KR20240017738A - Anti-inflammatory composition comprising N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient - Google Patents
Anti-inflammatory composition comprising N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient Download PDFInfo
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Classifications
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/41—Amines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Abstract
본 발명은 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 유효성분으로 포함하는 항염증용 조성물에 관한 것으로, 하기 화학식 1로 표시되는 화합물을 유효 성분으로 포함할 수 있다.
[화학식 1]
상기 화학식 1에서, R1 은 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고, R2 및 R3 는 서로 독립적으로 탄소수 1 내지 5의 알킬기이다.The present invention relates to an anti-inflammatory composition containing N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient, and may include a compound represented by the following formula (1) as an active ingredient.
[Formula 1]
In Formula 1, R 1 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms, and R 2 and R 3 are independently alkyl groups with 1 to 5 carbon atoms.
Description
본 발명은 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 유효성분으로 포함하는 항염증용 조성물에 관한 것이다.The present invention relates to an anti-inflammatory composition containing N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient.
염증이란 외부 세균의 침입에 의하여 형성되는 농양의 병리적 상태를 뜻하며, 염증반응은 생체의 세포나 조직에 어떠한 기질적 변화를 가져오는 침습으로 인한 손상을 수복 재생하기 위한 생체 방어 반응과정으로, 조직(세포)의 손상이나 외부감염원(박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발물질)에 감염되었을 때 국소 혈관과 체액 중 각종 염증 매개인자 및 면역세포가 관련되어 효소활성화, 염증매개물질 분비, 체액 침윤, 세포이동, 조직 파괴 등 일련의 복합적인 생리적 반응과 홍반, 부종 발열 통증 등과 같은 외적 증상을 나타낸다.Inflammation refers to the pathological condition of an abscess formed by the invasion of external bacteria, and the inflammatory response is a biological defense reaction process to repair and regenerate damage caused by invasion that causes any organic changes in the cells or tissues of the living body. When (cells) are damaged or infected with external infectious agents (bacteria, mold, viruses, various types of allergens), various inflammatory mediators and immune cells in local blood vessels and body fluids are involved, leading to enzyme activation, secretion of inflammatory mediators, and body fluids. It shows a series of complex physiological reactions such as invasion, cell migration, and tissue destruction, as well as external symptoms such as erythema, edema, fever, and pain.
정상인 경우 염증반응은 외부감염원을 제거하고 손상된 조직을 재생하여 생명체 기능회복작용을 하지만, 항원이 제거되지 않거나 내부물질이 원인이 되어 염증반응이 과도하거나 지속적으로 일어나면 질환의 주요 병리현상(과민성 질환, 만성염증)이 되며, 수혈, 약물투여, 장기 이식 등 치료과정에서도 장해요인이 된다.In normal cases, the inflammatory response removes external infectious agents and regenerates damaged tissues to restore the function of the organism, but if the inflammatory response occurs excessively or continuously due to antigens not being removed or internal substances as the cause, the main pathological phenomenon of the disease (hypersensitivity disease, It becomes chronic inflammation) and becomes a factor in treatment processes such as blood transfusion, drug administration, and organ transplant.
이러한 염증 증상을 완화하기 위하여, 비스테로이드계로 이부프로펜(ibuprofen), 인도메타신(indomethacin) 등을 사용하고, 스테로이드계 약물로는 덱사메타손(dexamethasone) 등을 사용하고 있으나, 안정성 면에서 부작용이 보고되고 있어, 그 사용이 제한되고 있다.To relieve these inflammatory symptoms, non-steroid drugs such as ibuprofen and indomethacin are used, and steroid drugs such as dexamethasone are used, but side effects are reported in terms of safety. , its use is restricted.
따라서, 최대의 효과와 최소의 부작용을 가지는 안전한 항염증 물질의 개발이 필요한 실정이다.Therefore, there is a need to develop safe anti-inflammatory substances with maximum effectiveness and minimum side effects.
본 발명의 일 목적은 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 유효성분으로 포함하는 항염증용 조성물을 제공하는 것이다.One object of the present invention is to provide an anti-inflammatory composition containing N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient.
본 발명의 일 목적은 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 유효성분으로 포함하는 아토피성 피부염 개선용 화장료 조성물을 제공하는 것이다.One object of the present invention is to provide a cosmetic composition for improving atopic dermatitis containing N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient.
본 발명의 일 목적은 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 유효성분으로 포함하는 류마티스 관절염의 예방 또는 치료용 약학 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for preventing or treating rheumatoid arthritis containing N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient.
본 발명의 일 목적은 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 활성성분으로 포함하는 궤양성 대장염 치료용 의약 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for treating ulcerative colitis containing N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient.
본 발명의 일 실시예에 따른 항염증용 조성물은 하기 화학식 1로 표시되는 화합물을 유효 성분으로 포함할 수 있다.The anti-inflammatory composition according to an embodiment of the present invention may include a compound represented by the following formula (1) as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1에서, R1 은 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고, R2 및 R3 는 서로 독립적으로 탄소수 1 내지 5의 알킬기이다.In Formula 1, R 1 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms, and R 2 and R 3 are independently alkyl groups with 1 to 5 carbon atoms.
일 실시예에서, 본 발명의 항염증용 조성물은 하기 화학식 1-1 내지 화학식 1-5 중에서 선택되는 화합물을 유효 성분으로 포함할 수 있다.In one embodiment, the anti-inflammatory composition of the present invention may include a compound selected from the following Chemical Formulas 1-1 to 1-5 as an active ingredient.
[화학식 1-1][Formula 1-1]
[화학식 1-2][Formula 1-2]
[화학식 1-3][Formula 1-3]
[화학식 1-4][Formula 1-4]
[화학식 1-5][Formula 1-5]
일 실시예에서, 상기 조성물은 아토피성 피부염, 류마티스 관절염 또는 궤양성 대장염을 포함하는 염증성 질환에 치료 효과를 가질 수 있다.In one embodiment, the composition may have a therapeutic effect on inflammatory diseases including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis.
일 실시예에서, 상기 조성물은 지질다당체에 의해 유도된 p38 MAP 키나아제와 JNK 의 활성화, 발현 및 생성을 억제하고, p38 MAPK-MK2 로 연결되는 염증 관련 신호 전달 경로를 억제할 수 있다.In one embodiment, the composition can inhibit the activation, expression, and production of p38 MAP kinase and JNK induced by lipopolysaccharide, and inhibit the inflammation-related signaling pathway leading to p38 MAPK-MK2.
일 실시예에서, 상기 조성물은 TNF-α, IL-1β 또는 IL-6 에서 선택되는 전염증성 사이토카인의 생성을 억제하고, NF- κB 의 전사인자 활성을 억제할 수 있다.In one embodiment, the composition may inhibit the production of pro-inflammatory cytokines selected from TNF-α, IL-1β, or IL-6, and inhibit the transcription factor activity of NF-κB.
일 실시예에서, 상기 조성물은 HO-1 (Heme oxygenase 1) 또는 Nrf2 (nuclear factor erythroid-related factor 2) 의 발현을 증가시켜 항산화 효능을 가질 수 있다.In one embodiment, the composition may have antioxidant efficacy by increasing the expression of HO-1 (Heme oxygenase 1) or Nrf2 (nuclear factor erythroid-related factor 2).
일 실시예에서, 상기 조성물은 케모카인 CINC-3 의 생성을 억제시킬 수 있다.In one embodiment, the composition can inhibit the production of the chemokine CINC-3.
일 실시예에서, 상기 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함될 수 있고, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.In one embodiment, the composition may be in various oral or parenteral dosage forms. When formulated, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and such solid preparations include one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. It can be prepared by mixing (lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate, talc, etc. may also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is.
비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 콩기름, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, soybean oil, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.
본 발명에 따른 조성물은, 쥐, 생쥐, 가축, 인간 등의 포유동물에 비경구, 경구 등의 다양한 경로로 투여될 수 있으며, 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사 등에 의해 투여될 수 있다.The composition according to the present invention can be administered to mammals such as rats, mice, livestock, and humans by various routes such as parenteral and oral, and all methods of administration can be expected, such as oral and rectal. Alternatively, it may be administered by intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebroventricular injection.
한편, 본 발명은 다른 실시 형태로 하기 화학식 2로 표시되는 화합물을 유효 성분으로 포함하는 아토피성 피부염 개선용 화장료 조성물을 제공할 수 있다.Meanwhile, in another embodiment, the present invention can provide a cosmetic composition for improving atopic dermatitis containing a compound represented by the following formula (2) as an active ingredient.
[화학식 2][Formula 2]
상기 화학식 2에서, R4 는 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고, R5 는 탄소수 1 내지 5의 알킬기이다.In Formula 2, R 4 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms, and R 5 is an alkyl group with 1 to 5 carbon atoms.
일 실시예에서, 상기 아토피성 피부염 개선용 화장료 조성물은 상기 화학식 1-1, 1-2, 1-3 및 1-5 로 표시되는 화합물 중에서 선택되는 화합물을 유효 성분으로 포함할 수 있다.In one embodiment, the cosmetic composition for improving atopic dermatitis may include a compound selected from the compounds represented by Formulas 1-1, 1-2, 1-3, and 1-5 as an active ingredient.
