KR101692378B1 - Novel Use of Sesquiterpene Derivatives - Google Patents
Novel Use of Sesquiterpene Derivatives Download PDFInfo
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- KR101692378B1 KR101692378B1 KR1020160120155A KR20160120155A KR101692378B1 KR 101692378 B1 KR101692378 B1 KR 101692378B1 KR 1020160120155 A KR1020160120155 A KR 1020160120155A KR 20160120155 A KR20160120155 A KR 20160120155A KR 101692378 B1 KR101692378 B1 KR 101692378B1
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Abstract
Description
본 발명은 세스퀴테르펜 유도체의 신규한 용도에 관한 것으로, 더욱 상세하게는 화학식 1로 표시되는 세스퀴테르펜 유도체 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 안구 내 혈관 누수에 의한 황반변성 또는 황반부종의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a novel use of a sesquiterpene derivative, and more particularly to a novel use of a sesquiterpene derivative compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Ameliorating or treating macular degeneration or macular edema.
황반부종(macular edema)은 망막 황반의 부기를 말하며, 부종은 망막 혈관으로부터의 액체 누출로 인하여 발생한다. 혈액은 약한 혈관벽에서 누출되어, 색상을 감지하는 신경 말단이며 낮 동안의 시력이 의존하는 망막 원추체가 풍부한 망막 황반의 극소 영역으로 유입된다. 이어서, 이미지가 중심영역의 중앙 또는 중앙 옆 오른쪽에서 희미하게 된다. 시력은 수개월 동안 점진적으로 감소한다. 연령관련 황반변성(Age-related macular degeneration, AMD)은 모두 황반부종과 연관되어 있다. 안구 내에서 혈관누수는 다양한 원인에 의하여 일어난다. 일례로 고혈압 환자에서 지속적인 혈압의 상승은 혈액-망막장벽의 파괴를 유발하며, 혈액-망막장벽의 손상으로 혈관 누출에 의해 망막부종이 발생하게 된다. 망막 황반은 때때로 백내장 치료를 위한 수정체 제거 후의 황반부기(macula tumentia)에 의해 손상된다.The macular edema refers to the swelling of the macula, and edema is caused by the leakage of fluid from the retinal vessels. Blood leaks from the weak blood vessel wall, enters the nerve endings of the retinal macula where the color of the nerve endings is sensitive to color and the daytime visual acuity depends on the retinal conic. The image is then faded to the right of the center or center of the center area. Visual acuity decreases gradually over several months. Age-related macular degeneration (AMD) is associated with macular edema. Vascular leakage in the eye can be caused by various causes. For example, persistent elevation of blood pressure in hypertensive patients leads to breakdown of the blood-retinal barrier, and blood-retinal barrier damage causes retinal edema due to blood vessel leakage. Retinal macular occasions are sometimes impaired by macula tumentia after lens removal for cataract treatment.
종래 황반부종의 치료로는 레이저 조사에 의한 광응고술, 유리체 수술, 전신 투여, 스테로이드의 유리체강 내 투여 및 서브테논(sub-Tenon) 투여 등을 수행하였다. 레이저 조사에 의한 광응고술은 액체 누출이 일어나는 혈관을 막아서 황반의 부기를 감소시킨다. 그러나, 레이저 조사 시에 극도로 취약한 중심와(fovea)를 피하도록 주의하여야 한다. 중심와가 이 시술에 의해 상처를 받으면 중심시야가 손상될 수 있다. 또한 복수의 레이저 시술이 부기를 제거하기 위해 종종 필요하다. 유리체 수술은 레이저 시술이 비효과적인 경우에 적용하지만, 이 방법은 가끔 수술 후 합병증 문제를 야기하는 높은 조직 침습 가능성과 연관되어 있다. 현재 사용되는 안과 조성물의 유리체강 내 투여는, 스테로이드를 투여했을 때 고안압증, 스테로이드성 녹내장 및 후부 수정체피막하 백내장을 일으킬 수 있다. 또한 스테로이드의 유리체강내 투여는 때때로 수술 후 합병증을 유발한다. Conventional macular edema has been treated by laser-assisted photocoagulation, vitreous surgery, systemic administration, steroid injection into the vitreous cavity and sub-tenon administration. Photocoagulation by laser irradiation reduces macular edema by blocking blood vessels that leak. However, care must be taken to avoid extremely weak fovea during laser irradiation. If the central vein is injured by this procedure, the central visual field may be damaged. Also, multiple laser procedures are often needed to remove the swelling. Although vitrectomy is used when laser surgery is ineffective, this method is often associated with the potential for high tissue invasiveness that can lead to postoperative complications. Intra-ocular administration of currently used ophthalmic compositions can cause ocular hypertension, steroid glaucoma, and posterior capsular cataracts when steroids are administered. In addition, intravitreal administration of steroids sometimes causes postoperative complications.
상기 스테로이드뿐만 아니라, 국소적으로 유리체강 내에 직접 투여하는 시판 약물들은 통상 4-6주 마다 반복적인 투여가 필요한 것으로 알려져 있으며, 유리체강 내 직접 투여로 인해 투약의 불편함과 고통 및 부작용을 수반하는 문제점이 있었다.In addition to the above steroids, it is known that commercial drugs that are administered directly into the vitreous cavity locally are required to be repeatedly administered every 4 to 6 weeks. It is known that direct administration into the vitreous cavity causes discomfort, pain, and side effects There was a problem.
이에 본 발명자들은 투약의 불편함은 감소시키고 장기투여 가능하며 황반부종 또는 이와 관련된 황반변성에 탁월한 치료효능을 나타내는 약제를 개발하고자 연구하던 중, 화학식 1로 표시되는 화합물이 안구 내 혈관누수(vascular leakage)를 효과적으로 억제하여 황반부종 또는 황반변성 동물모델에서 치료효과를 보임을 확인하였으며, 해당 화합물이 경구투여를 통해서도 안구까지 타겟팅(targeting)됨을 확인하여 본 발명을 완성하였다.Accordingly, the inventors of the present invention have found that when a compound represented by the formula (1) is used for the treatment of vascular leakage of ocular surface, And it was confirmed that the compounds were targeted to the eye through oral administration. Thus, the present invention was completed.
본 발명의 목적은 안구 내 혈관 누수에 의한 황반변성 또는 황반부종의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of macular degeneration or macular edema due to intra-ocular blood vessel leakage.
본 발명의 또 다른 목적은 안구 내 혈관 누수에 의한 황반변성 또는 황반부종의 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 macular degeneration or macular edema due to intra-ocular blood vessel leakage.
본 발명의 상기 목적들은 하기 설명되는 본 발명에 의하여 모두 달성될 수 있다.The above objects of the present invention can be achieved by the present invention described below.
상기와 같은 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 황반변성 또는 황반부종의 예방 또는 치료용 약학적 조성물을 제공한다:In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating macular degeneration or macular edema comprising, as an active ingredient, a compound represented by the following
[화학식 1][Chemical Formula 1]
화학식 1에서, In formula (1)
점선은 단일결합 또는 이중결합을 나타내며 The dotted line represents a single bond or a double bond
i) 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합일 때, R2b는 존재하지 않고 R2a는 CH2인 구조;i) when the bond between
ii) 3번 탄소와 4번 탄소의 결합이 이중결합일 때, 5번 탄소와 6번 탄소의 결합은 단일결합이고, R2b는 존재하지 않고 R2a는 CH3인 구조; 및ii) coupling of the 5-carbon and 6-carbon bond is a double bond when the 3 carbon of the 4-carbon is a single bond, R2b is absent R2a is CH 3 structure; And
*iii) 5번 탄소와 6번 탄소의 결합이 이중결합일 때, 3번 탄소와 4번 탄소의 결합은 단일결합일 때, R2a 및 R2b는 CH3인 구조로 구성된 군에서 선택되는 하나의 구조이고,* iii) when the double bond binding of the 5-carbon and 6-carbon, 3 bond of carbon and the 4-carbon is a structure selected from the group consisting of, R2a and R2b are CH 3 structure when the single bond ego,
R1은 H 또는 CH3이며,R1 is H or CH 3,
R3은 하기 R3a 내지 R3d로 구성된 군에서 선택되는 어느 하나의 작용기이고,R3 is any one functional group selected from the group consisting of the following R3a to R3d,
상기 R3a는Wherein R3a is
i) R4 및 R7이 각각 OH 또는 OCH3이고, R5, R6 및 R8은 H인 구조; 또는of i) R4 and R7 are each OH or OCH 3, and, R5, R6 and R8 are H structure; or
ii) R5가 COOCH3이고, R7은 H 또는 OH이며, R8은 OH이고, R4 및 R6은 H인 구조이며,ii) R5 is COOCH 3, R7 is H or OH, R8 is OH and a, R4, and R6 are H structure,
상기 R3b는R3b is
R9가 H, NH2, C1~C8 알콕시기 및 하기 R9a 내지 R9j로 구성된 군에서 선택되는 어느 하나의 작용기이고, R10은 H 또는 OH이고, And R9 is H, NH 2, C1 ~ C8 alkoxy group to which one functional group and is selected from the group consisting of R9a to R9j, R10 is H or OH,
상기 R3c는R3c is
R11 및 R12는 각각 OH 또는 OAc이고, R13은 H인 구조; 또는R11 and R12 are each OH or OAc, and R13 is H; or
R11 및 R12는 각각 OH 또는 OCH3이며 R13은 CH3인 구조이며R11 and R12 are OH or OCH 3, and each R13 is CH 3 and the structure
상기 R3d는 R14가 OCH3이고, R15 및 R16은 CH3인 구조.Wherein R3d is R14 is OCH 3, R15 and R16 are CH 3 structure.
본 발명은 또한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 안구 내 혈관 누수 억제용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for inhibiting intra-ocular blood vessel leakage comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 황반변성 또는 황반부종의 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for the prevention or amelioration of macular degeneration or macular edema comprising, as an active ingredient, a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
본 발명의 화학식 1의 화합물은 안구 내, 특히 망막 내의 혈관 누수(leakage)를 억제하여, 황반부종 및 황반변성 등의 안구 내 혈관누수에 의한 질환에 대하여 치료 효과가 있다. 뿐만 아니라 시판되고 있는 안구 내 질환 관련 치료제들이 유리체강 내로 직접 투여해야하는 불편함과 이에 따른 고통 및 부작용이 있는 것에 반해, 본 발명의 화합물은 유리체강 내 투여 이외의 다른 투여경로(경구투여, 복강주사 등)를 통해서도 타겟 조직(눈)에 분포하여, 투여경로에 구애받지 않고 치료효능을 가지므로 효과가 탁월하다.The compound of formula (I) of the present invention inhibits the leakage of blood into the eyeball, particularly the retina, and has a therapeutic effect against diseases caused by intraocular blood vessel leakage such as macular edema and macular degeneration. In addition, there are inconveniences that the commercially available intraocular disease-related therapeutic agents must be directly administered into the vitreous cavity, and thus pain and side effects, while the compounds of the present invention are administered by other routes other than intravesicular administration (such as oral administration, intraperitoneal injection Etc.), and is effective in the treatment effect regardless of the route of administration.
도 1은 Wnt-3a CM 처리에 의해 Wnt/β-catenin 경로가 활성화된 HEK293 세포에서, 본 발명의 화합물(제조예 30 화합물 또는 제조예 31 화합물)처리에 따른 β-catenin 발현 억제효과를 웨스턴 블롯으로 확인한 결과를 나타낸다.
도 2는 Wnt-3a CM 처리에 의해 Wnt/β-catenin 경로가 활성화된 HEK293 세포에서, 본 발명의 화합물(제조예 32 화합물)처리에 따른 β-catenin 발현 억제효과를 웨스턴 블롯으로 확인한 결과를 나타낸다.
도 3은 Wnt-3a CM 처리에 의해 Wnt/β-catenin 경로가 활성화된 인간 망막상피세포에서, 본 발명의 화합물(제조예 33 또는 제조예 34)처리에 따른 β-catenin 발현 억제효과를 웨스턴 블롯으로 확인한 결과를 나타낸다.
도 4는 황반부종 마우스 모델에서, 본 발명의 화합물(제조예 33)의 유리체강내 투여에 따른 혈액누수 억제 효과를 형광안저혈관촬영 및 빛간섭단층촬영 검사로 확인한 결과를 나타낸다(A 및 B는 DMSO를 주사 후에 촬영한 대조군(화합물 무처리군) 사진이고, C 및 D는 실험군(제조예 33)의 주사 후에 촬영한 사진이며, 화살표는 혈관 부위를 표시한 것임).
도 5는 황반부종 마우스 모델에서, 본 발명의 화합물(제조예 33)의 복강주사에 따른 혈액누수 억제 효과를 빛간섭단층촬영 검사로 확인한 결과를 나타낸다(A는 vehicle 투여군, B는 제조예 33 화합물 1mg/kg 투여군)
도 6은 본 발명의 화합물(제조예 33)을 ICR 마우스에 경구투여한 후, 타겟 조직(특히, 눈)에 대한 화합물 분포를 측정한 결과를 나타낸다.Fig. 1 shows the effect of inhibiting the expression of [beta] -catenin according to the treatment of the compound of the present invention (the compound of Preparation Example 30 or the preparation Example 31) in HEK293 cells in which the Wnt /? - catenin pathway was activated by Wnt- As shown in Fig.
FIG. 2 shows the results of western blotting of the inhibitory effect of β-catenin expression on the Wnt / β-catenin pathway-activated HEK293 cells treated with the compound of the present invention (compound of Preparation Example 32) by Wnt-3a CM treatment .
Fig. 3 shows the effect of inhibiting the expression of [beta] -catenin according to the treatment with the compound of the present invention (Production Example 33 or Production Example 34) in human retinal epithelial cells in which the Wnt / 3-catenin pathway was activated by Wnt- As shown in Fig.
4 shows the results of confirming the blood leakage inhibitory effect of intravitreal administration of the compound of the present invention (preparation example 33) by a fluorescein angiography and optical coherence tomography in a macular edema mouse model (A and B are DMSO (Group-free treatment group) photographs taken after the injection, C and D are photographs taken after the injection of the experimental group (preparation example 33), and arrows indicate the blood vessel area).
FIG. 5 shows the result of confirming the blood-leaking inhibitory effect of the compound of the present invention (Production Example 33) on macular edema mouse model by optical coherence tomography (A is a vehicle-administered group, and B is a compound of Preparation 33 1 mg / kg administration group)
Fig. 6 shows the results of measurement of the compound distribution with respect to a target tissue (particularly, eyes) after oral administration of the compound of the present invention (Production Example 33) to ICR mice.
본 발명에서는 투약의 불편함은 감소시키고 장기투여 가능하며 황반부종 또는 이와 관련된 황반변성에 탁월한 치료효능을 나타내는 약제를 개발하고자 연구하던 중, 화학식 1로 표시되는 화합물이 안구 내, 특히 망막 내의 혈관누수(vascular leakage)를 효과적으로 억제하여 황반부종 또는 황반변성 질환에 치료효과를 보임을 확인하였다.In the present invention, in order to reduce the inconvenience of medication and to develop a drug which can be administered for a long time and exhibits an excellent therapeutic effect on macular edema or related macular degeneration, the compound represented by the formula (1) vascular leakage), which is effective in treating macular edema or macular degeneration.
따라서, 본 발명은 일 관점에서, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 황반변성 또는 황반부종의 예방 또는 치료용 약학적 조성물에 관한 것이다.Accordingly, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating macular degeneration or macular edema comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
본 발명의 세스퀴테르펜 유도체 화합물은 상기 화학식 1로 표시되며, 상기 화학식 1에서 점선은 단일결합 또는 이중 결합을 나타내며 The sesquiterpene derivative compound of the present invention is represented by the above Formula 1, wherein the dotted line in Formula 1 represents a single bond or a double bond
i) 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합으로 이루어질 때, R2b는 존재하지 않고 R2a는 CH2인 구조;i) when the bond between
ii) 3번 탄소와 4번 탄소의 결합이 이중결합으로 이루어질 때, 5번 탄소와 6번 탄소의 결합은 단일 결합으로 이루어지며, R2b는 존재하지 않고 R2a는 CH3 인 구조; 및ii) when formed of three times is a double bond bond of carbon-carbon and 4, the combination of five-carbon and six-carbon is made by a single bond, R2b is absent R2a is CH 3 structure; And
iii) 5번 탄소와 6번 탄소의 결합이 이중결합으로 이루어질 때, 3번 탄소와 4번 탄소의 결합은 단일 결합으로 이루어지며, R2a 및 R2b는 CH3 인 구조로 구성된 군에서 선택되는 하나의 구조이고,iii) when made of a combination of the carbon is a double bond and the number 5
R1은 H 또는 CH3이며,R1 is H or CH 3,
R3은 하기 R3a 내지 R3d로 구성된 군에서 선택되는 어느 하나의 작용기이며,R3 is any functional group selected from the group consisting of the following R3a to R3d,
상기 R3a는Wherein R3a is
i) R4 및 R7이 각각 OH 또는 OCH3이고, R5, R6 및 R8은 H인 구조; 또는of i) R4 and R7 are each OH or OCH 3, and, R5, R6 and R8 are H structure; or
ii) R5가 COOCH3이고, R7은 H 또는 OH이며, R8은 OH이고, R4 및 R6은 H인 구조이고,ii) R5 is COOCH 3, R7 is H or OH, and R8 is OH and a, R4, and R6 are H structure,
상기 R3b는 R9가 H, NH2, C1~C8 알콕시기 및 하기 R9a 내지 R9j 로 구성된 군에서 선택되는 어느 하나의 작용기이고, R10은 H 또는 OH이며, R 3b is any functional group selected from the group consisting of H, NH 2 , C 1 -C 8 alkoxy groups and R 9a to R 9j,
상기 R3c는R3c is
R11 및 R12는 각각 OH 또는 OAc(아세톡시기, Acetoxy group)이고, R13은 H인 구조; 또는R11 and R12 are each OH or OAc (acetoxy group, Acetoxy group) and R13 is H; or
R11 및 R12는 각각 OH 또는 OCH3이며 R13은 CH3인 구조이고R11 and R12 are OH or OCH 3, and each R13 is CH 3 and the structure
상기 R3d는 R14가 OCH3이고, R15 및 R16은 CH3인 구조인 것을 특징으로 한다. Wherein R3d is characterized in that R14 is a OCH 3, R15 and R16 of the structure CH 3.
본 발명에서 용어 알콕시기(alkoxy group)는 산소와 결합된 알킬기(O-alkyl group)를 의미하는 것으로, 본 발명에서 메톡시기(C1), 에톡시기(C2), 프로폭시기(C3), 부톡시기(C4), 펜틸옥시기(C5), 헥실옥시기(C6), 헵틸옥시기(C7) 및 옥틸옥시(C8)를 포함하는 C1~C8 알콕시기로 구성된 군에서 선택되는 것일 수 있으나 이에 제한되지 않는다. 바람직하게 본 발명의 상기 알콕시기는 메톡시기 또는 에톡시기일 수 있다. In the present invention, the term alkoxy group refers to an alkyl group (O-alkyl group) bonded to oxygen. In the present invention, the alkoxy group (C1), ethoxy group (C2), propoxy group But are not limited to, a C1 to C8 alkoxy group including a C4 group, a pentyloxy group (C5), a hexyloxy group (C6), a heptyloxy group (C7) and an octyloxy group (C8) Do not. Preferably, the alkoxy group of the present invention may be a methoxy group or an ethoxy group.
상기 화학식 1에서In
i) 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합으로 이루어질 때, R2b는 존재하지 않고 R2a는 CH2인 구조는 하기 <화학식 1-1>로 표시되는 것일 수 있으며;when i) 3 times a combination of carbon and 4 bonds and 5-carbon and 6-carbon of the carbon is made by a single bond, R2b is absent R2a is CH 2 the structure is represented by the following <Formula 1-1>;
ii) 3번 탄소와 4번 탄소의 결합이 이중결합으로 이루어질 때, 5번 탄소와 6번 탄소의 결합은 단일 결합으로 이루어지며, R2b는 존재하지 않고 R2a는 CH3인 구조는 하기 <화학식 1-2>로 표시되는 것일 수 있고;ii) when formed of three times is a double bond combination of carbon and the 4-carbon, 5 times the carbon and 6 bond of carbon is made by a single bond, R2b is absent R2a is CH 3 in structure to <Formula 1 -2 >;
iii) 5번 탄소와 6번 탄소의 결합이 이중결합으로 이루어질 때, 3번 탄소와 4번 탄소의 결합은 단일 결합으로 이루어지며, R2a 및 R2b는 CH3인 구조는 하기 <화학식 1-3>으로 표시되는 것 일 수 있다.iii) when made of a combination of a carbon double bond and one carbon-5 # 6, a combination of 3-carbon and 4-carbon is made by a single bond, R2a and R2b are to CH 3 is the structure <EMI ID = 1-3>Lt; / RTI >
[화학식 1-1][Formula 1-1]
[화학식 1-2][Formula 1-2]
[화학식 1-3][Formula 1-3]
본 발명의 화학식 1의 화합물은, 구체적으로 하기 [표 1]에 기재된 구조의 화합물을 포함할 수 있으나, 이에 제한되지 않는다.The compound of formula (I) of the present invention may specifically include, but is not limited to, compounds having the structures shown in Table 1 below.
[표 1][Table 1]
바람직하게, 본 발명의 상기 세스퀴테르펜 유도체 화합물은 상기 화학식 1에서, 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합으로 이루어질 때 R2b는 존재하지 않고 R2a는 CH2인 화학식 1-1의 구조이고, R3은 상기 R3b 내지 R3d로 구성된 군에서 선택되는 어느 하나의 작용기인 것일 수 있다. Preferably, the sesquiterpene derivative compound of the present invention is a compound of formula (I) wherein R2b is absent when the bond between
상기 R3b는, 바람직하게 R9가 에톡시기, 메톡시기 및 상기 R9a로 구성된 군에서 선택된 어느 하나인 것일 수 있다.The R3b may preferably be any one selected from the group consisting of ethoxy group, methoxy group and R9a.
상기 R3c는, 바람직하게 R11은 OH이고 R12는 OCH3이며 R13은 CH3인 것일 수 있다.Wherein R3c is preferably R11 is OH and R12 is OCH 3, and R13 may be one of CH 3.
상기 R3d는, 바람직하게 R14가 OCH3이고, R15 및 R16은 CH3인 것일 수 있다.Wherein R3d is preferably R14 is OCH 3, R15 and R16 may be a CH 3.
더욱 바람직하게는 본 발명의 상기 화학식 1에서More preferably, in the
점선은 단일결합 또는 이중결합을 나타내며The dotted line represents a single bond or a double bond
i) 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합이며, R2b는 존재하지 않고 R2a는 CH2인 구조이고,i) and 3 is a single bond combination of carbon and 4 bonds and 5-carbon and 6-carbon of carbon, R2b is not present and R2a is CH 2 structure,
R1은 H 또는 CH3이며,R1 is H or CH 3,
R3은 하기 R3b 내지 R3d로 구성된 군에서 선택되는 어느 하나의 작용기이고,R3 is any one functional group selected from the group consisting of the following R3b to R3d,
상기 R3b는R3b is
R9가 에톡시기 및 R9a로 구성된 군에서 선택되는 어느 하나이고, R10은 H 또는 OH이며, R9 is any one selected from the group consisting of ethoxy groups and R9a, R10 is H or OH,
상기 R3c는R3c is
R11 및 R12는 각각 OH 또는 OCH3이며 R13은 CH3인 구조이며R11 and R12 are OH or OCH 3, and each R13 is CH 3 and the structure
상기 R3d는 R14가 OCH3이고, R15 및 R16은 CH3인 구조일 수 있다.Wherein R3d is R14 is OCH 3, R15 and R16 may be a CH 3 structure.
가장 바람직하게, 본 발명의 상기 화학식 1의 화합물은,Most preferably, the compound of formula (I)
3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-(2-페닐에틸아미노)시클로헥사-3,5-디엔-1,2-디온;3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3, 5-diene-1, 2-dione;
3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-2-히드록시-5-메톡시시클로헥사-2,5-디엔-1,4-디온;3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione;
3-[[(1S,2R,4aR,8aR)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-5-에톡시-2-히드록시시클로헥사-2,5-디엔-1,4-디온;3 - [[(1S, 2R, 4aR, 8aR) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;
18-메톡시-22-메틸-16-[{(5S,8S,9R,10S)-5,8,9-트리메틸-4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17-올; 및9-yl} methyl] benzo [d] oxazole-5-carboxylic acid (18S) Sol-17-ol; And
18-메톡시-22,22-디메틸-16-[{(5R,8S,9R,10S)-5,8,9-트리메틸-4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17(2H)-온;Methyl] benzo [d] thiophen-2-ylmethyl] -1,2,3,4-tetrahydro-naphthalen- -Oxazole-17 (2H) -one;
로 구성된 군에서 선택되는 어느 하나의 화합물일 수 있다. , And the like.
