Rg62.9%를 함유하고 있었다.100 g of ginseng was placed in a pressure sterilizer and heated at 130 ° C for 2 hours to obtain processed ginseng. This processed ginseng was refluxed with 500 ml of methanol to obtain a methanol extract. Then, methanol was removed by evaporation, and the remaining residue was suspended in 500 ml of water and extracted three times with 300 ml of ether. Then, the remaining aqueous layer was extracted three times with 300 ml of ethyl acetate, and the solvent was blown off under reduced pressure to obtain 3.5 g of ethyl acetate fraction. This fraction contains the compounds Rk 1 5.6%, Rk 2 2.9 %, Rk 3 2.6%, Rs 5 2.5%, Rs 7 and 2.1% is contained, the other ginsenoside Rg 3 17.9%, Rg 5 6.6 %, Rg 6 And 2.9%.
[실시예 2] 화학식 1의 화합물을 함유하는 인삼잎 추출물 분획의 제조[Example 2] Preparation of a fraction of ginseng leaf extract containing the compound of Chemical Formula 1
가압멸균기에 인삼잎 100g을 넣고 실시예 1에서와 동일한 과정으로 처리하여 에틸아세테이트 분획 6g을 얻었다. 이 분획에는 화합물 Rk13.2%, Rk22.9%, Rk32.6%, Rs51%, Rs71%가 함유되어 있으며, 그 밖에도 진세노사이드 Rg315.9%, Rg53.6%, Rg63.7%를 함유하고 있었다.100 g of ginseng leaf was placed in a pressure sterilizer and treated in the same manner as in Example 1 to obtain 6 g of an ethyl acetate fraction. This fraction contains the compounds Rk 1 3.2%, Rk 2 2.9 %, Rk 3 2.6%, Rs 5 1%, Rs 7 , and 1% is contained, the other binary 3 15.9% ginsenosides Rg, Rg 5 3.6%, Rg 6 3.7%.
[실시예 3] 화학식 1의 화합물의 분리 및 정제[Example 3] Separation and purification of the compound of Chemical Formula 1
상기 실시예 1 에서 수득한 에틸아세테이트 분획 1g을 대상으로 실리카겔 컬럼상에서 크로마토그래피를 수행하여 에틸아세테이트:메탄올:물=40:1:1로부터 시작하여 30:1:1, 20:1:1, 10:1:1 등으로 용매 강도를 증가시키면서 크로마토그래피를 실시하여 5개의 분획을 얻었다. 2번 분획을 대상으로 준분취 HPLC를 실시하여 화합물 Rs719mg과 화합물 Rk221mg을 얻었다. 4번 분획을 대상으로 에틸아세테이트/메탄올/물(10:1:1)을 전개용매로 질산은을 포함하는 분취용 실리카 박층크로마토그래피를 수행하여 화합물 Rk145mg를 얻었다. 3번 분획을 대상으로 에틸아세테이트/메탄올/물(10:1:1)을 전개용매로 질산은을 포함하는 분취용 실리카 박층크로마토그라피를 수행하여 화합물 Rs518mg과 화합물 Rk327mg을 얻었다. 상기 화합물들을 대상으로 질량 분광분석 및13C NMR 분석을 수행한 결과는 하기와 같다.1 g of the ethyl acetate fraction obtained in Example 1 was chromatographed on a silica gel column and eluted with ethyl acetate: methanol: water = 40: 1: 1 to 30: 1: 1, 20: : 1: 1, etc., to obtain five fractions. The fraction 2 was subjected to semi-preparative HPLC to obtain 19 mg of the compound Rs 7 and 21 mg of the compound Rk 2 . Fraction 4 was subjected to preparative silica thin layer chromatography using ethyl acetate / methanol / water (10: 1: 1) as developing solvent to obtain 45 mg of compound Rk 1 . The fraction No. 3 was subjected to preparative silica thin layer chromatography using ethyl acetate / methanol / water (10: 1: 1) as eluent to obtain silver nitrate to obtain 18 mg of compound Rs 5 and 27 mg of compound Rk 3 . Mass spectrometric analysis and 13 C NMR analysis of the above compounds were carried out as follows.