일 실시예에서, 상기 화장료 조성물은 피부 보습 성분, 화장품 제형 성분, 향료, 보존제, 및 정제수로 이루어진 군으로부터 선택된 1종 이상을 더 포함할 수 있다. 여기서, 상기 피부 보습 성분, 화장품 제형 성분, 향료, 보존제로는 공지된 물질을 사용할 수 있고, 예를 들어, 콩기름, 올리브 왁스 등을 사용할 수 있다.In one embodiment, the cosmetic composition may further include one or more selected from the group consisting of skin moisturizing ingredients, cosmetic formulation ingredients, fragrances, preservatives, and purified water. Here, known substances can be used as the skin moisturizing ingredients, cosmetic formulation ingredients, fragrances, and preservatives, for example, soybean oil, olive wax, etc.
일 실시예에서, 상기 화장료 조성물의 제형이 화장수, 크림, 에멀젼, 에센스, 겔, 세럼, 팩, 파우더, 피부외용연고, 첩보제, 현탁액, 스프레이 또는 미용액일 수 있다.In one embodiment, the formulation of the cosmetic composition may be a lotion, cream, emulsion, essence, gel, serum, pack, powder, external skin ointment, patch, suspension, spray, or serum.
한편, 본 발명은 다른 실시 형태로 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 류마티스 관절염의 예방 또는 치료용 약학 조성물을 제공할 수 있다.Meanwhile, in another embodiment, the present invention may provide a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
일 실시예에서, 상기 류마티스 관절염의 예방 또는 치료용 약학 조성물은 상기 화학식 1-1 또는 화학식 1-2로 표시되는 화합물을 유효 성분으로 포함할 수 있고, 바람직하게는, 상기 화학식 1로 표시되는 화합물은 상기 화학식 1-1로 표시되는 화합물일 수 있다.In one embodiment, the pharmaceutical composition for preventing or treating rheumatoid arthritis may include a compound represented by Formula 1-1 or Formula 1-2 as an active ingredient, and preferably, a compound represented by Formula 1 may be a compound represented by Formula 1-1 above.
일 실시예에서, 상기 약학 조성물은 경구 투여용일 수 있고, 이 경우, 상기 화학식 1로 표시되는 화합물이 15 내지 25 mg/kg (1회당 약 500㎍ 의 양으로 200 ㎕ 부피)의 용량으로 경구 투여되기에 적합한 단위 투여 형태로 제제화될 수 있다.In one embodiment, the pharmaceutical composition may be for oral administration, and in this case, the compound represented by Formula 1 is orally administered at a dose of 15 to 25 mg/kg (about 500 μg per time in a volume of 200 μl). It can be formulated in unit dosage form suitable for use.
일 실시예에서, 상기 약학 조성물은 1 내지 수회에 나누어 경구 투여할 수 있고, 특정 환자에 대한 투여용량은 환자의 체중, 연령, 성별, 건강 상태, 식이, 투여 시간, 투여 방법, 배설률, 질환의 중증도 등에 따라 변화될 수 있다.In one embodiment, the pharmaceutical composition can be administered orally in one to several divided doses, and the dosage for a specific patient is determined by the patient's weight, age, gender, health status, diet, administration time, administration method, excretion rate, and disease severity. It may change depending on severity, etc.
일 실시예에서, 상기 약학 조성물의 3주간 경구 투여는 2형 콜라겐에 의해 유도된 류마티스 자가 면역 질병 모델에서 AST 효소 및 ALT 효소의 활성에 전혀 영향을 주지 않을 수 있다.In one embodiment, oral administration of the pharmaceutical composition for 3 weeks may not have any effect on the activities of AST enzyme and ALT enzyme in a rheumatic autoimmune disease model induced by type 2 collagen.
한편, 본 발명의 다른 실시 형태로 상기 화학식 1로 표시되는 화합물 또는 이의 의약적으로 허용가능함 염을 포함하는 궤양성 대장염 치료용 의약 조성물을 들 수 있다.Meanwhile, another embodiment of the present invention includes a pharmaceutical composition for treating ulcerative colitis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
일 실시예에서, 상기 궤양성 대장염 치료용 의약 조성물은 상기 화학식 1-1 또는 화학식 1-2로 표시되는 화합물을 활성 성분으로 포함할 수 있고, 바람직하게는, 상기 화학식 1로 표시되는 화합물은 상기 화학식 1-2로 표시되는 화합물일 수 있다.In one embodiment, the pharmaceutical composition for treating ulcerative colitis may include a compound represented by Formula 1-1 or Formula 1-2 as an active ingredient, and preferably, the compound represented by Formula 1 is It may be a compound represented by Formula 1-2.
일 실시예에서, 상기 의약 조성물은 관장 투여용일 수 있고, 이 경우, 상기 의약 조성물은 1일당 유효 성분으로서 0.4 mg/ 몸무게 Kg 이하의 양(1회당 약 100 μg 양으로 500 μL 부피)으로 궤양성 대장염 환자에게 직접 관장 투여될 수 있다.In one embodiment, the pharmaceutical composition may be for enema administration, and in this case, the pharmaceutical composition is used as an active ingredient per day in an amount of less than 0.4 mg/Kg of body weight (about 100 μg per time in a volume of 500 μL). It can be administered directly as an enema to patients with colitis.
일 실시예에서, 상기 의약 조성물은 1 내지 수회에 나누어 관장 투여할 수 있고, 특정 환자에 대한 투여용량은 환자의 체중, 연령, 성별, 건강 상태, 식이, 투여 시간, 투여 방법, 배설률, 질환의 중증도 등에 따라 변화될 수 있다.In one embodiment, the pharmaceutical composition can be administered by enema in one to several divided doses, and the dosage for a specific patient depends on the patient's weight, age, gender, health status, diet, administration time, administration method, excretion rate, and disease. It may change depending on severity, etc.
일 실시예에서, 상기 의약 조성물의 투여 형태는 이들의 약학적 허용 가능함 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. 상기 염으로는 약학적으로 허용되는 것이면 특별히 한정되지 않으며, 예를 들어 염산, 황산, 질산 등을 사용할 수 있다.In one embodiment, the dosage form of the pharmaceutical composition may be used in the form of a pharmaceutically acceptable salt thereof, and may be used alone or in combination with other pharmaceutically active compounds, as well as in an appropriate combination. The salt is not particularly limited as long as it is pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, etc. can be used.
일 실시예에서, 상기 의약 조성물의 관장 투여는 케모카인 CINC-3 의 생성을 억제시킬 수 있다. 또한, 상기 의약 조성물의 관장 투여는 대식세포의 활성산소 발생을 저감시킬 수 있다.In one embodiment, enema administration of the pharmaceutical composition can inhibit the production of the chemokine CINC-3. Additionally, enema administration of the pharmaceutical composition can reduce the generation of active oxygen radicals in macrophages.
본 발명에 따른 N-벤질-N-메틸데칸-1-아민 또는 그 유도체는 지질다당체(LPS)에 의한 세포의 염증 반응을 억제하고, 대식세포의 활성산소 발생을 저감시키고, 케모카인 CNIC-3, 전염증성 사이토카인, 그리고 염증 복합체 단백질 발현 등을 억제함으로써 우수한 항염증 효과를 나타내며, 특히, 아토피성 피부염, 류마티스 관절염, 궤양성 대장염 등의 염증성 질환에 항염 효과가 있다.N-benzyl-N-methyldecan-1-amine or a derivative thereof according to the present invention suppresses the inflammatory response of cells caused by lipopolysaccharide (LPS), reduces the generation of reactive oxygen species in macrophages, and reduces the production of oxygen radicals in macrophages, It exhibits excellent anti-inflammatory effects by suppressing the expression of pro-inflammatory cytokines and inflammatory complex proteins, and is especially effective in treating inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, and ulcerative colitis.
구체적으로, 본 발명에 따른 N-벤질-N-메틸데칸-1-아민 또는 그 유도체를 피부에 도포하여 1,4-dinitrochlorobenzne(DNCB) 화합물로 유도된 아토피 피부염에 대한 우수한 항염 효과를 나타내고 있으며, 또한 경구 투여 방식에 의해 2형 콜라겐으로부터 유도된 류마티스 관절염에 대한 우수한 항염 효과를 나타내고, 관장 투여 방식에 의해 궤양성 대장염에 대한 우수한 항염 효과를 나타낼 수 있다.Specifically, applying N-benzyl-N-methyldecan-1-amine or its derivative according to the present invention to the skin shows an excellent anti-inflammatory effect on atopic dermatitis induced by 1,4-dinitrochlorobenzne (DNCB) compound, In addition, it can exhibit an excellent anti-inflammatory effect on rheumatoid arthritis induced from type 2 collagen by oral administration, and an excellent anti-inflammatory effect on ulcerative colitis by enema administration.
도 1은 본 발명의 일 실시예에 따라 합성된 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체(DMMA)의 합성 결과 및 구조를 H3-NMR 로 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체(DMMA)의 지질다당체에 의한 단핵구 세포주 THP-1의 염증 반응 억제 효과를 나타낸 것이다.
도 3은 DNBS에 의해 유도된 대장염 모델에서 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체(DMMA)의 관장 투여에 의한 항염증 효과를 나타내는 실험 결과이다.
도 4 및 5는 2형 콜라겐으로 유도된 류마티스 관절염 모델에서 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체(DMMA)의 경구 투여에 의한 항염증 효과를 나타낸 실험 결과이다.
도 6은 2형 콜라겐으로 유도된 류마티스 관절염 모델에서 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체(DMMA)의 경구 투여에 의한 염증 사이토카인 발현 및 항산화 유전자인 HO-1(Heme oxygenase-1) 및 Nrf2 (nuclear factor erythroid-related factor 2) 발현을 qRT-PCR와 면역브라팅으로 각각 조사한 결과를 나타낸다.
