KR20230071841A - New Thiourea derivatives as RORα Activators, and pharmaceutical compositions comprising the same - Google Patents
New Thiourea derivatives as RORα Activators, and pharmaceutical compositions comprising the same Download PDFInfo
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Classifications
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
본 발명은 RORα의 활성자로서의 신규한 티오우레아 유도체 및 이를 포함하는 약학적 조성물에 관한 것으로, 본 발명에 따른 화합물은 RORα의 다양한 생체 내 기능을 통해 대사성 질환과 염증성 질환의 치료와 예방에 효과가 있을 것으로 기대되며, 특히 간 성상세포 활성 억제를 통한 간 섬유증을 포함하는 대사성 질환 예방 및 치료에 유용할 것으로 기대된다. The present invention relates to a novel thiourea derivative as an activator of RORα and a pharmaceutical composition containing the same, and the compound according to the present invention is effective in the treatment and prevention of metabolic and inflammatory diseases through various in vivo functions of RORα. It is expected to be useful in the prevention and treatment of metabolic diseases including liver fibrosis through inhibition of hepatic stellate cell activity.
Description
본 발명은 RORα의 활성자로서의 신규한 티오우레아 유도체 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to a novel thiourea derivative as an activator of RORα and a pharmaceutical composition containing the same.
RORα (또는 NR1F1, RORA, RZR로도 명명됨)는 스테로이드 호르몬 수용체 슈퍼패밀리의 하나로, 유전자 발현을 조절하는 전사 인자이다. RORα는 N-말단 트랜스활성화 도메인, DNA-결합 도메인 및 C-말단 리간드 결합 도메인으로 이루어져 있다. RORα는 타겟 유전자의 프로모터에 있는 ROR-결합 반응 엘리먼트 (RORE)에 결합하며, RORE는 헥사뉴클레오타이드 모티프(5'-AGGTCA-3')와 이 헥사뉴클레오타이드에 선행하는 6개 베이스페어의 A/T rich 서열을 포함한다. RORα는 리간드가 C-말단 리간드 결합 도메인에 결합함으로써 활성이 조절되며, 알려진 리간드로는 콜레스테롤과 콜레스테롤 유도체, 멜라토닌 및 thiazolidinedione의 하나인 CGP52608이 있다. 한편, 엑스-레이 결정 분석법에 의해 콜레스테롤 및 콜레스테롤 유도체들이 RORα의 리간드 결합 도메인에 결합하는 것이 밝혀졌으며, 멜라토닌 역시 RORα에 특이적으로 결합해 RORα를 매개한 유전자 활성 조절을 일으키며, CGP52608 또한 이러한 멜라토닌과 경쟁적으로 RORα에 결합하는 합성 리간드임이 보고되었다. RORα (also called NR1F1, RORA, RZR) is a member of the steroid hormone receptor superfamily and is a transcription factor that regulates gene expression. RORα consists of an N-terminal transactivation domain, a DNA-binding domain and a C-terminal ligand binding domain. RORα binds to the ROR-binding response element (RORE) in the promoter of the target gene, and RORE has a hexanucleotide motif (5'-AGGTCA-3') and the A/T rich of 6 base pairs preceding this hexanucleotide. contains sequence. The activity of RORα is regulated by the ligand binding to the C-terminal ligand binding domain, and known ligands include cholesterol and cholesterol derivatives, melatonin, and CGP52608, one of thiazolidinedione. On the other hand, X-ray crystallization analysis revealed that cholesterol and cholesterol derivatives bind to the ligand binding domain of RORα, and melatonin also specifically binds to RORα to cause RORα-mediated gene activity regulation. It has been reported that it is a synthetic ligand that competitively binds to RORα.
한편, 본 발명자 등은 thiazolidinedione계 화합물 CGP52608을 선도 물질로 1차 구조활성연구를 수행하여, RORα에 선택적으로 활성을 나타내는 thiourea계 JC1-40를 개발한 바 있다(특허문헌 1). JC1-40을 마우스에 투여하였을 때 AMPK 활성화를 통한 지질 축적 억제로 비알콜성 지방간이 억제되었으며 항산화, 항염증 효과 및 쿠퍼세포 M2 극성 활성화를 통한 비알콜성 지방간염 억제 효과가 나타났다. On the other hand, the present inventors have developed a thiourea-based JC1-40 that is selectively active against RORα by conducting a primary structural activity study using the thiazolidinedione-based compound CGP52608 as a lead material (Patent Document 1). When JC1-40 was administered to mice, non-alcoholic fatty liver was suppressed by inhibition of lipid accumulation through activation of AMPK, and anti-oxidation, anti-inflammatory effects, and anti-alcoholic steatohepatitis were shown through activation of Kupffer cell M2 polarity.
비알콜성 지방간질환은 단순 지방간에서부터 간경화로 진행될 수 있는 만성 간 질환 중의 하나이다. 비알콜성 지방간염과 간경화에서 나타나는 간 섬유증은 만성 간 손상으로 인한 세포 외 기질의 축적이 일어난 상태이다. 간 섬유증은 간경화로 이어져 간 관련 사망률을 증가시키고 간 이식이 필요한 주요 병리학적 상태인 간암으로 진행될 수 있다.Non-alcoholic fatty liver disease is one of the chronic liver diseases that can progress from simple fatty liver to cirrhosis. Liver fibrosis in non-alcoholic steatohepatitis and liver cirrhosis is a state in which extracellular matrix accumulation occurs due to chronic liver damage. Liver fibrosis can lead to cirrhosis and progress to liver cancer, a major pathological condition that increases liver-related mortality and requires liver transplantation.
RORα 결손 마우스는 고지질 식이를 하였을 때 α-SMA 및 TGFβ1과 같은 섬유화 마커의 증가된 발현과 함께 증가된 콜라겐 침착을 보였으며, 이는 RORα가 간 섬유증에 대한 억제 효과를 가지며 관련 질병에 응용될 가능성을 시사하였다.RORα deficient mice showed increased collagen deposition along with increased expression of fibrosis markers such as α-SMA and TGFβ1 when fed a high-fat diet, suggesting that RORα has an inhibitory effect on liver fibrosis and can be applied to related diseases. suggested.
이에, 본 발명자들은 RORα 전사활성 증진 효과가 특허문헌 1의 화합물보다 현저히 우수한 신규 화합물을 발굴하였을 뿐만 아니라, 대사성 질환 치료제의 후보물질을 개발하고자 예의 노력을 기하였다.Accordingly, the present inventors not only discovered a novel compound with significantly better RORα transcriptional activity enhancing effect than the compound of
이에 본 발명자들은 RORα 단백질에 직접 결합하여 전사활성을 증가시키는 신규 화합물들을 발견하여, 본 발명을 완성하였다.Accordingly, the present inventors discovered novel compounds that directly bind to RORα protein and increase transcriptional activity, thereby completing the present invention.
따라서 본 발명의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.Accordingly, an object of the present invention is to provide a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
X는 C1-C5인 알킬기, 벤질기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C3-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하고;X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
Y는 수소, 히드록시기, 할로겐, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 시클로알킬기, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고; Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
Z는 N, O, 또는 S이고; Z is N, O, or S;
R1 내지 R4는 각각 독립적으로 수소, C1-C5인 알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이며,R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
상기 X가 메틸기일 때, Y는 수소가 아니다.When the above X is a methyl group, Y is not hydrogen.
본 발명의 다른 목적은제 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 대사성 질환 또는 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic or inflammatory diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항염 조성물을 제공하는 것이다.Another object of the present invention is to provide an anti-inflammatory composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
상기 본 발명의 목적을 달성하기 위하여, 본 발명자들은 RORα의 전사활성을 증가시키는 화합물들을 발굴하고, 상기 RORα의 전사활성 촉진 효과에 기초하여 대사성 질환 치료 효과를 확인함에 따라, 본 발명을 완성하였다.In order to achieve the object of the present invention, the present inventors discovered compounds that increase the transcriptional activity of RORα, and confirmed the therapeutic effect of metabolic diseases based on the effect of promoting the transcriptional activity of RORα, thereby completing the present invention.
따라서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.Accordingly, the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
X는 C1-C5인 알킬기, 벤질기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C3-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하고;X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
Y는 수소, 히드록시기, 할로겐, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 시클로알킬기, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고; Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
Z는 N, O, 또는 S이고; Z is N, O, or S;
R1 내지 R4는 각각 독립적으로 수소, C1-C5인 알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이며,R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
상기 X가 메틸기일 때, Y는 수소가 아니다.When the above X is a methyl group, Y is not hydrogen.
