KR101016787B1 - The diet composition containing the extract of Mori folium, fraction thereof or compounds isolated therefrom for prevention or improvement of depression or anxiety, or for inhibition of appetite as an active ingredient - Google Patents
The diet composition containing the extract of Mori folium, fraction thereof or compounds isolated therefrom for prevention or improvement of depression or anxiety, or for inhibition of appetite as an active ingredient Download PDFInfo
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- KR101016787B1 KR101016787B1 KR1020080083509A KR20080083509A KR101016787B1 KR 101016787 B1 KR101016787 B1 KR 101016787B1 KR 1020080083509 A KR1020080083509 A KR 1020080083509A KR 20080083509 A KR20080083509 A KR 20080083509A KR 101016787 B1 KR101016787 B1 KR 101016787B1
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- fraction
- dichloromethane
- upper leaf
- formula
- hexane
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Abstract
본 발명은 상엽 추출물, 이의 다이클로로메탄 분획물 또는 이로부터 분리된 활성분획물 또는 퍼퓨린-7 디메틸 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 또는 페오포르바이드 A 메틸에스테르 또는 이들의 혼합물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용 식품 조성물에 관한 것이다. 본 발명에 따른 조성물은 멜라닌 농축호르몬 수용체 아형-1(Melanin Concentration Hormone receptor subtype-1, MCH-1)과의 강한 길항적 작용을 나타내어 식욕억제효과, 체중감소효과 등을 나타내므로 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선에 유용하게 사용될 수 있다.The present invention relates to a leaf extract, a dichloromethane fraction thereof or an active fraction isolated therefrom or perpurin-7 dimethyl ethyl ester, hydroxy-phephorbide A ethyl ester, phephorbide A ethyl ester, didehydro- rodochlorine ethyl The present invention relates to a food composition for suppressing appetite, preventing and improving depression, or preventing and improving anxiety, containing methyl ester, hydroxy pheophorbide A methyl ester, or pheophorbide A methyl ester or a mixture thereof as an active ingredient. The composition according to the present invention exhibits a strong antagonistic action with Melanin Concentration Hormone receptor subtype-1 (MCH-1), thus exhibiting appetite suppression effect, weight loss effect, etc. It can be usefully used for prevention and improvement, or prevention and improvement of anxiety.
상엽 추출물, MCH, 비만, 퍼퓨린-7 디메틸 에틸에스테르, 페오포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르 Leaf Extract, MCH, Obesity, Perpurin-7 Dimethyl Ethyl Ester, Pheophorbide A Ethyl Ester, Hydroxy-Peophorbide A Ethyl Ester
Description
상엽 추출물, 이의 분획물 또는 이로부터 분리된 화합물을 유효성분으로 함유하는 MCH-1 수용체 길항활성에 근거한 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용 식품 조성물에 관한 것이다.The present invention relates to a food composition for suppressing appetite, preventing and improving depression, or preventing and improving anxiety based on MCH-1 receptor antagonistic activity containing an upper leaf extract, a fraction thereof or a compound separated therefrom as an active ingredient.
비만(obesity)이란 체내에 지방조직이 과다하게 축적되어 있는 상태를 말한다. 사람은 각자 자신에게 알맞은 표준체중이 있는데, 각 개인의 표준체중보다 120% 이상의 증가가 있을 때 비만이라고 정의하며 임상 및 역학분야에서 비만의 판 정법으로 가장 흔히 사용되는 체질량지수(Body Mass Index : BMI)에 의하면 성인남녀 모두에 있어서 BMI가 22 kg/m2 일 때 사망률이 최소이며, 27 kg/m2 이상일 때 사망 위험도가 증가된다. 구체적으로는 지방의 무게가 체중에서 차지하는 체지방 비율이 남자의 경우 25% 이상일 때, 여자의 경우 30% 이상일 때를 말한다[Van der Ploeg LH, Curr Opin Chem Biol. 4(4), pp452-460, 2000]. 비만은 에너지의 과다섭취, 운동 부족 등 환경적인 요인에 의해서도 유발되지만 신경 내분비적 원인, 약물원인, 유전적 요인이나 생화학적 반응에 의해서도 나타난다. 비만증은 개인의 탐욕이나 게으름 탓만은 아니며, 고혈압, 동맥경화증, 관상동맥질환, 제2형 당뇨병, 지방간, 고지혈증, 퇴행성관절염, 일부 암질환등 다양한 만성퇴행성 질환들을 유발하는 원인이 됨으로써 장기적인 관리가 필요한 만성질환중 하나이다. 특히, 동양인의 경우 서양인에 비해 체질량 지수가 적어도 복부 비만이 심하여 고혈압, 당뇨병, 고지혈증과 같은 동맥경화 관련 질환으로 인한 합병증의 감수성이 높기 때문에 비만증관리가 더욱 중요시되고 있다. Obesity (obesity) refers to a state in which the excessive accumulation of fat tissue in the body. Each person has a standard weight that suits him or her, which is defined as obesity when there is an increase of more than 120% of the individual's standard weight. ), The mortality rate is minimal when the BMI is 22 kg / m 2 in both adults and men, and the risk of death is increased when the BMI is above 27 kg / m 2 . Specifically, when the weight of fat accounts for more than 25% of body fat in men and more than 30% in women [Van der Ploeg LH, Curr Opin Chem Biol. 4 (4), pp 452-460, 2000]. Obesity is also caused by environmental factors such as overingestion of energy and lack of exercise, but also by neuroendocrine causes, drug causes, genetic factors and biochemical reactions. Obesity is not just a person's greed or laziness, but it causes long-term management by causing various chronic degenerative diseases such as hypertension, arteriosclerosis, coronary artery disease,
이러한 비만의 심각성이 더해지면서 비만의 예방 및 치료를 위한 물질과 제품에 대한 많은 연구와 개발이 이루어지고 있으나, 현재 개발된 항비만약물은 부작용이 문제가 되고 있다. As the severity of obesity is added, many researches and developments on materials and products for the prevention and treatment of obesity have been made, but currently developed anti-obesity drugs have side effects.
예를 들면, 미국식품의약국(FDA)에 의해 비만 치료제로 장기간 사용이 인정된 대표적인 약물로는 지방흡수억제제인 제니칼과 식욕억제제인 리덕틸 두 종류의 약이 있다. 하지만, 최근 보고에 의하면 시부트라민(sibutramine 상품명: 리덕틸) 은 시상하부(hypothalamus)에 작용하여 포만감을 증대시켜 식사 섭취를 억제하고 에너지 소비를 증가시킴으로써, 1년 복용 시 평균 6.1 kg의 체중 감량을 가져온다고 알려져 있으나, 혈압을 2 mmHg 상승시키고 맥박을 분당 3-6회 증가시키는 것으로 알려져 있어 약 복용 시 반드시 의사 처방이 필요하고 구강 건조와 변비, 불면, 식욕 항진, 오심의 부작용이 알려져 있다. For example, there are two types of drugs that are approved for long-term use by the US Food and Drug Administration (FDA) as obesity drugs. However, recent reports show that sibutramine (reductil) acts on the hypothalamus to increase satiety, inhibit eating, and increase energy consumption, resulting in an average weight loss of 6.1 kg per year. It is known, but it is known to increase blood pressure by 2 mmHg and increase pulse rate 3-6 times per minute.
또한, 최근 들어 폭발적인 판매를 올리고 있는 비만치료제의 전문의약품인 제니칼(Xenical, orlistat)의 경우, 섭취한 식이지방의 30%를 소화, 흡수시키지 않고 배출시킴으로써 200 Kcal의 에너지 손실을 유도하여 1년 동안 복용 시 평균 8.8 kg의 체중 감량 효과를 보이는 것으로 알려져 있다. 하지만 부작용으로 분비물을 동반한 가스 배출, 기름진 변 등이 있을 수 있어 계속적인 약물 복용의 장애가 되고 반드시 의사 처방이 필요한 것으로 보고되고 있다[Fujioka K et al., Diabetes Obes. Metab., 2(3), pp175-187, 2000 ; Leung WYS et al., Clinical Therapeutics, 25(1), pp58-80, 2003 ; McMahon FG et al., Arch. Int. Med., 160(14), pp2185-2191, 2000]. 따라서 비만의 개선 및 예방을 위한 부작용이 없는 새로운 기능성 소재의 개발이 끊임없이 요구되고 있다. In addition, Xenical (orlistat), an over-the-counter anti-obesity drug, induces energy loss of 200 Kcal by inducing 30% of dietary fat without digesting or absorbing it. It is known that the average weight loss effect is 8.8 kg. However, side effects may include secretion of gas discharge, oily stool, etc., which impedes continuous medication administration and requires doctor's prescription [Fujioka K et al., Diabetes Obes. Metab., 2 (3), pp 175-187, 2000; Leung WYS et al., Clinical Therapeutics, 25 (1), pp 58-80, 2003; McMahon FG et al., Arch. Int. Med., 160 (14), pp 2185-2191, 2000]. Therefore, the development of new functional materials without side effects for the improvement and prevention of obesity is constantly required.
한편, 19개의 아미노산으로 이루어진 MCH(melanin-concentrating hormone)의 음식물 섭취 행동상의 역할이 밝혀지면서, 최근 MCH의 작용을 길항함으로써 비만을 치료하고자하는 새로운 치료법이 주목받고 있다. Meanwhile, as the role of food intake behavior of melanin-concentrating hormone (MCH) consisting of 19 amino acids has been revealed, a new treatment for treating obesity by antagonizing the action of MCH has recently attracted attention.
MCH 효과를 매개하는 GPCR(G-protein coupled receptor) 중의 하나인 MCH-1 수용체를 조절할 수 있는 길항물질들은 음식물 섭취를 조절할 뿐만 아니라, 우울증이나 불안, 초조 등을 치료하는데 유용할 것이라 보고되었다[B. Borowsky et al., Nature Medicine, 8(8), 825-30, 2002]. MCH는 처음에는 경골어류에서 색변화를 조절하는 인자로 알려졌는데, 어류에서는 17개의 아미노산으로 구성되어 있고, 포유류에서는 19개의 아미노산으로 구성되어 있으며 이들 서열은 설치류와 토끼, 인간 등에서 동일하며, 이러한 MCH는 GPCR을 통하여 세포내로 신호전달을 하게 되는데, 현재까지 MCH-1(SLC-1, GPR24)과 MCH-2(SLT, GPRv17)의 두가지 종류의 수용체가 보고되어 있다. 1999년에 알려진 MCH-1의 경우 353개의 아미노산으로 구성되어 있으며 전형적인 GPCR의 특징들을 가진다고 보고되었는데, 소마토스타틴(somatostatin) 수용체와 35%정도의 유사성을 가지며 해당 유전자가 염색체 22q13.3 위치에 존재한다고 알려져 있다[P. Pssios et al., Trends Endocrinol Metab. 14(5), 243-8, 2003]. 동물모델을 대상으로 한 MCH 기능에 관한 연구결과, MCH를 투여한 쥐에서는 음식물 섭취량이 증가하게 되고, MCH가 결실된 마우스에서는 섭식저하와 대사속도증가에 기인하는 체중감소 현상이 나타났다[D. Qu., et al., Nature, 380(6571), 243-7, 1996]. 섭식행동에 대한 MCH의 효과는 MCH-1 수용체의 길항작용에 기인하는 것으로 알려져 있고, MCH-1 유전자 결손 동물(knock-out animal)에 MCH를 투여하면 섭식을 자극하거나 비만을 일으키지 않는 것으로 보고되었다[A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006]. 비만에 대한 에너지 발란스를 조절하는데 있어서의 MCH-1 시스템의 중요성에 관한 또 다른 연구결과는 MCH-1 수용체 길항제로서 SNAP-7941을 이용한 실험이다. 상기 화합물로 처리된 동물은 상당량의 체중 감소를 나타냈고, 식욕감퇴 효과 이외에도 부가의 불안제거 효과와 항우울 효과를 제공해 준다고 알려져 있다[B. Borowsky et al., Nature Medicine, 8(8), 825-30, 2002]. Antagonists that can modulate MCH-1 receptors, one of the G-protein coupled receptors (GPCRs) that mediate the effects of MCH, have been reported to be useful for treating depression, anxiety, anxiety, etc. [B] . Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002]. MCH was initially known as a factor controlling color change in tibial fish, which consists of 17 amino acids in fish and 19 amino acids in mammals, and these sequences are identical in rodents, rabbits, and humans. Intracellular signal transduction through GPCR. Two types of receptors, MCH-1 (SLC-1, GPR24) and MCH-2 (SLT, GPRv17), have been reported. MCH-1, known in 1999, consists of 353 amino acids and is reported to have typical GPCR characteristics, with about 35% similarity to the somatostatin receptor, and the gene is known to be located at chromosome 22q13.3. [P. Pssios et al., Trends Endocrinol Metab. 14 (5), 243-8, 2003]. The study of MCH function in animal models showed that food intake increased in MCH-treated mice and weight loss due to decreased feeding and increased metabolic rate in mice lacking MCH [D. Qu., Et al., Nature, 380 (6571), 243-7, 1996]. The effect of MCH on eating behavior is known to be due to antagonism of MCH-1 receptors, and it has been reported that administration of MCH to MCH-1 knock-out animals does not stimulate feeding or cause obesity. [A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006]. Another study of the importance of the MCH-1 system in regulating energy balance against obesity is the experiment using SNAP-7941 as an MCH-1 receptor antagonist. Animals treated with these compounds exhibited significant weight loss and are known to provide additional anxiety and antidepressant effects in addition to the loss of appetite [B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002].
