KR101811436B1 - Novel compound 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)propane-1,3-diol and use thereof - Google Patents
Novel compound 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)propane-1,3-diol and use thereof Download PDFInfo
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- KR101811436B1 KR101811436B1 KR1020170055495A KR20170055495A KR101811436B1 KR 101811436 B1 KR101811436 B1 KR 101811436B1 KR 1020170055495 A KR1020170055495 A KR 1020170055495A KR 20170055495 A KR20170055495 A KR 20170055495A KR 101811436 B1 KR101811436 B1 KR 101811436B1
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Abstract
Description
본 발명은 신규 화합물 2-아미노-2-(1-(2-(2-히드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올 유도체 및 이의 용도에 관한 것으로, 더욱 상세하게는 본 명세서에서 화학식 1로 표시되는 화합물과 이의 퇴행성 신경질환 또는 우울증에 대한 예방, 개선 또는 치료 용도에 관한 것이다.The present invention relates to novel compounds 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3- triazol- The present invention relates to a compound represented by the formula (1) and its use for preventing, ameliorating or treating neurodegenerative diseases or depression.
스핑고지질 대사는 정상적인 세포 신호전달을 조절하며, 스핑고지질 대사의 비정상적 변화는 알츠하이머병을 포함한 다양한 신경퇴행성 질환에 영향을 미친다. 한편, 스핑고지질 대사를 조절하는 효소인 ASM(acid sphingomyelinase)은 거의 모든 종류의 세포에서 발현되는 단백질로서, 스핑고지질 대사 및 세포막 턴오버(turnover)에 중요한 역할을 한다.Sphingolipid metabolism controls normal cell signaling, and abnormal changes in sphingolipid metabolism affect a variety of neurodegenerative diseases, including Alzheimer's disease. On the other hand, ASM (acid sphingomyelinase), an enzyme that regulates sphingolipid metabolism, is a protein expressed in almost all kinds of cells and plays an important role in sphingolipid metabolism and cell membrane turnover.
알츠하이머를 포함한 퇴행성 신경질환 환자의 뇌에서는 ASM의 발현이 정상인에 비해 현저히 증가되어 있으며, 과발현된 ASM의 발현을 저해하거나 ASM의 활성을 저해하면 아밀로이드-β(Aβ)의 축적이 억제되고 학습 및 기억력이 개선되어 퇴행성 신경질환의 치료효과가 나타날 수 있음이 보고된 바 있다(한국 등록특허 10-1521117). 또한 최근 우울증과 같은 신경 질환에서 ASM의 활성이 증가되어 있으며 이러한 ASM의 억제는 우울증 완화 효과를 보인다는 보고가 있다(Nature medicine. 2013 Jul 19(7):934-938, PLoS One. 2016 Sep 6;11(9):e0162498). 따라서 ASM 억제제, 즉 ASM의 발현 또는 활성을 억제할 수 있는 물질의 개발은, 신경퇴행성 질환 및 우울증을 포함하여 ASM의 증가로 인해 야기되는 다양한 질환들의 유용한 치료방법으로서 유망하다.The expression of ASM is significantly elevated in the brains of patients with neurodegenerative diseases including Alzheimer's disease. Inhibition of overexpressed ASM expression or inhibition of ASM activity inhibits accumulation of amyloid-β (Aβ) Has been reported to be effective for the treatment of neurodegenerative diseases (Korea Patent No. 10-1521117). Recently, the activity of ASM has been increased in neurological diseases such as depression, and it has been reported that the inhibition of ASM shows a depressive effect (Nature medicine.) 2013 Jul 19 (7): 934-938, PLoS One. ; 11 (9): e0162498). Thus, the development of a substance capable of inhibiting the expression or activity of an ASM inhibitor, i. E., ASM, is promising as a useful therapeutic modality for a variety of diseases caused by an increase in ASM, including neurodegenerative diseases and depression.
한편, 현재까지 직접적인 ASM 억제제는 개발되지 않았으나 간접적으로 ASM을 억제할 수 있는 몇 가지 억제제가 동정되었다. 먼저 ASM 간접적 억제제로 가장 널리 사용되는 tricyclic antidepressants (e.g. amitriptyline (AMI), desipramine, imipramine 등)는 항우울제 약물로 실제 임상에 사용되고 있다. 최초에 ASM 억제제로 개발된 것은 아니나 다양한 연구결과들에 의해 본 약물들이 ASM 억제 효과를 나타낸다는 것이 증명되었다. Tricyclic antidepressants의 주된 약리작용 (mode of action)은 신경세포에서 신경전달물질의 재흡수 억제를 통한 신경전달물질의 활성 증가이며, 부수적인 작용으로 ASM 억제 효과를 나타낸다. 그러나 tricyclic antidepressants의 경우 신경계 및 신경세포에 작용하여 몽롱함, 빛 감수성 증가, 구토 등의 부작용을 유발할 수 있으므로 새로운 ASM 활성 억제 약물 개발이 필요하다.On the other hand, to date, some inhibitors have not been developed which directly inhibit ASM. First, tricyclic antidepressants (eg, amitriptyline (AMI), desipramine, imipramine, etc.), which are most commonly used as indirect inhibitors of ASM, are used in clinical practice as antidepressant drugs. Although not initially developed as ASM inhibitors, various studies have demonstrated that these drugs exhibit ASM inhibitory effects. The main mode of action of tricyclic antidepressants is to increase the activity of neurotransmitters through the inhibition of neurotransmitter reuptake in neurons and to suppress ASM by ancillary action. However, in the case of tricyclic antidepressants, it is necessary to develop a new inhibitor of ASM activity because it acts on the nervous system and nerve cells and may cause side effects such as blurring, increased light sensitivity, and vomiting.
이에 본 발명자는 신규 ASM 억제제를 개발하고자 노력하던 중, 화학식 1의 구조를 갖는 신규 화합물인 2-아미노-2-(1-(2-(2-히드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올 유도체가 ASM 활성 억제효과가 현저하여 퇴행성 신경질환 및 우울증 치료에 있어서 우수한 효과를 보일 수 있음을 확인하고 본 발명을 완성하였다.Thus, the present inventors is ethyl, ethoxy), a novel compound, 2-amino-2- (1- (2- (2-hydroxy-2 having the structure of formula (I) of the effort was to develop a new ASM inhibitor) -1 H -1 , 2,3-triazol-4-yl) propane-1,3-diol derivatives exhibit a remarkable effect in inhibiting ASM activity and thus show excellent effects in the treatment of neurodegenerative diseases and depression, and completed the present invention .
따라서 본 발명의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 염을 제공하는 것이다:Accordingly, an object of the present invention is to provide a compound represented by the following formula (1) or a salt thereof:
<화학식 1>≪ Formula 1 >
상기 식에서 R1은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.Wherein R1 is hydrogen or an acetyl group, and n is a natural number of 2? N? 5.
본 발명의 다른 목적은, 상기 화학식 1로 표시되는 화합물의 제조방법을 제공하는 것이다. Another object of the present invention is to provide a process for producing a compound represented by the above formula (1).
본 발명의 또 다른 목적은, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating degenerative neurological diseases or depression comprising the compound of
본 발명의 또 다른 목적은, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 예방 또는 개선용 식품 조성물을 제공하는 것이다. It is still another object of the present invention to provide a food composition for preventing or ameliorating a neurodegenerative disease or depression, which comprises the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기와 같은 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 염을 제공한다:In order to achieve the above object, the present invention provides a compound represented by the following general formula (1) or a salt thereof:
<화학식 1>≪ Formula 1 >
상기 식에서 R1은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.Wherein R1 is hydrogen or an acetyl group, and n is a natural number of 2? N? 5.
본 발명의 다른 목적을 달성하기 위하여, 본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다. According to another aspect of the present invention, there is provided a process for preparing a compound represented by the formula (1).
본 발명의 또 다른 목적을 달성하기 위하여, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 예방 또는 치료용 약학적 조성물을 제공한다. In order to accomplish still another object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating degenerative neuropathy or depression comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적을 달성하기 위하여, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 예방 또는 개선용 식품 조성물을 제공한다. In order to accomplish still another object of the present invention, the present invention provides a food composition for preventing or ameliorating a neurodegenerative disease or depression comprising the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 염을 제공한다;The present invention provides a compound represented by the following formula (1) or a salt thereof;
<화학식 1>≪ Formula 1 >
상기 식에서 R1은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.Wherein R1 is hydrogen or an acetyl group, and n is a natural number of 2? N? 5.
상기 화학식 1의 화합물은 구체적으로 하기 화학식 1a(R1이 수소인 경우) 또는 화학식 1b(R1이 아세틸기인 경우)로 표시되는 화합물을 포함하는 것일 수 있다. The compound of formula (1) may specifically include a compound represented by the following formula (1a) (when R1 is hydrogen) or a compound represented by formula (1b) when R1 is an acetyl group.
<화학식 1a><Formula 1a>
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
<화학식 1b>≪ EMI ID =
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
더욱 구체적으로 본원 발명의 화학식 1의 화합물은 하기 화학식 1c(R1이 수소이며 n이 2인 경우) 및 화학식 1d(R1이 아세틸기이며 n이 2인 경우)로 표시되는 화합물을 포함한다; 본 명세서에서 화학식 1c는 2-아미노-2-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올(2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl) -1H-1,2,3-triazol-4-yl)propane-1,3-diol)을 의미하며 본 명세서에서‘JS-101_newPEG2’으로 칭할 수 있고, 화학식 1d는 2-아세틸아미노-2-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올(2-Acetyㅣamino-2-(1-(2-(2-hydroxyethoxy)ethyl) -1H-1,2,3-triazol-4-yl)propane-1,3-diol)를 의미한다. More specifically, the compound of formula (I) of the present invention includes compounds represented by the following formula (1c) (when R1 is hydrogen and n is 2) and formula 1d (when R1 is an acetyl group and n is 2); In the present specification, the compound represented by the formula (1c) is a compound represented by the general formula (1c): 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3-triazol- - diol (2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3-triazol-4-yl) propane- may be referred to herein as 'JS-101_newPEG2', the formula 1d is 2-acetylamino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3- triazole 4-yl) propane-1,3-diol (2-Acety l amino-2- (1- (2- ( 2-hydroxyethoxy) ethyl) -1 H -1,2,3-triazol-4-yl) propane-1,3-diol).
<화학식 1c>≪ Formula 1c >
<화학식 1d><Formula 1d>
본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다. 이하, 상기 화학식 1에서 R1의 구체적 잔기에 따른 각 화합물의 수득방법을 제공한다.The present invention provides a process for producing the compound represented by the above formula (1). Hereinafter, a method for obtaining each compound according to the specific residues of R1 in the above formula (1) is provided.
본 발명은 하기의 단계들을 포함하는, R1이 수소인 화학식 1의 화합물로서 하기 화학식 1a로 표시되는 화합물의 제조방법을 제공한다:The present invention provides a process for preparing a compound of formula (I), wherein R < 1 > is hydrogen, comprising the steps of:
(a) 하기 화학식 2의 화합물과 하기 화학식 3으로 표시되는 화합물을 반응시켜 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 및(a) reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) to prepare a compound represented by the following formula (4); And
(b) 상기 (a) 단계에서 제조한 하기 화학식 4의 화합물에서 (b) reacting a compound of the formula (4) prepared in the step (a) 부틸옥시카보닐기Butyloxycarbonyl group (( butyloxycarbonylbutyloxycarbonyl group) 및 group) and 아세토니드기(acetonide group)를The acetonide group 탈보호(deprotection)하여By deprotection, , R1이 수소인 화학식 1의 화합물로서 하기 화학식 la로 표시되는 화합물을 제조 및 수득하는 단계., ≪ / RTI > and R < 1 > is hydrogen.