본 발명의 상기 화학식 1의 화합물은 해면(sponge)으로부터 추출될 수 있다. 구체적으로, 로팔로에이데스 속(Rhopaloeides sp .), 스폰지아 속(Spongia sp .), 스메노스폰지아 속(Smenospongia sp .), 히포스폰지아 속(Hippospongia sp .), 닥틸로스폰지아 속(Dactylospongia sp .), 베롱귤라 속(Verongula sp .), 디사이데아 속(Dysidea sp .), Sponge SS-1047, Sponge SS-265 및 Sponge SS-1208로 구성된 군에서 선택되는 어느 하나 이상의 해면(Sponge)에 C1-C6의 유기용매를 가하여 추출하는 단계를 포함하는, 안구 내 혈관 누수에 의한 황반 변성 또는 황반 부종의 예방 또는 치료용 화학식 1의 화합물의 수득 방법에 의한 것일 수 있다.The compound of
상기 C1-C6의 유기용매는 C1-C6의 알코올(메탄올, 에탄올, 프로판올, 부탄올, 펜탄올, 헥산올), 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane), 시클로헥산(cyclohexane), 아세토니트릴(acetonitrile), 디클로로메탄(dichloromethane) 및 석유에테르(petroleum ether)로 구성된 군에서 선택된 것일 수 있다. The C1-C6 organic solvent may be a C1-C6 alcohol such as methanol, ethanol, propanol, butanol, pentanol, hexanol, acetone, ether, benzene, chloroform, And may be selected from the group consisting of ethyl acetate, methylene chloride, hexane, cyclohexane, acetonitrile, dichloromethane, and petroleum ether .
바람직하게, 본 발명의 화학식 1의 화합물은 상기 해면동물에 물, C1-C4 알코올 또는 이들의 혼합용액을 용매로서 가하고 추출하여 해면동물 추출물을 제조하는 단계; 및 상기 추출물에 2차 용매를 가하여 분획하고 크로마토그래피를 통해 분리하는 단계를 포함하는 방법에 의하여 수득될 수 있다. Preferably, the compound of formula (I) of the present invention is prepared by adding water, a C1-C4 alcohol or a mixed solution thereof to the sponge animal as a solvent and extracting the sponge animal extract; And extracting the extract with a secondary solvent, followed by fractionation by chromatography.
*상기 크로마토그래피는 실리카겔 칼럼 크로마토그래피(silica gel column chromatography), LH-20 칼럼 크로마토그래피(LH-20 column chromatography), 이온교환수지 크로마토그래피(ion exchange resin chromatography), 중압 액체 크로마토그래피 (medium pressure liquid chromatography), 박층 크로마토그래피(TLC; thin layer chromatography), 실리카겔 진공 액체 크로마토그래피(silica gel vacuum liquid chromatography) 및 고성능 액체 크로마토그래피(high performance liquid chromatography) 등을 포함하여, 당업자에게 공지된 크로마토그래피라면 그 종류가 제한되지 않는다. * The above chromatography is carried out by silica gel column chromatography, LH-20 column chromatography, ion exchange resin chromatography, medium pressure liquid chromatography Chromatography known to those skilled in the art, including chromatography, thin layer chromatography (TLC), silica gel vacuum liquid chromatography, and high performance liquid chromatography, There is no restriction on the kind.
해면동물 추출물의 제조에 이용되는 상기 C1-C4 알코올은 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올 및 이소부탄올로 이루어진 군에서 선택될 수 있다. The C1-C4 alcohol used in the preparation of the spongy animal extract may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and isobutanol.
상기 해면동물의 추출물을 분획하는 2차 용매로는 C1-C4 알코올, n-헥산, 메틸렌클로라이드, 아세톤, 클로로포름, 디클로로메탄, 에틸아세테이트, 아세토니트릴 및 이들의 혼합물 등의 용매를 사용할 수 있다.As the secondary solvent for fractionating the extract of sponge animal, a solvent such as C1-C4 alcohol, n-hexane, methylene chloride, acetone, chloroform, dichloromethane, ethyl acetate, acetonitrile and a mixture thereof may be used.
본 발명의 화학식 1의 화합물은 이의 약학적으로 허용가능한 염을 포함한다. 본 발명에서 용어 '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 의미한다.The compounds of formula (I) of the present invention include the pharmaceutically acceptable salts thereof. The term " pharmaceutically acceptable " as used herein means physiologically acceptable and, when administered to humans, does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or the like.
상기 약제학적으로 허용되는 염은 무기산 또는 유기산과의 산부가염이 포함된다. 산부가염으로는 약제학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 주석산, 푸마산, 포름산, 피로피온산, 옥살산, 트리플루오로아세트산, 메탄술폰산, 벤젠설폰산, 말레인산, 벤조산, 글루콘산, 글리콜산, 숙신산, 4-모폴린에탄술폰산, 캠포술폰산, 4-니트로벤젠술폰산, 히드록시-O-술폰산, 4-톨루엔술폰산, 칼룩투론산, 엠보산, 글루탐산, 아스파트산 등을 사용할 수 있다.Such pharmaceutically acceptable salts include acid addition salts with inorganic or organic acids. Acid addition salts formed by pharmaceutically acceptable free acids are useful as acid addition salts. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, Sulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-chloromethylbenzenesulfonic acid, and 4-chloromethylbenzenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, Toluenesulfonic acid, caliculosic acid, embossic acid, glutamic acid, aspartic acid, and the like.
본 발명의 일 실시예에서는, in vitro상에서 본 발명의 화학식 1의 화합물이 β-catenin 발현을 억제하는 것을 확인하여 Wnt/β-catenin 매커니즘의 저해를 통해 혈액 누수(vascular leakage)를 억제함을 밝혔다. 본 발명의 또 다른 실시예에서는, 실제로 in vivo 황반부종 동물모델에 본 발명 화합물의 처리를 통해 혈관 누수를 억제하여 치료효능을 나타냄을 확인하였다. 또한 유리체강 내로 직접 약물을 투여하는 것 이외에도 다른 투여경로(경구투여, 복강주사 등)를 통해서도 타겟 조직(눈)에 분포하여, 투여경로에 구애받지 않고 치료효능을 보임을 확인하였다.In one embodiment of the present invention, it was confirmed that the compound of
따라서 본 발명의 다른 관점은, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 안구 내 혈관 누수 억제용 약학적 조성물에 관한 것이다.Accordingly, another aspect of the present invention relates to a pharmaceutical composition for inhibiting intra-ocular blood vessel leakage comprising the compound of
본 발명에서 용어‘혈관누수(vascular leakage)’란 혈관의 완전성(integrity) 손상에 의한 체액 또는 혈장성분의 누출을 의미하는 것으로, 안구(eye ball)에서의 혈관누수는 다양한 안질환의 주요병태를 구성한다. 본 발명에서 용어 ‘안구 내 혈관누수’는 안구를 구성하는 다양한 조직(맥락막, 망막 등)에서의 혈관누수를 의미하는 것으로, 이에 제한되지 않으나 바람직하게 망막 내 혈관 누수일 수 있다.The term " vascular leakage " in the present invention refers to leakage of body fluids or plasma components due to integrity damage of blood vessels. Vascular leakage from the eye ball is a major condition of various ocular diseases . In the present invention, the term " blood vessel leakage in the eyeball " refers to blood vessel leakage in various tissues (choroid, retina, etc.) constituting the eyeball, and is not limited thereto, but may be preferably a blood vessel leakage in the retina.
본 발명의 약학적 조성물은 안구 내 혈관누수 질환에 대하여 예방 또는 치료효과가 있으며, 당업계에 안구 내 혈관누수 질환으로서 공지된 것이라면 질환의 종류가 특별히 제한되지 않으나, 예를 들어 망막변성(retianl degeneration), 황반변성(macular degeneration), 망막부종(retinal edema), 황반부종(macular edema)을포함한다. 바람직하게 본 발명의 안구 내 혈관누수 질환은 황반변성 또는 황반부종 일 수 있다. The pharmaceutical composition of the present invention has a preventive or therapeutic effect on intra-ocular vascular leakage diseases, and the type of disease is not particularly limited as long as it is known in the art as an intra-ocular vascular leakage disease. For example, retinal degeneration ), Macular degeneration, retinal edema, and macular edema. Preferably, the intra-ocular vascular leakage disease of the present invention may be macular degeneration or macular edema.
본 발명에 따른 약학적 조성물은 상기 화학식 1의 세스퀴테르펜 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 단독으로 함유하거나, 또는 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 함유할 수 있다.The pharmaceutical composition according to the present invention may contain the sesquiterpene derivative compound of
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. 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 담체로는 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, 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 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, 골수 내, 경막내, 심장내, 안구 내, 유리체강 내, 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, intraocular, intravitreal, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, Topical, sublingual, or rectal administration.
본 발명의 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다. The pharmaceutical composition of the present invention can be formulated into oral preparations or parenteral administration preparations according to the route of administration as described above.
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 하이드록시프로필메틸-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.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 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, 점안제, 연고제 크림제, 로션제, 오일제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다. For parenteral administration, they may be formulated in the form of injections, eye drops, ointment creams, lotions, oils, gels, aerosols and nasal inhalers by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 15th edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a commonly known formulary for all pharmaceutical chemistries.
바람직하게 본 발명의 상기 약학적 조성물은 경구제, 주사제, 점안제 및 연고제로 구성된 군에서 선택되는 어느 하나의 형태로 제조되는 것일 수 있다.Preferably, the pharmaceutical composition of the present invention may be prepared in any form selected from the group consisting of oral preparations, injections, eyedrops and ointments.
본 발명의 상기 세스퀴테르펜 유도체 화합물 또는 이의 약학적으로 허용가능한 염의 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. 상기 화합물 또는 이의 약학적으로 허용가능한 염의 용량은 약학적 조성물의 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율 등 다양한 요인들을 고려하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당 분야의 통상적인 지식을 가진 자라면 상기 세스퀴테르펜 유도체 또는 이의 약학적으로 허용가능한 염을 안구 내 혈액 누수 질환의 예방 또는 치료제로서의 특정한 용도에 따른 적절한 유효 투여량을 결정할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다.The total effective amount of the sesquiterpene derivative compound of the present invention or a pharmaceutically acceptable salt thereof may be administered to a patient in a single dose and may be administered by a divided treatment method which is administered over a long period in multiple doses fractionated treatment protocol. In the pharmaceutical composition of the present invention, the content of the active ingredient may be varied depending on the degree of the disease. The dose of the compound or a pharmaceutically acceptable salt thereof may be determined by taking into consideration various factors such as the patient's age, body weight, health status, sex, severity of disease, diet and excretion rate, It will be understood by those skilled in the art that the sesquiterpene derivative or a pharmaceutically acceptable salt thereof may be used in a specific use as a preventive or therapeutic agent for intraocular blood leaking disorders Lt; RTI ID = 0.0 > effective < / RTI > The pharmaceutical composition according to the present invention is not particularly limited to the formulation, administration route and administration method as long as the effect of the present invention is exhibited.
또한 본 발명의 또 다른 관점은, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 황반변성 또는 황반부종의 예방 또는 개선용 식품 조성물에 관한 것이다.Another aspect of the present invention relates to a food composition for the prevention or amelioration of macular degeneration or macular edema comprising the compound represented by
상기 본 발명의 식품 조성물은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food), 식품 첨가제(food additives) 및 사료 등의 모든 형태를 포함하며, 인간 또는 가축을 비롯한 동물을 취식대상으로 한다. 상기 유형의 식품 조성물은 당 업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다.The food composition of the present invention includes all forms of functional foods, nutritional supplements, health foods, food additives and feeds, . Food compositions of this type may be prepared in a variety of forms according to conventional methods known in the art.
*예를 들면, 건강식품으로는 본 발명의 상기 세스퀴테르페논 유도체 또는 상기 세스퀴테르페논을 함유하는 해면(sponge) 추출물 자체를 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한 본 발명의 상기 세스퀴테르페논 유도체 또는 상기 세스퀴테르페논을 함유하는 해면(sponge) 추출물을, 황반부종 또는 황반변성의 개선 및 예방효과가 있다고 알려진 공지의 활성 성분과 함께 혼합하여 조성물의 형태로 제조할 수 있다.* For example, as a health food, the sesquiterpenone derivative of the present invention or the sponge extract containing the sesquiterpenone itself may be prepared in the form of tea, juice and drink to be consumed, or granulated , Encapsulated and powdered. In addition, the sesquiterphenone derivative of the present invention or a sponge extract containing the sesquiterphenone may be mixed with known active ingredients known to be effective for the prevention and / or prevention of macular edema or macular degeneration, Can be manufactured.
또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마아말레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지 콘비이프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 상기 세스퀴테르페논 유도체 또는 상기 세스퀴테르페논을 함유하는 해면(sponge) 추출물을 첨가하여 제조할 수 있다. Functional foods also include beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruits, bottled, jam, maalmalade, etc.), fish, meat and processed foods such as ham, Etc.), breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, The sesquiterphenone derivative of the present invention or a sponge extract containing the sesquiterpenone may be added to a retort food, a frozen food, various kinds of seasonings (e.g., miso, soy sauce, sauce, etc.).
또한, 본 발명의 상기 세스퀴테르페논 유도체 또는 상기 세스퀴테르페논을 함유하는 해면(sponge) 추출물을 식품 첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.In addition, in order to use the sesquiterpenone derivative of the present invention or the sponge extract containing the sesquiterpenone in the form of a food additive, it may be used in the form of a powder or a concentrate.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.
[실시예][Example]
< 제조예 1> 메틸 3-[[( 1R,2S,4aR,8aS )-1,2, 4a,5 - 테트라메틸 -2,3,4,7,8,8a- 헥사히드로나프탈렌-1-일]메틸]-4,5-디히드록시벤조에이트의 수득 <Production Example 1> Methyl 3 - [[(1R, 2S , 4aR, 8aS) -1,2, 4a, 5 - tetramethyl-hexyl -2,3,4,7,8,8a- four tetrahydro-1-naphthalene Yl] methyl] -4,5-dihydroxybenzoate
EtOH에서 보존된 Hyrtios sp.(38 g dry weight) 샘플을, MeOH를 이용하여 남김없이 추출하였다. 상기 MeOH 추출물을 in vacuo 상태에서 증발시킨 후, 남은 잔여물(15.6 g)을 물과 CH2Cl2 용매를 이용하여 분획하였다. 유기상(organic phase)은 in vacuo 상태에서 증발되었으며, gum(5.32 g)을 수득하였다. 상기 gum 2.37 g은, 용리제로서 hexane 및 증가하는 농도의 EtOAc 용액을 이용하여 Si gel column으로 flash chromatography를 수행하였다. 이렇게 생성된 분획 중 일부를 hexane/EtOAc (100:0 to 50:50)를 이용하여 Si gel column으로 flash chromatography를 수행하였다. 2개의 UV positive-분획이 생성되었으며, HPLC (UV detection at 210 nm, eluent 90:10 MeOH/H2O)를 수행하여 추가 정제를 실시하여, 제조예 1의 화합물(3 mg)을 수득하였다. Samples of Hyrtios sp. (38 g dry weight) preserved in EtOH were extruded with MeOH. The MeOH extract was evaporated in vacuo and the remaining residue (15.6 g) was fractionated using water and CH 2 Cl 2 solvent. The organic phase was evaporated in vacuo and gum (5.32 g) was obtained. The gum (2.37 g) was subjected to flash chromatography on an Si gel column using hexane as an eluent and an increasing concentration of EtOAc solution. Some of the fractions thus generated were subjected to flash chromatography on a Si gel column using hexane / EtOAc (100: 0 to 50:50). Two UV positive-fractions were generated and further purification was carried out by HPLC (UV detection at 210 nm, eluent 90:10 MeOH / H 2 O) to give the compound of Preparation 1 (3 mg).
수득된 제조예 1의 화합물의 물리화학적 성질은 다음과 같으며,‘methyl 3-[[(1R,2S,4aR,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4,5-dihydroxybenzoate’화합물로 판명되었다. The physicochemical properties of the obtained compound of Preparation Example 1 are as follows: < 1 > - [(1R, 2S, 4aR, , 8,8a-hexahydronaphthalen-1-yl] methyl] -4,5-dihydroxybenzoate '.
amorphous solid; amorphous solid;
IR(film) 3339, 1680, 1303 cm-1; IR (film) 3339, 1680, 1303 cm < -1 & gt ;;
UV (CH3OH) λmax 221 (17440), 269 (7460), 305 nm (3341, sh); UV (CH 3 OH) λmax 221 (17440), 269 (7460), 305 nm (3341, sh);
UV (CH3OH/NaOH) λmax 210 (18520), 241 (13176), 284 (4310), 322 nm (6950); UV (CH 3 OH / NaOH) λmax 210 (18520), 241 (13176), 284 (4310), 322 nm (6950);
1H NMR (600 MHz) δ 7.49 (1H, d, 1.5), 7.45 (1H, d, 1.5), 5.32 (1H, bs), 3.87 (3H, s), 2.84 (1H, d, 14) and 2.60 (1H, d, 14) AB system, 1.64 (3H, bs), 0.98 (3H, d, 6), 0.95 (3H, s), 0.90 (3H, s); 1 H NMR (600 MHz) δ 7.49 (1H, d, 1.5), 7.45 (1H, d, 1.5), 5.32 (1H, bs), 3.87 (3H, s), 2.84 (1H, d, 14) and 2.60 (1H, d, 14) AB system, 1.64 (3H, bs), 0.98 (3H, d, 6), 0.95 (3H, s), 0.90 (3H, s);
13C-NMR (CDCl3, 150.87 MHz)데이터는 하기 [표 2] 참조 13 C-NMR (CDCl 3, 150.87 MHz) data for Table 2: Reference
[표 2][Table 2]
< 제조예 2> 3-[[(1S,2R,4aR,8aR)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-2,5-디히드록시시클로헥사-2,5-디엔-1,4-디온의 수득 <Production Example 2> 3 - [[(1S , 2R, 4aR, 8aR) -1,2,4a- -trimethyl-5-methylidene-hexahydro -3,4,6,7,8,8a- -2H- naphthalene -1-yl] methyl] -2,5-dihydroxycyclohexa-2,5-dien-1,4-dione
sponge Smenospongia sp. 샘플(2 kg)을 MeOH에 침지시키고,CHCl3/Me0H(l/l mixture)로 추가 추출하였다. 상기 추출물을 감압조건하에서 증발시키고, 이의 수용성 현탁액을 CH2Cl2로 추출(extract A)하였다. 상기 extract A(8 g)에 대하여 silica gel (CHCl3/증가하는 농도의 MeOH)을 이용해 chromatogmphy하였다. 이로부터, 2%- MeOH(in CHCl3)에서 용출된 fraction 1 및 5%- MeOH(in CHCl3)에서 용출된 fraction 2가 제조되었다. 상기 fraction 1을 30% AcOEt(in hexane)로 용출시켜, 제조예 2의 화합물(20 mg)을 수득하였다. sponge Smenospongia sp. The sample (2 kg) was immersed in MeOH and further extracted with CHCl 3 / MeOH (l / l mixture). The extract was evaporated under reduced pressure and its aqueous suspension was extracted with CH 2 Cl 2 (extract A). The extract A (8 g) was chromatographed using silica gel (CHCl 3 / increasing concentration of MeOH). From this, 2% of the eluted fraction is 2 was prepared in MeOH (in CHCl 3) - MeOH (in CHCl 3) The fraction eluted at 1 and 5%. The
수득된 제조예 2의 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione’화합물로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 2 were as follows: 3 - [[(1S, 2R, 4aR, 8aR) -1,2,4a-trimethyl- 5- methylidene- Methyl-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione 'compound:
C21H2804 ;C 21 H 28 O 4 ;
m.p. > 350m.p. > 350
SM m/e (%): 191 (40), 154 (12). 135 (44). 121 (65). 109 (56). 107 (87). 95 (100).SM m / e (%): 191 (40), 154 (12). 135 (44). 121 (65). 109 (56). 107 (87). 95 (100).
UV (EtOH)λmax nm(ε): 214,286.UV (EtOH) [lambda] max nm ([epsilon]): 214,286.
IR (KBr) υ cm-l: 3324,2940,1645,1535. IR (KBr) υ cm -l: 3324,2940,1645,1535.
1H NMR (MeOD, 80 MHz) δ ppm: 5.71(1H, s), 4.76 (2H, br s), 2.40 (2H, br s), 1.01 (3H, s), 0.92 (3H, d, J=7 HZ), 0.78 (3H,s). 1 H NMR (MeOD, 80 MHz ) δ ppm: 5.71 (1H, s), 4.76 (2H, br s), 2.40 (2H, br s), 1.01 (3H, s), 0.92 (3H, d, J = 7 Hz), 0.78 (3H, s).
13C NMR (δ ppm, CD3OD, 20.115 MHz) 데이터는 하기 [표 3] 참조 13 C NMR see (δ ppm, CD 3 OD, 20.115 MHz) data for Table 3
< 제조예 3> 3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-(3-메틸부틸아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 3> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene-hexahydro -3,4,6,7,8,8a- -2H- naphthalene -1-yl] methyl] -4-hydroxy-5- (3-methylbutylamino) cyclohexa-3,5-dien-1,2-dione
sponge Smenospongia sp. 의 건조물 44 g을 CH2Cl2로 추출한 뒤, MeOH로 추출(Extract B)하였다. 상기 Extract B(4g)을 silica gel column (CHCl3/ increasing amounts MeOH)으로 chromatography 수행하여, 2%- MeOH(in CHCl3)에서 용출된 fraction A 및 5%- MeOH(in CHC13)에서 용출된 fraction B가 제조되었다. 상기 faction A를 Sephadex LH 20 (MeOH/CHCl3: 60/40) column으로 정제하는 과정을 거쳐, 제조예 3의 화합물(20 mg) 및 하기 제조예 4의 화합물(5 mg)을 수득하였다.sponge Smenospongia sp. (44 g) was extracted with CH 2 Cl 2 and extracted with MeOH (Extract B). Extract B (4 g) was chromatographed on silica gel column (CHCl 3 / increasing amounts of MeOH) and eluted from fraction A and 5% -MeOH (in CHCl 3 ) eluted in 2% -MeOH (in CHCl 3 ) fraction B was prepared. The faction A was purified on a Sephadex LH 20 (MeOH / CHCl 3 : 60/40) column to give 20 mg of the compound of Preparation Example 3 and 5 mg of the compound of the following Preparation Example 4.
상기 수득된 제조예 3 화합물의 물리화학적 성질은 다음과 같으며,‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a- hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(3-methylbutylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다: The physicochemical properties of the obtained compound of Preparation Example 3 are as follows, and the physical and chemical properties of the obtained compound of Preparation Example 3 are as follows: 3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl- 3-methylbutylamino) cyclohexa-3,5-diene-1,2-dione 'compound:
C26H39N03; C 26 H 39 NO 3 ;
m.p.: 170-172m.p .: 170-172
SM m/e (%): 413 (4), 3ll (8), 283 (12), 223 (100), 191 (11), 167 (22), 153 (27), 149 (15), 135 (14), 121 (16), 109 (18), 107 (12), 95 (79).SM m / e (%): 413 (4), 3 (8), 283 (12), 223 (100), 191 (11), 167 (22), 153 (27), 149 14), 121 (16), 109 (18), 107 (12), 95 (79).
m/e 191.179, calc.191.179 for Cl4 H23; m/e 223.119, calc. 223.120 for C12H17NO3.m / e 191.179, calc.191.179 for C l4 H 23; m / e 223.119, calc. 223.120 for C 12 H 17 NO 3 .
UV(EtOH) λmax nm(ε): 204 (27230). 324 (14070).UV (EtOH) [lambda] max nm ([epsilon]): 204 (27230). 324 (14070).
IR (KBr) υ cm-l: 3417,3275,1640,1592. IR (KBr) υ cm -l: 3417,3275,1640,1592.
