KR20190059069A - A composition for arthritis comprising (2E)-3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one) - Google Patents
A composition for arthritis comprising (2E)-3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one) Download PDFInfo
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- KR20190059069A KR20190059069A KR1020170156640A KR20170156640A KR20190059069A KR 20190059069 A KR20190059069 A KR 20190059069A KR 1020170156640 A KR1020170156640 A KR 1020170156640A KR 20170156640 A KR20170156640 A KR 20170156640A KR 20190059069 A KR20190059069 A KR 20190059069A
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- Prior art keywords
- arthritis
- acid
- present
- compound
- methoxyphenyl
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Abstract
Description
본 발명은 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 관절염의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a method of treating arthritis comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en-1-one or a pharmaceutically acceptable salt thereof Prevention or treatment of cancer.
관절염(arthritis)은 여러 가지 원인에 의해 관절에 염증이 생긴 것으로, 이로 인해 나타나는 대표적인 증상은 관절의 통증이다. 그러나 관절에 통증이 있다고 해서 모두 관절염이라고 할 수는 없으며, 부종과 발열이 동반되어야 관절염이라고 할 수 있다. 관절염은 적어도 100가지 이상의 형태로 분류될 수 있으나 가장 빈번히 발병하는 것은 퇴행성 관절염(osteoarthritis, OA)과 류마티스 관절염(rheumatoid arthritis, RA)이다.Arthritis (arthritis) is caused by various causes of inflammation in the joints, which is a typical symptom of joint pain. However, joint pain can not be attributed to arthritis, and it should be accompanied by edema and fever. Arthritis can be categorized into at least 100 forms, but the most frequent manifestations are osteoarthritis (OA) and rheumatoid arthritis (RA).
류마티스 관절염은 전신성 염증질환으로 인구의 1%의 유병률을 가지는 가장 흔한 관절염의 하나로 자가면역 기전에 의해 유발되는 염증 반응으로, 심하고 급격한 관절 파괴와 이에 상응하는 기능 장애를 가져오는 대표적인 난치성 질환이다. 관절염 중에서도 가장 심각한 이환과 기능 장애를 일으키며 심각한 류마티스 관절염의 치명율은 장기적으로 볼 때 악성 종양이나 심혈관계 질환의 치명율과 비슷한 것으로 알려져 있다. 활막에 비세균성 염증 반응이 만성적으로 나타나며, 이로 인해 활막이 증식되고 활액의 양이 증가하여 관절의 부종과 동통을 초래하는 것을 특징으로 한다. 류마티스 관절염은 관절뿐만 아니라 몸의 여러 기관에 영향을 미치므로 류마티스성 질환으로 불리기도 하며 주요 특징으로는 면역반응의 활성화인데 이러한 반응을 일으키는 정확한 요인에 대해서는 아직 정확히 알려지지 않았으나 자가면역 반응이 이 질환의 만성화와 진행에 중요한 역할을 하는 것으로 알려져 있다. 즉, 류마티스 관절염은 염증성 매개체들과 사이토카인의 국소적인 방출과 함께 T 세포가 중요한 역할을 하여 결과적으로 관절을 파괴하는 지속적인 자가면역 반응으로, 나타나는 주요 증상은 피로, 무력감, 동통 등이며 관절염이 진행되면서 발열 및 체력쇠약을 동반한다.Rheumatoid arthritis is a systemic inflammatory disease. It is one of the most common arthritis with a prevalence of 1% of the population. It is an inflammatory reaction caused by autoimmune mechanism. It is a typical refractory disease that causes severe and sudden joint destruction and corresponding dysfunction. It is known that the fatal rate of severe rheumatoid arthritis, which causes the most severe morbidity and dysfunctions among arthritis, is similar to that of malignant tumors or cardiovascular diseases in the long term. The non-bacillary inflammatory reaction appears chronically in the synovial membrane, which is characterized by proliferation of synovial membrane and increased amount of synovial fluid resulting in edema and pain of the joint. Rheumatoid arthritis affects not only the joints but also the organs of the body, so it is sometimes referred to as rheumatic disease. The main features of the disease are activation of the immune response. The precise factors causing this reaction are not yet known. However, It is known to play an important role in chronicity and progression. In other words, rheumatoid arthritis is a persistent autoimmune reaction that causes T cells to play an important role in inflammatory mediators and cytokines, resulting in destruction of joints. The main symptoms that appear are fatigue, helplessness, pain and arthritis And accompanied by fever and weakness.
이러한 류마티스 관절염은 완치가 어렵고 통증이 점차 심해지면 정상적인 생활에까지 영향을 미치지만, 현재까지 치료제로는 류마티스 관절염을 포함한 만성염증성 관절질환에 대한 근원적 치료제보다는, 아스피린 등 nonsteroidal anti-inflammatory drugs (NSAIDs) 및 항류마토이드 약제 등을 이용하여 통증과 염증을 억제하고 관절의 기능 소실을 최소화하는데 불과한 수준이다. 그러나 염증은 대부분의 질환에서 유발되는 특성으로 이를 유발하는 사이토카인은 다양한 종류가 존재하여 이들의 조절로 관절염만을 특이적으로 억제하는 데에는 많은 어려움이 존재하였다. 이와 관련하여 최근 연구를 통해 류마티즘 관절염의 활성 또는 심각도(Shi-Tong Wei. et al, Med Sci Monit 2015; 21:4030-4038) 또는 골관절염(O. stannous et.al, Osteoarthritis and cartilage 18 (2010) 1441-1447)과 관련하여 TNF-α, IL-6의 혈청 수준이 중요한 역할을 한다는 사실이 확인되었다. 따라서 TNF-α, IL-6와 같은 병인관련 사이토카인의 작용을 억제 할 수 있는 억제제나 항체의 개발이 첨단 생명공학기술을 이용하여 개발 중이거나 일부 이용되고 있으나 그 치료 효과가 극히 제한적이다.Although this rheumatoid arthritis is difficult to cure and the pain gradually increases, it affects normal life. However, to date, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been used as therapeutic agents rather than the root remedy for chronic inflammatory joint diseases including rheumatoid arthritis The use of anti-rheumatic drugs to control pain and inflammation and minimize the loss of joint function is only a level. However, inflammation is a characteristic of most diseases. There are various kinds of cytokines that induce inflammation, and there are many difficulties in specifically controlling osteoarthritis by controlling them. Recent studies have shown that the activity or severity of rheumatoid arthritis (Shi-Tong Wei. Et al, Med Sci Monit 2015; 21: 4030-4038) or osteoarthritis (O. stannous et al, Osteoarthritis and cartilage 18 (2010) 1441-1447), it was confirmed that serum levels of TNF-α and IL-6 play an important role. Therefore, the development of inhibitors or antibodies capable of inhibiting the action of pathogenesis-related cytokines such as TNF-α and IL-6 is being developed or partially utilized by advanced biotechnology, but its therapeutic effect is extremely limited.