<화학식 2>(2)
<화학식 3>(3)
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
<화학식 4>≪ Formula 4 >
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
<화학식 1a><Formula 1a>
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
상기 (a) 단계에서는 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응식 1과 같이 반응시켜, 화학식 4로 표시되는 화합물을 제조 및 수득한다. 하기 반응식 1의 반응을 통하여, 화학식 2의 말단 알킨(terminal alkyne)과 화학식 3의 아자이드(azide) 영역에서 고리화 첨가반응(cycloaddition)이 일어나 트리아졸기를 형성한다.In the step (a), the compound represented by the formula (2) and the compound represented by the formula (3) are reacted as shown in the
[반응식 1][Reaction Scheme 1]
상기 반응식 1에서 n은 2≤ n ≤5의 자연수임. In the
상기 반응식 1의 반응은 화학식 2의 화합물과 화학식 3의 화합물을 적당한 용매에서 교반시키는 것으로 이루어진다. 이때 반응 용매로는 상기 화학식 2의 화합물과 화학식 3의 화합물을 동시에 용해시킬 수 있는 물질이라면 그 종류가 제한되지 않으나, 예를 들어 디메틸포름아마이드(dimethylformamide, DMF), 디메틸설폭사이드(dimethyl sulfoxide, DMSO), 다이클로로메테인 (dichloromethane, DCM), N-메틸-2-피롤리돈(N-Methyl-2-pyrrolidone, NMP)일 수 있다. 바람직하게 디메틸포름아마이드를 사용하는 것 일 수 있다. The reaction of
또한 상기 (a) 단계에서는 트리아졸 생성 반응의 속도 및 효율을 높이기 위한 공지의 촉매수단을 사용할 수 있으며, 일례로 구리 촉매를 사용할 수 있다. 상기 구리 촉매는 일례로 요오드화구리(아이오딘화 구리, CuI), 브롬화구리 (CuBr), 염화구리 (CuCl) 등을 포함하는 산화수가 1인 구리 촉매를 사용할 수 있고, 또는 황산구리 (CuSO4), 초산구리 (Cu(OAc)2), 질산구리 (Cu(NO3)2), 트리플루오로메탄설포네이트화구리 (Cu(OTf)2), 산화구리 (CuO) 등을 포함하는 산화수가 2인 구리 촉매를 사용할 수 있으나, 이에 제한되지 않는다. 바람직하게는 요오드화 구리를 사용할 수 있다. Also, in the step (a), known catalyst means for increasing the rate and efficiency of the triazole formation reaction may be used. For example, a copper catalyst may be used. The copper catalyst used may be copper iodide (iodine Chemistry copper, CuI), copper bromide (CuBr), the oxidation, or the like of copper chloride (CuCl) 1 a copper catalyst for example, or copper sulfate (CuSO 4), Containing 2 or more oxides including copper (Cu (OAc) 2 ), copper nitrate (Cu (NO 3 ) 2 ), copper trifluoromethanesulfonate (Cu (OTf) 2 ) Copper catalysts may be used, but are not limited thereto. Preferably, copper iodide can be used.
산화수가 1인 구리 촉매를 사용할 경우에는 염기도 함께 넣어주며, 중탄산 이온이나 탄산 이온의 알칼리 금속염, 또는 아민 염기인 트리에틸아민, 디이소프로필에틸아민, 피리딘, 루티딘, 콜리딘 등을 사용할 수 있으나, 이에 제한되지 않는다. When a copper catalyst having an oxidation number of 1 is used, bases are also added. Alkali metal salts of bicarbonate ions or carbonate ions, or amine bases such as triethylamine, diisopropylethylamine, pyridine, lutidine and collidine can be used , But is not limited thereto.
산화수가 2인 구리 촉매를 사용할 경우 소듐-아스코베이트, 소듐 설파이트 (Na2SO3), 디티오트레이톨 (dithiothreitol)로 이루어진 환원제를 추가로 사용할 수 있으며, 이에 제한되지 않는다. When a copper catalyst having an oxidation number of 2 is used, a reducing agent composed of sodium-ascorbate, sodium sulfite (Na 2 SO 3 ), and dithiothreitol may be additionally used, but not limited thereto.
또한, 상기 반응식 1에서의 반응 온도는 실온 내지 용매의 비등점까지의 범위 일 수 있고, 바람직하게 실온 내지 60℃의 범위 일 수 있다. The reaction temperature in
상기 (a) 단계의 반응식 1의 반응 이후에, 새롭게 생성된 화합물(즉, 화학식 4로 표시되는 화합물)을 고순도로 수득하기 위하여 정제단계를 임의로 추가할 수 있다. 상기 정제는 당업계에 알려진 화합물 정제 방법에 의한 것이라면 특별히 제한되지 않으나, 예를 들어 에틸아세테이트(ethyl acetate)를 첨가하여 방치한 후 생기는 침전 고체물질을 수득하는 방법에 의한 것 일 수 있다.After the reaction of
상기 화학식 2로 표시되는 화합물은 Tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트(Tert-butyl(5-ethinyl-2,2-dimetyl-1,3-dioxan-5-yl) carbamate)를 의미한다. 상기 화학식 3으로 표시되는 화합물은 n에 따라, n=2일 때 2-(2-아자이도에톡시)에탄올((2-(2-azidoethoxy)ethanol)), n=3일 때 2-[2-(2-아자이도에톡시)에톡시]-에탄올(2-[2-(2-azidoethoxy)ethoxy]-ethanol), n=4일 때 2-[2-[2-(2-아자이도에톡시)에톡시]에톡시]-에탄올(2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]-ethanol), n=5일 때 14-아자이도-3,6,9,12-테트라옥사테트라데카놀(14-Azido-3,6,9,12-tetraoxatetradecanol)을 의미한다. 상기 화학식 2 및 화학식 3으로 표시되는 화합물은 상업적으로 판매되는 것을 구입하여 사용할 수 있으며, 또는 당업계에 공지된 화학적 합성법으로 제조한 것을 사용할 수 있다. 일례로 본원 발명의 실시예에서는 하기 반응식 K에 따라 화학식 3의 화합물을 수득한 바 있다. The compound represented by the above general formula (2) Tert - butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate (Tert -butyl (5-ethinyl- 2,2-dimetyl -1,3-dioxan-5-yl) carbamate). (2-azidoethoxy) ethanol) when n = 2 and 2- [2- (2-azidoethoxy) ethanol) when n = 3, according to n, 2- [2- (2-azidoethoxy) ethoxy] -ethanol), when n = 4, 2- [2- [2- (2-azidoethoxy) ethoxy] 2-azidoethoxy) ethoxy] ethoxy] -ethanol), when n = 5, Refers to tetraoxatetradecanol (14-Azido-3,6,9,12-tetraoxatetradecanol). The compounds represented by the general formulas (2) and (3) can be purchased commercially or can be prepared by chemical synthesis methods known in the art. For example, in the examples of the present invention, the compound of
[반응식 K][Reaction formula K]
상기 반응식 K에서 n은 2≤ n ≤5의 자연수임. In the above reaction formula K, n is a natural number of 2? N? 5.
상기 (b) 단계에서는 상기 (a) 단계에서 제조된 화학식 4의 화합물에서 부틸옥시카보닐기(butyloxycarbonyl group) 및 아세토니드기(acetonide group)를 탈보호(deprotection)하여, 화학식 1a로 표시되는 화합물을 제조 및 수득한다.In step (b), a butyloxycarbonyl group and an acetonide group are deprotected in the compound of formula (4) prepared in step (a) to obtain a compound represented by formula (1a) ≪ / RTI >
상기 부틸옥시카보닐기(butyloxycarbonyl group, Boc) 및 아세토니드기(acetonide group)는 보호기(protection group)로서, (b) 단계를 통해 탈보호(deprotection) 시킨다. 기능기의 보호 및 탈보호는 당업계에 공지된 방법을 사용할 수 있으며 다음의 문헌을 참고로 할 수 있다: “Protective Groups in Organic Chemistry” 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999), “Protecting Groups” P.J. Kocienski, Georg Thieme Verlag (1994).The butyloxycarbonyl group (Boc) and the acetonide group are deprotected through step (b) as a protection group. For protection and deprotection of functional groups, methods known in the art can be used and reference can be made to the following references: " Protective Groups in Organic Chemistry " 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999), " Protecting Groups " Kocienski, Georg Thieme Verlag (1994).
[반응식 2][Reaction Scheme 2]
상기 반응식 2에서 n은 2≤ n ≤5의 자연수임. In the
일례로, 상기 (b) 단계에서 부틸옥시카보닐기 또는/ 및 아세토니드기의 탈보호는 상기 반응식 2와 같은 반응을 통하여 수행되는 것일 수 있다. 상기 반응식 2의 반응은 상기 화학식 4의 화합물과 보호기를 탈보호하는 것으로 알려진 임의의 화합물 Z를 적당한 용매에서 교반시키는 것으로 이루어진다. 상기 화합물 Z는 부틸옥시카보닐기 및 아세토니드기의 두 기능기를 동시에 탈보호화 할 수 있는 단일 물질 일 수 있으며, 또는 각각의 기능기를 탈보호화하는 이종 화합물의 혼합물일 수 있다. 상기 임의의 화합물 Z는 예를 들어 트리플루오로아세트산, 플루오로아세트산, 디프루오로아세트산, 트리클로로아세트산 등으로 이루어진 군에서 선택된 어느 하나 이상의 것 일 수 있으며 이에 제한되지 않는다. 바람직하게 상기 (b) 단계의 탈보호화는 상기 반응식 2에서 화합물 Z로서 트리플로오로아세트산(trifluoroacetic acid, TFA)을 첨가하여 반응시키는 방법일 수 있다. For example, the deprotection of the butyloxycarbonyl group and / or the acetonide group in the step (b) may be carried out through the reaction as shown in the reaction formula (2). The reaction of
상기 탈보호는 물 또는 수용성 공용매 시스템 하에서 수행되는 것 일 수 있다. 상기 수용성 공용매 시스템에 있어서, 물 이외에 포함되는 용매로는 상기 화학식 4의 화합물과 탈보호화를 위해 투입하는 물질을 동시에 용해시킬 수 있는 것이라면 그 종류가 특별히 제한되지 않으나, 다이클로로메테인 (dichloromethane, DCM), 디메틸포름아마이드(dimethylformamide, DMF), 디메틸설폭사이드(dimethyl sulfoxide, DMSO), N-메틸-2-피롤리돈(N-Methyl-2-pyrrolidone, NMP) 등 일 수 있고, 바람직하게는 다이클로로메테인(dichloromethane, DCM)일 수 있다.The deprotection may be carried out under water or a water-soluble cosolvent system. In the water-soluble solvent system, the solvent other than water is not particularly limited as long as it can simultaneously dissolve the compound of formula (4) and the material to be deprotonated, but dichloromethane, Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP) Dichloromethane (DCM). ≪ / RTI >
상기 반응식 2의 반응 온도는, 첨가되는 화합물 Z의 종류에 따라 당업자가 선택적으로 반응 온도를 설정할 수 있으며, 이에 제한되지 않으나 예를 들어 탈보호를 위해 트리플루오로아세트산을 사용하는 경우 반응 온도는 O℃ 내지 35℃ 의 범위에서 설정될 수 있고, 바람직하게 10℃ 내지 실온의 범위에서 설정 될 수 있다.The reaction temperature in
상기 (b) 단계의 반응식 2의 반응 이후에, 새롭게 생성된 화합물(즉, 화학식 1a로 표시되는 화합물)을 고순도로 수득하기 위하여 정제단계를 임의로 추가할 수 있다. 상기 정제는 당업계에 알려진 화합물 정제 방법에 의한 것이라면 이에 제한되지 않으나, 예를 들어 메탄올 (methanol)을 첨가하여 녹인 후 일부 부유물을 필터로 제거하고 용매를 농축시킨 것을, 다시 에틸에테르 (ethyl ether)에 침전시켜 필터로 솔리드(고체 침전물)를 회수한 후 진공으로 건조하는 방법에 의한 것 일 수 있다.After the reaction of
또한 본Also, 발명은 하기 화학식 1a로 표시되는 화합물의 The present invention relates to a compound represented by the following formula 아민기를Amine group N- N- 아세틸화(N-acetylation)하는Acetylated (N-acetylated) 단계를 포함하는, R1이 Wherein R1 is selected from the group consisting of 아세틸기인Acetyl group 화학식 1의 화합물로서 하기 화학식 lb로 표시되는 화합물의 제조방법을 제공한다. (1) as a compound of the formula (1).
<화학식 1a><Formula 1a>
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
<화학식 1b>≪ EMI ID =
상기 식에서 n은 2≤ n ≤5의 자연수임.Wherein n is a natural number of 2? N? 5.
아민기의 N-아세틸화는 당업계에 공지된 방법을 사용할 수 있으며, 일례로 아세틸화제 처리에 의한 것일 수 있다. 당업계에 공지된 아세틸화제로는 일례로 아세트산 무수물 또는 아세트산 클로라이드 등이 있으나 이에 제한되지 않는다. The N-acetylation of the amine group can be carried out by a method known in the art, for example, by treatment with an acetylating agent. Acetylating agents known in the art include, but are not limited to, acetic anhydride or acetic acid chloride.