이상과 같은 일련의 연구결과에 의하면 MCH-1 수용체 길항제는 비만치료제로 사용될 수 있을 뿐만 아니라 우울증, 불안증 제거에도 효과가 있다.According to the results of the series of studies, MCH-1 receptor antagonists can be used not only as an anti-obesity agent but also effective in removing depression and anxiety.
상엽(桑葉, Mori folium)은 뽕나무 및 동속 근녹식물의 잎을 건조한 것으로 맛은 고감하고 성질은 한하며 폐, 간경에 들어간다. 잎에는 루틴(rutin), 쿼서틴(quercetin), 모라세틴(moracetin), 베타-시토스테롤(β-sitosterol), 캄페스테롤(campesterol), 루페올(lupeol), 미오이노시놀(yoinositol), 이노코스테론(inokosterone) 등이 함유되어 있다. 상기 상엽은 양혈조습(피의 열을 없애고 수분을 줄여줌), 거풍명목(풍기운을 없애고 눈을 맑게 해줌), 말복 지도한(분말로 복용하면 식은땀을 없앰) 등의 효과가 있는 것으로 알려져 있다. 또한 본초강목 등의 동양의약서에 상백피, 누에고치 등과 함께 소갈증에 효과가 있음이 기록되어 있다[정보섭 및 신민교; 도해 향약(생약)대사전, 영림사, pp 545 - 546, 1998]. Mori folium is a dried leaf of mulberry and cousin myosin. Its taste is sensitive and its properties are limited. The leaves contain rutin, quercetin, moracetin, beta-sitosterol, campesterol, lupeol, myinositol and inos. It contains theinkosterone and the like. The upper lobe is known to have effects such as nourishing blood (reducing the heat of the blood and reducing moisture), big wind nominal (removing the wind and clearing the eyes), and instructing the abdomen (when taken in powder, eliminating cold sweat). . In addition, it has been recorded that the oriental medicines such as the herbaceous tree have an effect on small thirst along with baekbaekpi and silkworm cocoons. Dohae Herbal Medicine (Medicinal Herb) Dictionary, Younglimsa, pp 545-546, 1998].
그러나, 이와 같이 상엽의 효능과 관련하여, 상엽이 MCH-1 수용체에 대한 길항작용에 미치는 영향에 대해서는 아직 보고된 바 없다.However, in relation to the efficacy of the upper lobe, there is no report on the effect of the lobe on the antagonism of the MCH-1 receptor.
이에, 본 발명자들은 천연물 중에서 MCH-1 수용체 길항작용이 뛰어난 활성물 질을 탐색하던 중, 상엽 추출물 및 이로부터 분리된 화합물이 MCH-1 수용체에 대한 길항작용이 뛰어나 식욕억제와 체중감소를 유도하여 비만 및 이로부터 야기되는 각종 대사 장애 및 섭식 장애의 예방 및 개선에 유용하게 사용될 수 있음을 알아내고 본 발명을 완성하였다.Therefore, the inventors of the present invention, while searching for an active substance having excellent MCH-1 receptor antagonism in natural products, the extract of the upper leaf and the compound isolated therefrom have an excellent antagonism against the MCH-1 receptor, leading to appetite suppression and weight loss. The present invention has been found to be useful in the prevention and improvement of obesity and various metabolic disorders and eating disorders resulting therefrom.
본 발명의 목적은 MCH-1 수용체에 대한 길항작용이 뛰어난 상엽 추출물, 이의 분획물 또는 이로부터 분리된 화합물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용 식품 조성물을 제공하는 데 있다.SUMMARY OF THE INVENTION An object of the present invention is a food composition for inhibiting appetite, preventing and improving depression, or preventing and improving anxiety, containing an upper leaf extract having excellent antagonistic action against MCH-1 receptor, a fraction thereof or a compound separated therefrom as an active ingredient. To provide.
상기 목적을 달성하기 위하여 본 발명은 상엽 추출물, 이의 분획물 또는 이로부터 분리된 퍼퓨린-7 디메틸 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 또는 페오포르바이드 A 메틸에스테르의 화합물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용 식품 조성물을 제공한다.In order to achieve the above object, the present invention provides an extract of an upper leaf, a fraction thereof, or perpurin-7 dimethyl ethyl ester, hydroxy-phephorbide A ethyl ester, phephorbide A ethyl ester, and didehydro-chlorodochlorine ethyl. Provided is a food composition for suppressing appetite, preventing and improving depression, or preventing and improving anxiety, containing a compound of methyl ester, hydroxy pheophorbide A methyl ester, or pheophorbide A methyl ester as an active ingredient.
본 발명에 따른 상엽 추출물, 이의 분획물 또는 이로부터 분리, 정제된 퍼퓨린-7 디메틸 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 또는 페오포르바이드 A 메틸에스테르의 화합물을 유효성분으로 함유하는 조성물은 MCH-1 수용체와의 강한 길항적 작용을 나타내어 식욕억제효과, 체중감소효과 등을 나타내므로 MCH-1 수용체 길항활성에 근거한 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선에 유용하게 사용될 수 있다.Upper leaf extract according to the present invention, fractions thereof, or purified therefrom, purified purpurin-7 dimethyl ethyl ester, hydroxy-phephorbide A ethyl ester, phephorbide A ethyl ester, didehydro-lodochlorine ethylmethyl ester, A composition containing a compound of hydroxy pheophorbide A methyl ester or pheophorbide A methyl ester as an active ingredient exhibits a strong antagonistic action with the MCH-1 receptor, resulting in an appetite suppression effect, weight loss effect and the like. It can be usefully used for suppressing appetite based on 1 receptor antagonistic activity, preventing and improving depression, or preventing and improving anxiety.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 상엽 추출물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용 식품 조성물을 제공한다.The present invention provides a food composition for suppressing appetite, preventing and improving depression, or preventing and improving anxiety, containing the extract of the leaf as an active ingredient.
본 발명에 따른 상엽 추출물은 상엽 또는 이의 건조물로부터 추출하여 얻을 수 있으며, 상기 상엽은 재배한 것 또는 시판되는 것 등 제한없이 사용할 수 있다.The upper leaf extract according to the present invention can be obtained by extracting from the upper leaf or its dried product, and the upper leaf can be used without limitation, such as those grown or commercially available.
본 발명에 따른 상엽 추출물은 용매 추출법, 초음파 추출법, 여과법 및 환류추출법 등 당업계의 통상적인 추출방법을 사용할 수 있으며, 바람직하게는 용매 추출함으로써 제조할 수 있다. 구체적으로는 음건하여 세절한 상엽에 상엽 부피의 2 내지 200배, 바람직하게는 10 내지 30배의 추출용매를 가하고, 10 내지 30 ℃에서 1 내지 20일간, 바람직하게는 5 내지 10일간 추출하고 여과한 후 감압 농축함으로써 상엽 추출물을 제조할 수 있다. 이때, 추출용매로는 물, 유기용매 또는 이들의 혼합물을 사용할 수 있다. 이때 유기용매는 C1-C4의 알코올, 다이클로로메탄, 에틸아세테이트 및 이들의 혼합용매를 사용할 수 있으며, 바람직하게는 메탄올 또는 에 탄올을 사용할 수 있다.The upper leaf extract according to the present invention may use a conventional extraction method such as solvent extraction method, ultrasonic extraction method, filtration method and reflux extraction method, preferably can be prepared by solvent extraction. Specifically, 2 to 200 times, preferably 10 to 30 times, the extraction solvent of the upper leaf volume is added to the dry and fine upper leaves, and extracted at 10 to 30 ° C. for 1 to 20 days, preferably 5 to 10 days, and filtered. After that, the extract may be prepared by concentration under reduced pressure. In this case, water, an organic solvent or a mixture thereof may be used as the extraction solvent. At this time, the organic solvent may be C 1 -C 4 alcohol, dichloromethane, ethyl acetate and a mixed solvent thereof, preferably methanol or ethanol.
또한, 본 발명은 상엽 분획물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for suppressing appetite, preventing and improving depression, or preventing and improving anxiety, containing the upper fraction as an active ingredient.
본 발명에 따른 상엽 분획물은 상기 상엽 추출물을 증류수에 현탁한 후 부탄올, 다이클로로메탄 또는 에틸아세테이트로 분획하여 얻을 수 있으며, 바람직하게는 다이클로로메탄으로 분획할 수 있다. 본 발명의 바람직한 일례에 따르면, 상엽 또는 이의 건조물을 에탄올을 사용하여 7일간 냉침시킨 후 여과하고 여액을 감압 농축하여 에탄올 추출물을 얻고, 상기 에탄올 추출물을 증류수에 현탁한 후 동량의 다이클로로메탄으로 분획하고 감압 농축함으로써 상엽 분획물을 얻을 수 있다.The upper leaf fraction according to the present invention may be obtained by suspending the upper leaf extract in distilled water and fractionating it with butanol, dichloromethane or ethyl acetate, and preferably fractionating with dichloromethane. According to a preferred embodiment of the present invention, the upper leaf or its dried product is cooled for 7 days using ethanol, filtered and the filtrate is concentrated under reduced pressure to obtain an ethanol extract, the ethanol extract is suspended in distilled water and then fractions with the same amount of dichloromethane. The upper fractions can be obtained by concentrating under reduced pressure.
이후, 상기 다이클로로메탄 분획물에 헥산 또는 메탄올을 이용하여 분획과정을 추가로 수행할 수 있다.Thereafter, the dichloromethane fraction may be further fractionated using hexane or methanol.
나아가, 본 발명은 상기 상엽 분획물로부터 분리된 활성분획물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용을 제공한다.Furthermore, the present invention provides for inhibiting appetite, preventing and improving depression, or preventing and improving anxiety, containing the active fraction separated from the upper leaf fraction as an active ingredient.
본 발명에 따른 활성분획물은 크로마토그래피에 의해 분리 및 정제할 수 있다. 상기 크로마토그래피는 실리카겔 컬럼 크로마토그래피를 1 내지 2회 수행하는 것이 바람직하다. 이동상으로는 헥산/에틸아세테이트(100:1~1:1) 혼합용매를 사용할 수 있다. 이때, 사용한 용매는 농도를 비극성에서 극성으로 순차적으로 올려주 는 농도구배 용출방식(gradient elution)으로 용출 분리하며, 수집된 분리물의 혈압 강하효과를 측정하여 원하는 활성분획물을 수득할 수 있다. 이때, 상기 이동상의 유속은 2~4 ml/분인 것이 바람직하다.The active fractions according to the invention can be separated and purified by chromatography. The chromatography is preferably performed 1 to 2 times silica gel column chromatography. Hexane / ethyl acetate (100: 1 to 1: 1) mixed solvent can be used as a mobile phase. At this time, the solvent used is eluted by a gradient gradient elution method of raising the concentration sequentially from non-polar to polar, and the desired active fraction can be obtained by measuring the blood pressure lowering effect of the collected isolate. At this time, the flow rate of the mobile phase is preferably 2 ~ 4 ml / min.
또한, 본 발명은 하기 화학식 1로 표시되는 퍼퓨린-7 디메틸 에틸에스테르(Purpurin-7 dimethyl ethylester), 화학식 2로 표시되는 페오포르바이드 A 에틸에스테르(Pheophorbide A ethylester), 화학식 3으로 표시되는 하이드록시-페오포르바이드 A 에틸에스테르(Hydroxy-pheophorbide A ethylester), 화학식 4로 표시되는 디데하이드로-로도클로린 에틸메틸에스테르(Didehydro-rhodochlorin ethylmethylester), 화학식 5로 표시되는 하이드록시 페오포르바이드 A 메틸에스테르(Hydroxy-pheophorbide A methylester) 및 화학식 6으로 표시되는 페오포르바이드 A 메틸에스테르(Pheophorbide A ethylester) 또는 이들의 혼합물을 유효성분으로 함유하는 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선용을 제공한다.In addition, the present invention is a Purpurin-7 dimethyl ethyl ester (Purpurin-7 dimethyl ethylester) represented by the following formula (1), Pheophorbide A ethylester represented by the formula (2), hydroxy represented by the formula (3) -Hydroxy-pheophorbide A ethylester, Didehydro-rhodochlorin ethylmethylester represented by the formula (4), Hydroxy pheophorbide A methylester represented by the formula (5) -pheophorbide A methylester and Pheophorbide A methylester represented by the formula (6) or a mixture thereof as an active ingredient to suppress appetite, to prevent and improve depression, or to prevent and improve anxiety do.