관절염에 대한 근본적인 치료법이 없으므로 기초 치료법으로 물리, 운동요법을 행하고, 적당한 비스테로이드성 항염증 약물(NSAIDs)을 사용하여 염증을 완화시키며, 염증이 심하면 금염(gold salt) 요법 또는 페니실라민(penicillamine) 요법을 실시하고 있다. 상기의 방법이 효능이 없으면 스테로이드(steroid) 제제를 사용하며, 난치성인 경우 면역억제제를 사용하고, 변형 관절염으로 이행되면 수술요법을 실시한다. 관절염에 대한 소염진통 작용을 위해 사용되는 비스테로이드성 항염증 약물(NSAIDs)은 주로 사이클로옥시게나제(cyclooxygenase)를 억제하여 염증반응에 관여한 프로스타글란딘(prostaglandin)의 생성을 억제함으로써 항염증 작용을 나타내며, 그 중 인도메타신(indomethacin)과 페닐부타존(phenylbutazone)의 경우 다른 NSAIDs에 비해 강력한 항염증효과를 가지고 있다. 인도메타신은 염증을 유발하는 프로스타글란딘의 생성을 가장 강력하게 억제하는 약물 중에 하나로 경구 투여로 잘 흡수되나, 이러한 약물은 NSAIDs에서 나타나는 일반적인 위장관에 대한 부작용 이외에 현기증, 정신 착란, 드물게는 환각증을 동반한 정신병이 보고되는 등의 심한 독성을 갖고 있어 고용량에서 환자의 33%가 투약을 중지해야 하는 등 많은 부작용을 갖고 있다. 페닐부타존 역시 사용 초기 다른 NSAIDs에 비해 류마티스 관절염, 강직성 척추염, 급성 통풍성관절염 치료에 효과적으로 사용되어 왔으나, 과립구 감소증이나 재생불량성 빈혈 등을 일으키는 혈액학적 이상을 포함하는 심한 독성 때문에 현재 사용되지 않고 있다.Because there is no fundamental treatment for arthritis, physical and exercise therapy is performed as the basic treatment, and the appropriate nonsteroidal anti-inflammatory drugs (NSAIDs) are used to alleviate inflammation. If inflammation is severe, treatment with gold salt or penicillamine ). If the above method is not effective, a steroid preparation is used. In the case of refractory, an immunosuppressive agent is used. Nonsteroidal antiinflammatory drugs (NSAIDs), which are used for anti-inflammatory actions against arthritis, have anti-inflammatory effects by inhibiting cyclooxygenase and inhibiting the production of prostaglandins involved in inflammatory reactions Among them, indomethacin and phenylbutazone have strong anti-inflammatory effects compared to other NSAIDs. Indomethacin is one of the most potent inhibitors of inflammation-inducing prostaglandin production, and is well absorbed by oral administration, but these drugs have been associated with dizziness, delirium, and, in rare cases, with hallucinations, as well as side effects on the common gastrointestinal tract And mental illness are reported, and 33% of patients at high dose have severe side effects such as discontinuation of medication. Phenylbutazone has also been used effectively in the treatment of rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis compared to other early NSAIDs, but is currently not used due to severe toxicity including hematologic abnormalities such as granulocytopenia or aplastic anemia.
이런 NSAIDs에 비해 스테로이드 제제는 환자에게 사용할 수 있는 가장 빠른 방법으로, 항염증 효과가 빠르고 극적으로 나타나며 환자에게 쾌감을 주는 약물로 알려져 있다. 그러나 널리 알려진 것처럼 이 약물은 세균 감염에 대한 저항력을 약하게 하고, 당뇨병의 악화, 쿠싱(Cushing) 증후군, 부신 부전증, 정신 기능장애 등을 일으키는 것으로 독성이 매우 심각할 뿐만 아니라 치료를 시작하면 중지하기가 어렵기 때문에 사용상 주의를 요하며, 가능하면 금해야 하는 것으로 알려져 있다. 이처럼 합성 항염증제는 여러 가지 부작용을 수반하는 경우가 많으며, 관절염에 특이적이면서도 부작용이 적은 치료제의 개발이 꾸준히 요구되고 있는 실정이다. Compared to these NSAIDs, steroids are the fastest method available to patients, and they are known to be a drug that shows rapid and dramatic anti-inflammatory effects and pleasure to the patient. However, as is widely known, this drug is less resistant to bacterial infections and causes worsening diabetes, Cushing's syndrome, adrenal insufficiency, mental dysfunction, and is very toxic, It is known that it is difficult to use, and it should be avoided if possible. As such, synthetic anti-inflammatory drugs are often accompanied by various side effects, and there is a constant demand for the development of therapeutic agents which are specific for arthritis and have few side effects.
본 발명의 하나의 목적은 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 관절염의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- 1 -one or a pharmaceutically acceptable salt thereof, And to provide a pharmaceutical composition for preventing or treating arthritis.
본 발명의 다른 목적은 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용가능한 염을 포함하는 관절염의 예방 또는 개선용 의약외품 조성물을 제공하는 것이다.Another object of the present invention is to provide a method of treating arthritis comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- And to provide a quasi-product composition for prevention or improvement.