[화합물 Rk1][Compound Rk 1 ]
3β,12β-디하이드록시-다마르-20(21),24-디엔-3-O-β-D-글루코피라노실-(1→2)-β-D-파리노사이드3?, 12? -Dihydroxy-damar-20 (21), 24-diene-3-O-? -D-glucopyranosyl-
질량 스펙트럼(FAB+, m/z): 789([M+Na]+)Mass spectrum (FAB +, m / z): 789 ([M + Na] + )
13C NMR(δppm, 피리딘-d5): 15.8, 16.58, 16.45, 16.98, 17.74, 18.45, 25.74, 26.75, 27.08, 28.11, 30.77, 32.60, 32.67, 33.89, 35.36, 37.03, 39.30, 39.72, 40.21, 50.86, 48.23, 51.21, 52.49, 56.43, 62.76, 62.87, 71.65, 71.72, 72.47, 77.08, 77.96, 78.06, 78.19, 78.34, 83.45, 88.95, 105.09, 106.01, 108.15, 125.33, 131.21, 155.55. 13 C NMR (隆 ppm, pyridine-d 5 ): 15.8, 16.58, 16.45, 16.98, 17.74, 18.45, 25.74, 26.75, 27.08, 28.11, 30.77, 32.60, 32.67, 33.89, 35.36, 37.03, 39.30, 39.72, 50.86, 48.23, 51.21, 52.49, 56.43, 62.76, 62.87, 71.65, 71.72, 72.47, 77.08, 77.96, 78.06, 78.19, 78.34, 83.45, 88.95, 105.09, 106.01, 108.15, 125.33, 131.21, 155.55.
[화합물 Rk2][Compound Rk 2 ]
3β,12β-디하이드록시-다마르-20(21),24-디엔-3-O-β-D-글루코피라노사이드3?, 12? -Dihydroxy-damar-20 (21), 24-diene-3-0-? -D-glucopyranoside
질량 스펙트럼(FAB+, m/z): 627([M+Na]+)Mass spectrum (FAB +, m / z): 627 ([M + Na] + )
13C NMR(δppm, 피리딘-d5): 15.97, 16.64, 16.95, 17.16, 17.91, 18.63, 25.92, 26.92, 27.22, 28.32, 30.95, 32.78, 32.88, 34.01, 35.50, 37.23, 39.44, 39.86, 40.38, 48.44, 51.02, 51.38, 52.63, 56.57, 63.27, 72.07, 72.59, 75.98, 78.57, 78.95, 88.95, 107.16, 108.28, 125.52, 131.38, 155.71. 13 C NMR (隆 ppm, pyridine-d 5 ): 15.97, 16.64, 16.95, 17.16, 17.91, 18.63, 25.92, 26.92, 27.22, 28.32, 30.95, 32.78, 32.88, 34.01, 35.50, 37.23, 39.44, 39.86, 40.38, 48.44, 51.02, 51.38, 52.63, 56.57, 63.27, 72.07, 72.59, 75.98, 78.57, 78.95, 88.95, 107.16, 108.28, 125.52, 131.38, 155.71.