상기 화학식 1 내지 화학식 6의 활성물질은 하기의 제조방법으로 수득할 수 있다:The active material of Chemical Formulas 1 to 6 may be obtained by the following preparation method:
상엽을 물, 유기용매 또는 이들의 혼합물을 가하여 상엽 추출물을 수득하는 단계(단계 1);Adding the upper leaf with water, an organic solvent or a mixture thereof to obtain an upper leaf extract (step 1);
상기 단계 1에서 수득한 상엽 추출물을 물에 현탁시킨 후 다이클로로메탄으 로 분획하여 다이클로로메탄 분획물을 수득하는 단계(단계 2); Suspending the upper leaf extract obtained in step 1 in water and fractionating with dichloromethane to obtain a dichloromethane fraction (step 2);
상기 단계 2에서 수득한 다이클로로메탄 분획물을 n-헥산과 에틸아세테이트의 혼합용매를 이동상으로 사용하여 농도구배 컬럼 크로마토그래피를 수행하여 활성분획물을 수득하는 단계(단계 3);Dichloromethane fractions obtained in
상기 단계 3에서 수득한 활성 분획물을 n-헥산과 에틸아세테이트의 혼합용매를 이동상으로 사용하여 농도구배 컬럼 크로마토그래피를 재수행하여 활성분획을 분리하는 단계(단계 4); 및Separating the active fraction from the active fraction obtained in step 3 by performing concentration gradient column chromatography again using a mixed solvent of n-hexane and ethyl acetate as a mobile phase (step 4); And
상기 단계 4에서 분리된 분획물을 n-헥산과 에틸아세테이트의 혼합용매를 이동상으로 하되, 농도구배를 각각 달리하여 실리카겔 컬럼 크로마토그래피를 수행하여 화학식 1-6의 화합물을 분리하는 단계(단계 5).The fraction separated in
상기 제조방법에 있어서, 단계 1은 상엽을 물, 유기용매 또는 이의 혼합물을 가하여 상엽 추출물을 수득하는 단계이다.In the above production method, step 1 is a step of obtaining the upper leaf extract by adding the upper leaf to water, an organic solvent or a mixture thereof.
상기 유기용매는 C1-C4의 알코올, 다이클로로메탄 및 에틸아세테이트로 이루어지는 군으로부터 선택되는 어느 하나 또는 이들의 혼합용액을 사용할 수 있으며, 바람직하게는 메탄올 또는 에탄올을 사용할 수 있다.The organic solvent may be any one selected from the group consisting of C 1 -C 4 alcohol, dichloromethane and ethyl acetate, or a mixed solution thereof, preferably methanol or ethanol.
추출시에는 상엽 부피의 2 내지 200배, 바람직하게는 10 내지 30배의 유기용매를 가하고, 10 내지 30 ℃에서 1 내지 20일간, 바람직하게는 5 내지 10일간 추출하고 여과한 후 감압 농축함으로써 상엽 추출물을 제조할 수 있다. At the time of extraction, an organic solvent of 2 to 200 times the volume of the upper leaf, preferably 10 to 30 times is added, the extract is extracted at 10 to 30 ° C. for 1 to 20 days, preferably 5 to 10 days, filtered and concentrated under reduced pressure. Extracts can be prepared.
다음으로, 단계 2는 상기 단계 1에서 수득한 상엽 추출물을 물에 현탁시킨 후 다이클로로메탄으로 분획하여 다이클로로메탄 분획물을 수득하는 단계이다.Next,
이때, 상기 다이클로로메탄 분획물은 당업계에서 통상적으로 사용하는 방법을 이용할 수 있으며, 일례로는 상기 단계 1에서 수득한 상엽 에탄올 추출물을 증류수에 현탁한 후 동량의 다이클로로메탄으로 분획하고 감압 농축함으로써 다이클로로메탄 분획물을 얻을 수 있다.At this time, the dichloromethane fraction may be used a method commonly used in the art, for example, the upper leaf ethanol extract obtained in step 1 is suspended in distilled water, fractionated into the same amount of dichloromethane and concentrated under reduced pressure Dichloromethane fractions can be obtained.
다음으로 단계 3은 상기 단계 2에서 수득한 다이크롤로메탄 분획물을 n-헥산과 에틸아세테이트의 혼합용매를 이동상으로 사용하여 농도구배 컬럼 크로마토그래피를 수행하여 활성분획물을 수득하는 단계이다.Next, step 3 is a step of concentration gradient column chromatography using the dichloromethane fraction obtained in
상기 제조방법에 있어서, 상기 단계 3의 활성분획물은 상기 단계 2에서 수득한 다이크롤로메탄 분획물을 n-헥산과 에틸아세테이트의 혼합용매를 사용하여 농도구배 실리카겔 컬럼 크로마토그래피를 수행하여 수득할 수 있다. 이때, n-헥산과 에틸아세테이트의 혼합용매의 농도구배는 100:1 ~ 1:1인 것이 바람직하며, 2~4 ㎖/분의 속도로 용리시켜 수득할 수 있다.In the above method, the active fraction of step 3 may be obtained by performing a concentration gradient silica gel column chromatography on the dichloromethane fraction obtained in
다음으로, 단계 4는 상기 단계 3에서 수득한 활성분획물을 n-헥산과 에틸아세테이트의 혼합용매를 사용하여 농도구배 컬럼 크로마토그래피를 재수행하여 활성분획을 분리하는 단계이다.Next,
이때, 상기 단계 3에서 수득한 활성분획물인 제1 내지 제4 분획 중 제3 분획을 n-헥산과 에틸아세테이트의 혼합용매를 이동상으로 하고 농도구배를 30:1 ~ 1:1로 하여 플로리실 컬럼 크로마토그래피로 분리하는 것이 바람직하며, 상기 이동상의 유속은 2~4 ㎖/분인 것이 바람직하다.At this time, the third fraction in the first to fourth fractions of the active fraction obtained in step 3 is a mixed solvent of n-hexane and ethyl acetate as a mobile phase and the concentration gradient is 30: 1 to 1: 1 with a Florisil column It is preferable to separate by chromatography, and it is preferable that the flow rate of the said mobile phase is 2-4 ml / min.
다음으로, 단계 5는 상기 단계 4에서 분리된 분획물을 n-헥산과 에틸아세테이트의 혼합용매를 이동상으로 하되, 농도구배를 각각 달리하여 실리카겔 컬럼 크로마토그래피를 수행하여 화학식 1-6의 화합물을 분리하는 단계이다.Next, in step 5, the fraction separated in
상기 단계 5에서는 단계 4에서 9개의 분획으로 분리된 분획물 중, 제 3~6 분획에 대하여 실리카겔 컬럼 크로마토그래피를 이용하여 n-헥산과 에틸아세테이트의 혼합용매의 농도구배를 각각 15:1~1:1, 30:1~1:1 또는 5:1~1:1로 변화시켜 용리시킴으로써 화학식 1-6의 화합물을 분리하여 수득할 수 있다. 이때, 상기 이동상의 유속은 2~4 ㎖/분인 것이 바람직하다.In step 5, the concentration gradient of the mixed solvent of n-hexane and ethyl acetate is 15: 1 to 1: 3 using silica gel column chromatography for the third to sixth fractions of the fractions separated into nine fractions in
상기 단계를 거쳐 분리된 화학식 1 내지 화학식 6의 화합물은 NMR 분석을 통하여 각각 퍼퓨린-7 디메틸 에틸에스테르, 페로포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 및 페오포르바이드 A 메틸에스테르로 확인되었다.Compounds of Chemical Formulas 1 to 6 isolated through the above steps were obtained by NMR analysis, respectively, for Purpurin-7 dimethyl ethyl ester, ferrophorbide A ethyl ester, hydroxy-phefobide A ethyl ester, and didehydro-chlorodochlorine ethyl. It was identified as methyl ester, hydroxy pheophorbide A methyl ester and pheophorbide A methyl ester.
본 발명에 따른 상엽 추출물, 이의 분획물, 또는 이로부터 분리된 퍼퓨린-7 디메틸 에틸에스테르, 페로포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 및 페오포르바이드 A 메틸에스테르는 MCH-1 수용체 결합 억제실험에서 우수한 MCH-1 수용체 결합 억제작용을 나타냈다(표 1 및 표 2 참조). 또한, 본 발명에 따른 상엽 추출물 또는 이로부터 분리된 화합물을 이용한 비만생쥐모델로부터 식욕억제 및 체중감소 효과 실험에서, 본 발명에 따른 상엽 추출물 또는 이로부터 분리된 화합물은 대조군과 비교할 때 비만생쥐의 체중을 투여 2일 이후부터 감소시켰으며(도 1 참조), 실험기간 내내 지속적인 식욕저하를 나타내는 것으로 관찰되었다(도 2 참조). 이를 통해 본 발명의 상엽 추출물 또는 이로부터 분리된 화합물은 MCH-1 수용체 작용을 길항함으로써 식욕을 억제시키고, 체중을 감소시켜 MCH-1 수용체 길항활성에 근거한 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선에 유용하게 이용될 수 있다.Upper leaf extract according to the present invention, fractions thereof, or perpurin-7 dimethyl ethyl ester, ferrophorbide A ethyl ester, hydroxy-pheophorbide A ethyl ester, didehydro-rhodochlorine ethylmethyl ester, hydroxy separated therefrom Roxy pheophorbide A methyl ester and pheophorbide A methyl ester showed excellent MCH-1 receptor binding inhibitory activity in MCH-1 receptor binding inhibition experiment (see Table 1 and Table 2). In addition, in the appetite suppression and weight loss effect experiment from the obese mouse model using the upper leaf extract or the compound isolated therefrom, the upper leaf extract or the compound isolated from the weight of the obese mouse compared to the control group Was decreased from 2 days after administration (see FIG. 1 ), and was observed to show a sustained loss of appetite throughout the experiment (see FIG. 2 ). Through this, the upper leaf extract of the present invention or a compound isolated therefrom inhibits appetite by antagonizing MCH-1 receptor action, and decreases body weight by suppressing appetite based on MCH-1 receptor antagonistic activity, preventing and improving depression, or anxiety It can be usefully used for the prevention and improvement of.
본 발명의 조성물은 상기 상엽 추출물, 이의 분획물, 또는 이로부터 분리된 화합물에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다.The composition of the present invention may contain one or more active ingredients exhibiting the same or similar functions in addition to the above-mentioned leaf extract, fractions thereof, or compounds separated therefrom.
상기 효과를 나타내기 위하여 본 발명의 상엽 추출물, 이로부터 분리된 퍼퓨린-7 디메틸 에틸에스테르, 페로포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 및 페오포르바이드 A 메틸에스테르 또는 이들의 혼 합물을 첨가할 수 있는 식품으로는, 예를 들면 각종 식품류, 음료수, 스넥류, 과자류, 껌류, 아이스크림류, 티백차, 인스턴트차, 과립, 향료, 비타민 복합제, 및 그 밖의 건강보조식품류 등이 있으나, 이에 한정되는 것은 아니다.In order to achieve the above effect, the upper leaf extract of the present invention, Perpurin-7 dimethyl ethyl ester, ferrophorbide A ethyl ester, hydroxy-pheophorbide A ethyl ester, didehydro-rhodochlorine ethyl methyl ester, Examples of foods to which hydroxy pheophorbide A methyl ester and pheophorbide A methyl ester or mixtures thereof can be added include, for example, various foods, beverages, snacks, confectionery, gums, ice creams, tea bags, instant foods. Tea, granules, flavors, vitamin complexes, and other health supplements, but are not limited thereto.
