KR102348322B1 - Novel enamide compound and composition for preventing or treating diabetes comprising the same - Google Patents
Novel enamide compound and composition for preventing or treating diabetes comprising the same Download PDFInfo
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- KR102348322B1 KR102348322B1 KR1020180140504A KR20180140504A KR102348322B1 KR 102348322 B1 KR102348322 B1 KR 102348322B1 KR 1020180140504 A KR1020180140504 A KR 1020180140504A KR 20180140504 A KR20180140504 A KR 20180140504A KR 102348322 B1 KR102348322 B1 KR 102348322B1
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- foxo
- compound
- acrylamido
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- A—HUMAN NECESSITIES
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- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- 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
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A23V2200/00—Function of food ingredients
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Abstract
본 발명은 신규 에나마이드 화합물 및 이를 포함하는 당뇨병의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a novel enamide compound and a composition for preventing or treating diabetes comprising the same.
Description
본 발명은 신규 에나마이드 화합물 및 이를 포함하는 당뇨병의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a novel enamide compound and a composition for preventing or treating diabetes comprising the same.
당뇨병(diabetes)은 인슐린의 분비 결함 또는 인슐린 작용의 결함에서 기인한 만성 고혈당증(hyperglycemia)의 특징을 나타내는 다중적 병인의 대사장애를 말하며, 혈중의 포도당이 비정상적으로 높은 상태가 장기간 지속될 경우 만성적인 대사장애와 이에 따른 만성적 혈관손상으로 다양한 합병증이 발생한다.Diabetes is a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia resulting from defective insulin secretion or insulin action. Various complications occur due to disability and chronic vascular damage.
당뇨병은 대표적인 성인성 대사질환으로 세계인구의 약 5%가 앓고 있으며, 그로 인한 인명적, 경제적 손실은 실로 막대하다. 당뇨병 환자의 대부분은 경구용 치료제를 복용하고 있으나, 현재까지 안전한 치료제가 개발되어 있지 않은 실정이다. 인슐린 저항성(insulin resistance)이 가장 중요한 기전적 원인으로 알려져 있지만, 정확한 기전은 아직 확실하지 않으며, 다만 유전적인 소인과 환경의 복합적인 원인이 작용하는 것으로 밝혀져 있다.Diabetes is a representative adult metabolic disease, affecting about 5% of the world's population, and the resulting human and economic loss is enormous. Most of the diabetic patients are taking oral therapeutics, but a safe therapeutic agent has not been developed so far. Although insulin resistance is known as the most important mechanistic cause, the exact mechanism is not yet clear, but it has been found that a complex cause of genetic predisposition and environment is acting.
기존 당뇨 치료제는 크게 인슐린 제제, 설폰우레아 계열약물, 티아졸리딘디온(TZD)계열 약물, 비구아니드계열 약물, α-Glucosidase 저해제, 미글리티나이드계, 인크레틴 유사체(Incretin mimetics), DPP-IV 저해제 등으로 구분할 수 있다. 현재 임상에서 사용되는 경구용 당뇨병 치료제의 경우 장기 복용 시 저혈당 유발, 설사, 복부 팽만감, 체중증가, 젖산혈증, 심장독성, 간독성과 같은 다양한 부작용을 일으킬 뿐만 아니라 결국 인슐린 분비 기능을 하는 췌장의 베타세포가 비가역적으로 손상 및 파괴되고 인슐린 저항성이 생기기 때문에 약효가 떨어져 인슐린을 주사해야 하는 악순환이 발생하는 문제가 있다. 특히, 인슐린 제제의 경우 주사에 대한 불편함과 거부감이 크며 저혈당 유발 가능성이 매우 큰 문제점을 지니고 있다.Existing diabetes drugs are mainly insulin preparations, sulfonurea drugs, thiazolidinedione (TZD) drugs, biguanide drugs, α-glucosidase inhibitors, miglitinides, incretin mimetics, DPP-IV It can be classified as an inhibitor. In the case of oral antidiabetic drugs currently used in clinical practice, long-term administration causes various side effects such as hypoglycemia, diarrhea, abdominal bloating, weight gain, lactic acidemia, cardiotoxicity, and hepatotoxicity, as well as beta cells of the pancreas that eventually secrete insulin. Since it is irreversibly damaged and destroyed and insulin resistance develops, there is a problem that the drug efficacy is reduced and a vicious cycle of insulin injection occurs. In particular, in the case of insulin preparations, there is a large problem of discomfort and rejection to injection, and the possibility of hypoglycemia is very high.
이에, 기존 당뇨병 치료제에 대한 문제점을 근본적으로 개선하기 위한 신규 타겟의 치료제 개발이 요구되고 있다.Accordingly, there is a demand for the development of a new target therapeutic agent to fundamentally improve the problems with the existing diabetes drug.
본 발명의 목적은 신규 에나마이드 골격의 화합물을 제공하는 것이다. It is an object of the present invention to provide a compound having a novel enamide skeleton.
본 발명의 다른 목적은 상기 에나마이드 골격의 화합물을 포함하는 당뇨병 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetes comprising the compound of the enamide skeleton.
본 발명의 또 다른 목적은 상기 에나마이드 골격의 화합물을 포함하는 당뇨병 개선을 위한 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for improving diabetes comprising the compound of the enamide skeleton.