[화합물 Rk3][Compound Rk 3 ]
3β,6α,12β-트리하이드록시-다마르-20(21),24-디엔-6-O-β-D-글루코피라노사이드3?, 6 ?, 12? -Trihydroxy-damar-20 (21), 24-diene-6-O-? -D-glucopyranoside
질량 스펙트럼(FAB+, m/z) : 643([M+Na]+)Mass spectrum (FAB +, m / z): 643 ([M + Na] + )
13C NMR(δppm, 피리딘-d5): 16.34, 16.73, 17.33, 17.73, 17.33, 25.74, 27.02, 27.92, 30.71, 31.70, 32.50, 32.73, 33.70. 39.50, 39.71, 40.37, 41.26, 45.31, 48.27, 50.64, 51.13, 52.07, 61.44, 63.06, 71.82, 72.42, 75.45, 78.12, 78.56, 79.65, 80.05, 106.00, 108.11, 125.33, 131.18, 155.42. 13 C NMR (? Ppm, pyridine-d 5 ): 16.34, 16.73, 17.33, 17.73, 17.33, 25.74, 27.02, 27.92, 30.71, 31.70, 32.50, 32.73, 33.70. 39.50, 39.71, 40.37, 41.26, 45.31, 48.27, 50.64, 51.13, 52.07, 61.44, 63.06, 71.82, 72.42, 75.45, 78.12, 78.56, 79.65, 80.05, 106.00, 108.11, 125.33, 131.18, 155.42.
[화합물 Rs5][Compound Rs 5 ]
3β,12β-디하이드록시-다마르-20(21),24-디엔-3-O-β-D-글루코피라노실(1→2)-β-D-6"-O-아세틸글루코피라노사이드3?, 12? -Dihydroxy-damar-20 (21), 24-diene-3-O-? -D-glucopyranosyl (1? 2)? - D-6 "-O- acetylglucopyrano side
질량 스펙트럼(FAB+, m/z) : 831([M+Na]+)Mass spectrum (FAB +, m / z): 831 ([M + Na] + )
13C NMR(δppm, 피리딘-d5): 15.82, 16.43, 16.98, 17.74, 18.48, 20.88, 25.74, 26.79, 27.08, 28.01, 30.76, 32.60. 32.66, 33.87, 35.37, 37.06, 39.29, 39.74, 40.22, 48.24, 50.88, 51.21, 52.48, 56.47, 62.84, 64.74, 71.02, 71.42, 72.48, 75.35, 76.71, 77.92, 78.06, 78.52, 84.26, 89.21, 104.89, 106.14, 108.15, 125.33, 131.20, 155.55, 170.96. 13 C NMR (? Ppm, pyridine-d 5 ): 15.82, 16.43, 16.98, 17.74, 18.48, 20.88, 25.74, 26.79, 27.08, 28.01, 30.76, 32.60. 32.66, 33.87, 35.37, 37.06, 39.29, 39.74, 40.22, 48.24, 50.88, 51.21, 52.48, 56.47, 62.84, 64.74, 71.02, 71.42, 72.48, 75.35, 76.71, 77.92, 78.06, 78.52, 84.26, 89.21, 104.89, 106.14, 108.15, 125.33, 131.20, 155.55, 170.96.
[화합물 Rs7][Compound Rs 7]
3β,6α12β-트리하이드록시-다마르-20(21),24-디엔-6-O-β-D-6'-O-아세틸글루코피라노사이드3β, 6α12β-trihydroxy-damar-20 (21), 24-diene-6-0-β-D-6'-O-acetylglucopyranoside
질량 스펙트럼(FAB+, m/z) : 685([M+Na]+)Mass spectrum (FAB +, m / z): 685 ([M + Na] + )
13C NMR(δppm, 피리딘-d5): 16.51, 17.00, 17.41, 17.78, 20.93, 25.77, 27.12, 27.94, 30.76, 31.59, 32.71, 32.80, 33.99, 39.58, 39.82, 40.32, 41.46, 45.66, 48.22, 50.70, 51.27, 52.21, 61.49, 65.17, 71.47, 72.49, 75.17, 75.41, 78.61, 79.22, 79.72, 105.92, 108.24, 125.37, 131.25, 155.47, 170.86. 13 C NMR (隆 ppm, pyridine-d 5 ): 16.51, 17.00, 17.41, 17.78, 20.93, 25.77, 27.12, 27.94, 30.76, 31.59, 32.71, 32.80, 33.99, 39.58, 39.82, 40.32, 41.46, 45.66, 50.70, 51.27, 52.21, 61.49, 65.17, 71.47, 72.49, 75.17, 75.41, 78.61, 79.22, 79.72, 105.92, 108.24, 125.37, 131.25, 155.47, 170.86.
