KR20010086473A - Composition of essential oil having an inhibitary activity on the formation of leucotriens - Google Patents

Composition of essential oil having an inhibitary activity on the formation of leucotriens Download PDF

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KR20010086473A
KR20010086473A KR1020010049577A KR20010049577A KR20010086473A KR 20010086473 A KR20010086473 A KR 20010086473A KR 1020010049577 A KR1020010049577 A KR 1020010049577A KR 20010049577 A KR20010049577 A KR 20010049577A KR 20010086473 A KR20010086473 A KR 20010086473A
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formula
leukotriene
inhibitor
essential oil
alpha
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KR100372562B1 (en
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이형규
정근영
오세량
안경섭
이임선
박시형
김정희
장현욱
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박호군
한국과학기술연구원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

PURPOSE: Provided is a novel use of essential oil obtained by vapor distillation of plants and showing the inhibitory action against the production of leukotriene as a mediator of inflammation. CONSTITUTION: An inhibitor of leukotriene production comprises at least a compound selected from the group consisting of (-)-menthol, (+)-limonene, alpha-terpinene, gamma-terpinene, terpineol, beta-myrcene, (±)-linaloo, geraniol, citral, beta-cyclocitral, eugenol, safrole, (+)-alpha-pinene, (-)-alpha-pinene, and (+)-cis-verbenol, as an effective components. Preferably, the inhibitor comprises eugenol or safrole as an active ingredient. The inhibitor can be used for a variety of inflammatory diseases including asthma, whooping cough, psoriasis, arthritis, inflammatory intestine diseases, cystic fibrosis, chronic bronchitis, rheumatoid arthritis, septic shock, myocardial ischemia, cardiac anaphylaxis, cerebral vasospasm, ischemia and allergic rhinitis.

Description

류코트리엔 생성 저해활성을 가지는 정유 성분{Composition of essential oil having an inhibitary activity on the formation of leucotriens}Composition of essential oil having an inhibitary activity on the formation of leucotriens

본 발명은 정유 (精油; essential oil)를 유효성분으로 함유하는 류코트리엔 생성 저해제용 약학적 조성물에 관한 것으로, 보다 상세하게는 주성분으로 (-)-멘톨 (menthol; 화학식 1), (+)-리모넨 (limonene; 화학식 2), α-테르피넨 (terpinene; 화학식 3), γ-테르피넨 (terpinene; 화학식 4), 테르피네올 (terpineol; 화학식 5), β-미르센 (myrcene; 화학식 6), (±)-리나룰 (linalool; 화학식 7), 게라니올 (geraniol; 화학식 8), 사이트랄 (citral; 화학식 9), β-사이클로사이트랄 (cyclocitral; 화학식 10), 유게놀 (eugenol; 화학식 11), 사프롤 (safrole; 화학식 12), (+)-α-피넨 (pinene; 화학식 13), (-)-α-피넨 (pinene; 화학식 14) 및 (+)-cis-베르베놀 (verbenol; 화학식 15) 중에서 선택되는 하나 이상의 화합물을 포함하는 조성물의 류코트리엔 생성 저해제로서의 새로운 용도에 관한 것이다.The present invention relates to a pharmaceutical composition for leukotriene production inhibitor containing essential oil as an active ingredient, and more specifically, (-)-menthol (Formula 1), (+)-limonene as a main component (limonene; Formula 2), α-terpinene (Formula 3), γ-terpinene (Formula 4), terpineol (Formula 5), β-myrsen (myrcene; Formula 6), (±) -linalool (Formula 7), geraniol (Formula 8), citral (Formula 9), β-cyclocitral (Formula 10), eugenol (Formula) 11), safrole (Formula 12), (+)-α-pinene (Formula 13), (-)-α-pinene (pinene; Formula 14) and (+)- cis -verbenol (verbenol) A novel use as a leukotriene production inhibitor of a composition comprising at least one compound selected from formula (15).