1H NMR (CDC13 .200 MHz) δ ppm: 8.41 (1H exch., s), 6.41 (1H exch., t). 5.36 (lH, s), 4.43 (br s), 3.20 (2H. dt), 2.48 (d)-2.37 (d) (AB syst.). 2.31 (dt), 2.07 (2 H, m), 1.85 (lH, m), 1.80-1.05 (llH, m). 1.04 (3H. s). 0.95 (9H, 3d overlaped), 0.83 (3H, s), 0.78 (lH, dd). 1 H NMR (CDCl 3 200 MHz) δ ppm: 8.41 (1H ex., S), 6.41 (1H ex. 5.36 (1H, s), 4.43 (br s), 3.20 (2H, dt), 2.48 (d), 2.37 (d) (AB syst. 2.31 (dt), 2.07 (2H, m), 1.85 (1H, m), 1.80-1.05 (11H, m). 1.04 (3H, s). 0.95 (9H, 3d overlap), 0.83 (3H, s), 0.78 (1H, dd).
13C NMR (δ ppm, CDCl3, 20.115 MHz) 데이터는 하기 [표 3] 참조 13 C NMR (隆 ppm, CDCl 3 , 20.115 MHz) The data are shown in the following [Table 3]
[표 3][Table 3]
* may be reversed* may be reversed
< 제조예 4> 3-[[(1S,2R,4aR,8aR)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-(2-메틸프로필아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 4> 3 - [[(1S , 2R, 4aR, 8aR) -1,2,4a- -trimethyl-5-methylidene-hexahydro -3,4,6,7,8,8a- -2H- naphthalene -1-yl] methyl] -4-hydroxy-5- (2-methylpropylamino) cyclohexa-3,5-dien-1,2-dione
상기 제조예 3에서 전술한 바와 동일한 방법으로 제조예 4의 화합물을 수득하였다. 수득된 화합물(제조예 4)의 물리화학적 성질은 다음과 같으며, ‘3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-methylpropylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다: The compound of Preparation Example 4 was obtained in the same manner as in Preparation Example 3, The physicochemical properties of the obtained compound (Production Example 4) are as follows, and the physicochemical properties of the obtained compound (Production Example 4) are as follows: 3 - [[(1S, 2R, 4aR, 8aR) -1,2,4a-trimethyl-5-methylidene- , 7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -4-hydroxy-5- (2-methylpropylamino) cyclohexa-3,5-
C25H37NO3 C 25 H 37 NO 3
SM m/e (%): 399 (5). 209 (100). 191(17), 166 (36). 152 (18), 135 (11). 121(15). 109 (15), 107 (12). 95 (66).SM m / e (%): 399 (5). 209 (100). 191 (17), 166 (36). 152 (18), 135 (11). 121 (15). 109 (15), 107 (12). 95 (66).
UV (EtOH) λmax nm(ε): 210 (14000). 329 (20150).UV (EtOH) [lambda] max nm ([epsilon]): 210 (14000). 329 (20150).
IR (KBr) υ cm-l: 3417,3275, 1640,1592. IR (KBr) υ cm -l: 3417,3275, 1640,1592.
1H NMR (CDC13, 200 MHz) δ ppm: 6.53 (1H. s). 5.41 (1H. S), 4.45 (2H br s), 2.95 (2H, dt), 2.48 (lH, d), 2.45 (lH, d, J =13 Hz), 1.O3 (3H, s), 0.97 (9H. 3d overlaped), 0.82 (3H. s). 0.76 (lH, dd). 1 H NMR (CDCl 3 , 200 MHz) δ ppm: 6.53 (1H, s). (1H, d), 2.45 (1H, d), 2.45 (1H, d, J = 13 Hz) (9H, 3d overlaped), 0.82 (3H, s). 0.76 (1 H, dd).
< 제조예 5> 3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-5-아미노-4-히드록시시클로헥사-3,5-디엔-1,2-디온의 제조 <Production Example 5> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene-hexahydro -3,4,6,7,8,8a- -2H- naphthalene -1-yl] methyl] -5-amino-4-hydroxycyclohexa-3,5-diene-1,2-dione
Hippospongia sp.의 MeOH 및 DCM 조추출물을 모아서, 각각의 용매로 분획하여 각각 MeOH, DCM, hexane 및 BuOH 분획을 수득하였다. 상기 분획물 중 hexane, DCM 및 MeOH 분획에 대하여 flash column chromatography 및 semi-preparative RP-HPLC를 수행하여, 제조예 5의 화합물을 수득하였다. The MeOH and DCM crude extracts of Hippospongia sp. Were pooled and fractionated with each solvent to give MeOH, DCM, hexane and BuOH fractions, respectively. The hexane, DCM and MeOH fractions in the fractions were subjected to flash column chromatography and semi-preparative RP-HPLC to obtain the compound of Preparation Example 5.
수득된 화합물(제조예 5)의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-5-amino-4-hydroxycyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다: The physicochemical properties of the obtained compound (Production Example 5) are as follows, and the physicochemical properties of the obtained compound (Production Example 5) are as follows: 3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- , 7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -5-amino-4-hydroxycyclohexa-3,5-diene-
purple solid;purple solid;
C21H30O3N ( HRESIMS m/z 344.2295, [M+H]+); C 21 H 30 O 3 N ( HRESIMS m / z 344.2295, [M + H] +);
UV (MeOH) λmax (log ε) 315 (3.58) nm;UV (MeOH) [lambda] max (log [epsilon]) 315 (3.58) nm;
IR (KBr) 3835, 3566, 1624, 1536 cm-1;IR (KBr) 3835, 3566, 1624, 1536 cm < -1 & gt ;;
1H-NMR (400 MHz, CD3OD) δ: 2.17/1.43 (2H, m H-1), 1.39 (2H,m, H-2), 1.50/1.38 (2H, m, H-3), 2.34/2.05 (2H, m, H-6), 1.23/1.82 (2H, m, H-7), 1.23 (1H, m, H-8), 0.82(1H, m, H-10), 4.44 (2H, s, H-11), 1.05 (3H, s, H-12), 0.98 (3H, d, J = 6.4 Hz H-13), 0.84 (3H, s, H-14), 2.47/2.40 (2H, dd, J = 13.7 Hz, H-15), 5.51 (1H, s, H-19). 1 H-NMR (400 MHz, CD 3 OD)?: 2.17 / 1.43 (2H, m H-1), 1.39 (2H, m, H-6), 1.23 / 1.82 (2H, m, H-7), 1.23 (3H, s, H-12), 0.98 (3H, d, J = 6.4 Hz H-13), 0.84 2H, dd, J = 13.7 Hz, H-15), 5.51 (1H, s, H-19).
13C-NMR (100 MHz, CD3OD) δ: 22.8 (t, C-1), 27.5 (t, C-2), 36.4 (t, C-3), 160.1 (s, C-4), 39.9 (s, C-5), 32.5 (t, C-6), 28.3 (t, C-7), 37.6 (d, C-8), 42.1 (s, C-9), 49.7 (d, C-10), 101.1 (t, C-11), 19.4 (q, C-12), 16.9 (q, C-13), 16.2 (q, C-14), 31.6 (t, C-15), 113.7 (s, C-16), 159.4 (s, C-17), 183.2 (s, C-18), 93.6 (d, C-19), 183.2 (s, C-21). 13 C-NMR (100 MHz,
< 제조예 6> 2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-6-히드록시-3,4-디옥소시클로헥사-1,5-디엔-1-일]아미노]아세틱 에시드의 수득 <Production Example 6> 2 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro- -2H-naphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] acetic acid
sponge Dactylospongia elegans를 동결건조하고, 상기 동결건조된 해면(33 g 건조 중량)에 MeOH(3×1 L)를 가하여 추출물을 제조하여, in Vacuo 상태에서 농축하고, reversed-phase C18 vacuum liquid chromatography (0%, 20%, 50%, 70%, 90%, 100% MeOH in H2O, 및 1:1 CH2Cl2/MeOH)를 수행하였다. 각각 20%, 50% 및 70% MeOH 분획을 수득하여, C18 preparative HPLC(4 mL/min, gradient elution from 3:7 H2O/MeCN/0.1% formic acid to 100% MeCN/0.1% formic acid over 10 min, through a 150 × 10 mm, 5 ㎛ Phenomenex phenyl hexyl column)를 수행하였다. 이로부터 제조예 6 화합물(11.7 mg, 0.035%), 하기 제조예 7 화합물(1.4 mg, 0.004%) 및 제조예 8 화합물(0.8 mg, 0.002%)을 수득하였다. sponge D actylospongia Frozen elegans dried, the freeze-producing the extract was added to MeOH (3 × 1 L) to the dried surface of the sea (33 g dry weight), in Vacuo concentrated in state, and reversed-phase C18 vacuum liquid chromatography ( 0%, 20%, 50%, 70% , 90%, 100% MeOH in H 2 O, and 1: to perform a 1 CH 2 Cl 2 / MeOH) . MeOH / MeCN / 0.1% formic acid to 100% MeCN / 0.1% formic acid over gradient elution from 3: 7 H 2 O / MeCN / 10 min, through a 150 × 10 mm, 5 μm Phenomenex phenyl hexyl column). This gave the product of Preparation 6 (11.7 mg, 0.035%), the following compounds of Preparation 7 (1.4 mg, 0.004%) and the compounds of Preparation 8 (0.8 mg, 0.002%).
상기 수득된 제조에 6 화합물은 다음과 같은 물리화학적 성질을 지니며, ‘2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]acetic acid’화합물로 판명되었다:In the above-mentioned preparation, the
amorphous, red solid; amorphous, red solid;
[α]D +94.4 (c 0.018, MeOH);[[alpha]] D +94.4 (c 0.018, MeOH);
UV (PDA, CH3CN/H2O) λmax 218, 311, 494 nm; UV (PDA, CH 3 CN / H 2 O) λmax 218, 311, 494 nm;
IR (neat) νmax 3598, 2936, 2064, 1657 cm-1; IR (neat)? Max 3598, 2936, 2064, 1657 cm -1 ;
1H (300 MHz) 및 13C (75 MHz) NMR (CD3OD)데이터는 하기 [표 4] 참조 1 H (300 MHz) and 13 C (75 MHz) NMR (CD 3 OD) data are shown in Table 4 below
HRESIMS m/z 424.2104 [M + Na]+ (calcd for C23H31NO5Na, 424.2094, Δ 1.0 mmu).HRESIMS m / z 424.2104 [M + Na] + (calcd for C 23 H 31 NO 5 Na, 424.2094,? 1.0 mmu).
[표 4][Table 4]
< 제조예 7> 3-[[5-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-6-히드록시-3,4-디옥소시클로헥사-1,5-디엔-1-일]아미노]프로파노익 에시드의 수득 <Production Example 7> 3 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro- -2H-naphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] propanoic acid
상기 제조예 6에서 전술한 바와 동일한 방법으로, 제조예 7의 화합물을 수득하였다. 수득된 화합물(제조예 7)의 물리화학적 성질은 다음과 같으며, ‘3-[[5-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]propanoic acid’화합물로 판명되었다:The compound of Preparation 7 was obtained in the same manner as that described in Preparation Example 6 above. The physicochemical properties of the obtained compound (Production Example 7) were as follows, and the physical and chemical properties of the obtained compound (Production Example 7) were as follows. 3 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- , 4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien- Proved to be:
amorphous, red solid; amorphous, red solid;
[α]D +13 (c 0.06, MeOH); [?] D +13 (c 0.06, MeOH);
UV (PDA, CH3CN/H2O) λmax 233, 314, 494 nm; UV (PDA, CH 3 CN / H 2 O) λmax 233, 314, 494 nm;
IR (neat) νmax 3410, 2930, 1686, 1632, 1567 cm-1;IR (neat)? Max 3410, 2930, 1686, 1632, 1567 cm -1 ;
HRESIMS m/z 438.2264 [M + Na]+ (calcd for C24H33NO5Na, 438.2251, Δ 1.3 mmu):HRESIMS m / z 438.2264 [M + Na] + (calcd for C 24 H 33 NO 5 Na, 438.2251,? 1.3 mmu):
1H NMR (CD3OD, 300 MHz) δ 5.38 (1H, s, H-19), 4.40 (2H, s, H2-11), 3.45 (2H, t, J = 6.8 Hz, H2-23), 2.59 (2H, t, J = 6.8 Hz, H2-24), 2.47 (1H, d, J = 13.6 Hz, Ha-15), 2.38 (1H, d, J = 13.6 Hz, Hb-15), 2.32 (1H, m, Ha-3), 2.16 (1H, m, Ha-1), 2.04 (1H, m, Hb-3), 1.80 (1H, m, Ha-2), 1.48 (1H, m, Ha-6), 1.43 (1H, m, Hb-1), 1.41 (1H, m, Ha-7), 1.36 (1H, m, Hb-6), 1.35 (1H, m, Hb-7), 1.29 (1H, m, Hb-2), 1.21 (1H, m, H-8), 1.04 (3H, s, H3-12), 0.97 (3H, d, J = 6.4 Hz, H3-13), 0.83 (3H, s, H3-14), 0.81 (1H, m, H-10); 1 H NMR (CD 3 OD, 300 MHz) δ 5.38 (1H, s, H-19), 4.40 (2H, s, H 2 -11), 3.45 (2H, t, J = 6.8 Hz, H 2 -23 ), 2.59 (2H, t, J = 6.8 Hz, H 2 -24), 2.47 (1H, d, J = 13.6 Hz, H a -15), 2.38 (1H, d, J = 13.6 Hz, H b - 15), 2.32 (1H, m , H a -3), 2.16 (1H, m, H a -1), 2.04 (1H, m, H b -3), 1.80 (1H, m, H a -2) , 1.48 (1H, m, H a -6), 1.43 (1H, m, H b -1), 1.41 (1H, m, H a -7), 1.36 (1H, m, H b -6), 1.35 (1H, m, H b -7 ), 1.29 (1H, m, H b -2), 1.21 (1H, m, H-8), 1.04 (3H, s, H 3 -12), 0.97 (3H, d, J = 6.4 Hz, H 3 -13), 0.83 (3H, s, H 3 -14), 0.81 (1H, m, H-10);
13C NMR (CD3OD, 75 MHz) δ 183.4 (C, C-21), 179.6(C, C-18), 176.0 (C, C-25), 162.9 (C, C-4), 161.1 (C, C-17), 152.0 (C, C-20), 115.5 (C, C-16), 103.3 (CH2, C-11), 92.6 (CH, C-19), 51.1 (CH, C-10), 44.0 (C, C-9), 41.8 (C, C-5), 39.9 (CH2, C-23), 39.0 (CH, C-8), 38.2 (CH2, C-6), 34.5 (CH2, C-24), 34.2 (CH2, C-3), 33.4 (CH2, C-15), 30.0 (CH2, C-2), 29.4 (CH2, C-7), 24.3 (CH2, C-1), 21.4 (CH3, C-12), 18.7 (CH3, C-13), 18.1 (CH3, C-14). 13 C NMR (CD 3 OD, 75 MHz) δ 183.4 (C, C-21), 179.6 (C, C-18), 176.0 (C, C-25), 162.9 (C, C-4), 161.1 ( C, C-17), 152.0 (C, C-20), 115.5 (C, C-16), 103.3 (
< 제조예 8> 7-[[( 1R,2S,4aS,8aS )-1,2,4a- 트리메틸 -5- 메틸리덴 -3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-1,3-벤조옥사졸-5,6-디올의 수득 <Production Example 8> 7 - [[(1R , 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene-hexahydro -3,4,6,7,8,8a- -2H- naphthalene -1-yl] methyl] -1,3-benzoxazole-5,6-diol
상기 제조예 6에서 전술한 바와 동일한 방법으로, 제조예 8의 화합물을 수득하였다. 수득된 화합물(제조예 8)의 물리화학적 성질은 다음과 같으며, ‘7-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-1,3-benzoxazole-5,6-diol’화합물로 판명되었다:The compound of Preparation 8 was obtained in the same manner as that described in Preparation Example 6 above. The physicochemical properties of the obtained compound (Production Example 8) are as follows, and the physical and chemical properties of the obtained compound (Production Example 8) are as follows. 7 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- , 7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -1,3-benzoxazole-5,6-diol '
colorless solid;colorless solid;
[α]D -6.7 (c 0.075, MeOH); [[alpha]] D -6.7 (c 0.075, MeOH);
UV (PDA, CH3CN/H2O) λmax 236, 297, 323 (sh) nm; UV (PDA, CH 3 CN / H 2 O) λmax 236, 297, 323 (sh) nm;
IR (neat) νmax 3408,2927, 1541 cm-1 ;IR (neat)? Max 3408, 2927, 1541 cm -1 ;
1H (300 MHz) 및 13C (75 MHz) NMR (CD3OD)데이터는 하기 [표 5] 참조 1 H (300 MHz) and 13 C (75 MHz) NMR (CD 3 OD) data are shown in Table 5 below
HRESIMS m/z 378.2050 [M + Na]+ (calcd for C22H29NO3Na, 378.2040, Δ 1.0 mmu).HRESIMS m / z 378.2050 [M + Na] + (calcd for C 22 H 29
[표 5][Table 5]
< 제조예 9> [7-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-6-아세틸옥시-1,3-벤조옥사졸-5-yl] 아세테이트의 제조 <Production Example 9> [7 - [[( 1R, 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro--2H- Naphthalen-1-yl] methyl] -6-acetyloxy-1,3-benzoxazol-5-yl] acetate
제조예 5에서와 같이 sponge Dactylospongia elegans를 동결건조 하여, 상기 동결건조된 해면(33 g 건조 중량)에 MeOH(3×1 L)를 가하여 추출물을 제조한 후, 그 외에 MeOH에 용해되지 않는 물질(120 mg)을 pyridine(0.5 mL)에 넣은 용액에 (CH3CO)2O (0.5 mL)을 처리하고 상온에서 12시간동안 교반(stir)해주었다. 상기 반은 물질들을 in Vacuo 상태에서 농축하고, sequential reversed-phase HPLC 분리(A: H2O/MeCN + 0.1% formic acid (3:7) to 100% MeCN + 0.1% formic acid over 10 min at 4 mL/min and held for an additional 10 min on a 150 × 10 mm, 5 ㎛ Phenomenex Luna C18 column; B: H2O/MeOH with 0.1% formic acid (3:7) to 100% MeOH with 0.1% formic acid for 10 min at 4 mL/min and held for an additional 5 min on a 150 × 10 mm, 5㎛ Phenomenex Luna phenyl hexyl column)를 수행하였다. 이와 같은 방법으로 제조예 9의 화합물이 2.3 mg(0.007%) 수득되었으며, 이의 물리화학적 성질은 다음과 같고, ‘[7-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-6-acetyloxy-1,3-benzoxazol-5-yl] acetate’화합물로 판명되었다:As in Production Example 5, sponge Dactylospongia The extracts were prepared by adding MeOH (3 x 1 L) to the above lyophilized sponges (33 g dry weight), and furthermore, 120 mg of the substance not soluble in MeOH was dissolved in pyridine (0.5 mL ) Was treated with (CH 3 CO) 2 O (0.5 mL) and stirred at room temperature for 12 hours. The half-concentrated the material in the in Vacuo state, sequential reversed-phase HPLC separation (A: H 2 O / MeCN + 0.1% formic acid (3: 7) to 100% MeCN + 0.1% formic acid over 10 min at 4 B: H 2 O / MeOH with 0.1% formic acid (3: 7) to 100% MeOH with 0.1% formic acid for 10 min at 4 mL / min and for additional 5 min on a 150 × 10 mm, 5 μm Phenomenex Luna phenyl hexyl column). In this way, 2.3 mg (0.007%) of the compound of Production Example 9 was obtained, and its physicochemical properties were as follows. [7 - [[(1R, 2S, 4aS, 8aS) trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -6-acetyloxy-1,3-benzoxazol- It was:
colorless oil; colorless oil;
[α]D -170 (c 0.003, CHCl3);[?] D -170 (c 0.003, CHCl 3 );
UV (PDA, CH3CN/H2O) λmax 233, 278, 284, 300 (sh) nm; UV (PDA, CH 3 CN / H 2 O) λmax 233, 278, 284, 300 (sh) nm;
IR (neat) νmax 3488, 2927, 1775, 1630, 1458 cm-1; IR (neat)? Max 3488, 2927, 1775, 1630, 1458 cm -1 ;
HRESIMS m/z 462.2250 [M + Na]+ (calcd for C26H33NO5Na, 462.2251, Δ 0.1 mmu);HRESIMS m / z 462.2250 [M + Na] + (calcd for C 26 H 33 NO 5 Na, 462.2251, 0.1 mmu);
1H NMR (CDCl3, 300 MHz) δ 8.07 (1H, s, H-22), 7.54 (1H, s, H-19), 4.42 (1H, d, J = 1.6 Hz, Ha-11), 4.38 (1H, d, J = 1.6 Hz, Hb-11), 2.83 (1H, d, J = 14.2 Hz, Ha-15), 2.76 (1H, d, J = 14.2 Hz, Hb-15), 2.35 (1H, m, Ha-3), 2.34 (s, a-OCOCH3), 2.30 (s, b-OCOCH3), 2.08 (1H, m, Hb-3), 1.92 (1H, m, Ha-2), 1.58 (1H, m, Ha-1), 1.49 (1H, m, Ha-6), 1.45 (1H, m, Hb-1),1.43 (1H, m, H-8), 1.42 (2H, m, H2-7), 1.28 (1H, m, Hb-6), 1.26 (1H, m, Hb-2), 1.07 (3H, s, H3-12), 0.97 (3H, d, J = 5.6 Hz, H3-13), 0.94 (3H, s, H3-14), 0.92 (1H, m, H-10); 1 H NMR (CDCl 3, 300 MHz) δ 8.07 (1H, s, H-22), 7.54 (1H, s, H-19), 4.42 (1H, d, J = 1.6 Hz, H a -11), 4.38 (1H, d, J = 1.6 Hz, H b -11), 2.83 (1H, d, J = 14.2 Hz, H a -15), 2.76 (1H, d, J = 14.2 Hz, H b -15) , 2.35 (1H, m, H a -3), 2.34 (s, a-OCOCH 3), 2.30 (s, b-OCOCH 3), 2.08 (1H, m, H b -3), 1.92 (1H, m , H a -2), 1.58 ( 1H, m, H a -1), 1.49 (1H, m, H a -6), 1.45 (1H, m, H b -1), 1.43 (1H, m, H -8), 1.42 (2H, m , H 2 -7), 1.28 (1H, m, H b -6), 1.26 (1H, m, H b -2), 1.07 (3H, s, H 3 -12 ), 0.97 (3H, d, J = 5.6 Hz, H 3 -13), 0.94 (3H, s, H 3 -14), 0.92 (1H, m, H-10);
13C NMR (CDCl3, 150 MHz) δ168.1 (C, a-OCOCH3), 167.9 (C, b-OCOCH3), 159.1 (C, C-4), 152.7 (CH, C-22), 147.9 (C, C-21), 140.4 (C, C-17), 137.4 (C, C-18), 136.6 (C, C-20), 118.3 (C, C-16), 111.9 (CH, C-19), 102.2 (CH2, C-11), 50.1 (CH, C-10), 43.0 (C, C-9), 40.3 (C, C-5), 37.6 (CH, C-8), 36.2 (CH2, C-6), 35.6 (CH2, C-15), 32.6 (CH2, C-3), 28.3 (CH2, C-2), 27.7 (CH2, C-7), 23.1 (CH2, C-1), 20.1 (2 × CH3, -OCOCH3), 19.9 (CH3, C-12), 18.1 (CH3, C-13), 16.8 (CH3, C-14). 13 C NMR (CDCl 3, 150 MHz) δ168.1 (C, a-OCOCH 3), 167.9 (C, b-OCOCH 3), 159.1 (C, C-4), 152.7 (CH, C-22), (C, C-17), 137.4 (C, C-18), 136.6 -19), 102.2 (CH 2, C-11), 50.1 (CH, C-10), 43.0 (C, C-9), 40.3 (C, C-5), 37.6 (CH, C-8), 36.2 (CH 2, C-6 ), 35.6 (
< 제조예 10> 3-[[( 1R,2S,4aS,8aS )-1,2, 4a,5 - 테트라메틸 -2,3,4,7,8,8a- 헥사히드로나프탈렌-1-일]메틸]-2-히드록시-5-메톡시시클로헥사-2,5-디엔-1,4-디온의 수득 <Production Example 10> 3 - [[(1R , 2S, 4aS, 8aS) -1,2, 4a, 5 - tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] -2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione
sponge Spongiidae SS-1047(0.30 kg, wet weight)를 'Yohei Takahashi et al., 2010' 문헌에 기재된 바와 같이 수득하고 추출하였다. 간략하게, EtOAc 용해성 물질들(1.2 g)을 silica gel column (n-hexane/EtOAc)으로 분획하여, 극성이 낮은 분획 1 및 분획 2, 분획 3, 극성 분획 4를 제조하였다. 상기 분획 3은 C18 column (MeOH/H2O) 및 C18 HPLC (Luna 5u Phenyl-Hexyl, 250 × 10 mm; eluent, MeOH/H2O/CF3CO2H, 85:15:0.05; flow rate, 2.5 mL/min; UV detection at 320 nm)으로 분획 및 정제하여, 각각 제조예 10 및 하기 제조예 11에 해당하는 화합물을 수득하였다. Sponge Spongiidae SS-1047 (0.30 kg, wet weight) was obtained and extracted as described in Yohei Takahashi et al., 2010 '. Briefly, EtOAc-soluble materials (1.2 g) were fractionated with silica gel column (n-hexane / EtOAc) to produce
상기 수득된 제조예 10 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione’화합물로 판명되었다: The physicochemical properties of the obtained compound of Preparation Example 10 are as follows, and the physical and chemical properties of the obtained compound are as follows. ≪ 2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione '
mp 95-98 ; mp 95-98;
[α]20 579 +64.4° (c0.27 CHCl3); [?] 20 579 + 64.4 (c 0.27 CHCl 3 );
IR (film) 3341, 1652, 1645, 1609, 1243 cm-1; IR (film) 3341, 1652, 1645, 1609, 1243 cm- 1 ;
UV(CH3OH) λmax 213 (9600), 288 nm (13485); UV (CH 3 OH) λmax 213 (9600), 288 nm (13485);
UV (CH3OH/NaOH) λmax 210 (12850), 290 (8930), 526 nm (1650); UV (CH 3 OH / NaOH) λmax 210 (12850), 290 (8930), 526 nm (1650);
1H NMR(600 MHz, CDCl3, δ, J in Hz) 데이터는 하기 [표 6] 참조 1 H NMR, see (600 MHz, CDCl 3, δ , J in Hz) is data to Table 6
13C NMR(150.87 MHz, CDCl3) 데이터는 하기 [표 6] 참조 13 C NMR (150.87 MHz, CDCl 3) data for Table 6, see
HREIMS m/z 358.2151 [M+](12, calcd for C22H30O4, 358.2144), 191.1803 (15, calcd for C14H23, 191.1800), 168.0423 (41, calcd for C8H8O4, 168.0422), 121.1013 (12, calcd for C9H13, 121.1017), 107.0859 (30, calcd for C8H11, 107.0861), 95.0861 (100, calcd for C7H11, 95.0861).HREIMS m / z 358.2151 [M + ] (12, calcd for C 22 H 30 O 4, 358.2144), 191.1803 (15, calcd for C 14 H 23, 191.1800), 168.0423 (41, calcd for C 8 H 8 O 4, Calcd for C 9 H 13 , 121.1017), 107.0859 (30, calcd for C 8 H 11 , 107.0861), 95.0861 (100, calcd for C 7 H 11 , 95.0861).