[실시예 4] 화합물 Rk[Example 4] Synthesis of Compound Rk 1One 의 합성Synthesis of
진세노사이드 Rg350mg을 취하여 감압건조한 후 여기에 피리딘 0.5㎖, 아세트산 무수물 0.5㎖를 가하여 상온에서 10시간 동안 교반하였다. 용매를 날려보낸 후, 벤젠 5㎖, 톨루엔설폰산 25㎎을 가하여 2시간 동안 가온하면서 환류시킨 다음,용매를 감압하에 날려보냈다. 남은 잔사를 메탄올 5㎖에 녹이고, 여기에 K2CO330㎎을 물 0.5㎖에 녹인 용액을 가하여 상온에서 6시간 동안 교반하였다. 용매를 감압하에 날려보낸 후 이를 물에 현탁시킨 후 에틸아세테이트로 추출하였다. 추출된 에틸아세테이트층을 대상으로 에틸아세테이트/메탄올/물(10:1:1)을 전개용매로 질산은을 포함하는 분취용 실리카 박층크로마토그래피를 수행하여 화합물 Rk120mg을 수득하였다.50 mg of ginsenoside Rg 3 was taken out and dried under reduced pressure. Then 0.5 ml of pyridine and 0.5 ml of acetic anhydride were added thereto, followed by stirring at room temperature for 10 hours. After the solvent was blown off, 5 ml of benzene and 25 mg of toluene sulfonic acid were added and refluxed while heating for 2 hours, and then the solvent was blown off under reduced pressure. The remaining residue was dissolved in 5 ml of methanol, and a solution of 30 mg of K 2 CO 3 in 0.5 ml of water was added thereto, followed by stirring at room temperature for 6 hours. After the solvent was blown off under reduced pressure, it was suspended in water and extracted with ethyl acetate. Ethyl acetate / methanol / water as the destination of the extracted ethyl acetate layer (10: 1: 1), the minutes containing silver nitrate as a developing solvent to perform a preparative silica thin layer chromatography to give compound Rk 1 20mg.
[실시예 5] 화합물 Rk[Example 5] Synthesis of Compound Rk 22 의 합성Synthesis of
실시예 4에서, 진세노사이드 Rh2를 사용한 것을 제외하고는 실질적으로 동일하게 실시하여, 화합물 Rk220mg을 수득하였다.In Example 4, substantially the same procedure was carried out except that ginsenoside Rh 2 was used, to obtain 20 mg of compound Rk 2 .
[실시예 6] 화합물 Rk[Example 6] Synthesis of Compound Rk 33 의 합성Synthesis of
실시예 4에서, 진세노사이드 Rh1을 사용한 것을 제외하고는 실질적으로 동일하게 실시하여, 화합물 Rk315mg을 수득하였다.In Example 4, substantially the same procedure was carried out except that ginsenoside Rh 1 was used to obtain 15 mg of compound Rk 3 .
[실험예 1] 화학식 1의 화합물의 항암 효과[Experimental Example 1] Anticancer effect of the compound of Chemical Formula 1
본 발명에 따른 화학식 1의 화합물의 항암 효과를 하기와 같은 티미딘 도입량 측정법에 의하여 평가하였다.The anticancer effect of the compound of formula (1) according to the present invention was evaluated by the following method of measuring the amount of thymidine introduced.