더욱 구체적으로 본 발명은 하기의 단계들을 포함하는, R1이 수소이며 n이 2인 화학식 1의 화합물로서 하기 화학식 1c로 표시되는 화합물의 제조방법을 제공한다:More specifically, the present invention provides a process for preparing a compound represented by the formula (1c): wherein R1 is hydrogen and n is 2, comprising the steps of:
(i) 하기 화학식 2의 화합물과 하기 화학식 3a로 표시되는 화합물을 반응시켜 하기 화학식 4a로 표시되는 화합물을 제조하는 단계; 및(i) reacting a compound represented by the following formula (2) and a compound represented by the following formula (3a) to prepare a compound represented by the following formula (4a); And
(ii) 상기 (i) 단계에서 제조한 하기 화학식 4a의 화합물에서 (ii) the compound of formula (4a) prepared in step (i) 부틸옥시카보닐기Butyloxycarbonyl group (( butyloxycarbonylbutyloxycarbonyl group) 및 group) and 아세토니드기(acetonide group)를The acetonide group 탈보호(deprotection)하여By deprotection, , R1이 수소이며 n이 2인 화학식 1의 화합물로서 하기 화학식 lc로 표시되는 화합물을 제조 및 수득하는 단계., R1 is hydrogen and n is 2, to prepare and obtain a compound represented by the following formula (1c).
<화학식 2>(2)
<화학식 3a>≪ EMI ID =
<화학식 4a>≪ Formula 4a &
<화학식 1c>≪ Formula 1c >
상기 (i) 및 (ii) 단계를 포함하는 화학식 lc로 표시되는 화합물의 제조방법은, 전술한 (a) 및 (b) 단계를 포함하는 화학식 1a로 표시되는 화합물의 제조방법의 일례로서, 상기 화학식 3으로 표시되는 화합물 중 n=2인 구체적 일례로서 화학식 3a에 해당하는 화합물을 이용하는 것을 특징으로 한다.The method for preparing the compound represented by the formula (1c) including the steps (i) and (ii) is an example of a method for producing the compound represented by the formula (1a) including the steps (a) As a specific example of the compound represented by the general formula (3) wherein n = 2, the compound represented by the general formula (3a) is used.
구체적으로 상기 (i) 단계에서는 화학식 2로 표시되는 화합물과 화학식 3a로 표시되는 화합물을 반응식 1a와 같이 반응시켜, 화학식 4a로 표시되는 화합물을 제조 및 수득한다. 하기 반응식 1a의 반응을 통하여, 화학식 2의 말단 알킨(terminal alkyne)과 화학식 3a의 아자이드(azide) 영역에서 고리화 첨가반응(cycloaddition)이 일어나 트리아졸기를 형성한다.Specifically, in step (i), the compound represented by formula (2) and the compound represented by formula (3a) are reacted as shown in reaction formula (1a) to prepare and obtain a compound represented by formula (4a). Through the reaction of the following Reaction Scheme 1a, cycloaddition occurs at the terminal alkyne of
[반응식 1a][Reaction Scheme 1a]
상기 화학식 2로 표시되는 화합물은 Tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트(Tert-butyl(5-ethinyl-2,2-dimetyl-1,3-dioxan-5-yl) carbamate)를 의미하며, 상기 화학식 3a로 표시되는 화합물은 2-(2-아자이도에톡시)에탄-1-올(2-(2-azidoethoxy)ethanol)을 의미한다. 상기 화학식 2 및 화학식 3a으로 표시되는 화합물은 상업적으로 판매되는 것을 구입하여 사용할 수 있으며, 또는 당업계에 공지된 화학적 합성법으로 제조한 것을 사용할 수 있다. 일례로 본 발명에서 화학식 3a로 표시되는 화합물은, 반응식 K 중 n=2인 경우로서, 2-(2-클로로에톡시)에탄-1-올로부터 반응식 K-1에 따라 수득된 바 있다. The compound represented by the above general formula (2) Tert - butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate (Tert -butyl (5-ethinyl- 2,2-dimetyl -1,3-dioxan-5-yl) carbamate, and the compound represented by the above formula (3a) is 2- (2-azidoethoxy) ethanol. . The compounds represented by
상기 (i) 단계에서 반응에 필요한 용매, 반응온도, 촉매 수단 및 추가 정제 단계 등에 대해서는 상기 화학식 1a로 표시되는 화합물의 제조방법 중 (a) 단계에서 전술한 바와 같다. The solvent, the reaction temperature, the catalyst and the further purification step necessary for the reaction in the step (i) are as described above in the step (a) of the process for producing the compound represented by the above formula (1a).
상기 (ii) 단계에서는 상기 (i) 단계에서 제조된 화학식 4a의 화합물에서 부틸옥시카보닐기(butyloxycarbonyl group) 및 아세토니드기(acetonide group)를 탈보호(deprotection)하여, 화학식 1c로 표시되는 화합물을 제조 및 수득한다. In the step (ii), the butyloxycarbonyl group and the acetonide group are deprotected in the compound of the formula (4a) prepared in the step (i) to obtain the compound represented by the formula (1c) ≪ / RTI >
상기 부틸옥시카보닐기(butyloxycarbonyl group, Boc) 및 아세토니드기(acetonide group)의 보호기(protection group)를 탈보호 시키는 방법에 대해서는 상기 (b) 단계에서 전술한 바와 같으며, 구체적 일례로 임의의 화합물 Z에 의하여 하기 반응식 2a의 반응을 통해 수행되는 것일 수 있다. The method for deprotecting the protecting group of the butyloxycarbonyl group (Boc) and the acetonide group is as described above in the step (b). For example, Z, < / RTI >
[반응식 2a][Reaction Scheme 2a]
상기 (ii) 단계에서 반응에 필요한 용매, 반응온도 및 추가 정제 단계 등에 대해서는 상기 화학식 1a로 표시되는 화합물의 제조방법 중 (b) 단계에서 전술한 바와 같다. The solvent required for the reaction in the step (ii), the reaction temperature, the additional purification step and the like are as described above in the step (b) of the production method of the compound represented by the formula (1a).
또한 본Also, 발명은, 화학식 1c로 표시되는 화합물의 The present invention relates to a compound represented by the formula 아민기(NH2 group)를The amine group (NH2 group) N- N- 아세틸화(N-acetylation)하는Acetylated (N-acetylated) 단계를 포함하는, R1이 Wherein R1 is selected from the group consisting of 아세틸기이며Acetyl group n이 2인 화학식 1의 화합물로서 화학식 ld로 표시되는 화합물의 제조방법을 제공한다. the present invention provides a process for producing a compound represented by the formula (1d) as a compound represented by the formula (1) wherein n is 2.
아민기의 N-아세틸화는 당업계에 공지된 방법을 사용할 수 있으며, 일례로 아세틸화제 처리에 의한 것일 수 있다. 당업계에 공지된 아세틸화제로는 일례로 아세트산 무수물 또는 아세트산 클로라이드 등이 있으나 이에 제한되지 않는다. The N-acetylation of the amine group can be carried out by a method known in the art, for example, by treatment with an acetylating agent. Acetylating agents known in the art include, but are not limited to, acetic anhydride or acetic acid chloride.
본 발명은 상기 화학식 1로 표시되는 화합물뿐만 아니라, 이의 약학적으로 허용 가능한 염, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 라세미체, 또는 입체이성질체를 모두 포함한다.The present invention includes not only the compounds represented by the above formula (1), but also pharmaceutically acceptable salts thereof, possible solvates, hydrates, racemates or stereoisomers thereof.
본 발명의 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, , Naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한, 이 혼합물에서 용매나 과량의 산을 증발시켜서 건조하거나 또는 석출 된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving the compound represented by the formula (1) in an excess amount of an acid aqueous solution, and then mixing the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile ≪ / RTI > It is also possible to prepare the mixture by evaporating a solvent or an excess acid in the mixture, or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
본 발명에서 화학식 1의 화합물은 ASM(acid sphingomyelinase) 억제효과가 탁월하다. 이는 본 발명의 명세서 실시예에 잘 나타나 있다. 본 발명의 일실시예에 따르면, 본 발명의 화합물은 ASM을 억제하는 활성이 매우 우수하여, 알츠하이머 뇌 환경에서 Aβ 플라크를 감소시키고 기억력 및 불안증을 개선시키며, 신경염증을 완화하는 등의 치료효과가 있어 알츠하이머병을 포함하는 퇴행성 신경질환 및 우울증의 예방 또는 치료제로 사용될 수 있음을 확인하였다.In the present invention, the compound of
따라서 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating degenerative neurological disease or depression comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 상기 퇴행성 신경질환은, 당업계에 스핑고지질 대상 이상 또는/및 ASM의 활성 또는 발현의 증가가 병인(病因)으로 작용하는 신경질환이라면 그 종류가 특별히 제한되지 않으나, 예를 들어 알츠하이머병, 파킨슨병, 진행성 핵상마비, 다계통 위축증, 감람핵-뇌교-소뇌 위축증(OPCA), 샤이-드래거 증후군, 선조체-흑질 퇴행증, 헌팅톤병, 근위축성 측색 경화증(ALS), 본태성 진전증, 피질-기저핵 퇴행증, 미만성 루이 소체 질환, 파킨스-ALS-치매 복합증, 픽병, 뇌허혈 및 뇌경색으로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the degenerative neurological disease is not particularly limited as long as it is a neurological disease that is more susceptible to sphingemia in the art and / or an increase in activity or expression of ASM acts as a pathogen, (OPCA), Shire-Drager syndrome, striatum-black degeneration, Huntington's disease, amyotrophic lateral sclerosis (ALS), essential hypertrophy , Corticobasal degeneration, diffuse rheisome disease, Parkinson-ALS-dementia complex, Pick's disease, cerebral ischemia and cerebral infarction.
본 발명의 우울증, 즉 우울장애는 의욕 저하와 우울감을 주요 증상으로 하여 다양한 인지, 정신 및 신체적 증상을 일으켜 일상 기능의 저하를 가져오는 질환을 의미한다. 본 발명의 우울증은 당업계에 우울장애로 알려진 것이라면 그 세부 종류가 특별히 제한되지 않으나, 예를 들어 상기 우울증은 주요 우울 장애(MDD), 혈관치매성 우울증, 양극성 장애(이극성 장애), 단극성 우울증, 계절성 정동 장애(SAD), 경우울증, 기분부전증 또는 퇴행성 신경질환과 동반되는 우울증 등을 포함한다. 바람직하게 ASM 활성의 비정상적 증가(활성 과잉)에 의한 우울증 일 수 있다.The depression of the present invention, that is, the depressive disorder, refers to a disease that causes deterioration in daily function due to various cognitive, mental and physical symptoms caused by depressed motivation and depression. The depression of the present invention is not particularly limited as long as it is known in the art as a depressive disorder. For example, the depressive disorder may include major depressive disorder (MDD), vascular dementia depression, bipolar disorder (bipolar disorder) Depression, seasonal affective disorder (SAD), light depression, dysthymia, or depression associated with degenerative neurological disorders. Preferably a depression due to an abnormal increase in ASM activity (overactivity).
본 발명에 따른 약학적 조성물은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 단독으로 함유하거나 약학적으로 허용되는 담체와 함께 적합한 형태로 제형화 될 수 있으며, 부형제 또는 희석제를 추가로 함유할 수 있다. 상기에서 '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 비독성의 조성물을 말한다.The pharmaceutical composition according to the present invention may be formulated into a suitable form together with a compound of the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof alone or together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent can do. &Quot; Pharmaceutically acceptable " as used herein refers to a nontoxic composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans.
약학적으로 허용되는 담체로는 예컨대, 경구 투여용 담체 또는 비경구 투여용 담체를 추가로 포함할 수 있다. 경구 투여용 담체는 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등을 포함할 수 있다. 아울러, 펩티드 제제에 대한 경구투여용으로 사용되는 다양한 약물전달물질을 포함할 수 있다. 또한, 비경구 투여용 담체는 물, 적합한 오일, 식염수, 수성 글루코오스 및 글리콜 등을 포함할 수 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸-또는 프로필-파라벤 및 클로로부탄올이 있다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현택제 등을 추가로 포함할 수 있다. 그 밖의 약학적으로 허용되는 담체 및 제제는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, it may contain various drug delivery materials used for oral administration to peptide preparations. In addition, the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, etc. in addition to the above components. Other pharmaceutically acceptable carriers and preparations can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
본 발명의 조성물은 인간을 비롯한 포유동물에 어떠한 방법으로도 투여할 수 있다. 예를 들면, 경구 또는 비경구적으로 투여할 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장내 투여일 수 있다.The composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration Lt; / RTI >
본 발명의 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다. 경구 투여용 제제의 경우에 본 발명의 조성물은 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 슬러리제, 현탁액 등으로 당업계에 공지된 방법을 이용하여 제형화될 수 있다. 예를 들어, 경구용 제제는 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. 적합한 부형제의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈,메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필 메틸-셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다. 나아가, 본 발명의 약학적 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention can be formulated into oral preparations or parenteral administration preparations according to the administration route as described above. In the case of a preparation for oral administration, the composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a liquid, a gel, a syrup, a slurry, . For example, an oral preparation can be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and then processing the mixture into a granular mixture. Examples of suitable excipients include, but are not limited to, sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, Cellulose such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose and the like, fillers such as gelatin, polyvinylpyrrolidone and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant. Further, the pharmaceutical composition of the present invention may further comprise an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
비경구 투여용 제제의 경우에는 주사제, 크림제, 로션제, 외용연고제, 오일제, 보습제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, PA,1995)에 기재되어 있다.In the case of a preparation for parenteral administration, it can be formulated by a method known in the art in the form of injection, cream, lotion, external ointment, oil, moisturizer, gel, aerosol and nasal aspirate. These formulations are described in Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, Pa., 1995, which is a commonly known formulary for all pharmaceutical chemistries.