본 발명의 일 구현예에서, 상기 R1 또는 R2가 치환 아릴기 또는 치환 헤테로아릴기인 경우, 방향족 환(aromatic ring)이 C1-C3인 알킬기, C1-C3인 알콕시기, 트리플루오로메틸기 또는 t-부틸기로 치환되는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, when R 1 or R 2 is a substituted aryl group or a substituted heteroaryl group, an aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, or a tree It may be substituted with a fluoromethyl group or a t-butyl group, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 R3와 R4는 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C6-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, R 3 and R 4 are bonded to each other to form a substituted or unsubstituted C 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 6 -C 20 heterocycloalkyl ring, or a substituted or unsubstituted C It may form a 6 -C 20 aryl ring or a substituted or unsubstituted C 3 -C 20 heteroaryl ring, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 Y가 치환 아릴기, 또는 치환 헤테로아릴기일 때 방향족 환(aromatic ring)이 C1-C3인 알킬기, C1-C3인 알콕시기, 트리플루오로메틸기 또는 t-부틸기로 치환되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, when Y is a substituted aryl group or a substituted heteroaryl group, the aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or It may be substituted with a t-butyl group, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 X는 C1-C4인 알킬기, 벤질기, 치환 또는 비치환 C6-C10 아릴기, 또는 치환 또는 비치환 C3-C10 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C10 헤테로아릴 고리를 형성하고;In another embodiment of the present invention, X is a C 1 -C 4 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted C 3 -C 10 heteroaryl group, or Z Combined with each other to form a substituted or unsubstituted C 3 -C 10 heteroaryl ring;
상기 Y는 수소, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고; Y is hydrogen, OR 1 , CO 2 R 2 , NR 3 R 4 , a substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 is a heteroaryl group;
상기 Z는 N, 또는 S이고; wherein Z is N or S;
상기 R1은 수소이고;wherein R 1 is hydrogen;
상기 R2는 수소 또는 t-부틸기이고;R 2 is hydrogen or a t-butyl group;
상기 R3 및 R4는 각각 독립적으로 수소, C1-C5인 알킬기인 것일 수 있으나, 이에 제한되는 것은 아니다.The R 3 and R 4 may each independently be hydrogen or a C 1 -C 5 alkyl group, but are not limited thereto.
본 발명의 다른 구현예에서, 상기 화학식 1로 표시되는 화합물은 하기 구조식을 가진 화합물로 이루어진 군으로부터 선택된 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of compounds having the following structural formula, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 화학식 1로 표시되는 화합물은 RORα 단백질의 활성화제일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the compound represented by Formula 1 may be an activator of RORα protein, but is not limited thereto.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 대사성 질환 또는 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating metabolic or inflammatory diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 구현예에서, 상기 대사성 질환은 인슐린 저항성 증후군, 간섬유증, 지방간, 지방간염, 간경화, 제2형 당뇨병, 고지혈증, 심혈관 질환, 및 동맥경화증으로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the metabolic disease may be one or more selected from the group consisting of insulin resistance syndrome, hepatic fibrosis, fatty liver, steatohepatitis, liver cirrhosis,
본 발명의 다른 구현예에서, 상기 대사성 질환은 대사성 간 질환일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the metabolic disease may be a metabolic liver disease, but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 대사성 질환은 지질 대사 관련 질환일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the metabolic disease may be a lipid metabolism-related disease, but is not limited thereto.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항염 조성물을 제공한다.In addition, the present invention provides an anti-inflammatory composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 구현예에서, 상기 화합물은 전염증성 사이토카인의 발현 또는 분비 저해, 또는 M2 대식세포의 상향 조절에 의해 염증을 억제하거나 감소시키는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the compound may inhibit or reduce inflammation by inhibiting the expression or secretion of pro-inflammatory cytokines or upregulating M2 macrophages, but is not limited thereto.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 약학적 조성물을 개체에 투여하는 단계를 포함하는, 대사성 질환 또는 염증성 질환을 예방 또는 치료하는 방법을 제공한다.In addition, the present invention provides a method for preventing or treating metabolic or inflammatory diseases, comprising administering to a subject a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 조성물의 대사성 질환 또는 염증성 질환의 예방 또는 치료 용도를 제공한다.In addition, the present invention provides a use of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating metabolic or inflammatory diseases.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 대사성 질환 또는 염증성 질환 치료용 약제를 제조하기 위한 용도를 제공한다.In addition, the present invention provides a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for preparing a drug for treating metabolic or inflammatory diseases.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 약학적 조성물을 개체에 투여하는 단계를 포함하는, 염증 억제 방법을 제공한다.In addition, the present invention provides a method for inhibiting inflammation, comprising administering to a subject a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 조성물의 항염 용도를 제공한다.In addition, the present invention provides an anti-inflammatory use of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 소염제를 제조하기 위한 용도를 제공한다.In addition, the present invention provides a use for preparing an anti-inflammatory agent of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명에 따른 화합물은 RORα의 다양한 생체내 기능을 통해 대사성 질환 또는 염증성 질환의 치료와 예방에 효과가 있을 것으로 기대되며, 특히 간 성상세포 활성 억제를 통한 간 섬유증을 포함하는 대사성 간 질환 예방 및 치료에 유용할 것으로 기대된다. The compound according to the present invention is expected to be effective in the treatment and prevention of metabolic or inflammatory diseases through various in vivo functions of RORα, and in particular, prevention and treatment of metabolic liver diseases including liver fibrosis through inhibition of hepatic stellate cell activity. is expected to be useful for
도 1은 RORα 활성자 후보물질로서 합성된 신규화합물들의 화학 구조식을 나타낸 것이다.
도 2는 신규화합물들이 RORα의 전사활성에 미치는 효과를 나타낸 것이다.
도 3은 ODH-08의 농도에 따른 RORα 전사 활성 변화를 나타낸 것이다.
도 4는 ODH-08의 RORα와의 결합 예상 부위를 도킹 시뮬레이션 분석을 통해 나타낸 것이다.
도 5는 ODH-08의 농도에 따른 RORα와의 결합력을 플라스몬 공명 실험을 통해 나타낸 것이다.
도 6a 및 도 6b는 ODH-08의 RORα 전사활성 조절의 선택성을 루시퍼라제 활성 분석을 통해 나타낸 것이다.
도 7a 및 도 7b는 ODH-08가 간세포의 지질 축적에 미치는 효과를 확인하기 위하여 나일레드 염색 및 중성지방(트리글리세라이드, triglyceride) 정량화 수행 결과를 나타낸 것이다.
도 8a 및 도 8b는 ODH-08가 쿠퍼세포의 극성 조절에 미치는 효과를 RT-PCR 분석을 통해 나타낸 것이다.
도 9a 및 도 9b는 ODH-08가 간 성상세포주에서 섬유화 유전자 발현에 미치는 효과를 나타낸 것이다. 도 9a는 웨스턴 블롯팅 분석을 통해 Pro-COL1A1, α-SMA 단백질의 발현을 확인한 것이고, 도 9b는 RT-PCR 분석을 통해 α-SMA, COL1A1, TGFβ1의 mRNA의 발현을 확인한 결과이다.
도 10a 및 도 10b는 ODH-08가 간 성상세포주에서 SMAD 전사활성에 미치는 효과를 확인하기 위하여 루시퍼라제 활성 분석을 수행한 결과를 나타낸 것이다.
도 11a 및 도 11b는 ODH-08의 서양식 식이 유도 간 섬유화 동물 모델에서의 간 손상 억제 효과를 나타낸 것이다. 도 11a는 간 무게를 측정한 결과이며, 도 11b는 혈중 AST 및 ALT 농도를 측정한 결과를 나타낸 것이다.
도 12a 내지 도 12d는 ODH-08의 서양식 식이 유도 간 섬유화 동물 모델에서의 섬유화 억제 효과를 나타낸 것이다. 도 12a는 H&E 염색 결과를 나타낸 것이고, 도 12b는 시리우스 레드 염색 결과를 나타낸 것이고, 도 12c는 웨스턴 블롯팅 분석을 통해 Pro-COL1A1, α-SMA 단백질의 발현을 확인한 것이고, 도 12d는 RT-PCR 분석을 통해 α-SMA, COL1A1, COL1A2, COL3A1, MMP2, TIMP1의 mRNA의 발현을 확인한 결과이다.1 shows the chemical structural formulas of novel compounds synthesized as RORα activator candidates.
Figure 2 shows the effect of the new compounds on the transcriptional activity of RORα.
Figure 3 shows the change in RORa transcriptional activity according to the concentration of ODH-08.
Figure 4 shows the expected binding site of ODH-08 with RORα through docking simulation analysis.