[표 6][Table 6]
< 제조예 11> 2-히드록시-5- 메톡시 -3-[[( 1R,2S )-1,2,5,5- 테트라메틸 -2,3,6,7,8,8a-헥사히드로나프탈렌-1-일]메틸]시클로헥사-2,5-디엔-1,4-디온의 수득 <Preparation Example 11> 2-hydroxy-5-methoxy -3 - [[(1R, 2S ) -1,2,5,5- tetramethyl - 2,3,6,7,8,8a- hexahydro- Naphthalen-1-yl] methyl] cyclohexa-2,5-diene-1,4-dione
상기 제조예 10에서 전술한 바와 같은 방법으로, 제조예 11의 화합물을 수득하였다. 수득된 화합물(제조예 11)의 물리화학적 성질은 다음과 같으며, ‘2-hydroxy-5-methoxy-3-[[(1R,2S)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen-1-yl]methyl]cyclohexa-2,5-diene-1,4-dione’화합물로 판명되었다:The compound of Preparative Example 11 was obtained in the same manner as described in Preparation Example 10 above. The physicochemical properties of the obtained compound (Production Example 11) are as follows, and the results are shown in Table 1. The physicochemical properties of the obtained compound (Production Example 11) are as follows: 2-hydroxy-5-methoxy-3 - [[(1R, 2S) -1,2,5,5-tetramethyl- , 6,7,8,8a-hexahydronaphthalen-1-yl] methyl] cyclohexa-2,5-diene- 1,4-dione '
pale yellow feathery solid; pale yellow feathery solid;
m.p. 108.5-109.5; m.p. 108.5-109.5;
C22H3004 (high resolution FABMS (M+ 358.2146, Δ0.2 mmu, C22H3004; MH+ 359.2223, Δ0.1 mmu, C22H3104));C 22 H 30 0 4 (high resolution FABMS (M + 358.2146 , Δ0.2 mmu, C 22 H 30 0 4; MH + 359.2223, Δ0.1 mmu, C 22 H 31 0 4));
lH NMR (500 MHz, CDCl3) δ: 0.73 (s, 3H), 0.90 (sh, lH), 0.92 (s, 3H), 0.96 (d, J=7 Hz, 3H), 0.99 (s, 3H), I.12 (ddd, J=13.5,13.5, 4.3 Hz, 1H), 1.33-1.45 (complex mult., 4H), 1.73 (mult, lH), 1.79 (br d, lH), 1.95 (ddd, J=18, 17.5, 4.5 Hz, 1H), 2.08 (br d, J=13 Hz, 1H), 2.45 (d, cJ=13.0 HZ, lH), 2.58 (d, J=13.0 Hz, lH), 3.84 (s, 3H), 5.35 (br s, lH), 5.84 (s, 1H), 7.45 (s, 1H); l H NMR (500 MHz, CDCl 3) δ: 0.73 (s, 3H), 0.90 (sh, lH), 0.92 (s, 3H), 0.96 (d, J = 7 Hz, 3H), 0.99 (s, 3H ), 1.12 (ddd, J = 13.5, 13.5, 4.3 Hz, 1H), 1.33-1.45 (complex mult., 4H), 1.73 (D, J = 13.0 Hz, 1H), 2.84 (d, J = 13.0 Hz, 1H) (s, 3H), 5.35 (brs, 1H), 5.84 (s, 1H), 7.45 (s, 1H);
13C NMR (500 MHz, CDCl3), δ (mult., proton asignments): 16.0 (q, 0.73, C-14), 16.5 (q, 0.92, C-11), 22.7 (t, 1.40, 1.46, C-2), 27.9 (q, 0.96, C-13), 29.7 (q, 0.99, C-12). 30.6 (t, 0.90, 1.79, C-l), 31.5 (t, 1.73, 1.95, C-7), 32.7 (t, 2.45,2.58, C-15), 36.3 (s, C-4), 36.4 (d, 1.36, C-8), 40.9 (s, C-g), 41.2 (t, 1.13, 1.32, C-3), 41.7 (s, 2.08, C-10), 56.8 (q, 3.86, C-22), 102.0 (d, 5.85, C-19),114.8 (d, 5.35, C-6), 118.3 (s, C-16), 146.3 (s, C-5), 152.8 (s, -OH, C-17), 161.5 (s, C-20), 182.0 (s, C-21), 182.4 (s, C-18). 13 C NMR (500 MHz, CDCl 3), δ (mult, proton asignments.): 16.0 (q, 0.73, C-14), 16.5 (q, 0.92, C-11), 22.7 (t, 1.40, 1.46, C-2), 27.9 (q, 0.96, C-13), 29.7 (q, 0.99, C-12). (T, 0.90, 1.79, Cl), 31.5 (t, 1.73, 1.95, C-7), 32.7 C-3), 41.7 (s, 2.08, C-10), 56.8 (q, 3.86, C-22), 102.0 C-16), 146.3 (s, C-5), 152.8 (s, -OH, C-17) , 161.5 (s, C-20), 182.0 (s, C-21), 182.4 (s, C-18).
< 제조예 12> 3-[[(1R,2S,8aS)-1,2,5,5-테트라메틸-2,3,6,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-(2-페틸에틸아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 12> 3 - [[(1R , 2S, 8aS) -1,2,5,5- tetramethyl -2,3,6,7,8,8a--hexahydro-1-yl] methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3,5-diene-1,2-dione
상기 제조예 10에서 수득된 분획 1은 C18 column (MeOH/H2O) 및 C18 HPLC (Wakosil-II 5C18AR, Wako Pure Chemical Industries, Ltd., 250 × 10 mm; eluent, MeCN/H2O/CF3CO2H, 90:10:0.05; flow rate, 2.0 mL/min; UV detection at 300 nm)으로 재분획하여, 각각 제조예 11의 화합물 (2.8 mg, 0.00093% wet weight) 및 하기 제조예 12의 화합물(24.7 mg, 0.0082%)을 수득하였다.The
수득된 제조예 12 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,8aS)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다: The physicochemical properties of the obtained compound of Preparation Example 12 were as follows, and the physical and chemical properties of the obtained compound were as follows: 3 - [[(1R, 2S, 8aS) -1,2,5,5-tetramethyl-2,3,6,7,8,8a -hexahydronaphthalen-1-yl] methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3,5-diene-
purple-red, amorphous solid; purple-red, amorphous solid;
[α]23 D -14 (c 0.2, CHCl3); [?] 23 D -14 (c 0.2, CHCl 3 );
IR (film) νmax 3290, 1730, 1650, 1590, 1510, 1460, 1380, 1360, 1220 cm-1; IR (film) ν max 3290, 1730, 1650, 1590, 1510, 1460, 1380, 1360, 1220 cm - 1;
UV (MeOH) λmax 336 (log 4.28), 507 nm (2.84);UV (MeOH) [lambda] max 336 (log 4.28), 507 nm (2.84);
1H NMR (CDCl3)데이터는 하기 [표 7] 참조; 1 H NMR (CDCl 3 ) data are shown in Table 7 below;
13C NMR (CDCl3)데이터는 하기 [표 7] 참조; 13 C NMR (CDCl 3 ) data are shown in Table 7 below;
EIMS m/z (%) 447 (M+, 9), 257 (100), 191 (2), 166 (20), 152 (5), 105 (10), 95 (15); HREIMS m/z 447.2790 [M]+ (calcd for C29H37NO3, 447.2773).EIMS m / z (%) 447 (M +, 9), 257 (100), 191 (2), 166 (20), 152 (5), 105 (10), 95 (15); HREIMS m / z 447.2790 [M] + (calcd for C 29 H 37 NO 3 , 447.2773).
[표 7][Table 7]
< 제조예 13> 3-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-(2-페일에틸아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 13> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] -4-hydroxy-5- (2-pheylethylamino) cyclohexa-3,5-dien-1,2-dione
상기 제조예 12에서 전술한 바와 같은 방법으로, 제조예 13의 화합물을 수득하였다. 수득된 화합물(제조예 13)의 물리화학적 성질은 다음과 같으며,‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a- hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다;The compound of Preparation Example 13 was obtained in the same manner as described in Preparation Example 12 above. The physicochemical properties of the obtained compound (Preparation Example 13) are as follows, and the physicochemical properties of the obtained compound (Production Example 13) are as follows: 3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl- , 8,8a-hexahydronaphthalen-1-yl] methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3,5-diene-1,2-dione;
purple-red. amorphous solid; purple-red. amorphous solid;
[α]25 D +180 (c 0.1, CHCl3); [?] 25 D +180 (c 0.1, CHCl 3 );
IR (film) νmax 3270, 1730, 1640, 1590, 1510, 1460, 1380, 1210 cm-1; IR (film)? Max 3270, 1730, 1640, 1590, 1510, 1460, 1380, 1210 cm -1 ;
UV (MeOH) λmax 335 (log 4.20), 502 nm (2.74); UV (MeOH) [lambda] max 335 (log 4.20), 502 nm (2.74);
1H NMR (CDCl3)데이터는 하기 [표 8] 참조; 1 H NMR (CDCl 3 ) data are shown in Table 8 below;
13C NMR (CDCl3)데이터는 하기 [표 8] 참조; 13 C NMR (CDCl 3 ) data are shown in Table 8 below;
EIMS m/z (%) 447 (M+, 25), 257 (100), 209 (17), 191 (18), 168 (45), 166 (48), 152 (17), 119 (42), 105 (40); EIMS m / z% 447 (M +, 25), 257 (100), 209 (17), 191 (18), 168 (45), 166 (48), 152 (17), 119 (40);
HREIMS m/z 447.2783 [M]+ (calcd for C29H37NO3, 447.2773).HREIMS m / z 447.2783 [M] + (calcd for C 29 H 37 NO 3 , 447.2773).
[표 8][Table 8]
< 제조예 14> 3-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-(2-메틸프로필아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 14> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] -4-hydroxy-5- (2-methylpropylamino) cyclohexa-3,5-diene-1,2-dione
상기 제조예 10에서 수득된 분획 2로 C18 column (MeOH/H2O/CF3CO2H) 및 C18 HPLC (Luna 5u Phenyl-Hexyl, Phenomenex, 250 × 10 mm; eluent, MeCN/H2O/CF3CO2H, 80:20:0.05; flow rate, 2.0 mL/min; UV detection at 300 nm)를 수행하여, 제조예14의 화합물( 0.9 mg, 0.00030%)과 각각 γ분획 및 δ분획을 수득하였다. C18 column (MeOH / H 2 O / CF 3 CO 2 H) and C 18 HPLC (Luna 5u Phenyl-Hexyl, Phenomenex, 250 × 10 mm; eluent, MeCN / H 2 O / CF 3 CO 2 H, 80: 20: 0.05; flow rate, 2.0 mL / min; by performing the UV detection at 300 nm), the compound of Preparation 14 (0.9 mg, 0.00030%) and γ fraction and a δ fraction respectively .
상기 수득된 제조예 14의 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(2-methylpropylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다; The physicochemical properties of the compound of Preparation Example 14 were as follows, and the physical and chemical properties of the obtained compound of Preparation Example 14 were as follows. 3 '- [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl- , 8,8a-hexahydronaphthalen-1-yl] methyl] -4-hydroxy-5- (2-methylpropylamino) cyclohexa-3,5-diene-1,2-dione;
purple-red, amorphous solid; purple-red, amorphous solid;
[α]23 D +160 (c 0.1, CHCl3); [?] 23 D +160 (c 0.1, CHCl 3 );
IR (film) νmax 3270, 1730, 1640, 1590, 1510, 1380, 1210 cm-1;IR (film)? Max 3270, 1730, 1640, 1590, 1510, 1380, 1210 cm -1 ;
UV (MeOH) λmax 334 (log 4.29), 509 nm (2.86); UV (MeOH) [lambda] max 334 (log 4.29), 509 nm (2.86);
1H NMR (CDCl3)데이터는 하기 [표 9] 참조; 1 H NMR (CDCl 3) data to see Table 9;
13C NMR (CDCl3)데이터는 하기 [표 9] 참조; 13 C NMR (CDCl 3) data to see Table 9;
EIMS m/z (%) 399 (M+, 8), 209 (100), 191 (3), 166 (11), 152 (9), 107 (9), 95 (22); EIMS m / z (%) 399 (M +, 8), 209 (100), 191 (3), 166 (11), 152 (9), 107 (9), 95 (22);
HREIMS m/z 399.2790 [M]+ (calcd for C25H37NO3, 399.2773).HREIMS m / z 399.2790 [M] + (calcd for C 25 H 37
[표 9][Table 9]
< 제조예 15> 3-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-[[(2S)-2-메틸부틸]아미노]시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 15> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] -4-hydroxy-5 - [[(2S) -2-methylbutyl] amino] cyclohexa-3,5-dien-1,2-dione
상기 제조예 14에서 수득된 γ분획을 다시 C18 HPLC (Luna 5u C18(2), Phenomenex, 250 × 10 mm; MeOH/H2O/Et2NH, 70:30:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm)으로 정제하여, 제조예 15의 화합물(1.4 mg, 0.00047%) 및 제조예 16의 화합물(4.0 mg, 0.0013%)을 수득하였다. The γ fraction obtained in Preparation Example 14 was further purified by C18 HPLC (Luna 5u C18 (2), Phenomenex, 250 × 10 mm; MeOH / H 2 O / Et 2 NH, 70: (1.4 mg, 0.00047%) and the compound of Preparation 16 (4.0 mg, 0.0013%) were obtained.
상기 제조예15의 화합물의 물리화학적 성질은 다음과 같았으며, 이에 따라 ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-[[(2S)-2-methylbutyl]amino]cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다:The physicochemical properties of the compound of Preparation Example 15 were as follows, and thus, the physical and chemical properties of the compound of Preparation Example 15 were as follows. Thus, 3 '[[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl- , 8,8a-hexahydronaphthalen-1-yl] methyl] -4-hydroxy-5 - [[(2S) -2-methylbutyl] amino] cyclohexa-3,5-diene-1,2-dione ' :
purple-red, amorphous solid; purple-red, amorphous solid;
[α]21 D +136 (c 0.25, CHCl3); [?] 21 D +136 (c 0.25, CHCl 3 );
IR (film) νmax 3270, 1680, 1650, 1590, 1510, 1450, 1380, 1210 cm-1; IR (film)? Max 3270, 1680, 1650, 1590, 1510, 1450, 1380, 1210 cm -1 ;
UV (MeOH) λmax 336 (log 4.09), 505 nm (2.67); UV (MeOH) [lambda] max 336 (log 4.09), 505 nm (2.67);
1H NMR (CDCl3)데이터는 하기 [표 10] 참조; 1 H NMR (CDCl 3 ) data are shown in Table 10 below;
13C NMR (CDCl3)데이터는 하기 [표 10] 참조; 13 C NMR (CDCl 3) data to reference [Table 10];
HREIMS m/z 413.2940 [M]+ (calcd for C26H39NO3, 413.2930).HREIMS m / z 413.2940 [M] + (calcd for C 26 H 39 NO 3 , 413.2930).
[표 10][Table 10]
< 제조예 16> 3-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-(3-메틸부틸아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 16> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] -4-hydroxy-5- (3-methylbutylamino) cyclohexa-3,5-diene-1,2-dione
상기 제조예 15에서 전술한 바와 같이 제조예 16의 화합물을 수득하였으며, 이의 물리화학적 성질은 다음과 같았으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(3-methylbutylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다:The physical and chemical properties of the compound of Preparation 16 were as described in Preparation Example 15, as described above, and the physicochemical properties thereof were as follows. [0353] 3 - [[(1R, 2S, 4aS, 8aS) -tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl] methyl] -4-hydroxy-5- (3- methylbutylamino) cyclohexa-3,5-diene- Proved to be:
purple-red, amorphous solid; purple-red, amorphous solid;
[α]21 D +124 (c 0.25, CHCl3); [α] 21 D +124 (c 0.25, CHCl 3);
IR (film) νmax 3270, 1680, 1640, 1590, 1510, 1380, 1210 cm-1; IR (film)? Max 3270, 1680, 1640, 1590, 1510, 1380, 1210 cm -1 ;
UV (MeOH) λmax 336 (log 4.17), 515 nm (2.55); UV (MeOH) [lambda] max 336 (log 4.17), 515 nm (2.55);
1H NMR (CDCl3)데이터는 하기 [표 11] 참조; 1 H NMR (CDCl 3) data, refer to Table 11;
13C NMR (CDCl3)데이터는 하기 [표 11] 참조; 13 C NMR (CDCl 3) data to reference Table 11;
EIMS m/z (%) 413 (M+, 7), 223 (100), 191 (3), 166 (8), 152 (9), 107 (8), 95 (18); EIMS m / z (%) 413 (M +, 7), 223 (100), 191 (3), 166 (8), 152 (9), 107 (8), 95 (18);
HREIMS m/z 413.2947 [M]+ (calcd for C26H39NO3, 413.2930).HREIMS m / z 413.2947 [M] + (calcd for C 26 H 39 NO 3 , 413.2930).
[표 11][Table 11]
< 제조예 17> 3-[[(1R,2S,8aS)-1,2,5,5-테트라메틸-2,3,6,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-[[(2S)-2-메틸부틸]아미노]시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 17> 3 - [[(1R , 2S, 8aS) -1,2,5,5- tetramethyl -2,3,6,7,8,8a--hexahydro-1-yl] methyl] -4-hydroxy-5 - [[(2S) -2-methylbutyl] amino] cyclohexa-3,5-dien-1,2-dione
상기 제조예 14에서 수득된 δ분획은 C18 HPLC (Luna 5u Phenyl-Hexyl, 250 × 10 mm; MeOH/H2O/Et2NH, 65:35:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm)으로 재분획하여, 각각 제조예 17의 화합물(0.7 mg, 0.00023%) 및 하기 제조예18의 화합물(1.6 mg, 0.00053%)을 수득하였다.The 隆 fraction obtained in Preparative Example 14 was analyzed by C18 HPLC (Luna 5u Phenyl-Hexyl, 250 x 10 mm; MeOH / H 2 O / Et 2 NH, 65: 35: 0.1; flow rate, 2.0 mL / at 300 nm) to obtain the compound of Preparation 17 (0.7 mg, 0.00023%) and the compound of Preparation 18 (1.6 mg, 0.00053%), respectively.
상기 수득된 제조예 17 화합물의 물리화학적 성질은 다음과 같으며,‘3-[[(1R,2S,8aS)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen -1-yl]methyl]-4-hydroxy-5-[[(2S)-2-methylbutyl]amino]cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 17 were as follows, and the physical properties of the compound were as follows: 3 - [[(1R, 2S, 8aS) -1,2,5,5-tetramethyl- 4-hydroxy-5 - [[(2S) -2-methylbutyl] amino] cyclohexa-3,5-diene-1,2-dione '
purple-red, amorphous solid;purple-red, amorphous solid;
[α]23 D -42 (c 0.25, CHCl3); [α] 23 D -42 (c 0.25, CHCl 3);
IR (film) νmax 3290, 1680, 1650, 1590, 1520, 1460, 1390, 1200 cm-1; IR (film)?
UV (MeOH) λmax 338 (log 4.06), 511 nm (2.63); UV (MeOH) [lambda] max 338 (log 4.06), 511 nm (2.63);
1H NMR (CDCl3)데이터는 하기 [표 12] 참조; 1 H NMR (CDCl 3 ) data are shown in Table 12 below;
13C NMR (CDCl3)데이터는 하기 [표 12] 참조; 13 C NMR (CDCl 3) data to reference [Table 12];
EIMS m/z (%) 413 (M+, 15), 223 (100), 191 (10), 168 (15), 166 (14), 152 (16), 119 (18); EIMS m / z (%) 413 (M +, 15), 223 (100), 191 (10), 168 (15), 166 (14), 152 (16), 119 (18);
HREIMS m/z 413.2916 [M]+ (calcd for C26H39NO3, 413.2930).HREIMS m / z 413.2916 [M] + (calcd for C 26 H 39 NO 3 , 413.2930).
[표 12][Table 12]
< 제조예 18> 3-[[(1R,2S,8aS)-1,2,5,5-테트라메틸-2,3,6,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-4-히드록시-5-(3-메틸부틸아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 18> 3 - [[(1R , 2S, 8aS) -1,2,5,5- tetramethyl -2,3,6,7,8,8a--hexahydro-1-yl] methyl] -4-hydroxy-5- (3-methylbutylamino) cyclohexa-3,5-diene-1,2-dione
상기 제조예 17에서 전술한 바와 같이 제조예 18의 화합물을 수득하였으며, 이의 물리화학적 성질은 다음과 같았으며,‘3-[[(1R,2S,8aS)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen -1-yl]methyl]-4-hydroxy-5-(3-methylbutylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다:The compound of Preparation 18 was obtained as described in Preparation Example 17, and the physicochemical properties of the compound were as follows. Synthesis of 3 - [[(1R, 2S, 8aS) -1,2,5,5-tetramethyl -2,3,6,7,8,8a-hexahydronaphthalen-1-yl] methyl] -4-hydroxy-5- (3- methylbutylamino) cyclohexa-3,5-diene-1,2-dione It was:
purple-red, amorphous solid; purple-red, amorphous solid;
[α]21 D -38 (c 0.2, CHCl3); [?] 21 D -38 (c 0.2, CHCl 3 );
IR (film) νmax 3270, 1680, 1650, 1590, 1510, 1460, 1380, 1200 cm-1 ;IR (film)?
