KR101849399B1 - Novel diterpene derivatives isolated from A. holophylla and identified and use thereof - Google Patents
Novel diterpene derivatives isolated from A. holophylla and identified and use thereof Download PDFInfo
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- KR101849399B1 KR101849399B1 KR1020170006292A KR20170006292A KR101849399B1 KR 101849399 B1 KR101849399 B1 KR 101849399B1 KR 1020170006292 A KR1020170006292 A KR 1020170006292A KR 20170006292 A KR20170006292 A KR 20170006292A KR 101849399 B1 KR101849399 B1 KR 101849399B1
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Abstract
Description
본 발명은 신규한 다이테르펜 유도체 또는 이의 약학적으로 허용 가능한 염, 및 이들을 유효성분으로 포함하는 신경 염증 또는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel diterpene derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising these as an active ingredient.
염증 반응은 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 효소 활성화, 염증매개물질 분비, 체액 침윤, 세포 이동, 조직 파괴 등 일련의 복합적인 생리적 반응과 홍반, 부종, 발열, 통증 등 외적 증상을 나타낸다. 정상인 경우 염증 반응은 외부감염원을 제거하고 손상된 조직을 재생하여 생명체 기능회복작용을 하지만, 항원이 제거되지 않거나 내부물질이 원인이 되어 염증반응이 과도하거나 지속적으로 일어나면 오히려 점막 손상을 촉진하고, 그 결과 일부에서는 암 발생 등의 질환을 이끈다.Inflammatory reactions are caused by various inflammatory mediators and immune cells in the local blood vessels and body fluids when they are infected with tissue (cell) damage or external infectious agents (bacteria, fungi, viruses, various kinds of allergens) It exhibits a series of complex physiological responses such as substance secretion, fluid infiltration, cell migration, and tissue destruction, and external symptoms such as erythema, edema, fever, and pain. In normal cases, the inflammatory reaction removes the external infectious agent and regenerates the damaged tissue to regenerate the organism's function. However, if the antigen is not removed or the internal substance causes the inflammatory reaction to occur excessively or continuously, Some lead to diseases such as cancer.
최근 염증반응이 신경퇴행을 유발하는 주요 기전의 하나라는 사실이 밝혀지고 있다. 즉 중추신경계에 존재하는 면역세포인 소신경교세포는 다양한 외인성, 내인성 물질로 인해 활성화될 수 있으며, 활성화된 소신경교세포는 염증성 사이토카인인 TNF-α 및 IL-1β, 일일산화질소, 프로스타글란딘, 초과산화물 등의 물질을 생산, 방출한다(Gao 등, J Neurochem, 81, 1285-97, 2002; Nelson, PT. 등, Ann Med, 34, 491-500, 2002; Griffin, W.S. 등, J Neuroinflammation, 3, 5, 2006). 이러한 물질들의 생성은 단기적으로는 면역반응을 유발하지만, 그 과도한 생산이나 지속적인 생산은 근접한 신경세포들의 사멸을 유도하여 결국 신경퇴행을 유발한다는 것이다. 또 사멸 중인 신경세포가 방출하는 물질들이 소신경교세포의 활성을 다시 유발하게 되므로, 신경퇴행은 지속적인 악순환에 빠지게 된다. 실제로 소신경교세포의 활성이 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 크로이츠펠트야콥병(Creutzfelt-Jakob Disease, CJD), 다발성 경화증 등의 다양한 퇴행성 신경질환과 관계가 있음이 보고된 바 있다.Recently, it has been found that inflammatory reaction is one of the main mechanism causing neurodegeneration. In other words, the immune cells of the central nervous system, the small ganglion cells, can be activated by various exogenous and endogenous substances, and the activated small glioblastoma cells are activated by the inflammatory cytokines TNF-α and IL-1β, daily nitric oxide, prostaglandins, (Neo et al., J Neurochem, 81, 1285-97, 2002; Nelson, PT et al., Ann Med, 34, 491-500, 2002; Griffin, WS et al., J Neuroinflammation, 3 , 5, 2006). The production of these substances induces an immune response in the short term, but excessive production or sustained production induces neuronal death of adjacent neurons, resulting in neural degeneration. In addition, since the substances released by the nerve cells that are killing lead to activation of the cervical ganglion cells, the neural degeneration falls into a constant vicious cycle. Actually, the activity of small glial cells has been reported to be related to various degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfelt-Jakob Disease (CJD) and multiple sclerosis.
이와 같이 퇴행성 뇌신경 질환에서의 신경염증성 반응의 중요성을 고려한다면, 이러한 소신경교세포 내에서 전염증성 매개 인자들의 발현 수준을 감소시킴으로써 신경염증 및 이로부터 발병될 수 있는 퇴행성 뇌신경 질환을 치료할 수 있다 할 것이다.Taking into consideration the importance of neuroinflammatory responses in degenerative brain diseases, it is possible to treat neuroinflammation and degenerative brain diseases that may be caused by it by decreasing the expression level of proinflammatory mediators in these small glial cells .
이에, 본 발명자들은 신경 염증 및/또는 치매와 같은 퇴행성 뇌질환을 예방 또는 치료할 수 있는 천연물 유래 화합물을 발굴하기 위하여 예의 연구 및 노력한 결과, 전나무 추출물로부터 분리하여 동정한 일련의 화합물들이 일산화질소의 생성을 억제하거나 신경성장인자(nerve growth factor; NGF)의 분비를 촉진함을 확인하고, 본 발명을 완성하였다.Accordingly, the inventors of the present invention have conducted intensive studies and efforts to discover compounds derived from natural materials that can prevent or treat degenerative brain diseases such as neuroinflammation and / or dementia. As a result, it has been found that a series of compounds identified from fir extract, And promotes the secretion of nerve growth factor (NGF). Thus, the present invention has been completed.
본 발명의 목적은 일련의 신규한 다이테르펜 유도체 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.It is an object of the present invention to provide a series of novel diterpene derivatives or pharmaceutically acceptable salts thereof.