주로 식물을 수증기 증류하여 얻어지는 정유는 특유한 향기를 갖는 방향유 (芳香油)로서, 고대로부터 현대에 이르기까지 천연향료, 식품의 방향제, 미각제 등의 원료로 사용되어 왔다. 정유의 향기 성분은 대부분이 모노테르펜 (monoterpene) 화합물로서 방향제나 향신료로 이용될 뿐만 아니라, 근대에 와서는 치료적인 용도로도 다양하게 개발되어 상처나 화상의 치료 및 흥분, 진정, 혈압강하, 구충, 살충 등의 생리작용이 강한 것들이 있으며, 곤충 페로몬 (pheromone) 작용이 있는 것도 있다 (우 원식, 1996, 천연물화학연구법, 서울, 서울대학교출판부).Essential oils obtained mainly by steam distillation of plants are fragrance oils with distinctive scents and have been used as raw materials for natural fragrances, food fragrances and taste agents from ancient times to the present. The fragrance components of essential oils are mostly used as a fragrance or spice as a monoterpene compound, and have been developed in various ways for therapeutic use in modern times. Some of them have strong physiological effects such as insecticides and insecticides, and some have insect pheromone action (Woo Won-sik, 1996, Natural Products Chemistry Research, Seoul, Seoul National University Press).

한편, 류코트리엔은, 분자량 약 78 kDa의 Ca2+및 ATP 의존성 효소인 5-리폭시게나제에 의해, 세포막에서 떨어져 나온 아라키돈 산 (arachidonic acid)으로부터 여러 단계를 거쳐 대사되어, 다양한 생물활성을 나타내는 염증 매개인자 중의 한 부류의 물질로 생합성된다 (Samuelsson B.,Science,220, 568-575, 1983). 생합성된 류코트리엔은 술피도펩티도류코트리엔 (sulfidopeptidoleukotrienes), LTC4, LTD4, LTE4및 LTB4등의 염증 매개인자들로써 호산구, 비만세포, 호염구, 대식세포, 호중구, 단핵세포 등의 다양한 염증세포에서 분비되어 다양한 생물활성을 나타내는데, 예를 들면, 평활근 수축, 점막분비 증가, 미세혈관 투과성 촉진 등의 효과를 나타내고, 프로스타글란딘 (prostaglandin, PG)의 분비를 촉진하며, 백혈구에 대하여 호중구의 부착 (adhesion) 촉진, 화학주성 (chemotaxis), 응집 및 탈과립화 증가 등의 효과가 나타나고, 혈관 투과성 증가 및 보체(C3b) 발현을 증가시킨다.이러한 류코트리엔의 생물학적 효과의 결과는 천식, 낭포성 섬유화 (cystic fibrosis), 만성기관지염, 통풍, 류마치스성 관절염, 기관지염, 엘러지성 비염, 건선 (psoriasis) 등의 피부질환, 관절염, 염증성 장질환 등에 중요한 역할을 하며 패혈증 (endotoxemia), ARDS, 심근허혈증 (myocardial ischemia), 심장과민증 (cardiac anaphylaxis), 뇌혈관경련 (cerebral vasospasm), 허혈 (ischemia) 등을 포함한 다양한 심폐질환에 관여하는 것으로 보고 있다 (Hay DWP and Griswold D., 1993, in Cunningham F. (ed.) Handbook of Immunology, Vol. 10, Academic Press, London, 117-179; Feuerstein G., 1985, J. Autonomic Pharmacol. 5, 149-168; Hammarstrom S.et al., 1985, Progress Clin. Biol. Res. 59, 35-46; Drazen J. M. and Austen K. F., 1987, Am. Rev. Respir. Dis. 136, 985-998). 이 중에서, 천식은 류코트리엔이 중추적인 역할을 한다는 가장 믿을 만한 증거가 있는 질환이어서 대부분의 류코트리엔 연구의 초점이 이 분야에 맞추어지고 있다. 특히, 펩티도류코트리엔 (Peptidoleukotrienes)은 인체 기도에 대해서 매우 강력한 기관지 수축 작용 (in vitro, in vivo)을 나타나는데, 히스타민이나 콜린성 효능제 (cholinergic agonist)보다 1000배 이상의 효력 (potency)을 갖는다. 그들은 인체 기도에서 강력하게 점막분비를 촉진하고 (in vitro), 모세혈관 투과성을 증가시킨다. 이 결과는 천식환자의 체액에서의 류코트리엔 수준이 높게 나타나고, 함량의 상관관계가 질환의 심각성과 밀접하게 나타남으로서 알 수 있다.Meanwhile, leukotriene is metabolized by various steps from arachidonic acid separated from the cell membrane by 5-lipoxygenase, a Ca 2+ and ATP dependent enzyme having a molecular weight of about 78 kDa, and exhibits various biological activities. Biosynthesized from one class of mediators (Samuelsson B., Science , 220 , 568-575, 1983). Biosynthesized leukotrienes are inflammatory mediators such as sulfidodopeptidoleukotrienes, LTC 4 , LTD 4 , LTE 4 and LTB 4 and are used in various inflammatory cells such as eosinophils, mast cells, basophils, macrophages, neutrophils, and monocytes. Secreted to show various biological activities, for example, smooth muscle contraction, increased mucosal secretion, promoting microvascular permeability, promoting the secretion of prostaglandin (PG), adhesion of neutrophils to leukocytes (adhesion) It has effects such as palpation, chemotaxis, increased aggregation and degranulation, increased vascular permeability and complement (C3b) expression. The biological effects of leukotrienes are asthma, cystic fibrosis, Chronic bronchitis, gout, rheumatoid arthritis, bronchitis, allergic rhinitis, psoriasis and other skin diseases, arthritis, inflammatory bowel disease It plays an important role in back and is believed to be involved in various cardiopulmonary diseases including endotoxemia, ARDS, myocardial ischemia, cardiac anaphylaxis, cerebral vasospasm and ischemia. (Hay DWP and Griswold D., 1993, in Cunningham F. (ed.) Handbook of Immunology, Vol. 10, Academic Press, London, 117-179; Feuerstein G., 1985, J. Autonomic Pharmacol. 5, 149- 168; Hammarstrom S. et al. , 1985, Progress Clin. Biol. Res. 59, 35-46; Drazen JM and Austen KF, 1987, Am. Rev. Respir. Dis. 136, 985-998). Of these, asthma is the most reliable evidence that leukotriene plays a pivotal role, so the focus of most leukotrienes research is focused on this area. In particular, peptidoleukotrienes have a very strong bronchial contraction effect ( in vitro, in vivo ) on the human airway, which is 1000 times more potent than histamine or cholinergic agonist. They strongly promote mucosal secretion ( in vitro ) in the human airways and increase capillary permeability. This result is indicated by the high level of leukotriene in the body fluids of asthma patients, and the correlation of content is closely related to the severity of the disease.