본 발명의 조성물의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 본 발명의 약학적 조성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있다. 바람직하게 본 발명의 약학적 조성물의 바람직한 전체 용량은 1일당 환자 체중 1㎏ 당 약 0.01㎍ 내지 10,000mg, 가장 바람직하게는 0.1㎍ 내지 100mg일 수 있다. 그러나 상기 약학적 조성물의 용량은 제제화 방법, 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율등 다양한 요인들을 고려하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당분야의 통상적인 지식을 가진 자라면 본 발명의 조성물의 적절한 유효 투여량을 결정할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다.The total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol administered over a prolonged period of time in multiple doses. In the pharmaceutical composition of the present invention, the content of the active ingredient may be varied depending on the degree of the disease. Preferably, the total preferred dose of the pharmaceutical composition of the present invention may be from about 0.01 μg to 10,000 mg, and most preferably from 0.1 μg to 100 mg per kg body weight of the patient per day. However, the dosage of the pharmaceutical composition may be determined depending on various factors such as the formulation method, administration route and frequency of treatment, as well as the patient's age, body weight, health condition, sex, severity of disease, diet and excretion rate, It will be possible to determine the appropriate effective dose of the composition of the present invention by those of ordinary skill in the art in view of this point. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
또한 본Also, 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. 가능한염을Possible salts 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 예방 또는 개선용 식품 조성물을 제공한다. The present invention provides a food composition for preventing or ameliorating a degenerative neurological disease or depression which is contained as an active ingredient.
본 발명에 따른 식품용 조성물은 기능성 식품(functional food), 영양보조제(nutritional supplement), 건강식품(health food) 및 식품첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형들은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다.The composition for food according to the present invention includes all forms such as functional food, nutritional supplement, health food and food additives. These types can be prepared in various forms according to conventional methods known in the art.
예를 들면, 건강식품으로는 본 발명의 식품용 조성물 자체를 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한 본 발명의 식품용 조성물은 퇴행성 신경질환 또는 우울증 예방, 개선 또는 치료 효과가 있다고 알려진 공지의 물질 또는 활성 성분과 함께 혼합하여 조성물의 형태로 제조할 수 있다.For example, as a health food, the food composition itself of the present invention may be prepared in the form of tea, juice, and drink and then consumed, granulated, encapsulated, and powdered. In addition, the food composition of the present invention may be prepared in the form of a composition by mixing with known substances or active ingredients known to be effective for preventing, improving or treating degenerative neurological diseases or depression.
또한 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예를 들어 과일 통조림, 병조림, 잼, 마아말레이드 등), 어류, 육류 및 그 가공식품(예를 들어 햄, 소시지콘비이프 등), 빵류 및 면류(예를 들어 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예를 들어 버터, 치이즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예를 들어 된장, 간장, 소스 등) 등에 본 발명의 식품용 조성물을 첨가하여 제조할 수 있다.Functional foods also include beverages (including alcoholic beverages), fruits and their processed foods (such as canned fruits, bottled, jam, maalmalade, etc.), fish, meats and processed foods such as ham, (Such as udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, , Vegetable protein, retort food, frozen food, various kinds of seasoning (for example, soybean paste, soy sauce, sauce, etc.).
본 발명에 따른 식품용 조성물의 바람직한 함유량으로는 이에 한정되지 않지만 바람직하게는 최종적으로 제조된 식품 총 중량 중 0.01 내지 50중량% 이다. 본 발명의 식품용 조성물을 식품첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.The preferred content of the food composition according to the present invention is not particularly limited, but is preferably 0.01 to 50% by weight based on the total weight of the final food product. In order to use the food composition of the present invention in the form of a food additive, it may be used in the form of powder or concentrate.
본 발명의 화학식 1의 ASM 신규 억제화합물은 ASM 억제 효과가 탁월하고, 알츠하이머 뇌환경에서 Aβ 플라크 감소, 기억력 및 불안증 개선, 신경염증 완화 등의 치료효과가 있어, 알츠하이머병을 포함하는 퇴행성 신경질환 예방 또는 치료제 개발에 매우 유용하게 사용될 수 있다. 또한, ASM의 억제는 우울증 완화에 효과적이라는 종래 보고와 같이, 본 발명의 화학식 1의 ASM 신규 억제화합물은 우울증을 포함하는 신경 질환의 예방 또는 치료제로서도 유용하게 사용될 수 있다.The novel inhibitory compound of ASM of formula (I) of the present invention has excellent ASM inhibitory effect, has a therapeutic effect such as reduction of A? Plaque, improvement of memory and anxiety and alleviation of nerve inflammation in Alzheimer's brain environment and prevention of degenerative neurological diseases including Alzheimer's disease Or can be very useful for the development of therapeutic agents. In addition, as shown in the prior reports that inhibition of ASM is effective for relieving depression, the ASM novel inhibitory compound of
도 1은 ASM 억제 신규화합물인 JS-101_newPEG2(도 1A, 화합물명: 2-아미노-2-(1-(2-(2-히드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올)와 JS-101_newPEG4(도 1B, 화합물명: 2-아미노-2-(1-(2-(2-(2-(2-히드록시에톡시)에톡시)에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올)의 구조식 및 화학식, 분자량을 나타낸다.
도 2는 ASM 활성이 증가된 알츠하이머 환자의 섬유아세포(PS1 fibroblast)에 본 발명의 신규화합물인 JS-101_newPEG2 또는 JS-101_newPEG4를 처리한 후 나타나는 ASM 활성변화를 나타낸 결과이다(n=3/그룹, *p<0.05).
도 3은 APP/PS1 마우스에 본 발명의 신규화합물인 JS-101_newPEG2를 음수공급한 후 APP/PS1 마우스의 혈청(도 3A) 및 뇌조직(도 3B)에서 ASM 농도 변화를 나타낸 결과이다(n=3/그룹, *p<0.05) (WT: 야생형, AD: 알츠하이머 동물모델(APP/PS1 마우스)).
도 4는 본 발명의 신규화합물들(대표적으로, JS-101_newPEG2)이 퇴행성 신경질환(특히, 알츠하이머병)에 미치는 영향을 알아보기 위하여 수행한 in vivo 실험의 개요를 나타낸다.
도 5는 ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스에 대하여, 뇌 수질(Cortex, 도 5A) 및 해마(Hippocampus, 도 5B)에서 티오플라빈 S(ThioS, 원섬유성 아밀로이드 베타 플라그를 염색함)로 면역형광염색하고 원섬유성 아밀로이드 베타 플라그가 차지하고 있는 면적을 정량화한 결과이다 (n=3/그룹, **p<0.01) (AD: 알츠하이머 동물모델(APP/PS1 마우스)).
도 6은 ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스의 뇌조직에서 Aβ40(도 6A) 및 Aβ42(도 6B)의 축적 정도를 면역형광염색하고, 이를 정량화하여 나타낸 결과이다 (n=3/그룹, *p<0.05, **p<0.01)(AD: 알츠하이머 동물모델(APP/PS1 마우스)).
도 7은 APP/PS1 마우스에서 ASM 억제 신규화합물인 JS-101_newPEG2 공급이 학습 및 인지기능을 회복시켰음을 나타내는 결과이다 (n=7-8/그룹, *p<0.05) (WT: 야생형, AD: 알츠하이머 동물모델(APP/PS1 마우스)).
도 7A는 야생형 마우스(WT, n=8), ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급한 APP/PS1 마우스(n=7) 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스(control, n=8)에대하여, 모리스 워터메이즈(MWM) 테스트를 이용하여 10일동안 학습 및 기억력을 평가한 결과이다.
도 7B는 MWM 테스트 11일째에 표적 플랫폼에서 머무른 시간을 나타낸 결과이다.
도 7C는 MWM 테스트 시험 11일째에 표적 플랫폼의 타겟 지역 내로 들어간 횟수를 나타낸다.
도 7D는 fear conditioning 실험 동안에 contextual 및 tone task의 결과를 나타낸 것이다.
도 8은 APP/PS1 마우스에서 ASM 억제 신규화합물인 JS-101_newPEG2의 공급이 활동성 및 불안감을 호전시켰음을 나타내는 결과이다 (n=7-8/그룹, *p<0.05) (ASM 억제 신규화합물인 JS-101_newPEG2를 공급하지 않은 APP/PS1 마우스(control, n=8), ASM 억제 신규화합물인 JS-101_newPEG2를 공급한 APP/PS1 마우스 (n=7)).
도 8A는 오픈필드 테스트 동안에 마우스가 벽면에서 소요한 시간을 측정한 결과이다.
도 8B는 오픈필드 테스트 동안에 마우스가 중심부에서 소요한 시간을 측정한 결과이다.
도 8C는 오픈필드 테스트 동안에 중심부의 비율을 나타낸 결과이다.
도 8D는 오픈필드 테스트 동안에 마우스의 이동 경로를 나타낸 것이다.
도 8E는 dark & light 테스트 동안에 마우스가 어두운 곳에서 소요한 시간을 측정한 결과이다.
도 8F는 dark & light 테스트 동안에 마우스가 밝은 곳에서 소요한 시간을 측정한 결과이다.
도 8G는 dark & light 테스트 동안에 마우스가 어두운 곳과 밝은 곳을 왕복한 횟수이다.
도 8H는 dark & light 테스트 동안에 마우스가 최초로 어두운 곳에서 밝은 곳으로 옮겨간 시간을 측정한 결과이다.
도 8I는 dark & light 테스트 동안에 마우스의 이동 경로를 나타낸 것이다.
도 9는 APP/PS1 마우스(AD)에서 증가된 신경염증이 ASM 억제 신규화합물인 JS-101_newPEG2 공급에 의해 감소됨을 확인한 결과이다 (n=3/그룹, *p<0.05, **p<0.01).
도 9A는 야생형 마우스(WT), ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스(control)의 뇌 수질에서 별아교세포(GFAP)의 면역형광 이미지(왼쪽) 및 이를 정량화환 결과(오른쪽)를 나타낸다.
도 9B는 야생형 마우스, ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스(control)의 뇌 수질에서 염증성 마커(TNF-α, IL-1β, IL-6)의 mRNA 발현수준을 평가한 결과이다. Figure 1 is a novel compound inhibiting the ASM JS-101_newPEG2 (Fig. 1A, compound name: 2- amino-2- (1- (2- (2-hydroxy) ethyl) -1 H -1,2,3- 1,3-diol) and JS-101_new PEG4 (FIG. 1B, name: 2-amino-2- (1- (2- (2- (2- Ethoxy) ethoxy) ethyl) -1H-1,2,3-triazol-4-yl) propane-1,3-diol).
Figure 2 shows the results of ASM activity changes after treatment of JS-101_newPEG2 or JS-101_newPEG4 of the present invention with fibroblasts of Alzheimer's patients with increased ASM activity (n = 3 / group, * p < 0.05).
Figure 3 shows the results of ASM concentration changes in serum (Figure 3A) and brain tissue (Figure 3B) of APP / PS1 mice after negative administration of JS-101_newPEG2, a novel compound of the present invention, to APP / 3 / group, * p < 0.05) (WT: wild type, AD: Alzheimer's animal model (APP / PS1 mouse)).
Figure 4 shows the effect of the novel compounds of the present invention (representative, JS-101_newPEG2) on degenerative neurological diseases (particularly Alzheimer's disease) in vivo An outline of the experiment is shown.
FIG. 5 is a graph showing the effect of the ASM inhibitory compound JS-101_newPEG2 in the brain water (Cortex (FIG. 5A) and hippocampus (FIG. 5B) for APP / PS1 mice or APP / (N = 3 / group, ** p < 0.01), which is the result of immunofluorescence staining with thioflavin S (staining of fibrillar amyloid beta plaques) and the area occupied by fibrillar amyloid beta plaques (AD: Alzheimer's animal model (APP / PS1 mouse)).