본 발명의 다른 목적은 일련의 다이테르펜 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 신경 염증 또는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising a series of diterpene derivatives or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 상기 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 신경 염증 또는 퇴행성 뇌질환의 치료 방법을 제공하는 것이다.It is still another object of the present invention to provide a method for treating neuroinflammation or degenerative brain diseases comprising administering the pharmaceutical composition to a subject in need thereof.
본 발명의 또 다른 목적은 일련의 다이테르펜 유도체 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 신경 염증 또는 퇴행성 뇌질환의 예방 또는 개선용 건강기능성 식품 첨가물을 제공하는 것이다.It is still another object of the present invention to provide a health functional food additive for preventing or ameliorating neuroinflammation or degenerative brain diseases comprising a series of diterpene derivatives or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다:According to one aspect of the present invention, there is provided a compound represented by the following formula (1): < EMI ID =
[화학식 1][Chemical Formula 1]
상기 화학식에서,In the above formulas,
R1은 C1-6 알킬, C1-6 히드록시알킬, -COOH, -CH2OCOCH3 또는 
R2는 수소 또는 C1-6 알콕시이고,R 2 is hydrogen or C 1-6 alkoxy,
R3 및 R4는 각각 독립적으로 산소, 히드록시 또는 수소이거나,R 3 and R < 4 > are each independently oxygen, hydroxy or hydrogen,
R5는 부재하거나, 히드록시, C1-6 알콕시, 수소 또는 산소이고,R 5 is absent, hydroxy, C 1-6 alkoxy, hydrogen or oxygen,
R6는 수소, 히드록시 또는 산소이거나,R < 6 > is hydrogen, hydroxy or oxygen,
R5과 R6는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 6 may be connected to each other via one oxygen atom,
R7은 부재하거나, 히드록시, 산소 또는 C1-6 알콕시이거나,R 7 is absent, hydroxy, oxygen or C 1-6 alkoxy,
R6과 R7은 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 6 and R 7 may be connected to each other via one oxygen atom,
R8은 수소 또는 히드록시이고,R < 8 > is hydrogen or hydroxy,
R9는 수소 또는 산소이거나,R < 9 > is hydrogen or oxygen,
R7과 R9는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 9 may be connected to each other via one oxygen atom,
R5와 R9는 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 9 may be connected to each other via two oxygen atoms,
R10은 부재하거나, 수소, 또는 산소이고,R < 10 > is absent, hydrogen, or oxygen,
R7과 R10은 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 10 may be connected to each other via two oxygen atoms,
b1 내지 b6는 각각 독립적으로 단일결합 또는 이중결합임.b1 to b6 are each independently a single bond or a double bond.
예컨대, 상기 R1은 메틸, 히드록시메틸, -COOH, -CH2OCOCH3 또는 
R2는 수소 또는 메톡시이고,R < 2 > is hydrogen or methoxy,
R3 및 R4는 각각 독립적으로 산소, 히드록시 또는 수소이거나,R 3 and R < 4 > are each independently oxygen, hydroxy or hydrogen,
R5는 부재하거나, 히드록시, 메톡시, 수소 또는 산소이고,R < 5 > is absent, hydroxy, methoxy, hydrogen or oxygen,
R6는 수소, 히드록시 또는 산소이거나,R < 6 > is hydrogen, hydroxy or oxygen,
R5과 R6는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 6 may be connected to each other via one oxygen atom,
R7은 부재하거나, 히드록시, 산소 또는 메톡시이거나,R < 7 > is absent, hydroxy, oxygen or methoxy,
R6과 R7은 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 6 and R 7 may be connected to each other via one oxygen atom,
R8은 수소 또는 히드록시이고,R < 8 > is hydrogen or hydroxy,
R9는 수소 또는 산소이거나,R < 9 > is hydrogen or oxygen,
R7과 R9는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 9 may be connected to each other via one oxygen atom,
R5와 R9는 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 9 may be connected to each other via two oxygen atoms,
R10은 부재하거나, 수소, 또는 산소이고,R < 10 > is absent, hydrogen, or oxygen,
R7과 R10은 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 10 may be connected to each other via two oxygen atoms,
b1 내지 b6는 각각 독립적으로 단일결합 또는 이중결합일 수 있다.b1 to b6 each independently may be a single bond or a double bond.
구체적으로, 상기 화합물은Specifically, the compound
1) 
4) 
7) 
10) 
상기 본 발명의 화합물들은 전나무 추출물 또는 이의 분획물로부터 분리하여 동정한 다이테르펜 유도체일 수 있다. 예컨대, 전나무의 천연, 잡종, 변종식물의 뿌리, 지상부, 줄기, 가지, 잎, 열매 또는 식물 조직 배양물 등으로부터 추출하여 분획하여 수득할 수 있다. 예컨대, 전나무를 메탄올로 추출하고, n-헥산, 클로로포름, 에틸아세테이트, n-부탄올과 같은 일련의 유기용매로 차례로 분획하여 수득한 분획물로부터 분리하여 생산할 수 있으나, 이에 제한되지 않는다.The compounds of the present invention may be diterpene derivatives isolated from fir extract or fractions thereof. For example, it can be obtained by extracting and extracting from natural, hybrid, fungal root, ground part, stem, branch, leaf, fruit or plant tissue culture of fir, etc. For example, fir is extracted with methanol and separated from a fraction obtained by successive fractionation with a series of organic solvents such as n-hexane, chloroform, ethyl acetate, and n-butanol, but not limited thereto.