상기와 같은 목적을 달성하기 위한 본 발명의 일 측면은 하기 화학식 1로 표시되는 에나마이드(enamide) 골격을 포함하는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.One aspect of the present invention for achieving the above object provides a compound comprising an enamide skeleton represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 식에서, R은 에나마이드 골격에 결합된 페닐기의 5개 탄소 중 어느 하나 이상의 위치에 결합되는 치환기로서, 수소, 탄소수 1 내지 20의 알킬기, 탄소수 6 내지 30의 아릴기, 탄소수 3 내지 20의 알릴기, 탄소수 6 내지 30의 아릴알킬기 또는 탄소수 1 내지 20의 아실기, 니트로기, 아미노기, 아미노알킬기, 아미노아릴기, 에폭시기, 아크릴기 및 카르복실기로 이루어진 군에서 선택된 1종 이상이다.In the above formula, R is a substituent bonded to any one or more positions of 5 carbons of the phenyl group bonded to the enamide skeleton, hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 30 carbon atoms, allyl having 3 to 20 carbon atoms It is at least one selected from the group consisting of a group, an arylalkyl group having 6 to 30 carbon atoms or an acyl group having 1 to 20 carbon atoms, a nitro group, an amino group, an aminoalkyl group, an aminoaryl group, an epoxy group, an acryl group, and a carboxyl group.
구체적으로, 상기 화학식 1의 화합물은 메틸-4-(3-(벤조[d][1,3]다이옥소-5-닐)아크릴아미도)벤조에이트, 메틸-2-(3-(벤조[d][1,3]다이옥소-5-닐)아크릴아미도)벤조에이트 또는 다이메틸-5-(3-(벤조[d][1,3]다이옥소-5-닐)아크릴아미도)이소프탈레이트일 수 있으나, 이에 한정되는 것은 아니다.Specifically, the compound of Formula 1 is methyl-4-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)benzoate, methyl-2-(3-(benzo[ d][1,3]dioxo-5-yl)acrylamido)benzoate or dimethyl-5-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido) It may be isophthalate, but is not limited thereto.
또한 구체적으로, 상기 상기 화학식 1로 표시되는 화합물은 당뇨병 예방 또는 치료용도인 것일 수 있다.In addition, specifically, the compound represented by Formula 1 may be used for preventing or treating diabetes.
본 발명의 다른 측면은 하기 화학식 2로 표시되는 에나마이드(enamide) 골격을 포함하는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.Another aspect of the present invention provides a compound comprising an enamide skeleton represented by the following Chemical Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 2][Formula 2]
상기 식에서, R은 에나마이드 골격에 결합된 페닐기의 5개 탄소 중 어느 하나 이상의 위치에 결합되는 치환기로서, 수소, 탄소수 1 내지 20의 알킬기, 탄소수 6 내지 30의 아릴기, 탄소수 3 내지 20의 알릴기, 탄소수 6 내지 30의 아릴알킬기 또는 탄소수 1 내지 20의 아실기, 니트로기, 아미노기, 아미노알킬기, 아미노아릴기, 에폭시기, 아크릴기 및 카르복실기로 이루어진 군에서 선택된 1종 이상이다.In the above formula, R is a substituent bonded to any one or more positions of 5 carbons of the phenyl group bonded to the enamide skeleton, hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 30 carbon atoms, allyl having 3 to 20 carbon atoms It is at least one selected from the group consisting of a group, an arylalkyl group having 6 to 30 carbon atoms or an acyl group having 1 to 20 carbon atoms, a nitro group, an amino group, an aminoalkyl group, an aminoaryl group, an epoxy group, an acryl group, and a carboxyl group.
구체적으로, 상기 화학식 2의 화합물은 다이메틸-5-(3-(3,4-다이메톡시페닐)아크릴아미도)이소프탈레이트, 메틸-4-(3-(3,4-다이메톡시페닐)아크릴아미도)벤조에이트 또는 메틸-2-(3-(3,4-다이메톡시페닐)아크릴아미도)벤조에이트일 수 있으나, 이에 한정되는 것은 아니다.Specifically, the compound of Formula 2 is dimethyl-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate, methyl-4-(3-(3,4-dimethoxyphenyl) ) acrylamido)benzoate or methyl-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate, but is not limited thereto.
구체적으로, 상기 화학식 2로 표시되는 화합물은 당뇨병 예방 또는 치료용도인 것일 수 있다.Specifically, the compound represented by Formula 2 may be used for preventing or treating diabetes.
본 발명의 신규 화합물은 에나마이드(enamide) 골격을 포함하는 것으로서, 에나마이드 화합물은 Aza-ene 반응, Michael 반응, Friedel-Craft 반응, Cycloaddition 반응, Arylation 반응과 같이 탄소-탄소 및 탄소-질소 결합 생성 반응에 사용되는 유용한 화합물이다. 특히, 에나마이드 화합물은 의약, 재료, 생명화학 등 다양한 분야에 유용한 합성 출발물질로서도 사용될 수 있으며, 아래의 구조를 포함할 수 있다.The novel compound of the present invention includes an enamide skeleton, and the enamide compound generates carbon-carbon and carbon-nitrogen bonds such as Aza-ene reaction, Michael reaction, Friedel-Craft reaction, Cycloaddition reaction, and Arylation reaction. It is a useful compound used in the reaction. In particular, the enamide compound may be used as a synthetic starting material useful in various fields such as medicine, material, biochemistry, and the like, and may include the following structure.