UV (MeOH) λmax 338 (log 4.21), 515 nm (2.63); UV (MeOH) [lambda] max 338 (log 4.21), 515 nm (2.63);
1H NMR (CDCl3)데이터는 하기 [표 13] 참조; 1 H NMR (CDCl 3 ) data are shown in Table 13 below;
13C NMR (CDCl3)데이터는 하기 [표 13] 참조; 13 C NMR (CDCl 3) data to reference [Table 13];
EIMS m/z (%) 413 (M+, 24), 223 (100), 191 (13), 166 (20), 152 (17), 119 (20); EIMS m / z (%) 413 (M +, 24), 223 (100), 191 (13), 166 (20), 152 (17), 119 (20);
HREIMS m/z 413.2947 [M]+ (calcd for C29H37NO3, 413.2930).HREIMS m / z 413.2947 [M] + (calcd for C 29 H 37 NO 3 , 413.2930).
[표 13][Table 13]
< 제조예 19> 3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-[[(2S)-2-메틸부틸]아미노]시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 19> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro-naphthalene -2H- -1-yl] methyl] -4-hydroxy-5 - [[(2S) -2-methylbutyl] amino] cyclohexa-3,5-dien-1,2-dione
sponge Spongiidae SS-265를 'Yohei Takahashi et al., 2010' 문헌에 기재된 바와 같이 수득하고 추출하였다. 간략하게, sponge SS-265 (1.4 kg, wet weight) 조각에 MeOH (4.3 및 3.2 L)를 가하여 추출물을 제조하였다. MeOH 추출물(68.4 g)을 CHCl3 및 H2O로 분획하였다. CHCl3-용해성 물질들(2.3 g)은 silica gel column (n-hexane/EtOAc), C18 column (MeOH/H2O), silica gel column (n-hexane/acetone), 및 반복적으로 C18 HPLC (Wakosil-II 5C18AR, 250 × 10 mm; eluent, MeCN/H2O/CF3CO2H, 90:10:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm and Luna 5u C18(2), 250 × 10 mm; MeOH/H2O/Et2NH, 70:30:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm)를 수행하여, 제조예 19(1.8 mg, 0.00013%)의 화합물을 분리 수득하였다. Sponge Spongiidae SS-265 was obtained and extracted as described in 'Yohei Takahashi et al., 2010'. Briefly, extracts were prepared by adding MeOH (4.3 and 3.2 L) to a piece of sponge SS-265 (1.4 kg, wet weight). The MeOH extract (68.4 g) was fractionated with CHCl 3 and H 2 O. CHCl 3 solubility materials (2.3 g) were purified by silica gel column (n-hexane / EtOAc), C18 column (MeOH / H2O), silica gel column (n-hexane / acetone) Flow rate, 2.0 mL / min; UV detection at 300 nm and Luna 5u C18 (2), 250 x 10 cm; eluent, MeCN / H 2 O / CF 3 CO 2 H, 90: The compound of Preparation 19 (1.8 mg, 0.00013%) was obtained as a white solid by carrying out the procedure of Example 19 (10 mg; MeOH / H 2 O / Et 2 NH, 70: 30: 0.1; flow rate, 2.0 mL / min; UV detection at 300 nm) Respectively.
상기 수득된 제조예 19 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-[[(2S)-2-methylbutyl]amino]cyclohexa-3,5-diene-1,2-dione’화합물인 것으로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 19 are as follows, and the physical and chemical properties of the obtained compound of
purple-red, amorphous solid; purple-red, amorphous solid;
[α]22 D +33 (c 0.2, CHCl3); [?] 22 D +33 (c 0.2, CHCl 3 );
IR (film) νmax 3280, 1640, 1590, 1510, 1380, 1200 cm-1 IR (film)?
UV (MeOH) λmax 501 (log 2.88), 327 (4.17), 243 (3.86), 208 nm (4.25); UV (MeOH)? Max 501 (log 2.88), 327 (4.17), 243 (3.86), 208 nm (4.25);
1H NMR (CDCl3)데이터는 하기 [표 14] 참조; 1 H NMR (CDCl 3) data to reference [Table 14];
13C NMR (CDCl3)데이터는 하기 [표 14] 참조; 13 C NMR (CDCl 3 ) data are shown in Table 14 below;
EIMS m/z (%) 413 (M+, 15), 223 (100), 191 (3), 166 (10), 152 (10), 95 (10); EIMS m / z (%) 413 (M +, 15), 223 (100), 191 (3), 166 (10), 152 (10), 95 (10);
HREIMS m/z 413.2934 [M]+ (calcd for C26H39NO3, 413.2930).HREIMS m / z 413.2934 [M] + (calcd for C 26 H 39 NO 3 , 413.2930).
[표 14][Table 14]
< 제조예 20> 2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-6-히드록시-3,4-디옥소시클로헥사-1,5-디엔-1-일]아미노]에탄술포닉 에시드의 수득 <Production Example 20> 2 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl-hexyl -2,3,4,7,8,8a- four dihydro naphthalene -1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] ethane sulfonic acid
sponge Spongiidae SS-1208를 'Yohei Takahashi et al., 2010' 문헌에 기재된 바와 같이 수득하고 추출하였다. 간략하게, sponge SS-1208(0.4 kg, wet weight)에 MeOH (3 × 0.8 L) 및 MeOH/toluene (3:1) (1 × 0.8 L)용액을 가하여 추출물을 제조하였다. 상기 혼합추출물(15.9 g)을 CHCl3 및 H2O (3 × 500 mL)로 분획하였다. CHCl3-용해성 분획(2.7 g)을 silica gel column (n-hexane/EtOAc 및 CHCl3/MeOH), C18 column (MeOH/H2O/CF3CO2H), 및 반복적으로 C18 HPLC (Luna 5u Phenyl-Hexyl, 250 × 10 mm; eluent, MeCN/H2O/CF3CO2H, 70:30:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm and Wakosil-II 5C18AR, 250 × 10 mm; eluent, MeCN/H2O/CF3CO2H, 75:25:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm)로 분리하는 과정을 통해, 제조예 20의 화합물(0.8 mg, 0.00020%)을 수득하였다. Sponge Spongiidae SS-1208 was obtained and extracted as described in Yohei Takahashi et al., 2010 '. Briefly, extracts were prepared by adding MeOH (3 x 0.8 L) and MeOH / toluene (3 x 1) (1 x 0.8 L) solution to sponge SS-1208 (0.4 kg, wet weight). The combined extract (15.9 g) was fractionated into CHCl 3 and H 2 O (3 × 500 mL). The CHCl 3 -soluble fraction (2.7 g) was purified by silica gel column (n-hexane / EtOAc and CHCl 3 / MeOH), C18 column (MeOH / H 2 O / CF 3 CO 2 H) Phenyl-Hexyl, 250 x 10 mm eluent, MeCN / H 2 O / CF 3 CO 2 H, 70: 30: 0.1; flow rate, 2.0 mL / min; UV detection at 300 nm and Wakosil-II 5C18AR, , And the solvent was distilled off under reduced pressure (10 mL), eluent, MeCN / H 2 O / CF 3 CO 2 H, 75: 25: 0.1; flow rate, 2.0 mL / min; UV detection at 300 nm) 0.8 mg, 0.00020%).
상기 수득된 제조예 20 화합물의 물리화학적 성질은 다음과 같으며, ‘2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]ethanesulfonic acid’화합물인 것으로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 20 were as follows, and the physical and chemical properties of the obtained compound were as follows; [2 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl- 4,7,8,8a-hexahydronaphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] ethanesulfonic acid '
purple-red, amorphous solid; purple-red, amorphous solid;
[α]22 D +38 (c 0.2, MeOH); [α] 22 D +38 (c 0.2, MeOH);
IR (KBr) νmax 3450, 1640, 1600, 1530, 1380, 1210 cm-1;IR (KBr)? Max 3450, 1640, 1600, 1530, 1380, 1210 cm -1 ;
UV (MeOH) λmax 237 (log 2.8), 345 (4.00), 513 nm (2.47); UV (MeOH)? Max 237 (log 2.8), 345 (4.00), 513 nm (2.47);
1H NMR (DMSO-d6)데이터는 하기 [표 15] 참조; 1 H NMR (DMSO-d 6 ) data are shown in Table 15 below;
13C NMR (DMSO-d6)데이터는 하기 [표 15] 참조; 13 C NMR (DMSO-d 6 ) data are shown in Table 15 below;
ESIMS (neg) m/z 450 [M - H]-;ESIMS (neg) m / z 450 [M - H] - ;
HRESIMS (neg) m/z 450.1955 [M - H]-(calcd for C23H32NO6S, 450.1950).HRESIMS (neg) m / z 450.1955 [M - H] - (calcd for C 23 H 32 NO 6 S, 450.1950).
[표 15][Table 15]
< 제조예 21> 메틸 3-[[( 1R,2S,4aS,8aS )-1,2,4a- 트리메틸 -5- 메틸리덴 -3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시벤조에이트의 수득 <Production Example 21> Methyl 3 - [[(1R, 2S , 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro--2H- Naphthalen-1-yl] methyl] -4-hydroxybenzoate
sponge Dactylospongia elegans를 동결시키고, 동결시킨 해면(2.6 kg, wet weight)을 조각낸 후 MeOH에 침지시키고 overnight하여 추출물을 제조하였다. MeOH 추출물을 hexane, 90% methanol, n-BuOH, 및 H2O phases로 용매 분획하였다. 상기 90% methanol 분획을 감압조건 하에서 증발시켜, 12 g의 90% MeOH 추출물을 수득하였다. 상기 90% MeOH 추출물 2g을 SiO2 column (hexane-AcOEt-acetone-MeOH)으로 분리하여, 각각 Fr. A (0.42 g), Fr. B (0.73 g), Fr. C (0.83 g)의 3개 분획을 수득하였다. 상기 분획들 중 Fr. A 및 Fr.B를 ODS column (MeOH-H2O) 또는 HPLC (Cosmosil 5SL, hexane-AcOEt= 7 : 1)로 분리하여, 각각 제조예 21의 화합물(20 mg, 1%) 및 제조예 22의 화합물(17 mg, 0.85%)을 수득하였다. sponge Dactylospongia After freezing of the elegans , the frozen sea surface (2.6 kg, wet weight) was sliced, immersed in MeOH and dried overnight to prepare an extract. MeOH extracts were solvent fractionated with hexane, 90% methanol, n-BuOH, and H 2 O phases. The 90% methanol fraction was evaporated under reduced pressure to obtain 12 g of a 90% MeOH extract. 2 g of the 90% MeOH extract was separated by SiO 2 column (hexane-AcOEt-acetone-MeOH) A (0.42 g), Fr. B (0.73 g), Fr. C < / RTI > (0.83 g). Of these fractions, Fr. A and Fr.B were separated by ODS column (MeOH-H 2 O) or HPLC (Cosmosil 5SL, hexane-AcOEt = 7: 1) to give the compound of Preparation 21 (20 mg, 1% (17 mg, 0.85%).
상기 수득된 제조예 21 화합물의 물리화학적 성질은 다음과 같으며, ‘methyl 3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxybenzoate’화합물로 판명되었다: The physicochemical properties of the obtained compound of Preparation Example 21 are as follows, and the physical and chemical properties of the obtained compound of Preparation 21 are as follows: Methyl 3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- , 7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -4-hydroxybenzoate '
white solid;white solid;
[α]27 D +17.3 (c 0.12, CHCl3). [α] 27 D +17.3 (c 0.12, CHCl 3).
1H NMR (500 MHz, CDCl3) δ: 7.77 (1H, s), 7.77-7.74 (1H, m), 6.77 (1H, d, J = 8.0 Hz), 6.01 (1H, s), 4.41 (1H, s), 4.36 (1H, s), 3.87 (3H, s), 2.68 (1H, d, J = 14.3 Hz), 2.64 (1H, d, J = 14.3 Hz), 2.33 (1H, td, J = 13.7, 5.2 Hz), 2.08 (2H, d, J = 13.7 Hz), 1.93-1.89 (1H, m), 1.61-1.56 (1H, m), 1.47 (1H, dt, J = 12.2, 3.2 Hz), 1.41-1.38 (3H, m), 1.31-1.27 (1H, m), 1.22-1.19 (1H, m), 1.06 (3H, s), 1.02 (3H, d, J = 6.9 Hz), 0.96 (1H, dd, J = 12.0, 1.7 Hz), 0.88 (3H, s); 1 H NMR (500 MHz, CDCl 3) δ: 7.77 (1H, s), 7.77-7.74 (1H, m), 6.77 (1H, d, J = 8.0 Hz), 6.01 (1H, s), 4.41 (1H d, J = 14.3 Hz), 2.33 (1H, t, J = 14.3 Hz), 4.36 (1H, s), 3.87 M), 1.47 (1H, dt, J = 12.2, 3.2 Hz), 2.01 (2H, d, J = 13.7 Hz), 1.93-1.89 (3H, m), 1.31-1.27 (1H, m), 1.22-1.19 (1H, m), 1.06 dd, J = 12.0, 1.7 Hz), 0.88 (3H, s);
13C NMR (125 MHz, CDCl3) δ: 167.6, 160.0, 159.2, 135.0, 129.3, 125.2, 121.6, 115.3, 102.8, 52.0, 48.0, 42.0, 40.2, 37.0, 36.5, 36.3, 33.0, 27.8, 27.7, 23.2, 20.5, 17.62, 17.59; 13 C NMR (125 MHz, CDCl 3) δ: 167.6, 160.0, 159.2, 135.0, 129.3, 125.2, 121.6, 115.3, 102.8, 52.0, 48.0, 42.0, 40.2, 37.0, 36.5, 36.3, 33.0, 27.8, 27.7, 23.2, 20.5, 17.62, 17.59;
IR (KBr): 3341, 1686, 1601, 1426, 1287 cm-1;IR (KBr): 3341, 1686, 1601, 1426, 1287 cm < -1 & gt ;;
MS (ESI-TOF) m/z: 379 [M+Na]+;MS (ESI-TOF) m / z: 379 [M + Na] < + >;
HRMS (ESI-TOF) m/z: 379.2249 (Calcd for C23H32O3Na; Found: 379.2266).HRMS (ESI-TOF) m / z: 379.2249 (Calcd for C 23 H 32 O 3 Na; Found: 379.2266).
< 제조예 22> 메틸 3-[[( 1S,2R,4aR,8aR )-1,2,4a- 트리메틸 -5- 메틸리덴 -3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4,5-디히드록시벤조에이트의 수득 <Production Example 22> Methyl 3 - [[(1S, 2R , 4aR, 8aR) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro--2H- Naphthalen-1-yl] methyl] -4,5-dihydroxybenzoate
상기 제조예 21에서 전술한 바와 같은 방법으로 제조예 22의 화합물을 수득하였으며, 이의 물리화학적 성질은 다음과 같고, ‘methyl 3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4,5-dihydroxybenzoate’화합물로 판명되었다: The physicochemical properties of the compound of Preparation 22 were as described in Preparation Example 21, and the physicochemical properties thereof were as follows: ' methyl 3 - [[(1S, 2R, 4aR, 8aR) 5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -4,5-dihydroxybenzoate '
white solid;white solid;
[α]26 D +10.4 (c 0.19, CHCl3); [α] 26 D +10.4 (c 0.19, CHCl 3);
1H NMR (500 MHz, CDCl3) δ: 7.49 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 5.90 (2H, S), 4.41 (1H, s), 4.37 (1H, s), 3.87 (3H, s), 2.68 (1H, d, J = 14.3 Hz), 2.65 (1H, d, J = 14.3 Hz), 2.34 (1H, td, J = 13.7, 5.0 Hz), 2.09 (2H, d, J = 14.3 Hz), 1.93-1.91 (1H, m), 1.60-1.55 (1H, m), 1.47 (1H, dt, J = 11.6, 2.7 Hz), 1.43-1.35 (3H, m), 1.33-1.19 (2H, m), 1.06 (3H, s), 1.03(3H, d, J = 6.3 Hz), 0.96 (1H, d, J = 11.5 Hz), 0.88 (3H, s); 1 H NMR (500 MHz, CDCl 3) δ: 7.49 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 5.90 (2H, S), 4.41 (1H, s), Dd, J = 14.3 Hz), 2.34 (1H, d, J = 13.7, 5.0 Hz) M), 1.47 (1H, dt, J = 11.6, 2.7 Hz), 1.43-1.35 (1H, m), 2.09 (2H, d, J = 14.3 Hz), 1.93-1.91 3H, m), 1.33-1.19 (2H, m), 1.06 (3H, s), 1.03 (3H, d, J = 6.3 Hz), 0.96 );
13C NMR(125 MHz, CDCl3) δ: 167.7, 160.1, 148.7, 142.3, 127.4, 125.2, 13 C NMR (125 MHz, CDCl 3 )?: 167.7, 160.1, 148.7, 142.3, 127.4, 125.2,
120.3, 114.0, 102.8, 52.1, 48.0, 42.1, 40.2, 37.0, 36.5, 36.3, 33.0,120.3, 114.0, 102.8, 52.1, 48.0, 42.1, 40.2, 37.0, 36.5, 36.3, 33.0,
27.9, 27.7, 23.2, 20.6, 17.64, 17.59;27.9, 27.7, 23.2, 20.6, 17.64, 17.59;
IR (KBr): 3341, 1686, 1601, 1426, 1287 cm-1; IR (KBr): 3341, 1686, 1601, 1426, 1287 cm < -1 & gt ;;
MS (ESI-TOF) m/z: 395 [M+Na]+MS (ESI-TOF) m / z: 395 [M + Na] < + &
HRMS(ESI-TOF) m/z: 395.2198 (Calcd for C23H32O4Na; Found: 395.2214).HRMS (ESI-TOF) m / z: 395.2198 (Calcd for C 23 H 32 O 4 Na; Found: 395.2214).
< 제조예 23> (-)-( 1R,4aS,8aS )- 1β,2β,4β ,- 트리메틸 - 1α [(2',5'- 디메톡시페닐)메틸]-5-엑소-메틸렌-(3H)-1, 4,4a,5,6,7,8,8aα-옥타히드로나프탈렌의 제조 <Production Example 23> (-) - (1R , 4aS, 8aS) - 1β, 2β, 4β, - trimethyl - 1α [(2 ', 5'- dimethoxyphenyl) methyl] -5-exo-methylene-(3H ) -1, 4, 4a, 5,6,7,8,8a-octahydronaphthalene
7.5 mL의 benzene에 무수(anhydrous) 95% potassium tert.-butoxide (217 mg, 1.93 mmol)을 넣은 교반 현탁액을 제조하고, 여기에 657 mg(0.62 mmol)의 methyltriphenylphosphonium bromide를 첨가하였다. 이렇게 생성된 밝은 노란색의 용액에 30분간 열을 가고, 환류(reflux)하였다. 3 mL의 benzene에 212 mg(0.62 mmol)의 ketone (-)-(1R,4aS,8aS)-1β,2β,4aβ-Trimethyl-1α[(2',5'-dimethoyphenyl)methyl]-1,2,3,4,4a,5,6,7,8,8aα-decahydronaphthalen-5-one이 녹아있는 용액에 대하여 열을 가한 일리드(ylide) 용액을 점적(dropwise) 방식으로 첨가하였다. 22시간 동안 추가적인 열처리를 한 후에, 반응 혼합물을 식히고 10 mL의 ether 및 3 mL의 H2O를 순차적으로 넣어주어 빠르게 교반하며 희석하였다. 층 분리가 되었고, 유기상(organic phase)을 2 mL의 H2O 및 3 mL의 saturated brine으로 세척하였으며, 건조(MgSO4)하였다. 감압조건 하에서 농축한 결과 거의 무색의 오일(oil)이 수득되었으며, 이를 silica gel column (10×2.5 cm)을 이용한 chromatography로 분리하였고, 5% EtOAc(in hexane)으로 용리하여 제조예 23의 화합물(180 mg, 85%)을 수득하였다Anhydrous 95% potassium tert.-butoxide (217 mg, 1.93 mmol) in 7.5 mL of benzene was added to the stirred suspension, and 657 mg (0.62 mmol) of methyltriphenylphosphonium bromide was added thereto. The resulting light yellow solution was heated for 30 minutes and refluxed. To a solution of 212 mg (0.62 mmol) of ketone (-) - (1R, 4aS, 8aS) -1β, 2β, 4aβ-Trimethyl-1α [(2 ', 5'-dimethoxyphenyl) methyl] , 3,4,4a, 5,6,7,8,8aa-decahydronaphthalen-5-one was dissolved was added dropwise to the solution. After an additional heat treatment for 22 hours, the reaction mixture was cooled and 10 mL of ether and 3 mL of H 2 O were added sequentially, followed by rapid stirring and dilution. The layers were separated and the organic phase was washed with 2 mL of H 2 O and 3 mL of saturated brine and dried (MgSO 4 ). The filtrate was concentrated under reduced pressure to give an almost colorless oil which was isolated by chromatography on a silica gel column (10 x 2.5 cm) and eluted with 5% EtOAc (in hexane) to give the compound of Preparation 23 180 mg, 85%) was obtained
상기 수득된 제조예 23 화합물의 물리화학적 성질은 다음과 같으며, ‘(-)-(1R,4aS,8aS)-1β,2β,4β,-Trimethyl-1α[(2',5'-dimetho xyphenyl)methyl]-5-exo-methylene-(3H)-1, 4,4a,5,6,7,8,8aα-octahydronaphthalene’화합물로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 23 were as follows, and the physical and chemical properties of the obtained compound of Preparation Example 23 were as follows: (-) - (1R, 4aS, 8aS) -1β, 2β, 4β, -Trimethyl-1α [(2 ', 5'-dimetho xyphenyl ) methyl] -5-exo-methylene- (3H) -1,4,4a, 5,6,7,8,8aa-octahydronaphthalene '
[α]25 D -40.4° (c 0.5, CH2Cl2); [?] 25 D -40.4 (c 0.5, CH 2 Cl 2 );
mp 77-78; mp 77-78;
silica gel TLC Rf 0.70 (15% EtOAc in hexanes); silica gel TLC R f 0.70 (15% EtOAc in hexanes);
1H NMR (CDCl3) δ 0.86 (s, 3H), 1.01 (d, 3H, J=5.5 Hz), 1.07 (s, 3H), 1.15-1.65 (m, 7H), 1.70-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.20-2.45 (m,1H), 2.64 (AB q, 2H, J=14 Hz), 3.72 (s, 3H), 3.75 (s, 3H), 4.33-4.47 (m, 2H), 6.65-6.77 (m, 3H). 1 H NMR (CDCl 3 )? 0.86 (s, 3H), 1.01 (d, 3H, J = 5.5 Hz), 1.07 (s, 3H), 1.15-1.65 (m, 7H), 1.70-1.95 3H), 3.75 (s, 3H), 4.33-4.47 (m, 2H), 2.05-2.15 (m, 2 H), 6.65 - 6.77 (m, 3 H).
Anal Calcd for C23H34O2 : C, 80.65; H, 10.00. Found: C, 80.82; H, 10.04.Anal Calcd for C 23 H 34 O 2 : C, 80.65; H, 10.00. Found: C, 80.82; H, 10.04.
< 제조예 24> 2-[[( 1R,2S,4aS,8aS )-1,2, 4a,5 - 테트라메틸 -2,3,4,7,8,8a- 헥사히드로나프탈렌-1-일]메틸]벤젠-1,4-디올의 디메틸 에테르 제조 <Production Example 24> 2 - [[(1R , 2S, 4aS, 8aS) -1,2, 4a, 5 - tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] benzene-1,4-diol
11 mL의 EtOH 용액에 제조예 23의 화합물(108.5 mg, 0.317 mmol) 및 rhodium trichloride hydrate(16.7 mg, 0.06 mmol, 20 mol%)를 첨가하여 제조된 혼합물에 열을 가하여 환류(reflux)하였다. 20시간의 열처리 후, 반응 혼합물을 식히고 5 mL의 H2O 첨가하여 냉각(quench)하였다. 수상(aqueous phase)은 3번 CH2Cl2 10 mL portion으로 추가 추출되었고, 추출물을 한데 모아 건조(MgSO4) 및 농축하여 희미하게 색깔을 띄는 오일(oil)을 수득하였다. 잔여물(residue)을 silica gel(10% EtOAc in hexanes) plug로 정제하고, 농축하여 맑은 무색의 오일을 수득하였다. 그 후 고압조건에서 천천히 굳히는 과정을 통하여 제조예 24의 화합물을 수득하였다. 수득된 제조예 24 화합물의 물리화학적 성질은 다음과 같으며,‘Dimethyl Ether of 2-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]benzene-1,4-diol’화합물인 것으로 판명되었다: The compound prepared in Preparation 23 (108.5 mg, 0.317 mmol) and rhodium trichloride hydrate (16.7 mg, 0.06 mmol, 20 mol%) were added to an 11 mL EtOH solution and the mixture was refluxed with heat. After 20 hours of heat treatment, the reaction mixture was cooled and quenched by adding 5 mL of H 2 O. The aqueous phase was washed with 3 × CH 2 Cl 2 10 mL portions were further extracted and the combined extracts were dried (MgSO 4 ) and concentrated to give a faintly colored oil. The residue was purified with a plug of silica gel (10% EtOAc in hexanes) and concentrated to give a clear, colorless oil. The compound of Preparation 24 was then obtained by slow curing at high pressure. The physical and chemical properties of the obtained compound of Preparation 24 are as follows: Dimethyl Ether of 2 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl- 7,8,8a-hexahydronaphthalen-1-yl] methyl] benzene-1,4-diol 'compound:
[α]25 D +8.88° (c 0.18, CH2Cl2); [?] 25 D + 8.88 (c 0.18, CH 2 Cl 2 );
mp 63-68, mp 63-68,
silica gel TLC Rf 0.71 (15% EtOAc in hexanes), 0.37 (5% EtOAc in hexanes); silica gel TLC R f 0.71 (15% EtOAc in hexanes), 0.37 (5% EtOAc in hexanes);
1H NMR (CDCl3) δ 0.75-1.15 (m, 4H), 0.87 (s, 3H), 1.01 (s, 3H), 1.24-1.65 (m, 9H), 2.0-2.15 (br m, 3H), 2.70 (br s, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 5.15 (br s, 1H), 6.65-6.85 (m, 3H); 1 H NMR (CDCl 3 )? 0.75-1.15 (m, 4H), 0.87 (s, 3H) 2.70 (br s, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 5.15 (br s, 1H), 6.65 - 6.85 (m, 3H);
mass spectrum (chemical ionization, negative ion), m/z 341 (M-1)-.mass spectrum (chemical ionization, negative ion), m / z 341 (M-1) - .