또 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 신경 염증 또는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물을 제공한다:In another aspect, the present invention provides a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1] [Chemical Formula 1]
상기 화학식에서,In the above formulas,
R1은 C1-6 알킬, C1-6 히드록시알킬, -COOH, -CH2OCOCH3 또는 
R2는 수소 또는 C1-6 알콕시이고,R 2 is hydrogen or C 1-6 alkoxy,
R3 및 R4는 각각 독립적으로 산소, 히드록시 또는 수소이거나,R 3 and R < 4 > are each independently oxygen, hydroxy or hydrogen,
R5는 부재하거나, 히드록시, C1-6 알콕시, 수소 또는 산소이고,R 5 is absent, hydroxy, C 1-6 alkoxy, hydrogen or oxygen,
R6는 수소, 히드록시 또는 산소이거나,R < 6 > is hydrogen, hydroxy or oxygen,
R5과 R6는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 6 may be connected to each other via one oxygen atom,
R7은 부재하거나, 히드록시, 산소 또는 C1-6 알콕시이거나,R 7 is absent, hydroxy, oxygen or C 1-6 alkoxy,
R6과 R7은 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 6 and R 7 may be connected to each other via one oxygen atom,
R8은 수소 또는 히드록시이고,R < 8 > is hydrogen or hydroxy,
R9는 수소 또는 산소이거나,R < 9 > is hydrogen or oxygen,
R7과 R9는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 9 may be connected to each other via one oxygen atom,
R5와 R9는 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 9 may be connected to each other via two oxygen atoms,
R10은 부재하거나, 수소, 또는 산소이고,R < 10 > is absent, hydrogen, or oxygen,
R7과 R10은 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 10 may be connected to each other via two oxygen atoms,
b1 내지 b6는 각각 독립적으로 단일결합 또는 이중결합임.b1 to b6 are each independently a single bond or a double bond.
예컨대, 상기 R1은 메틸, 히드록시메틸, -COOH, -CH2OCOCH3 또는 
R2는 수소 또는 메톡시이고,R < 2 > is hydrogen or methoxy,
R3 및 R4는 각각 독립적으로 산소, 히드록시 또는 수소이거나,R 3 and R < 4 > are each independently oxygen, hydroxy or hydrogen,
R5는 부재하거나, 히드록시, 메톡시, 수소 또는 산소이고,R < 5 > is absent, hydroxy, methoxy, hydrogen or oxygen,
R6는 수소, 히드록시 또는 산소이거나,R < 6 > is hydrogen, hydroxy or oxygen,
R5과 R6는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 6 may be connected to each other via one oxygen atom,
R7은 부재하거나, 히드록시, 산소 또는 메톡시이거나,R < 7 > is absent, hydroxy, oxygen or methoxy,
R6과 R7은 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 6 and R 7 may be connected to each other via one oxygen atom,
R8은 수소 또는 히드록시이고,R < 8 > is hydrogen or hydroxy,
R9는 수소 또는 산소이거나,R < 9 > is hydrogen or oxygen,
R7과 R9는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 9 may be connected to each other via one oxygen atom,
R5와 R9는 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 9 may be connected to each other via two oxygen atoms,
R10은 부재하거나, 수소, 또는 산소이고,R < 10 > is absent, hydrogen, or oxygen,
R7과 R10은 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 10 may be connected to each other via two oxygen atoms,
b1 내지 b6는 각각 독립적으로 단일결합 또는 이중결합일 수 있다.b1 to b6 each independently may be a single bond or a double bond.
구체적으로, 상기 화합물은Specifically, the compound
1) 
4) 
7) 
10) 
13) 
16) 
19) 
22) 
25) 
28) 
본 발명에 따른 화합물은 염증관련 인자로 알려진 일산화질소의 생성을 억제하거나, 신경성장인자의 분비를 촉진할 수 있으므로, 신경염증 또는 이로부터 발병할 수 있는 퇴행성 뇌질환의 예방 또는 치료에 사용될 수 있다.The compounds according to the present invention can inhibit the production of nitrogen monoxide known as an inflammation-related factor or promote the secretion of nerve growth factor and thus can be used for the prevention or treatment of neuroinflammation or degenerative brain diseases that may be caused therefrom .
본 발명에서 "신경염증"은 신경계, 즉 신경세포, 신경조직 등에 발생하는 염증성 반응을 포괄적으로 지칭하는 용어일 수 있다. 중추신경계에 존재하는 면역세포인 소신경교세포가 다양한 외인성, 내인성 물질로 인해 활성화되어, 염증성 인자인 일산화질소 등을 생산, 방출하는 현상을 포함할 수 있다. 이러한 물질들의 생성은 단기적으로는 면역반응을 유발하지만, 그 과도한 생산이나 지속적인 생산은 근접한 신경세포들의 사멸을 유도하여 결국 신경퇴행을 유발한다고 알려져 있다.In the present invention, "neuroinflammation" may be a term collectively referred to as an inflammatory reaction occurring in the nervous system, that is, a nerve cell, a neural tissue, or the like. Small intestinal gliomas, which are immune cells present in the central nervous system, can be activated by various exogenous and endogenous substances and produce and release inflammatory factors such as nitrogen monoxide. The production of these substances induces an immune response in the short term, but it is known that excessive production or sustained production induces neuronal degeneration by inducing the death of adjacent neurons.
본 발명에서 "퇴행성 뇌신경 질환"은 중추신경계의 신경세포에 퇴행성 변화가 나타나면서 여러 가지 증상을 유발하는 질환을 총칭하며, 구체적으로 인지 기능, 학습 또는 기억력이 손상되거나, 신경염증 반응을 동반하는뇌신경 질환을 포함할 수 있다. 예컨대, 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 약학적 조성물을 이용하여 예방 또는 치료할 수 있는, 상기 퇴행성 뇌질환은 혈관성 인지장애, 치매(dermentia), 알츠하이머(Alzheimer's disease), 파킨슨병(Parkinson's disease), 루이체병(Lewy body disease), 전측두엽 변성(frontotemporal lobar degeneration), 뇌졸중(Stroke), 뇌동맥 경화증(cerebral arteriosclerosis), 중풍, 헌팅턴병(Huntington's disease), 피크병(Pick's disease), 크로이츠펠트-야콥병(Creutzfeldt-Jakob disease), 근위축성 축삭 경화증(Amyotrophic lateral sclerosis), 다발성 경화증(multiple sclerosis), 허혈성 뇌질환(ischemic brain disease), 뇌경색(cerebral infarct), 피질기조퇴행(corticobasal degeneration), 퇴행성 핵상마비(progressive supranuclear palsy), 또는 다운증후군(Down syndrome)일 수 있다.The term "degenerative brain disease" in the present invention refers to diseases that cause degenerative changes in nerve cells of the central nervous system and cause various symptoms, and specifically, disorders of cognitive function, learning or memory, ≪ / RTI > For example, the degenerative brain diseases which can be prevented or treated by using a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient include vascular cognitive disorder, dermentia, Alzheimer's disease Parkinson ' s disease, Lewy body disease, frontotemporal lobar degeneration, stroke, cerebral arteriosclerosis, stroke, Huntington's disease, Pick's the present invention relates to the use of the compounds of the present invention for the treatment of diseases such as Creutzfeldt-Jakob disease, Amyotrophic lateral sclerosis, multiple sclerosis, ischemic brain disease, cerebral infarct, corticobasal degeneration, progressive supranuclear palsy, or Down syndrome.