Figure 5 shows the binding force with RORα according to the concentration of ODH-08 through a plasmon resonance experiment.
6a and 6b show the selectivity of ODH-08 for regulating RORa transcriptional activity through luciferase activity assay.
7a and 7b show the results of Nile Red staining and neutral fat (triglyceride) quantification in order to confirm the effect of ODH-08 on lipid accumulation in hepatocytes.
8a and 8b show the effect of ODH-08 on the polarity regulation of Kupffer cells through RT-PCR analysis.
9a and 9b show the effect of ODH-08 on fibrosis gene expression in hepatic stellate cell lines. 9a shows the expression of Pro-COL1A1 and α-SMA proteins through Western blotting analysis, and FIG. 9B shows the mRNA expression of α-SMA, COL1A1 and TGFβ1 through RT-PCR analysis.
10a and 10b show the results of luciferase activity assay to confirm the effect of ODH-08 on SMAD transcriptional activity in hepatic stellate cell lines.
11a and 11b show the effect of ODH-08 on inhibiting liver damage in an animal model of liver fibrosis induced by a Western-style diet. 11a is a result of measuring liver weight, and FIG. 11b is a result of measuring AST and ALT concentrations in blood.
12a to 12d show the effect of ODH-08 on inhibiting fibrosis in an animal model of liver fibrosis induced by a Western diet. Figure 12a shows the results of H&E staining, Figure 12b shows the results of Sirius red staining, Figure 12c shows the expression of Pro-COL1A1 and α-SMA proteins through Western blotting analysis, and Figure 12d shows RT-PCR. This is the result of confirming the mRNA expression of α-SMA, COL1A1, COL1A2, COL3A1, MMP2, and TIMP1 through analysis.
상기 본 발명의 목적을 달성하기 위하여, 본 발명자들은 기존 티오우레아 유도체와 비교하여 RORα 활성화 효과가 뛰어난 화합물들을 발견하여, 본 발명을 완성하였다.In order to achieve the object of the present invention, the present inventors have found compounds with excellent RORα activating effect compared to existing thiourea derivatives, and completed the present invention.
따라서 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염에 관한 것이다.Accordingly, the present invention relates to a compound represented by
[화학식 1][Formula 1]
상기 화학식 1에서,In
X는 C1-C5인 알킬기, 벤질기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C3-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하고;X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
Y는 수소, 히드록시기, 할로겐, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 시클로알킬기, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고; Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
Z는 N, O, 또는 S이고; Z is N, O, or S;
R1 내지 R4는 각각 독립적으로 수소, C1-C5인 알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이며,R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
상기 X가 메틸기일 때, Y는 수소가 아니다.When the above X is a methyl group, Y is not hydrogen.
상기 화학식 1로 표시되는 화학식을 갖는 화합물은 본 발명자에 의하여 처음으로 규명된 것으로서, 이는 본 발명의 명세서 실시예에 잘 나타나 있다.The compound having the formula represented by
본 발명에서 사용된 용어 “C1-C5 알킬”은 탄소원자수 1 내지 5, 또는 2 내지 5의 1가 알킬기를 의미한다. 이 용어는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, tert-부틸 등과 같은 기능기를 예로 들 수 있다. 본 발명에 기재된 알킬, 및 그 외 알킬 부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함한다. 치환된 알킬은 수소원자 중 하나 이상의 수소원자가 다른 치환기로 치환된 것을 의미하는 것으로, 치환기는 제한되지는 않으나, 할로겐, N, O, S 등을 포함한다. The term “C 1 -C 5 alkyl” as used herein refers to a monovalent alkyl group having 1 to 5 carbon atoms or 2 to 5 carbon atoms. This term is exemplified by functional groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl and the like. Alkyl and substituents containing other alkyl moieties described in the present invention include both straight-chain and branched forms. Substituted alkyl means that one or more hydrogen atoms among hydrogen atoms are substituted with another substituent, and the substituent includes, but is not limited to, halogen, N, O, S, and the like.
본 발명에서 사용된 용어 “할로겐”은 플루오로(F), 클로로(Cl), 및 브로모(Br), 요오드(I) 를 포함할 수 있다.The term “halogen” used in the present invention may include fluoro (F), chloro (Cl), bromo (Br), and iodine (I).
본 발명에서 사용된 용어 “C1-C3 알콕시”는 -O-R기를 의미하며, 여기서 R은 "C1-C3 알킬"을 의미한다. 바람직한 알콕시기는 예를 들면, 메톡시, 에톡시, 2-메톡시에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시 등을 포함한다.As used herein, the term “C 1 -C 3 alkoxy” means a group —OR, where R means “C 1 -C 3 alkyl”. Preferred alkoxy groups include, for example, methoxy, ethoxy, 2-methoxyethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and the like.
본 발명에서 사용된 용어 "C6-C20 아릴"은 단일링(예를 들면 페닐) 또는 복수의 축합링(예를 들면 나프틸)을 갖는 탄소원자수 6 내지 20의 불포화 방향족 고리화합물을 의미한다. 상기 아릴은 페닐, 나프틸, 비페닐, 터페닐, 안트릴, 인데닐, 플루오레닐, 페난트릴, 트라이페닐레닐, 피렌일, 페릴렌일, 크라이세닐, 나프타세닐, 및 플루오란텐일로 이루어지는 군으로부터 선택될 수 있다.As used herein, the term "C 6 -C 20 aryl" refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg phenyl) or a plurality of condensed rings (eg naphthyl). . The aryl is a group consisting of phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenenyl, chrysenyl, naphthacenyl, and fluoranthenyl can be selected from.
본 발명에서 사용된 용어 “C3-C20 헤테로아릴”은 S, O 및 N으로부터 선택되는 1 내지 3개의 이종원자를 포함하는 아릴기로서, 다이옥솔일, 피리미딜, 퓨라닐, 퓨릴, 티오펜일, 피롤릴, 피란일, 이미다졸릴, 피라졸릴, 티아졸릴, 티아디아졸릴, 이소티아졸릴, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 트리아진일, 테트라진일, 트리아졸릴, 테트라졸릴, 퓨라잔일, 피리딜, 피라진일, 피리미딘일, 피리다진일 등의 단환 헤테로아릴; 및 벤조퓨란일, 벤조티오펜일, 이소벤조퓨란일, 벤조이미다졸릴, 벤조티아졸릴, 벤조이소티아졸릴, 벤조이속사졸릴, 벤조옥사졸릴, 이소인돌릴, 인돌릴, 인다졸릴, 벤조티아디아졸릴, 퀴놀릴, 이소퀴놀릴, 신놀리닐, 퀴나졸리닐, 퀴놀리진일, 퀴녹살리닐, 카바졸릴, 페난트리딘일, 벤조디옥솔릴 등의 다환식 헤테로아릴로 이루어지는 군으로부터 선택될 수 있으나, 이에 제한되지 않는다.As used herein, the term “C 3 -C 20 heteroaryl” refers to an aryl group containing 1 to 3 heteroatoms selected from S, O and N, and includes dioxolyl, pyrimidyl, furanyl, furyl, and thiophenyl. , pyrrolyl, pyranyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furazanyl , monocyclic heteroaryl such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and benzofuranyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, isoindolyl, indolyl, indazolyl, benzothiadia It may be selected from the group consisting of polycyclic heteroaryls such as zolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinolizinyl, quinoxalinyl, carbazolyl, phenanthridinyl, and benzodioxolyl, Not limited to this.
본 발명에서 사용된 용어 “C3-C20 시클로알킬 고리”는 3 내지 20개의 탄소 원자의 완전히 포화 또는 부분적으로 불포화된 탄화수소 고리로부터 유도된 유리 라디칼을 의미하며, 아릴 또는 헤테로아릴이 융합되어 있는 경우도 포함하며, "헤테로시클로알킬"은 B, N, O, S, Se, -P(=O)-, -C(=O)-, Si 및 P 등으로부터 선택된 하나 이상의 헤테로원자를 포함하는 3 내지 20개의 고리원자를 포함하는 일환상 또는 다환상 비방향족 고리로부터 유도된 유리 라디칼을 의미한다.As used herein, the term "C 3 -C 20 cycloalkyl ring" refers to a free radical derived from a fully saturated or partially unsaturated hydrocarbon ring of 3 to 20 carbon atoms, aryl or heteroaryl fused Including cases, "heterocycloalkyl" includes one or more heteroatoms selected from B, N, O, S, Se, -P(=O)-, -C(=O)-, Si and P, etc. It means a free radical derived from a monocyclic or polycyclic non-aromatic ring containing 3 to 20 ring atoms.