상기 R1 및 R2는 치환기를 의미하며, 치환기의 형태는 제한되지 않는다.R1 and R2 represent a substituent, and the type of the substituent is not limited.
본 발명 일 실시예에서는 본 발명의 화학식 1및 2로 표시되는 화합물들이 폭소-1(FoxO-1)의 활성을 억제함을 확인하였는 바, 당뇨병의 예방 및 치료, 개선에 새로운 타겟으로 활용될 수 있음을 확인하였다.In one embodiment of the present invention, it was confirmed that the compounds represented by Chemical Formulas 1 and 2 of the present invention inhibit the activity of FoxO-1, which can be utilized as a new target for the prevention, treatment and improvement of diabetes. confirmed that there is.
상기 '폭소-1(FoxO-1)'은 인슐린 반응성 장기인 간, 근육, 지방, 췌장 등에서 다양한 역할을 하는 것으로 알려져 있다. The 'FoxO-1' is known to play various roles in the liver, muscle, fat, pancreas, etc., which are insulin-responsive organs.
간에서는 포도당신생과정(gluconeogenesis)과 관련된 포스포에놀피루베이트 카르복시키나제(Phosphoenolpyruvate Carboxykinase, PEPCK), 글루코즈-6-포스파타제(Glucose-6-Phosphatase, G6Pase) 등의 효소의 발현이 증가하여 포도당신생작용을 유도하여, 골격근과 지방세포의 분화를 억제하고 췌장 베타세포의 분화를 감소시키는 작용이 나타나는 것으로 보고되어 있다. 포도당신생의 핵심전사인자(transcription factor)인 FoxO-1은 인슐린 반응조직에 작용하여 인슐린 저항성을 나타내며, FoxO-1을 저해하여 인슐린 저항성이 개선되는 것이 보고된 바 있다(Nature Communications volume 6, Article number: 7079 (2015), 「FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization」). 본 발명의 신규 화합물들은 FoxO-1의 활성을 억제하는 바, 새로운 당뇨병의 예방 및 치료, 당뇨병의 개선을 위한 용도로 활용될 수 있다.In the liver, the expression of enzymes such as Phosphoenolpyruvate Carboxykinase (PEPCK) and Glucose-6-Phosphatase (G6Pase) related to gluconeogenesis increases, resulting in gluconeogenesis. It has been reported that it inhibits the differentiation of skeletal muscle and adipocytes and reduces the differentiation of pancreatic beta cells. It has been reported that FoxO-1, a key transcription factor for gluconeogenesis, acts on insulin-responsive tissues and shows insulin resistance, and that insulin resistance is improved by inhibiting FoxO-1 (Nature Communications volume 6, Article number) : 7079 (2015), 「FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization」). Since the novel compounds of the present invention inhibit the activity of FoxO-1, they can be utilized for prevention and treatment of new diabetes, and for improvement of diabetes.
나아가, 본 발명 일 실시예에서는 화학식 1및 2로 표시되는 화합물들이 FoxO-3a 및 FoxO-4 에 대해서도 억제 효과를 나타냄을 확인하였는 바, 당뇨병을 일으키는 과도한 당 생산의 영향이 되는 FoxO 패밀리(family)에 대한 억제효과를 통해 당뇨병의 예방 및 치료, 개선효과를 나타낼 수 있음을 확인하였다.Furthermore, in one embodiment of the present invention, it was confirmed that the compounds represented by Formulas 1 and 2 also exhibit inhibitory effects on FoxO-3a and FoxO-4, FoxO family that is affected by excessive sugar production causing diabetes It was confirmed that through the inhibitory effect of
본 발명의 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 포함하는, 당뇨병 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 폭소-1(FoxO-1), 폭소-3a(FoxO-3a) 또는 폭소-4(FoxO-4)의 활성을 억제하는 것일 수 있다.Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).
또한, 본 발명의 다른 일 측면은 상기 화학식 2로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 포함하는, 당뇨병 예방 또는 치료용 약학적 조성물을 제공한다.In addition, another aspect of the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising the compound represented by Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 폭소-1(FoxO-1), 폭소-3a(FoxO-3a) 또는 폭소-4(FoxO-4)의 활성을 억제하는 것일 수 있다.Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).
본 발명에 따른 약학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 잘 알려진 방법을 사용하여 약학적 제형으로 제조될 수 있다. 제형의 제조에 있어서, 본 발명에 따른 약학적 조성물은 본 발명 화합물의 활성을 저해하지 않는 범위 내에서 추가적으로 약제학적으로 허용가능한 담체를 포함할 수 있다.The pharmaceutical composition according to the present invention may be prepared into a pharmaceutical formulation using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In the preparation of the formulation, the pharmaceutical composition according to the present invention may additionally include a pharmaceutically acceptable carrier within a range that does not inhibit the activity of the compound of the present invention.