본 발명에서 "예방"은 상기 조성물의 투여로 신경염증 또는 퇴행성 뇌질환의 발병을 억제 또는 지연시키는 모든 행위를 말하며, "치료"는 상기 조성물에 의해 신경염증 또는 퇴행성 뇌질환에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 말한다.In the present invention, "prevention" refers to any action that inhibits or delays the onset of neuroinflammation or degenerative brain disease upon administration of the composition, and "treatment" means that the composition alleviates symptoms due to neuroinflammation or degenerative brain disease It refers to all actions that benefitfully change.
본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형체 또는 희석제를 추가로 포함할 수 있다. 이때, 상기 조성물에 포함되는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염은 특별히 이에 제한되지 않으나, 조성물 총 중량에 대하여 0.001 중량% 내지 99 중량%로, 바람직하게는 0.01 중량% 내지 50 중량%를 포함할 수 있다.The pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may further comprise an appropriate carrier, adduct or diluent conventionally used in the production of a pharmaceutical composition. The compound of the present invention or a pharmaceutically acceptable salt thereof may be used in an amount of 0.001% by weight to 99% by weight, preferably 0.01% by weight to 50% by weight, based on the total weight of the composition, . ≪ / RTI >
상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결 건조제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있으며, 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 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 단순희석제인 물, 리퀴드파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition may be any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, nonaqueous solvents, suspensions, emulsions, And may be oral or parenteral formulations of various forms. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
또 다른 양태로서, 본 발명은 상기 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는 신경 염증 또는 퇴행성 뇌질환의 치료 방법을 제공한다.In another aspect, the present invention provides a method of treating neuroinflammation or degenerative brain disease comprising administering the pharmaceutical composition to a subject in need thereof.
본 발명에서 상기 개체는 상기 질환이 신경염증 또는 퇴행성 뇌질환이 발병하였거나 발병할 수 있는 인간을 포함한 모든 동물을 의미하며, 본 발명의 약학적 조성물을 상기 개체에 투여함으로써 개체에서 상기 질환이 발병하는 것을 차단하거나, 발병한 질환을 효율적으로 치료할 수 있다. 상기 약학적 조성물 및 신경염증 또는 퇴행성 뇌질환에 대해서는 상기에서 설명한 바와 같다.In the present invention, the term " individual " refers to all animals including humans, in which the disease has developed or may cause neuroinflammation or degenerative brain diseases. By administering the pharmaceutical composition of the present invention to the individual, Or can treat the disease that has occurred efficiently. The pharmaceutical composition and neuroinflammation or degenerative brain disease are as described above.
본 발명에서 "투여"는 어떠한 적절한 방법으로 신경염증 또는 퇴행성 뇌질환의 의심 개체에게 본 발명의 약학적 조성물을 도입하는 것으로서, 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.In the present invention, "administering " is intended to introduce the pharmaceutical composition of the present invention to suspect individuals of neuroinflammation or degenerative brain disease by any suitable method, and the administration route may include various routes of oral or parenteral administration ≪ / RTI >
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여할 수 있다.The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.
본 발명에서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The term " pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will vary depending on the species and severity, age, sex, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.
본 발명의 약학적 조성물은 신경염증 또는 퇴행성 뇌질환을 목적으로 하는 개체이면 특별히 한정되지 않고, 어떠한 것이든 적용 가능하다. 예를 들면, 원숭이, 개, 고양이, 토끼, 모르모트, 랫트, 마우스, 소, 양, 돼지, 염소 등과 같은 비인간동물, 인간, 조류 및 어류 등 어느 것이나 사용할 수 있으며, 상기 약학적 조성물은 비 경구, 피하, 복강 내, 폐 내 및 비강 내로 투여될 수 있고, 국부적 치료를 위해, 필요하다면 병변 내 투여를 포함하는 적합한 방법에 의하여 투여될 수 있다. 본 발명의 상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 예를 들어, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention is not particularly limited as long as it is a subject for neuroinflammation or degenerative brain disease, and any of them can be applied. For example, any non-human animal such as a monkey, a dog, a cat, a rabbit, a guinea pig, a rat, a mouse, a cattle, a sheep, a pig or a goat can be used. Subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and may be administered by a suitable method, including localized administration, if necessary, for localized treatment. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and body weight of the individual, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. For example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.
적합한 총 1일 사용량은 올바른 의학적 판단범위 내에서 처치의에 의해 결정될 수 있으며, 일반적으로 0.001 내지 1000 mg/kg의 양, 바람직하게는 0.05 내지 200 mg/kg, 보다 바람직하게는 0.1 내지 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다.Suitable total daily doses may be determined by the treatment within the scope of sound medical judgment and are generally in the range of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg can be administered once or several times a day.