도 7은 2형 콜라겐으로 유도된 류마티스 관절염 모델에서 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체(DMMA)의 경구 투여에 의한 AST 및 ALT 활성 측정 결과를 나타낸다.
도 8은 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA)의 유도체들 (Benzyl-decyl-metyl-amine, Benzyl-dodecyl-methyl-amine, decyl-(4-fluoro-benzyl)-methyl-amine)의 지질다당체에 의한 단핵구 세포주 THP-1의 염증 반응 억제 효과를 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 N-벤질-N-메틸데칸-1-아민(BMDA) 및 그 유도체들을 포함하는 화장료 조성물의 아토피성 피부염 개선 효능 평가 결과를 나타낸 것이다.
도 10 및 도 11은 도 9A와 도 9B의 결과를 더 지지하는 상세 결과이다.Figure 1 shows the synthesis results and structures of N-benzyl-N-methyldecan-1-amine (BMDA) and its derivative (DMMA) synthesized according to an embodiment of the present invention using H 3 -NMR.
Figure 2 shows the effect of suppressing inflammatory response in the monocyte cell line THP-1 by lipopolysaccharide of N-benzyl-N-methyldecan-1-amine (BMDA) and its derivative (DMMA) according to an embodiment of the present invention. .
Figure 3 shows the anti-inflammatory effect of enema administration of N-benzyl-N-methyldecan-1-amine (BMDA) and its derivative (DMMA) according to an embodiment of the present invention in a colitis model induced by DNBS. This is the result of the experiment.
Figures 4 and 5 show the anti-inflammatory effect of oral administration of N-benzyl-N-methyldecan-1-amine (BMDA) and its derivative (DMMA) according to an embodiment of the present invention in a type 2 collagen-induced rheumatoid arthritis model. This is an experimental result showing an inflammatory effect.
Figure 6 shows inflammatory cytokines caused by oral administration of N-benzyl-N-methyldecan-1-amine (BMDA) and its derivative (DMMA) according to an embodiment of the present invention in a type 2 collagen-induced rheumatoid arthritis model. The results of examining the expression of the antioxidant genes HO-1 (Heme oxygenase-1) and Nrf2 (nuclear factor erythroid-related factor 2) using qRT-PCR and immunoblotting, respectively.
Figure 7 shows AST and ALT by oral administration of N-benzyl-N-methyldecan-1-amine (BMDA) and its derivative (DMMA) according to an embodiment of the present invention in a type 2 collagen-induced rheumatoid arthritis model. Shows the activity measurement results.
Figure 8 shows derivatives of N-benzyl-N-methyldecan-1-amine (BMDA) (Benzyl-decyl-metyl-amine, Benzyl-dodecyl-methyl-amine, decyl-(4) according to an embodiment of the present invention. -fluoro-benzyl)-methyl-amine) lipopolysaccharide showed the effect of suppressing the inflammatory response of the monocyte cell line THP-1.
Figure 9 shows the results of evaluating the effectiveness of atopic dermatitis improvement of a cosmetic composition containing N-benzyl-N-methyldecan-1-amine (BMDA) and its derivatives according to an embodiment of the present invention.
Figures 10 and 11 are detailed results that further support the results of Figures 9A and 9B.
이하에서는 본 발명의 다양한 실시예들 및 실험예들에 대해 상술한다. 다만, 하기의 실시예들은 본 발명의 일부 실시예에 불과한 것으로서, 본 발명이 하기 실시예들에 한정되는 것으로 해석되어서는 아니된다.Hereinafter, various embodiments and experimental examples of the present invention will be described in detail. However, the following examples are only some examples of the present invention, and the present invention should not be construed as being limited to the following examples.
<실시예 1: BMDA(FMJ-G0)와 그 유도체(FMJ-G4)의 구조 및 합성 확인><Example 1: Confirmation of structure and synthesis of BMDA (FMJ-G0) and its derivative (FMJ-G4)>
1M의 N-벤질메틸아민(N-benzylmethylamine)와 데크알데하이드(decanal)을 메탄올이 들어 있는 상태에서 섞고, 20분간 교반시켰다. 이후, sodium triacetoxyborohydride [NaBH(OAc)3]을 첨가하고 1시간 더 교반시켰다. 진공상태에서 휘발성 유기 용매는 제거하고 불순한 BMDA(Benzyl-decyl-methyl-amine)는 탄산수소나트륨(sodium hydrogen carbonate)으로 포화된 에틸 아세트산으로 추출하였다. 더 순수한 BMDA는 컬럼 크로마토그래피로 정제하여 수득하였으며, 그 구조는 H3-NMR(도 1A 참조)로 확인하였다. 합성된 물질의 화학 구조는 하기 화학식 1-1로 표시된다.1M N-benzylmethylamine and decanal were mixed in methanol and stirred for 20 minutes. Afterwards, sodium triacetoxyborohydride [NaBH(OAc) 3 ] was added and stirred for another hour. The volatile organic solvent was removed under vacuum, and impure BMDA (Benzyl-decyl-methyl-amine) was extracted with ethyl acetic acid saturated with sodium hydrogen carbonate. Purer BMDA was obtained by purification by column chromatography, and its structure was confirmed by H 3 -NMR (see Figure 1A). The chemical structure of the synthesized material is represented by the following formula 1-1.
[화학식 1-1][Formula 1-1]
한편, 동일한 방식으로 1-(4-메톡시페닐)-N-메틸메탄아민(1-(4-methoxyphenyl)-N-methylmethanamine)와 데크알데하이드(decanal)으로부터 시작하여 FMJ-G4 물질(DMMA, Decyl-(4-methoxy-benzyl)-methyl-amine)을 합성하고, 이 구조 또한 H3-NMR(도 1B 참조)로 확인하였다. 합성된 물질의 화학 구조는 하기 화학식 1-2로 표시된다.Meanwhile, in the same way, starting from 1-(4-methoxyphenyl) -N- methylmethanamine and decanal, FMJ-G4 material (DMMA, Decyl -(4-methoxy-benzyl)-methyl-amine) was synthesized, and its structure was also confirmed by H 3 -NMR (see Figure 1B). The chemical structure of the synthesized material is represented by the following formula 1-2.
[화학식 1-2][Formula 1-2]
<실시예 2: BMDA(FMJ-G0)와 그 유도체(DMMA, FMJ-G4)의 항염 효능 평가><Example 2: Evaluation of anti-inflammatory efficacy of BMDA (FMJ-G0) and its derivatives (DMMA, FMJ-G4)>
1. BMDA(FMJ-G0)와 그 유도체(DMMA)의 지질다당체(LPS)에 의해 유도된 염증 관련 신호전달 활성화방해와 TNF-α 와 IL-β 염증 사이토카인의 생성 억제 효능 평가1. Evaluation of the efficacy of BMDA (FMJ-G0) and its derivative (DMMA) in inhibiting the activation of inflammation-related signaling induced by lipopolysaccharide (LPS) and the production of TNF-α and IL-β inflammatory cytokines
6 well 플레이트(plate)에 BMDA 와 DMMA 를 4 μM, 2 μM, 및 1 μM 농도로 넣은 상태에서, 인간 THP-1 단핵구 세포주(5x10^5 세포수/ well)를 3시간 동안 배양하고, 각 웰(well)에 지질다당체(lipopolysaccharide)을 1 mg/ml 농도로 처리하고 한 시간 뒤에 원심분리하여 상층액은 염증성 사이토카인 평가를 위한 ELISA 로 사용하고, 회수된 THP-1 세포들은 세포용해액을 넣어 면역브라팅으로 사용하였다.Human THP-1 mononuclear cell line (5x10^5 cells/well) was cultured for 3 hours with BMDA and DMMA at concentrations of 4 μM, 2 μM, and 1 μM in a 6-well plate, and then incubated in each well. Lipopolysaccharide was treated at a concentration of 1 mg/ml in the well and centrifuged one hour later. The supernatant was used for ELISA to evaluate inflammatory cytokines, and the recovered THP-1 cells were added to the cell lysate. It was used for immunoblotting.
또한, 동일한 조건으로 지질다당체(LPS)와 BMDA / DMMA 가 처리된 단핵구 THP-1 세포주는 세포질과 핵 부분으로 분획하여, NF-κB P65 단백질의 세포질 및 핵 내의 분포를 면역브라팅으로 살펴보았다.In addition, the mononuclear THP-1 cell line treated with lipopolysaccharide (LPS) and BMDA/DMMA under the same conditions was fractionated into cytoplasmic and nuclear parts, and the distribution of NF-κB P65 protein in the cytoplasm and nucleus was examined by immunoblotting.
그 결과, 도 2A - 2B를 참조하면, BMDA(FMJ-G0) 와 그 유도체인 DMMA(FMJ-G4) 저분자 물질은 LPS에 의해 활성화된 p38 MAPK 와 JNK 활성을 억제시켰다. 그리고 p38 MAPK-MK2으로 연결되는 염증 관련 신호 경로도 억제하였다. 그리고 이 결과를 통해 이들 저분자 화합물이 농도-의존적인 것을 확인하였다.As a result, referring to Figures 2A-2B, BMDA (FMJ-G0) and its derivative DMMA (FMJ-G4) small molecule substances inhibited p38 MAPK and JNK activities activated by LPS. In addition, inflammation-related signaling pathways linked to p38 MAPK-MK2 were also inhibited. And through these results, it was confirmed that these low-molecular-weight compounds were concentration-dependent.