상기 약제학적으로 허용가능한 담체는 통상적으로 사용되는 것들, 예컨대 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 등을 포함하나 이에 국한되지 않는다. 또한, 본 발명의 약학적 조성물은 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제, 기타 약제학적으로 허용 가능한 첨가제를 포함할 수 있다.The pharmaceutically acceptable carriers include those commonly used, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, the pharmaceutical composition of the present invention may include a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and other pharmaceutically acceptable additives.
본 발명에 따른 약학적 조성물의 투여는 약제학적으로 유효한 양을 투여할 수 있다. "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 예방 또는 치료하기에 충분한 양을 의미한다. 유효 용량 수준은 제제화 방법, 환자의 상태 및 체중, 환자의 성별, 연령, 질환의 정도, 약물형태, 투여경로 및 기간, 배설 속도, 반응 감응성 등과 같은 요인들에 따라 당업자에 의해 다양하게 선택될 수 있다. 유효량은 당업자에게 인식되어 있듯이 처리의 경로, 부형제의 사용 및 다른 약제와 함께 사용할 수 있는 가능성에 따라 변할 수 있다. 그러나, 바람직한 효과를 위해서, 경구 투여제의 경우 일반적으로 성인에게 1일에 체중 1 ㎏당 본 발명의 조성물을 1일 0.0001 내지 100 ㎎/㎏으로, 바람직하게는 0.001 내지 100 ㎎/㎏으로 투여할 수 있으나, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Administration of the pharmaceutical composition according to the present invention may be administered in a pharmaceutically effective amount. "Pharmaceutically effective amount" means an amount sufficient to prevent or treat a disease with a reasonable benefit/risk ratio applicable to medical treatment. The effective dose level may be variously selected by those skilled in the art according to factors such as formulation method, patient's condition and weight, patient's sex, age, disease severity, drug form, administration route and duration, excretion rate, reaction sensitivity, etc. have. An effective amount will vary depending on the route of treatment, the use of excipients, and the potential for use with other agents, as will be appreciated by those skilled in the art. However, for desirable effects, in the case of oral administration, the composition of the present invention is generally administered to adults at an amount of 0.0001 to 100 mg/kg, preferably 0.001 to 100 mg/kg of the composition of the present invention per kg of body weight per day to adults. However, the dosage does not limit the scope of the present invention in any way.
본 발명의 약학적 조성물은 마우스, 가축, 인간 등의 포유동물에 다양한 경로를 통해 투여될 수 있다. 구체적으로, 본 발명의 약학적 조성물은 경구 또는 비경구 투여(예를 들어, 도포 또는 정맥 내, 피하, 복강 내 주사)할 수 있으나 경구 투여가 바람직하다. 질염의 예방 및 치료를 위해서는 질 내로 투여할 수 있다. 경구 투여를 위한 고형제제에는 산제, 과립제, 정제, 캡슐제, 연질캡슐제, 환제 등이 포함될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제, 에어로졸 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제로는 각각 통상의 방법에 따라 멸균된 수용액, 액제, 비수성용제, 현탁제, 에멀젼, 점안제, 안연고제, 시럽, 좌제, 에어로졸 등의 외용제 및 멸균 주사제제의 형태로 제형화하여 사용될 수 있으며, 바람직하게는 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 안연고제, 점안제, 파스타제 또는 카타플 라스마제의 약제학적 조성물을 제조하여 사용할 수 있으나, 이에 한정되는 것은 아니다. 국소 투여를 위한 제제는 임상적 처방에 따라 무수형 또는 수성형일 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention may be administered to mammals such as mice, livestock, and humans through various routes. Specifically, the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, application or intravenous, subcutaneous, or intraperitoneal injection), but oral administration is preferred. For the prevention and treatment of vaginitis, it may be administered intravaginally. Solid preparations for oral administration may include powders, granules, tablets, capsules, soft capsules, pills, and the like. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, aerosols, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are included. can Formulations for parenteral administration include sterile aqueous solutions, solutions, non-aqueous solutions, suspensions, emulsions, eye drops, eye ointments, syrups, suppositories, aerosols, etc. can be used, preferably, a pharmaceutical composition of cream, gel, patch, spray, ointment, warning agent, lotion, liniment, eye ointment, eye drop, pasta, or cataplasma can be prepared and used. , but is not limited thereto. Formulations for topical administration may be anhydrous or aqueous, depending on the clinical prescription. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 또 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 대상체에 투여하는 단계를 포함하는, 당뇨병 예방 또는 치료방법을 제공한다.Another aspect of the present invention provides a method for preventing or treating diabetes, comprising administering to a subject the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 폭소-1(FoxO-1), 폭소-3a(FoxO-3a) 또는 폭소-4(FoxO-4)의 활성을 억제하는 것일 수 있다.Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).
또한, 본 발명의 또 다른 일 측면은 상기 화학식 2로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 대상체에 투여하는 단계를 포함하는, 당뇨병 예방 또는 치료방법을 제공한다.In addition, another aspect of the present invention provides a method for preventing or treating diabetes, comprising administering to a subject the compound represented by Formula 2, a stereoisomer or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 폭소-1(FoxO-1), 폭소-3a(FoxO-3a) 또는 폭소-4(FoxO-4)의 활성을 억제하는 것일 수 있다.Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).