본 발명의 또 다른 목적은 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용가능한 염을 포함하는 관절염의 예방 또는 개선용 건강기능 식품을 제공하는 것이다It is another object of the present invention to provide a method for treating arthritis comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- And to provide a health functional food for preventing or improving
본 발명의 또 다른 목적은 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용가능한 염을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 관절염의 예방 또는 치료방법에 관한 것이다.It is another object of the present invention to provide a compound which is (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- To a subject suffering from arthritis.
이하에서는, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
한편, 본원에서 개시되는 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본원에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술되는 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 할 수 없다.On the other hand, each description and embodiment disclosed herein can be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein are within the scope of the present invention. Further, the scope of the present invention can not be said to be limited by the following detailed description.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 출원에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다. In addition, those of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described in this application. Further, such equivalents are intended to be included in the present invention.
상기 과제를 해결하기 위한 본 발명의 하나의 양태는 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 관절염의 예방 또는 치료용 약학적 조성물을 제공한다. One aspect of the present invention for solving the above problems is a compound of the formula (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- There is provided a pharmaceutical composition for preventing or treating arthritis, which comprises an acceptable salt.
본 발명에 따른 조성물은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로서 포함한다.The composition according to the present invention contains a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1로 표시되는 화합물은 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온)으로 명명되며, 화학적 합성, 이를 포함하는 식물 등으로부터 분리 정제하거나, 시판 화합물을 구입하여 사용될 수 있으나, 이의 입수처는 특별히 이에 제한되지 않는다.The compound represented by Formula 1 is named as (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- Or a commercially available compound may be purchased and used. However, the present invention is not particularly limited to this.
상기 염의 종류는 특별히 제한되지는 않는다. 다만, 개체, 예컨대 포유류에게 안전하고 효과적인 형태인 것이 바람직하나, 특별히 이에 제한되는 것은 아니다. The kind of the salt is not particularly limited. However, it is preferable to be a safe and effective form for an individual such as a mammal, but the present invention is not particularly limited thereto.
상기 용어, "약학적으로 허용되는"은 의약학적 판단의 범위 내에서，과도한 독성，자극, 또는 알레르기 반응 등을 유발하지 않고 원하는 용도에 효과적으로 사용 가능한 물질을 의미한다. The term " pharmaceutically acceptable " means a substance that can be effectively used in a desired application without causing undue toxicity, irritation, or allergic reaction within the scope of medical judgment.
본 발명에서 용어, "약학적으로 허용되는 염" 이란 약학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함한다.The term " pharmaceutically acceptable salt " as used herein includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
예를 들어 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 주석산 및 황산 등으로 제조된 무기산염, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산, 만델산, 뮤크산, 질산, 파모산, 판토텐산, 숙신산, 타르타르산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 캄포르설폰산, 또는 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트리메틸아민, 트리에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민 염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.For example, inorganic ion salts made of calcium, potassium, sodium and magnesium, inorganic acid salts made of hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, , Malonic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, Organic acid salts prepared from organic acids such as acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, vanillyric acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, Sulfonic acid salts prepared with camphorsulfonic acid, or naphthalenesulfonic acid, amino acid salts prepared with glycine, arginine, lysine, etc., and amino acid salts prepared with trimethylamine, triethylamine, ammonia, pyridine, Picoline, and the like. However, the types of salts as defined in the present invention are not limited by these listed salts.
본 발명에서, 약학적 조성물은 연고, 겔, 크림, 패취 및 분무제로 이루어지는 군으로부터 선택되는 제형일 수 있다. 또한, 상기 약학적 조성물은 경구용 제제 또는 주사용 제제일 수 있다. 상기 경구용 제제는 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸, 현탁제, 내용액제, 유제 또는 시럽제이고, 상기 주사용 제제는 멸균 주사제 형태의 제형일 수 있다.In the present invention, the pharmaceutical composition may be a formulation selected from the group consisting of ointments, gels, creams, patches and sprays. In addition, the pharmaceutical composition may be an oral preparation or a injectable preparation. The oral preparation may be a powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, suspension, solution, emulsion or syrup, and the injectable preparation may be in the form of a sterile injectable preparation.
본 발명에서, 약학적 조성물은 약학적으로 허용되는 담체를 첨가하여 제제화할 수 있으며, 제제화에 관한 내용은 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA의 문헌을 참조할 수 있다. 상기 약학적으로 허용 가능한 담체는 의약 발명 부분에 속하는 통상의 기술자에게 의약 조성물 제조시 통상적으로 사용되는 것을 의미한다. 예를 들어, 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 또한, 약학적으로 허용되는 담체는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함한다. 예를 들어, 경구용 고형 제제는 정제, 환제, 산제, 과립제, 캡슐제 등은 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 포함할 수 있으며, 마그네슘 스테아레이트, 탈크 같은 윤활제 등을 포함할 수 있다. 경구용 액상 제제는 현탁제, 내용액제, 유제, 시럽제 등을 포함하며, 물, 리퀴드 파라핀 등의 희석제, 습윤제, 감미제, 방향제, 보존제 등을 포함할 수 있다. 비경구용 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제를 포함하며, 비수성 용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르류 등을 포함한다. 그러나, 상기 열거된 약학적으로 허용되는 담체 등으로 본 발명이 한정되는 것은 아니며, 이들은 단지 예시에 불과하다. 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다.In the present invention, the pharmaceutical composition may be formulated by adding a pharmaceutically acceptable carrier. For formulation, refer to Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA. The pharmaceutically acceptable carrier means those conventionally used in the manufacture of a pharmaceutical composition for a person skilled in the art to which the present invention belongs. For example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl Pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Pharmaceutically acceptable carriers also include diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like. For example, tablets, pills, powders, granules, capsules and the like may be prepared by dissolving at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin Etc., and may include lubricants such as magnesium stearate, talc, and the like. Oral liquid preparations include suspensions, solutions, emulsions, syrups, and the like, and may contain diluents such as water and liquid paraffin, wetting agents, sweetening agents, fragrances, preservatives and the like. Examples of the non-aqueous solution include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions and freeze-dried preparations, and non-aqueous solvents and suspensions include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, And the like. However, the present invention is not limited to the above-mentioned pharmaceutically acceptable carriers and the like, and these are merely illustrative. The carrier may comprise a non-naturally occuring carrier.