본 발명에서 사용된 용어 "치환"은 다르게 명시되지 않으면, 적어도 하나의 치환체, 예를 들어, 할로겐 원자, 니트로, 히드록시, 시아노, 아미노, 티올, 카르복실, 아미드, 니트릴, 설파이드, 디설파이드, 술페닐, 포르밀, 포르밀옥시 또는 포르밀아미노를 하나 또는 둘 이상 포함하는 것을 의미한다. 달리 명시하지 않는 한, 이러한 치환에 의해 얻어진 구조가 본 발명의 화학식 1로 표시되는 화합물의 성질(특히, 본 발명에서 목적하는 용도와 관련된 활성)에 현저하게 악영향을 미치지 않는 경우에, 본 발명의 화학식 1로 표시되는 화합물에 대해 기술된 임의기 또는 구조가 치환될 수 있다.As used herein, the term "substitution", unless otherwise specified, includes at least one substituent such as a halogen atom, nitro, hydroxy, cyano, amino, thiol, carboxyl, amide, nitrile, sulfide, disulfide, one or more than one of sulfenyl, formyl, formyloxy or formylamino. Unless otherwise specified, in the case where the structure obtained by such substitution does not significantly adversely affect the properties of the compound represented by
본 발명에서, 상기 R1 또는 R2가 치환 아릴기 또는 치환 헤테로아릴기인 경우, 방향족 환(aromatic ring)이 C1-C3인 알킬기, C1-C3인 알콕시기, 트리플루오로메틸기 또는 t-부틸기로 치환되는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when R 1 or R 2 is a substituted aryl group or a substituted heteroaryl group, an aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or It may be substituted with a t-butyl group, but is not limited thereto.
본 발명에서, 상기 상기 R3와 R4는 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C6-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the R 3 and R 4 are bonded to each other to form a substituted or unsubstituted C 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 6 -C 20 heterocycloalkyl ring, or a substituted or unsubstituted C 6 -C It may form a 20 aryl ring or a substituted or unsubstituted C 3 -C 20 heteroaryl ring, but is not limited thereto.
본 발명에서, Y가 치환 아릴기, 또는 치환 헤테로아릴기일 때 방향족 환(aromatic ring)이 C1-C3인 알킬기, C1-C3인 알콕시기, 트리플루오로메틸기 또는 t-부틸기로 치환되는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when Y is a substituted aryl group or a substituted heteroaryl group, the aromatic ring is substituted with a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or a t-butyl group It may be, but is not limited thereto.
본 발명에서, 상기 X는 C2-C4인 알킬기, 벤질기, 치환 또는 비치환 C6-C10 아릴기, 또는 치환 또는 비치환 C3-C10 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C10 헤테로아릴 고리를 형성하고;In the present invention, X is a C 2 -C 4 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted C 3 -C 10 heteroaryl group, or combined with Z form a substituted or unsubstituted C 3 -C 10 heteroaryl ring;
상기 Y는 수소, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고; Y is hydrogen, OR 1 , CO 2 R 2 , NR 3 R 4 , a substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 is a heteroaryl group;
상기 Z는 N, 또는 S이고; wherein Z is N or S;
상기 R1은 수소이고;wherein R 1 is hydrogen;
상기 R2는 수소 또는 t-부틸기이고;R 2 is hydrogen or a t-butyl group;
상기 R3 및 R4는 각각 독립적으로 수소, C1-C5인 알킬기인 것일 수 있으나, 이에 제한되는 것은 아니다.The R 3 and R 4 may each independently be hydrogen or a C 1 -C 5 alkyl group, but are not limited thereto.
본 발명에서, 상기 화학식 1로 표시되는 화합물은 하기 구조식을 가진 화합물로 이루어진 군으로부터 선택된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the compound represented by
본 발명에서, 상기 화학식 1로 표시되는 화합물은 RORα 단백질의 활성화제일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the compound represented by
본 발명에서, 용어 “RORα를 활성화시키는 활성자(activator)"는 (a) RORα 유전자의 발현 활성화; 및/또는 (b) 발현된 RORα 단백질의 전사 활성능 증진을 의미한다. In the present invention, the term “activator that activates RORα” means (a) activating the expression of the RORα gene; and/or (b) enhancing the transcriptional activity of the expressed RORα protein.
상기 화합물은 보다 구체적으로, 도 1에 나타난 화합물 1 내지 21일 수 있으나, 이에 제한되는 것은 아니다.More specifically, the compounds may be
도 1에 개시된 화합물 1 내지 21의 이름은 다음과 같다:The names of
상기 화학식 1로 표시되는 화합물은 비방향족 이중 결합 및 하나 이상의 비대칭 중심을 가질 수 있다. 따라서, 이들은 라세미체 및 라세미체 혼합물, 단일 거울상이성질체, 개별적인 부분입체이성질체, 부분입체이성질체 혼합물 및 시스- 또는 트랜스-이성질체로서 발생할 수 있다. 모든 이러한 이성질체 형태가 고려된다.The compound represented by
또한, 본 발명은 상기 화학식 1로 표시되는 화합물의 수화물 또는 각각의 곁사슬에 당(glucose) 등의 화합물이 결합된 배당체와 같은 유도체 화합물을 포함할 수 있다.In addition, the present invention may include a derivative compound such as a hydrate of the compound represented by
본 발명에 따른 화합물은 반응식 1 내지 3의 화학적 합성법, 천연으로부터 분리, 또는 당 업계에 공지된 화합물의 화학적 합성법으로 제조할 수 있다.The compound according to the present invention can be prepared by the chemical synthesis methods of
본 발명의 화합물은 천연 식물로부터 분리 및 정제할 수도 있다. 즉, 종래의 물질을 추출하고 분리하는 방법을 이용하여 식물 또는 식물의 일부로부터 수득될 수 있다. 줄기, 뿌리 또는 잎은 목적하는 추출물을 획득하기 위하여 적절히 건조하여 침연(macerated)하거나, 단지 건조시켜 적절한 유기용매로 추출하고, 목적하는 추출물은 본 발명이 속하는 기술분야의 당업자에게 알려진 정제 방법을 이용하여 정제될 수 있다. The compounds of the present invention may be isolated and purified from natural plants. That is, it can be obtained from plants or plant parts using conventional methods for extracting and separating substances. The stem, root or leaf is appropriately dried and macerated to obtain the desired extract, or only dried and extracted with an appropriate organic solvent, and the desired extract is obtained using a purification method known to those skilled in the art to which the present invention pertains. can be purified.
또한, 본 발명은 화학식 1로 표시되는 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함할 수 있다. 본 발명에서 용어, "약학적으로 허용 가능한 염"이란 약학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함한다. In addition, the present invention may include a pharmaceutically acceptable salt of the compound represented by
적합한 산의 예로는 염산, 브롬산, 황산, 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산, 시트르산, 메탄설폰산, 포름산, 벤조산, 말론산, 글루콘산, 나프탈렌-2-설폰산, 벤젠설폰산 등을 들 수 있다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 메탄올, 에탄올, 아세톤 또는 아세토니트릴과 같은 수혼화성 유기 용매를 사용하여 침전시켜서 제조할 수 있다. 또한, 동몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Acid addition salts can be prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of excess acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can also be prepared by heating equimolar amounts of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or suction filtering the precipitated salt.