본 발명의 상엽 추출물, 이로부터 분리된 퍼퓨린-7 디메틸 에틸에스테르, 페로포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 디데하이드로-로도클로린 에틸메틸에스테르, 하이드록시 페오포르바이드 A 메틸에스테르 및 페오포르바이드 A 메틸에스테르 또는 이들의 혼합물을 식품 제조시 원료 물질에 첨가하거나 조리된 식품에 적절히 혼합하여 상기한 건강 증진용 식품 또는 음료를 제조할 수 있으며, 이 경우 최종적으로 제조된 식품 또는 음료 중에 상엽 추출물, 이로부터 분리된 퍼퓨린-7 디메틸 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 페오포르바이드 A 에틸에스테르 또는 이들의 혼합물의 함량은 각각 0.01 내지 30 중량% 범위일 수 있다.Leaf extract of the present invention, Perpurin-7 dimethyl ethyl ester, ferrophorbide A ethyl ester, hydroxy-phephorbide A ethyl ester, didehydro-rhodochlorine ethylmethyl ester, hydroxy perobide A isolated therefrom Methyl esters and pheophorbide A methyl esters or mixtures thereof may be added to the raw materials in the manufacture of foods or mixed appropriately with the cooked foods to prepare the above-mentioned health-promoting foods or beverages, in which case the final foods Or the content of the lettuce extract, Perpurin-7 dimethyl ethyl ester, hydroxy-phephorbide A ethyl ester, phephorbide A ethyl ester, or mixtures thereof, in the beverage may range from 0.01 to 30% by weight, respectively. have.
본 발명의 건강 증진용 식품 또는 음료는 목적하는 효과를 상승시키거나 보완하기 위해 약학적으로 허용되는 다른 생약재 또는 이의 추출물을 추가로 포함할 수 있으며, 그러한 생약재의 대표적인 예로는 백복령, 백출, 의이인, 적소두, 목통, 차전자 등을 들 수 있다. 상기 생약재는 조성물의 총 중량을 기준으로 0.01 내지 50 중량%의 양으로 사용될 수 있다.The health promoting food or beverage of the present invention may further include other medicinal herbs or extracts thereof that are pharmaceutically acceptable to enhance or supplement the desired effect, and representative examples of such herbal medicines are Baekbokryeong, Baekchul, Uiin, Red bean head, neck, cha-chan and the like. The herbal medicine may be used in an amount of 0.01 to 50% by weight based on the total weight of the composition.
이하, 본 발명을 실시예, 실험예 및 제제예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail by Examples, Experimental Examples and Formulation Examples.
단, 하기 실시예, 실험예 및 제제예는 본 발명을 구체적으로 예시하는 것이며, 본 발명의 내용이 실시예, 실험예 및 제제예에 의해 한정되는 것은 아니다.However, the following Examples, Experimental Examples, and Formulation Examples specifically illustrate the present invention, and the content of the present invention is not limited to Examples, Experimental Examples, and Formulation Examples.
<실시예 1> 상엽 추출물의 제조Example 1 Preparation of Upper Leaf Extract
<1-1> 상엽의 에탄올 추출물의 제조<1-1> Ethanol Extract of Upper Leaf
건조된 상엽 잎을 세절한 후 1.8 kg을 추출 용기에 넣고 상온에서 100%에탄올 5배에 침지하여 일주일간 냉침시킨 후 여과지로 여과하였다. 상기 추출액을 농축기를 사용하여 용액이 완전히 증발할 때까지 50 ℃에서 감압 농축하여 에탄올 추출물 370 g을 얻었다. After cutting the dried upper leaf leaves 1.8 kg into an extraction container and immersed in 100% ethanol 5 times at room temperature, cooled for one week and filtered through a filter paper. The extract was concentrated under reduced pressure at 50 ° C. until the solution was completely evaporated using a concentrator to obtain 370 g of ethanol extract.
<1-2> 상엽의 물 추출물의 제조<1-2> Preparation of Water Extract of Upper Leaf
상기 <1-1>의 제조방법에서 에탄올 대신 물을 사용하는 것 외에 동일한 방법으로 상엽의 물 추출물 300 g을 수득하였다.300 g of the water extract of the upper leaf was obtained in the same manner as in addition to using water instead of ethanol in the method of <1-1>.
<< 실시예Example 2> 2> 상엽의Upper lobe 다이클로로메탄Dichloromethane 분획물의Fraction 제조 Produce
상기 실시예 <1-1>에서 제조한 상엽 에탄올 추출물(370 g)을 증류수 2L에 현탁시킨 후, 동량의 다이클로로메탄으로 추출하고, 다이클로로메탄 층을 분리하고 감압 농축하여 상엽의 다이클로로메탄 분획물(59 g)을 수득하였으며, 남은 물층을 동결 건조시켰다. The upper leaf ethanol extract (370 g) prepared in Example <1-1> was suspended in 2 L of distilled water, extracted with the same amount of dichloromethane, the dichloromethane layer was separated and concentrated under reduced pressure to give the upper dichloromethane. Fractions (59 g) were obtained and the remaining water layer was lyophilized.
<< 실시예Example 3> 3> 상엽의Upper lobe 다이클로로메탄Dichloromethane 분획물의Fraction 헥산Hexane 분획물의Fraction 제조 Produce
상기 실시예 2에서 제조한 다이클로로메탄 분획물(57 g)을 증류수 2L에 현탁시킨 후, 동량의 헥산으로 추출하고, 헥산 층을 분리하고 감압 농축하여 헥산 분획물(30 g)을 수득하였으며, 남은 물층을 동결 건조시켰다.The dichloromethane fraction (57 g) prepared in Example 2 was suspended in 2 L of distilled water, extracted with the same amount of hexane, the hexane layer was separated and concentrated under reduced pressure to obtain a hexane fraction (30 g). Was lyophilized.
<< 실시예Example 4> 4> 상엽의Upper lobe 다이클로로메탄Dichloromethane 분획물의Fraction 메탄올 Methanol 분획물의Fraction 제조 Produce
상기 실시예 2에서 제조한 다이클로로메탄 분획물(57 g)을 증류수 2L에 현탁시킨 후, 동량의 메탄올으로 추출하고, 메탄올 층을 분리하고 감압 농축하여 메탄올 분획물(32 g)을 수득하였으며, 남은 물층을 동결 건조시켰다. The dichloromethane fraction (57 g) prepared in Example 2 was suspended in 2 L of distilled water, extracted with the same amount of methanol, the methanol layer was separated and concentrated under reduced pressure to obtain a methanol fraction (32 g), and the remaining water layer Was lyophilized.
<< 실시예Example 5> 5> 상엽Upper lobe 다이클로로메탄Dichloromethane 분획물로부터From fractions 활성분획물의Active fraction 제조 Produce
상기 실시예 2의 분획물(57 g)을 n-헥산과 에틸아세테이트의 혼합용매(100:1 ~ 1:1)를 사용하여 3 ml/분의 유속으로 흘려주시면서 농도구배 실리카겔 칼럼 크로마토그래피를 실시하여 총 4개의 분획(제1 분획 내지 제4 분획)으로 나누었다. 이 중 제3 분획을 활성분획물으로서 수득하였다.The fraction of Example 2 (57 g) was run at a flow rate of 3 ml / min using a mixed solvent (100: 1 to 1: 1) of n-hexane and ethyl acetate, and then subjected to concentration gradient silica gel column chromatography. The total was divided into four fractions (first fraction to fourth fraction). A third fraction of this was obtained as an active fraction.
<< 실시예Example 6> 6> 상엽Upper lobe 활성분획물로부터From active fraction 화학식 1의 화합물의 제조 Preparation of Compound of Formula 1
상기 실시예 5에서 수득한 활성분획물을 플로리실 컬럼 크로마토그래피(이동상으로서 n-헥산:에틸아세테이트=30:1~1:1, 유속 3 ml/분)로 분리하여 9개의 분획으로 나눈 후, 제3-4 분획에 대해 다시 실리카겔 컬럼 크로마토그래피(n-헥산:에틸아세테이트=15:1~1:1)를 실시하여 44 mg의 화학식 1의 퍼퓨린-7 디메틸 에틸에스테르를 분리하였다.The active fraction obtained in Example 5 was separated by Florisil column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1 as mobile phase, flow rate 3 ml / min), divided into nine fractions, Silica gel column chromatography ( n -hexane: ethyl acetate = 15: 1 ~ 1: 1) was performed on the 3-4 fractions to separate 44 mg of Perpurin-7 dimethyl ethyl ester of Chemical Formula 1.
1H-NMR(300 MHz, 클로로포름-d) δ 9.51 (1H, s, H-10), 9.10 (1H, s, H-5), 8.45 (1H, s, H-20), 7.71 (3H, dd, J=17.9, 11.4Hz, H-31), 6.16 (1H, d, J=17.9Hz, H-32 a) 6.02 (1H, d, J=11.4Hz, H-32 b), 4.82 (1H, dd, J=9.0, 2.0 Hz, H-17), 4.43 (1H, q, J=7.2Hz, H-18), 4.26 (3H, s, H-153), 4.10 (2H, q, J=7.1Hz, H-174), 4.00 (3H, s, H-132), 3.64 (3H, s, H-121), 3.49 (2H, q, J=7.6Hz, H-81), 3.28 (3H, s, H-21), 3.01 (3H, s, H-71), 2.44 (1H, m, H-171 a), 2.23 (1H, m, H- 71 b), 2.10 (2H, m, H-172), 1.91 (3H, d, J=7.2Hz, H-181), 1.20 (3H, t, J=7.1Hz, H-175), 0.00 (2H, br.s, NH) 1 H-NMR (300 MHz, Chloroform-d) δ 9.51 (1H, s, H-10), 9.10 (1H, s, H-5), 8.45 (1H, s, H-20), 7.71 (3H, dd, J = 17.9, 11.4 Hz, H-3 1 ), 6.16 (1H, d, J = 17.9 Hz, H-3 2 a ) 6.02 (1H, d, J = 11.4 Hz, H-3 2 b ), 4.82 (1H, dd, J = 9.0, 2.0 Hz, H-17), 4.43 (1H, q, J = 7.2 Hz, H-18), 4.26 (3H, s, H-15 3 ), 4.10 (2H, q, J = 7.1 Hz, H-17 4 ), 4.00 (3H, s, H-13 2 ), 3.64 (3H, s, H-12 1 ), 3.49 (2H, q, J = 7.6 Hz, H- 8 1 ), 3.28 (3H, s, H-2 1 ), 3.01 (3H, s, H-7 1 ), 2.44 (1H, m, H-17 1 a ), 2.23 (1H, m, H-7 1 b ), 2.10 (2H, m, H-17 2 ), 1.91 (3H, d, J = 7.2 Hz, H-18 1 ), 1.20 (3H, t, J = 7.1 Hz, H-17 5 ), 0.00 (2H, br.s, NH)