< 제조예 25> 2-[[( 1R,2S,4aS,8aS )-1,2, 4a,5 - 테트라메틸 -2,3,4,7,8,8a- 헥사히드로나프탈렌-1-일]메틸]시클로헥사-2,5-디엔-1,4-디온의 수득 <Production Example 25> 2 - [[(1R , 2S, 4aS, 8aS) -1,2, 4a, 5 - tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] cyclohexa-2,5-diene-1,4-dione
3.5 mL의 THF에 상기 제조예 24의 화합물(70.0 mg, 0.204 mmol)을 넣은 교반 용액에 448 mg(0.82 mmol)의 ceric ammonium nitrate 용액(in 3.5 mL of H2O)을 점적(dropwise) 방식으로 처리하였다. 15분 후, 반응 혼합물을 3 mL saturated brine 및 10 mL ethyl ether로 연속하여 희석하였다. 층 분리가 되었고, 수상(aqueous phase) 분획은 3번 CH2Cl2 10mL portion으로 추가 추출과정을 거쳤다. 이렇게 추출한 용액을 한데 모아 건조(Na2SO4) 및 농축하고, silica gel column (15×2 cm)을 사용한 chromatography를 통해 정제하여 주황색의 오일(oil)을 수득하였다. 5% EtOAc(in hexane)로 용리하여 제조예 25(25 mg, 40%)의 화합물을 수득하였다. 수득된 화합물의 물리화학적 성질은 다음과 같으며, ‘2-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]cyclohexa-2,5-diene-1,4-dione’화합물로 판명되었다:To a stirred solution of the compound of Preparation 24 (70.0 mg, 0.204 mmol) in 3.5 mL of THF was added dropwise 448 mg (0.82 mmol) of ceric ammonium nitrate solution (3.5 mL of H 2 O) Respectively. After 15 min, the reaction mixture was successively diluted with 3 mL saturated brine and 10 mL ethyl ether. Layer separation, and the aqueous phase fraction was washed with 3 × CH 2 Cl 2 Additional extraction was done in 10 mL portions. The extracted solution was combined, dried (Na 2 SO 4 ), concentrated, and purified by chromatography using a silica gel column (15 × 2 cm) to obtain an orange oil. And eluted with 5% EtOAc (in hexane) to give the compound of Preparation 25 (25 mg, 40%). The physicochemical properties of the obtained compound are as follows: < 1 > - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl-2,3,4,7,8,8a- hexahydronaphthalen-1-yl] methyl] cyclohexa-2,5-diene-1,4-dione '
[α]25 D +21° (c 0.02, CH2Cl2); [?] 25 D + 21 (c 0.02, CH 2 Cl 2 );
silica gel TLC Rf 0.55 (15% EtOAc in hexanes); λmax (CH3OH) 292 nm; silica gel TLC R f 0.55 (15% EtOAc in hexanes); λmax (CH 3 OH) 292 nm ;
1H NMR (CDCl3) δ 0.80-2.15 (m, 5H), 0.85 (s, 3H), 0.93 (d, 3H, J=6.5 Hz), 1.00 (s, 3H), 1.53 (br s, 1H), 2.45-2.67 (AB q, 2H, J=13.5 Hz), 5.14 (br s, 1H), 6.51 (br s, 1H), 6.71 (m, 2H); 1 H NMR (CDCl 3) δ 0.80-2.15 (m, 5H), 0.85 (s, 3H), 0.93 (d, 3H, J = 6.5 Hz), 1.00 (s, 3H), 1.53 (br s, 1H) , 2.45-2.67 (AB q, 2H, J = 13.5 Hz), 5.14 (br s, 1H), 6.51 (br s, 1H), 6.71 (m, 2H);
mass spectrum (chemical ionization) m/z 312 (M+1)+ ; mass spectrum (electron impact), m/z 311.199 (C21H27O2 requires 311.201).mass spectrum (chemical ionization) m / z 312 (M + 1) +; mass spectrum (electron impact), m / z 311.199 (C 21 H 27 O 2 requires 311.201).
< 제조예 26> 2-[[( 1R,2S,4aS,8aS )-1,2, 4a,5 - 테트라메틸 -2,3,4,7,8,8a- 헥사히드로나프탈렌-1-일]메틸]벤젠-1,4-디올의 수득 <Production Example 26> 2 - [[(1R , 2S, 4aS, 8aS) -1,2, 4a, 5 - tetramethyl-hexamethylene -2,3,4,7,8,8a- Hi draw-1-yl ] Methyl] benzene-1,4-diol
상기 제조예 25의 화합물 25 mg(0.08 mmol)을 2 mL의 ethyl ether에 용해하고, 이러한 용액을 세게 교반하며 Na2S2O4용액(56 mg Na2S2O4 in 2 mL of H2O, 0.32 mol)을 점적(dropwise)방식으로 넣어주었다. 45분 후에, 반응 혼합물은 2 mL의 saturated brine과 10 mL의 ethyl ether로 희석하였다. 층 분리가 되었고, 수상(aqueous phase) 분획은 3번 ethyl ether 10 mL portion으로 추가 추출과정을 거쳤다. 이렇게 추출한 ether 용액을 한데 모아 건조(Na2SO4) 및 농축하고, silica gel column (18×1 cm)을 이용한 chromatography로 정제하여, 유성 잔류물(oily residue)을 수득하였다. 15% EtOAc(in hexane) 용액으로 용리하여, 맑은 무색의 오일을 수득하였으며, 이를 진공상태에서 굳혀, 제조예 26의 화합물(23 mg, 92%)을 수득하였다. 수득된 화합물의 물리화학적 성질은 다음과 같으며, ‘2-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]benzene-1,4-diol’화합물로 로 판명되었다25 mg (0.08 mmol) of the compound of Preparative Example 25 was dissolved in 2 mL of ethyl ether, and this solution was stirred vigorously and a Na 2 S 2 O 4 solution (56 mg Na 2 S 2 O 4 in 2 mL of H 2 O, 0.32 mol) was added dropwise. After 45 minutes, the reaction mixture was diluted with 2 mL of saturated brine and 10 mL of ethyl ether. Layer separation, and the aqueous phase fraction was eluted with
(+)-1: [α]25 D +22.0° (c 1.35, CDCl3); (+) - 1: [α ] 25 D + 22.0 ° (c 1.35, CDCl 3);
(-)-1: [α]25 D -19.5° (c 1.0, CKCl3); (-) - 1: [?] 25 D -19.5 (c 1.0, CKCl 3 );
mp 125-127 .;mp 125-127 .;
silica gel TLC Rf 0.10 (15% EtOAc in hexanes); λmax (DMSO) 305 nm; silica gel TLC R f 0.10 (15 % EtOAc in hexanes); ? max (DMSO) 305 nm;
1H NMR (CDCl3) δ 0.86 (s, 3H), 0.99 (d, 3H, J=8 Hz), 1.02 (s, 3H), 1.51 (br s, 3H), 1.2-1.65 (m, 7H), 1.9-2.15 (m, 3H), 2.54-2.70 (AB q, 2H, J=14 HZ), 4.38 (br s, 1H), 4.41 (br s, 1H), 5.14 (br s, 1H) and 6.59 (m, 3H); mass spectrum (chemical ionization), m/z 315 (M+1)+, 1 H NMR (CDCl 3) δ 0.86 (s, 3H), 0.99 (d, 3H, J = 8 Hz), 1.02 (s, 3H), 1.51 (br s, 3H), 1.2-1.65 (m, 7H) , 4.14 (br s, 1 H), 5.14 (br s, 1 H) and 6.59 (br s, (m, 3 H); mass spectrum (chemical ionization), m / z 315 (M + l) +,
mass spectrum (electron impact), m/z 314.225 (M)+ (C21H30O2 requires 314.225).mass spectrum (electron impact), m / z 314.225 (M) + (C 21 H 30
< 제조예 27> 2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-6-히드록시-3,4-디옥소시클로헥사-1,5-디엔-1-일]아미노]아세틱 에시드의 제조 <Production Example 27> 2 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl-hexyl -2,3,4,7,8,8a- four dihydro naphthalene -1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] acetic acid
EtOH(1 mL)용액에 제조예 10의 화합물(3.0 mg, 8.4 μmol)과 giycine (0.8 mg, 10 μmol)을 넣고, NaHC03(11 mg, 130 umol)의 존재 하에서 24시간 상온에서 저어주었다. 여과 및 증발과정을 거쳐 제조된 잔여물(residue)에 Cl8 reversed-phase HPLC (YMC-Pack AM-323, 1.0 x 25 cm; flow rate 2.5 mL/min; UV detection at 300 nm; eluent CH3CN/H20/CF3CO2H, 85: 15:O.l)을 수행하여, 제조예 27의 화합물(1.6 mg, 47%)을 수득하였다.(3.0 mg, 8.4 μmol) and garcine (0.8 mg, 10 μmol) were added to EtOH (1 mL), and the mixture was stirred at room temperature for 24 hours in the presence of NaHCO 3 (11 mg, 130 μmol). To the residue prepared by filtration and evaporation was added Cl8 reversed-phase HPLC (YMC-Pack AM-323, 1.0 x 25 cm; flow rate 2.5 mL / min; UV detection at 300 nm; eluent CH 3 CN /
상기 수득된 제조예 27 화합물의 물리화학적 성질은 다음과 같으며, ‘2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]acetic acid’ 화합물로 판명되었다;The physicochemical properties of the compound of Preparation Example 27 were as follows, and the physical and chemical properties of the obtained compound of Preparation 27 were as follows: < 1 > 4,7,8,8a-hexahydronaphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] acetic acid ';
mp. 156 - 158 ; mp. 156 - 158;
[α]20 D -71.7°(C 1.0, MeOH); [α] 20 D -71.7 ° ( C 1.0, MeOH);
IR (KBr) Vmax 3300, 1720, 1640, 1580, 1370, 1200 cm-l; IR (KBr)
UV(MeOH) λmax 317 (ε 11800) 및 488 nm (860); UV (MeOH) [lambda] max 317 ([epsilon] 11800) and 488 nm (860);
ELMS m/z (%) 401 (M+, 1). 385(l), 357(4). 343(3), 211(20), 191(25) 및 95(100); ELMS m / z (%) 401 (M < + >, 1). 385 (1), 357 (4). 343 (3), 211 (20), 191 (25), and 95 (100);
FABMS (positive) m/z 404 (M+2H+H)+; HRFABMS m/z 404.2461 (M+2H+H)+, calcd for C23H34N05, 404.2437; FABMS (positive) m / z 404 (M + 2H + H) < + >; HRFABMS m / z 404.2461 (M + 2H + H) + calcd for C 23 H 34 N 5 , 404.2437;
1H NMR (CD3OD)데이터는 하기 [표 16] 참조; 1 H NMR (CD 3 OD) data are as follows [Table 16];
13C NMR (CD3OD)데이터는 하기 [표 16] 참조. 13 C NMR (CD 3 OD) data are shown in Table 16 below.
[표 16][Table 16]
< 제조예 28> (2S)-2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-6-히드록시-3,4-디옥소시클로헥사-1,5-디엔-1-일]아미노]-3-히드록시프로파노익 에시드의 제조 <Production Example 28> (2S) -2 - [ [5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl - 2,3,4,7,8,8a- 1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] -3-hydroxypropanoic acid
EtOH(1 mL)용액에 제조예 10의 화합물(3.0 mg, 8.4 μmol) 및 L-serine (1.3 mg, 10 pmol)을 넣고, NaHC03(27 mg, 34 Mmol)의 존재 하에서 24시간 40에서 저어주었다. 여과 및 증발과정을 거쳐 제조된 잔여물(residue)에 Cl8 reversed-phase HPLC (YMC-Pack AM-323, 1.0 x 25 cm; flow rate 2.5 mL/min; UV detection at 300 nm; eluent CH3CN/H20/CF3CO2H, 85: 15:O.l)을 수행하여, 제조예 28의 화합물(1.7 mg, 46%)을 수득하였다. (3.0 mg, 8.4 μmol) and L-serine (1.3 mg, 10 pmol) were added to a solution of the compound of Example 10 in EtOH (1 mL) and stirred at 40 for 24 hours in the presence of NaHCO 3 gave. To the residue prepared by filtration and evaporation was added Cl8 reversed-phase HPLC (YMC-Pack AM-323, 1.0 x 25 cm; flow rate 2.5 mL / min; UV detection at 300 nm; eluent CH 3 CN / H 2 O / CF 3 CO 2 H, 85: 15: Ol) to give the compound of Preparation 28 (1.7 mg, 46%).
상기 수득된 제조예 28 화합물의 물리화학적 성질은 다음과 같으며, ‘(2S)-2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]-3-hydroxypropanoic acid’ 화합물로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 28 were as follows, and the physical and chemical properties of the obtained compound of Preparation 28 were as follows: (2S) -2 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5- 2, 3, 4, 7, 8, 8a-hexahydronaphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien- Proved to be:
*mp. 198-200; * mp. 198-200;
[α]17 D-71°(c0.73, EtOH); [α] 17 D -71 ° ( c0.73, EtOH);
IR (K Br) Vmax 3400, 1670, 1630, 1590, 1540, 1380, 1200 cm-1; IR (K Br)
UV (MeOH) λmax 321 (ε12100) 및 498 nm (920); UV (MeOH) [lambda] max 321 ([epsilon] 12100) and 498 nm (920);
FABMS (negative, diethanolamine matrix) m/z 432 (M+2H-H)-;FABMS (negative, diethanolamine matrix) m / z 432 (M + 2H-H) -;
HRFABMS m/z 432.2381 (M+2H-H)-, calcd for C24H34N06 432.2386;HRFABMS m / z 432.2381 (M + 2H-H) -, calcd for C 24 H 34 N0 6 432.2386;
1H NMR (DMSO-d6)데이터는 하기 [표 17] 참조; 1 H NMR (DMSO-d 6 ) data to reference [Table 17];
13C NMR (DMSO-d6)데이터는 하기 [표 17] 참조. 13 C NMR (DMSO-d 6 ) data to reference [Table 17].
[표 17][Table 17]
< 제조예 29> (2S)-2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-테트라메틸-2,3,4,7,8,8a-헥사히드로나프탈렌-1-일]메틸]-6-히드록시-3,4-디옥소시클로헥사-1,5-디엔-1-일]아미노]-3-히드록시부타노익 에시드의 제조 <Production Example 29> (2S) -2 - [ [5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5- tetramethyl - 2,3,4,7,8,8a- 1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl] amino] -3-hydroxybutanoic acid
EtOH(1 mL)용액에 제조예 10의 화합물(3.0 mg, 8.4μmol) 및 L-threonine (1.3 mg, 13 umol), 을 넣고, NaHC03(11 mg, 130 umol)의 존재 하에서 24시간 40에서 저어주었다. 여과 및 증발과정을 거쳐 제조된 잔여물(residue)에 Cl8 reversed-phase HPLC (YMC-Pack AM-323, 1.0 x 25 cm; flow rate 2.5 mL/min; UV detection at 300 nm; eluent CH3CN/H20/CF3CO2H, 85: 15:O.l)을 수행하여, 제조예 29의 화합물(1.3 mg, 35%)을 수득하였다. (3.0 mg, 8.4 μmol) and L-threonine (1.3 mg, 13 μmol) were added to a solution of the compound of
상기 수득된 제조예 29 화합물의 물리화학적 성질은 다음과 같으며, ‘(2S)-2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]-3-hydroxybutanoic acid’화합물로 판명되었다:The physicochemical properties of the obtained compound of Preparation Example 29 were as follows, and the physical and chemical properties of the obtained compound of Preparation 29 were as follows: (2S) -2 - [[5 - [[(1R, 2S, 4aS, 8aS) -1,2,4a, 5-tetramethyl- 2, 3, 4, 7, 8, 8a-hexahydronaphthalen-1-yl] methyl] -6-hydroxy-3,4-dioxocyclohexa-1,5-dien- Proved to be:
mp. 188-191; mp. 188-191;
[α]17 D -183° (c 1.0, EtOH); [α] 17 D -183 ° ( c 1.0, EtOH);
IR (K Br) Vmax 3400, 1670, 1630, 1590, 1540, 1380, 1200 cm-1; IR (K Br)
UV (MeOH) λmax 317 (ε 12600) 및 490nm(1000); UV (MeOH) [lambda] max 317 ([epsilon] 12600) and 490 nm (1000);
FABMS (negative, diethanolamine matrix) m/z 446 (M+2HH)-;FABMS (negative, diethanolamine matrix) m / z 446 (M + 2H) -;
HRFABMS m/z 446.2524 (M+2H-H)-, calcd for C25H36N06, 446.2906; HRFABMS m / z 446.2524 (M + 2H-H) -, Calcd for C25H36NO6, 446.2906;
1H NMR (DMSO-d6)데이터는 하기 [표 18] 참조; 1 H NMR (DMSO-d 6 ) data to reference [Table 18];
13C NMR (DMSO-d6)데이터는 하기 [표 18] 참조. 13 C NMR (DMSO-d 6 ) data are shown in Table 18 below.
[표 18][Table 18]
< 제조예 30> 18- 메톡시 -22,22-디메틸-16- [{(5R,8S,9R,10S) -5,8,9- 트리메틸 -4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17(2H)-온의 수득 <Production Example 30> 18-methoxy -22,22- dimethyl -16- [{(5R, 8S, 9R, 10S) -5,8,9- trimethyl-4-methylene-9-yl} methyl decahydronaphthalene ] Benzo [d] -oxazole-17 (2H) -one
Smenospongia aurea 및 Smenospongia cerebriformis를 균질화(homogenize)하고, Verongula rigida 와 함께 에탄올 용액에 넣어, 일주일동안 인큐베이션(incubation)하였다. 상기 세가지 해면의 혼합물에 대한 에탄올 추출물을 건조시킨 것(3.6 kg)을 silica gel VLC (36 kg, 14 (H) × 17.5 (D) cm) 수행하고, 단계적인 농도의 hexanes (100%), hexanes-acetone (80:20, 60:40, 50:50, 40:60, 20:80), acetone (100%), acetone-MeOH (80:20, 60:40, 50:50), MeOH (100%), MeOH-H2O (50:50), 및 H2O(100%)으로 용출시켜, 13개의 분획(Fr. 1~13)을 수득하였다. 분획 10(39.3 g)은 hexanes-acetone 혼합용액(95:5, 90:10, 85:15, 80:20), MeOH (100%), 및 MeOH-H2O(50:50)로 silica gel VLC (12 (H) × 17.5 (D) cm)를 이용하여 9개의 분획(Fr. 10-1 ~ 10-9)으로 추가 분획하였다. 분획 10-7(3.7 g)을 MeOH-H2O(85:15)의 등용매(isocratic condition) 조건에서 C18 MPLC (15.5 × 4 cm) 수행하여, 6개의 소분획 (Fr. 10-7-1 ~ 10-7-6)을 제조하였다. 분획 10-7-3(115.8 mg)을 MeOH-H2O(83:17)로 C18 HPLC (250 × 21.20 mm, 10μm) chromatography를 수행하고 3개의 분획(Fr. 10-7-3-1 ~ 10-7-3-3)을 제조하였다. 분획 10-7-3-2 (12.4 mg)은 MeOH-H2O(75:25)로 C18 HPLC (250 × 4.60 mm and 150 × 4.60 mm, 5 ㎛, connected in line)를 수행하여, 제조예 30의 화합물 및 이의 epimer 혼합물을 수득하였다. Smenospongia aurea and Smenospongia cerebriformis were homogenized and V erongula rigida in an ethanol solution, and incubated for one week. Drying of the ethanol extract (3.6 kg) against the mixture of the three sponges was carried out with silica gel VLC (36 kg, 14 (H) × 17.5 (D) cm) and stepwise concentrations of hexanes (100%), hexanes -acetone (80:20, 60:40, 50:50, 40:60, 20:80), acetone (100%), acetone-MeOH (80:20, 60:40, 50:50), MeOH %), MeOH-H 2 O (50:50), and H 2 O (100%) to give 13 fractions (Fr. 1-13). Fraction 10 (39.3 g) was dissolved in a mixture of hexanes-acetone (95: 5, 90:10, 85:15, 80:20), MeOH (100%), and MeOH-H 2 O (50:50) The fractions were further fractionated into nine fractions (Fr. 10-1 to 10-9) using VLC (12 (H) x 17.5 (D) cm). Fraction 10-7 (3.7 g) was subjected to C18 MPLC (15.5 x 4 cm) under isocratic conditions of MeOH-H 2 O (85:15) to give 6 small fractions (Fr. 10-7- 1 to 10-7-6). Fraction 10-7-3 (115.8 mg) was subjected to C18 HPLC (250 × 21.20 mm, 10 μm) chromatography with MeOH-H 2 O (83:17) and three fractions (Fr. 10-7-3-1- 10-7-3-3). The fraction 10-7-3-2 (12.4 mg) was subjected to C18 HPLC (250 x 4.60 mm and 150 x 4.60 mm, 5 m, connected in line) with MeOH-H2O (75:25) Compound and its epimer mixture.
상기 수득된 물질의 물리화학적 성질은 다음과 같았으며, ‘18-methoxy-22,22-dimethyl-16-[{(5R,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17(2H)-one’화합물로 판명되었다: The physicochemical properties of the obtained material were as follows: 18-methoxy-22,22-dimethyl-16 - [{(5R, 8S, 9R, 10S) -5,8,9-trimethyl-4-methylenedecahydronaphthalene -9-yl} methyl] benzo [d] -oxazol-17 (2H) -one '
yellow, amorphous solid; yellow, amorphous solid;
[α]25 D +21 (c0.1, MeOH); [α] 25 D +21 (c0.1 , MeOH);
UV (MeOH) λmax 297 nm; UV (MeOH) [lambda] max 297 nm;
lH NMR (150 MHz, CDCl3) 데이터는 하기 [표 19] 참조; l H NMR (150 MHz, CDCl 3) data to reference [Table 19];
13C NMR (150 MHz, CDCl3)데이터는 하기 [표 19] 참조. 13 C NMR (150 MHz, CDCl 3 ) data are shown in Table 19 below.
HRFABMS m/z 398.2696 [M + H]+ (calcd for C25H36NO3, 398.2695), 420.2509 [M + Na]+ (calcd for C25H35NO3Na, 420.2515). HRFABMS m / z 398.2696 [M + H] + (calcd for C 25 H 36
[표 19][Table 19]
< 제조예 31> 18- 메톡시 -22- 메틸 -16- [{(5S,8S,9R,10S) -5,8,9- 트리메틸 -4- 메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17-올의 수득 <Production Example 31> 18-methoxy-22-methyl -16- [{(5S, 8S, 9R, 10S) -5,8,9- trimethyl-4-methyl-9-yl} methyl alkylene decahydronaphthalene; Benzo [d] -oxazol-17-ol
상기 제조예 30의 과정 중, 분획10-7-3-3(9.7 mg)은 MeOH-H2O(78:22)로 C18 HPLC (250×4.60 mm 및 150×4.60 mm, 5 ㎛, connected in line)을 수행하고, 120분 동안의 MeOH-H2O 농도 변화 조건(80:20 100:0)에서 C18 HPLC (250 × 4.60 mm, 5 ㎛)를 수행하여, 제조예 31의 화합물(1.8 mg)을 수득하였다. In the course of Preparative Example 30, fraction 10-7-3-3 (9.7 mg) was purified by C18 HPLC (250 x 4.60 mm and 150 x 4.60 mm, 5 μm, connected in) with MeOH-H 2 O (78:22) C18 HPLC (250 × 4.60 mm, 5 μm) was carried out under the conditions of changing the MeOH-H 2 O concentration for 120 minutes (80:20 100: 0) to give the compound of Preparation 31 (1.8 mg ).