본 발명에서 '화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염', 화학식 2로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염'등의 용어는 상기에서 설명한 바와 동일하다.In the present invention, terms such as 'a compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof', a compound represented by Formula 2, a stereoisomer or a pharmaceutically acceptable salt thereof, etc. same as bar
상기 대상체는 동물을 말하며, 전형적으로 본 발명의 화합물을 이용한 치료로 유익한 효과를 나타낼 수 있는 포유동물일 수 있다. 이러한 대상체의 바람직한 예로 인간과 같은 영장류가 포함될 수 있다. 또한 이와 같은 대상체들에는 당뇨 질환의 증상을 갖거나 이와 같은 증상을 가질 위험이 있는 대상체들이 모두 포함될 수 있다.The subject refers to an animal, and may typically be a mammal capable of exhibiting a beneficial effect by treatment with the compound of the present invention. Preferred examples of such subjects may include primates such as humans. Also, such subjects may include all subjects having symptoms of diabetic disease or a risk of having such symptoms.
본 발명의 또 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 포함하는, 당뇨병 개선을 위한 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for improving diabetes, comprising the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 폭소-1(FoxO-1), 폭소-3a(FoxO-3a) 또는 폭소-4(FoxO-4)의 활성을 억제하는 것일 수 있다.Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).
또한, 본 발명의 또 다른 일 측면은 상기 화학식 2로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염을 포함하는, 당뇨병 개선을 위한 식품 조성물을 제공한다.In addition, another aspect of the present invention provides a food composition for improving diabetes, comprising the compound represented by Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 폭소-1(FoxO-1), 폭소-3a(FoxO-3a) 또는 폭소-4(FoxO-4)의 활성을 억제하는 것일 수 있다.Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).
더욱 구체적으로, 상기 식품 조성물은 건강기능식품일 수 있다.More specifically, the food composition may be a health functional food.
본 발명에서, 건강기능식품이란, 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 말한다. 본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In the present invention, health functional food refers to food manufactured and processed using raw materials or ingredients useful for the human body in accordance with Health Functional Food Act No. 6727, and controls nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes, such as physiological action or the like. The health functional food of the present invention may contain normal food additives, and whether or not it is suitable as a food additive is evaluated on the item according to the general rules and general test methods of food additives approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the relevant standards and standards.
상기 건강기능 식품은 식품의 생체 조절 기능을 강조한 식품으로 물리적, 생화학적, 생물공학적인 방법을 이용하여 특정 목적에 작용 및 발현하도록 부가가치를 부여한 식품이다. 이러한 건강기능 식품의 성분은 생체 방어와 신체 리듬의 조절, 질환의 방지 및 회복에 관계하는 신체 조절 기능을 생체에 대하여 충분히 발휘하도록 설계하여 가공하게 되며, 식품으로 허용 가능한 식품 보조 첨가제, 감미료 또는 기능성 원료를 함유할 수 있다. The health functional food is a food that emphasizes the bioregulatory function of food, and is a food with added value to act and express for a specific purpose using a physical, biochemical, and bioengineering method. The ingredients of these health functional foods are designed and processed to sufficiently exert the body control functions related to the body defense, regulation of body rhythm, prevention and recovery of diseases, and are food supplementary additives, sweeteners or functionalities that are acceptable as food. It may contain raw materials.
본 발명의 상기 '화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염', '화학식 2로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용 가능한 염'을 포함하는 건강기능식품 또는 건강기능 음료에 포함하여 사용할 경우, 상기 화합물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용하고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 또한, 혼합량은 그의 사용 목적(예방, 건강 또는 개선, 치료적 처치)에 따라 적합하게 결정될 수 있다.Health function comprising the 'compound represented by the formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof', and a 'compound represented by the formula 2, a stereoisomer or a pharmaceutically acceptable salt thereof' of the present invention When used in food or health functional beverage, the compound may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. In addition, the mixing amount may be appropriately determined depending on the intended use thereof (prevention, health or improvement, therapeutic treatment).
본 발명이 적용될 수 있는 식품의 종류에는 특별한 제한은 없다. 본 발명의 화합물, 이의 입체이성질체를 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함하는 낙농제품, 각종 스프, 음료, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 포함될 수 있으며, 통상적인 의미에서의 식품을 모두 포함할 수 있다.There is no particular limitation on the kind of food to which the present invention can be applied. Examples of foods to which the compound of the present invention and its stereoisomer can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, and various soups. , beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc. may be included, and may include all foods in a conventional sense.
상기 외에 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 상기 식품은 공지의 제조방법에 따라 정제, 과립, 분말, 캅셀, 액상의 용액 및 환 등의 제형으로도 제조될 수 있다. 또한, 통상의 여러가지 향미제 또는 천연 탄수화물 등을 추가성분으로서 포함할 수 있다.In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol , a carbonation agent used in carbonated beverages, and the like. In addition, it may contain the pulp for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination. In addition, the food can be prepared in the form of tablets, granules, powders, capsules, liquid solutions and pills according to known manufacturing methods. In addition, various conventional flavoring agents or natural carbohydrates may be included as additional ingredients.