한편, 이 결과의 생물학적 의미는 본 발명의 BMDA(FMJ-GO) 와 그 유도체인 DMMA(FMJ-G4) 저분자 물질은 TNF-α 와 IL-1β 염증 사이토카인의 생성을 억제함을 ELISA 로 확인한 것이며(도 2C), 이들 저분자 화합물들은 NF-κB 의 전사인자 활성도 억제하고 NF-κB 발현과 핵 내 이동을 억제함을 알 수 있었다(도 2D).Meanwhile, the biological significance of this result is that BMDA (FMJ-GO) and its derivative, DMMA (FMJ-G4), small molecule substances of the present invention inhibit TNF-α and IL-1β. It was confirmed by ELISA that the production of inflammatory cytokines was suppressed (Figure 2C), and it was found that these small molecule compounds also inhibited the transcription factor activity of NF-κB and inhibited NF-κB expression and movement into the nucleus (Figure 2D). .
2. DNBS에 의하여 유도된 대장염 모델에서 BMDA(FMJ-G0)와 그 유도체(DMMA, FMJ-G4)의 항염 효능 평가2. Evaluation of anti-inflammatory efficacy of BMDA (FMJ-G0) and its derivatives (DMMA, FMJ-G4) in DNBS-induced colitis model
실험적 대장염은 수컷 SD 랫트 (250-260 g) 종을 대장염을 일으키기 하루 전, 단식을 시킨다. 다만 물만 먹을 수 있도록 물병을 준비하여 놓았다. 이후, 마취 후에 항문으로 고무 삽입관을 넣고, 50% 알코올 0.4 mL에 48.0 mg DNBS 를 녹인 물질을 그 삽입관을 통해 집어 넣는다. 이를 3일간 반복하였다.For experimental colitis, male SD rats (250-260 g) are fasted one day before causing colitis. However, a water bottle was prepared so that only water could be consumed. Afterwards, after anesthesia, a rubber insertion tube is inserted into the anus, and 48.0 mg DNBS dissolved in 0.4 mL of 50% alcohol is inserted through the insertion tube. This was repeated for 3 days.
DNBS를 삽입한 4일부터, 마취 후에 항문을 통해 BMDA(FMJ-G0)와 그 유도체(DMMA, FMJ-G4)을 PBS 로 희석하여 200 ㎍/mL 농도로 500 μL 주입하고, 이를 5일간 반복한다. 대조구는 DMSO 를 PBS 에 같은 비율로 희석하여 5일간 동일하게 주입하였다. 이후, 6일째에 랫트를 질식사시키고, 대장을 떼어내어 대장염의 정도를 공지된 방법에 따라 평가하였다.Starting on the 4th day after insertion of DNBS, after anesthesia, inject 500 μL of BMDA (FMJ-G0) and its derivatives (DMMA, FMJ-G4) diluted with PBS at a concentration of 200 μg/mL through the anus, and repeat for 5 days. . In the control group, DMSO was diluted in the same ratio in PBS and injected in the same manner for 5 days. Then, on the 6th day, the rat was killed by asphyxiation, the large intestine was removed, and the degree of colitis was evaluated according to a known method.
또한, 대장의 일부를 떼어, 세포 용해 완충액(20 mM Tris-HCl [pH 7.5], 150 mM NaCl, 1 mM EDTA, 1% Triton X-100. 0.5% SDS)에 넣고 초음파 처리하여 원심분리를 통해 상층액만 회수하고, 단백질을 정량한 후, 면역브라팅을 실시하였다.Additionally, a part of the large intestine was removed, placed in cell lysis buffer (20mM Tris-HCl [pH 7.5], 150mM NaCl, 1mM EDTA, 1% Triton X-100, 0.5% SDS), sonicated, and centrifuged. Only the supernatant was recovered, protein was quantified, and immunoblotting was performed.
한편, 면역브라팅을 위해 준비된 원심분리 후 상층액 일부는 케모카인 CINC-3 (Cytokine-induced neutrophil chemoattractant)의 양을 ELISA로 측정하였다. 또한, 원위결장 부위에 유입된 대식세포의 활성 정도를 측정하기 위해, MPO (Myeloperoxidase)의 역가를 측정하였다. 원위결장 부위를 초음속 분쇄기에서 분쇄하고 원심분리 후 상층액에 과산화수소수를 넣어 분해되면서, 460 nm 에서 1분 동안 흡광도의 변화를 측정하였다.Meanwhile, the amount of the chemokine CINC-3 (Cytokine-induced neutrophil chemoattractant) in some of the supernatants prepared for immunoblotting after centrifugation was measured by ELISA. Additionally, to measure the level of activity of macrophages introduced into the distal colon, the titer of MPO (Myeloperoxidase) was measured. The distal colon was pulverized in a supersonic grinder, centrifuged, and dissolved by adding hydrogen peroxide to the supernatant, and the change in absorbance was measured at 460 nm for 1 minute.
그 결과, 도 3A -3B 를 참조하면, BMDA(FMJ-G0) 와 그 유도체인 DMMA(FMJ-G4) 저분자 물질은 DNBS에 의한 염증 반응을 상당히 의미있는 수준으로 감소시켰다.As a result, referring to Figures 3A-3B, BMDA (FMJ-G0) and its derivative DMMA (FMJ-G4) low molecular weight substances reduced the inflammatory response caused by DNBS to a significantly significant level.
대장을 비교하였을 때, DNBS + PBS 를 처리하였을 때, 대장의 길이는 아주 짧아져 있고, 궤양 딱지가 상당히 큰 것을 알 수 있다(도 3A - 3B). 하지만, DMMA(FMJ-G4) 처리한 랫트의 대장은 DNBS + PBS 처리한 그룹보다 대장의 길이가 길어진 것을 알 수 있었으며, 궤양으로 생긴 딱지가 작아진 것을 알 수 있다. 특히, 유도체 DMMA(FMJ-G4) 를 처리한 쥐가 BMDA(FMJ-G0)를 처리한 쥐보다 대장의 길이가 조금 더 길고 궤양 딱지 또한 작아진 결과를 보였다. BMDA(FMJ-G0)를 처리한 쥐는 DNBS + PBS 처리한 그룹과 비교하여, 대장의 길이는 큰 차이가 없지만 궤양 정도는 훨씬 나아진 모습을 보였다. 하지만 BMDA(FMJ-G0)와 DMMA(FMJ-G4) 처리는 DNBS 처리로 감소된 몸무게를 회복시키지는 못하였다(도 3C).When comparing the large intestine, it can be seen that when treated with DNBS + PBS, the length of the large intestine is very short and the ulcer scab is quite large (Figures 3A-3B). However, the length of the colon of rats treated with DMMA (FMJ-G4) was found to be longer than that of the DNBS + PBS treated group, and the scabs formed by ulcers were found to be smaller. In particular, rats treated with the derivative DMMA (FMJ-G4) showed slightly longer colons and smaller ulcer scabs than rats treated with BMDA (FMJ-G0). Compared to the DNBS + PBS treated group, mice treated with BMDA (FMJ-G0) showed no significant difference in colon length, but the degree of ulcers showed much improvement. However, BMDA (FMJ-G0) and DMMA (FMJ-G4) treatment did not restore the body weight lost by DNBS treatment (Figure 3C).
한편, BMDA(FMJ-G0)와 그 유도체인 DMMA(FMJ-G4) 저분자 물질을 관장 투여한 쥐의 대장에서 DNBS + PBS 처리한 쥐의 대장보다 훨씬 낮은 대식세포의 과산화효소 활성를 나타냈고(도 3D), 호중구를 유인하는 케모카인 CNIC-3 양도 낮게 생성되어 있음을 관찰하였다(도 3E).Meanwhile, the colon of mice administered enema with BMDA (FMJ-G0) and its derivative, DMMA (FMJ-G4), a low-molecular-weight substance, showed much lower macrophage peroxidase activity than the colon of mice treated with DNBS + PBS (Figure 3D) ), it was observed that the amount of CNIC-3, a chemokine that attracts neutrophils, was also produced at a low level (Figure 3E).
3. 2형 소 콜라겐에 의하여 유도된 류마티스 관절염 모델에서 BMDA(FMJ-G0)와 그 유도체 (DMMA, FMJ-G4)의 항염증 효과3. Anti-inflammatory effect of BMDA (FMJ-G0) and its derivatives (DMMA, FMJ-G4) in a rheumatoid arthritis model induced by type 2 bovine collagen.
7주령의 DBA/J1 수컷 마우스에 류마티스 관절염을 유도하였다. 2 mg/mL 농도의 2형 콜라겐을 CFA(Complete Freund’s Adjuvant)와 같은 1:1 비율로 완전히 잘 섞어, 혼합액 0.1 mL(100 mg)을 꼬리 기저부에서 2 센티미터 떨어져 피내 주사(intradermal)한다. 2주일 후에 동일하게 CFA 대신 IFA 로 2형 콜라겐으로 1:1 비율로 잘 섞어, 꼬리 기저부의 피하에 1차 주사와 마찬가지로 같은 양, 같은 부피로 투여하고, 3일 후에 4개의 그룹으로 나누어 2차 투여하였다.Rheumatoid arthritis was induced in 7-week-old DBA/J1 male mice. Type 2 collagen at a concentration of 2 mg/mL is thoroughly mixed with CFA (Complete Freund’s Adjuvant) in a 1:1 ratio, and 0.1 mL (100 mg) of the mixture is injected intradermally 2 centimeters away from the base of the tail. Two weeks later, mix well with IFA and type 2 collagen instead of CFA in a 1:1 ratio and administer the same amount and volume as the first injection subcutaneously at the base of the tail. After three days, divide into four groups and administer the second injection. administered.