본 발명에서 약학적 조성물의 구체적인 투여량은 제제화 방법, 환자의 상태 및 체중, 환자의 성별, 연령, 질병의 정도, 약물형태, 투여경로 및 기간, 배설 속도, 반응 감응성 등과 같은 요인들에 따라 당업자에 의해 다양하게 선택될 수 있으며, 투여량 및 횟수는 어떠한 면에서든 본 발명의 범위를 제한하는 것은 아니다.The specific dosage of the pharmaceutical composition in the present invention may vary according to factors such as the formulation method, the patient's condition and body weight, the patient's sex, age, degree of disease, drug form, administration route and period, excretion rate, And the dosage and the number of times do not limit the scope of the present invention in any way.
본 발명에서 약학적 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로를 통해 투여될 수 있다. 투여의 모든 방식은 예상될 수 있으며, 예를 들어 경구, 정맥, 근육 또는 피하 주사에 의해 투여될 수 있다.In the present invention, the pharmaceutical composition can be administered to mammals such as rats, mice, livestock, humans, and the like through various routes. All modes of administration may be expected and may be administered, for example, by oral, intravenous, intramuscular or subcutaneous injection.
본 발명에서 용어, "관절염"은 관절에 영향을 주는 질환을 말한다. 상기 관절염은 통증, 부종, 및/또는 뻣뻣한 증상 등을 수반할 수 있다. In the present invention, the term " arthritis " refers to a disease that affects joints. The arthritis may involve pain, edema, and / or stiff symptoms.
본 발명에서, 관절염이란 모든 종류의 관절염을 포함하고, 그 중 급성 류마티스성 관절염, 만성 류마티스성 관절염, 퇴행성 관절염, 타박성 관절염, 통풍성 관절염, 위축성 관절염, 만성 염증성 관절염, 변형성 관절염, 감염성 관절염, 폐경기 관절염, 단절성 관절염, 비대증 관절염, 또는 화농성 관절염 등일 수 있으며, 이에 제한되지 않는다.In the present invention, arthritis refers to all kinds of arthritis, and includes all types of arthritis, including acute rheumatoid arthritis, chronic rheumatoid arthritis, degenerative arthritis, obturating arthritis, gouty arthritis, atrophic arthritis, chronic inflammatory arthritis, Arthritis, cutaneous arthritis, hypertrophic arthritis, or pyogenic arthritis, and the like.
보다 구체적으로, 본 발명에서 상기 관절염은 류마티스성 관절염, 퇴행성 관절염, 타박성 관절염, 또는 통풍성 관절염일 수 있으나, 특별히 이에 제한되지는 않는다. More specifically, in the present invention, the arthritis may be rheumatoid arthritis, degenerative arthritis, obliteration arthritis, or gouty arthritis, but is not particularly limited thereto.
한편, (2E)-3-(4-히드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1온 또는 이의 염을 포함하는 본 발명에 따른 조성물은 관절염에서 부종 및/또는 통증을 완화시킬 뿐만 아니라, 관절염의 주요 사이토카인, 즉 TNF-알파, IL-6, 및/또는 PGE2의 발현을 억제시키고, 단백질 분해효소 (예, MMP-1)의 발현을 감소시킬 수 있다. 따라서, 본 발명의 조성물은 관절염 유발 물질의 분비 차단을 통한 근본적인 관절염 치료를 달성할 수 있다. 그러나, 특별히 이에 제한되는 않는다. On the other hand, a composition according to the present invention comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- Or pain, as well as inhibit the expression of major cytokines of arthritis, namely TNF-alpha, IL-6, and / or PGE2 and reduce the expression of proteolytic enzymes (e.g., MMP-1) . Thus, the composition of the present invention can achieve a fundamental arthritis treatment through the secretion of arthritis-inducing substances. However, it is not particularly limited thereto.
본 발명의 다른 하나의 양태는 (2E)-3-(4-히드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1온 화합물 또는 이의 허용가능한 염을 포함하는 관절염의 예방 또는 개선용 의약외품 조성물을 제공한다.Another aspect of the present invention is a method of treating arthritis comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2- Prevention or improvement of the composition.
본 발명에서, 용어 "의약외품"은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미하는 것으로, 예를 들어 대한민국 약사법에 따르면 의약외품이란 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람ㆍ동물의 질병 치료나 예방에 쓰이는 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않는 제품 등이 포함된다.In the present invention, the term " quasi-drug " refers to products which are used for diagnosis, treatment, improvement, alleviation, treatment or prevention of diseases of humans or animals, Quasi-drugs are products that are used for the purpose of treating or preventing diseases of humans or animals, products that are mild or have no direct action on the human body.
본 발명에서, 의약외품 조성물은 바디 클렌저, 폼, 비누, 마스크, 연고제, 크림, 로션, 에센스 및 스프레이로 이루어진 군에서 선택되는 형태로 제조할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the quasi-drug composition can be manufactured in a form selected from the group consisting of body cleanser, foam, soap, mask, ointment, cream, lotion, essence and spray, but is not limited thereto.
본원의 (2E)-3-(4-히드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1온 화합물 또는 이의 염을 의약외품 첨가물로 사용할 경우, 본원의 (2E)-3-(4-히드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1온 화합물 또는 이의 염을 그대로 첨가하거나 다른 의약외품 또는 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. When the compound (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en-1-one of the present invention or a salt thereof is used as a quasi-drug additive, 3-methoxyphenyl) -1-phenylprop-2-en-1-one or its salt can be used as it is or can be used in combination with other quasi-drugs or quasi-drug components, It can be used appropriately.
본 발명의 또 다른 하나의 양태는 (2E)-3-(4-히드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1온 화합물 또는 이의허용 가능한 염을 포함하는 관절염의 예방 또는 개선용 건강기능 식품을 제공한다.Another aspect of the present invention is a method of treating arthritis comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop- Or a pharmaceutically acceptable salt thereof.