Fig. 6 is a graph showing the degree of accumulation of A? 40 (Fig. 6A) and A? 42 (Fig. 6B) in brain tissue of APP / PS1 mice fed with AZS inhibitory novel compound JS-101_newPEG2 or APP / (N = 3 / group, * p <0.05, ** p <0.01) (AD: Alzheimer's animal model (APP / PS1 mouse)).
Figure 7 shows the results of the ASM inhibition of the novel compound, JS-101_newPEG2, in APP / PS1 mice restoring learning and cognitive function (n = 7-8 / group, * p < 0.05) (WT: wild type, AD: Alzheimer's animal model (APP / PS1 mouse)).
FIG. 7A is a graph showing the results of an APP / PS1 mouse (n = 7) in which wild type mouse (WT, n = 8), ASM inhibitory novel compound JS-101_newPEG2 was negatively supplied, or APP / PS1 mouse 8) were assessed for 10 days of learning and memory using the Morris Water Maze (MWM) test.
FIG. 7B shows the time spent on the target platform on the 11th day of the MWM test.
Figure 7C shows the number of times the target platform entered the target area on the eleventh day of the MWM test.
Figure 7D shows the results of the contextual and tone tasks during the fear conditioning experiment.
Figure 8 shows that the supply of JS-101_newPEG2, a new ASM inhibiting compound in APP / PS1 mice, improved activity and anxiety (n = 7-8 / group, * p < 0.05) APP / PS1 mouse (control = n = 8), ASM inhibitor APP / PS1 mouse (n = 7), which supplied the novel compound JS-101_newPEG2.
8A is a result of measuring the time spent by the mouse on the wall during the open field test.
8B is a result of measuring the time spent at the center of the mouse during the open field test.
Figure 8C shows the ratio of the center portion during the open field test.
8D shows the movement path of the mouse during the open field test.
8E is a result of measuring the time spent in a dark place during a dark & light test.
8F is a result of measuring the time spent by the mouse in a bright place during the dark & light test.
FIG. 8G shows the number of times the mouse has made a round trip in the dark and light during the dark & light test.
8H is the result of measuring the time taken for the mouse to move from a dark place to a bright place during the dark & light test.
Figure 8I shows the movement path of the mouse during the dark & light test.
Figure 9 shows the results (n = 3 / group, * p < 0.05, ** p < 0.01) confirming that increased neuroinflammation in APP / PS1 mouse (AD) was reduced by feeding the ASM inhibitor JS-101_newPEG2, .
FIG. 9A is a graph showing the results of experiments using a wild type mouse (WT) ASM Suppression The immunofluorescence image (left) of astrocytic cells (GFAP) in the brain water of an APP / PS1 mouse or JS-101_newPEG2 negative-fed APP / PS1 mouse without this compound, Represents the result (right).
FIG. 9B is a graph showing the expression of inflammatory markers (TNF-a, IL-1beta) in brain waters of wild-type mice, APP / PS1 mice fed negative with ASM inhibition novel compound JS-101_newPEG2 or APP / , IL-6), respectively.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.
<실시예 1>≪ Example 1 >
신규 화합물 JS-101_newPEG2의 제작Production of new compound JS-101_newPEG2
2-아미노-2-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올(2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl) propane-1,3-diol, ‘JS-101_newPEG2’로 약칭)은 하기 일련의 공정을 통해 제작하였다. 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3- triazol-4-yl) propane-1,3-diol (2-amino -2- (1- (2- (2- hydroxyethoxy) ethyl) -1 H -1,2,3-triazol-4-yl) propane-1,3-diol, referred to as 'JS-101_newPEG2' to have) A series of processes were carried out.
물질시료로서 2-(2-클로로에톡시)에탄-1-올, 소듐 아자이드, tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트, 아이오딘화구리, 2-(2-아자이도에톡시)에탄-1-올, N,N-디이소프로필에틸아민, tert-부틸(5-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)-2,2-디메틸-1,3-다이옥산-5-일)카바메이트 및 트리플루오르아세트산이 하기의 방법에 따라 제조에 이용되었으며, 100% 디메틸설폭사이드 (DMSO)에서 현탁하여 -20 ℃에서 보관하며 사용하였다.As a material sample, a mixture of 2- (2-chloroethoxy) ethan-1-ol, sodium azide, tert -butyl (5-ethynyl-2,2-dimethyl- N, N -diisopropylethylamine, tert -butyl (5- (1- (2- (2-hydroxyphenyl) 1 H -1,2,3-triazol-4-yl) -2,2-dimethyl-1,3-dioxan-5-yl) carbamate and trifluoroacetic acid are prepared according to the following method And suspended in 100% dimethylsulfoxide (DMSO) and stored at -20 ° C.
<1-1> 2-(2-아자이도에톡시)에탄-1-올 제조<1-1> Preparation of 2- (2-azadioethoxy) ethan-1-ol
[반응식 K][Reaction formula K]
상기 반응식 K에서 n은 2≤n≤5의 자연수임.In the above reaction formula K, n is a natural number of 2? N? 5.
상기 반응식 K에서 n=2 일때에 해당하는 2-(2-클로로에톡시)에탄-1-올을 출발물질로 하여 2-(2-아자이도에톡시)에탄-1-올을 수득하였다. 2- (2-azaidoethoxy) ethan-1-ol was obtained using 2- (2-chloroethoxy) ethan-1-ol corresponding to the
[반응식 K-1][Reaction Scheme K-1]
구체적으로 상기 반응식 K-1의 반응을 일으키기 위하여, 2-(2-클로로에톡시)에탄-1-올(1000 mg, 8.0 mmol)과 소듐 아자이드(NaN3, 780 mg, 12 mmol)를 2차 증류수(6.0 mL)에 녹인 후, 80 ℃에서 26 시간동안 교반 및 환류하였다. 이후, 반응 혼합물을 디클로로메테인(12 mL)로 희석하고 물을 추가하여 소듐 클로라이드 포화 수용액으로 세척하였다. 유기층을 마그네슘 설페이트로 건조하고 용매를 감압, 제거하여 목적 화합물인 2-(2-아자이도에톡시)에탄-1-올(690 mg, 65% 수율)을 수득하였다. Specifically, 2- (2-chloroethoxy) ethan-1-ol (1000 mg, 8.0 mmol) and sodium azide (NaN 3 , 780 mg, 12 mmol) After dissolving in distilled water (6.0 mL), the mixture was stirred and refluxed at 80 ° C for 26 hours. The reaction mixture was then diluted with dichloromethane (12 mL) and water was added and washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the target compound, 2- (2-azaidoethoxy) ethan-1-ol (690 mg, 65% yield).
1H NMR [400 MHz, (CD3)2CO),d (ppm)]: 3.39 (t, J = 4.9 Hz, 2H), 3.57 (m, 2H), 3.68 (m, 4H). 1 H NMR [400 MHz, ( CD 3) 2 CO), d (ppm)]: 3.39 (t, J = 4.9 Hz, 2H), 3.57 (m, 2H), 3.68 (m, 4H).
<1-2> <1-2> TertTert -부틸 (5-(1-(2-(2-Butyl (5- (1- (2- (2- 하이드록시에톡시Hydroxyethoxy )에틸)-1) Ethyl) -1 HH -1,2,3--1,2,3- 트리아졸Triazole -4-일)-2,2-디메틸-1,3-Yl) -2,2-dimethyl-1,3- 다이옥산Dioxane -5-일)카바메이트 제조-5-yl) carbamate
[반응식 1a][Reaction Scheme 1a]
Tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트(1.3 g, 5.2 mmol)를 디메틸포름아마이드(DMF, 17 mL)에 녹인 다음 아이오딘화구리(CuI, 0.5 g, 2.6 mmol), 2-(2-아자이도에톡시)에탄-1-올(690 mg, 16 mmol), N,N-디이소프로필에틸아민(DIPEA, 2.7 mL , 16 mmol)을 순서대로 추가하였다. 질소 하에 반응 혼합물을 상온에서 12 시간 동안 교반하였다. 이후 암모늄 클로라이드 포화 수용액을 넣어 반응을 마무리한 후 용매를 12 시간 동안 동결 건조하였다. 건조된 화합물에 물을 추가하여 에틸아세테이트로 추출하였고 소듐 클로라이드 포화수용액으로 세척하였다. 마그네슘 설페이트로 건조한 뒤, 실리카겔 관 크로마토그래피(에틸아세테이트 100%로 부산물(Rf=0.9)제거 후, 아세톤 100% 로 용리액 변경)를 통해, 목적 화합물인 Tert-부틸 (5-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)-2,2-디메틸-1,3-다이옥산-5-일)카바메이트(1.1 g, 55% 수율, Rf=0.3)를 수득하였다. Tert - dissolved in butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate (1.3 g, 5.2 mmol) to dimethylformamide (DMF, 17 mL) and then iodine (690 mg, 16 mmol), N, N -diisopropylethylamine (DIPEA, 2.7 mL, 1.6 mmol) and triphenylphosphine 16 mmol) were added in this order. The reaction mixture was stirred at room temperature under nitrogen for 12 hours. After the reaction was completed by adding a saturated aqueous solution of ammonium chloride, the solvent was lyophilized for 12 hours. Water was added to the dried compound, extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Been dried over magnesium sulfate and purified by silica gel column chromatography with (ethyl acetate as a by-product 100% (Rf = 0.9) and then removed, eluent changed to 100% acetone), the desired compound of Tert - butyl (5- (1- (2 (2-hydroxyethoxy) ethyl) -1 H -1,2,3- triazol-4-yl) -2,2-dimethyl-1,3-dioxan-5-yl) carbamate (1.1 g, 55% yield, Rf = 0.3).
1H NMR [(400 MHz, CD2Cl2)d (ppm)]: 1.40 (s, 9H), 1.48 (s, 4H), 2.44 (s, 1H), 3.50 (t, J = 4.0 Hz, 2H), 3.61 (t, J = 4.0 Hz, 2H), 3.84 (t, J = 4.0 Hz, 2H), 4.11 (d, J = 8.0 Hz, 2H), 4.24 (d, J = 12.0 Hz, 2H), 4.51 (t, J = 4.0 Hz, 2H), 5.63 (s, 1H), 7.76 (s, 1H). 1 H NMR [(400 MHz,
<1-3> 2-아미노-2-(1-(2-(2-하이드록시에톡시)에틸)-1<1-3> 2-Amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 HH -1,2,3-트리아졸-4-일)프로판-1,3-디올 제조-1,2,3-triazol-4-yl) propane-1,3-diol
[반응식 2a][Reaction Scheme 2a]
Tert-부틸 (5-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)-2,2-디메틸-1,3-다이옥산-5-일)카바메이트(1.1 g, 2.9 mmol)을 트리플루오로아세트산(TFA, 2.0 mL), 디클로로메테인(DCM, 2.0 mL), 물(1.0 mL)의 혼합 수용액에 추가하여 상온에서 12 시간동안 교반하였다. 이후 질소 하에 건조 시킨 후, 메탄올과 디에틸에테르를 통해 재결정하여, 목적 화합물로서 화학식 1c에 해당하는 2-아미노-2-(1-(2-(2-하이드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올 (570 mg, 80% 수율)을 수득하였다. 상기 수득된 목적 화합물을 이하에서 JS-101_newPEG2으로 칭한다. 신규 화합물 JS-101_newPEG2(C9H18N4O4)는 도 1A에서 보는 바와 같은 구조식을 지니며 분자량 246.2670(Exact mass: 246.1328)이었다. Tert -butyl (5- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3-triazol-4-yl) -2,2- Yl) carbamate (1.1 g, 2.9 mmol) was added to a mixed aqueous solution of trifluoroacetic acid (TFA, 2.0 mL), dichloromethane (DCM, 2.0 mL) and water (1.0 mL) Stir for 12 hours. After drying under nitrogen, the residue was recrystallized from methanol and diethyl ether to give 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3-triazol-4-yl) propane-1,3-diol (570 mg, 80% yield). The object compound thus obtained is hereinafter referred to as JS-101_newPEG2. The novel compounds JS-101_newPEG2 (C 9 H 18 N 4 O 4) is a molecular weight of 246.2670 said Genie the structure as shown in 1A: was (Exact mass 246.1328).