적합한 염기로부터 유도된 염은 나트륨, 칼륨 등의 알칼리 금속, 마그네슘 등의 알칼리 토금속, 및 암모늄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. 알칼리 금속 또는 알칼리 토금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻을 수 있다. 이 때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable for pharmaceutical purposes to prepare a sodium, potassium or calcium salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명자들은 신규한 티오우레아계 화합물들이 RORα의 전사활성을 기존 티오우레아계 화합물 JC1-40과 비교하여 현저히 증진시키며, 이러한 효과는 RORα에 선택적으로 나타남을 확인하였으며(실험예 1 내지 5 참조),The present inventors confirmed that the novel thiourea-based compounds markedly enhance the transcriptional activity of RORα compared to the existing thiourea-based compound JC1-40, and that this effect appeared selectively for RORα (see Experimental Examples 1 to 5),
RORα의 전사활성 증진 효과가 가장 우수한 ODH-08 화합물의 간세포내 지질 축적 억제 효과가 우수함을 확인하였으며(실험예 6 참조),It was confirmed that the ODH-08 compound, which has the highest effect of enhancing the transcriptional activity of RORα, has an excellent effect of inhibiting lipid accumulation in hepatocytes (see Experimental Example 6),
ODH-08 화합물의 처리에 의해 대식세포 M1 표지 인자의 발현이 현저히 감소되며, M2 표지 인자의 발현이 유의미하게 증가됨을 확인하였는 바, ODH-08이 쿠퍼 세포의 극성화를 조절한다는 사실을 확인하였으며(실험예 7 참조),As it was confirmed that the expression of the macrophage M1 marker was significantly reduced and the expression of the M2 marker was significantly increased by treatment with the ODH-08 compound, it was confirmed that ODH-08 regulates the polarization of Kupffer cells. (See Experimental Example 7),
ODH-08가 간 성상세포에서 섬유화 단백질 Pro-COL1A1, α-SMA 발현 및 유전자 α-SMA, COL1A1 및 TGFβ1 전사체 발현을 농도의존적으로 감소시키는 것을 확인하였으며(실험예 8 참조),It was confirmed that ODH-08 reduced the expression of fibrotic proteins Pro-COL1A1 and α-SMA and the expression of genes α-SMA, COL1A1 and TGFβ1 transcripts in a concentration-dependent manner in hepatic stellate cells (see Experimental Example 8),
ODH-08가 간 성상세포주에서 SMAD 전사활성을 유의하게 억제함을 확인하였으며(실험예 9 참조),It was confirmed that ODH-08 significantly inhibited SMAD transcriptional activity in hepatic stellate cell lines (see Experimental Example 9),
ODH-08가 식이 유도 간 섬유화 동물 모델에서 간 무게 증가를 억제하고, 혈중 AST 및 ALT 농도를 유의미하게 감소시킴에 따라 간 손상을 억제함을 확인하였으며(실험예 10 참조),It was confirmed that ODH-08 inhibited liver damage in a diet-induced liver fibrosis animal model by suppressing the increase in liver weight and significantly reducing blood AST and ALT concentrations (see Experimental Example 10),
ODH-08가 식이 유도 간 섬유화 동물 모델에서 간 조직의 섬유화 진행을 억제하고, 콜라겐 축적을 감소시키며, 간 섬유화 관련 단백질 및 유전자를 억제함을 확인하였다(실험예 11 참조).It was confirmed that ODH-08 inhibits the progress of liver tissue fibrosis, reduces collagen accumulation, and inhibits proteins and genes related to liver fibrosis in a diet-induced liver fibrosis animal model (see Experimental Example 11).
따라서, 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 대사성 질환 또는 염증성 질환의 예방 또는 치료용 약학적 조성물 또는 항염용 조성물로서 제공될 수 있다.Therefore, the compound represented by
본 발명에서 ‘대사성 질환’은 에너지 과잉 섭취 또는 호르몬 불균형 등 다양한 원인으로 체내 에너지 대사가 비정상적으로 일어나 지방이 과다하게 합성되거나 축적되어 발생하는 질환을 의미한다. 상기 대사성 질환은 구체적으로는 인슐린 저항성 증후군, 간섬유증, 지방간, 지방간염, 간경화, 제2형 당뇨병, 고지혈증, 심혈관 질환, 또는 동맥경화증일 수 있다.In the present invention, 'metabolic disease' refers to a disease caused by excessive synthesis or accumulation of fat due to abnormal energy metabolism in the body due to various causes such as excessive energy intake or hormonal imbalance. Specifically, the metabolic disease may be insulin resistance syndrome, liver fibrosis, fatty liver, steatohepatitis, liver cirrhosis,
한편, 본 발명에서 용어 ‘지방간’은 지방간에서 지방간염, 지방간 연관 간경변증까지의 전체 질환의 양상을 포괄하는 질환군을 의미하는 것일 수 있다.On the other hand, in the present invention, the term 'fatty liver' may mean a group of diseases covering all aspects of diseases from fatty liver to steatohepatitis and fatty liver-associated cirrhosis.
상기 ‘지방간’이란 과도한 지방이나 알코올 섭취, 간의 지방합성 증가, 중성지방 배출 및 연소 감소 등으로 인하여 간에 지방이 축적되어 발생하며 일반적으로 간에서 축적된 지방의 비중이 5% 이상일 때 지방간으로 정의한다. 지방간에서 축적된 지방의 대부분은 중성지방(트리글리세라이드, triglyceride)이다.The 'fatty liver' is caused by accumulation of fat in the liver due to excessive fat or alcohol intake, increased fat synthesis in the liver, reduced neutral fat emission and combustion, etc. Generally, it is defined as fatty liver when the proportion of fat accumulated in the liver is 5% or more. . Most of the fat accumulated in the fatty liver is triglycerides (triglycerides).
지방간은 크게 과음으로 인한 알코올성 지방과 간과 비만, 당뇨병, 고지혈증 또는 약물 등으로 인한 비알코올성 지방간으로 나눌 수 있다. 알코올성 지방간은 알코올을 과다 섭취하여 간에서 지방 합성이 촉진되고 정상적인 에너지 대사가 이루어지지 않아 발생하게 된다. 반면 비알콜성 지방간은 비만, 인슐린 과민증, 당뇨병 등을 앓고 있는 사람들에게서 많이 발생한다. 이러한 현상은 인슐린 저항성이나 과도한 지방 분해에 의해 혈액 내 유리 지방산의 농도가 높아지는 것에 의하여 비알콜성 지방간이 발생될 수 있음을 시사한다.Fatty liver can be largely divided into alcoholic fat caused by excessive drinking and non-alcoholic fatty liver caused by liver and obesity, diabetes, hyperlipidemia or drugs. Alcoholic fatty liver occurs when excessive intake of alcohol promotes fat synthesis in the liver and prevents normal energy metabolism. On the other hand, non-alcoholic fatty liver occurs frequently in people suffering from obesity, insulin hypersensitivity, and diabetes. This phenomenon suggests that non-alcoholic fatty liver may be caused by an increase in the concentration of free fatty acids in the blood due to insulin resistance or excessive lipolysis.
본 발명에서 상기 지방간은 알콜성 지방간, 비알콜성 지방간, 영양성 지방간, 기아성 지방간, 비만성 지방간, 당뇨병성 지방간으로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 바람직하게는 비알콜성 지방간, 비만성 지방간, 당뇨병성 지방간일 수 있으며, 가장 바람직하게는 당뇨병성 지방간일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the fatty liver may be any one or more selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver, nutritional fatty liver, starvation fatty liver, obese fatty liver, and diabetic fatty liver, preferably non-alcoholic fatty liver, obese fatty liver It may be fatty liver, diabetic fatty liver, and most preferably diabetic fatty liver, but is not limited thereto.
본 발명에서 용어 ‘지방간염’은 간 내 지방침착을 보이면서 간세포 손상(풍선변성)을 동반한 염증소견 또는 섬유화 병변이 있는 경우를 의미하는 것으로, 간 내 지방 침착을 보이지만 간세포 손상(풍선변성) 및 섬유화의 소견은 없는 경우인 ‘지방간’과 구별되어 사용된다.In the present invention, the term 'steatohepatitis' refers to a case of inflammatory findings or fibrotic lesions accompanied by liver cell damage (balloon degeneration) while showing fat deposition in the liver. It is used to differentiate from 'fatty liver', which is a case where there is no evidence of fibrosis.
본 발명에서 용어 ‘지방간 연관 간경변증’은 조직학적으로 지방간이나 지방간염의 소견이 동반된 간경변증, 혹은 과거에 조직학적으로 증명된 지방간 또는 지방간염 환자에서 발생된 간경변증을 의미한다.In the present invention, the term 'fatty liver-associated cirrhosis' refers to liver cirrhosis accompanied by histological findings of fatty liver or steatohepatitis, or liver cirrhosis that has occurred in patients with fatty liver or steatohepatitis that have been histologically proven in the past.
본 발명에서 용어 ‘간 섬유증’은 만성염증상태에 있는 간 조직이 손상과 재생을 반복하여, 조직 중에 콜라겐 등과 같은 결합조직이 과도하게 축적됨으로써, 간 조직에 흉터(scar)가 생기는 질환을 의미한다. 간섬유증은 가역적(reversible)이고, 얇은 원섬유(thin fibril)로 구성되며, 결절(nodule)형성이 없다. 또한, 간 손상의 원인이 소실되면 정상회복이 가능할 수 있다. 그러나 이러한 간섬유화 기작이 반복적으로 지속되면, 결합조직 간의 교차결합(crosslinking)이 증가하여 두꺼운 원섬유(thick fibril)가 축적되며, 간소엽의 정상구조를 상실하여 결절을 형성하는 것을 특징으로 하는 비가역적인(irreversible) 간경변으로 진행된다. In the present invention, the term 'liver fibrosis' refers to a disease in which scars occur in liver tissue due to excessive accumulation of connective tissue such as collagen in the tissue due to repeated damage and regeneration of liver tissue in a chronic inflammatory state. . Liver fibrosis is reversible, consists of thin fibrils, and lacks nodule formation. In addition, if the cause of liver damage disappears, normal recovery may be possible. However, if this liver fibrosis mechanism continues repeatedly, crosslinking between connective tissues increases, thick fibrils accumulate, and the normal structure of liver lobules is lost to form nodules. It progresses to irreversible cirrhosis.