본 발명의 에나마이드 골격의 신규 화합물은 FoxO패밀리의 활성을 억제함으로써 인슐린 저항성을 감소시켜 당뇨병의 예방 및 치료에 대한 새로운 타겟으로서 활용될 수 있다. The novel compound of the enamide skeleton of the present invention can be utilized as a new target for the prevention and treatment of diabetes by reducing insulin resistance by inhibiting the activity of the FoxO family.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.It should be understood that the effects of the present invention are not limited to the above-described effects, and include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples only illustrate the present invention, and the present invention is not limited by the following examples.
제조예 1. 신규 에나마이드(enamide)골격의 화합물 합성Preparation Example 1. Synthesis of a novel enamide (enamide) skeleton compound
하기 화학식 3및 4의 화합물을 하기 화학식 5의 카스트로 시약 (Castro's reagent, BOP) 및 유기 용매의 존재 하에 하기 화학식 6의 화합물과 반응시켜 화학식 1 및 화학식 2의 구조를 가지는 신규 에나마이드 골격의 화합물을 합성하였다.The compounds of Formulas 3 and 4 below are reacted with a compound of Formula 6 in the presence of Castro's reagent (BOP) of Formula 5 and an organic solvent to obtain a compound of a novel enamide skeleton having structures of Formulas 1 and 2 synthesized.
상기 과정의 반응식은 아래와 같다.The reaction formula of the above process is as follows.
[반응식 1][Scheme 1]
[반응식 2][Scheme 2]
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
1-1. 메틸 (E)-4-(3-(벤조[d][1,3]다이옥소-5-닐)아크릴아미도)벤조에이트(methyl (E)-4-(3-(benzo[d][1,3]dioxol-5-yl)acrylamido)benzoate)1-1. methyl (E) -4- (3- (benzo [d] [1,3] dioxo-5-yl) acrylamido) benzoate (methyl (E) -4- (3- (benzo [d] [ 1,3]dioxol-5-yl)acrylamido)benzoate)
디클로로메탄 (30 mL)에 녹인 화학식 3의 화합물 5 mmol 및 메틸 4-아미노벤조에이트 5.5 mmol을 교반 후 용액에 벤조트리아졸릴 옥시트리스 (디메틸 아미노) 포스포늄 헥사플루오로 포스페이트 (BOP) 6 mmol 및 트리에틸아민 (TEA) 20 mmol을 가하고, 반응 혼합물을 실온에서 24 시간 동안 교반하였다. 이후 반응 혼합물을 10 % 시트르산 (2 × 20 mL), 물 (20 mL) 및 포화 NaHCO3 용액 (2 × 20 mL) 또는 NaOH (2 × 20 mL) 및 염수 (20 mL)로 세척하였다. 유기층을 무수 황산나트륨상에서 건조시키고, 여과한 후 감압 하에 농축시켰다. After stirring 5 mmol of the compound of formula 3 and 5.5 mmol of methyl 4-aminobenzoate in dichloromethane (30 mL), 6 mmol of benzotriazolyl oxytris (dimethyl amino) phosphonium hexafluorophosphate (BOP) and tri 20 mmol of ethylamine (TEA) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then washed with 10% citric acid (2×20 mL), water (20 mL) and saturated NaHCO 3 solution (2×20 mL) or NaOH (2×20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
이후 생성물을 컬럼 크로마토그래피로 정제하거나 적절한 용매로부터 결정화 시켰다. 합성된 화합물은 1H NMR를 이용하여 확인하였다.Thereafter, the product was purified by column chromatography or crystallized from an appropriate solvent. The synthesized compound was confirmed using 1 H NMR.
₁H-NMR (400MHz, DMSO) δ 10.35 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.52 (t, J = 16 Hz, 1H), 7.48 (d, J = 12 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 6.09 (s, 2H), 3.87 (s, 3H). ₁ H-NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.52 ( t, J = 16 Hz, 1H), 7.48 (d, J = 12 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 6.09 (s, 2H), 3.87 (s, 3H).
1-2. 메틸 (E)-2-(3-(벤조[d][1,3]다이옥소-5-닐)아크릴아미도)벤조에이트 (methyl (E)-2-(3-(benzo[d][1,3]dioxol-5-yl)acrylamido)benzoate)1-2. methyl (E) -2- (3- (benzo [d] [1,3] dioxo-5-yl) acrylamido) benzoate (methyl (E) -2- (3- (benzo [d] [ 1,3]dioxol-5-yl)acrylamido)benzoate)
상기 1-1과 동일한 제조방법을 이용하였으며, 화학식 3의 화합물 및 메틸 2-아미노벤조에이트를 넣고 반응시켜 합성하였다. 이후 1H NMR를 이용하여 확인하였다.The same preparation method as in 1-1 was used, and the compound of Formula 3 and methyl 2-aminobenzoate were added and reacted for synthesis. Thereafter, it was confirmed using 1 H NMR.
₁H-NMR (400MHz, DMSO) δ 10.35 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.52 (t, J = 16 Hz, 1H), 7.48 (d, J = 12 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 6.09 (s, 2H), 3.93 (s, 3H). ₁ H-NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.52 ( t, J = 16 Hz, 1H), 7.48 (d, J = 12 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 6.09 (s, 2H), 3.93 (s, 3H).