또 다른 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 신경 염증 또는 퇴행성 뇌질환의 예방 또는 개선용 건강기능성 식품 첨가물을 제공한다:In another aspect, the present invention provides a health functional food additive for preventing or ameliorating a neuroinflammation or degenerative brain disease comprising, as an active ingredient, a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
상기 화학식에서,In the above formulas,
R1은 C1-6 알킬, C1-6 히드록시알킬, -COOH, -CH2OCOCH3 또는 
R2는 수소 또는 C1-6 알콕시이고,R 2 is hydrogen or C 1-6 alkoxy,
R3 및 R4는 각각 독립적으로 산소, 히드록시 또는 수소이거나,R 3 and R < 4 > are each independently oxygen, hydroxy or hydrogen,
R5는 부재하거나, 히드록시, C1-6 알콕시, 수소 또는 산소이고,R 5 is absent, hydroxy, C 1-6 alkoxy, hydrogen or oxygen,
R6는 수소, 히드록시 또는 산소이거나,R < 6 > is hydrogen, hydroxy or oxygen,
R5과 R6는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 6 may be connected to each other via one oxygen atom,
R7은 부재하거나, 히드록시, 산소 또는 C1-6 알콕시이거나,R 7 is absent, hydroxy, oxygen or C 1-6 alkoxy,
R6과 R7은 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 6 and R 7 may be connected to each other via one oxygen atom,
R8은 수소 또는 히드록시이고,R < 8 > is hydrogen or hydroxy,
R9는 수소 또는 산소이거나,R < 9 > is hydrogen or oxygen,
R7과 R9는 1개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 9 may be connected to each other via one oxygen atom,
R5와 R9는 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 5 and R 9 may be connected to each other via two oxygen atoms,
R10은 부재하거나, 수소, 또는 산소이고,R < 10 > is absent, hydrogen, or oxygen,
R7과 R10은 2개의 산소 원자를 매개로 서로 연결될 수 있으며,R 7 and R 10 may be connected to each other via two oxygen atoms,
b1 내지 b6는 각각 독립적으로 단일결합 또는 이중결합임.b1 to b6 are each independently a single bond or a double bond.
상기 신경염증 또는 퇴행성 뇌질환에 대해서는 상기에서 설명한 바와 같다.The nerve inflammation or degenerative brain disease is as described above.
본 발명에서 "개선"은 본 발명의 화합물 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물을 이용하여 예방 또는 치료되는 신경염증 또는 퇴행성 뇌신경 질환과 같은 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, the term "improvement" refers to the use of a composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient to prevent or treat symptoms of suspected or suspected diseases such as neuroinflammation or degenerative brain disease It refers to all acts that are improved or benefited.
구체적으로, 본 발명의 화합물 또는 이의 식품학적으로 허용 가능한 염을 신경염증 또는 퇴행성 뇌신경 질환의 예방 또는 개선을 목적으로 건강기능성 식품 조성물에 첨가할 수 있다.Specifically, a compound of the present invention or a pharmaceutically acceptable salt thereof may be added to a health functional food composition for the purpose of preventing or ameliorating neuroinflammation or degenerative brain disease.
본 발명의 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함할 수 있으며, 본 발명의 화합물 또는 이의 식품학적으로 허용 가능한 염을 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다.The food composition of the present invention may be in the form of pills, powders, granules, infusions, tablets, capsules or liquid preparations, and the kind of food to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be added There are no limitations, for example, various beverages, gums, tea, vitamin complex, and health supplement foods.
상기 식품 조성물에는 본 발명의 화합물 또는 이의 식품학적으로 허용 가능한 염 이외에도 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있으며, 이에 제한되지 않는다.In addition to the compound of the present invention or its pharmaceutically acceptable salt, other ingredients may be added to the food composition, and the kind thereof is not particularly limited. For example, it may contain various herbal medicine extracts, food-acceptable food-aid additives or natural carbohydrates such as ordinary food, but is not limited thereto.
상기 "식품보조첨가제"는 식품에 보조적으로 첨가될 수 있는 구성요소로서, 각 제형의 건강기능식품을 제조하는데 첨가될 수 있으며 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The above-mentioned "food-aid additive" is a component that can be added to food, and it can be added to make a health functional food of each formulation and can be appropriately selected and used by those skilled in the art. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated beverage. However, the types of the food auxiliary additives of the present invention are not limited by the above examples.
상기 천연 탄수화물의 예는 포도당, 과당 등의 단당류; 말토스, 수크로스 등의 이당류; 및 덱스트린, 시클로덱스트린 등의 다당류와, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이 있으며, 상기한 것 이외의 향미제로서 천연 향미제(타우마틴 등), 스테비아 추출물(레바우디오시드 Ａ, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose and the like; And polysaccharides such as dextrin and cyclodextrin and sugar alcohols such as xylitol, sorbitol and erythritol. In addition to the above, natural flavorings (such as tau mart), stevia extracts (rebaudioside A, Etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
본 발명의 식품 조성물에는 건강기능성 식품이 포함될 수 있다. 상기 "건강기능성 식품"은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 기능성이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 말한다. 본 발명의 건강기능성 식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다.The food composition of the present invention may include a health functional food. The above-mentioned "health functional food" refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids, and circles by using raw materials and components having useful functions in the human body. The term "functional" as used herein refers to the structure and function of the human body, which has a beneficial effect on health uses such as controlling nutrients or physiological actions. The health functional food of the present invention can be manufactured by a method commonly used in the art and can be prepared by adding raw materials and ingredients which are conventionally added in the art. Also, unlike general medicine, there is an advantage that there is no side effect that can occur when a medicine is used for a long time by using food as a raw material, and it is excellent in portability.
유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품의 제조 시에 본 발명의 화합물 또는 이의 식품학적으로 허용 가능한 염은 원료 조성물 중 1 내지 50 중량%, 바람직하게는 5 내지 10 중량%의 양으로 첨가될 수 있으나, 이에 제한되는 것은 아니다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다.The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, the compound of the present invention or a pharmaceutically acceptable salt thereof may be added in an amount of 1 to 50% by weight, preferably 5 to 10% by weight of the raw material composition, no. However, in the case of long-term ingestion intended for health and hygiene purposes or for the purpose of controlling health, the amount can also be used in the above-mentioned range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능성 식품을 모두 포함할 수 있다.There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, An alcoholic beverage, and a vitamin complex, and may include all health functional foods in a conventional sense.
본 발명의 화합물 또는 이의 식품학적으로 허용 가능한 염은 천연물인 전나무로부터 분리하여 동정한 물질로 독성이나 부작용이 없으면서도, 염증관련 인자인 일산화질소 발생을 억제하거나 신경전달물질 분비를 촉진할 수 있으므로 신경염증 또는 퇴행성 뇌질환의 예방 또는 치료에 유용하게 사용될 수 있다.The compound of the present invention or a pharmaceutically acceptable salt thereof is a substance isolated from a natural fir and is capable of inhibiting the generation of nitrogen monoxide, an inflammation-related factor, or promoting the secretion of neurotransmitters, without toxicity or side effects. Inflammatory or degenerative brain diseases.