한편, 21일 동안 2.5 mg/mL의 농도로 BMDA(FMJ-G0)와 그 유도체(DMMA, FMJ-G4)를 수컷 마우스에 200 μL 부피 (20 mg/몸무게 Kg) 로 경구 투여하였고, 대조군으로 콩기름을 경구 투여하였다.Meanwhile, BMDA (FMJ-G0) and its derivatives (DMMA, FMJ-G4) at a concentration of 2.5 mg/mL were orally administered to male mice in a volume of 200 μL (20 mg/kg body weight) for 21 days, and soybean oil was administered as a control. was administered orally.
실험 동안, 일주일에 3번씩 앞다리와 뒷다리 발등을 캘리퍼(caliper)로 측정하고 마지막에 질식사시키고 관절부위를 면역조직화학적 염색와 면역브라팅을 위해 준비하였다. 또한, 지라를 떼어 내고 그 크기를 비교하였다. 또 한편, 간문맥을 통해 혈액을 뽑아 혈청을 준비하였다. 구체적인 방법은 다음과 같다.During the experiment, the dorsum of the front and hind limbs were measured with a caliper three times a week, and at the end, the animals were asphyxiated and the joints were prepared for immunohistochemical staining and immunoblotting. Additionally, the spleen was removed and its size was compared. Meanwhile, blood was drawn through the portal vein and serum was prepared. The specific method is as follows.
1) 앞다리의 발목을 포함하는 관절부위는 파라핀 섹션을 준비한다. 이때, 탈 칼슘화 작업을 먼저 하고 4 mm두께로 절편하여 H&E 염색을 한다.1) Prepare a paraffin section of the joint area including the ankle of the forelimb. At this time, decalcification is performed first, sectioned at 4 mm thickness, and H&E stained.
2) 세포 용해 용액을 넣고, 초음파 파쇄기로 조직을 분쇄시키고 면역브라팅을 위해 준비한다.2) Add the cell lysis solution, crush the tissue with an ultrasonicator, and prepare for immunoblotting.
3) 관절 조직은 Trisol 용액을 넣고 초음파 분쇄기에서 조직을 분쇄시키고, 원심분리하고 전체 RNA 분리를 위해 Trisol 용액을 단백질과 DNA를 침전시켜 원심분리후 상층액에서 전체 RNA를 회수하고, oligo-dT 프라이머와 역전사 효소를 이용하여 c-DNA를 합성하여 정량적 qRT-PCR와 면역 브라팅을 시도하였다.3) For joint tissue, add Trisol solution, pulverize the tissue in an ultrasonic grinder, centrifuge, and precipitate protein and DNA with Trisol solution to isolate total RNA. Total RNA is recovered from the supernatant after centrifugation, and oligo-dT primer is added. and reverse transcriptase were used to synthesize c-DNA, and quantitative qRT-PCR and immunoblotting were attempted.
그 결과, 도 4A - 4B 를 참조하면, 콩기름을 사용한 대조군에 발의 붓기에 비해 BMDA(FMJ-G0)와 DMMA(FMJ-G4)을 경구 투여시킨 마우스는 발의 붓기가 훨씬 낮은 결과를 보였다. BMDA(FMJ-G0) 와 DMMA(FMJ-G4) 의 경구 투여시 콜라겐에 의하여 유도된 류마티스에 의한 몸무게 감소는 회복시키지 못하였으나(도 4B), 대조군에 비해, BMDA(FMJ-G0) 와 DMMA(FMJ-G4)를 처리한 쥐의 지라는 길이가 줄어들어 있었고, 무게도 감소되어 있었다 (도 4C - 4D).As a result, referring to Figures 4A-4B, compared to the swelling of the feet in the control group using soybean oil, the swelling of the feet of mice administered orally with BMDA (FMJ-G0) and DMMA (FMJ-G4) was much lower. Oral administration of BMDA(FMJ-G0) and DMMA(FMJ-G4) did not restore body weight loss due to collagen-induced rheumatism (Figure 4B), but compared to the control group, BMDA(FMJ-G0) and DMMA( The spleen of mice treated with FMJ-G4) was reduced in length and weight (Figures 4C - 4D).
한편, 도 5A -5B를 보면, 관절 조직을 염색하여 조사하였을 때, 콜라겐 유도하여 콩기름을 경구 투여한 쥐는 심한 염증과 윤활막염이 관찰 되었으나, BMDA(FMJ-G0) 와 DMMA(FMJ-G4)의 경구투여는 이런 염증과 활막염이 상당 부분 줄어들었음을 관찰할 수 있다. 특히, BMDA(FMJ-G0)의 경구투여에서 염증의 현저한 감소가 관찰되었다.Meanwhile, looking at Figures 5A-5B, when joint tissue was stained and examined, severe inflammation and synovitis were observed in mice that were orally administered soybean oil to induce collagen, but BMDA (FMJ-G0) and DMMA (FMJ-G4) It can be observed that oral administration significantly reduces inflammation and synovitis. In particular, a significant reduction in inflammation was observed upon oral administration of BMDA (FMJ-G0).
한편, 관절부위에 염증 사이토카인을 qRT-PCR로 발현을 조사하니, 마찬가지로 콩기름을 투여한 마우스 지라에서 낮은 염증 사이토카인 TNF-α, IL-1β, IL-6 이 관찰되었다 (도 6A). 이와는 반대로 항산화 반응에 관여하는 두 단백질 HO-1와 Nrf2의 발현은 BMDA(FMJ-G0) 와 DMMA(FMJ-G4)의 경구 투여한 동물의 관절부위에서 증가되어 나타났다(도 6B).Meanwhile, when the expression of inflammatory cytokines in the joint area was examined using qRT-PCR, low levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 were observed in the spleen of mice administered soybean oil (Figure 6A). In contrast, the expression of HO-1 and Nrf2, two proteins involved in antioxidant response, was increased in the joints of animals administered orally with BMDA (FMJ-G0) and DMMA (FMJ-G4) (Figure 6B).
무엇보다도, 3주간의 BMDA(FMJ-G0)와 DMMA(FMJ-G4)의 경구 투여는 간독성의 지표로 알려진 AST 및 ALT 효소의 활성을 증가시키지 않음을 아무 것도 처리하지 않은 대조구 마우스 혈청과 비슷한 효소 활성을 나타내는 결과로 확인하였다(도 7 참조).Above all, oral administration of BMDA (FMJ-G0) and DMMA (FMJ-G4) for 3 weeks did not increase the activity of AST and ALT enzymes, known as indicators of hepatotoxicity, similar to the serum of untreated control mice. This was confirmed as a result showing activity (see Figure 7).
<실시예 3: BMDA(FMJ-G0)의 유도체 합성 및 이의 항염 효능 평가><Example 3: Synthesis of derivative of BMDA (FMJ-G0) and evaluation of its anti-inflammatory efficacy>
상기 실시예 1와 반응물질을 달리한 것을 제외하고는 동일한 방법으로 FMJ-G0의 유도체인 벤질-데실-에틸-아민(FMJ-G1), 벤틸-도데실-메틸-아민(FMJ-G2), 데실-)4-플루오로-벤질)-메틸-아민(FMJ-G3)를 각각 합성하였다.Benzyl-decyl-ethyl-amine (FMJ-G1), a derivative of FMJ-G0, bentyl-dodecyl-methyl-amine (FMJ-G2), and Decyl-)4-fluoro-benzyl)-methyl-amine (FMJ-G3) was synthesized, respectively.
구체적으로, FMJ-G1 유도체는 각각 1M 의 농도로 N-벤질에틸아민(N-benzylethylamine)와 데크알데하이드(decanal)를, FMJ-G2 유도체는 N-벤질메틸아민(N-benzylmethylamine)와 도데칸알(dodecanal)을, 그리고 FMJ-G3 유도체는 1-(4-플루오로페닐)-N-메틸메탄아민(1-(4-flurophenyl)-N-methylmethanamine)과 데크알데하이드(decanal)을 메탄올에 섞어, 환원적 아미노화 (the reductive amination) 방법으로 합성하여 컬럼을 통하여 정제하였다. 합성된 물질들의 화학 구조는 하기 화학식 1-3 내지 1-5로 표시된다. (도 8A 참조)Specifically, the FMJ-G1 derivative contains N-benzylethylamine and decanal at a concentration of 1M, and the FMJ-G2 derivative contains N-benzylmethylamine and dodecanal ( dodecanal), and the FMJ-G3 derivative is reduced by mixing 1-(4-fluorophenyl)-N-methylmethanamine and decanal in methanol. It was synthesized using the reductive amination method and purified through a column. The chemical structures of the synthesized materials are represented by the following formulas 1-3 to 1-5. (See Figure 8A)
[화학식 1-3][Formula 1-3]
[화학식 1-4][Formula 1-4]
[화학식 1-5][Formula 1-5]
이후, 합성된 FMJ-G0의 유도체 FMJ-G1, FMJ-G2, FMJ-G3 를 THP-1 세포주에 1시간 동안 4 μM 농도에서 전처리하고, 지질 다당체(1 μg/mL)가 첨가된 조건에서 4시간 동안 그 세포주를 배양한다. 바로 그 세포주를 회수하여 염증성 사이토카인 합성에 관여되는 신호경로를 확인하고 그 결과를 도 8B에 나타냈다.Afterwards, the synthesized derivatives of FMJ-G0, FMJ-G1, FMJ-G2, and FMJ-G3, were pretreated in the THP-1 cell line at a concentration of 4 μM for 1 hour, and then incubated for 4 hours in the presence of lipopolysaccharide (1 μg/mL). Cultivate the cell line for an hour. The cell line was recovered, the signaling pathway involved in inflammatory cytokine synthesis was identified, and the results are shown in Figure 8B.