1-3. 다이메틸 (E)-5-(3-(벤조[d][1,3]다이옥소-5-일)아크릴아미도)이소프탈레이트 (dimethyl (E)-5-(3-(benzo[d][1,3]dioxol-5-yl)acrylamido)isophthalate)1-3. Dimethyl (E)-5-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)isophthalate (dimethyl (E)-5-(3-(benzo[d] [1,3]dioxol-5-yl)acrylamido)isophthalate)
상기 1-1과 동일한 제조방법을 이용하였으며, 화학식 3의 화합물 및 다이메틸 5-아미노이소프탈레이트를 넣고 반응시켜 합성하였다. 이후 1H NMR를 이용하여 확인하였다.The same preparation method as in 1-1 was used, and the compound of Formula 3 and dimethyl 5-aminoisophthalate were added and reacted for synthesis. Thereafter, it was confirmed using 1 H NMR.
₁H-NMR (400MHz, DMSO) δ 10.61 (s, 1H), 8.59 (s, 2H), 8.17 (s, 1H), 7.22 (s, 1H), 6.14 (s, 1H), 6.10-6.06 (m, 3H), 5.75 (s, 2H), 3.90 (s, 6H). ₁ H-NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.59 (s, 2H), 8.17 (s, 1H), 7.22 (s, 1H), 6.14 (s, 1H), 6.10-6.06 (m) , 3H), 5.75 (s, 2H), 3.90 (s, 6H).
1-4. 다이메틸 (E)-5-(3-(3,4-다이메톡시페닐)아크릴아미도)이소프탈레이트 (dimethyl (E)-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate)1-4. Dimethyl (E)-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate (dimethyl (E)-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate)
상기 1-1과 동일한 제조방법을 이용하였으며, 화학식 4의 화합물 및 다이메틸 5-아미노이소프탈레이트를 넣고 반응시켜 합성하였다. 이후 1H NMR를 이용하여 확인하였다.The same preparation method as in 1-1 was used, and the compound of Formula 4 and dimethyl 5-aminoisophthalate were added and reacted for synthesis. Thereafter, it was confirmed using 1 H NMR.
₁H-NMR (400MHz, CDCl₃) δ 8.42 (d, J = 8 Hz, 2H), 8.07 (t, J = 8 Hz, 1H), 7.67 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.83 (s, 6H), 3.65 (s, 6H). ₁ H-NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 8 Hz, 2H), 8.07 (t, J = 8 Hz, 1H), 7.67 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.83 (s, 6H), 3.65 (s, 6H).
1-5. 메틸 (E)-4-(3-(3,4-다이메톡시페닐)아크릴아미도)벤조에이트(methyl (E)-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate) 1-5. methyl (E)-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate (methyl (E)-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate)
상기 1-1과 동일한 제조방법을 이용하였으며, 화학식 4의 화합물 및 메틸 4-아미노벤조에이트를 넣고 반응시켜 합성하였다. 이후 1H NMR를 이용하여 확인하였다.The same preparation method as in 1-1 was used, and the compound of Formula 4 and methyl 4-aminobenzoate were added and reacted for synthesis. Thereafter, it was confirmed using 1 H NMR.
₁H-NMR (400MHz, CDCl₃) δ 8.13 (d, J = 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 7.67 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 6H). ₁ H-NMR (400 MHz, CDCl₃) δ 8.13 (d, J = 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 7.67 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 6H).
1-6. 메틸 (E)-2-(3-(3,4-다이메톡시페닐)아크릴아미도)벤조에이트 ((methyl (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate)1-6. methyl (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate ((methyl (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate)
상기 1-1과 동일한 제조방법을 이용하였으며, 화학식 4의 화합물 및 메틸 2-아미노벤조에이트를 넣고 반응시켜 합성하였다. 이후 1H NMR를 이용하여 확인하였다.The same preparation method as in 1-1 was used, and the compound of Formula 4 and methyl 2-aminobenzoate were added and reacted for synthesis. Thereafter, it was confirmed using 1 H NMR.
₁H-NMR (400MHz, CDCl₃) δ 8.55 (d, J = 8 Hz, 1H), 8.04 (s, 2H), 7.87 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 6.93 (d, J = 8 Hz, 1H), 6.60 (d, J = 8 Hz, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.83 (s, 3H). ₁ H-NMR (400 MHz, CDCl₃) δ 8.55 (d, J = 8 Hz, 1H), 8.04 (s, 2H), 7.87 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 6.93 (d, J = 8 Hz, 1H), 6.60 (d, J = 8 Hz, 1H), 4.00 (s, 3H), 3.96 ( s, 3H), 3.83 (s, 3H).
실험예 1. 에나마이드 골격을 가지는 신규 유도체의 FoxO-1 활성 억제 효과 확인Experimental Example 1. Confirmation of FoxO-1 activity inhibitory effect of novel derivatives having an enamide skeleton
상기 제조예 1에서 합성된 에나마이드 골격을 가지는 유도체의 FoxO-1 활성 억제 효과를 확인하였다. HepG2 세포(인간 유래 간암세포주)에 FoxO-1 단백질을 발현하는 벡터인 pcDNA3-Flag-FoxO-1과 insulin response element(IRE) 및 루시퍼라아제(luciferase)를 발현하는 벡터인Pgl3-IRE-Luc를 형질감염(transfection)하고 합성된 각 유도체를 처리하여 의해 FoxO-1과 IRE 결합에 의해 나타나는 루시퍼라아제 활성의 변화를 측정하였다.The inhibitory effect on FoxO-1 activity of the derivative having an enamide skeleton synthesized in Preparation Example 1 was confirmed. pcDNA3-Flag-FoxO-1, a vector expressing FoxO-1 protein, and Pgl3-IRE-Luc, a vector expressing insulin response element (IRE) and luciferase in HepG2 cells (a human-derived liver cancer cell line) The change in luciferase activity shown by FoxO-1 and IRE binding was measured by transfection and treatment with each synthesized derivative.