DMEM(Dulbecco's Modified Eagle's Medium, Gibco사 제품) 13.8g을 탈이온수 1ℓ에 용해시킨 후, 탄산나트륨과 염산 용액을 사용하여 pH를 7.4로 조정하고, 인슐린 1×107M, 겐타마이신 50mg/ℓ가 되도록 가하여 0.22㎛ 여과멸균기로 멸균한 후, 송아지 혈청을 5%가 되도록 가하여 배양액으로 사용하였다. 이 배양액에 서울대학교 암연구소로부터 분양받은 인체 간암세포주 SK-HEP-1를 T 플라스크의 면적 25cm2당, 1×106세포의 비율로 접종하여 탄산가스 5%를 유지하는 37℃의 배양기내에서 48시간 배양하였다. 이 배양물을 24 웰(well) 배양용기에 옮겨 1일 동안 계대배양한 후, 화합물 Rk1, Rk2, Rk3, Rg3, Rg5가 각각 0.1 내지 50μM이 되도록 가하였다. 대조군에는 상기 화합물 대신 용매인 70% 에탄올을 동량 처리하였다. 상기 화합물을 처리한지 12시간 후에3H로 표지된 티미딘을 1μCi/㎖ 농도가 되도록 처리하고 12시간 경과 후 각 웰로부터 배지를 제거하고, 메탄올을 사용하여 세포를 고정시키고 PBS로 세척하였다. 10% 트리클로로아세트산으로 2회 세척하여 미반응 방사성 티미딘을 제거하였다. 상기 세포를 0.2M 수산화나트륨-0.5% SDS(sodium dodesylsulfate)로 용해시키고 염산으로 중화시킨 후, DNA에 도입된 방사능을 섬광계수기로 측정하였다. 그 결과를 표 2에 나타내었다.After dissolving 13.8 g of DMEM (Dulbecco's Modified Eagle's Medium, manufactured by Gibco) in 1 L of deionized water, the pH was adjusted to 7.4 with sodium carbonate and hydrochloric acid solution, and the concentration was adjusted to 1 × 10 7 M of insulin and 50 mg / After sterilization with a 0.22 μm filter sterilizer, calf serum was added to 5% and used as a culture medium. The human liver carcinoma cell line SK-HEP-1, which has been distributed from the Cancer Research Institute of Seoul National University, was inoculated into this culture at a rate of 1 × 10 6 cells per 25 cm 2 of the T-flask and incubated in a 37 ° C. incubator And cultured for 48 hours. The cultures were transferred into a 24-well culture vessel and subcultured for 1 day. Then, the compounds Rk 1 , Rk 2 , Rk 3 , Rg 3 , and Rg 5 were added so as to be 0.1 to 50 μM, respectively. In the control group, the same amount of 70% ethanol as a solvent was treated in place of the above compound. Twelve hours after the treatment of the compound, thymidine labeled with 3 H was treated to a concentration of 1 μCi / ml. After 12 hours, the medium was removed from each well, and the cells were fixed with methanol and washed with PBS. Unreacted radioactive thymidine was removed by washing twice with 10% trichloroacetic acid. The cells were dissolved in 0.2 M sodium hydroxide-0.5% SDS (sodium dodecylsulfate) and neutralized with hydrochloric acid, and the radioactivity introduced into the DNA was measured with a scintillation counter. The results are shown in Table 2.
상기 화합물 모두 1μM 이상에서 방사성 티미딘 도입량을 현저하게 감소하는 것으로 나타나 간암세포주 SK-HEP-1의 세포성장을 억제하는 것으로 나타났다. 한편 기존에 알려진 인삼사포닌인 Rg3는 본 발명에 의한 화합물에 비해 간암세포의 성장 억제능이 훨씬 약하였으며, Rg1은 오히려 방사성 티미딘 도입량을 증가시켜 간암세포의 성장을 촉진시키는 것으로 나타났다.It was shown that the above compounds significantly decreased the amount of radioactive thymidine introduced at a concentration of 1 μM or more, thereby inhibiting the cell growth of the liver cancer cell line SK-HEP-1. On the other hand shown to a known Ginsenoside Rg3 is a conventional growth inhibitory ability of the cancer cells was more than about a compound of the invention, Rg 1 is rather to increase the introduced amount of radioactive thymidine promote the growth of cancer cells.