상기 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용 가능한 염 및 관절염에 대해서는 앞서 설명한 바와 같다.The compound (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en-1-one) or its acceptable salts and arthritis is as described above.
본 발명에서 용어 건강기능식품은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 건강기능식품은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 관절염을 예방 또는 개선시키기 위한 보조제로 섭취가 가능하다.The term health functional food in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids, and circles by using raw materials and components having useful functions in the human body. The term "functional" as used herein means that the structure and function of the human body have a beneficial effect on health uses such as controlling nutrients or physiological actions. The health functional food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients that are conventionally added in the art. In addition, the formulations of the above health functional foods may also be manufactured without limitations as long as they are acceptable as health functional foods. The health functional food of the present invention can be manufactured in various formulations, and unlike general pharmaceuticals, it has advantages in that it does not have side effects that may occur when a food is used as a raw material for a long period of time, and has excellent portability. Can be ingested as an adjuvant to prevent or improve arthritis.
본 발명의 건강기능식품은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.The health functional food of the present invention may contain various flavors or natural carbohydrates as an additional ingredient. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau Martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like.
상기 외에 본 발명의 건강기능식품은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 건강식품 100 중량부 당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이나 이에 제한되지 않는다.In addition to the above, the health functional food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and its salts, protective colloid thickener, pH adjuster, stabilizer, preservative, glycerin, A carbonating agent used in a carbonated beverage, and the like. These components may be used independently or in combination. Although the proportion of such additives is not critical, it is generally, but not exclusively, selected from the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health food of the present invention.
본 발명의 또 다른 하나의 양태는 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용가능한 염을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 관절염의 예방 또는 치료방법에 관한 것이다.Another embodiment of the present invention is the use of a compound of formula (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en- To a subject in need thereof. ≪ Desc /
본 발명의 관절염을 예방 또는 치료하는 방법에 있어서, 양태는 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용가능한 염 및 투여에 대해서는 앞서 설명한 바와 같다.In a method of preventing or treating arthritis of the present invention, the embodiment is a method for preventing or treating arthritis comprising administering to a mammal an effective amount of a compound selected from the group consisting of (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop- The permissible salts and administration thereof are as described above.
본 발명의 양태는 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 허용가능한 염은 유효량으로 이를 필요로 하는 개체에게 투여될 수 있다.An embodiment of the present invention relates to a pharmaceutical composition comprising (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en-1-one) ≪ / RTI >
유효용량 수준은 관절염의 예방 또는 치료효과가 나타나는 정도로 당업자가 통상적인 상식에 기초하여 결정할 수 있다.Effective dose levels may be determined by those of ordinary skill in the art based on common sense to the extent that prophylactic or therapeutic effects of arthritis are exhibited.
본 발명의 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 하는 관절염의 예방 및 치료제로 유용하게 사용할 수 있다. (2E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylprop-2-en-1-one) compound of the invention or a pharmaceutically acceptable salt thereof. As a prophylactic and therapeutic agent.
도 1a 내지 1c는 캐리지난/카올린 유도 관절염 질환 동물모델에서의 JC3 화합물 투여에 따른 슬건절의 두께(도 1a), 슬관절의 굴절에 따른 울음소리 점수(도 1b), 양발 체중 분배 비율(도 1c) 효과를 나타낸 결과이다.
도 2는 캐리지난 유도 통각과민 반응 유도 동물모델의 통각 반응에 대한 JC3 화합물의 효과를 나타낸 결과이다.
도 3a 내지 3c는 ELISA 기법에 의해 캐리지난/카올린 유도 관절염 질환 동물모델에서 염증성 사이토카인(TNF-α, IL-6, PGE2)의 발현에 대한 JC3 화합물의 억제효과를 나타낸 결과이다.
도 4는 ELISA 기법에 의해 캐리지난/카올린 유도 관절염 질환 동물모델에서 단백질 분해효소 중 하나인 MMP-1의 발현에 대한 JC3 화합물의 억제효과를 나타낸 결과이다.
도 5a 및 5b는 IL-1β를 처리한 활막세포(FLS cell)에서 염증성 사이토카인(L-6, PGE2)의 발현에 대한 JC3 화합물의 억제효과를 나타낸 결과이다.
도 6은 IL-1β를 처리한 활막세포(FLS cell)에서 혈관신생인자(IL-8)의 발현에 대한 JC3 화합물의 억제효과를 나타낸 결과이다.
도 7은 IL-1β를 처리한 활막세포(FLS cell)에서 단백질 분해효소 중 하나인 MMP-1의 발현에 대한 JC3 화합물의 억제효과를 나타낸 결과이다.FIGS. 1A-1C are graphs showing the thickness of haggling (FIG. 1A), the score of crying (FIG. 1B) and the ratio of two-way weight distribution (FIG. 1C) according to refraction of the knee according to administration of JC3 compound in Carrie / Kaolin- .
FIG. 2 shows the effect of JC3 compound on the painful response of the caries-induced hyperalgesia-inducing animal model.
Figures 3A-3C show the inhibitory effect of JC3 compounds on the expression of inflammatory cytokines (TNF-a, IL-6, PGE2) in an animal model of Carrie / Kaolin induced arthritis disease by ELISA technique.
Figure 4 shows the inhibitory effect of the JC3 compound on the expression of MMP-1, one of the proteolytic enzymes, in an animal model of Carrie / Kaolin induced arthritis disease by ELISA.
FIGS. 5A and 5B show the inhibitory effects of JC3 compounds on the expression of inflammatory cytokines (L-6, PGE2) in IL-1β-treated synovial cells (FLS cells).
FIG. 6 shows the inhibitory effect of JC3 compound on the expression of angiogenic factor (IL-8) in IL-1β-treated synovial cells (FLS cells).
FIG. 7 shows the inhibitory effect of JC3 compound on the expression of MMP-1, one of the proteolytic enzymes, in synovial cells (FLS cells) treated with IL-1 ?.