그 결과, FMJ-G1, FMJ-G2 및 FMJ-G3 의 전처리는 지질다당체(LPS)에 의한 p38 MAP 키나아제, JNK, 그리고 MK2 인산화를 억제하는 결과를 보였으며, FMJ-G0 유도체 화합물이 염증 반응을 억제함을 확인할 수 있었다.As a result, pretreatment with FMJ-G1, FMJ-G2, and FMJ-G3 showed that lipopolysaccharide (LPS)-induced phosphorylation of p38 MAP kinase, JNK, and MK2 was inhibited, and FMJ-G0 derivative compounds inhibited the inflammatory response. Suppression could be confirmed.
<실시예 4: BMDA(FMJ-G0)와 그 유도체를 포함하는 화장료 조성물의 제조 및 아토피성 피부염 개선 효능 평가><Example 4: Preparation of a cosmetic composition containing BMDA (FMJ-G0) and its derivatives and evaluation of efficacy in improving atopic dermatitis>
1. 화장료 조성물 제조1. Preparation of cosmetic composition
유리 튜브 (15 ml)에 콩기름 (Sigma-Aldrich) 2 mL에 올리브 왁스 0.3 g을 넣고, 75℃ 수욕조(water-bath)에 넣어, 10분 간격으로 교반(vortex)을 하면서 올리브 왁스가 녹을 수 있도록 30분간 중탕한다. 같은 조건에서, 정제수 7.7 ml을, 75℃ 수욕조(water-bath)에 넣어 30분간 데워준다. 다음으로, 정제수 7.5 ml을 올리브 왁스가 들어 있는 튜브에 붓고, 교반(vortex)하여 잘 섞어준다. 이후, 상기 실시예 1, 실시예 3에서 합성된 BMDA 및 이의 유도체(FMJ-G0, FMJ-G4, FMJ-G1, FMJ-G2, FMJ-G3) 30 mg (0.3%) 를 넣어 잘 섞어준 뒤에 얼음 안에서 식혀 화장품 크림 형태로 제조하였다.Add 0.3 g of olive wax to 2 mL of soybean oil (Sigma-Aldrich) in a glass tube (15 ml), place in a 75°C water bath, and vortex at 10-minute intervals to allow the olive wax to melt. Boil in a double boiler for 30 minutes. Under the same conditions, 7.7 ml of purified water is placed in a 75°C water-bath and heated for 30 minutes. Next, pour 7.5 ml of purified water into the tube containing the olive wax and mix well by vortexing. Afterwards, 30 mg (0.3%) of BMDA and its derivatives (FMJ-G0, FMJ-G4, FMJ-G1, FMJ-G2, FMJ-G3) synthesized in Examples 1 and 3 were added and mixed well. It was cooled in ice and prepared in the form of cosmetic cream.
2. 아토피성 피부염 개선 효능 평가2. Evaluation of efficacy in improving atopic dermatitis
5주령의 Balb/C 마우스를 이용하여 아토피 피부염을 유도하기 위하여, 마우스 등의 털을 제모하고, 하루가 지난 뒤에 DNCB(2,4-dinitrochlorobenzne)을 아세톤과 올리브 오일(3:1)로 섞은 용액에 0.5% 용액을 만들어 150μL씩 3일간 연속하여 바른다. 이후, 1주일에 두 번씩 같은 농도로 제모된 등 부위를 도포하여 2주간 지속한다. 한편, 이렇게 유도된 아토피 피부염을 완화하기 위하여, 제조한 본 발명의 BMDA(FMJ-G0) 및 그 유도체 (FMJ-G4, FMJ-G1, FMJ-G2, FMJ-G3) 함유 화장품 크림을 아토피 피부염이 유발된 쥐 등 부위에 2주간 도포하여 피부염증의 변화를 살펴보았다.To induce atopic dermatitis using 5-week-old Balb/C mice, hair on the back of the mouse was removed, and one day later, a solution of DNCB (2,4-dinitrochlorobenzne) mixed with acetone and olive oil (3:1) was added. Make a 0.5% solution and apply 150 μL for 3 consecutive days. Afterwards, apply the same concentration to the hair-removed back area twice a week for 2 weeks. Meanwhile, in order to alleviate atopic dermatitis induced in this way, the cosmetic cream containing BMDA (FMJ-G0) and its derivatives (FMJ-G4, FMJ-G1, FMJ-G2, FMJ-G3) of the present invention was used to treat atopic dermatitis. Changes in skin inflammation were observed by applying it to the affected area on the back of mice for two weeks.
그 결과, 도 9A에 나타난 바와 같이, BMDA(FMJ-G0)와 DMMA(FMJ-G4)가 들어 있는 화장품 크림은 확연하게, DNCB로 유도된 아토피 피부염을 완화시켰으며, 완화된 피부에 털이 다시 자라나오는 부위도 관찰되었다. 또한, 도 9B를 보면, DNCB로 유도된 급성 아토피 피부염에 면역세포들이 활성화되어 지라가 크게 나타남을 관찰할 수 있었으나, BMDA(FMJ-G0)와 DMMA(FMJ-G4) 가 들어 있는 화장품 크림의 피부 도포한 마우스의 지라는 거의 아토피를 유도하지 않은 마우스의 지라와 크기가 비슷함을 관찰하였다. 그리고 사타구니 림프절(Inguinal lymph node) 의 크기도 지라와 같은 패턴의 결과를 얻었다.As a result, as shown in Figure 9A, the cosmetic cream containing BMDA (FMJ-G0) and DMMA (FMJ-G4) clearly alleviated DNCB-induced atopic dermatitis, and hair regrowth occurred on the alleviated skin. The area where it comes out was also observed. In addition, looking at Figure 9B, it was observed that immune cells were activated in acute atopic dermatitis induced by DNCB and the spleen appeared large, but the skin of the cosmetic cream containing BMDA (FMJ-G0) and DMMA (FMJ-G4) It was observed that the spleen of the applied mice was almost similar in size to the spleen of mice that did not induce atopy. Also, the size of the inguinal lymph node showed the same pattern as the spleen.
한편, 상용 스테로이드 연고(리도맥스) (0.15%) 를 같은 조건으로 피부에 도포한 결과, 유효 성분이 들어 있지 않은 화장품 크림의 비교군(vehicle)과 유사한 피부염 정도와 지라 크기, 림프 크기를 나타낸 결과를 확인하였다(도 9A - B). Meanwhile, as a result of applying a commercial steroid ointment (Lidomax) (0.15%) to the skin under the same conditions, the results showed the degree of dermatitis, spleen size, and lymph size similar to the comparison group (vehicle) of a cosmetic cream that does not contain active ingredients. was confirmed (Figures 9A - B).
또한, 실시예 3에서 합성된 유도체를 함유한 화장품 크림을 도포한 결과를 나타낸 도 9C를 보면, FMJ-G1와 FMJ-G3 화장품 크림의 도포는 아토피 피부염을 현저히 완화시킴을 관찰 할 수 있다. 하지만, FMJ-G2 화장품 크림의 처리는 마치 비교군(Vehicle)처럼 DNCB에 의한 급성 피부염을 진행을 막지 못하는 결과를 보였다. 이러한 결과는 지라와 림프의 크기와 상당히 밀접한 연관관계를 가짐을 알 수 있다. 즉, 도 9D를 보면, FMJ-G2 포함 화장품 크림이 도포된 마우스의 지라와 림프의 크기가 비교군(Vehicle)이 처리된 마우스와 같이 커져 있는 것을 확인할 수 있다.In addition, looking at Figure 9C, which shows the results of applying the cosmetic cream containing the derivative synthesized in Example 3, it can be observed that the application of FMJ-G1 and FMJ-G3 cosmetic cream significantly alleviates atopic dermatitis. However, treatment with FMJ-G2 cosmetic cream did not prevent the progression of acute dermatitis caused by DNCB, like the comparison group (Vehicle). It can be seen that these results have a very close relationship with the size of the spleen and lymph. That is, looking at Figure 9D, it can be seen that the size of the spleen and lymph of the mouse to which the cosmetic cream containing FMJ-G2 was applied was enlarged like that of the mouse treated with the comparison group (Vehicle).
도 10A와 10B는 FMJ-G0와 FMJ-G4를 피부에 도포함에 의해, DNCB에 의한 급성 피부염을 현저히 막아 진피의 두께가 상당히 가라앉은 모습을 보여 주고 있다. Figures 10A and 10B show that by applying FMJ-G0 and FMJ-G4 to the skin, acute dermatitis caused by DNCB was significantly prevented and the thickness of the dermis decreased significantly.