[실험예 2] 화학식 1의 화합물의 세포독성시험[Experimental Example 2] Cytotoxicity test of the compound of Chemical Formula 1
본 발명에 따른 화학식 1의 화합물의 독성을 하기와 같은 혈소판 효소(LDH)의 유출 시험으로 평가하고자 하였다.The toxicity of the compound of formula (1) according to the present invention was evaluated by a leakage test of platelet enzyme (LDH) as follows.
흰쥐로부터 분리한 혈소판에 화학식 1의 화합물을 농도가 1000㎍/㎖가 되도록 가하고 37℃에서 각각 30, 60, 90, 120분간 배양하였다(시료 투여군). 이와는별도로, 음성 대조군에는 시료를 용해시켰던 용매만을 가하고, 메나디온 투여군에는 독성을 갖는 것으로 알려진 메나디온을 농도가 250μM이 되도록 투여한 후 시료 투여군과 동일한 조건으로 배양하였다. 각 시간대별로 베양액 100㎕를 취하여 17000rpm에서 2분간 원심분히한 후 상징액 25㎕를 취하였다. 여기에 트리스-EDTA-NADH 완충용액(pH 7.4) 1.0㎖를 가하고 37℃에서 10분간 배양하였다. 여기에 37℃에서 미리 배양시켜 놓았던 14mM 피루베이트 0.1㎖을 가하고 339nm에서 흡광도의 감소를 측정함으로써 혈소판 효소의 유출 정도를 알아보았다. 그 결과를 표 3에 나타내었다.The compound of Chemical Formula 1 was added to the platelets isolated from the rats to a concentration of 1000 μg / ml and cultured at 37 ° C. for 30, 60, 90, and 120 minutes, respectively. Separately, only the solvent in which the sample was dissolved was added to the negative control, and menadione, which is known to be toxic to the menadione group, was administered at a concentration of 250 μM and then cultured under the same conditions as the group administered with the sample. 100 ㎕ of the venous solution was taken at each time of day, centrifuged at 17000 rpm for 2 minutes, and 25 상 of the supernatant was taken. 1.0 ml of Tris-EDTA-NADH buffer solution (pH 7.4) was added thereto and cultured at 37 占 폚 for 10 minutes. To this was added 0.1 ml of 14 mM pyruvate which had been previously cultured at 37 ° C, and the extent of platelet enzyme leaching was determined by measuring the decrease in absorbance at 339 nm. The results are shown in Table 3.
표 3에 나타낸 바와 같이, 음성 대조군은 배양 시간에 따라 거의 변화가 없었으며, 메나디온 투여군은 배양 시간에 따라 독성이 현저하게 증가하는 것으로 나타났다. 시료 투여군(Rk1, Rk2, Rk3 투여군)은 매우 고농도인 1000㎍/㎖에서도 음성 대조군과 큰 차이를 나타내지 않아 본 발명의 화합물이 매우 안전한 화합물임을 알 수 있었다.As shown in Table 3, the negative control group showed almost no change with the incubation time, and the menadione group showed a marked increase in toxicity according to the incubation time. The compounds of the present invention (Rk1, Rk2, and Rk3-treated group) did not show a significant difference from the negative control group even at a very high concentration of 1000 μg / ml, indicating that the compound of the present invention is a very safe compound.
상기 실시예에서 수득한 화합물을 다양한 약제학적 담체와 배합 제제하였다.The compounds obtained in the above examples were formulated with various pharmaceutical carriers.