도 1은 본 발명에 따른 전나무로부터 추출 및 분획하여 화학식 1 내지 28의 화합물을 수득하는 방법을 개략적으로 나타낸 도이다.
도 2는 본 발명에 따른 화합물 1 및 3의 주요 1H-1H COSY(굵은 선) 및 HMBC(화살표) 상관관계를 나타낸 도이다.
도 3은 본 발명에 따른 화합물 1, 3 및 6-9의 주요 NOESY 상관관계를 나타낸 도이다.
도 4는 본 발명에 따른 화합물 3, 6, 9, 10 및 11 유래의 두 개의 MTPA 에스테르의 δ 값(δ S-δ R) (ppm)을 나타낸 것이다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 schematically shows a method for obtaining compounds of
FIG. 2 is a graph showing the major 1 H- 1 H COZY (bold line) and HMBC (arrow) correlation of
Figure 3 shows the major NOESY correlations of
Figure 4 shows the δ values ( δ S - δ R ) (ppm) of two MTPA esters from
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.
실시예Example 1: 시료 준비 1: Sample preparation
2012년 1월 서울에서 전나무(A. holophylla) 줄기(trunk)를 채취하였으며, 식물은 발명자 중 한 명인 이강노 교수가 동정하였다. 확증표본(voucher specimen, SKKU-NPL 1205)은 대한민국 수원 소재의 성균관대학교 약학대학 식물표본실(herbarium)에 보관하고 있다.In January 2012, a trunk of A. holophylla was collected from Seoul, and the plant was identified by one of the inventors, Professor Yi Jangno. A voucher specimen (SKKU-NPL 1205) is stored in the herbarium of the College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
실시예Example 2: 추출 2: Extraction
전나무 줄기(5.0 kg)를 환류 하에 80% aq. 메탄올로 추출하고 여과하였다. 여과액을 감압 증류하여 메탄올 추출물(280 g)을 수득하였고, 증류수에 현탁시키고 n-헥산, CHCl3, EtOAc 및 n-부탄올로 연속적으로 분획하여 각각 23, 43, 17, 및 35 g의 잔여물을 수득하였다. The fir stalks (5.0 kg) were refluxed with 80% aq. Extraction with methanol and filtration. The filtrate was distilled under reduced pressure to obtain a methanol extract (280 g), suspended in distilled water and successively fractionated with n-hexane, CHCl 3 , EtOAc and n-butanol to obtain 23, 43, 17, ≪ / RTI >
구체적인 추출 및 분획 방법을 도 1에 예시하였다.Specific extraction and fractionation methods are illustrated in FIG.
실시예Example 3: 화합물의 분리 및 동정 3: Isolation and identification of compounds
n-헥산 가용성 분획(23g)의 화학적 연구를 통해, 대규모 컬럼 크로마토그래피 분리법(extensive column chromatography separation; RP-C18 실리카겔, 실리카겔, 및 HPLC 컬럼)을 사용하여, 하기 화합물 2, 4, 5, 6, 8-11, 17-18, 20-22, 24, 27 및 28의 다이테르펜 유도체를 분리하고 동정하였다.The following compounds 2, 4, 5, 6, 7, and 8 were prepared using the extensive column chromatography (RP-C18 silica gel, silica gel, and HPLC column) The diterpene derivatives of 8-11, 17-18, 20-22, 24, 27 and 28 were isolated and identified.
분리된 화합물들의 구조는 1H 및 13C NMR, DEPT, 1H-1H COSY, HMQC, HMBC, 및 NOESY 등의 다양한 NMR 분석법으로 확인하였다.The structures of the separated compounds were confirmed by various NMR analyzes such as 1 H and 13 C NMR, DEPT, 1 H- 1 H COZY, HMQC, HMBC, and NOESY.
또한, CHCl3 가용성 분획(20g)의 화학적 연구를 통해, 대규모 컬럼 크로마토그래피 분리법(extensive column chromatography separation; Lobar-A Si 60 컬럼, 실리카겔, 및 HPLC 컬럼)을 사용하여, 하기 화합물 1, 3, 7, 12-16, 19, 23, 25 및 26의 다이테르펜 유도체를 분리하고 동정하였다. Also, CHCl 3 Using the extensive column chromatography (Lobar-A Si 60 column, silica gel, and HPLC column) through the chemical study of the soluble fraction (20 g), the following
brd (12.8)1.83,
brd (12.8)
1.75, overlap
7.0)2.71, dd (11.2,
7.0)
6.3)1.69, dd (9.1,
6.3)
4.2)2.43, ddd (13.3, 9.1,
4.2)
2.8)2.20, ddd (12.6, 9.1,
2.8)
sept (7.0)2.00,
sept (7.0)
sept (7.0)1.98,
sept (7.0)
sept (7.0)2.04,
sept (7.0)
d (6.8)1.04,
d (6.8)
d (7.0)1.03,
d (7.0)
d (7.0)1.03,
d (7.0)
d (7.0)1.05,
d (7.0)
d (7.0)1.02,
d (7.0)
d (7.0)0.92,
d (7.0)
d (7.1)1.01,
d (7.1)
d (7.0)1.00,
d (7.0)
d (7.0)1.03,
d (7.0)
d (7.0)1.05,
d (7.0)
d (7.0)1.02,
d (7.0)
d (7.0)0.86,
d (7.0)
td (13.3, 4.2)1.03,
td (13.3, 4.2)
td (13.3,
4.2)1.17,
td (13.3,
4.2)
brd (12.6)1.78,
brd (12.6)
td (14.0,
4.2)1.86,
td (14.0,
4.2)
brd (12.6)1.71,
brd (12.6)
d (12.7)2.57,
d (12.7)
d (12.6)1.99,
d (12.6)
d (12.7)3.58,
d (12.7)
dd (12.6,
7.7)1.46,
dd (12.6,
7.7)
td (14.0, 4.9)2.21,
td (14.0, 4.9)
dt (14.0, 2.8)1.41,
dt (14.0, 2.8)
brd (4.9)2.01,
brd (4.9)
2.1)eq 2.04, ddd (14.7, 4.9,
2.1)
overlapeq 2.13,
overlap
3.5)2.17, ddd (15.4, 6.3,
3.5)