도 10의 A 및 B의 결과는, 도 9와 같이 상기 그룹의 마우스 등쪽에 피부조직을 떼어 내어, 10% 포름 알데히드에 48시간 두어 고정시키고, 파라핀 조각을 만들고, 4 um로 두께로 얇게 조각을 만들어 hematoxylin-esoin 염색을 하여 Leica 응용 프로그램(Leica Microsystems, Swistzerland)이 장착된 광학 현미경으로 훼손된 피부 조직이 FMJ-G0와 -G4에 의하여 회복되었는지 조사한 결과이다. The results in A and B of Figure 10 are as shown in Figure 9, skin tissue was removed from the back of the mice in the above group, fixed in 10% formaldehyde for 48 hours, made into paraffin slices, and sliced into thin slices with a thickness of 4 um. This is the result of examining whether damaged skin tissue was recovered by FMJ-G0 and -G4 using a light microscope equipped with a Leica application (Leica Microsystems, Swistzerland) after hematoxylin-esoin staining.
FMJ-G0/G4의 처리는 DNCB에 의한 염증으로 인한 진피층의 두께가 얇아지는 짐이 확인된다. 진피 층은 도 10의 A의 사진에 위에서부터 2번째 층이다. 첫 번째 진한 보라색 층은 표피 층이고, 그 아래는 옆은 분홍색 층이 진피 층이고, 그 아래의 진한 색은 피하층 그 아래는 근육에 해당한다. It is confirmed that the treatment of FMJ-G0/G4 causes the thickness of the dermal layer to become thinner due to inflammation caused by DNCB. The dermal layer is the second layer from the top in the photo of A in Figure 10. The first dark purple layer is the epidermis layer, the pink layer below it is the dermis layer, and the dark color below it corresponds to the subcutaneous layer and the muscles below it.
도 10의 C는 토루이딘-블루(toluidine-blue) 염색을 통하여 FMJ-G0와 FMJ-G4의 처리는 진피에 비만세포의 침습을 막아주어 진피에서 염증 반응을 억제함을 제공한다. 도 10의 C는 도 10A-B에서 준비된 얇은 조각의 일부를 toluidine-blue 용액으로 염색하여 상기의 방법으로 진피층에 침습하여 들어온 비만세포를 광학 현미경으로 관찰한 결과이다. 이런 진피층에 비만 세포의 침습을 방해하여 진피층에서 비만세포으로 부터 염증을 보호한다.Figure 10C shows that treatment with FMJ-G0 and FMJ-G4 prevents mast cell invasion into the dermis and suppresses inflammatory response in the dermis through toluidine-blue staining. Figure 10C shows the results of staining part of the thin slice prepared in Figures 10A-B with toluidine-blue solution and observing mast cells that had invaded the dermal layer using the above method using an optical microscope. It prevents mast cell invasion into the dermal layer and protects against inflammation from mast cells in the dermal layer.
도 10의 D는 FMJ-G0와 FMJ-G4를 처리한 마우스에 혈액 내에서 알러지 반응과 밀접한 연관이 있는 IgE의 농도 또한 현전히 비교군과 비교하였을 때, 낮음을 제공한다. 도 10의 D는 도 9에서 아토피 피부염을 유발하고, FMJ-G0와 -G4를 처리한 후 2주 뒤에 상기 그룹들의 쥐들의 간정맥에서 혈액 (500 ul)를 채취하여, 30분간 상온에 방치한 후, 원심 분리 뒤에 혈청을 분리하여 준비하고, 이렇게 준비된 혈청을 이용하여 ELISA 방법을 통하여 알러지 반응에 관련된 IgE 농도를 측정한 결과이다. Figure 10D shows that the concentration of IgE, which is closely related to allergic reactions, in the blood of mice treated with FMJ-G0 and FMJ-G4 was also significantly lower compared to the comparison group. In Figure 10D, atopic dermatitis was induced in Figure 9, and blood (500 ul) was collected from the hepatic vein of the rats in the above groups 2 weeks after treatment with FMJ-G0 and -G4, and left at room temperature for 30 minutes. , Serum was separated and prepared after centrifugation, and the IgE concentration related to allergic reaction was measured using the prepared serum using ELISA method.
96well plate에 anti-mouse IgE (Pharmingen, CA, USA)를 PBS (pH 7.4) 로 희석하여 96 well plate에 100 μL씩 각각 코팅한 다음, 4℃에서 12시간 동안 방치하였다. 이 plate를 0.05% tween이 함유된 PBS로 세정 후 1% BSA, 5% sucrose, 0.05% NaN3를 함유한 PBS로 1시간동안 blocking을 실시하였다. Washing buffer를 이용하여 여러 번 세정한 다음 recombinant IgE 및 혈청을 첨가한 후 37℃에서 2시간 동안 반응시킨 후 각 well을 다시 세정하고 biotinylated IgE (Pharmingen,CA, USA)를 첨가하여 이를 다시 2시간 동안 반응시켰다. Well을 세척한 다음 avidin peroxidase를 첨가하고 37℃에서 30분동안 반응시킨 후, 다시 well을 세정한 다음 기질인 ABTS 용액을 첨가하여, ELISA reader (Epoch2, BioTek, VT, USA)를 사용하여 405 nm에서 흡광도를 측정하였다. FMJ-G0/G4의 처리는 알러지 반응에 관련된 IgE생성도 억제함을 알 수 있다.Anti-mouse IgE (Pharmingen, CA, USA) was diluted with PBS (pH 7.4) in a 96-well plate, 100 μL was coated on each 96-well plate, and the mixture was left at 4°C for 12 hours. The plate was washed with PBS containing 0.05% tween and then blocked for 1 hour with PBS containing 1% BSA, 5% sucrose, and 0.05% NaN3. After washing several times using washing buffer, recombinant IgE and serum were added and reacted at 37°C for 2 hours. Each well was washed again and biotinylated IgE (Pharmingen, CA, USA) was added and incubated for another 2 hours. reacted. After washing the wells, add avidin peroxidase and react at 37°C for 30 minutes, wash the wells again, add ABTS solution as a substrate, and scan at 405 nm using an ELISA reader (Epoch2, BioTek, VT, USA). The absorbance was measured. It can be seen that treatment with FMJ-G0/G4 also suppresses IgE production related to allergic reactions.
도 11은 도 9에서 설명한 바와 같이 아토피 피부염을 유발하고, FMJ-G0와 -G4를 처리한 후 2주 뒤에 상기 그룹들의 쥐들의 피부조직을 일부를 Trisol 용액을 넣고 초음파 분쇄기에서 조직을 분쇄시키고, 원심분리하고 전체 RNA 분리를 위해 Trisol 용액을 단백질과 DNA를 침전시켜 원심 분리 후 상층액에서 전체 RNA를 회수하고, oligo-dT 프라이머와 역전사 효소를 이용하여 c-DNA를 합성하여, TNF-α, IL-1β, IL-6, iNOS, Cox2 전사체양을 qRT-PCR의 정량 데이터이다. Figure 11 shows atopic dermatitis as described in Figure 9, and 2 weeks after treatment with FMJ-G0 and -G4, some of the skin tissues of the rats in the above groups were pulverized in an ultrasonic grinder by adding Trisol solution, After centrifugation, proteins and DNA were precipitated using Trisol solution to separate total RNA. After centrifugation, total RNA was recovered from the supernatant. c-DNA was synthesized using oligo-dT primer and reverse transcriptase, and TNF-α, IL-1β, IL-6, iNOS, and Cox2 transcript amounts are quantitative data from qRT-PCR.
DNCB를 처리된 비교군의 피부에서 염증성 사이토카인 TNF-α, IL-1β, 그리고 IL-6, 염증성 매개체(NO, PDE2)를 만드는 단백질 iNOS와 COX2 들의 전사체의 양이 급격히 증가 되어 나타나며, 여기에 FMJ-G0와 -G4의 처리는 현격히 이들의 전사체의 양을 낮추게 하였다(도 11A-C). In the skin of the comparison group treated with DNCB, the amount of transcripts of the inflammatory cytokines TNF-α, IL-1β, and IL-6, and the proteins iNOS and COX2 that produce inflammatory mediators (NO, PDE2) were rapidly increased. Treatment with FMJ-G0 and -G4 significantly lowered the amount of their transcripts (Figure 11A-C).
이들의 단백질들의 전사에 영향을 미치는 신호 단백질의 활성을 면역브라팅으로 조사하였을 때, 앞선 결과를 지지 하듯이 FMJ-G0와 -G4 처리는 염증에 관련이 있는 JNK, p38MAPK 그리고 NF-κB의 인산화 수준을 비교군에 비해 상당히 낮추게 한다(도 11D). When the activity of signaling proteins that affect the transcription of these proteins was examined by immunoblotting, supporting the previous results, FMJ-G0 and -G4 treatment resulted in phosphorylation of JNK, p38MAPK, and NF-κB, which are related to inflammation. The level is significantly lowered compared to the comparison group (Figure 11D).
상기에서는 본 발명의 바람직한 실시예를 참조하여 설명하였지만, 해당 기술 분야의 숙련된 당업자는 하기의 특허 청구 범위에 기재된 본 발명의 사상 및 영역으로부터 벗어나지 않는 범위 내에서 본 발명을 다양하게 수정 및 변경시킬 수 있음을 이해할 수 있을 것이다.Although the present invention has been described above with reference to preferred embodiments, those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention as set forth in the following patent claims. You will understand that it is possible.
Claims (22)
[화학식 1]
상기 화학식 1에서,
R1 은 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고,
R2 및 R3 는 서로 독립적으로 탄소수 1 내지 5의 알킬기이다.An anti-inflammatory composition comprising a compound represented by the following formula (1) as an active ingredient:
[Formula 1]
In Formula 1,
R 1 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms,
R 2 and R 3 are independently alkyl groups having 1 to 5 carbon atoms.