1H NMR [(400 MHz, (CD3)2SO)d (ppm)]: 3.43 (m, 2H), 3.47 (m, 2H), 3.77 (s, 4H), 3.81 (t, J = 6.0 Hz, 2H), 4.55 (t, J = 4.0 Hz, 2H), 4.65 (s, 1H), 5.55 (s, 2H), 8.14 (s, 1H), 8.32 (s, 2H). 1 H NMR [(400 MHz, (CD 3) 2 SO) d (ppm)]: 3.43 (m, 2H), 3.47 (m, 2H), 3.77 (s, 4H), 3.81 (t, J = 6.0 Hz 2H), 4.55 (t, J = 4.0 Hz, 2H), 4.65 (s, 1H), 5.55 (s, 2H), 8.14 (s, 1H), 8.32 (s, 2H).
13C NMR [(100 MHz, (CD3)2SO)d (ppm)]: 49.7, 58.9, 60.1, 62.1, 68.7, 72.1, 123.9, 143.8. 13 C NMR [(100 MHz, (CD 3 ) 2 SO) d (ppm)]: 49.7, 58.9, 60.1, 62.1, 68.7, 72.1, 123.9, 143.8.
HRMS: Calcd. for [M + H]+,247.1401;Found,247.1356.HRMS: Calcd. for [M + H] < + >,247.1401; Found, 247.1356.
<실시예 2>≪ Example 2 >
신규 화합물 JS-101_newPEG3의 제작Production of new compound JS-101_newPEG3
상기 반응식 K에서 n=3 일때에 해당하는 2-[2-(2-클로로에톡시)에톡시]-에탄올을 출발물질로 하여 2-[2-(2-아자이도에톡시)에톡시]-에탄올을 수득하였다. 그 후 상기 실시예 1과 동일한 방법으로 Tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트와 반응시키고 부틸옥시카보닐기 및 아세토니드기를 탈보호화시켜 n=3인 화학식 1a의 화합물인 2-아미노-2-(1-(2-(2-(2-히드록시에톡시)에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올을 수득하였다. 2- [2- (2-azadioethoxy) ethoxy] - ethoxy] -ethanol as a starting material, with 2- [2- (2- chloroethoxy) ethoxy] Ethanol. After that described in Example 1 in the same manner as Tert - butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate was reacted with butyl oxy carbonyl group and an acetonide Talbot 2- (1- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -1H-1,2,3-triazole, which is a compound of formula Yl) propane-1,3-diol.
<실시예 3>≪ Example 3 >
신규 화합물 JS-101_newPEG4의 제작Production of new compound JS-101_newPEG4
상기 반응식 K에서 n=4 일때에 해당하는 2-[2-[2-(2-클로로에톡시)에톡시]에톡시]-에탄올을 출발물질로 하여 2-[2-[2-(2-아자이도에톡시)에톡시]에톡시]-에탄올을 수득하였다. 그 후 상기 실시예 1과 동일한 방법으로 Tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트와 반응시키고 부틸옥시카보닐기 및 아세토니드기를 탈보호화시켜 n=4인 화학식 1a의 화합물인 2-아미노-2-(1-(2-(2-(2-(2-히드록시에톡시)에톡시)에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올을 수득하였다. 신규 화합물 JS-101_newPEG4(C13H26N4O6)는 도 1B에서 보는 바와 같은 구조식을 지니며 분자량 334.3730(Exact mass: 334.1852)이었다. 2- [2- (2- (2-Chloroethoxy) ethoxy] ethoxy] -ethanol as a starting material, corresponding to 2-4- Ethoxy] ethoxy] -ethanol. ≪ / RTI > After that described in Example 1 in the same manner as Tert - butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate was reacted with butyl oxy carbonyl group and an acetonide Talbot 2- (1- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) -1H-1, which is a compound of
<실시예 4><Example 4>
신규 화합물 JS-101_newPEG5의 제작Production of new compound JS-101_newPEG5
상기 반응식 K에서 n=5 일때에 해당하는 14-클로로-3,6,9,12-테트라옥사테트라데카놀을 출발물질로 하여 14-아자이도-3,6,9,12-테트라옥사테트라데카놀을 수득하였다. 그 후 상기 실시예 1과 동일한 방법으로 Tert-부틸(5-에틴일-2,2-디메틸-1,3-디옥산-5-일)카바메이트와 반응시키고 부틸옥시카보닐기 및 아세토니드기를 탈보호화시켜 n=5인 화학식 1a의 화합물인 2-아미노-2-(1-(14-히드록시-3,6,9,12-테트라옥사테트라데실)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올을 수득하였다.Using 14-chloro-3,6,9,12-tetraoxatetradecanol corresponding to n = 5 in Scheme K as the starting material, 14-azido-3,6,9,12-tetraoxatetradeca Knol. After that described in Example 1 in the same manner as Tert - butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate was reacted with butyl oxy carbonyl group and an acetonide Talbot 2-amino-2- (1- (14-hydroxy-3,6,9,12-tetraoxatetradecyl) -1H-1,2,3-triazole Yl) propane-1,3-diol.
<실시예 5>≪ Example 5 >
신규 화합물의 신경퇴행성 질환 및 우울증 억제 효능 확인Identification of neurodegenerative diseases and depression suppression efficacy of new compounds
[실험재료 및 실험방법][Experimental Materials and Experimental Methods]
1. 마우스 1. Mouse
IACUC(Kyungpook National University Institutional Animal Care and Use Committee)에서 마우스 실험에 대한 승인을 받았다. 우울증 및 퇴행성 신경질환(특히, 알츠하이머) 동물모델로서, C57BL/6 마우스(Charles River, UK)를 바탕으로 APPswe(hAPP695swe) 및 PS1(presenilin-1M146V)를 과발현시킨 형질전환 마우스 라인을 이용하였다[이하, APP/PS1 마우스(AD로 표기), GlaxoSmithKline 社]IACUC (Kyungpook National University Institutional Animal Care and Use Committee) approved the mouse experiment. Transgenic mouse lines were used that overexpress APPswe (hAPP695swe) and PS1 (presenilin-1M146V) based on C57BL / 6 mice (Charles River, UK) as an animal model of depression and degenerative neurological diseases , APP / PS1 mouse (denoted as AD), GlaxoSmithKline]
신규화합물 JS-101_newPEG2의 퇴행성 신경질환 및 우울증 치료효과를 확인하기 위해, 도 4에 나타낸 실험 개요(스케쥴)에 따라 동물모델에 실험물질을 투여하였다. 구체적으로, 7.5개월령의 마우스에 신규화합물인 JS-101_newPEG2를 100mg/kg/day 용량으로 음수를 통해 공급하였다. 상기 화합물이 포함된 음수공급 1개월 후 행동학적 분석을 실시하였고, 행동분석기간에도 지속적으로 시험물질이 음수를 통해 구강투여되었다. 행동학적 분석 후(상기 화합물 포함 음수공급 2개월 차, 즉 마우스 9.5 주령 차)에 마우스의 뇌조직을 샘플링하였다. In order to confirm the therapeutic effect of the new compound JS-101_new PEG2 on degenerative neuropathy and depression, the experimental material was administered to the animal model according to the experimental outline (schedule) shown in Fig. Specifically, a new compound, JS-101_newPEG2, was administered to mice at 7.5 months of age at a dose of 100 mg / kg / day through the water. Behavioral analysis was performed one month after the supply of the water containing the compound, and the test substance was orally administered via the negative water continuously during the behavioral analysis period. After the behavioral analysis (two-month supply of the compound-containing solution containing the compound, i.e., mouse 9.5 weeks old), the brain tissue of the mouse was sampled.
2. 면역형광법2. Immunofluorescence
마우스의 대뇌 및 해마를 고정 후, 0.5% thioflavin S (Sigma-Aldrich), Aβ 42에 대한 항-20G10(마우스, 1:1000) 및 Aβ40에 대한 항-G30(토끼, 1:1000), 항-GFAP(토끼, 1:500, DAKO)을 함께 배양하였다. 상기 부위를 Fluoview SV1000 이미징 소프트웨어(Olympus FV1000, Japan)를 장착한 레이저 스캐닝 공초점 현미경 또는 Olympus BX51 현미경을 이용하여 분석하였다. Metamorph software(Molecular Devices)를 이용하여 총 조직의 넓이에 대한 염색된 부위의 넓이의 퍼센트를 정량화하고 분석하였다.(Mouse, 1: 1000) against Aβ 42 and anti-G30 (rabbit, 1: 1000) against Aβ40, anti- GFAP (rabbit, 1: 500, DAKO) were co-cultured. The sites were analyzed using a laser scanning confocal microscope equipped with Fluoview SV1000 imaging software (Olympus FV1000, Japan) or an Olympus BX51 microscope. Percentage of area of stained area to total tissue area was quantified and analyzed using Metamorph software (Molecular Devices).
3. 실시간 정량 PCR(Real-time quantitative PCR)3. Real-time quantitative PCR
염증반응 관련 사이토카인 (TNF-a, IL-1β, IL-6)의 발현량을 측정하기 위하여 실시간 정량 PCR법을 사용하였다. RNeasy Plus 미니 키트 (Qiagen, Korea, Ltd)를 사용하여 뇌조직으로부터 RNA를 추출하고, Clontech (Mountain View, CA)사의 키트를 사용하여 총 5㎍의 RNA로부터 cDNA를 합성하였다. 또한, Corbett research RG-6000 real-time PCR 기기를 사용하여, 95℃, 10분; 95℃, 10초; 58℃, 15초; 72℃, 20초를 1 사이클로 하여 40 사이클을 반복하는 실시간 정량 PCR을 수행하였다. To quantify the expression levels of inflammatory cytokines (TNF-a, IL-1β, and IL-6), real-time quantitative PCR was used. RNA was extracted from brain tissue using RNeasy Plus mini kit (Qiagen, Korea, Ltd.) and cDNA was synthesized from total 5 μg of RNA using a kit of Clontech (Mountain View, CA). Also, using Corbett research RG-6000 real-time PCR instrument, PCR was performed at 95 ° C for 10 minutes; 95 캜, 10 seconds; 58 캜, 15 seconds; 72 < [deg.] ≫ C for 20 seconds as one cycle, and 40 cycles were repeated.
상기 실시간 정량 PCR에 사용한 프라이머는 표 1과 같다.The primers used for the real-time quantitative PCR are shown in Table 1.
4. 행동실험4. Behavioral Experiment
학습 및 기억에 대한 잠재적 효과를 확인하기 위하여, MWM(Morris water maze)와 fear conditioning 실험을 수행하였다. MWM는 마우스에 대하여 10일 동안 하루에 4 번씩 과제를 학습시켰고, 11일째 되는 날에 플랫폼을 제거하고, 탐침시험(probe trial)을 수행하였다. Fear conditioning은 첫째 날은 마우스를 conditioning chamber에 넣고, 소리 자극(10 kHz, 70 dB) 및 전기자극(0.3 mA, 1 s)을 주었다. 둘째 날은 첫째 날과 같은 conditioning chamber에서 자극 없이 공간에 대한 기억력을 확인했고, 셋째 날은 다른 conditioning chamber에서 소리자극만 주었을 때 두려움에 대한 기억력 테스트를 수행하였다. 활동성과 불안감을 평가하기 위해 오픈필드 테스트와 Dark and light 테스트를 수행하였다. 오픈필드 테스트는 마우스를 10분 동안 사각형의 박스에 넣어 전반적인 활동성과 벽면 및 가운데(중심부)를 돌아다닌 시간을 측정하였다. Dark and light 테스트는 마우스를 10분 동안 어두운 박스와 밝은 박스로 구성된 사각형의 박스에 넣어 각각의 박스 내에 머무른 시간, 박스 왕복 횟수 및 최초로 밝은 박스내로 들어간 시간을 측정하였다. Morris water maze (MWM) and fear conditioning experiments were performed to identify potential effects on learning and memory. MWM learned the task four times a day for 10 days on the mouse, removed the platform on the eleventh day, and conducted a probe trial. On the first day of the Fear conditioning, the mice were placed in a conditioning chamber and subjected to sound stimulation (10 kHz, 70 dB) and electrical stimulation (0.3 mA, 1 s). On the second day, we checked the memory of the room without stimulation in the same conditioning chamber as the first day, and on the third day we performed a memory test for fear when only the sound stimulation was given in the other conditioning chamber. Open field tests and dark and light tests were conducted to assess activity and anxiety. In the open field test, the mouse was placed in a square box for 10 minutes to measure overall activity and time spent walking around the center and the wall. Dark and light tests were performed by placing the mouse in a square box consisting of a dark box and a light box for 10 minutes, measuring the time spent in each box, the number of round trips, and the time in the first bright box.