간 성상세포의 활성화는 간 섬유증의 주요 원인으로서 정상 간에서 간 성상세포는 비증식성, 정지성 및 비타민 A 저장 표현형을 유지하지만 활성화되면 증식성, 수축성, 섬유성 및 화학주성인 근섬유 모세포로 전환된다. 간 성상세포 활성화의 주요 매개체에는 일련의 사이토 카인, 반응성 산소 중간체 및 기타 파라크린 및 자가 분비 신호가 포함된다. 활성화된 간 성상세포의 증식은 주로 형질 전환 성장 인자 β(TGFβ), 혈소판 유래 성장 인자, 혈관 내피 성장 인자 및 결합 조직 성장 인자를 통한 경로를 따른다. 그 중 TGFβ1은 일반적으로 가장 영향력 있는 섬유 원성 사이토 카인으로 알려져 있다. 유형 I 수용체(TGFR1)의 TGFβ 결합 및 인산화는 하류 SMAD 단백질, 주로 SMAD3의 인산화를 유도한다. 활성화 과정에서 간 성상세포는 α-SMA 및 collagen type I and type II, fibronectin, 및 hyaluronan을 포함한 세포외 기질 성분을 발현한다. 따라서 간 성상세포의 섬유 생성 활성화는 간 섬유증 치료에 중요한 표적이 된다. Activation of hepatic stellate cells is a major cause of liver fibrosis. In normal liver, hepatic stellate cells maintain a non-proliferative, quiescent, and vitamin A storage phenotype, but when activated, they transform into proliferative, contractile, fibrotic, and chemotactic myofibroblasts. Key mediators of hepatic stellate cell activation include a series of cytokines, reactive oxygen intermediates, and other paracrine and autocrine signals. Proliferation of activated hepatic stellate cells mainly follows a pathway through transforming growth factor β (TGFβ), platelet-derived growth factor, vascular endothelial growth factor and connective tissue growth factor. Among them, TGFβ1 is generally known as the most influential fibrogenic cytokine. TGFβ binding and phosphorylation of the type I receptor (TGFR1) induces phosphorylation of downstream SMAD proteins, primarily SMAD3. During the activation process, hepatic stellate cells express α-SMA and extracellular matrix components including collagen type I and type II, fibronectin, and hyaluronan. Thus, the activation of hepatic stellate cell fibrogenesis is an important target for the treatment of liver fibrosis.
본 발명자들은 지질 축적 및 간 섬유증을 효과적으로 억제할 수 있는 물질을 개발하고자 예의 연구 노력한 결과, RORα 유전자를 활성화시키는 활성자(activator)가 간세포 내의 지질 축적을 억제할 수 있음을 발견하였다. 또한, 간에 존재하는 대식세포인 쿠퍼세포는 M2 극성화가 진행될 때 지방간질환을 완화시키는 것으로 알려져 있었다. 본 발명자들은 RORα 활성자가 쿠퍼세포에서 RORα를 과발현하였을 때 M2 극성 마커인 IL-10, Arg1, 그리고 CD163의 발현을 증가시킴을 증명한 바 있다. 또한, RORα 결손 마우스에 고지질 식이로 비알콜성 지방간질환을 유발하였을 때 간 조직 내 α-SMA 및 TGFβ1과 같은 섬유화 마커의 단백질 발현이 증가되었고, Col1A1, α-SMA, TGFβ, MMP-2, TIMP1 전사체 발현이 증가되어 있음을 확인하였다.As a result of intensive research efforts to develop a substance capable of effectively inhibiting lipid accumulation and liver fibrosis, the present inventors have found that an activator activating the RORα gene can inhibit lipid accumulation in hepatocytes. In addition, Kupffer cells, which are macrophages present in the liver, are known to alleviate fatty liver disease when M2 polarization progresses. The present inventors have demonstrated that when RORα activator overexpresses RORα in Kupffer cells, the expression of M2 polarity markers IL-10, Arg1, and CD163 is increased. In addition, when non-alcoholic fatty liver disease was induced with a high-fat diet in RORα-defective mice, protein expression of fibrosis markers such as α-SMA and TGFβ1 in liver tissue was increased, and Col1A1, α-SMA, TGFβ, MMP-2, It was confirmed that TIMP1 transcript expression was increased.
본 발명에서, 상기 대사성 질환은 대사성 간 질환일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the metabolic disease may be a metabolic liver disease, but is not limited thereto.
본 발명에서, 상기 대사성 질환은 지질 대사 관련 질환일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the metabolic disease may be a lipid metabolism-related disease, but is not limited thereto.
본 발명에 있어서 "항염"은 염증성 질환의 예방, 개선, 또는 치료를 포함하는 의미로, 상기 염증성 질환은 천식, 알레르기성 및 비-알레르기성 비염, 위염, 장염, 궤양성 위염, 신장염, 간염, 만성 폐쇄성 폐질환, 폐섬유종, 과민성 대장증후군, 염증성 통증, 편두통, 두통, 허리 통증, 섬유 근육통, 근막 질환, 바이러스 감염(예컨대, C형 감염), 박테리아 감염, 곰팡이 감염, 화상, 외과적 또는 치과적 수술에 의한 상처, 통풍, 관절염, 류머티스성 관절염, 강직성 척추염, 호지킨병, 췌장염, 결막염, 홍채염, 공막염, 포도막염, 피부염(아토피성 피부염 포함), 습진, 및 다발성 경화증으로 이루어진 군으로부터 선택되는 하나 이상일 수 있으나, 이에 제한되지 않는다.In the present invention, "anti-inflammatory" means to include prevention, improvement, or treatment of inflammatory diseases, and the inflammatory diseases include asthma, allergic and non-allergic rhinitis, gastritis, enteritis, ulcerative gastritis, nephritis, hepatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, back pain, fibromyalgia, myofascial disease, viral infection (eg hepatitis C infection), bacterial infection, fungal infection, burns, surgical or dental selected from the group consisting of surgical wounds, gout, arthritis, rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, iritis, scleritis, uveitis, dermatitis (including atopic dermatitis), eczema, and multiple sclerosis It may be one or more, but is not limited thereto.
본 발명에서, 상기 화합물은 전염증성 사이토카인의 발현 또는 분비 저해, 또는 M2 대식세포의 상향 조절에 의해 염증을 억제하거나 감소시키는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the compound may inhibit or reduce inflammation by inhibiting the expression or secretion of pro-inflammatory cytokines or upregulating M2 macrophages, but is not limited thereto.
본 발명의 조성물 내의 상기 화합물 또는 이의 약학적으로 허용가능한 염의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 또는 0.001 내지 50중량%일 수 있으나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다.The content of the compound or a pharmaceutically acceptable salt thereof in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight based on the total weight of the composition, Or it may be 0.001 to 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount after removing the solvent.
본 발명에 따른 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 상기 부형제는 예를 들어, 희석제, 결합제, 붕해제, 활택제, 흡착제, 보습제, 필름-코팅 물질, 및 제어방출첨가제로 이루어진 군으로부터 선택된 하나 이상일 수 있다. The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.
본 발명에 따른 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 서방형 과립제, 장용과립제, 액제, 점안제, 엘실릭제, 유제, 현탁액제, 주정제, 트로키제, 방향수제, 리모나아데제, 정제, 서방형정제, 장용정제, 설하정, 경질캅셀제, 연질캅셀제, 서방캅셀제, 장용캅셀제, 환제, 틴크제, 연조엑스제, 건조엑스제, 유동엑스제, 주사제, 캡슐제, 관류액, 경고제, 로션제, 파스타제, 분무제, 흡입제, 패취제, 멸균주사용액, 또는에어로졸 등의 외용제 등의 형태로 제형화하여 사용될 수 있으며, 상기 외용제는 크림, 젤, 패치, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 등의 제형을 가질 수 있다. The pharmaceutical compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, and limonadese, respectively, according to conventional methods. , tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusate, It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta agents, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external agents are creams, gels, patches, sprays, ointments, and warning agents. , lotion, liniment, pasta, or cataplasma may have formulations such as the like.