이하, 하기 실시예에 의하여 본 발명을 보다 상세하게 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
실시예Example 1: (2E)-3-(4- 1: (2E) -3- (4- 하이드록시Hydroxy -3--3- 메톡시페닐Methoxyphenyl )-1-)-One- 페닐프로프Phenylprop -2-엔-1-온) 의 합성2-en-1-one)
[반응식 1][Reaction Scheme 1]
상기 반응식 1에서 출발 물질로 사용되는 화학식 2의 화합물은 손쉽게 구입할 수 있는 화합물로서 이를 실험실적으로 간단하게 tert-뷰틸다이메틸실릴 트리플루오로메탕설폰네이트 [tert-butyldimethylsilyl trifluoromethanesulfonate, TBSOTf]로 보호하고 (Cowan, D. O.; Mosher, H. S. J. Org . Chem. 1962, 27, 1-5; Ashby, E. C.; Oswald, J. J. Org . Chem. 1988, 53, 6068-6076; 참고) 화합물 3을 그리냐드 화합물과 반응시킴으로서 화학식 4의 라세믹 2차 알코올화합물을 높은 수율로 제조할 수 있다. 제조된 화학식 4의 화합물을 산화제를 이용하여 간단하게 산화시킨후 테트라뷰틸암모니움플로라이드 (TBAF) 를 테트라하이드로퓨란 용매하에 탈 보호하여 고순도, 고수율로 목적화합물인 화학식 JC3 화합물로 표시되는 (2E)-3-(4-하이드록시-3-메톡시페닐)-1-페닐프로프-2-엔-1-온) 화합물을 제조한다 [Jae -Chul Jung, Seikwan Oh, Soyong Jang, Inn-Oc Han, Archives of Pharmacal Research, 29(6) 469-475, 2006].In the
실시예Example 2: JC3 화합물의 행동학적 효능 분석 2: Behavioral efficacy analysis of JC3 compounds
캐리지난/카올린 유도 관절염 동물모델에서 행동학적 특성(슬관절 부종, 울음소리, 양발 체중 분배 비율)에 대한 실시예 1에서 수득한 화합물인 JC3의 영향을 확인하였다.The effect of JC3, a compound obtained in Example 1, on behavioral characteristics (knee edema, crying, dual body weight distribution ratio) in the Carrie / Kaolin induced arthritis animal model was confirmed.
상기 실시예 1로부터 합성된 JC3 화합물이 관절염을 유발한 동물모델에서 나타나는 행동학적 특징에 대한 효능을 검색하였다. 행동을 분석하기 위하여 관절염 유도 후 6일간 매일 측정하였다. The efficacy of the JC3 compound synthesized from Example 1 on the behavioral characteristics in the arthritis-induced animal model was examined. The behavior was analyzed daily for 6 days after induction of arthritis.
JC3 화합물의 효능을 위한 실험군으로는 NOR (정상군), ART(관절염 유도군), ART+JC3_5 (관절염 유도+JC3 5 mg/kg 처치군), ART+JC3_10 (관절염 유도+JC3 10 mg/kg 처치군)으로 구분하였다. JC3 화합물의 투여는 관절염 유도 후 24시간 뒤부터 매일 행동실험 진행 한 시간 전에 복강내 주사로 처치하였다.JC3 10 (arthritis induction +
슬관절의 부종 같은 경우 슬관절의 두께를 전자두께 측정기계로 측정하는 방법으로 JC3 화합물의 효과가 5일째부터 나타나기 시작하였다(도 1a). In the case of knee edema, the effect of the JC3 compound started to appear from the fifth day by measuring the thickness of the knee with an electronic thickness measuring machine (FIG. 1A).
슬관절의 굴절에 의한 울음소리 측정 방법은 발목을 구부리고 펴는 과정에서 발생하는 울음소리는 측정하여 기록하는 방법이다. 실험방법을 간략하게 설명하면 쥐에게 스트레스를 최소화하면서 홀더에 넣은 후 왼쪽 발을 구부리고 펴는 것을 1회로 하여 총 10회 반복하여 반복시마다 쥐에게서 울음소리가 나타나면 1점을 주어 최대 10점으로 기록하는 방법으로 진행하였고 JC3 화합물의 효과가 5일째부터 나타나기 시작하였다(도 1b). The measurement method of crying due to the refraction of the knee is to measure and record the crying that occurs during the bending and stretching of the ankle. The experimental method is briefly described. The mouse is placed in a holder with minimal stress, and the left foot is bent and stretched one time. Repeat a total of 10 times, and if the mouse cries at every repetition, And the effect of the JC3 compound started to appear from the fifth day (Fig. 1B).
양발 체중 분배 비율은 뒷다리에 실리는 무게의 차이를 무력화도 측정기(incapacitajnce Meter)로 측정하여 무게의 백분율의 비율을 측정하는 방식으로, 실험 방법을 간략하게 설명하면 두 발을 센서에 올려 놓은 후 측정을 시작하며 5초 동안의 평균을 측정하게 되며, 이것을 3회 반복한 평균을 가지고 차이를 비교하는 방식으로 체중 분배 비율을 구하는 공식은 다음과 같으며 WDR = 100 × (동측 사지에서의 체중/양쪽 사지에서의 체중), JC3 화합물의 효과가 5일째부터 나타나기 시작하였다(도 1c). The two-way weight distribution ratio is the ratio of the weight percentage measured by incapacitajnce meter to the difference in weight placed on the hind legs. Briefly, the experimental method is described as follows. And the average for 5 seconds. The formula for calculating the weight distribution ratio by comparing the difference with the average of 3 repetitions is as follows. WDR = 100 × (body weight in the eastern limb / Body weight in the limbs) and the effect of the JC3 compound began to appear from the fifth day (Fig. 1C).