상기와 같은 류코트리엔의 해로운 작용을 조절하는 약물을 개발하기 위해서 사용된 방법 중의 하나는 류코트리엔 생성 저해제를 사용하는 것인데, 이들 저해제는 펩티도류코트리엔과 LTB4의 분비를 억제하여 놀라운 치료적인 가능성을 갖는다. 현재까지 다양한 계열의 류코트리엔 생성 저해제가 보고되었으며, 동물모델에서 항염증활성을 나타낸 바 있다. 예를 들면, 히드록시우레아 (hydroxyurea), 히드록삼 산 (hydroxamic acid) 유도체들은 철-킬레이트 생성능(iron-chelating capacity)에 의해서 5-리폭시게나제 억제활성을 나타내는 것으로, 대표적인 화합물로 A64077 (zileuton)이 있다. 이 물질은 가장 앞선 류코트리엔 생성 저해제로서 최근에 임상 Ⅲ단계를 거쳐 상품화되었으며, 치료범위는 천식, 염증성 장질환, 관절염이다 (Bell R. L. et al., 1992, Int. J. Immunopharmac. 14, 505-510). BWA4C 도 작용시간이 상대적으로 긴 강력한 류코트리엔 생성 저해제인데, 임상시험을 진행하고 있다. 가장 최근의 화합물로는 ICI D2138 과 같은 메톡시알킬 티아졸계 (methoxyalkyl thiazoles) 화합물인데, 이는 새로운 계열의 강력하고 선택적인 5-리폭시게나제 활성 저해제로서, 작용기전은 산화환원 억제 (redox inhibition)나 철-킬레이트 (iron-chelation) 작용보다는 효소에 대한 경쟁적 저해를 포함한 직접적인 작용기전에 의한 것으로 보이며, 현재 천식약에 대한 임상 Ⅱ단계에 있다 (McMillan R. M. and Walker E.R.H., 1992, TIPS 13, 323-330). 그 외에 류코트리엔 생성을 저해하는 MK-886과 MK-0591이 있는데, 이들은 5-리폭시게나제 효소 자체가 아니라 5-리폭시게나제 활성화 단백질 (activating protein; FLAP)와의 상호작용으로 활성을 나타낸다. 이 중, MK-0591은 현재 천식약으로 임상 Ⅱ단계에 있다 (Gillard J. et al., 1989, Can. J. Physiol. Pharmacol. 67, 17-28; Brideau C. et al., 1992, Can. J. Physiol. Pharmacol. 70, 799-807).One of the methods used to develop such drugs that modulate the deleterious action of leukotriene is to use leukotriene production inhibitors, which have surprising therapeutic potential by inhibiting the secretion of peptidoleukotrienes and LTB 4 . To date, various classes of inhibitors of leukotriene production have been reported and have shown anti-inflammatory activity in animal models. For example, hydroxyurea and hydroxamic acid derivatives exhibit 5-lipoxygenase inhibitory activity by iron-chelating capacity. A64077 (zileuton) There is this. This substance is the most advanced inhibitor of leukotriene production and has recently been commercialized through Phase III clinical trials. The range of treatment is asthma, inflammatory bowel disease and arthritis (Bell RL et al., 1992, Int. J. Immunopharmac. ). BWA4C is also a potent inhibitor of leukotriene production, which is relatively long in duration, and is undergoing clinical trials. The most recent compounds are methoxyalkyl thiazoles, such as ICI D2138, which are a new class of potent and selective 5-lipoxygenase activity inhibitors, the mechanism of action being redox inhibition or It appears to be due to direct mechanisms of action, including competitive inhibition of enzymes rather than iron-chelation, and are currently in Phase II clinical trials for asthma drugs (McMillan RM and Walker ERH, 1992, TIPS 13, 323-330). . In addition, there are MK-886 and MK-0591 which inhibit leukotriene production, which are active by interaction with 5-lipoxygenase activating protein (FLAP), not 5-lipoxygenase enzyme itself. Of these, MK-0591 is currently in clinical stage II asthma medicine (Gillard J. et al., 1989, Can. J. Physiol. Pharmacol. 67, 17-28; Brideau C. et al., 1992, Can J. Physiol.Pharmacol. 70, 799-807).