본 발명에 따른 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
본 발명에 따른 정제, 산제, 과립제, 캡슐제, 환제, 트로키제의 첨가제로 옥수수전분, 감자전분, 밀전분, 유당, 백당, 포도당, 과당, 디-만니톨, 침강탄산칼슘, 합성규산알루미늄, 인산일수소칼슘, 황산칼슘, 염화나트륨, 탄산수소나트륨, 정제 라놀린, 미결정셀룰로오스, 덱스트린, 알긴산나트륨, 메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 카올린, 요소, 콜로이드성실리카겔, 히드록시프로필스타치, 히드록시프로필메칠셀룰로오스(HPMC), HPMC 1928, HPMC 2208, HPMC 2906, HPMC 2910, 프로필렌글리콜, 카제인, 젖산칼슘, 프리모젤 등 부형제; 젤라틴, 아라비아고무, 에탄올, 한천가루, 초산프탈산셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스칼슘, 포도당, 정제수, 카제인나트륨, 글리세린, 스테아린산, 카르복시메칠셀룰로오스나트륨, 메칠셀룰로오스나트륨, 메칠셀룰로오스, 미결정셀룰로오스, 덱스트린, 히드록시셀룰로오스, 히드록시프로필스타치, 히드록시메칠셀룰로오스, 정제쉘락, 전분호, 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 폴리비닐알코올, 폴리비닐피롤리돈 등의 결합제가 사용될 수 있으며, 히드록시프로필메칠셀룰로오스, 옥수수전분, 한천가루, 메칠셀룰로오스, 벤토나이트, 히드록시프로필스타치, 카르복시메칠셀룰로오스나트륨, 알긴산나트륨, 카르복시메칠셀룰로오스칼슘, 구연산칼슘, 라우릴황산나트륨, 무수규산, 1-히드록시프로필셀룰로오스, 덱스트란, 이온교환수지, 초산폴리비닐, 포름알데히드처리 카제인 및 젤라틴, 알긴산, 아밀로오스, 구아르고무(Guar gum), 중조, 폴리비닐피롤리돈, 인산칼슘, 겔화전분, 아라비아고무, 아밀로펙틴, 펙틴, 폴리인산나트륨, 에칠셀룰로오스, 백당, 규산마그네슘알루미늄, 디-소르비톨액, 경질무수규산 등 붕해제; 스테아린산칼슘, 스테아린산마그네슘, 스테아린산, 수소화식물유(Hydrogenated vegetable oil), 탈크, 석송자, 카올린, 바셀린, 스테아린산나트륨, 카카오지, 살리실산나트륨, 살리실산마그네슘, 폴리에칠렌글리콜(PEG) 4000, PEG 6000, 유동파라핀, 수소첨가대두유(Lubri wax), 스테아린산알루미늄, 스테아린산아연, 라우릴황산나트륨, 산화마그네슘, 마크로골(Macrogol), 합성규산알루미늄, 무수규산, 고급지방산, 고급알코올, 실리콘유, 파라핀유, 폴리에칠렌글리콜지방산에테르, 전분, 염화나트륨, 초산나트륨, 올레인산나트륨, dl-로이신, 경질무수규산 등의 활택제;가 사용될 수 있다.Corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, phosphoric acid as additives for tablets, powders, granules, capsules, pills, and troches according to the present invention Calcium monohydrogen, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethyl excipients such as cellulose (HPMC), HPMC 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose phthalate acetate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin Binders such as hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, purified shellac, starch arc, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone may be used, Hydroxypropyl Methyl Cellulose, Corn Starch, Agar Powder, Methyl Cellulose, Bentonite, Hydroxypropyl Starch, Sodium Carboxymethyl Cellulose, Sodium Alginate, Calcium Carboxymethyl Cellulose, Calcium Citrate, Sodium Lauryl Sulfate, Silicic Anhydride, 1-Hydroxy Propyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopod, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogen Added soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acid, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, Lubricants such as starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid; may be used.
본 발명에 따른 액제의 첨가제로는 물, 묽은 염산, 묽은 황산, 구연산나트륨, 모노스테아린산슈크로스류, 폴리옥시에칠렌소르비톨지방산에스텔류(트윈에스텔), 폴리옥시에칠렌모노알킬에텔류, 라놀린에텔류, 라놀린에스텔류, 초산, 염산, 암모니아수, 탄산암모늄, 수산화칼륨, 수산화나트륨, 프롤아민, 폴리비닐피롤리돈, 에칠셀룰로오스, 카르복시메칠셀룰로오스나트륨 등이 사용될 수 있다.Additives for the liquid formulation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like may be used.
본 발명에 따른 시럽제에는 백당의 용액, 다른 당류 혹은 감미제 등이 사용될 수 있으며, 필요에 따라 방향제, 착색제, 보존제, 안정제, 현탁화제, 유화제, 점조제 등이 사용될 수 있다.In the syrup according to the present invention, a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.
본 발명에 따른 유제에는 정제수가 사용될 수 있으며, 필요에 따라 유화제, 보존제, 안정제, 방향제 등이 사용될 수 있다.Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.
본 발명에 따른 현탁제에는 아카시아, 트라가칸타, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 미결정셀룰로오스, 알긴산나트륨, 히드록시프로필메칠셀룰로오스, HPMC 1828, HPMC 2906, HPMC 2910 등 현탁화제가 사용될 수 있으며, 필요에 따라 계면활성제, 보존제, 안정제, 착색제, 방향제가 사용될 수 있다.Acacia, tragacantha, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, HPMC 2910, etc. and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.
본 발명에 따른 주사제에는 주사용 증류수, 0.9%염화나트륨주사액, 링겔주사액, 덱스트로스주사액, 덱스트로스+염화나트륨주사액, 피이지(PEG), 락테이티드 링겔주사액, 에탄올, 프로필렌글리콜, 비휘발성유-참기름, 면실유, 낙화생유, 콩기름, 옥수수기름, 올레인산에칠, 미리스트산 이소프로필, 안식향산벤젠과 같은 용제; 안식향산나트륨, 살리실산나트륨, 초산나트륨, 요소, 우레탄, 모노에칠아세트아마이드, 부타졸리딘, 프로필렌글리콜, 트윈류, 니정틴산아미드, 헥사민, 디메칠아세트아마이드와 같은 용해보조제; 약산 및 그 염(초산과 초산나트륨), 약염기 및 그 염(암모니아 및 초산암모니움), 유기화합물, 단백질, 알부민, 펩톤, 검류와 같은 완충제; 염화나트륨과 같은 등장화제; 중아황산나트륨(NaHSO3)이산화탄소가스, 메타중아황산나트륨(Na2S2O5), 아황산나트륨(Na2SO3), 질소가스(N2), 에칠렌디아민테트라초산과 같은 안정제; 소디움비설파이드 0.1%, 소디움포름알데히드 설폭실레이트, 치오우레아, 에칠렌디아민테트라초산디나트륨, 아세톤소디움비설파이트와 같은 황산화제; 벤질알코올, 클로로부탄올, 염산프로카인, 포도당, 글루콘산칼슘과 같은 무통화제; 시엠시나트륨, 알긴산나트륨, 트윈 80, 모노스테아린산알루미늄과 같은 현탁화제를 포함할 수 있다.Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; tonicity agents such as sodium chloride; Stabilizers such as sodium bisulfite (NaHSO 3 ) carbon dioxide gas, sodium metabisulfite (Na 2 S 2 O 5 ), sodium sulfite (Na 2 SO 3 ), nitrogen gas (N 2 ), and ethylenediamine tetraacetic acid; Sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, ethylenediamine disodium tetraacetate, acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; Suspending agents such as Siemesis sodium, sodium alginate, Tween 80, aluminum monostearate may be included.
본 발명에 따른 좌제에는 카카오지, 라놀린, 위텝솔, 폴리에틸렌글리콜, 글리세로젤라틴, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 스테아린산과 올레인산의 혼합물, 수바날(Subanal), 면실유, 낙화생유, 야자유, 카카오버터+콜레스테롤, 레시틴, 라네트왁스, 모노스테아린산글리세롤, 트윈 또는 스판, 임하우젠(Imhausen), 모놀렌(모노스테아린산프로필렌글리콜), 글리세린, 아뎁스솔리두스(Adeps solidus), 부티룸 태고-G(Buytyrum Tego-G), 세베스파마 16 (Cebes Pharma 16), 헥사라이드베이스 95, 코토마(Cotomar), 히드록코테 SP, S-70-XXA, S-70-XX75(S-70-XX95), 히드록코테(Hydrokote) 25, 히드록코테 711, 이드로포스탈 (Idropostal), 마사에스트라리움(Massa estrarium, A, AS, B, C, D, E, I, T), 마사-MF, 마수폴, 마수폴-15, 네오수포스탈-엔, 파라마운드-B, 수포시로(OSI, OSIX, A, B, C, D, H, L), 좌제기제 IV 타입 (AB, B, A, BC, BBG, E, BGF, C, D, 299), 수포스탈 (N, Es), 웨코비 (W, R, S, M ,Fs), 테제스터 트리글리세라이드 기제 (TG-95, MA, 57)와 같은 기제가 사용될 수 있다.The suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lannet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolen (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Buytyrum Tego-G -G),
경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc. ) or by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.