[조성예 1][Composition example 1]
옥수수전분 44gCorn starch 44g
결정성 셀룰로스 40gCrystalline cellulose 40 g
카르복시메틸셀룰로스칼슘 5g5 g of carboxymethylcellulose calcium
마그네슘 스테아레이트 1g1 g of magnesium stearate
실시예 3에서 수득한 화합물 Rs510g10 g of the compound Rs 5 obtained in Example 3
계 100gTotal 100g
상기한 조성에 따라 각 성분을 균일하게 혼합한 다음 타정기에서 압축성형하여 1정당 중량이 500mg인 정제를 제조하였다. 이 정제 1정에는 실시예 3에서 수득한 화합물 Rs550mg이 함유되어 있다.Each component was homogeneously mixed according to the above composition and then compression molded in a tablet machine to prepare tablets having a weight per tablet of 500 mg. This tablet contains 50 mg of the compound Rs 5 obtained in Example 3.
[조성예 2][Composition example 2]
결정성 셀룰로스 40gCrystalline cellulose 40 g
10% 하이드록시프로필셀룰로스 에탄올 용액 50g10% hydroxypropylcellulose ethanol solution 50 g
카르복시메틸셀룰로스칼슘 5g5 g of carboxymethylcellulose calcium
마그네슘스테아레이트 0.5g0.5 g of magnesium stearate
실시예 3에서 수득한 화합물 Rs710g10 g of the compound Rs 7 obtained in Example 3
계 100gTotal 100g
상기한 조성에 따라 각 성분을 균일하게 혼합하여 통상의 방법에 따라 조립기를 이용하여 건조시키고 분쇄한 후 카르복시메틸셀룰로스칼슘, 마그네슘스테아레이트를 혼합하여 타정기에서 압축성형하여 1정 중량이 500mg인 정제를 제조하였다. 이 정제 1정에는 실시예 3에서 수득한 화합물 Rs750mg이 함유되어 있다.Each component was uniformly mixed according to the above composition, dried and ground using a granulator according to a conventional method, and then carboxymethyl cellulose calcium and magnesium stearate were mixed and compression molded in a tablet machine to prepare tablets each having a tablet weight of 500 mg . This tablet contains 50 mg of the compound Rs 7 obtained in Example 3.
[조성예 3][Composition example 3]
주사용 증류수 86.5gDistilled water for injection 86.5g
에탄올 5gEthanol 5 g
대두인지질 2.5gSoybean phospholipid 2.5g
글리세린 5gGlycerin 5 g
실시예 4에서 수득한 Rk11g 1 g of Rk 1 obtained in Example 4
계 100gTotal 100g
상기한 조성에 따라 실시예 4에서 수득한 화합물 Rk1을 에탄올 및 대두인지질에 용해시키고 여기에 주사용증류수와 글리세린의 용액을 가하여 유화시켜 주사액을 제조하였다.Compound Rk 1 obtained in Example 4 was dissolved in ethanol and soybean phospholipid according to the above composition, and an injection solution was prepared by adding distilled water and glycerin solution for emulsification.
[조성예 4][Composition example 4]
(ⅰ)염산피리독신(I) pyridoxine hydrochloride
(ⅱ)니코틴산아미드(Ii) Preparation of nicotinic acid amide
(ⅲ)칼슘판토테네이트(Iii) Calcium Pantothenate
(ⅳ)음양곽 엑기스(Iv)
(ⅴ)리보플라빈(V) riboflavin
(ⅵ)시트르산(Vi) Citric acid
(ⅶ)실시예 5에서 수득한 화합물 Rk2 (Iii) Compound Rk 2 obtained in Example 5
(ⅷ)물(Ⅷ) Water
총 10ℓTotal 10ℓ
상기한 조성에 따라 (ⅰ)∼(ⅶ)을 (ⅷ)에 용해시켜 액제를 제조하였다. 이 액제 100㎖은 실시예에서 수득한 화합물 Rk2200mg을 함유한다.A solution was prepared by dissolving (i) to (iii) in (i) according to the above composition. The liquid 100㎖ contains a compound 200mg obtained in Example 2 Rk.