이에 본 발명자들은 류코트리엔 생성 저해 활성을 갖는 물질의 개발하기 위하여 노력하여 오던 중, 다양한 식물들로부터 추출된 정유 및 이들 정유의 주성분인 화합물들이 류코트리엔 생성 저해 활성을 가진다는 사실을 알아내어 본 발명을 완성하였다.Accordingly, the present inventors have been working to develop a substance having leukotriene production inhibitory activity, and have completed the present invention by finding out that essential oils extracted from various plants and compounds which are the main components of these essential oils have leukotriene production inhibitory activity. It was.

본 발명의 목적은 정유 성분의 류코트리엔 생성 저해제로서의 새로운 용도를 제공하는 것이다.It is an object of the present invention to provide novel uses of essential oil components as inhibitors of leukotriene production.

상기 목적을 달성하기 위하여 본 발명에서는 하기 화학식 1 내지 화학식 15의 화합물 중 하나 이상의 화합물이 주성분인 정유를 함유하는 류코트리엔 생성 저해제용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for a leukotriene production inhibitor containing an essential oil of one or more compounds of the formulas (1) to (15).

이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명에서는 우선, 정유를 유효성분으로 함유하는 류코트리엔 생성 저해제용 약학적 조성물을 제공한다.First, the present invention provides a pharmaceutical composition for leukotriene production inhibitor containing essential oil as an active ingredient.