13C-NMR(125 MHz, 클로로포름-d) δ 186.6 (C-151), 174.5 (C-1), 173.2 (C-173), 168.0 (C-131), 166.7 (C-152), 164.3 (C-19), 156.2 (C-9), 155.8 (C-6), 149.1 (C-11), 145.7 (C-8), 138.7 (C-14), 136.7 (C-4), 136.6 (C-16), 136.3 (C-3), 135.8 (C-7), 131.4 (C-2), 129.7 (C-12), 128.7 (C-31), 122.6 (C-32), 119.5 (C-13), 106.4 (C-10), 106.3 (C-15), 97.7 (C-5), 93.8 (C-20), 60.5 (C-175), 53.4 (C-132), 52.8 (C-17), 52.1 (C-153), 49.8 (C-18), 32.0 (C-171), 31.4 (C-172), 23.3 (C-181), 19.4 (C-81), 17.6 (C-82), 14.3 (C-174), 13.1 (C-121), 12.0 (C-21), 11.0 (C-71) 13 C-NMR (125 MHz, Chloroform-d) δ 186.6 (C-15 1 ), 174.5 (C-1), 173.2 (C-17 3 ), 168.0 (C-13 1 ), 166.7 (C-15 2 ), 164.3 (C-19), 156.2 (C-9), 155.8 (C-6), 149.1 (C-11), 145.7 (C-8), 138.7 (C-14), 136.7 (C-4) , 136.6 (C-16), 136.3 (C-3), 135.8 (C-7), 131.4 (C-2), 129.7 (C-12), 128.7 (C-3 1 ), 122.6 (C-3 2 ), 119.5 (C-13), 106.4 (C-10), 106.3 (C-15), 97.7 (C-5), 93.8 (C-20), 60.5 (C-17 5 ), 53.4 (C-13 2 ), 52.8 (C-17), 52.1 (C-15 3 ), 49.8 (C-18), 32.0 (C-17 1 ), 31.4 (C-17 2 ), 23.3 (C-18 1 ), 19.4 (C-8 1 ), 17.6 (C-8 2 ), 14.3 (C-17 4 ), 13.1 (C-12 1 ), 12.0 (C-2 1 ), 11.0 (C-7 1 )
<< 실시예Example 7> 7> 상엽Upper lobe 활성분획물로부터From active fraction 화학식 2의 화합물의 제조 Preparation of Compound of Formula (2)
상기 실시예 5에서 수득한 활성분획물을 플로리실 컬럼 크로마토그래피(이동상으로서 n-헥산:에틸아세테이트=30:1~1:1, 유속 3 ml/분)로 분리하여 9개의 분획으로 나눈 후, 제3-5 분획에 대해 다시 실리카겔 컬럼 크로마토그래피(n-헥산:에틸아세테이트=30:1~1:1)를 실시하여 22 mg의 화학식 2의 페오포르바이드 A 에틸에스테르를 분리하였다.The active fraction obtained in Example 5 was separated by Florisil column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1 as mobile phase, flow rate 3 ml / min), divided into nine fractions, Silica gel column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1) was performed on the 3-5 fraction to separate 22 mg of Pheophorbide A ethyl ester of
1H-NMR(300 MHz, 클로로포름-d) δ 9.42 (1H, s, H-10), 9.26 (1H, s, H-5), 8.54 (1H, s, H-20), 7.91 (3H, dd, J=17.8, 11.6Hz, H-31), 6.26 (1H, s, H-132), 6.15 (1H, d, J=17.8Hz, H-32 a), 6.11 (1H, d, J=11.6Hz, H-32 b), 4.46 (1H, q, J=7.2Hz, H-18), 4.13 (1H, br.d, J=8.1Hz, H-17), 4.02 (2H, q, J=6.9Hz, H-174), 3.89 (3H, s, H-134), 3.66 (3H, s, H-121), 3.54 (2H, q, J=7.4Hz, H-81), 3.36 (3H, s, H-21), 3.13 (3H, s, H-71), 2.61 (1H, m, H-171 a), 2.43 (1H, m, H-172 a), 2.33 (1H, m, H-71 b), 2.24 (1H, m, 172 b), 1.82 (3H, d, J=7.2Hz, H-181), 1.64 (3H, t, J=6.9Hz, H-175), 1.11 (3H, t, J=7.4Hz, H-82), -1.68 (2H, br.s, NH) 1 H-NMR (300 MHz, Chloroform-d) δ 9.42 (1H, s, H-10), 9.26 (1H, s, H-5), 8.54 (1H, s, H-20), 7.91 (3H, dd, J = 17.8, 11.6Hz, H-3 1 ), 6.26 (1H, s, H-13 2 ), 6.15 (1H, d, J = 17.8Hz, H-3 2 a ), 6.11 (1H, d , J = 11.6 Hz, H-3 2 b ), 4.46 (1H, q, J = 7.2 Hz, H-18), 4.13 (1H, br.d, J = 8.1 Hz, H-17), 4.02 (2H , q, J = 6.9 Hz, H-17 4 ), 3.89 (3H, s, H-13 4 ), 3.66 (3H, s, H-12 1 ), 3.54 (2H, q, J = 7.4Hz, H -8 1 ), 3.36 (3H, s, H-2 1 ), 3.13 (3H, s, H-7 1 ), 2.61 (1H, m, H-17 1 a ), 2.43 (1H, m, H- 17 2 a ), 2.33 (1H, m, H-7 1 b ), 2.24 (1H, m, 17 2 b ), 1.82 (3H, d, J = 7.2 Hz, H-18 1 ), 1.64 (3H, t, J = 6.9 Hz, H-17 5 ), 1.11 (3H, t, J = 7.4 Hz, H-8 2 ), -1.68 (2H, br.s, NH)
13C-NMR(125 MHz, 클로로포름-d) δ 189.9 (C-131), 173.2 (C-173), 172.4 (C-19), 169.8 (C-133), 161.4 (C-16), 155.8 (C-6), 151.1 (C-14), 149.9 (C-9), 145.3 (C-8), 142.2 (C-1), 138.1 (C-11), 136.7 (C-4), 136.4 (C-7), 136.3 (C-3), 132.0 (C-2), 129.2 (C-31), 129.2 (C-12), 129.1 (C-13), 122.9 (C-32), 105.4 (C-15), 104.6 (C-10), 97.7 (C-5), 93.3 (C-20), 64.9 (C-132), 60.7 (C-174), 53.1 (C-134), 51.3 (C-17), 50.3 (C-18), 31.4 (C-171), 30.0 (C-172), 23.3 (C-181), 19.6 (C-81), 17.6 (C-82), 14.3 (C-175), 12.3 (C-121), 12.3 (C-21), 11.4 (C-71) 13 C-NMR (125 MHz, Chloroform-d) δ 189.9 (C-13 1 ), 173.2 (C-17 3 ), 172.4 (C-19), 169.8 (C-13 3 ), 161.4 (C-16) , 155.8 (C-6), 151.1 (C-14), 149.9 (C-9), 145.3 (C-8), 142.2 (C-1), 138.1 (C-11), 136.7 (C-4), 136.4 (C-7), 136.3 (C-3), 132.0 (C-2), 129.2 (C-3 1 ), 129.2 (C-12), 129.1 (C-13), 122.9 (C-3 2 ) , 105.4 (C-15), 104.6 (C-10), 97.7 (C-5), 93.3 (C-20), 64.9 (C-13 2 ), 60.7 (C-17 4 ), 53.1 (C-13 4 ), 51.3 (C-17), 50.3 (C-18), 31.4 (C-17 1 ), 30.0 (C-17 2 ), 23.3 (C-18 1 ), 19.6 (C-8 1 ), 17.6 (C-8 2 ), 14.3 (C-17 5 ), 12.3 (C-12 1 ), 12.3 (C-2 1 ), 11.4 (C-7 1 )
<< 실시예Example 8> 8> 상엽Upper lobe 활성분획물로부터From active fraction 화학식 3의 화합물의 제조 Preparation of Compound of Formula 3
상기 실시예 5에서 수득한 활성분획물을 플로리실 컬럼 크로마토그래피(이동상으로서 n-헥산:에틸아세테이트=30:1~1:1, 유속 3 ml/분)로 분리하여 9개의 분획으로 나눈 후, 제3-6 분획에 대해 다시 실리카겔 컬럼 크로마토그래피(n-헥산:에틸아세테이트=5:1~1:1)를 실시하여 130 mg의 화학식 3의 하이드록시-페오포르바이드 A 에틸에스테르를 분리하였다.The active fraction obtained in Example 5 was separated by Florisil column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1 as mobile phase, flow rate 3 ml / min), divided into nine fractions, Silica gel column chromatography ( n -hexane: ethyl acetate = 5: 1 to 1: 1) was performed on the 3-6 fractions to separate 130 mg of hydroxy-phenophorbide A ethyl ester of Chemical Formula 3.
1H-NMR(300 MHz, 클로로포름-d) δ 9.51 (1H, s, H-10), 9.34 (1H, s, H-5), 8.63 (1H, s, H-20), 7.92 (3H, dd, J=17.8, 11.6Hz, H-31), 6.23 (1H, d, J=17.8Hz, H-32 a) 6.13 (1H, d, J=11.6Hz, H-32 b), 5.54 (0.6H, s, H-132), 5.34 (0.4H, s, H-132), 4.69 (0.4H, m, H-17), 4.48 (1H, q, J=7.0Hz, H-18), 4.01 (2H, q, J=7.0Hz, H-174), 3.71 (3H, s, H-134), 3.68 (0.6H, m, H-17), 3.62 (3H, s, H-121), 3.57 (2H, q, J=7.6Hz, H-81), 3.39 (3H, s, H-21), 3.13 (3H, s, H-71), 2.89 (1H, m, H-171 a), 2.57 (1H, m, H-172 a), 2.42 (1H, m, H-71 b), 2.01 (1H, m, 172 b), 1.61 (3H, d, J=7.0Hz, H-181), 1.61 (3H, t, J=7.6Hz, H-82), 1.17 (3H, t, J=7.0Hz, H-175), -1.88 (br.s, NH) 1 H-NMR (300 MHz, Chloroform-d) δ 9.51 (1H, s, H-10), 9.34 (1H, s, H-5), 8.63 (1H, s, H-20), 7.92 (3H, dd, J = 17.8, 11.6 Hz, H-3 1 ), 6.23 (1H, d, J = 17.8 Hz, H-3 2 a ) 6.13 (1H, d, J = 11.6 Hz, H-3 2 b ), 5.54 (0.6H, s, H-13 2 ), 5.34 (0.4H, s, H-13 2 ), 4.69 (0.4H, m, H-17), 4.48 (1H, q, J = 7.0 Hz, H -18), 4.01 (2H, q, J = 7.0 Hz, H-17 4 ), 3.71 (3H, s, H-13 4 ), 3.68 (0.6H, m, H-17), 3.62 (3H, s , H-12 1 ), 3.57 (2H, q, J = 7.6 Hz, H-8 1 ), 3.39 (3H, s, H-2 1 ), 3.13 (3H, s, H-7 1 ), 2.89 ( 1H, m, H-17 1 a ), 2.57 (1H, m, H-17 2 a ), 2.42 (1H, m, H-7 1 b ), 2.01 (1H, m, 17 2 b ), 1.61 ( 3H, d, J = 7.0 Hz, H-18 1 ), 1.61 (3H, t, J = 7.6 Hz, H-8 2 ), 1.17 (3H, t, J = 7.0 Hz, H-17 5 ),- 1.88 (br.s, NH)
13C-NMR(125 MHz, 클로로포름-d) δ 192.0 (C-131), 189.9 (C-173), 172.8 (C-19), 172.4 (C-133), 162.4 (C-16), 155.5 (C-6), 151.0 (C-14), 150.2 (C-9), 145.1 (C-8), 142.1 (C-1), 137.8 (C-11), 136.4 (C-7), 136.3 (C-3), 136.2 (C-4), 131.9 (C-2), 129.6 (C-31), 129.3 (C-12), 129.3 (C-13), 122.8 (C-32), 107.6 (C-15), 104.2 (C-10), 97.9 (C-5), 93.6 (C-20), 60.6 (C-174), 60.4 (C-132), 53.8 (C-134), 51.8 (C-17), 50.3 (C-18), 31.6 (C-171), 29.7 (C-172), 22.7 (C-181), 19.4 (C-81), 17.4 (C-82), 14.1 (C-175), 12.3 (C-121), 12.1 (C-21), 11.2 (C-71) 13 C-NMR (125 MHz, Chloroform-d) δ 192.0 (C-13 1 ), 189.9 (C-17 3 ), 172.8 (C-19), 172.4 (C-13 3 ), 162.4 (C-16) , 155.5 (C-6), 151.0 (C-14), 150.2 (C-9), 145.1 (C-8), 142.1 (C-1), 137.8 (C-11), 136.4 (C-7), 136.3 (C-3), 136.2 (C-4), 131.9 (C-2), 129.6 (C-3 1 ), 129.3 (C-12), 129.3 (C-13), 122.8 (C-3 2 ) , 107.6 (C-15), 104.2 (C-10), 97.9 (C-5), 93.6 (C-20), 60.6 (C-17 4 ), 60.4 (C-13 2 ), 53.8 (C-13 4 ), 51.8 (C-17), 50.3 (C-18), 31.6 (C-17 1 ), 29.7 (C-17 2 ), 22.7 (C-18 1 ), 19.4 (C-8 1 ), 17.4 (C-8 2 ), 14.1 (C-17 5 ), 12.3 (C-12 1 ), 12.1 (C-2 1 ), 11.2 (C-7 1 )
<<
실시예Example
9> 9>
상엽Upper lobe
활성분획물로부터From active fraction
화학식 4의 화합물의 제조 Preparation of Compound of
상기 실시예 5에서 수득한 활성분획물을 플로리실 컬럼 크로마토그래피(이동상으로서 n-헥산:에틸아세테이트=30:1~1:1, 유속 3 ml/분)로 분리하여 9개의 분획으로 나눈 후, 제3-3 분획에 대해 다시 실리카겔 컬럼 크로마토그래피(n-헥산:에틸아세테이트=30:1~1:1)를 실시하여 4 mg의 화학식 4의 디데하이드로-로도클로린 에틸메틸에스테르를 분리하였다.The active fraction obtained in Example 5 was separated by Florisil column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1 as mobile phase, flow rate 3 ml / min), divided into nine fractions, Silica gel column chromatography ( n -hexane: ethyl acetate = 30: 1 ~ 1: 1) was performed on the 3-3 fractions to separate 4 mg of didehydro- rodochlorine ethylmethyl ester of the formula (4).