[조성예 5][Composition example 5]
결정성 셀룰로스 440gCrystalline cellulose 440 g
마그네슘스테아레이트 10gMagnesium stearate 10 g
실시예 6에서 수득한 화합물 Rk350g50 g of the compound Rk 3 obtained in Example 6
계 500gTotal 500g
상기한 조성에 따라 각 성분을 균일하게 혼합하여 통상의 방법에 따라 조립기를 이용하여 조립하고 충전기에서 충전하여 캅셀당 500mg의 캅셀제를 제조하였다. 이 캅셀제 1 캅셀에는 실시예 6에서 수득한 화합물 Rk350mg이 함유되어 있다.Each component was homogeneously mixed according to the above composition, assembled using a granulator according to a conventional method, and filled in a charger to prepare a capsule of 500 mg per capsule. One capsule of this capsule contains 50 mg of the compound Rk 3 obtained in Example 6.
본 발명에 따른 화학식 1의 화합물은 기존의 공지된 인삼 사포닌 화합물과는 상이한 신규한 구조를 갖는 화합물로서, 탁월한 항암 효과를 가짐으로써, 다양한 암 질환에 대한 치료제 또는 예방제로 사용될 수 있다.The compound of formula (I) according to the present invention is a compound having a novel structure which is different from the known ginseng saponin compound, and has excellent anticancer effect and can be used as a therapeutic or preventive agent for various cancer diseases.
Claims (5)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100517899B1 (en) * | 2002-01-30 | 2005-09-30 | 주식회사 일화 | Bioconversion ginseng composite using microorganism and fabrication method thereof |
| KR101083350B1 (en) * | 2011-01-12 | 2011-11-15 | 주식회사 진생사이언스 | A Food additive comprising a polysaccharide having anti-rotavirus activity |
| KR101083349B1 (en) * | 2011-01-12 | 2011-11-15 | 주식회사 진생사이언스 | A Health care food comprising a polysaccharide having anti-rotavirus activity |
| KR101083348B1 (en) * | 2003-10-09 | 2011-11-15 | 주식회사 진생사이언스 | Polysaccharide having anti-rotavirus activity |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086439A1 (en) * | 2002-04-08 | 2003-10-23 | Ginseng Science Inc. | Novel use of the extract of processed panax genus plant and saponin compound isolated therefrom |
| WO2003086438A1 (en) * | 2002-04-08 | 2003-10-23 | Ginseng Science Inc. | Extract of processed panax genus plant, the preparation method thereof, and compositions containing the same |
| KR100594353B1 (en) | 2002-05-28 | 2006-07-03 | 주식회사 엠디바이오알파 | Active fraction having anti-cancer and anti-metastic activity isolated from leaves and stems of Ginseng |
| WO2008076900A1 (en) * | 2006-12-15 | 2008-06-26 | The Uab Research Foundation | Novel ginsenoside compounds, compositions, and methods of use |
| KR101377569B1 (en) | 2012-01-19 | 2014-03-25 | (주)시지바이오 | Antimicrobial Wound Dressing and Preparing Method of the Same |
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1998
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100517899B1 (en) * | 2002-01-30 | 2005-09-30 | 주식회사 일화 | Bioconversion ginseng composite using microorganism and fabrication method thereof |
| KR101083348B1 (en) * | 2003-10-09 | 2011-11-15 | 주식회사 진생사이언스 | Polysaccharide having anti-rotavirus activity |
| KR101083350B1 (en) * | 2011-01-12 | 2011-11-15 | 주식회사 진생사이언스 | A Food additive comprising a polysaccharide having anti-rotavirus activity |
| KR101083349B1 (en) * | 2011-01-12 | 2011-11-15 | 주식회사 진생사이언스 | A Health care food comprising a polysaccharide having anti-rotavirus activity |
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| KR20000014189A (en) | 2000-03-06 |
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