11.9, 2.1)ax 1.95, ddd (14.7,
11.9, 2.1)
overlapeq 1.75,
overlap
d (2.8)3.40,
d (2.8)
overlapax 1.50,
overlap
d (7.0)0.98,
d (7.0)
d (7.0)1.08,
d (7.0)
d (7.0)1.11,
d (7.0)
d (6.8)0.89,
d (6.8)
d (7.0)0.91,
d (7.0)
d (7.0)0.94,
d (7.0)
실시예Example 4: 세포 4: Cell 생존률Survival rate 분석 analysis
3-(4,5-디메틸티아졸-2-일)-2,5-디페닐-테트라졸리움 브로마이드(MTT) 어세이를 이용하여 세포 생존률을 측정하였다. 구체적으로, 96-웰 플레이트에 배양한 세포를 LPS와 함께 또는 LPS 없이 각기 다른 농도의 본 발명의 다이테르펜 유도체들로 처리하였다. 24시간 동안 인큐베이션한 후, 배지를 제거하고 세포에 최종 0.5 mg/mL 농도로 MTT 용액을 첨가하여 1시간 더 인큐베이션하였다. 배지를 조심스럽게 제거하고, 각 웰에 200 μl의 디메틸술폭사이드(DMSO)를 첨가하였다. 플레이트 리더로 570 nm에서 광학밀도(optical density; OD)를 측정하였다. 노란색의 MTT를 보라색의 포르마잔으로 환원시키는 생존 세포의 활성을 관찰하여 세포 생존률을 평가하였으며, 결과는 대조군(비처리 세포)에 대한 백분율로 하기 표 4에 나타내었다.Cell viability was measured using a 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide (MTT) assay. Specifically, cells cultured in 96-well plates were treated with different concentrations of the diterpene derivatives of the present invention with or without LPS. After incubation for 24 hours, the medium was removed and MTT solution was added to the cells at a final concentration of 0.5 mg / mL and incubated for an additional 1 hour. The medium was carefully removed and 200 [mu] l of dimethylsulfoxide (DMSO) was added to each well. The optical density (OD) was measured at 570 nm with a plate reader. Cell viability was evaluated by observing the activity of viable cells reducing yellow MTT to purple formazan and the results are shown in Table 4 below as a percentage of the control (untreated cells).
실시예Example 5: 일산화질소(NO) 측정 5: Measurement of nitrogen monoxide (NO) 어세이Assay
생쥐 BV2 신경교세포를 이용하여 본 발명의 다이테르펜 유도체들의 LPS-유도 일산화질소 합성에 대한 억제 효과를 연구하였다. BV2 세포를 96-웰 플레이트에 4×104 세포/웰의 밀도로 분주하고 본 발명의 화합물의 존/부재 하에 100 ng/mL LPS로 24시간 동안 처리하였다. 그리스 시약(Griess reagent, 1% 술파닐아미드(sulfanilamide) 및 0.1% N-1-나프틸에틸렌디아민 디하이드로클로라이드(N-1-napthylethylenediamine dihydrochloride)의 5% 인산 용액)을 이용하여 배양 배지 내의 아질산염 농도(nitrite level)를 측정하였다. 상층액 50 μl를 동일한 부피의 그리스 시약과 혼합하고 570 nm에서 OD를 측정하였다. 공지의 일산화질소 합성효소(nitric oxide synthase; NOS) 억제제인 NG-모노-메틸-L-아르기닌(NG-Mono-methyl-L-arginine; L-NMMA)을 양성대조군으로 사용하였다. The inhibitory effect of the diterpene derivatives of the present invention on LPS-induced nitric oxide synthesis was studied using mouse BV2 glial cells. The BV2 cells in a 96-well plate at 4 × 10 4 cells / 100 ng to under the dispensing zone and / absence of the compounds of the present invention the density of the well / mL LPS for 24 hours. The nitrite concentration in the culture medium was measured using a grease reagent (5% phosphoric acid solution of Griess reagent, 1% sulfanilamide and 0.1% N-1-naphthylethylenediamine dihydrochloride) (nitrite level) was measured. 50 μl of supernatant was mixed with an equal volume of grease reagent and the OD was measured at 570 nm. A; (NOS nitric oxide synthase) inhibitors, N G - monomethyl - methyl -L- arginine nitric oxide synthase of the known (N-methyl-L-arginine -Mono G; L-NMMA) was used as a positive control.
상기 표 4에서 알 수 있듯이, 화합물 4, 15 및 18은 20 μM에서 상당한 세포독성없이 30.1 ± 6.5, 57.3 ± 0.2, 및 56.1 ± 3.3 μM의 IC50 값을 가지며 중간수준의 활성을 나타냈다. 다른 화합물은 약하거나 활성을 보이지 않았다. 양성대조군으로 사용된 L-NMMA의 IC50은 24.8 ± 4.6 μM이었다. As can be seen in Table 4 above, compounds 4, 15 and 18 exhibited moderate activity with IC 50 values of 30.1 ± 6.5, 57.3 ± 0.2, and 56.1 ± 3.3 μM without significant cytotoxicity at 20 μM. Other compounds were weak or did not show activity. The IC 50 of L-NMMA used as a positive control was 24.8 ± 4.6 μM.
실시예Example 6: 신경성장인자( 6: Nerve Growth Factor ( NGFNGF ) 방출 및 세포 ) Release and cell 생존률Survival rate 어세이Assay
C6 신경교종(glioma) 세포를 본 발명의 화합물 20 μM로 처리하여 배양 배지로의 신경성장인자(nerve growth factor; NGF) 방출을 측정하였다. C6 glioma cells were treated with 20 [mu] M of the compound of the present invention to measure nerve growth factor (NGF) release into the culture medium.