상기 정유는 주성분으로, 하기 화학식 1의 (-)-멘톨, 화학식 2의 (+)-리모넨), 화학식 3의 α-테르피넨, 화학식 4의 γ-테르피넨, 화학식 5의 테르피네올,화학식 6의 β-미르센, 화학식 7의 (±)-리나룰, 화학식 8의 게라니올, 화학식 9의 사이트랄, 화학식 10의 β-사이클로사이트랄, 화학식 11의 유게놀, 화학식 12의 사프롤, 화학식 13의 (+)-α-피넨, 화학식 14의 (-)-α-피넨 및 화학식 15의 (+)-cis-베르베놀 중에서 선택되는 하나 이상의 화합물을 포함한다.The essential oil is a main component, (-)-menthol of formula (1), (+)-limonene of formula (2), α-terpinene of formula (3), γ-terpinene of formula (4), terpineol of formula (5), Β-myrcene of 6, (±) -linalul of formula 7, geraniol of formula 8, citral of formula 9, β-cyclocytral of formula 10, eugenol of formula 11, saprolol of formula 12 , (+)-Α-pinene of Formula 13, (-)-α-pinene of Formula 14 and (+)- cis -verbenol of Formula 15.

또한 본 발명에서는 정유의 주성분인 상기 화학식 1 내지 화학식 15의 화합물 및 그들의 유도체들 중 하나 이상을 유효성분으로 함유하는 류코트리엔 생성 저해제용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for leukotriene production inhibitor containing at least one of the compounds of Formula 1 to Formula 15 and derivatives thereof as the active ingredient as an active ingredient.

상기 류코트리엔 생성 저해제는 류코트리엔 활성과 관련된 질환의 예방제, 치료제 및 치료보조제로 유용하게 사용될 수 있다. 구체적으로, 상기 질환에는 천식, 백일해, 건선, 관절염, 염증성 장질환, 낭포성 섬유화 (cystic fibrosis), 만성 기관지염, 통풍, 류마치스성 관절염, 패혈증 (septic shock; endotoxemia), 심근허혈증 (myocardial ischemia), 심장과민증 (cardiac anaphylaxis), 뇌혈관경련 (cerebral vasospasm), 허혈 (ischemia) 및 알레르기성 비염 등을 포함하는 다양한 염증질환이 포함된다.The leukotriene production inhibitor may be usefully used as a prophylactic, therapeutic and therapeutic aid for diseases related to leukotriene activity. Specifically, the disease includes asthma, pertussis, psoriasis, arthritis, inflammatory bowel disease, cystic fibrosis, chronic bronchitis, gout, rheumatoid arthritis, septic shock (endotoxemia), myocardial ischemia, Various inflammatory diseases include cardiac anaphylaxis, cerebral vasospasm, ischemia and allergic rhinitis.

본 발명의 류코트리엔 생성 저해제용 약학적 조성물은 약제학적으로 허용 가능한 담체 또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다.Pharmaceutical compositions for leukotriene production inhibitors of the present invention may be prepared in unit dose form or formulated in a multi-dose container by formulating with a pharmaceutically acceptable carrier or excipient.

이 때 제제 형태는 오일 또는 수성 매질 중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수 있으며, 분산제, 현탁제 또는 안정화제를 포함할 수 있다.The preparation form can then be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of extracts, powders, granules, tablets or capsules, and can include dispersants, suspensions or stabilizers.

본 발명에 따른 유효성분의 인체 투여량은 체내에서 활성성분의 흡수도, 불활성화율 및 배설속도, 환자의 연령, 성별 및 상태, 치료할 질병의 중증정도 등에 따라 적절히 선택되나, 일반적으로 성인에게 15∼1500 mg 정도를 투여하나 100∼800 mg 정도를 투여하는 것이 바람직하다. 따라서 본 발명의 단위투여형 제제는 전술한 유효량 범위를 고려하여 본 발명의 활성물질을 5∼500 mg 의 함량이 되도록 제조한다. 바람직하게는 10∼300 mg을 함유하도록 제형화하는 것이 좋다. 이렇게 제형화된 단위투여형 제제는 필요에 따라 약제의 투여를 감시하거나 관찰하는 전문가의 판단과 개인의 요구에 따라 전문화된 투약법을 사용하거나. 일정 시간 간격으로 투여할 수 있으며, 바람직하기로는 하루에 1회 내지 3회 투여할 수 있다.The human dose of the active ingredient according to the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the disease to be treated, but generally 15 to adult It is preferable to administer about 1500 mg, but about 100 to 800 mg. Therefore, the unit dosage form of the present invention is prepared to have an amount of 5 to 500 mg of the active substance of the present invention in consideration of the above-mentioned effective amount range. Preferably formulated to contain 10-300 mg. Such dosage unit dosage forms may be formulated using specialized dosing regimens as determined by the expert and by the needs of the individual to monitor or observe the administration of the medication as needed. It may be administered at regular time intervals, preferably from one to three times a day.