1H-NMR(300 MHz, 클로로포름-d) δ 9.86 (1H, s, H-15), 9.72 (1H, s,H-10), 9.59 (1H, s, H-5), 8.76 (1H, s, H-20), 8.05 (3H, dd, J=18.0, 12.0Hz, H-31), 6.33 (1H, d, J=18.0Hz, H-32 a) 6.14 (1H, d, J=12.0Hz, H-32 b), 4.54 (1H, q, J=7.2Hz, H-18), 4.39 (3H, s, H-132), 4.14 (2H, q, J=7.2Hz, H-174), 4.13 (1H, br.d, J=8.1Hz, H-17), 3.75 (2H, q, J=7.8Hz, H-81), 3.66 (3H, s, H-121), 3.36 (3H, s, H-21), 3.13 (3H, s, H-71), 2.79 (1H, m, H-172 a), 2.63 (1H, m, H-171 a), 2.52 (2H, m, H-172 b), 2.52 (2H, m, H-171 b), 1.93 (3H, d, J=7.2Hz, H-181), 1.73 (3H, t, J=7.8Hz, H-82), 1.22 (3H, t, J=7.2Hz, H-175), 0.14 (1H, br.s, NH) 1 H-NMR (300 MHz, Chloroform-d) δ 9.86 (1H, s, H-15), 9.72 (1H, s, H-10), 9.59 (1H, s, H-5), 8.76 (1H, s, H-20), 8.05 (3H, dd, J = 18.0, 12.0 Hz, H-3 1 ), 6.33 (1H, d, J = 18.0 Hz, H-3 2 a ) 6.14 (1H, d, J = 12.0 Hz, H-3 2 b ), 4.54 (1H, q, J = 7.2 Hz, H-18), 4.39 (3H, s, H-13 2 ), 4.14 (2H, q, J = 7.2 Hz, H-17 4 ), 4.13 (1H, br.d, J = 8.1 Hz, H-17), 3.75 (2H, q, J = 7.8 Hz, H-8 1 ), 3.66 (3H, s, H-12 1 ), 3.36 (3H, s, H-2 1 ), 3.13 (3H, s, H-7 1 ), 2.79 (1H, m, H-17 2 a ), 2.63 (1H, m, H-17 1 a ), 2.52 (2H, m, H-17 2 b ), 2.52 (2H, m, H-17 1 b ), 1.93 (3H, d, J = 7.2 Hz, H-18 1 ), 1.73 (3H, t, J = 7.8 Hz, H-8 2 ), 1.22 (3H, t, J = 7.2 Hz, H-17 5 ), 0.14 (1H, br.s, NH)
13C-NMR(125 MHz, 클로로포름-d) δ 173.7 (C-173), 171.5 (C-19), 167.3 (C-131), 166.9 (C-14), 154.4 (C-6), 149.7 (C-9), 145.0 (C-8), 140.2 (C-1), 140.1 (C-11), 137.2 (C-16), 136.3 (C-7), 135.1 (C-3), 134.7 (C-4), 130.5 (C-12), 130.3 (C-2), 129.6 (C-31), 122.0 (C-32), 119.1 (C-13), 102.2 (C-10), 99.0 (C-5), 96.4 (C-15), 93.1 (C-20), 60.6 (C-174), 55.0 (C-17), 52.1 (C-132), 48.8 (C-18), 32.7 (C-172), 31.5 (C-171), 23.7 (C-181), 19.8 (C-81), 17.9 (C-82), 14.4 (C-175), 13.8 (C-121), 12.3 (C-21), 11.5 (C-71) 13 C-NMR (125 MHz, chloroform-d) δ 173.7 (C-17 3 ), 171.5 (C-19), 167.3 (C-13 1 ), 166.9 (C-14), 154.4 (C-6), 149.7 (C-9), 145.0 (C-8), 140.2 (C-1), 140.1 (C-11), 137.2 (C-16), 136.3 (C-7), 135.1 (C-3), 134.7 (C-4), 130.5 (C-12), 130.3 (C-2), 129.6 (C-3 1 ), 122.0 (C-3 2 ), 119.1 (C-13), 102.2 (C-10), 99.0 (C-5), 96.4 (C-15), 93.1 (C-20), 60.6 (C-17 4 ), 55.0 (C-17), 52.1 (C-13 2 ), 48.8 (C-18) , 32.7 (C-17 2 ), 31.5 (C-17 1 ), 23.7 (C-18 1 ), 19.8 (C-8 1 ), 17.9 (C-8 2 ), 14.4 (C-17 5 ), 13.8 (C-12 1 ), 12.3 (C-2 1 ), 11.5 (C-7 1 )
<< 실시예Example 10> 10> 상엽Upper lobe 활성분획물로부터From active fraction 화학식 5의 화합물의 제조 Preparation of Compound of Formula 5
상기 실시예 5에서 수득한 활성분획물을 플로리실 컬럼 크로마토그래피(이동 상으로서 n-헥산:에틸아세테이트=30:1~1:1, 유속 3 ml/분)로 분리하여 9개의 분획으로 나눈 후, 제3-3 분획에 대해 다시 실리카겔 컬럼 크로마토그래피(n-헥산:에틸아세테이트=30:1~1:1)를 실시하여 140 mg의 화학식 5의 하이드록시 페오포르바이드 A 메틸에스테르를 분리하였다.The active fraction obtained in Example 5 was separated by Florisil column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1 as a mobile phase, flow rate 3 ml / min), divided into nine fractions, Silica gel column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1) was performed on the 3-3 fraction to separate 140 mg of hydroxy perobide A methyl ester of Chemical Formula 5.
1H-NMR(300 MHz, 클로로포름-d) δ 9.47 (1H, s, H-10), 9.29 (1H, s, H-5), 8.61 (1H, s, H-20), 7.89 (1H, dd, J=18.0Hz, 12.0Hz, H-31), 6.21 (1H, d, J=18.0Hz, H-32), 6.11 (1H, d, J=12.0Hz, H-32), 5.50 (1H, s, H-132/OH),4.48 (1H, q, J=7.2Hz, H-18), 4.15 (1H, dd, J=9.0, 2.0Hz, H-17), 3.70 (3H, s, H-121), 3.65 (3H, s, H-134), 3.62 (3H, s, H-174), 3.40 (2H, q, J=7.7Hz, H-81), 3.37 (3H, s, H-21), 3.10 (3H, s, H-71), 2.96 (1H, m, H-171a), 2.57 (1H, m, H-172a), 2.34 (1H, m, H-171b), 2.27 (1H, m, H-172b), 1.59 (3H, d, J=7.2Hz, H-181),1.59 (2H, t, J=7.7Hz, H-82), -1.91 (2H, br.s, NH) 1 H-NMR (300 MHz, Chloroform-d) δ 9.47 (1H, s, H-10), 9.29 (1H, s, H-5), 8.61 (1H, s, H-20), 7.89 (1H, dd, J = 18.0 Hz, 12.0 Hz, H-3 1 ), 6.21 (1H, d, J = 18.0 Hz, H-3 2 ), 6.11 (1H, d, J = 12.0 Hz, H-3 2 ), 5.50 (1H, s, H-13 2 / OH), 4.48 (1H, q, J = 7.2 Hz, H-18), 4.15 (1H, dd, J = 9.0, 2.0 Hz, H-17), 3.70 ( 3H, s, H-12 1 ), 3.65 (3H, s, H-13 4 ), 3.62 (3H, s, H-17 4 ), 3.40 (2H, q, J = 7.7 Hz, H-8 1 ) , 3.37 (3H, s, H-2 1 ), 3.10 (3H, s, H-7 1 ), 2.96 (1H, m, H-17 1 a), 2.57 (1H, m, H-17 2 a) , 2.34 (1H, m, H-17 1 b), 2.27 (1H, m, H-17 2 b), 1.59 (3H, d, J = 7.2 Hz, H-18 1 ), 1.59 (2H, t, J = 7.7 Hz, H-8 2 ), -1.91 (2H, br.s, NH)
13C-NMR(125 MHz, 클로로포름-d) δ 192.2 (C-131), 174.2 (C-173), 173.0 (C-1), 172.6 (C-133), 162.6 (C-19), 155.5 (C-9), 151.2 (C-11), 150.0 (C-16), 145.3 (C-8), 142.2 (C-4), 138.0 (C-14), 136.6 (C-3), 136.4 (C-6), 136.4 (C-7), 131.9 (C-2), 129.5 (C-12), 129.2 (C-31), 127.1 (C-13), 123.0 (C-32), 107.9 (C-15), 104.4 (C-10),98.1 (C-5), 93.8 (C-20), 89.2 (C-132), 53.6 (C-134), 52.0 (C-17), 51.9 (C-174), 50.5 (C-18), 31.7 (C-171), 31.4 (C-172), 22.9 (C-181), 19.6 (C-81), 17.6 (C-82), 12.5 (C-121), 12.3 (C-21), 11.3 (C-71) 13 C-NMR (125 MHz, Chloroform-d) δ 192.2 (C-13 1 ), 174.2 (C-17 3 ), 173.0 (C-1), 172.6 (C-13 3 ), 162.6 (C-19) , 155.5 (C-9), 151.2 (C-11), 150.0 (C-16), 145.3 (C-8), 142.2 (C-4), 138.0 (C-14), 136.6 (C-3), 136.4 (C-6), 136.4 (C-7), 131.9 (C-2), 129.5 (C-12), 129.2 (C-3 1 ), 127.1 (C-13), 123.0 (C-3 2 ) , 107.9 (C-15), 104.4 (C-10), 98.1 (C-5), 93.8 (C-20), 89.2 (C-13 2 ), 53.6 (C-13 4 ), 52.0 (C-17 ), 51.9 (C-17 4 ), 50.5 (C-18), 31.7 (C-17 1 ), 31.4 (C-17 2 ), 22.9 (C-18 1 ), 19.6 (C-8 1 ), 17.6 (C-8 2 ), 12.5 (C-12 1 ), 12.3 (C-2 1 ), 11.3 (C-7 1 )
<<
실시예Example
11> 11>
상엽Upper lobe
활성분획물로부터From active fraction
화학식 6의 화합물의 제조 Preparation of Compound of
상기 실시예 5에서 수득한 활성분획물을 플로리실 컬럼 크로마토그래피(이동상으로서 n-헥산:에틸아세테이트=30:1~1:1, 유속 3 ml/분)로 분리하여 9개의 분획으로 나눈 후, 제3-4 분획에 대해 다시 실리카겔 컬럼 크로마토그래피(n-헥산:에틸아세테이트=30:1~1:1)를 실시하여 31 mg의 화학식 6의 페오포르바이드 A 메틸에스테르를 분리하였다.The active fraction obtained in Example 5 was separated by Florisil column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1 as mobile phase, flow rate 3 ml / min), divided into nine fractions, Silica gel column chromatography ( n -hexane: ethyl acetate = 30: 1 to 1: 1) was performed on the 3-4 fractions to separate 31 mg of the pheophorbide A methyl ester of the formula (6).