구체적으로 NGF 수준을 측정하기 위하여, C6 세포를 24-웰 플레이트에 1×105 세포/웰의 밀도로 분주하였다. 24시간 후, 세포를 다양한 농도의 LNE와 함께 무혈청 DMEM(serum free DMEM) 및 항생제(antibiotics)로 24시간 더 처리하였다. 배양 플레이트로부터 배지 상층액을 회수하여 NGF 어세이에 사용하였다. ELISA 현상 키트(development kit)를 사용하여 NGF 농도를 측정하였다. 공지의 NGF 생산 유도제인 6-쇼가올(6-Shogaol)을 양성 대조군으로 사용하였다. 방출된 NGF 수준은 대조군(비처리 세포)에 대한 백분율로 하기 표 5에 나타내었다., And dividing the C6 cells in a 24-well plate at a density of 1 × 10 5 cells / well in order to specifically measure the level of NGF. Twenty-four hours later, the cells were treated with various concentrations of LNE for 24 hours in serum-free DMEM and antibiotics. The culture supernatant was collected from the culture plate and used for NGF assay. NGF concentration was measured using an ELISA development kit. 6-Shogaol, a known inducer of NGF production, was used as a positive control. NGF levels released are shown in Table 5 below as a percentage of control (untreated cells).
상기 표 4에서 알 수 있듯이, 화합물 2, 5-7, 9-10, 13, 15-16, 18-24, 26-28은 20 μM 에서 세포독성 효과를 나타내지 않고, 양성 대조군인 6-쇼가올(6-Shogaol) 보다 높은 NGF 방출 효과를 나타내었다.As shown in Table 4, the compounds 2, 5-7, 9-10, 13, 15-16, 18-24, and 26-28 did not show cytotoxic effects at 20 μM and the positive control group, (6-Shogaol).
실시예Example 7: 세포독성시험 7: Cytotoxicity test
화합물 1 내지 28의 세포독성 활성은 SRB 바이오어세이법을 사용하여 A549, SK-OV-3, SK-MEL-2 및 HCT-116 셀 라인(cell lines)에 대하여 평가하였다. Etoposide(≥98%; Sigma Chemical Co.)가 양성 대조군으로 사용되었다. 그 결과 본 발명의 화합물들은 A549, SK-OV-3, SK-MEL-2 및 HCT-116에 대하여 모두 비활성인 것으로 평가되었다(IC50 > 10 μM).The cytotoxic activity of
Claims (10)
1)
4)
7)
10)
A compound selected from the group consisting of the following compounds:
One)
4)
7)
10)
1)
4)
7)
10)
13)
16)
19)
22)
25)
28)
A pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising, as an active ingredient, a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
One)
4)
7)
10)
13)
16)
19)
22)
25)
28)
상기 퇴행성 뇌질환은 혈관성 인지장애, 치매(dementia), 알츠하이머(Alzheimer's disease), 파킨슨병(Parkinson's disease), 루이체병(Lewy body disease), 전측두엽 변성(frontotemporal lobar degeneration), 뇌졸중(Stroke), 뇌동맥 경화증(cerebral arteriosclerosis), 중풍, 헌팅턴병(Huntington's disease), 피크병(Pick's disease), 크로이츠펠트-야콥병(Creutzfeldt-Jakob disease), 근위축성 축삭 경화증(Amyotrophic lateral sclerosis), 다발성 경화증(multiple sclerosis), 허혈성 뇌질환(ischemic brain disease), 뇌경색(cerebral infarct), 피질기조퇴행(corticobasal degeneration), 퇴행성 핵상마비(progressive supranuclear palsy), 또는 다운증후군(Down syndrome)인 것인 약학적 조성물.
The method according to claim 6,
The degenerative brain disease may be selected from the group consisting of vascular cognitive disorders, dementia, Alzheimer ' s disease, Parkinson ' s disease, Lewy body disease, frontotemporal lobar degeneration, Cerebral arteriosclerosis, stroke, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic Ischemic brain disease, cerebral infarct, corticobasal degeneration, progressive supranuclear palsy, or Down syndrome.
A method for treating neuroinflammation or degenerative brain disease comprising administering the pharmaceutical composition of claim 6 or 7 to a subject in need thereof excluding a human.
1)
A health functional food additive for preventing or ameliorating a neuroinflammatory or degenerative brain disease comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof as an active ingredient:
One)
상기 퇴행성 뇌질환은 혈관성 인지장애, 치매(dementia), 알츠하이머(Alzheimer's disease), 파킨슨병(Parkinson's disease), 루이체병(Lewy body disease), 전측두엽 변성(frontotemporal lobar degeneration), 뇌졸중(Stroke), 뇌동맥 경화증(cerebral arteriosclerosis), 중풍, 헌팅턴병(Huntington's disease), 피크병(Pick's disease), 크로이츠펠트-야콥병(Creutzfeldt-Jakob disease), 근위축성 축삭 경화증(Amyotrophic lateral sclerosis), 다발성 경화증(multiple sclerosis), 허혈성 뇌질환(ischemic brain disease), 뇌경색(cerebral infarct), 피질기조퇴행(corticobasal degeneration), 퇴행성 핵상마비(progressive supranuclear palsy), 또는 다운증후군(Down syndrome)인 것인 건강기능성 식품 첨가물.10. The method of claim 9,
The degenerative brain disease may be selected from the group consisting of vascular cognitive disorders, dementia, Alzheimer ' s disease, Parkinson ' s disease, Lewy body disease, frontotemporal lobar degeneration, Cerebral arteriosclerosis, stroke, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic Wherein the active ingredient is an ischemic brain disease, cerebral infarct, corticobasal degeneration, progressive supranuclear palsy, or Down syndrome.
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| JP2008214252A (en) * | 2007-03-02 | 2008-09-18 | Iwate Univ | Protein phosphatase 2c activation agent |
| WO2012055894A1 (en) | 2010-10-27 | 2012-05-03 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Diterpenoid derivatives endowed of biological properties |
| WO2013186766A1 (en) | 2012-06-11 | 2013-12-19 | Regenera Pharma Ltd. | Extracts and therapeutic uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008214252A (en) * | 2007-03-02 | 2008-09-18 | Iwate Univ | Protein phosphatase 2c activation agent |
| WO2012055894A1 (en) | 2010-10-27 | 2012-05-03 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Diterpenoid derivatives endowed of biological properties |
| WO2013186766A1 (en) | 2012-06-11 | 2013-12-19 | Regenera Pharma Ltd. | Extracts and therapeutic uses thereof |
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| Journal of Natural Products, 78(7), pp. 1563-1569(2015.06.25.)* |
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