상기 수득된 화합물(제조예 31)의 물리화학적 성질은 다음과 같으며, ‘18-methoxy-22-methyl-16-[{(5S,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17-ol’ 화합물로 판명되었다The physicochemical properties of the obtained compound (Preparation 31) are as follows, and the physical properties of the compound are as follows: 18-methoxy-22-methyl-16 - [{(5S, 8S, 9R, 10S) -5,8,9- 4-methylenedecahydronaphthalen-9-yl} methyl] benzo [d] -oxazol-17-ol '
white, amorphous solid; white, amorphous solid;
[α]25 D -29 (c 0.1, MeOH); [α] 25 D -29 (c 0.1, MeOH);
UV (MeOH) λmax 295 nm; UV (MeOH) [lambda] max 295 nm;
lH NMR (150 MHz, CDCl3) 데이터는 하기 [표 20] 참조; l H NMR (150 MHz, CDCl 3) data to reference [Table 20];
13C NMR (150 MHz, CDCl3)데이터는 하기 [표 20] 참조. 13 C NMR see (150 MHz, CDCl 3) data to [Table 20].
HRFABMS m/z 384.2540 [M + H]+ (calcd for C24H34NO3, 384.2539),HRFABMS m / z 384.2540 [M + H] + (calcd for C 24 H 34 NO 3 , 384.2539),
406.2357[M + Na]+ (calcd for C24H33NO3Na, 406.2358).406.2357 [M + Na] + (calcd for C 24 H 33 NO 3 Na, 406.2358).
[표 20][Table 20]
< 제조예 32> 3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-(2-페닐에틸아미노)시클로헥사-3,5-디엔-1,2-디온의 수득 <Production Example 32> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro-naphthalene -2H- -1-yl] methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3,5-dien-1,2-dione
상기 제조예 30에서 전술한바와 같은 방법으로 Fr.10-7-1 내지 10-7-6의 소분획을 제조한 후, Fr.10-7-4(53 mg)에 대해 MeOH-H2O(87:13) 등용매 조건에서 C18HPLC(25 X 2.1 cm,10 ㎛)를 반복적으로 수행하여, 제조예 32의 화합물(tR = 113 min)을 수득하였다.After producing a predetermined fraction of Fr.10-7-1 to 10-7-6 in the same way as described above hanba in Preparative Example 30, for Fr.10-7-4 (53 mg) MeOH-H 2 O (T R = 113 min) was obtained by repeatedly performing C 18 HPLC (25 X 2.1 cm, 10 탆) under the isopropyl alcohol (87:13) isomerization conditions.
수득된 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione’화합물로 판명되었다;The physicochemical properties of the obtained compound are as follows: [3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- 8a-hexahydro-2H-naphthalen-1-yl] methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3,5-diene-1,2-dione;
C29H37NO3 C 29 H 37 NO 3
mp. : 168-170.mp. : 168-170.
SM m/e(%): 447 (7)s 257 (64). 191 (ll), 166 (59). 152 (25). 135 (16), 121 (23). 109 (23). 107 (20). 95 (100).SM m / e (%): 447 (7) s 257 (64). 191 (11), 166 (59). 152 (25). 135 (16), 121 (23). 109 (23). 107 (20). 95 (100).
m/e 166.0495. Calc. 166.0504 for C8H8N03; m/e 191.1795. calc. 191.1799 for C14H23; m/e 257.104, calc. 257.105 for C15H15NO3.m / e 166.0495. Calc. 166.0504 for C 8 H 8 NO 3 ; m / e 191.1795. calc. 191.1799 for C 14 H 23; m / e 257.104, calc. 257.105 for C 15 H 15 NO 3 .
IR (KBr) υcm-l: 3265,1600,1395. IR (KBr) υcm -l: 3265,1600,1395 .
1H NMR(CDCl3, 250 MHz) δ ppm: 6.47 (1H exch., s), 5.41 (lH, s), 4.45 (2H, br s). 3.43 (2H, q), 2.87 (2H, t), 2.52-2.51 (dd, AB syst., J= 14 및 2 Hz), 1.05 (3H, s), 0.98 (3H, d, J = 7.5 Hz), 0.84 (3H, s), 0.79 (1H. dd, J = 11.2 및 2 Hz); 1 H NMR (CDCl 3 , 250 MHz)? Ppm: 6.47 (1H ex., S), 5.41 (1H, s), 4.45 (2H, br s). 3H, d, J = 7.5 Hz), 3.43 (2H, q), 2.87 (2H, t), 2.52-2.51 (dd, AB syst., J = 14 and 2 Hz) , 0.84 (3H, s), 0.79 (1H, dd, J = 11.2 and 2 Hz);
13C NMR (ppm; CDCl3)데이터는 하기 [표 21] 참조. 13 C NMR; see (ppm CDCl 3) data to [Table 21].
[표 21][Table 21]
< 제조예 33> 3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-2-히드록시-5-메톡시시클로헥사-2,5-디엔-1,4-디온의 수득 <Production Example 33> 3 - [[(1R , 2S, 4aS, 8aS) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro-naphthalene -2H- -1-yl] methyl] -2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione
Smenospongia aurea , Smenospongia cerebriformis 및 Verongula rigida의 세 종류의 해면동물을 혼합한 후, 여기에 에탄올(98%)을 가하여 에탄올 추출물을 제조하였다. 상기 에탄올 추출물을 헥산, 아세톤, 메탄올, 물 등의 용매를 이용하여 실리카겔 칼럼으로 분리하여 총 13분획을 얻었고, 그 중 4, 5, 6 및 10분획을 농축한 후 이동상(메탄올 : 물 = 1:1~3:1)을 사용하여, C18 RP 충진제를 사용한 칼럼 크로마토그래피로 분리하여 순수한 화합물(제조예 33 화합물)을 얻었다. 화합물의 확인은 HPLC(Agilent Technologies 1260 infinity) 장치를 이용하였고 검출기는 자외부 흡광광도계(203 nm), 칼럼으로는 Bluespher AB2(150×2 ㎜)를 사용하였다. 이동상으로 물-메탄올(78:22), 유속 1㎖/min, 온도 40℃ 조건에서 진행하였으며 114분에서 해당 화합물의 피크가 검출되었다. Smenospongia aurea , Smenospongia cerebriformis And Verongula rigida were mixed with ethanol (98%) to prepare an ethanol extract. The ethanol extract was separated into a silica gel column using a solvent such as hexane, acetone, methanol and water to obtain a total of 13 fractions. The
수득된 화합물의 물리화학적 성질은 다음과 같으며, ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione’화합물로 판명되었다:The physicochemical properties of the obtained compound are as follows: [3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- 2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione '
Yellow Solid ;Yellow Solid;
C22H30O4 C 22 H 30 O 4
분자량 : 358.47 ;Molecular Weight: 358.47;
m.p. : 72.5 ;m.p. : 72.5;
IT-TOF/MS : m/z 381.1972[M+Na]+IT-TOF / MS: m / z 381.1972 [M + Na] +
1H-NMR (CDCl3, 600 MHz) : 2.08, 1.42 (each 1H, m, H2-1), 1.84, 1.16(each 1H, m, H2-2), 2.29, 2.05 (each 1H, ddd, J = 13.7, 8.6, 5.4, H2-3), 1.49,1.32 (each 1H, m, H2-6), 1.37 (2H, m, H2-7), 1.14 (1H, m, H-8), 0.74 (1H, d, J= 12.0, H-10), 4.43, 4.41 (each 1H, s, H2-11), 1.02 (3H, s, H3-12), 0.96 (3H,d, J = 6.4, H3-13), 0.82 (3H, s, H3-14), 2.51, 2.45 (each 1H, d, J = 13.7, H2-15), 5.83 (1H, s, H-19), 3.84 (3H, s, H3-22) ; 1 H-NMR (CDCl 3 , 600 MHz): 2.08, 1.42 (each 1H, m, H 2 -1), 1.84, 1.16 (each 1H, m, H 2 -2), 2.29, 2.05 , J = 13.7, 8.6, 5.4 , H 2 -3), 1.49,1.32 (each 1H, m, H 2 -6), 1.37 (2H, m, H 2 -7), 1.14 (1H, m, H- 8), 0.74 (1H, d , J = 12.0, H-10), 4.43, 4.41 (each 1H, s, H 2 -11), 1.02 (3H, s, H 3 -12), 0.96 (3H, d , J = 6.4, H 3 -13 ), 0.82 (3H, s, H 3 -14), 2.51, 2.45 (each 1H, d, J = 13.7, H 2 -15), 5.83 (1H, s, H- 19), 3.84 (3H, s , H 3 -22);
13C-NMR (CDCl3, 150 MHz) : 23.34 (C-1), 28.11 (C-2), 33.13 (C-3), 160.69 (C-4), 40.63 (C-5), 36.82 (C-6), 28.80 (C-7), 38.25 (C-8), 43.50 (C-9), 50.30 (C-10), 102.66 (C-11), 20.73 (C-12), 18.01 (C-13), 17.52 (C-14),32.52 (C-15), 117.49 (C-16), 153.49 (C-17), 182.51 (C-18), 102.17 (C-19), 161.90 (C-20), 182.20 (C-21), 57.01 (C-22). 13 C-NMR (CDCl 3, 150 MHz): 23.34 (C-1), 28.11 (C-2), 33.13 (C-3), 160.69 (C-4), 40.63 (C-5), 36.82 (C C-10), 102.66 (C-11), 20.73 (C-12), 18.01 (C- 13), 17.52 (C-14), 32.52 (C-15), 117.49 (C-16), 153.49 (C-17), 182.51 ), 182.20 (C-21), 57.01 (C-22).
< 제조예 34> 3-[[(1S,2R,4aR,8aR)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-5-에톡시-2-히드록시시클로헥사-2,5-디엔-1,4-디온의 제조 <Production Example 34> 3 - [[(1S , 2R, 4aR, 8aR) -1,2,4a- -trimethyl-5-methylidene - 3,4,6,7,8,8a- hexahydro-naphthalene -2H- -1-yl] methyl] -5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione
라운드 플라스크에 제조예 33의 화합물 400 ㎎을 20 ㎖의 에탄올로 용해하였다. 용해된 반응 혼액에 10.5 ㎖의 1M 수산화칼륨(KOH) 용액을 넣고 70에서 한 시간 교반하였다. 교반된 반응 혼액에 1M 염산 용액을 넣고 감압 농축 후 분별 깔때기에 옮겨 에틸아세테이트 및 증류수에 녹여 분액하였으며, 에틸아세테이트 층을 모아 황산마그네슘으로 탈수 후 여과하여 감압농축하여 농축액을 얻었다. 순수한 반응산물을 얻기 위해 상기 농축액을 이동상(n-헥산 : 에틸아세테이트 = 10:1)을 사용하여 실리카겔 칼럼 크로마토그래피로 분리하여 최종 화합물(제조예 34)을 얻었다.In a round flask, 400 mg of the compound of Preparation 33 was dissolved in 20 ml of ethanol. 10.5 ml of 1M potassium hydroxide (KOH) solution was added to the dissolved reaction mixture, and the mixture was stirred at 70 for one hour. 1M hydrochloric acid solution was added to the stirred reaction mixture, and the mixture was concentrated under reduced pressure. The residue was transferred to a separatory funnel and dissolved in ethyl acetate and distilled water. The ethyl acetate layer was collected and dehydrated with magnesium sulfate, filtered and concentrated under reduced pressure to obtain a concentrate. The concentrate was separated by silica gel column chromatography using a mobile phase (n-hexane: ethyl acetate = 10: 1) to obtain a pure reaction product to obtain the final compound (Preparation 34).
상기 최종 화합물(제조예 34)의 물리화학적 성질은 하기와 같으며.‘3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a- hexahydro-2H-naphthalen-1-yl]methyl]-5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione’화합물로 판명되었다;The physicochemical properties of the final compound (Preparation 34) are as follows. &Apos; 3 - [[(1S, 2R, 4aR, 8aR) -1,2,4a-trimethyl-5-methylidene- , 7,8,8a-hexahydro-2H-naphthalen-1-yl] methyl] -5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;
Yellow Semi-solid ;Yellow Semi-solid;
C23H32O4 ;C 23 H 32 O 4 ;
분자량 : 372.5 ;Molecular Weight: 372.5;
IT-TOF/MS : m/z 395.2146[M+Na]+;IT-TOF / MS: m / z 395.2146 [M + Na] < + >;
1H-NMR (CDCl3, 600 MHz) : 7.47 (1H, s), 5.83 (1H, s), 4.46, 4.44 (each 1H, s), 4.06 (2H, q, J = 7.2 Hz), 2.50 (2H, dd, J = 12, 6.0 Hz), 2.33 (1H, dt, J = 12, 6.0 Hz), 2.17-1.66 (4H, m), 1.49 (3H, t, J = 7.2 Hz), 1.46-1.09 (7H, m), 1.04 (3H, m), 0.98 (3H, d, J = 6 Hz), 0.84 (3H, s) ; 1 H-NMR (CDCl 3, 600 MHz): 7.47 (1H, s), 5.83 (1H, s), 4.46, 4.44 (each 1H, s), 4.06 (2H, q, J = 7.2 Hz), 2.50 ( (2H, d, J = 12, 6.0 Hz), 2.33 (1H, dt, J = 12,6.0 Hz), 2.17-1.66 (4H, m), 1.49 (7H, m), 1.04 (3H, m), 0.98 (3H, d, J = 6 Hz), 0.84 (3H, s);
13C-NMR (CDCl3, 150 MHz) : 182.68, 182.26, 161.19, 160.75, 153.35, 117.45, 102.63, 102.40, 66.10, 50.35, 43.45, 40.63, 38.29, 36.82, 33.14, 32.63, 28.79, 28.12, 23.32, 20.73, 18.46, 18.05, 13.97. 13 C-NMR (CDCl 3 , 150 MHz): 182.68, 161.19, 160.75, 153.35, 117.45, 102.63, 102.40, 66.10, 50.35, 43.45, 40.63, 38.29, 36.82, 33.14, 32.63, 28.79, 28.12, 23.32, 20.73, 18.46, 18.05, 13.97.
<실시예 1> ≪ Example 1 > Wnt/β-catenin 경로의 억제활성 평가Evaluation of inhibitory activity of Wnt / β-catenin pathway
제조된 화합물 들 중 구조적으로 대표성을 띠는 몇 가지 화합물에 대하여 Wnt/β-catenin을 억제하는지 여부를 확인하였다. Β-catenin was inhibited by some of the structurally representative compounds.
<1-1> <1-1> 제조예 30 및 31 화합물의 Wnt/β-catenin 경로의 억제활성Inhibitory activity of the Wnt / [beta] -catenin pathway of the compounds of Preparation Examples 30 and 31
HEK293 (human embryonic kidney cell) 및 Wnt3a-분비 L 세포는 ATCC(American Type 은 ATCC(American Type Culture Collection, USA)에서 구입하였으며, 10% FBS(fetal bovine serum), 120 ㎍/㎖ 페니실린 및 200 ㎍/㎖ 스트렙토마이신이 포함된 DMEM(Dulbecco’s modified Eagle’s medium)에서 배양하였다.HEK293 (human embryonic kidney cell) and Wnt3a-secreting L cells were purchased from ATCC (American Type Culture Collection, USA) and cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 120 ug / ml penicillin, Ml streptomycin in Dulbecco's modified Eagle's medium.
Wnt3a-CM(Wnt3a-conditioned medium)은 Wnt3a-분비 L 세포를 10%[v/v] FBS(fetal bovine serum)가 포함된 DMEM에서 4일간 배양한 후, 상기 배양된 DMEM 배지를 수거하여 0.22 ㎛ 필터로 멸균하여 준비하였다. 이 후, 세포에 새 DMEM(10%[v/v] FBS 포함) 배지를 첨가하여 3일간 추가 배양 하고 같은 방법으로 배지를 수거한 것을, 상기에서 수득한 Wnt3a-CM과 합쳐주었다. Wnt3a-CM medium (Wnt3a-CM medium) was prepared by culturing Wnt3a-secreting L cells in DMEM containing 10% [v / v] FBS (fetal bovine serum) for 4 days, collecting the cultured DMEM medium, Sterilized with a filter. Thereafter, fresh DMEM (containing 10% [v / v] FBS) medium was added to the cells, and the cells were further cultured for 3 days, and the medium was collected in the same manner as the Wnt3a-CM obtained above.
상기 Wnt3a-CM과, 각각 제조예 30의 화합물 또는 제조예 31의 화합물을 농도별(각각 10,20, 및 40 μM)로 15시간동안 HEK293세포에 처리하고, 상기 세포에서 세포질 단백질을 추출한 후, Wnt/β-카테닌 경로의 CRT(β-catenin response transcription)를 조절하는 세포 내 β-카테닌 양을 β-카테닌 항체(BD Transduction Laboratories, USA) 및 ECL 시스템(Santa Cruze Biotechnology)를 이용한 웨스턴 블롯으로 확인하였으며, 이를 [도 1]에 나타내었다.The Wnt3a-CM and the compound of Preparation Example 30 or the compound of Preparation Example 31 were treated with HEK293 cells for 15 hours at concentrations of 10, 20 and 40 μM, respectively, and the cytoplasmic proteins were extracted from the cells, Intracellular β-catenin levels that regulate CRT (β-catenin response transcription) in the Wnt / β-catenin pathway were confirmed by western blotting using β-catenin antibody (BD Transduction Laboratories, USA) and ECL system (Santa Cruze Biotechnology) , Which is shown in FIG.
웨스턴블롯 결과 [도 1]에서 보는 바와 같이, Wnt3a-CM이 처리된 세포에서 세포질 내 β-카테닌 발현이 증가하였으나, 본 발명의 제조예 30 화합물 또는 제조예 31 화합물의 처리를 통하여 β-카테닌 수준이 감소한 것을 확인하였다. As shown in FIG. 1, western blot results showed that intracellular β-catenin expression was increased in cells treated with Wnt3a-CM. However, by treating the compound of Preparation Example 30 or the preparation Example 31 of the present invention, .
<1-2> <1-2> 제조예 32 화합물의 Wnt/β-catenin 경로의 억제활성Production Example 32 Inhibitory Activity of Wnt /? -Catenin Pathway of Compound
상기 실시예 <1-1> 과 같은 방법으로 제조예 32 화합물의 Wnt/β-catenin 경로 억제활성을 평가하였다. 간략하게, 상기 Wnt3a-CM과, 제조예 32의 화합물을 농도별(각각 10 또는 20μM)로 15시간동안 HEK293세포에 처리하고, 상기 세포에서 세포질 단백질을 추출한 후, Wnt/β-카테닌 경로의 CRT(β-catenin response transcription)를 조절하는 세포 내 β-카테닌 양을 β-카테닌 항체(BD Transduction Laboratories, USA) 및 ECL 시스템(Santa Cruze Biotechnology)을 이용한 웨스턴 블롯으로 확인하였으며, 이를 [도 2]에 나타내었다.The Wnt / β-catenin pathway inhibitory activity of the compound of Preparation Example 32 was evaluated in the same manner as in Example <1-1>. Briefly, the Wnt3a-CM and the compound of Preparation Example 32 were treated with HEK293 cells for 15 hours at concentrations (10 or 20 μM, respectively), and the cytoplasmic proteins were extracted from the cells, and then the Wnt / (BD Transduction Laboratories, USA) and an ECL system (Santa Cruze Biotechnology) to determine the amount of intracellular [beta] -catenin that regulates [beta] -catenin response transcription. Respectively.
웨스턴블롯 결과 [도 2]에서 보는 바와 같이, Wnt3a-CM이 처리된 세포에서 세포질 내 β-카테닌 발현이 증가하였으나, 본 발명의 제조예 32 화합물의 처리를 통하여 β-카테닌 수준이 감소한 것을 확인하였다. As a result of Western blotting, as shown in FIG. 2, the cytoplasmic β-catenin expression was increased in the Wnt3a-CM treated cells, but the β -catenin level was decreased through the treatment of the compound of Preparation Example 32 of the present invention .
<1-3> <1-3> 제조예 33 및 34 화합물의 Wnt/β-catenin 경로의 억제활성Inhibitory activity of the Wnt / [beta] -catenin pathway of the compounds of Preparation Examples 33 and 34
ARPE-19세포(인간 망막상피세포)와 Wnt3a-분비 L 세포는 ATCC(American Type Culture Collection, USA)에서 구입하였으며, 10% FBS, 120 ㎍/㎖ 페니실린 및 200 ㎍/㎖ 스트렙토마이신이 포함된 DMEM(Dulbecco’s modified Eagle’s medium)에서 배양하였다. Wnt3a-CM(Wnt3a-conditioned medium)은 Wnt3a-분비 L 세포를 10%[v/v] FBS(fetal bovine serum)가 포함된 DMEM에서 4일간 배양한 후, 상기 배양된 DMEM 배지를 수거하여 0.22 ㎛ 필터로 멸균하여 준비하였다. 이 후, 세포에 새 DMEM(10%[v/v] FBS 포함)을 첨가하여 3일간 추가 배양 후, 다시 한번 Wnt3a-CM을 수득하였다. ARPE-19 cells (human retinal epithelial cells) and Wnt3a-secreting L cells were purchased from ATCC (American Type Culture Collection, USA) and cultured in DMEM supplemented with 10% FBS, 120 / / ml penicillin and 200 / / (Dulbecco's modified Eagle's medium). Wnt3a-CM medium (Wnt3a-CM medium) was prepared by culturing Wnt3a-secreting L cells in DMEM containing 10% [v / v] FBS (fetal bovine serum) for 4 days, collecting the cultured DMEM medium, Sterilized with a filter. Thereafter, new DMEM (containing 10% [v / v] FBS) was added to the cells, followed by further incubation for 3 days, and Wnt3a-CM was once again obtained.
상기 Wnt3a-CM과, 각각 제조예 33의 화합물 또는 제조예 34의 화합물(각각 3 및 6μM)이 24시간 처리된 ARPE-19 세포에서 세포질 단백질을 추출한 후, Wnt/β-카테닌 경로의 CRT(β-catenin response transcription)를 조절하는 세포 내 β-카테닌 양을 β-카테닌항체(BD Transduction Laboratories, USA) 및 ECL 시스템(Santa Cruze Biotechnology)를 이용한 웨스턴 블롯으로 확인하였으며, 이를 [도 3]에 나타내었다.The cytoplasmic proteins were extracted from ARPE-19 cells treated with Wnt3a-CM and the compound of Preparation Example 33 or the compound of Preparation 34 (3 and 6 μM, respectively) for 24 hours, and then the Wnt / -catenin response transcription) was confirmed by western blotting using a β-catenin antibody (BD Transduction Laboratories, USA) and an ECL system (Santa Cruze Biotechnology), which is shown in FIG. 3 .
[도 3]에서 보는 바와 같이, Wnt3a-CM이 처리된 세포에서 세포질 내 β-카테닌 발현이 증가하였으나, 본 발명의 제조예 33 화합물 또는 제조예 34 화합물의 처리를 통하여 β-카테닌 발현이 감소하여 상기 화합물이 인간망막상피세포에서 Wnt/β-카테닌 경로를 억제함을 확인하였다. 한편, 상기 제조예 33의 화합물을 분리해내기 위해 사용한 해면(sponge) 에탄올 추출물에서는 이러한 작용이 확인되지 않았다(데이터 미도시). As shown in FIG. 3, in the cells treated with Wnt3a-CM, cytoplasmic β-catenin expression was increased, but β-catenin expression was decreased through the treatment of the compound of Preparation Example 33 or the preparation Example 34 of the present invention It was confirmed that the compound inhibited the Wnt /? -Catenin pathway in human retinal epithelial cells. On the other hand, this effect was not confirmed in the sponge ethanol extract used for isolating the compound of Production Example 33 (data not shown).