하기 화학식 1-1 내지 화학식 1-5 중에서 선택되는 화합물을 유효 성분으로 포함하는 항염증용 조성물:
[화학식 1-1]
[화학식 1-2]
[화학식 1-3]
[화학식 1-4]
[화학식 1-5]
According to paragraph 1,
An anti-inflammatory composition comprising a compound selected from the following Chemical Formulas 1-1 to 1-5 as an active ingredient:
[Formula 1-1]
[Formula 1-2]
[Formula 1-3]
[Formula 1-4]
[Formula 1-5]
상기 조성물은 아토피성 피부염, 류마티스 관절염 또는 궤양성 대장염을 포함하는 염증성 질환에 치료 효과를 갖는 항염증용 조성물.According to paragraph 1,
The composition is an anti-inflammatory composition having a therapeutic effect on inflammatory diseases including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis.
상기 조성물은 지질다당체에 의해 유도된 p38 MAP 키나아제와 JNK 의 활성화, 발현 및 생성을 억제하고, p38 MAPK-MK2 로 연결되는 염증 관련 신호 전달 경로를 억제하는 것을 특징으로 하는 항염증용 조성물.According to paragraph 1,
The composition is an anti-inflammatory composition, characterized in that it inhibits the activation, expression, and production of p38 MAP kinase and JNK induced by lipopolysaccharide, and inhibits the inflammation-related signaling pathway connected to p38 MAPK-MK2.
상기 조성물은 TNF-α, IL-1β 또는 IL-6 에서 선택되는 전염증성 사이토카인의 생성을 억제하고, NF- κB 의 전사인자 활성을 억제하는 것을 특징으로 하는 항염증용 조성물.According to paragraph 1,
The composition is an anti-inflammatory composition, characterized in that it inhibits the production of pro-inflammatory cytokines selected from TNF-α, IL-1β or IL-6 and inhibits the transcription factor activity of NF-κB.
상기 조성물은 HO-1 (Heme oxygenase 1) 또는 Nrf2 (nuclear factor erythroid-related factor 2)의 발현을 증가시켜 항산화 효능을 갖는 것을 특징으로 하는 항염증용 조성물.According to paragraph 1,
The composition is an anti-inflammatory composition characterized in that it has antioxidant efficacy by increasing the expression of HO-1 (Heme oxygenase 1) or Nrf2 (nuclear factor erythroid-related factor 2).
상기 조성물은 케모카인 CINC-3 의 생성을 억제시키는 것을 특징으로 하는 항염증용 조성물.According to paragraph 1,
The composition is an anti-inflammatory composition characterized in that it inhibits the production of the chemokine CINC-3.
[화학식 2]
상기 화학식 2에서,
R4 는 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고,
R5 는 탄소수 1 내지 5의 알킬기이다.A cosmetic composition for improving atopic dermatitis comprising a compound represented by the following formula (2) as an active ingredient:
[Formula 2]
In Formula 2,
R 4 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms,
R 5 is an alkyl group having 1 to 5 carbon atoms.
하기 화학식 1-1, 1-2, 1-3 및 1-5 로 표시되는 화합물 중에서 선택되는 화합물을 유효 성분으로 포함하는 아토피성 피부염 개선용 화장료 조성물:
[화학식 1-1]
[화학식 1-2]
[화학식 1-3]
[화학식 1-5]
According to clause 8,
A cosmetic composition for improving atopic dermatitis comprising as an active ingredient a compound selected from the compounds represented by the following formulas 1-1, 1-2, 1-3 and 1-5:
[Formula 1-1]
[Formula 1-2]
[Formula 1-3]
[Formula 1-5]
상기 화장료 조성물이 피부 보습 성분, 화장품 제형 성분, 향료, 보존제, 및 정제수로 이루어진 군으로부터 선택된 1종 이상을 더 포함하는 아토피성 피부염 개선용 화장료 조성물.According to clause 8,
A cosmetic composition for improving atopic dermatitis, wherein the cosmetic composition further includes at least one selected from the group consisting of skin moisturizing ingredients, cosmetic formulation ingredients, fragrances, preservatives, and purified water.
상기 화장료 조성물의 제형이 화장수, 크림, 에멀젼, 에센스, 겔, 세럼, 팩, 파우더, 피부외용연고, 첩보제, 현탁액, 스프레이 또는 미용액인 것인 아토피성 피부염 개선용 화장료 조성물.According to any one of claims 8 to 10,
A cosmetic composition for improving atopic dermatitis, wherein the formulation of the cosmetic composition is lotion, cream, emulsion, essence, gel, serum, pack, powder, external skin ointment, patch, suspension, spray or serum.
[화학식 1]
상기 화학식 1에서,
R1 은 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고,
R2 및 R3 는 서로 독립적으로 탄소수 1 내지 5의 알킬기이다.Pharmaceutical composition for preventing or treating rheumatoid arthritis comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
R 1 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms,
R 2 and R 3 are independently alkyl groups having 1 to 5 carbon atoms.
하기 화학식 1-1 또는 화학식 1-2로 표시되는 화합물을 유효 성분으로 포함하는 류마티스 관절염의 예방 또는 치료용 약학 조성물:
[화학식 1-1]
[화학식 1-2]
According to clause 12,
Pharmaceutical composition for preventing or treating rheumatoid arthritis comprising a compound represented by the following Chemical Formula 1-1 or Chemical Formula 1-2 as an active ingredient:
[Formula 1-1]
[Formula 1-2]
상기 화학식 1로 표시되는 화합물은 하기 화학식 1-1로 표시되는 화합물인 것인 류마티스 관절염의 예방 또는 치료용 약학 조성물:
[화학식 1-1]
According to clause 13,
A pharmaceutical composition for preventing or treating rheumatoid arthritis, wherein the compound represented by Formula 1 is a compound represented by the following Formula 1-1:
[Formula 1-1]
상기 약학 조성물은 경구 투여용임을 특징으로 하는 약학 조성물.According to clause 12,
A pharmaceutical composition, characterized in that the pharmaceutical composition is for oral administration.
상기 화학식 1로 표시되는 화합물이 15 내지 25 mg/kg 의 용량으로 경구 투여되기에 적합한 단위 투여 형태로 제제화되는 것을 특징으로 하는 약학 조성물.According to clause 15,
A pharmaceutical composition, characterized in that the compound represented by Formula 1 is formulated in a unit dosage form suitable for oral administration at a dose of 15 to 25 mg/kg.
[화학식 1]
상기 화학식 1에서,
R1 은 수소, 플루오르, 탄소수 1 내지 5의 알킬기, 또는 탄소수 1 내지 5의 알콕시기이고,
R2 및 R3 는 서로 독립적으로 탄소수 1 내지 5의 알킬기이다.A pharmaceutical composition for treating ulcerative colitis comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
R 1 is hydrogen, fluorine, an alkyl group with 1 to 5 carbon atoms, or an alkoxy group with 1 to 5 carbon atoms,
R 2 and R 3 are independently alkyl groups having 1 to 5 carbon atoms.
하기 화학식 1-1 또는 화학식 1-2로 표시되는 화합물을 활성 성분으로 포함하는 궤양성 대장염 치료용 의약 조성물:
[화학식 1-1]
[화학식 1-2]
According to clause 17,
A pharmaceutical composition for treating ulcerative colitis comprising a compound represented by the following Chemical Formula 1-1 or Chemical Formula 1-2 as an active ingredient:
[Formula 1-1]
[Formula 1-2]
상기 화학식 1로 표시되는 화합물은 하기 화학식 1-2로 표시되는 화합물인 것인 궤양성 대장염 치료용 의약 조성물:
[화학식 1-2]
According to clause 18,
A pharmaceutical composition for treating ulcerative colitis, wherein the compound represented by Formula 1 is a compound represented by the following Formula 1-2:
[Formula 1-2]
상기 의약 조성물은 관장 투여용임을 특징으로 하는 의약 조성물.According to clause 17,
A pharmaceutical composition, characterized in that the pharmaceutical composition is for enema administration.
상기 의약 조성물은 1일당 유효 성분으로서 0.4 mg/kg 이하로 궤양성 대장염 환자에게 직접 관장 투여되는 것인 의약 조성물.According to clause 20,
The pharmaceutical composition is administered directly as an enema to a patient with ulcerative colitis in an amount of 0.4 mg/kg or less as an active ingredient per day.
상기 의약 조성물의 관장 투여는 케모카인 CINC-3 의 생성을 억제시키는 것을 특징으로 하는 의약 조성물.According to clause 17,
A pharmaceutical composition, characterized in that enema administration of the pharmaceutical composition inhibits the production of the chemokine CINC-3.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310908076.3A CN117482074A (en) | 2022-08-01 | 2023-07-24 | Anti-inflammatory composition comprising N-benzyl-N-methyl-dec-1-amine or derivative thereof as active ingredient |
| US18/363,123 US20240041796A1 (en) | 2022-08-01 | 2023-08-01 | Anti-inflammatory composition comprising n-benzyl-n-methyldecan-1-amine or a derivative thereof as an active ingredient |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20220095425 | 2022-08-01 | ||
| KR1020220095425 | 2022-08-01 |
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|---|---|
| KR20240017738A true KR20240017738A (en) | 2024-02-08 |
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| KR1020230059573A KR20240017738A (en) | 2022-08-01 | 2023-05-09 | Anti-inflammatory composition comprising N-benzyl-N-methyldecan-1-amine or a derivative thereof as an active ingredient |
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| Country | Link |
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| KR (1) | KR20240017738A (en) |
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