1H-NMR(300 MHz,클로로포름-d) δ 9.51 (1H, s, H-10), 9.37 (1H, s, H-5), 8.56 (1H, s, H-20), 7.97 (3H, dd, J=17.8, 11.6Hz, H-31), 6.28 (1H, d, J=17.8Hz, H-32 a), 6.25 (1H, s, H-132), 6.13 (1H, d, J=11.6Hz, H-32 b), 4.45 (1H, q, J=7.2Hz, H-18), 4.14 (1H, br.d, J=8.1Hz, H-17), 3.87 (32H, s, H-174), 3.71 (3H, s, H-134), 3.59 (3H, s, H-121), 3.53 (2H, q, J=7.4Hz, H-81), 3.39 (3H, s, H-21), 3.20 (3H, s, H-71), 2.61 (1H, m, H-171 a), 2.55 (1H, m, H-172 a), 2.35 (1H, m, H-71 b), 2.21 (1H, m, 172 b), 1.80 (3H, d, J=7.2Hz, H-181), 1.26 (3H, t, J=7.4Hz, H-82), -1.68 (2H, br.s, NH) 1 H-NMR (300 MHz, Chloroform-d) δ 9.51 (1H, s, H-10), 9.37 (1H, s, H-5), 8.56 (1H, s, H-20), 7.97 (3H, dd, J = 17.8, 11.6Hz, H-3 1 ), 6.28 (1H, d, J = 17.8Hz, H-3 2 a ), 6.25 (1H, s, H-13 2 ), 6.13 (1H, d , J = 11.6 Hz, H-3 2 b ), 4.45 (1H, q, J = 7.2 Hz, H-18), 4.14 (1H, br.d, J = 8.1 Hz, H-17), 3.87 (32H , s, H-17 4 ), 3.71 (3H, s, H-13 4 ), 3.59 (3H, s, H-12 1 ), 3.53 (2H, q, J = 7.4 Hz, H-8 1 ), 3.39 (3H, s, H-2 1 ), 3.20 (3H, s, H-7 1 ), 2.61 (1H, m, H-17 1 a ), 2.55 (1H, m, H-17 2 a ), 2.35 (1H, m, H-7 1 b ), 2.21 (1H, m, 17 2 b ), 1.80 (3H, d, J = 7.2 Hz, H-18 1 ), 1.26 (3H, t, J = 7.4 Hz, H-8 2 ), -1.68 (2H, br.s, NH)
13C-NMR(125 MHz, 클로로포름-d) δ 189.8 (C-131), 173.5 (C-173), 172.4 (C-19), 169.8 (C-133), 161.4 (C-16), 155.8 (C-6), 151.1 (C-14), 149.8 (C-9), 145.4 (C-8), 142.2 (C-1), 138.1 (C-11), 136.7 (C-4), 136.4 (C-7), 136.3 (C-3), 132.0 (C-2), 129.2 (C-31), 129.2 (C-12), 129.1 (C-13), 123.0 (C-32), 105.3 (C-15), 104.6 (C-10), 97.7 (C-5), 93.3 (C-20), 64.9 (C-132), 53.1 (C-134), 51.9 (C-174), 51.3 (C-17), 50.3 (C-18), 31.2 (C-171), 30.0 (C-172), 23.3 (C-181), 19.6 (C-81), 17.6 (C-82), 12.3 (C-121), 12.3 (C-21), 11.4 (C-71) 13 C-NMR (125 MHz, Chloroform-d) δ 189.8 (C-13 1 ), 173.5 (C-17 3 ), 172.4 (C-19), 169.8 (C-13 3 ), 161.4 (C-16) , 155.8 (C-6), 151.1 (C-14), 149.8 (C-9), 145.4 (C-8), 142.2 (C-1), 138.1 (C-11), 136.7 (C-4), 136.4 (C-7), 136.3 (C-3), 132.0 (C-2), 129.2 (C-3 1 ), 129.2 (C-12), 129.1 (C-13), 123.0 (C-3 2 ) , 105.3 (C-15), 104.6 (C-10), 97.7 (C-5), 93.3 (C-20), 64.9 (C-13 2 ), 53.1 (C-13 4 ), 51.9 (C-17 4 ), 51.3 (C-17), 50.3 (C-18), 31.2 (C-17 1 ), 30.0 (C-17 2 ), 23.3 (C-18 1 ), 19.6 (C-8 1 ), 17.6 (C-8 2 ), 12.3 (C-12 1 ), 12.3 (C-2 1 ), 11.4 (C-7 1 )
<< 실험예Experimental Example 1> 1> MCHMCH -1 수용체 결합 억제효과 측정-1 receptor binding inhibitory effect
본 발명에 따른 상엽 추출물, 이의 분획물 또는 활성물질의 MCH-1 수용체 결합 억제활성을 알아보기 위하여 다음과 같은 실험을 수행하였다.In order to determine the MCH-1 receptor binding inhibitory activity of the leaf extract, fractions or active substances thereof according to the present invention was carried out as follows.
완충용액은 세척용액(25 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2)과 실험용액(세척용액에 BSA를 0.5% 되게 첨가) 두 종류를 준비하고, MCH-1 수용체(Euroscreen, Gosselies, Belgium)와 1 μM 유로피움으로 표지된 멜라닌 농축호르몬(Europium(Eu)-labeled MCH, PerkinElmer, Turku, Finland) 및 1 mM 멜라닌 농축호르몬(MCH, #070-47, Phoenix, Belmont CA, USA)은 4 ℃를 유지시켰다. 1 μM Eu-labeled MCH와 1 mM MCH는 각기 8 nM(최종 반응농도는 2 nM)과 2 μM(최종 반응농도는 0.5 μM)이 되게 희석시켰다. 모든 희석과 준비과정에서 사용되는 완충용액은 실험용액이며, 세척용액은 마지막에 플레이트를 씻어 줄 때만 사용했다. The buffer solution is prepared by two types of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH-1 receptor (Euroscreen, Gosselies). , Belgium) and 1 μM europium labeled melanin enriched hormone (Europium (Eu) -labeled MCH, PerkinElmer, Turku, Finland) and 1 mM melanin enriched hormone (MCH, # 070-47, Phoenix, Belmont CA, USA) Was kept at 4 ° C. 1 μM Eu-labeled MCH and 1 mM MCH were diluted to 8 nM (
MCH-1 수용체(200 assays/vial)는 우선 1 ml의 실험용액에 희석하여 균질화 시켰다. 이후, 시험물질로서 실시예 1, 4-11에서 제조된 상엽 추출물 또는 이로부터 분리된 화합물을 준비한 후, 여과지가 부착된 미소판(Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA)에 8채널 파이펫(multi 8-channel, Eppendorf, Hamburg, Germany)을 이용하여, 각 웰당 전체부피가 100 μl가 되게 상기 실시예 실시예 1, 4-11에서 제조된 상엽 추출물 또는 이로부터 분리된 화합물을 분주하였다. 이때 대조군으로 비특이적결합(non specific binding)은 Eu-labeled MCH 25 μl와 수용체 50 μl 및 MCH 25 μl를, 그리고 전체결합(total binding)은 10% DMSO 실험용액 25 μl와 Eu-labeled MCH 25 μl 및 수용체 50 μl를 혼합하였다. 마지막으로, 실험군은 시험물질 25 μl와 Eu-labeled MCH 25 μl 및 수용체 50 μl를 혼합하였다. 이렇게 모두 분주한 후 15 초간 약하게 흔들어 주고 상온에서 90 분간 반응시켰다. MCH-1 receptor (200 assays / vial) was first homogenized by diluting in 1 ml of experimental solution. Thereafter, the leaf extract prepared in Example 1, 4-11 or a compound separated therefrom was prepared as a test substance, and then the filter plate attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). Using an 8-channel pipette (multi 8-channel, Eppendorf, Hamburg, Germany), the extract of the upper leaf prepared in Examples 1, 4-11 or separated therefrom so that the total volume is 100 μl per well Compounds were dispensed. In this case, non-specific binding is 25 μl of Eu-labeled MCH and 50 μl of receptor and 25 μl of MCH, and total binding is 25 μl of 10% DMSO experimental solution and 25 μl of Eu-labeled MCH and 50 μl of receptor was mixed. Finally, the experimental group mixed 25 μl of test substance with 25 μl of Eu-labeled MCH and 50 μl of receptor. After all of this was shaken gently for 15 seconds and reacted at room temperature for 90 minutes.
반응이 끝나면 부분적으로 수정하여 자체 제작한 세척기(microplate washer, EMBLA, Molecular Devices)에 압력을 걸어 플레이트를 세척했다. 세척용액으로 웰당 300 μl 씩 3회 여과시켰다. 이 과정을 통해 반응하지 않고 남아 있는 Eu-labeled MCH가 제거된다. 이후, 바닥의 물기를 닦아내고 웰당 150 μl가 되게 해리용액(DELFIA Enhancement solution, PerkinElmer, Turku, Finland)을 첨가하였다. 약하게 10분간 흔들어준 후 측정하거나, 또는 상온에서 그대로 2~4시간 방치 반응시켜 시차성 형광(Time-resolved fluorescence, TRF) 값을 측정하였다. 측정방법으로 방출파장(emission wave)은 615 nm, 여기파장(excitation wave)은 340 nm로 하여, 다기능 형광측정기(multilabel counter, Victor2, PerkinElmer, Turku, Finland)로 측정했다. 시차성 형광 억제율을 하기 수학식 1에 의해 계산하였다At the end of the reaction, the plate was partially cleaned by applying pressure to a self-made washer (microplate washer, EMBLA, Molecular Devices). The wash solution was filtered three times at 300 μl per well. This process removes the remaining Eu-labeled MCH without reacting. Then, the bottom of the water was wiped off and the dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) was added to 150 μl per well. After shaking for 10 minutes or measured, or reacted for 2 to 4 hours as it is at room temperature to measure the time-resolved fluorescence (TRF) value. As a measurement method, the emission wavelength was 615 nm and the excitation wavelength was 340 nm, which was measured by a multi-label fluorometer (multilabel counter, Victor2, PerkinElmer, Turku, Finland). Differential fluorescence inhibition was calculated by the following equation (1).
1차적으로 10 μM에서의 시차성 형광 억제율을 측정한 후, 50% 이상 억제된 시험물질에 한하여 IC50값을 계산하였다. 50% 이상 억제된 시험물질은 각기 0.01, 0.1, 1.0 및 10.0 μM 등 네 농도에서 시차성 형광값을 구하여 선형회귀분석을 통하여 IC50 값을 계산하였으며, 그 결과를 표 1 및 표 2에 나타내었다.After primarily measuring the differential fluorescence inhibition at 10 μM, the IC 50 value was calculated only for test substances inhibited by 50% or more. For the test substances inhibited by more than 50%, the differential fluorescence values were obtained at four concentrations of 0.01, 0.1, 1.0, and 10.0 μM, respectively, and IC 50 values were calculated through linear regression analysis. The results are shown in Tables 1 and 2. .
표 1에 나타낸 바와 같이, 본 발명에 따른 상엽 에탄올 추출물, 그리고 이의 다이클로로메탄 분획물 및 에틸아세테이트 분획물들의 MCH-1 수용체 결합 억제활성에 대한 IC50 값은 0.97 ~ 6.67 ㎍/ml를 나타냄으로서 우수한 MCH-1 수용체 결합 억제 작용을 나타냄을 알 수 있다. 반면 부탄올 분획물 및 물 분획물은 MCH-1 수용체 결합 억제 작용이 거의 없는 것으로 나타났다(IC50 > 30 ㎍/ml). 상엽 메탄올 추출물, 그리고 이의 다이클로로메탄 분획물 및 에틸아세테이트 분획물들의 MCH-1 수용체 결합 억제활성에 대한 IC50 값은 2.42 ~ 6.34 ㎍/ml를 나타내었고, 부탄올 분획물 및 물 분획물은 MCH-1 수용체 결합 억제 작용이 거의 없는 것으로 나타나 (IC50 > 30 ㎍/ml), 상엽 에탄올 추출물의 효과와 비슷한 양상을 보였다.As shown in Table 1, the IC 50 value for the MCH-1 receptor binding inhibitory activity of the upper leaf ethanol extract, and the dichloromethane fraction and ethyl acetate fraction thereof according to the present invention is excellent MCH by showing 0.97 ~ 6.67 ㎍ / ml It can be seen that -1 receptor binding inhibitory action. Butanol fraction and water fraction showed little MCH-1 receptor binding inhibitory activity (IC 50 > 30 ㎍ / ml). The IC 50 values of MCH-1 receptor binding inhibitory activity of the methanol extract of the upper leaf, and its dichloromethane fractions and ethyl acetate fractions ranged from 2.42 to 6.34 ㎍ / ml, but the butanol fraction and water fraction inhibited MCH-1 receptor binding. It showed little action (IC 50 > 30 ㎍ / ml), showing a similar pattern to that of the ethanol extract of the lobe.
표 2에 나타낸 바와 같이, 본 발명에 따른 상엽 추출물에서 분리한 화합물의 MCH-1 수용체 결합 억제활성에 대한 IC50 값은 0.11 ~ 14.94 ㎍/ml를 나타냄으로서 우수한 MCH-1 수용체 결합 억제 작용을 나타냄을 알 수 있다. 특히, 퍼퓨린-7 디메틸 에틸에스테르, 페오포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 에틸에스테르, 하이드록시-페오포르바이드 A 메틸에스테르 등의 화합물들은 추출물의 효과보다 약 10배 정도 강한 것으로 나타났다.As shown in Table 2, IC 50 on the MCH-1 receptor binding inhibitory activity of the compounds isolated from the extract of the upper leaf according to the present invention Values of 0.11 to 14.94 µg / ml indicate that the MCH-1 receptor binding inhibitory activity is excellent. In particular, compounds such as Perpurin-7 dimethyl ethyl ester, pheophorbide A ethyl ester, hydroxy-phenophorbide A ethyl ester, and hydroxy- pheophorbide A methyl ester are about 10 times stronger than the extract effect. appear.
따라서, 본 발명에 따른 상엽 추출물 또는 이로부터 분리된 화합물은 뛰어난 MCH-1 수용체 결합 억제 작용을 나타내므로 식욕 억제, 우울증의 예방 및 개선, 또는 불안증의 예방 및 개선에 유용하게 이용될 수 있다.Therefore, the upper leaf extract according to the present invention or a compound isolated therefrom exhibits excellent MCH-1 receptor binding inhibitory action, and thus can be usefully used for suppressing appetite, preventing and improving depression, or preventing and improving anxiety.
<< 실험예Experimental Example 2> 식욕 억제 효과 및 체중 감소 효과 측정 2> Measuring appetite suppression effect and weight loss effect
본 발명에 따른 상엽 추출물, 이의 분획물 또는 활성물질의 식욕 억제 효과 및 체중 감소 효과를 알아보기 위하여 다음과 같은 실험을 수행하였다.In order to determine the appetite suppression effect and weight loss effect of the upper leaf extract, fractions or active substances thereof according to the present invention was carried out as follows.