실시예Example 3: JC3 화합물의 3: of the JC3 compound 항통각Anti-inflammatory 효능 분석 Efficacy analysis
캐리지난 유도 통각과민 반응 유도 동물모델에서 압력을 가하여 통각을 측정하는 방식으로 쥐에게 스트레스를 최소화하면서 가볍게 잡은 후 왼쪽 발을 압력측정 장치에 올려 두고 일정하게 증가하는 압력을 가하였을 시 발을 회피하거나 쥐에게서 울음소리가 나타나는 경우의 압력 수치를 기록하는 방법으로 진행하였고 JC3 화합물의 효과가 10 mg/kg의 복강 투여 농도부터 항통각 효능이 나타나기 시작하였다(도 2).Carrie Induction Hypersensitivity Reaction Induced hypersensitivity reaction In an animal model, pressure is applied to measure the pain intensity. The rat is lightly held while minimizing stress and then the left foot is placed on the pressure measuring device and the pressure is constantly increased. The procedure was carried out by recording the pressure at which a crying sound appeared in the rat, and the effect of the JC3 compound started to show anticancer efficacy from the intraperitoneal dose of 10 mg / kg (FIG. 2).
실시예Example 4: JC3 화합물의 염증성 사이토카인 발현 억제 효과 4: Inhibitory effect of JC3 compound on inflammatory cytokine expression
캐리지난 유도 통각과민 반응 유도 동물모델에서 관절염에서의 주요 사이토카인(TNF-α, IL-6, PGE2)의 발현을 확인하고자 ELISA 기법을 이용하였다. 구체적으로, 우선 실험동물의 혈액에서 혈청을 분리한 후, 표준액 및 검액은 1시간, 비오티닐화된 항체 시약은 2시간, 스트렙타비딘-HRP 용액은 30분간 반응시키고, TMB 기질 용액을 30분간 반응시켜 발색시킨 후 종말 용액으로 반응을 정지시키고 ELISA 리더기로 450 nm에서 흡광도를 측정하였다. 각각의 TNF-α, IL-6, PGE2의 발현은 JC3 화합물의 처치에 따라 10 mg/kg의 투여 농도부터 발현이 억제하는 것을 확인 할 수 있으며 이 결과로 관절염의 억제 효능이 있다는 것을 알 수 있었다(도 3a 내지 3c).ELISA was used to determine the expression of major cytokines (TNF-α, IL-6, PGE2) in arthritis in an inducible induction hypersensitive animal model. Specifically, the serum was first separated from the blood of the experimental animals, and then the standard solution and the test solution were allowed to react for 1 hour, the biotinylated antibody reagent was allowed to react for 2 hours, the streptavidin-HRP solution was allowed to react for 30 minutes, the TMB substrate solution was allowed to react for 30 minutes The reaction was terminated with a final solution and absorbance was measured at 450 nm with an ELISA reader. Expression of each TNF-α, IL-6, and PGE2 was inhibited by the administration of JC3 compound at a dose of 10 mg / kg, and as a result, the inhibitory effect of arthritis was confirmed (Figs. 3A to 3C).
실시예Example 5: JC3 화합물의 단백질 분해효소 억제 효과 5: Protease inhibitory effect of JC3 compound
캐리지난 유도 통각과민 반응 유도 동물모델에서 단백질 분해효소 중 하나인 MMP-1의 발현을 확인하고자 ELISA 기법을 이용하였으며, 간략하게 설명하면 우선 실험동물의 혈액에서 혈청을 분리한 후, 표준액 및 검액은 1시간, 비오티닐화된 항체 시약은 2시간, 스트렙타비딘-HRP 용액은 30분간 반응시키고, TMB 기질 용액을 30분간 반응시켜 발색시킨 후 종말 용액으로 반응을 정지시키고 ELISA 리더기로 450 nm에서 흡광도를 측정하였다. MMP-1의 발현은 JC3 화합물의 처치에 따라 10 mg/kg의 투여 농도부터 발현이 억제하는 것을 확인 할 수 있으며 이 결과로 관절염의 콜라겐 단백질 분해 억제 효능이 있다는 것을 알 수 있었다(도 4). To elucidate the expression of MMP-1, one of the proteolytic enzymes, in the induction hypersensitivity reaction model of Carrie induced hyperalgesia, ELISA technique was used. In brief, serum was isolated from the blood of experimental animals, 1 hour, 2 hours for biotinylated antibody reagent, 30 minutes for streptavidin-HRP solution, and reacted with TMB substrate solution for 30 minutes. After stopping the reaction with the final solution, the absorbance at 450 nm was measured with an ELISA reader Were measured. The expression of MMP-1 was found to be suppressed at a dose of 10 mg / kg according to the treatment of JC3 compound. As a result, it was found that arthritis has an inhibitory effect on collagen protein degradation (FIG. 4).
실시예Example 6: JC3 화합물의 6: of the JC3 compound 활막세포Synovial cell 내 염증성 사이토카인 발현 억제 효과 Inhibitory effect of inflammatory cytokine expression
IL-1β를 처리한 활막세포에서 염증성 사이토카인(IL-6, PGE2)의 발현을 확인하고자 ELISA 기법을 이용하였으며, 간략하게 설명하면 1 X 106 세포 수/ml의 활막세포에 JC3 화합물을 각각 1, 5, 및 10 μg/ml의 농도로 처리하고 한시간 후에 10 ng/ml의 IL-1β를 처리 후, 24시간 배양 후, 펠렛을 제거한 상층액을 사용하였으며, 표준액 및 검액은 1시간, 비오티닐화된 항체 시약은 2시간, 스트렙타비딘-HRP 용액은 30분간 반응시키고, TMB 기질 용액을 30분간 반응시켜 발색시킨 후 종말 용액으로 반응을 정지시키고 ELISA 리더기로 450 nm에서 흡광도를 측정하였다. 각각의 IL-6, PGE2의 발현은 JC3 화합물의 처치에 따라 IL-6는 5, 10 μg/ml의 투여 농도, PGE2는 10 μg/ml의 투여 농도부터 발현이 억제하는 것을 확인 할 수 있으며 이 결과로 관절염의 억제 효능이 있다는 것을 알 수 있었다(도 5).In order to confirm the expression of inflammatory cytokines (IL-6, PGE2) in synovial cells treated with IL-1β, ELISA was used. Briefly, JC3 compounds were added to synovial cells at 1 × 10 6 cells / 1, 5, and 10 μg / ml, treated with 10 ng / ml of IL-1β for one hour, cultured for 24 hours, and then the supernatant from which the pellet was removed was used. The reaction was stopped for 2 hours with the ottinylated antibody reagent and 30 minutes with the streptavidin-HRP solution, reacted with the TMB substrate solution for 30 minutes, stopped with the final solution, and absorbance was measured at 450 nm with an ELISA reader. Expression of IL-6 and PGE2 was inhibited by IL-6 at a dose of 5 and 10 μg / ml and PGE2 at a dose of 10 μg / ml according to the treatment of JC3 compound, As a result, it was found that there was an inhibitory effect of arthritis (Fig. 5).