<실시예 2> ≪ Example 2 > 안구 내 혈관 누수 억제 활성 평가Assessment of the inhibitory effect of intravenous vascular leakage
<2-1> 유리체강 내 투여≪ 2-1 >
상기 실시예 1에서 좋은 활성을 보였던 제조예 33의 화합물을 대상으로, 황반부종을 유발한 마우스 모델에서 황반변성 또는 황반부종의 원인이 되는 혈관누수에 대한 억제 작용이 있는지 여부를 확인하였다. 레이저를 조사하여 10주령 C57BL/6 마우스에 황반부종을 유발하였다. 케타민(ketamine, 70 mg/kg)과 자일라진(xylazine, 30 ㎎/kg)으로 마취하고, 1% 트로피카마이드(tropicamide)로 동공을 산대시켰다. 히드록시프로필 메틸셀룰로스(hydroxypropyl methycellulose)를 눈에 점안하고, 커버글라스(microscope cover glass)를 콘택트 렌즈(contact lens)로 사용하였다. 이후, 시신경유두 둘레의 혈관 사이사이 공간에 5개의 레이저 번(laser burns)을 만들었다(Zeiss 1149-630, laser power 180 mW, duration 0.1s, spot size 50 ㎛). 이 상태에서 형광안저혈관촬영(fluorescein angiography, FA) 및 빛 간섭단층촬영(optical coherence tomography, OCT)으로 혈관의 크기 및 투과성을 확인하였다. 레이저 조사 후 24시간 째에, 마우스 유리체강 내로, 대조군에는 DMSO(dimethyl sulfoxide) 0.5 ㎕를, 실험군에는 DMSO에 용해한 제조예 33 화합물 100 ng/0.5 ㎕를 주사하고 1주일 후 다시 형광안저혈관촬영 및 빛간섭단층촬영 검사를 수행하였고, 대조군과 화합물 처리군의 사진을 대조 촬영하여 [도 4]에 개시하였다.The compound of Production Example 33, which showed good activity in Example 1, was examined in the mouse model that induced macular edema to determine whether it inhibits vascular leakage which is a cause of macular degeneration or macular edema. Laser irradiation was used to induce macular edema in 10-week-old C57BL / 6 mice. Anesthesia was anesthetized with ketamine (70 mg / kg) and xylazine (30 mg / kg) and the pups were incubated with 1% tropicamide. Hydroxypropyl methycellulose was not visible, and microscope cover glass was used as a contact lens. Thereafter, five laser burns were made in the space between the blood vessels around the optic nipple (Zeiss 1149-630, laser power 180 mW, duration 0.1 s, spot size 50 μm). In this state, fluorescence angiography (FA) and optical coherence tomography (OCT) were used to confirm the size and permeability of the blood vessels. Twenty-four hours after the laser irradiation, 0.5 μl of DMSO (dimethyl sulfoxide) was injected into the mouse glass body cavity, 100 ng / 0.5 μl of the compound of Preparation Example 33 dissolved in DMSO in the experimental group, and fluorescein angiography Optical coherence tomography was performed, and photographs of the control group and the compound-treated group were contrast-photographed and shown in FIG.
[도 4]에서 보는 바와 같이 형광 안저 혈관 촬영과 빛 간섭 단층활영 검사 결과, 대조군(도 4의 A 및 B)과 비교하여 실험군(도 4의 C 및 D)의 황반변성 또는 황반부종의 원인이 되는 혈관누수가 명확히 감소한 것을 확인하였다. As shown in FIG. 4, the results of fluorescein angiography and optical coherence tomography showed that the cause of the macular degeneration or macular edema in the experimental group (C and D in FIG. 4) as compared with the control group (A and B in FIG. 4) The blood vessel leakage was clearly reduced.
<2-2> 복강투여<2-2> Peritoneal administration
C57BL/6 마우스에 황반부종을 유발하고 제조예33의 화합물을 복강투여 한 후, 막막 내 혈관 누수 여부를 확인하였다.The macular edema was induced in C57BL / 6 mice, and the compound of Preparation Example 33 was intraperitoneally administered, and then it was confirmed whether or not blood vessel leakage occurred in the membrane.
간략하게, 8~12 주령 C57BL/6 마우스를 Zoletil (40 mg/kg)과 xylazine (5 mg/kg) 복강으로 마취하고, 1% tropicamide로 동공을 산대시켰다. Hydroxypropyl methycellulose를 눈에 점안하고, microscope cover glass를 contact lens로 사용하였다. 시신경유두 둘레의 망막혈관 사이사이 공간에 3~5개의 laser burns을 만들었다(Zeiss 1149-630, laser power 200 mW, duration 0.05 s, spot size 50μm).Briefly, 8- to 12-week-old C57BL / 6 mice were anesthetized with Zoletil (40 mg / kg) and xylazine (5 mg / kg) peritoneal cavity and the pups were incubated with 1% tropicamide. Hydroxypropyl methycellulose was used as a contact lens and microscope cover glass was used as a contact lens. Three or five laser burns were made in the interocular spaces between the optic nipples (Zeiss 1149-630, laser power 200 mW, duration 0.05 s, spot size 50 μm).
레이저 조사 후, 대조군(도 5의 A)에는 Vehicle로서 증류수를 10 ml/kg, 실험군(도 5의 B)에는 제조예 33의 화합물을 1 mg/kg 용량(증류수에 녹임)으로 7일 동안 매일 복강 투여하였다. 6일 째 되는 날, 10% sodium fluorecein을 복강주입하여 빛간섭단층촬영을 수행하였다. After the laser irradiation, 10 ml / kg of distilled water was used as a vehicle in the control group (A in FIG. 5), and 7 mg / kg of the compound of Preparation Example 33 in the test group (B in FIG. 5) Lt; / RTI > On the 6th day, 10% sodium fluorecein was injected intraperitoneally to perform optical coherence tomography.
그 결과 [도 5]에서 보는 바와 같이, 본 발명의 화합물은 복강주사 시에도 황반변성 또는 황반부종의 원인이 되는 혈관누수를 억제한 것을 확인하였다. As a result, as shown in Fig. 5, it was confirmed that the compound of the present invention inhibited vascular leakage which causes macular degeneration or macular edema even during abdominal injection.
<실시예 3> ≪ Example 3 > 경구투여 후 After oral administration in vivoin vivo PK(Pharmacokinetics) PK (Pharmacokinetics)
Samtako Co. (Osan, Korea)로부터 수컷 ICR 마우스(8 weeks, 30-35 g)를 구입하였다. 구입한 실험동물은 1주일동안 다음과 같은 조건에서 안정화(acclimatize)되었다: 온도 23 ± 2℃, 상대습도 55 ± 10%, 조도(illumination intensity) 150-300 lux, 환기빈도 15-20 times/h 및 조명 주기(illumination cycle) 12h (07:00-19:00). 모든 동물실험은 Animal Care and Use Committee of Kyungpook National University (Study No. 2016-0043)의 승인을 받았다.Samtako Co. Male ICR mice (8 weeks, 30-35 g) were purchased from the National Institutes of Health (Osan, Korea). The purchased animals were acclimatized for one week under the following conditions: temperature 23 ± 2 ° C, relative humidity 55 ± 10%, illumination intensity 150-300 lux, ventilation frequency 15-20 times / h And an illumination cycle 12h (07: 00-19: 00). All animal studies were approved by the Animal Care and Use Committee of Kyungpook National University (Study No. 2016-0043).
약물을 투여하기 전 12h 동안 마우스들을 단식시켰다. 임의(ad libitum )로 먹이와 물을 공급하였다. 제조예33의 화합물을 DW:PEG400=60:40 (v/v)용액에 용해한 후 10 mg/kg dose를 경구 위관 영양법(oral gavage)으로 투여하였다. Mice were fasted for 12 h before drug administration. In any (ad libitum) they were fed food and water. The compound of Preparation Example 33 was dissolved in a solution of DW: PEG400 = 60: 40 (v / v) and then administered at a dose of 10 mg / kg by oral gavage.
상기 경구투여 0. 5h 및 2 h 후에, 복대동맥(abodominal artery)으로부터 혈액 샘플을 채취하였다. 상기 혈액샘플을 13,000 rpm에서 5분동안 원심분리한 후, 혈장 샘플 50 mL을 수득하였고, 분석에 사용 전까지 -80℃로 보관하였다. 눈(eye)샘플을 마우스로부터 수직하고, 9-fold saline을 이용하여 균질화하여, 10%의 세포분쇄액(homogenate)을 수득하였다. 분취액(aliquot) 50 mL을 수득하여 분석에 사용 전까지 -80℃로 보관하였다.Blood samples were taken from the abdominal artery after 0.5 h and 2 h of oral administration. The blood sample was centrifuged at 13,000 rpm for 5 minutes, then 50 mL of plasma sample was obtained and stored at -80 DEG C until use for analysis. An eye sample was taken from the mouse and homogenized using a 9-fold saline to obtain a 10% cell homogenate. 50 mL of aliquot was obtained and stored at -80 ° C until use for analysis.
0.5 ng/mL의 propranolol이 함유된 acetonitrile 용액 200 μL에 상기 분취액(aliquot)의 50 μL 혈장을 첨가하였다(internal standard). 10분동안 vortex mixing하고 13,000 rpm으로 10분동안 원심분리한 후, 상층액(supernatant)을 새 tube에 옮기고 nitrogen gas 하에서 증발시켰다. 잔여물(residue)를 150 μL의 이동상에 넣고, 5 μL의 분취액(aliquot)을 LC-MS/MS system에 직접적으로 주사하여 분석하였다.An aliquot of 50 μL plasma was added to 200 μL of an acetonitrile solution containing 0.5 ng / mL propranolol (internal standard). After vortexing for 10 min and centrifuging at 13,000 rpm for 10 min, the supernatant was transferred to a new tube and evaporated under nitrogen gas. The residue was placed in 150 μL of mobile phase and 5 μL aliquot was analyzed by direct injection into the LC-MS / MS system.
타겟 영역에서 본 발명의 화합물의 조직 분포를 조사하기 위하여, 10 mg/kg농도로 경구 투여후 혈장 및 눈(eye)에서의 화합물 농도를 측정하였다. 샘플링 시점인 0.5 h 및 2 h는 각각 peak plasma concentration과 distribution phase을 기초로하여 선택되었다. [도 6]에서 보는 바와 같이, 본 발명의 화합물(특히, 제조예 33의 화합물)은 타겟 조직에 높은 투과성을 나타내었고, 경구투여를 통해서도 눈(eye)에 높은 수준으로 타겟팅 되는 것을 확인하였다. 이러한 결과를 통해, 본 발명의 제조예 33의 화합물은 유리체강 내로 직접 약물을 투여하는 것 이외에도, 다른 투여경로(경구투여, 복강주사, 정맥주사 등)를 통해서도 치료적 효능을 보일 수 있음을 확인하였다. 즉, 시판되고 있는 안구 내 질환 관련 치료제들이 유리체강 내로 직접 투여해야하는 불편함과 이에 따른 고통 및 부작용이 있는 것에 반해, 본 발명의 화합물은 경구투여 가능한 것으로 확인되었다.To examine the tissue distribution of the compounds of the present invention in the target area, compound concentrations in plasma and eyes were measured after oral administration at a concentration of 10 mg / kg. The sampling times, 0.5 h and 2 h, were selected based on peak plasma concentration and distribution phase, respectively. As shown in FIG. 6, the compound of the present invention (particularly, the compound of Production Example 33) showed high permeability to the target tissue and it was confirmed that it was targeted to a high level in the eye through oral administration. From these results, it can be seen that the compound of Production Example 33 of the present invention shows therapeutic efficacy through other administration route (oral administration, intraperitoneal injection, intravenous injection, etc.) in addition to direct drug administration into the vitreous cavity Respectively. That is, it has been confirmed that the compound of the present invention is orally administrable, while the commercially available intraocular disease-related therapeutic agents are inconvenient to be directly administered into the vitreous cavity and thus suffer pain and side effects.
<실시예 4> <Example 4> 화합물 안전성 평가Compound safety evaluation
<4-1> 급성 독성 평가<4-1> Evaluation of acute toxicity
제조예 33의 화합물을 단기간에 과량을 섭취하였을 때, 급성적(24시간 이내)으로 동물체내에 미치는 독성을 조사하고, 치사율을 결정하기 위하여 본 실험을 수행하였다. 일반적인 마우스인 ICR 마우스 계통 20마리를 대조군과 실험군에 각각 10마리씩 배정하였다. 대조군에는 PEG-400:트윈-80:에탄올(8:1:1, v:v:v) 만을 투여하고, 실험군은 제조예 33의 화합물을 상기 PEG-400:트윈-80:에탄올(8:1:1, v:v:v)에 녹여 각각 경구투여하였다. 투여 24시간 후에 각각의 치사율을 조사한 결과, 대조군과 2g/㎏/day 농도의 제조예 33 화합물을 투여한 실험군에서 마우스가 모두 생존하는 것으로 확인되었다.This experiment was conducted to examine the toxicity of the compound of Preparation Example 33 to animals in an acute (within 24 hours) dose and to determine the mortality rate when an excessive amount of the compound of Preparation Example 33 was consumed in a short period of time. Twenty ICR mice were injected into each of the control and experimental groups. In the control group, only the PEG-400: Tween-80: ethanol (8: 1: 1, v: v: : 1, v: v: v). After 24 hours of administration, the respective mortality rates were examined. As a result, it was confirmed that mice were alive in the control group and in the experimental group administered with the compound of Preparation 33 at a concentration of 2 g / kg / day.
<4-2> 조직 독성 평가<4-2> Evaluation of tissue toxicity
장기 독성 실험은 제조예 33의 화합물을 각 농도로 8주 동안 C57BL/6J 마우스(각 군당 10마리)에 투여하여 실험하였다. 동물의 각 장기(조직)에 미치는 영향을 조사하기 위하여 제조예 33의 화합물을 투여한 실험군과 PEG-400:트윈-80:에탄올(8:1:1, v:v:v)만을 투여한 대조군의 동물들로부터 8주 후 혈액을 채취하여 GPT(glutamate-pyruvate transferase) 및 BUN(blood urea nitrogen)의 혈액 내 농도를 Select E(Vital Scientific NV, Netherland) 기기를 이용하여 측정하였다. 그 결과, 간독성과 관계있는 것으로 알려진 GPT와 신장 독성과 관계있는 것으로 알려진 BUN의 경우, 대조군과 비교하여 실험군은 별다른 차이를 보이지 않았다. 또한, 각 동물로부터 간과 신장을 절취하여 통상적인 조직 절편 제작과정을 거쳐 광학현미경으로 조직학적 관찰을 시행하였으며 모든 조직에 서 특이한 이상이 관찰되지 않았다.In the long-term toxicity test, the compound of Preparation Example 33 was administered to C57BL / 6J mice (10 mice per group) for 8 weeks at each concentration. In order to investigate the effect on the organs (tissues) of the animals, the test group to which the compound of Production Example 33 was administered and the control group which was administered only PEG-400: Tween-80: ethanol (8: 1: 1, v: v: Blood samples were collected from the animals at 8 weeks post-transfusion. Glutamate-pyruvate transferase (GPT) and blood urea nitrogen (BUN) concentrations were measured using Select E (Vital Scientific NV, Netherland). As a result, GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group. In addition, liver and kidney were cut from each animal and histological observation was performed with an optical microscope through a conventional tissue section production process. No abnormalities were observed in all tissues.
<제제예> <Formulation example> 약학적 제제의 제조Production of pharmaceutical preparations
<제제예 1> 정제의 제조≪ Formulation Example 1 > Preparation of tablets
본 발명의 화합물 200 g을 락토오스 175.9 g, 감자전분 180 g 및 콜로이드성 규산 32 g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160 g, 활석 50 g 및 스테아린산 마그네슘 5 g을 첨가해서 얻은 혼합물을 정제로 만들었다.200 g of the compound of the present invention were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
<제제예 2> 주사액의 제조≪ Formulation Example 2 > Preparation of injection solution
본 발명의 화합물 1 g, 염화나트륨 0.6 g 및 아스코르브산 0.1 g을 증류수에 용해시켜서 100 ㎖를 만들었다. 이 용액을 병에 넣고 20에서 30분간 가열하여 멸균시켰다.1 g of the compound of the present invention, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was placed in a bottle and sterilized by heating for 20 to 30 minutes.
이상 살펴본 바와 같이, 본 발명은 세스퀴테르펜 유도체의 신규한 용도에 관한 것으로, 더욱 상세하게는 본 발명의 화학식 1로 표시되는 세스퀴테르펜 유도체 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 안구 내 혈관 누수에 의한 황반변성 또는 황반부종의 예방, 개선 또는 치료용 조성물에 관한 것이다.As described above, the present invention relates to a novel use of a sesquiterpene derivative, and more particularly, to a novel use of a sesquiterpene derivative compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient Or preventing macular degeneration or macular edema due to intra-ocular blood vessel leakage.
본 발명의 화학식 1의 화합물은 안구 내, 특히 망막 내의 혈관 누수(leakage)를 억제하여, 황반부종 및 황반변성 등의 안구 내 혈관누수에 의한 질환에 대하여 치료 효과가 있다. 뿐만 아니라 시판되고 있는 안구 내 질환 관련 치료제들이 유리체강 내로 직접 투여해야 하는 불편함과 이에 따른 고통 및 부작용이 있는 것에 반해, 본 발명의 화합물은 유리체강 내 투여 이외의 다른 투여경로(경구투여, 복강주사 등)를 통해서도 타겟 조직(눈)에 분포하여, 투여경로에 구애받지 않고 치료효능을 가지므로 산업상 이용가능성이 높다.The compound of formula (I) of the present invention inhibits the leakage of blood into the eyeball, particularly the retina, and has a therapeutic effect against diseases caused by intraocular blood vessel leakage such as macular edema and macular degeneration. In addition, there are inconveniences that the commercially available intraocular diseases-related therapeutic agents must be directly administered into the vitreous cavity, and thus pain and side effects, the compounds of the present invention can be administered by other routes other than the intravesicular administration (oral administration, Injection, etc.) in the target tissues (eyes) and has therapeutic efficacy regardless of the route of administration.
Claims (6)
[화학식 1]
화학식 1에서,
점선은 단일결합 또는 이중결합을 나타내며
i) 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합이며, R2b는 존재하지 않고 R2a는 CH2인 구조이고,
R1은 H 또는 CH3이며,
R3은 하기 R3b 내지 R3d로 구성된 군에서 선택되는 어느 하나의 작용기이고,
상기 R3b는
R9가 에톡시기 및 R9a로 구성된 군에서 선택되는 어느 하나이고, R10은 H 또는 OH이며,
상기 R3c는
R11 및 R12는 각각 OH 또는 OCH3이며 R13은 CH3인 구조이며
상기 R3d는 R14가 OCH3이고, R15 및 R16은 CH3인 구조임.
A pharmaceutical composition for preventing or treating macular degeneration or macular edema comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
In formula (1)
The dotted line represents a single bond or a double bond
i) and 3 is a single bond combination of carbon and 4 bonds and 5-carbon and 6-carbon of carbon, R2b is not present and R2a is CH 2 structure,
R1 is H or CH 3,
R3 is any one functional group selected from the group consisting of the following R3b to R3d,
R3b is
R9 is any one selected from the group consisting of ethoxy groups and R9a, R10 is H or OH,
R3c is
R11 and R12 are OH or OCH 3, and each R13 is CH 3 and the structure
Wherein R3d is R14 is OCH 3, R15 and R16 being CH 3 or structure.
3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-(2-페닐에틸아미노)시클로헥사-3,5-디엔-1,2-디온;
3-[[(1S,2R,4aR,8aR)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-5-에톡시-2-히드록시시클로헥사-2,5-디엔-1,4-디온;
18-메톡시-22-메틸-16-[{(5S,8S,9R,10S)-5,8,9-트리메틸-4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17-올; 및
18-메톡시-22,22-디메틸-16-[{(5R,8S,9R,10S)-5,8,9-트리메틸-4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17(2H)-온;
으로 구성된 군에서 선택되는 어느 하나의 화합물인 것을 특징으로 하는 약학적 조성물.
The compound of claim 1, wherein the compound of formula (1)
3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3, 5-diene-1, 2-dione;
3 - [[(1S, 2R, 4aR, 8aR) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;
9-yl} methyl] benzo [d] oxazole-5-carboxylic acid (18S) Sol-17-ol; And
Methyl] benzo [d] thiophen-2-ylmethyl] -1,2,3,4-tetrahydro-naphthalen- -Oxazole-17 (2H) -one;
≪ / RTI > or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 1, wherein the composition is prepared in any one form selected from the group consisting of oral preparations, injections, eyedrops and ointments.
The pharmaceutical composition according to claim 1, wherein the macular degeneration or macular edema is caused by intra-ocular blood vessel leakage.
[화학식 1]
화학식 1에서,
점선은 단일결합 또는 이중결합을 나타내며
i) 3번 탄소와 4번 탄소의 결합 및 5번 탄소와 6번 탄소의 결합이 단일결합이며, R2b는 존재하지 않고 R2a는 CH2인 구조이고,
R1은 H 또는 CH3이며,
R3은 하기 R3b 내지 R3d로 구성된 군에서 선택되는 어느 하나의 작용기이고,
상기 R3b는
R9가 에톡시기 및 R9a로 구성된 군에서 선택되는 어느 하나이고, R10은 H 또는 OH이며,
상기 R3c는
R11 및 R12는 각각 OH 또는 OCH3이며 R13은 CH3인 구조이며
상기 R3d는 R14가 OCH3이고, R15 및 R16은 CH3인 구조임.
A food composition for the prevention or amelioration of macular degeneration or macular edema comprising, as an active ingredient, a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
In formula (1)
The dotted line represents a single bond or a double bond
i) and 3 is a single bond combination of carbon and 4 bonds and 5-carbon and 6-carbon of carbon, R2b is not present and R2a is CH 2 structure,
R1 is H or CH 3,
R3 is any one functional group selected from the group consisting of the following R3b to R3d,
R3b is
R9 is any one selected from the group consisting of ethoxy groups and R9a, R10 is H or OH,
R3c is
R11 and R12 are OH or OCH 3, and each R13 is CH 3 and the structure
Wherein R3d is R14 is OCH 3, R15 and R16 being CH 3 or structure.
3-[[(1R,2S,4aS,8aS)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-4-히드록시-5-(2-페닐에틸아미노)시클로헥사-3,5-디엔-1,2-디온;
3-[[(1S,2R,4aR,8aR)-1,2,4a-트리메틸-5-메틸리덴-3,4,6,7,8,8a-헥사히드로-2H-나프탈렌-1-일]메틸]-5-에톡시-2-히드록시시클로헥사-2,5-디엔-1,4-디온;
18-메톡시-22-메틸-16-[{(5S,8S,9R,10S)-5,8,9-트리메틸-4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17-올; 및
18-메톡시-22,22-디메틸-16-[{(5R,8S,9R,10S)-5,8,9-트리메틸-4-메틸렌데카히드로나프탈렌-9-일}메틸]벤조[d]-옥사졸-17(2H)-온;
으로 구성된 군에서 선택되는 어느 하나의 화합물인 것을 특징으로 하는 식품 조성물.The compound of claim 5, wherein the compound of formula (1)
3 - [[(1R, 2S, 4aS, 8aS) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -4-hydroxy-5- (2-phenylethylamino) cyclohexa-3, 5-diene-1, 2-dione;
3 - [[(1S, 2R, 4aR, 8aR) -1,2,4a-trimethyl-5-methylidene- 3,4,6,7,8,8a-hexahydro-2H-naphthalen- Methyl] -5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;
9-yl} methyl] benzo [d] oxazole-5-carboxylic acid (18S) Sol-17-ol; And
Methyl] benzo [d] thiophen-2-ylmethyl] -1,2,3,4-tetrahydro-naphthalen- -Oxazole-17 (2H) -one;
≪ RTI ID = 0.0 > 1, < / RTI >
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EP3482750A4 (en) * | 2016-07-07 | 2020-04-15 | Kookmin University Industry Academy Cooperation Foundation | Novel use of sesquiterpene derivative |
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EP3482750A4 (en) * | 2016-07-07 | 2020-04-15 | Kookmin University Industry Academy Cooperation Foundation | Novel use of sesquiterpene derivative |
US10918625B2 (en) | 2016-07-07 | 2021-02-16 | Kookmin University Industry Academy Cooperation Foundation | Use of sesquiterpene derivative |
KR20180138109A (en) | 2017-06-20 | 2018-12-28 | 한국식품연구원 | Composition for preventing, improving, alleviating or treating macular disease |
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