본 발명의 항천식 효능제용 약학적 조성물에 대하여 독성 실험을 행하였다. 본 발명의 약학적 조성물을 마우스 (군당 10마리)에 각각 투여한 후 30일 동안 관찰하여 사망률을 측정하였다. 이 때 본 발명의 약학적 조성물은 300 mg/kg, 100 mg/kg의 2단계로 투여하였고, 50% 치사량 (LD50)은 300 mg/kg 이상이었다.Toxicity experiments were conducted with respect to the pharmaceutical composition for an asthma agonist of the present invention. The mortality was measured by observing for 30 days after each administration of the pharmaceutical composition of the present invention to mice (10 per group). At this time, the pharmaceutical composition of the present invention was administered in two stages of 300 mg / kg, 100 mg / kg, and 50% lethal dose (LD 50 ) was 300 mg / kg or more.

이하 실시예에 의하여 본 발명을 상세히 설명한다. 단 실시예는 발명을 예시하는 것일 뿐 본 발명이 하기 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples. However, the examples are only to illustrate the invention and the present invention is not limited by the following examples.

<실시예 1> 류코트리엔 생성 저해활성 시험<Example 1> leukotriene production inhibitory activity test

본 발명의 정유 성분들의 류코트리엔 생성 저해활성 시험은 쥐 (male BALB/cJ mice)로부터 채취한 골수를 50 % 증강 배지 (enriched medium; 100 units/㎖ 페니실린, 100 ㎎/㎖ 스트렙토마이신, 10 ㎎/㎖ 겐타마이신, 2mM L-글루타민, 0.1 mM 비필수아미노산, 10 % 우태혈청을 함유하는 RPMI 1640)와 IL-3의 공급원으로 50 % WEHI-3 세포 조절 배지 (cell conditioned medium)를 사용하여 배양하여 약 4주 후 98 % 이상의 골수유래 비만세포를 얻었다. 얻어진 골수유래 비만세포를 1×106cells/㎖의 농도로 하여 100 ng/㎖ 골수세포증식인자 및 검체 2.5 ㎍/㎖의 혼합조건에서 37 ℃의 CO2배양기 내에서 30분 동안 배양한 후, 반응물을 원심분리 (4℃, 120×g, 5분)하여 상층액으로부터 유리된 LTC4의 양을, LTC4측정 키트 (LTC4assay kit; Amersham, Buckinghamshire, UK)를 사용하여 측정하였다.The leukotriene production inhibitory activity test of essential oil components of the present invention was carried out using 50% enriched medium (100 units / ml penicillin, 100 mg / ml streptomycin, 10 mg / ml) of bone marrow collected from male BALB / cJ mice. Gentamicin, RPMI 1640 containing 2 mM L-glutamine, 0.1 mM non-essential amino acid, 10% fetal calf serum) and 50% WEHI-3 cell conditioned medium as a source of IL-3 After 4 weeks, more than 98% bone marrow-derived mast cells were obtained. The obtained bone marrow-derived mast cells were incubated at a concentration of 1 × 10 6 cells / ml for 30 minutes in a CO 2 incubator at 37 ° C. under a mixed condition of 100 ng / ml bone marrow cell proliferation factor and 2.5 μg / ml of the sample. the amount of LTC 4 to the glass centrifuge reaction (4 ℃, 120 × g, 5 minutes) from the supernatant, LTC 4 assay kit was measured using the (LTC 4 assay kit Amersham, Buckinghamshire , UK).

상기의 방법으로 정유성분들을 각각 첨가하여 류코트리엔 생성 저해 활성을 측정하여, 그 결과를 표 1에 나타내었다.By adding the essential oil components in the above manner to measure the leukotriene production inhibitory activity, the results are shown in Table 1.