구체적으로, HepG2 세포주를 1×104 cell/100 ul로 96 웰(well) 플레이트에 분주하여 24시간 배양 후 무혈청, 무항생제 배지로 교환하였다. 이후 X-tream, FoxO-1벡터 및 IRE 벡터를 각 웰 당 50 ng/ul이 되도록 혼합하고 상온에서 15 분간 방치한 후 각 웰에 100 ul씩 분주하여 형질감염을 진행하였다. 24 시간 배양 후, Dual Luciferase Reporter Assay Kit (Promega)을 이용하여 프로모터의 활성 분석을 통해 루시퍼라아제 프로모터 활성을 측정하였다.Specifically, the HepG2 cell line was aliquoted in a 96-well plate at 1×10 4 cell/100 ul and cultured for 24 hours, followed by exchange with a serum-free, antibiotic-free medium. Thereafter, X-tream, FoxO-1 vector and IRE vector were mixed so as to be 50 ng/ul per well, left at room temperature for 15 minutes, and then transfection was carried out by dispensing 100 ul into each well. After culturing for 24 hours, the luciferase promoter activity was measured by analyzing the promoter activity using the Dual Luciferase Reporter Assay Kit (Promega).
상기 제조예에서 합성된 각 유도체를 50 uM 씩 가하여 FoxO-1에 대한 억제 활성을 평가한 후 FoxO-1 억제 활성을 50 % 이상 나타내는 유도체에 대하여 농도별로 다시 처리하여 억제 활성을 측정하고, 억제 정도를 IC50으로 정량화하였다. 본 결과에서 IC50 값이 낮을수록 더 낮은 농도에서 억제 활성을 나타내는 것을 말하는 바, IC50 값이 낮을수록 억제 활성이 더욱 우수함을 나타낸다.After evaluating the inhibitory activity against FoxO-1 by adding 50 uM of each of the derivatives synthesized in the above preparation example, the derivatives exhibiting 50% or more of FoxO-1 inhibitory activity were treated again by concentration to measure the inhibitory activity, and the inhibitory activity was measured. was quantified as IC 50 . In this result, a lower IC 50 value indicates that the inhibitory activity is exhibited at a lower concentration, and a lower IC 50 value indicates better inhibitory activity.
각 유도체의 FoxO-1에 대한 억제 활성은 하기 표 1에 나타난 바와 같다.The inhibitory activity of each derivative on FoxO-1 is shown in Table 1 below.
@50μMInhibition (%)
@50μM
실험예 2. 에나마이드 골격을 가지는 신규 유도체의 FoxO-3a 및 FoxO-4 활성 억제 효과 확인Experimental Example 2. Confirmation of the inhibitory effect of FoxO-3a and FoxO-4 activity of novel derivatives having an enamide skeleton
상기 실험예 1과 동일한 실험방법을 이용하여FoxO-3a 및 FoxO-4에 대한 억제 효과를 확인하였다. 다만, FoxO-1벡터 대신 FoxO-3a, FoxO-4가 삽입된 벡터를 각각 이용하였다.The inhibitory effect on FoxO-3a and FoxO-4 was confirmed using the same experimental method as in Experimental Example 1. However, instead of the FoxO-1 vector, FoxO-3a and FoxO-4 inserted vectors were used, respectively.
상기와 같이 본 발명의 에나마이드 골격을 포함하는 신규 화합물이 인슐린 반응조직에 작용하여 인슐린에 대해 저항성을 나타내도록 하는 FoxO-1, FoxO-3a 및 FoxO-4에 대한 억제 활성을 나타냄을 확인하였는바, 당뇨병에 대한 새로운 치료 및 개선용도로 활용될 수 있음을 확인하였다.As described above, it was confirmed that the novel compound containing the enamide skeleton of the present invention exhibits inhibitory activity against FoxO-1, FoxO-3a and FoxO-4, which act on insulin-responsive tissues to show resistance to insulin. , confirmed that it can be used for new treatment and improvement of diabetes.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present invention.
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Non-Patent Citations (6)
Title |
---|
Acta Pharmaceutica Sinica, 1997, 제32권, 제7호, 페이지 515-523* |
DATABASE REGISTRY [Online], CAS Registry Number: 496029-63-1 (2003.02.28.)* |
DATABASE REGISTRY [Online], CAS Registry Number: 541522-90-1 (2003.07.03.)* |
DATABASE REGISTRY [Online], CAS Registry Number: 59282-18-7 (1984.11.16.)* |
EMBO Molecular Medicine, 2018.03.12., 제10권, 문헌번호 e8689, 페이지 1-15* |
약학회지, 1982, 제26권, 제4호, 페이지 189-196* |
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