5. 세포배양5. Cell culture
정상(Normal) 및 알츠하이머 환자의 섬유아세포주(PS1 fibroblast)를 Coriell Institute에서 얻어 15% FBS를 포함하는 DMEM에서 37℃ 및 5%의 CO2에서 배양하여 사용하였다. 이후, 상기 세포주에 본 발명의 신규화합물인 JS-101_newPEG2 (10uM) 또는 JS-101_newPEG4 (10uM)를 처리 한 후 ASM 활성도 변화를 측정하였다. Normal and Alzheimer's fibroblasts were obtained from Coriell Institute and cultured in DMEM containing 15% FBS at 37 ° C and 5% CO 2 . Then, the cell line was treated with JS-101_newPEG2 (10uM) or JS-101_newPEG4 (10uM), which is a novel compound of the present invention, and then ASM activity was measured.
6. ASM 활성 측정6. ASM activity measurement
ASM의 농도 수준을 아래와 같이 측정하였다. 구체적으로 마우스의 혈청, 뇌조직 또는 섬유아세포 시료 3㎕를 ASM 활성 완충액과 혼합하여 37℃에서 보관하였다. 114㎕의 에탄올을 가하여 가수분해 반응을 종료시킨 후, 원심분리하였다. 30㎕의 상층액을 유리 바이알에 옮긴 후, 5㎕를 UPLC 시스템에 적용시켰다. 상기 ASM 농도 수준을 스핑고미엘린 및 세라마이드와 결합된 Bodipy(aminoacetaldehyde)와 비교함으로써 정량화하였다. 상기 스핑고미엘린 및 세라미이드의 추출 및 정량화는 공지된 방법으로 수행하였다. 간략하게, 시료에서 지질을 추출 및 건조하고, 상기 건조된 지질 추출물을 25㎕의 0.2% Igepal CA-630(Sigma-Aldrich)에 재부유시키고, 각각의 지질의 농도 수준을 UPLC 시스템을 이용하여 정량화하였다. The concentration level of ASM was measured as follows. Specifically, 3 쨉 l of mouse serum, brain tissue, or fibroblast sample was mixed with ASM activity buffer and stored at 37 째 C. 114 占 퐇 of ethanol was added to complete the hydrolysis reaction, followed by centrifugation. 30 [mu] l of the supernatant was transferred to a glass vial and 5 [mu] l was applied to the UPLC system. The ASM concentration level was quantified by comparison with siping myelin and Bodipy (aminoacetaldehyde) conjugated with ceramide. The extraction and quantification of the sphingomyelin and ceramide were carried out by a known method. Briefly, lipids were extracted from the sample and dried, and the dried lipid extract was resuspended in 25 μl of 0.2% Igepal CA-630 (Sigma-Aldrich) and the concentration levels of the respective lipids were quantified using the UPLC system Respectively.
7. 통계학적 분석7. Statistical analysis
두 그룹의 비교를 위하여 학생의 T-test를 수행하는 반면, 다수의 그룹의 비교를 위해서는 SAS 통계학적 패키지 (release 9.1; SAS Institute Inc., Cary, NC)에 따라서 Tukey’s HSD 테스트 및 분산 테스트의 반복측정분석을 수행하였다. p<0.05를 유의적인 것으로 간주하였다. For comparison of the two groups, students were asked to perform a T-test. For comparison of multiple groups, repeat the Tukey's HSD test and distribution test according to the SAS statistical package (release 9.1; SAS Institute Inc., Cary, NC) Measurement analysis was performed. p <0.05 was considered significant.
[실험결과] [Experiment result]
<5-1> <5-1> in vitroin vitro 본 발명 신규 화합물들의 ASM 활성 조절 효과 확인 Identification of ASM activity modulating effect of the novel compounds of the present invention
알츠하이머 환자의 섬유아세포에 본 발명에서 제조한 신규화합물들을 처리하여 이들의 효능을 확인하였다. 구체적으로 전술한 실시예에서 제조한 신규화합물인 JS-101_newPEG2(도 1A) 또는 JS-101_newPEG4 (도 1B)의 ASM 활성억제 효과를 확인하기 위하여 알츠하이머 환자 유래 섬유아세포(PS1 fibroblast)에 JS-101_newPEG2 또는 JS-101_newPEG4를 10 uM 농도로 처리한 후 ASM의 활성 변화를 측정하였다. Fibroblasts of Alzheimer's patients were treated with the novel compounds prepared in the present invention to confirm their efficacy. Specifically, in order to confirm the ASM activity inhibitory effect of the novel compound JS-101_newPEG2 (FIG. 1A) or JS-101_newPEG4 (FIG. 1B) prepared in the above-mentioned example, JS-101_newPEG2 JS-101_newPEG4 was treated with 10 uM concentration, and the activity change of ASM was measured.
도 2에 나타난 바와 같이, PS1 섬유아세포(control)에서는 정상인 유래 섬유아세포에 비해 ASM 활성이 현저하게 증가되어 있었으나, 이는 ASM 억제 신규화합물인 JS-101_newPEG2 또는 JS-101_newPEG4 처리에 의해 현저하게 감소되었다. 이에 따라 본 발명의 화학식 1로 표시되는 화합물들은 ASM 억제 효능이 우수한 것으로 사료되었다.As shown in Fig. 2, in the PS1 fibroblast control, the ASM activity was significantly increased as compared with that of the normal fibroblast, but this was markedly decreased by the ASM inhibitory compound JS-101_newPEG2 or JS-101_newPEG4 treatment. Accordingly, the compounds represented by
<5-2> 퇴행성 신경질환 <5-2> Degenerative neurological diseases in vivo in vivo 모델에서 본 발명 신규 화합물들의 치료 효과 확인Identification of the therapeutic effects of the novel compounds of the invention in the model
1. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 ASM 활성 변화 확인1. Determination of ASM activity in APP / PS1 mice treated with the novel compounds of the present invention
ASM 억제 효능이 있는 본 발명의 화학식 1로 표시되는 화합물들 중 대표적으로 JS-101_newPEG2를 사용하여 in vivo 상에서 우울증 및 퇴행성 신경질환에 대한 효능을 확인하였다. Among the compounds represented by
구체적인 실험방법은 다음과 같다. 도 4에 나타낸 실험스케쥴에 따라, 우울증 및 퇴행성 신경질환(특히, 알츠하이머) 동물모델인 APP/PS1 마우스(7.5개월령)에 JS-101_newPEG2를 100mg/kg/day씩 2개월간 음수(飮水)를 통해 구강투여 하였다. 음수를 통한 구강투여 종료 후 (9.5개월령), 혈장 및 뇌조직에서 ASM 농도(활성) 수준을 확인하였다. 상기 마우스에서 ASM의 농도 수준을 도 3에 나타내었다. Specific experimental methods are as follows. According to the experimental schedule shown in Fig. 4, JS-101_newPEG2 was administered to APP / PS1 mice (7.5 months old), which is an animal model of depression and neurodegenerative diseases (particularly Alzheimer's disease) by drinking water at 100 mg / kg / day for 2 months Oral administration. After oral administration of oral water (9.5 months), ASM levels (activity) levels were determined in plasma and brain tissue. The concentration level of ASM in the mouse is shown in Fig.
도 3A 및 도 3B에서 보는 바와 같이, APP/PS1 마우스의 혈장 및 뇌조직의 ASM 농도 수준이 정상군(WT) 대비 상당히 높은 것으로 나타났으며, 이와 비교하여 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 마우스의 혈장 및 뇌조직의 ASM 농도는 그 수준이 현저히 낮음을 확인하였다.As shown in FIGS. 3A and 3B, ASM concentration levels of plasma and brain tissues of APP / PS1 mice were significantly higher than those of the normal group (WT), and compared with the novel compound of the present invention, JS-101_newPEG2 The levels of ASM in plasma and brain tissues of the administered mice were confirmed to be significantly low.
2. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 아밀로이드-β 침착 확인2. Confirmation of amyloid-beta deposition in APP / PS1 mice treated with the novel compounds of the present invention
ASM 억제 신규화합물인 JS-101_newPEG2이 알츠하이머 병변에 미치는 영향을 확인하기 위해, 도 4에 나타낸 실험스케쥴에 따라 알츠하이머 동물모델인 APP/PS1 마우스(7.5개월령)에 JS-101_newPEG2를 100mg/kg/day씩 2개월간 음수(飮水)를 통해 구강투여하고, 상기 마우스로부터 알츠하이머 병변인 아밀로이드-β(Aβ) 프로파일을 규명하였다. 먼저 마우스의 대뇌 수질 (Cortex) 및 해마 (Hippocampus) 부위를 공지된 방법에 따라 티오플라빈 S(ThioS)로 염색하여 원섬유성 아밀로이드-β 침착을 확인하였다. 또한, Aβ40 및 Aβ42의 면역형광 염색을 실시하여 아밀로이드-β 침착을 확인하였다. ASM Suppression To confirm the effect of the new compound JS-101_newPEG2 on Alzheimer's disease, JS-101_newPEG2 was administered to APP / PS1 mouse (7.5 months of age), which is an animal model of Alzheimer's disease, at 100 mg / kg / day The mice were orally administered via drinking water for 2 months, and the mice were examined for the amyloid-beta (A [beta]) profile of Alzheimer's disease. Cortic and hippocampus sites of mice were stained with thioflavin S (ThioS) according to a known method to confirm fibrillary amyloid-β deposition. Immunofluorescent staining of A? 40 and A? 42 was also performed to confirm amyloid-beta deposition.
실험 결과, APP/PS1 마우스와 비교해 JS-101_newPEG2를 투여한 APP/PS1 마우스에서 원섬유성 Aβ 침착 (도 5A 및 도 5B 참조) 및 Aβ40과 Aβ42의 침착이 현저히 낮은 것을 확인하였다(도 6A 및 도 6B 참조). As a result, it was confirmed that fibrillar A [beta] deposits (see Figs. 5A and 5B) and deposition of A [beta] 40 and A [beta] 42 were significantly lower in APP / PS1 mice administered with JS-101_new PEG2 as compared to APP / PS1 mice 6B).
3. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 학습, 3. In APP / PS1 mice treated with the novel compounds of the present invention, 인지력Cognitive ability , 활동성 및 불안감의 호전 확인, Improvement of activity and anxiety
퇴행성신경질환에 있어서 본 발명 신규화합물의 학습 및 인지력에 대한 잠재적 효과를 확인하기 위하여, 도 4에 나타낸 실험스케쥴에 따라 퇴행성 신경질환(특히, 알츠하이머) 동물모델인 APP/PS1 마우스(7.5개월령)에 JS-101_newPEG2를 100mg/kg/day씩 1개월간 음수(飮水)를 통해 구강투여 하고, MWM (Morris water maze) 및 fear conditioning 테스트를 수행하였다. In order to confirm the potential effects of the novel compounds of the present invention on neurodegenerative diseases in the degenerative neurological diseases, APP / PS1 mice (7.5 months old), which is an animal model of degenerative neurological diseases (especially Alzheimer) according to the experimental schedule shown in FIG. 4 JS-101_new PEG2 was orally administered via oral water for 1 month at 100 mg / kg / day, and MWM (Morris water maze) and fear conditioning tests were performed.
도 7에 나타낸 바와 같이, APP/PS1 마우스는 공간기억, 인지력 및 기억력 형성에 심각한 장애를 보였으나, 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스는 이러한 장애가 개선됨을 확인하였다(도 7A 내지 도 7C 참조). JS-101_newPEG2는 fear conditioning test에서도 기억력의 개선 효과를 나타냄을 확인하였다 (도 7D 참조).As shown in FIG. 7, APP / PS1 mice exhibited severe obstacles to spatial memory, cognition and memory formation, whereas APP / PS1 mice treated with the novel compound of the present invention, JS-101_newPEG2, 7A to 7C). JS-101_new PEG2 also showed improvement in memory performance in the fear conditioning test (see FIG. 7D).
또한, JS-101_newPEG2 화합물이 활동성 및 불안감에 미치는 영향을 확인하기 위해 오픈필드 테스트와 Dark & Light 테스트를 실시하였다. In addition, open field tests and dark & light tests were conducted to determine the effect of JS-101_newPEG2 on activity and anxiety.
도 8에 나타난 바와 같이, APP/PS1 마우스에 비해 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스에서 활동성 및 불안감이 크게 호전되는 현상을 확인하였다 (도 8A 내지 도 8I 참조).As shown in FIG. 8, activity and anxiety were significantly improved in APP / PS1 mice administered with JS-101_newPEG2, a novel compound of the present invention, compared to APP / PS1 mice (see FIGS. 8A to 8I).
4. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 신경염증 변화 확인4. Identification of neuroinflammatory changes in APP / PS1 mice treated with the novel compounds of the present invention
APP/PS1 마우스에서 본 발명의 신규화합물인 JS-101_newPEG2 투여가 신경염증 변화에 미치는 영향을 확인하기 위해서, 도 4에 나타낸 실험스케쥴에 따라 퇴행성 신경질환(특히, 알츠하이머) 동물모델인 APP/PS1 마우스(7.5개월령)에 JS-101_newPEG2를 100mg/kg/day씩 2개월간 음수(飮水)를 통해 구강투여 하고, 마우스를 희생하여 뇌에서 별아교세포의 변화를 관찰하였다. To confirm the effect of JS-101_new PEG2 administration of the novel compound of the present invention on neuroinflammatory changes in APP / PS1 mice, APP / PS1 mice, which are animal models of degenerative neurological diseases (especially Alzheimer) JS-101_newPEG2 was administered orally to mice at a dose of 100 mg / kg / day for 2 months, and mice were sacrificed to observe changes in astrocytes in the brain.
실험 결과 도 9에서 보는 바와 같이, APP/PS1 마우스와 비교하여 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스에서는 별아교세포의 활성이 현저히 저하됨을 확인하였다(도 9A 참조). APP/PS1 마우스에서는 야생 마우스에 비해 염증성 사이토카인인 TNF-a, IL-1b 및 IL-6의 유전자 발현이 현저히 증가되어 있었으나, 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스에서는 염증성 사이토카인의 발현이 정상수준으로 회복됨을 확인하였다(도 9B 참조). 이러한 결과들을 통해 본 발명의 신규화합물인 JS-101_newPEG2의 투여는 퇴행성 신경질환(특히, 알츠하이머) 뇌환경에서 신경 염증 반응을 조절한다는 것을 확인할 수 있었다 . Experimental Results As shown in FIG. 9, the activity of astrocytes was significantly reduced in APP / PS1 mice administered with JS-101_new PEG2, which is a novel compound of the present invention, compared to APP / PS1 mice (see FIG. 9A). In the APP / PS1 mouse, gene expression of the inflammatory cytokines TNF-a, IL-lb and IL-6 was significantly increased compared with wild mice. However, in the APP / PS1 mouse administered with the novel compound JS-101_newPEG2 of the present invention And the expression of inflammatory cytokines was restored to normal levels (see FIG. 9B). These results confirm that the administration of the novel compound of the present invention, JS-101_newPEG2, regulates the neuroinflammatory response in the neurodegenerative disease (especially Alzheimer's) brain environment.
상기의 결과들을 종합하면, 본 발명의 신규 화합물들(특히, JS-101_newPEG2와 JS-101_newPEG4)은 알츠하이머 환자 유래 섬유아세포에서 증가된 ASM 활성을 억제시켜줄 수 있음을 알 수 있었다. 특히, APP/PS1 마우스에서 ASM 억제 신규화합물인 JS-101_newPEG2의 투여는 Aβ 플라크 침착과 염증반응을 감소시킴을 알 수 있었다. 또한 ASM 억제 신규화합물인 JS-101_newPEG2은 퇴행성 신경질환(특히, 알츠하이머) 동물에서 학습, 기억능력을 향상시킴으로써, 알츠하이머를 포함하는 퇴행성 뇌질환 치료제로서 활용이 가능하다는 사실을 알 수 있었다. Taken together, the above results indicate that the novel compounds of the present invention (particularly, JS-101_newPEG2 and JS-101_newPEG4) can inhibit increased ASM activity in fibroblasts derived from Alzheimer's patients. In particular, administration of JS-101_newPEG2, a novel compound inhibiting ASM in APP / PS1 mice, was found to reduce Aβ plaque deposition and inflammatory responses. In addition, the new ASM inhibitor, JS-101_newPEG2, can be used as a treatment for degenerative brain diseases, including Alzheimer's disease, by enhancing learning and memory skills in degenerative neurological diseases, particularly Alzheimer's disease.
이상 살펴본 바와 같이, 본 발명은 화학식 1로 표시되는 신규 화합물 2-아미노-2-(1-(2-(2-히드록시에톡시)에틸)-1H-1,2,3-트리아졸-4-일)프로판-1,3-디올 유도체 및 이의 용도에 관한 것이다. 본 발명의 화학식 1의 ASM 신규 억제화합물은 ASM 억제 효과가 탁월하고, 알츠하이머 뇌환경에서 Aβ 플라크 감소, 기억력 및 불안증 개선, 신경염증 완화 등의 치료효과가 있으며, 알츠하이머병을 포함하는 퇴행성 신경질환의 예방 또는 치료제 개발에 매우 유용하게 사용될 수 있어 산업상 이용가능성이 매우 우수하다. 또한 ASM의 억제는 우울증 완화에 효과적임이 이미 알려져 있으므로 본 발명의 화학식 1의 ASM 신규 억제화합물은 우울증을 포함하는 신경 질환의 예방 또는 치료제로서도 유용하게 사용될 수 있다. As described above, the present invention provides a novel compound 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 H -1,2,3-triazole- 4-yl) propane-1,3-diol derivatives and uses thereof. The novel inhibitory compound of ASM of formula (I) of the present invention has excellent ASM inhibitory effect, has therapeutic effect such as reduction of A? Plaque, improvement of memory and anxiety, alleviation of nerve inflammation in Alzheimer's brain environment and prevention of degenerative neurological diseases including Alzheimer's disease It can be very useful for development of a preventive or therapeutic agent, and is highly industrially applicable. In addition, it has already been known that inhibition of ASM is effective for relieving depression. Therefore, the novel ASM inhibitory compound of the present invention can be usefully used as a preventive or therapeutic agent for neurological diseases including depression.
<110> Kyungpook National University Industry-Academic Cooperation Foundation <120> Novel compound 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)pro pane-1,3-diol and use thereof <130> NP17-0027 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mTNF-a <400> 1 gattatggct cagggtccaa 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mTNF-a <400> 2 gctccagtga attcggaaag 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-1 beta <400> 3 cccaagcaat acccaaagaa 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-1 beta <400> 4 gcttgtgctc tgcttgtgag 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-6 <400> 5 ccggagagga gacttcacag 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-6 <400> 6 ttgccattgc acaactcttt 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mGAPDH <400> 7 tgaatacggc tacagcaaca 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mGAPDH <400> 8 aggcccctcc tgttattatg 20 <110> Kyungpook National University Industry-Academic Cooperation Foundation <120> Novel compound 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1H-1,2,3-triazol-4-yl) pro pane-1,3-diol and use thereof <130> NP17-0027 <160> 8 <170> KoPatentin 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mTNF-a <400> 1 gattatggct cagggtccaa 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mTNF-a <400> 2 gctccagtga attcggaaag 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-1 beta <400> 3 cccaagcaat acccaaagaa 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-1 beta <400> 4 gcttgtgctc tgcttgtgag 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-6 <400> 5 ccggagagga gacttcacag 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mIL-6 <400> 6 ttgccattgc acaactcttt 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mGAPDH <400> 7 tgaatacggc tacagcaaca 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for mGAPDH <400> 8 aggcccctcc tgttattatg 20
Claims (7)
<화학식 1>
상기 식에서 R1은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.
A compound represented by the following formula (1) or a salt thereof:
≪ Formula 1 >
Wherein R1 is hydrogen or an acetyl group, and n is a natural number of 2? N? 5.
(a) 하기 화학식 2의 화합물과 하기 화학식 3으로 표시되는 화합물을 반응시켜 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 및
(b) 상기 (a) 단계에서 제조한 하기 화학식 4의 화합물에서 부틸옥시카보닐기(butyloxycarbonyl group) 및 아세토니드기(acetonide group)를 탈보호(deprotection)하여, R1이 수소인 제1항의 화합물로서 하기 화학식 la로 표시되는 화합물을 제조 및 수득하는 단계.
<화학식 2>
<화학식 3>
상기 식에서 n은 2≤ n ≤5의 자연수임.
<화학식 4>
상기 식에서 n은 2≤ n ≤5의 자연수임.
<화학식 1a>
상기 식에서 n은 2≤ n ≤5의 자연수임.
1. A process for preparing a compound represented by the formula (I), wherein R 1 is hydrogen, comprising the steps of:
(a) reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) to prepare a compound represented by the following formula (4); And
(b) deprotecting a butyloxycarbonyl group and an acetonide group in the compound of formula (IV) prepared in the step (a) to obtain a compound of the formula Preparing and obtaining a compound represented by the following formula (la).
(2)
(3)
Wherein n is a natural number of 2? N? 5.
≪ Formula 4 >
Wherein n is a natural number of 2? N? 5.
<Formula 1a>
Wherein n is a natural number of 2? N? 5.
<화학식 1a>
상기 식에서 n은 2≤ n ≤5의 자연수임.
<화학식 1b>
상기 식에서 n은 2≤ n ≤5의 자연수임.
A process for producing a compound represented by the following formula (1b), wherein R 1 is an acetyl group, comprising the step of N-acetylating an amine group of a compound represented by the following formula (1a).
<Formula 1a>
Wherein n is a natural number of 2? N? 5.
≪ EMI ID =
Wherein n is a natural number of 2? N? 5.
<화학식 1>
상기 식에서 R1은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.
A pharmaceutical composition for preventing or treating degenerative neuropathy or depression comprising, as an active ingredient, a compound of the following formula (1) or a pharmaceutically acceptable salt thereof:
≪ Formula 1 >
Wherein R1 is hydrogen or an acetyl group, and n is a natural number of 2? N? 5.
[Claim 5] The pharmaceutical composition according to claim 4, wherein the compound of formula (I) inhibits ASM (acid sphingomyelinase) activity.
5. The method of claim 4, wherein the degenerative neurological disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, olfactory nuclear-pongo-cerebellar atrophy (OPCA), Shire-Drager syndrome, , Amyotrophic lateral sclerosis (ALS), essential hypertrophy, cortical-basal ganglia degeneration, diffuse rheisome disease, parkins-ALS-dementia complex, Pick disease, cerebral ischemia and cerebral infarction A pharmaceutical composition.
<화학식 1>
상기 식에서 R1은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.A food composition for preventing or ameliorating a degenerative neurological disease or depression comprising, as an active ingredient, a compound of the following formula (1) or a pharmaceutically acceptable salt thereof:
≪ Formula 1 >
Wherein R1 is hydrogen or an acetyl group, and n is a natural number of 2? N? 5.
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| PCT/KR2018/004641 WO2018199562A1 (en) | 2017-04-28 | 2018-04-20 | 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1h-1,2,3-triazole-4-yl)propane-1,3-diol derivative which is novel compound, and use thereof |
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| WO2019212196A1 (en) * | 2018-04-30 | 2019-11-07 | 경북대학교 산학협력단 | 2-amino-2-(1,2,3-triazole-4-yl)propane-1,3-diol derivative of novel compound for directly inhibiting asm activity, and use thereof |
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| KR101521117B1 (en) | 2013-05-07 | 2015-05-18 | 경북대학교 산학협력단 | Composition for preventing or treating neurodegenerative disorder comprising acid sphingomyelinase inhibitor |
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| EP2379075A4 (en) * | 2008-12-16 | 2012-05-30 | Merck Sharp & Dohme | Triazole derivatives for treatment of alzheimer's disease |
| EP2289900A1 (en) * | 2009-08-26 | 2011-03-02 | Humboldt Universität zu Berlin | Bisphosphonates as inhibitors of acid sphingomyelinase |
| KR101811436B1 (en) * | 2017-04-28 | 2017-12-21 | 경북대학교 산학협력단 | Novel compound 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)propane-1,3-diol and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018199562A1 (en) * | 2017-04-28 | 2018-11-01 | 경북대학교 산학협력단 | 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1h-1,2,3-triazole-4-yl)propane-1,3-diol derivative which is novel compound, and use thereof |
| WO2019212196A1 (en) * | 2018-04-30 | 2019-11-07 | 경북대학교 산학협력단 | 2-amino-2-(1,2,3-triazole-4-yl)propane-1,3-diol derivative of novel compound for directly inhibiting asm activity, and use thereof |
| CN112351974A (en) * | 2018-04-30 | 2021-02-09 | 庆北大学校产学协力团 | Novel compound 2-amino-2- (1,2, 3-triazole-4-yl) -1, 3-propylene glycol derivative for directly inhibiting ASM activity and application thereof |
| RU2759856C1 (en) * | 2018-04-30 | 2021-11-18 | Киунгпоок Нэшнл Юниверсити Индастри-Академик Кооперейшн Фаундейшн | New compound for direct inhibition of asm activity, which is derivative of 2-amino-2-(1,2,3-triazol-4-yl)propane-1,3-diol, and its application |
| CN112351974B (en) * | 2018-04-30 | 2024-01-26 | 庆北大学校产学协力团 | Novel compound 2-amino-2- (1, 2, 3-triazole-4-yl) -1, 3-propanediol derivative capable of directly inhibiting ASM activity and application thereof |
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