실시예Example 7: JC3 화합물의 7: of the JC3 compound 활막세포Synovial cell 내 of mine 혈관신생인자Angiogenic factor 발현 억제 효과 Expression inhibitory effect
IL-1β를 처리한 활막세포에서 혈관신생인자인 IL-8의 발현을 확인하고자 ELISA 기법을 이용하였으며, 간략하게 설명하면 1 X 106 세포 수/ml의 활막세포에 JC3 화합물을 각각 1, 5, 및 10 μg/ml의 농도로 처리하고 한시간 후에 10 ng/ml의 IL-1β를 처리 후, 24시간 배양 후, 펠렛을 제거한 상층액을 사용하였으며, 표준액 및 검액은 1시간, 비오티닐화된 항체 시약은 2시간, 스트렙타비딘-HRP 용액은 30분간 반응시키고, TMB 기질 용액을 30분간 반응시켜 발색시킨 후 종말 용액으로 반응을 정지시키고 ELISA 리더기로 450 nm에서 흡광도를 측정하였다. IL-8의 발현은 JC3 화합물의 처치에 따라 10 μg/ml의 투여 농도부터 발현이 억제하는 것을 확인 할 수 있었다(도 6). In order to confirm the expression of IL-8, an angiogenic factor in synovial cells treated with IL-1β, ELISA was used. Briefly, JC3 compounds were added to synovial cells at 1 × 10 6 cells / , And 10 μg / ml, treated with 10 ng / ml of IL-1β for one hour, cultured for 24 hours, and then the supernatant from which the pellet was removed was used. The standard solution and the sample solution were incubated for 1 hour with biotinylated The antibody reaction was allowed to proceed for 2 hours and the streptavidin-HRP solution was allowed to react for 30 minutes. The TMB substrate solution was reacted for 30 minutes to develop color. The reaction was terminated with the terminal solution and the absorbance at 450 nm was measured with an ELISA reader. The expression of IL-8 was inhibited by the administration of JC3 compound at a dose of 10 μg / ml (FIG. 6).
실시예Example 8: JC3 화합물의 8: of the JC3 compound 활막세포Synovial cell 내 염증성 단백질 분해효소 억제 효과 Inflammatory protease inhibitory effect
IL-1β를 처리한 활막세포에서 염증성 단백질 분해효소인 MMP-1의 발현을 확인하고자 ELISA 기법을 이용하였으며, 간략하게 설명하면 1 X 106 세포 수/ml의 활막세포에 JC3 화합물을 각각 1, 5, 및 10 μg/ml의 농도로 처리하고 한시간 후에 10 ng/ml의 IL-1β를 처리 후, 24시간 배양 후, 펠렛을 제거한 상층액을 사용하였으며, 표준액 및 검액은 1시간, 비오티닐화된 항체 시약은 2시간, 스트렙타비딘-HRP 용액은 30분간 반응시키고, TMB 기질 용액을 30분간 반응시켜 발색시킨 후 종말 용액으로 반응을 정지시키고 ELISA 리더기로 450 nm에서 흡광도를 측정하였다. MMP-1의 발현은 JC3 화합물의 처치에 따라 10 μg/ml의 투여 농도부터 발현이 억제하는 것을 확인할 수 있었다(도 7). In order to confirm the expression of MMP-1, an inflammatory protease, in IL-1β-treated synoviocytes, ELISA was used. In summary, JC3 compounds were added to 1 × 10 6 cells / 5, and 10 μg / ml, treated with 10 ng / ml of IL-1β for one hour, cultured for 24 hours, and then the supernatant from which the pellet was removed was used. The reaction was stopped for 2 hours and the streptavidin-HRP solution was reacted for 30 minutes, and the TMB substrate solution was reacted for 30 minutes. The reaction was terminated with the terminal solution and absorbance was measured at 450 nm with an ELISA reader. The expression of MMP-1 was confirmed to be suppressed at a dose of 10 μg / ml according to the treatment with the JC3 compound (FIG. 7).
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
Claims (5)
[화학식 1]
A pharmaceutical composition for the prevention or treatment of arthritis, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
The pharmaceutical composition for preventing or treating arthritis according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient or diluent.
상기 관절염은 급성 류마티스성 관절염, 만성 류마티스성 관절염, 퇴행성 관절염, 타박성 관절염, 통풍성 관절염, 위축성 관절염, 만성 염증성 관절염, 변형성 관절염, 감염성 관절염, 폐경기 관절염, 단절성 관절염, 비대증 관절염 및 화농성 관절염 중 어느 하나 이상인 것을 특징으로 하는, 관절염의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
Wherein the arthritis is selected from the group consisting of acute rheumatoid arthritis, chronic rheumatoid arthritis, degenerative arthritis, obturator arthritis, gouty arthritis, atrophic arthritis, chronic inflammatory arthritis, deformed arthritis, infectious arthritis, menopausal arthritis, Of the total amount of the pharmaceutical composition for preventing or treating arthritis.
[화학식 1]
A quasi-drug composition for preventing or ameliorating arthritis comprising a compound represented by the following formula (1) or an acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
[화학식 1]
A health functional food for preventing or improving arthritis comprising a compound represented by the following formula (1) or an acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
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