정유성분의 류코트리엔 생성 저해활성Inhibitory Activity of Leukotriene Formation by Essential Oils 저해활성 (IC50, μM)Inhibitory activity (IC 50 , μM) (-)-멘톨(-)-menthol 5.85.8 (+)-리모넨(+)-Limonene 11.811.8 α-테르피넨α-terpinene 17.617.6 γ-테르피넨γ-terpinene 18.418.4 테르피네올Terpineol 135.1135.1 β-미르센β-myrcene 76.576.5 (±)-리나룰(±) -linarul 284.4284.4 게라니올Geraniol 158.4158.4 사이트랄Sightral 215.2215.2 β-사이클로사이트랄β-cyclocytral 232.2232.2 유게놀Eugenol 0.40.4 사프롤Saffrol 10.510.5 (+)-α-피넨(+)-α-pinene 244.1244.1 (-)-α-피넨(-)-α-pinene 331.6331.6 (+)-시스-베르베놀(+)-Cis-verbenol 75.075.0

상기에서 살펴본 바와 같이, 본 발명의 정유 성분 즉, 화학식 1 내지 화학식 15의 화합물은 류코트리엔 생성 저해활성이 우수하여 생체내 또는 생체외에서 류코트리엔의 활성조절에 사용될 수 있는데, 구체적으로 류코트리엔의 활성과 관련된 질환 즉, 천식, 백일해, 건선, 관절염, 염증성 장질환, 낭포성 섬유화, 만성 기관지염, 통풍, 류마치스성 관절염, 패혈증, 심근허혈증, 심장과민증, 뇌혈관경련, 허혈, 알레르기성 비염 등을 포함하는 다양한 염증질환의 예방제, 치료제 및 치료보조제로 유용하게 사용될 수 있다.As described above, the essential oil component of the present invention, that is, the compound of Formula 1 to Formula 15, may be used for regulating the activity of leukotriene in vivo or ex vivo due to its excellent leukotriene production inhibitory activity, specifically, a disease related to the activity of leukotriene That is, various inflammations including asthma, whooping cough, psoriasis, arthritis, inflammatory bowel disease, cystic fibrosis, chronic bronchitis, gout, rheumatoid arthritis, sepsis, myocardial ischemia, heart hypersensitivity, cerebrovascular spasm, ischemia, allergic rhinitis, etc. It can be usefully used as a prophylactic, therapeutic and therapeutic aid for diseases.

Claims (1)

하기 화학식 1의 유게놀(eugenol) 또는 화학식 2의 사프롤(safrole)을 유효성분으로 함유하는 류코트리엔 생성 저해제.A leukotriene production inhibitor containing eugenol of formula 1 or safrole of formula 2 as an active ingredient. 화학식 1Formula 1 화학식 2Formula 2
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WO2006029142A3 (en) * 2004-09-02 2006-09-08 Univ Florida Methods and systems for treating asthma and other respiratory diseases
KR100878586B1 (en) * 2007-08-08 2009-01-15 바이오스펙트럼 주식회사 Compositions for improving skin conditions comprising citral as an active ingredient
WO2010140170A1 (en) * 2009-06-05 2010-12-09 Sunev Pharma Solution Limited Topical micro-emulsions for the treatment of rheumatic disorders
EP1748771B1 (en) * 2004-04-23 2014-04-30 Aisa Therapeutics Composition for treating or preventing cell degeneration using at least one molecule capable of maintaining adhesion molecule expression reversibility and vascular endothelium actin fibre polymerisation

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KR100873946B1 (en) 2007-06-11 2008-12-12 바이오스펙트럼 주식회사 Agents for improving wrinkles on skin comprising alpha-pinene as an active ingredient

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EP1748771B1 (en) * 2004-04-23 2014-04-30 Aisa Therapeutics Composition for treating or preventing cell degeneration using at least one molecule capable of maintaining adhesion molecule expression reversibility and vascular endothelium actin fibre polymerisation
WO2006029142A3 (en) * 2004-09-02 2006-09-08 Univ Florida Methods and systems for treating asthma and other respiratory diseases
KR100878586B1 (en) * 2007-08-08 2009-01-15 바이오스펙트럼 주식회사 Compositions for improving skin conditions comprising citral as an active ingredient
WO2010140170A1 (en) * 2009-06-05 2010-12-09 Sunev Pharma Solution Limited Topical micro-emulsions for the treatment of rheumatic disorders
US9345660B2 (en) 2009-06-05 2016-05-24 Sunev Pharma Solution Limited Micro-emulsions for the treatment of rheumatic disorders

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