식이유도 비만생쥐모델은 생후 5주부터 14주까지 9주간 고지방식이(총칼로리의 60% 지방함유식이: D12492. Research diet)를 공급하여 단시일 내에 대조군(총칼로리의 6.5% 지방함유식이: Purina Rodent chow 5008; Ralston-purina) 대비 현저한 체중증가(25%이상 체중증가)를 보이며 사람에서의 중증비만과 유사한 비만동물 모델을 완성하였다. 이때 사용된 쥐는 미국 Jacson lab. 에서 C57BL/6J계 마우스 4주령을 구입하여 1주일 적응기간을 거친 후 5주령부터 사용하였다. 실험 전 5주령 평균체중은 18.7±0.88 g 이었으며, 비만모델로 완성된 14주령의 평균체중은 37.0±0.2 g (64 마리)로 대조군의 평균체중 29.6±0.5 g (9 마리)과 현저한 체중차이를 보였다. 본 실험에 사용된 각 군당 식이유도 비만생쥐의 수는 10-12 마리로 하였다. 식이는 고지방식이(총칼로리의 60% 지방함유식이: D12492. Research diet)를 그대로 유지하였으며, 상기 실시예 1에서 제조한 상엽 추출물을 0.5% tween 80에 용해하여 매일 하루에 두 번 100, 250, 500 mg/kg로 경구 투여하였으며, 32 일간 2일 간격으로 섭식량 변화와 체중변화를 측정하였다. 사육실의 온도는 25±2 ℃로 유지하였고 낮/밤 주기는 12시간 주기로 교차하였으며, 물과 고지방식이는 자유로이 먹도록 하였다. 이때 0.5% tween 80 용액만을 경구투여 한 군을 대조군으로 하였고, 식욕억제제인 sibutramin 3 mg/kg을 경구 투여한 군을 비교군으로 하였다. 32일간 매일 각 군의 마우스의 몸무게 변화와 섭식량을 측정하였다.Dietary-induced obese mice were fed a high-fat diet (60% fat in total calories: D12492. Research diet) for 9 weeks from 5 to 14 weeks of age, and within a short period of time, the control group (6.5% fat in total calories: Purina). A model of obesity similar to severe obesity in humans was completed, with significant weight gain (more than 25%) compared to Rodent chow 5008 (Ralston-purina). The mice used were Jacson lab, USA. C57BL / 6J mice were purchased at 4 weeks of age and were used from 5 weeks of age after one week of adaptation. The mean weight of 5 weeks old before the experiment was 18.7 ± 0.88 g, and the mean weight of 14 weeks old was 37.0 ± 0.2 g (64), which was significantly different from the average body weight of 29.6 ± 0.5 g (9). Seemed. The number of dietary-induced obese mice in each group was 10-12. The diet was maintained as a high fat diet (60% fat-containing diet of total calories: D12492. Research diet), and the extract of the upper leaf prepared in Example 1 was dissolved in 0.5% tween 80 twice a
측정 결과를 도 1 및 도 2에 나타내었다.The measurement results are shown in FIGS . 1 and 2 .
도 1은 본 발명에 따른 상엽 추출물 투여에 대한 마우스의 몸무게 변화를 나타낸 그래프이다. 도 1에 나타난 바와 같이, 본 발명에 따른 상엽 추출물 100 mg/kg 투여군에서는 대조군과 비교할 때 유의성있는 차이가 나타나지 않았으나, 250, 500 mg/kg을 투여한 비만생쥐의 체중은 대조군과 비교할 때 투여 2일 이후부터 점차로 감소하는 경향을 보였다. 특히, 250 mg/kg 투여군에서는 투여 4일부터, 500 mg/kg 투여군에서는 14일부터 유의성 있는 차이가 나타났다. 한편, 비교군인 sibutramine은 투여 2일 후부터 유의성 있는 감소를 나타냈으며, 이후에는 체중감소가 둔화되기 시작하여, 26일째부터는 대조군과 비교할 때 유의성 있는 차이가 없어지는 것으로 나타났다. Figure 1 is a graph showing the weight change of the mouse for administration of the upper leaf extract according to the present invention. As shown in Figure 1 , the
도 2는 본 발명에 다른 상엽 추출물 투여에 대한 마우스의 섭식량 변화를 나타낸 그래프이다. 도 2에 나타난 바와 같이, 본 발명에 따른 상엽 추출물 100, 250, 500 mg/kg을 투여한 모든 투여군에서 사료 섭취량이 줄어들어, 실험기간 내내 지속적인 식욕저하를 나타내는 것으로 관찰되었다. 한편, 비교군인 sibutramine을 투여한 군에서는 사료섭취량이 급격히 감소하였다가, 다시 급격히 증가하는 양상을 나타내었다. Figure 2 is a graph showing the change in feeding amount of the mouse to the administration of the extract of the upper leaf to the present invention. As shown in Figure 2 , the feed intake was reduced in all the administration groups administered 100, 250, 500 mg / kg of the upper leaf extract according to the present invention, it was observed to show a sustained appetite decrease throughout the experimental period. On the other hand, the sibutramine-administered group showed a sharp decrease in feed intake, and then increased rapidly.
따라서, 본 발명에 따른 상엽 추출물은 체중감소 및 식욕저하를 유도하므로 비만 예방 및 개선에 유용하게 사용될 수 있다.Therefore, the upper leaf extract according to the present invention can be usefully used for preventing and improving obesity because it induces weight loss and decreased appetite.
하기에 본 발명의 조성물을 위한 제제예를 예시한다.Examples of formulations for the composition of the present invention are illustrated below.
<< 제제예Formulation example 1> 식품의 제조 1> Manufacture of food
<1-1> <1-1> 선식Wire
현미, 보리, 찹쌀, 율무를 공지의 방법으로 알파화시켜 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 만들었다. 검정콩, 검정깨, 들깨도 공지의 방법으로 쪄서 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 만들었다.Brown rice, barley, glutinous rice, and yulmu were alphad by a known method, and then dried and roasted to make a powder having a particle size of 60 mesh. Black beans, black sesame seeds, and perilla were also steamed and dried in a known manner, and then ground to a powder having a particle size of 60 mesh.
본 발명의 상엽 추출물 또는 화학식 1~6의 화합물을 진공 농축기에서 감압 농축하고, 분무 열풍건조기로 건조하여 얻은 건조물을 분쇄기로 입도 60 메쉬로 분쇄하여 상엽 추출물 건조 분말을 얻었다.The upper leaf extract of the present invention or the compound of Chemical Formulas 1 to 6 were concentrated under reduced pressure in a vacuum concentrator, and the dried product obtained by drying with a spray hot air dryer was pulverized to a particle size of 60 mesh with a grinder to obtain a dry leaf extract powder.
상기에서 제조한 곡물류, 종실류 및 상엽 추출물 또는 화학식 1~6의 화합물의 건조 분말을 다음의 비율로 배합하여 과립을 만들었다.Granules were prepared by combining the grains, seeds and leaf extracts prepared above or the dry powder of the compound of Formulas 1 to 6 in the following ratios.
곡물류 : 현미 30 중량%, 율무 15 중량%, 보리 20 중량%, 찹쌀 9 중량%,Cereals: Brown rice 30% by weight, barley 15% by weight,
종실류 : 들깨 7 중량%, 검정콩 8 중량%, 검정깨 7 중량%,Seeds: perilla 7% by weight,
상엽 추출물 또는 화학식 1~6의 화합물의 건조 분말 3 중량%, 영지 0.5 중량%, 지황 0.5 중량%3% by weight of the dry leaf extract or the dry powder of the compound of formulas 1-6, Ganoderma lucidum 0.5%
<1-2> <1-2> 츄잉껌Chewing gum
껌 베이스 20 중량%, 설탕 76.9 중량%, 향료 1 중량% 및 물 2 중량%와 본 발명의 상엽 추출물 0.1 중량%를 배합하여 통상의 방법으로 츄잉껌을 제조하였다.Chewing gum was prepared in a conventional manner by combining 20% by weight of gum base, 76.9% by weight of sugar, 1% by weight of perfume, and 2% by weight of water, and 0.1% by weight of the leaf extract of the present invention.
<1-3> 캔디<1-3> candy
설탕 60 중량%, 물엿 39.8 중량% 및 향료 0.1 중량%와 본 발명의 상엽 추출물 또는 화학식 1~6의 화합물 0.1 중량%를 배합하여 통상의 방법으로 캔디를 제조하였다.Candy was prepared in a conventional manner by combining 60% by weight of sugar, 39.8% by weight of starch syrup, and 0.1% by weight of fragrance, and 0.1% by weight of the upper leaf extract of the present invention or the compound of Formulas 1-6.
<1-4> <1-4> 비스켓Biscuits
박력 1급 25.59 중량%, 중력 1급 22.22 중량%, 정백당 4.80 중량%, 식염 0.73 중량%, 포도당 0.78 중량%, 팜쇼트닝 11.78 중량%, 암모늄 1.54 중량%, 중조 0.17 중량%, 중아황산나트륨 0.16 중량%, 쌀가루 1.45 중량%, 비타민 B₁0.0001 중량%, 비타민 B₂0.0001 중량%, 밀크향 0.04 중량%, 물 20.6998 중량%, 전지분유 1.16 중량%, 대용분유 0.29 중량%, 제1인산칼슘 0.03 중량%, 살포염 0.29 중량% 및 분무유 7.27 중량%와 본 발명의 상엽 추출물 또는 화학식 1~6의 화합물 1 중량%를 배합하여 통상의 방법으로 비스켓을 제조하였다. Force 25.59% by weight, 22.22% by weight of gravity, 4.80% by weight, white salt 0.73% by weight, 0.78% by weight, palm shortening 11.78%, ammonium 1.54% by weight, 0.17% by weight sodium bisulfite 0.16% by weight , Rice flour 1.45%, Vitamin B₁0.0001%, Vitamin B₂0.0001%, Milk flavor 0.04%, Water 20.6998%, Whole milk powder 1.16%, Substitute milk powder 0.29%, Monobasic calcium phosphate 0.03% , Biscuits were prepared by combining 0.29 wt% of spray salt and 7.27 wt% of spray oil with 1 wt% of the upper leaf extract of the present invention or the compound of Formulas 1-6.
<1-5> 건강 음료 <1-5> health drink
꿀 0.26 중량%, 치옥토산아미드 0.0002 중량%, 니코틴산아미드 0.0004 중량%, 염산리보플라빈나트륨 0.0001 중량%, 염산피리독신 0.0001 중량%, 이노시톨 0.001 중량%, 오르트산 0.002 중량% 및 물 98.7362 중량%와 본 발명의 상엽 추출물 또는 화학식 1~6의 화합물 1 중량%를 배합하여 통상의 방법으로 건강 음료를 제조하였다.0.26% by weight of honey, 0.0002% by weight of thioctoamide, 0.0004% by weight of nicotinic acid, 0.0001% by weight of sodium riboflavinate, 0.0001% by weight of pyridoxine hydrochloride, 0.001% by weight of inositol, 0.002% by weight of orthoic acid and 98.7362% by weight of water 1% by weight of the extract of the upper leaves or the compound of Formulas 1 to 6 were prepared in a conventional manner for the health beverage.
<1-6> 건강보조식품<1-6> Health Supplement
스피루리나 55 중량%, 구아검효소 분해물 10 중량%, 비타민 B₁염산염 0.01중량%, 비타민 B6 염산염 0.01 중량%, DL-메티오닌 0.23 중량%, 스테아린산 마그네슘 0.7 중량%, 유당 22.2 중량% 및 옥수수전분 1.85 중량%와 본 발명의 상엽 추출물 또는 화학식 1~6의 화합물 10 중량%를 배합하여 통상의 방법으로 정제형 건강보조식품을 제조하였다.55% by weight of spirulina, 10% by weight of guar gum enzyme digestion, 0.01% by weight of vitamin B ₁ hydrochloride, 0.01% by weight of vitamin B 6 hydrochloride, 0.23% by weight of DL-methionine, 0.7% by weight of magnesium stearate, 22.2% by weight of lactose and 1.85% by weight of corn starch % And 10% by weight of the leaf extract of the present invention or the compound of Formulas 1 to 6 were prepared in a conventional dietary supplement.
도 1은 본 발명의 일실시예에 따른 상엽 추출물의 투여량에 따른 식이유도 비만쥐의 체중감소정도를 나타내는 그래프이다.. 1 is a graph showing the weight loss of dietary-induced obese mice according to the dosage of the upper leaf extract according to an embodiment of the present invention.
도 2는 본 발명의 일실시예에 따른 상엽 추출물의 투여량에 따른 식이유도 비만쥐의 섭식량의 변화를 나타내는 그래프이다. Figure 2 is a graph showing the change in feeding amount of dietary-induced obese rats according to the dosage of the extract of the upper lobe according to an embodiment of the present invention.
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