본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 본 발명이 속하는 기술분야에 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구 복용, 피하 주사, 복강 투여, 정맥 주사, 근육 주사, 척수 주위 공간(경막내) 주사, 설하 투여, 볼점막 투여, 직장 내 삽입, 질 내 삽입, 안구 투여, 귀 투여, 비강 투여, 흡입, 입 또는 코를 통한 분무, 피부 투여, 경피 투여 등에 따라 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
본 발명의 약학적 조성물은 치료할 질환, 투여 경로, 환자의 연령, 성별, 체중 및 질환의 중등도 등의 여러 관련 인자와 함께 활성성분인 약물의 종류에 따라 결정된다.The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient.
본 발명에서 “개체”란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐 (mouse), 쥐 (rat), 개, 고양이, 말, 및 소 등의 포유류일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, etc. It may be a mammal of, but is not limited thereto.
본 발명에서 “투여”란 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.In the present invention, "administration" means providing a given composition of the present invention to a subject by any suitable method.
본 발명에서 “예방”이란 목적하는 질환의 발병을 억제하거나 지연시키는 모든 행위를 의미하고, “치료”란 본 발명에 따른 약학적 조성물의 투여에 의해 목적하는 질환과 그에 따른 대사 이상 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미하며, “개선”이란 본 발명에 따른 조성물의 투여에 의해 목적하는 질환과 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다. In the present invention, “prevention” refers to any action that suppresses or delays the onset of a desired disease, and “treatment” means that the desired disease and its resulting metabolic abnormality are improved or improved by administration of the pharmaceutical composition according to the present invention. All actions that are advantageously altered are meant, and "improvement" means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administration of the composition according to the present invention.
본 발명에서 화학식 1로 표시되는 화합물은 하기 반응식들에 도시된 방법에 의해 화학적으로 합성될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the compound represented by
[반응식1][Scheme 1]
반응식 1은 화학식 1의 범위에 속하는 화합물은 치환된 아민 형태의 기질을 Diethyl ether 또는 Methylene Chloride 용매 하에 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠과 커플링하여 원하는 thiourea 모핵의 컴파운드를 합성한다. 염의 경우 Triethylamine(TEA)를 적가하며, 시작물질이 녹지 않을 경우 메탄올이나 DMF(dimethylformamide)도 사용할 수 있다.
반응식 1의 R은 화학식 1의 “-X-Y”를 의미한다.R in
X는 C1-C5인 알킬기, 벤질기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고;X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
Y는 수소, 히드록시기, 할로겐, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 시클로알킬기, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이다.Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted A C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group.
R1 내지 R5 및 기타 치환기에 관한 설명은 상기 언급한 바와 같다.Descriptions of R 1 to R 5 and other substituents are as described above.
[반응식2][Scheme 2]
반응식 2는 (벤질옥시-페닐)-메탄아민을 카복실다이이미다졸과 Triethylamine(TEA)를 통해 DMF(dimethylformamide) 용매 하에서 1-(벤질옥시)-4-(아이소사이아나토메틸)-벤젠 중간체를 합성한다. 이후 화학식 1의 범위에 속하는 화합물은 치환된 아민 형태의 기질을 Diethyl ether 또는 Methylene Chloride 용매(시작물질이 녹지 않을 경우 메탄올이나 DMF(dimethylformamide)도 사용) 하에 1-(벤질옥시)-4-(아이소사이아나토메틸)-벤젠과 커플링하여 원하는 urea 모핵의 컴파운드를 합성한다. 염의 경우 Triethylamine(TEA)를 적가한다.
R은 상기 언급한 바와 같다.R is as mentioned above.
[반응식3][Scheme 3]
반응식 3은 다이아미노벤젠 구조에 Thiourea를 반응시켜 다양한 치환기를 가진 thiourea 모핵의 컴파운드를 합성한다. 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠을 디클로로메탄 용매 하에서 N,N-디메틸벤젠-1,2,4-트리아민을 사용하여 중간체를 만들고, 여기에 산화수은, 황, 그리고 에탄올을 넣고 가열하여 원하는 물질인 벤지미다졸을 합성한다.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, a preferred embodiment is presented to aid understanding of the present invention. However, the following examples are provided to more easily understand the present invention, and the content of the present invention is not limited by the following examples.
[실시예] [Example]
실시예 1. 1-(4-벤질옥시-벤질)-3-메틸-thiourea (JC1-40) 제조Example 1. Preparation of 1-(4-benzyloxy-benzyl)-3-methyl-thiourea (JC1-40)
[반응식 1][Scheme 1]
반응식 1과 같이 메틸아민 40% 수용액(0.76ml, 9.79mmol)에 디클로로메탄 용매를 넣은 후, 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠 (500mg, 1.96mmol)을 넣은 후 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인 후, 에틸아세테이트와 1M 염산수용액으로 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하여 백색 고체(457mg, 1.60mmol)를 얻었다. (수율: 81%) As shown in
1H-NMR (400MHZ, CDCl3) δ 7.45-7.28 (m, 5H), 7.28-7.25 (s, 1H), 7.24-7.20 (s, 1H), 7.05-6.87 (d, J=8.67, 2H), 6.02-5.64 (br, 1H), 5.13-4.98 (s, 2H), 4.63-4.52 (br, 1H), 3.09-2.86 (s, 2H), 1.60-1.55 (s, 3H) 1H -NMR (400MHZ, CDCl3) δ 7.45-7.28 (m, 5H), 7.28-7.25 (s, 1H), 7.24-7.20 (s, 1H), 7.05-6.87 (d, J=8.67, 2H), 6.02-5.64 (br, 1H), 5.13-4.98 (s, 2H), 4.63-4.52 (br, 1H), 3.09-2.86 (s, 2H), 1.60-1.55 (s, 3H)
실시예 2. 1-(4-벤질옥시-벤질)-3-에틸-thiourea (1) 제조Example 2. Preparation of 1-(4-benzyloxy-benzyl)-3-ethyl-thiourea (1)
반응식 1과 같이 에틸아민 염산염(105mg, 1.289mmol)에 메틸렌 클로라이드 용매 하에 TEA(TriEthylAmine, 0.108ml, 0.77mmol)을 넣은 후, 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠(164.6mg, 0.645mmol)을 넣어 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인한 후, 에틸아세테이트와 물로 추출하고 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하였다. 여과된 유기층을 실리카 컬럼을 통해 분리하며 백색 고체(130.7mg, 0.44mmol)를 얻었다(수율: 68%).As shown in
1H-NMR (300MHZ, DMSO) δ 7.69 (br, 1H), 7.43-7.28 (m, 6H), 7.22-7.19 (d, J= 8.25Hz, 2H), 6.97-6.93 (d, J= 8.25Hz, 2H), 5.08 (s, 2H), 4.56-4.54 (br, 2H), 3.34 (s, 2H), 10.8-1.05 (t, J= 3.93Hz, 3H) 1H -NMR (300MHZ, DMSO) δ 7.69 (br, 1H), 7.43-7.28 (m, 6H), 7.22-7.19 (d, J= 8.25Hz, 2H), 6.97-6.93 (d, J= 8.25Hz , 2H), 5.08 (s, 2H), 4.56-4.54 (br, 2H), 3.34 (s, 2H), 10.8-1.05 (t, J= 3.93Hz, 3H)
실시예 3. 1-(4-벤질옥시-벤질)-3-프로필-thiourea (2) 제조Example 3. Preparation of 1-(4-benzyloxy-benzyl)-3-propyl-thiourea (2)
상기 실시예 2와 같은 방법으로 프로필아민을 사용하여 백색 고체(184mg, 0.59mmol)를 얻었다(수율: 99%).A white solid (184mg, 0.59mmol) was obtained using propylamine in the same manner as in Example 2 (yield: 99%).
1H-NMR (300MHZ, DMSO) δ 7.7 (br, 1H), 7.44-7.28 (m, 6H) 7.22-7.18 (d, J= 8.61Hz, 2H), 6.97-6.93 (d, J= 8.61Hz, 2H), 5.08 (s, 2H), 4.54 (br, 2H), 3.33 (s, 2H), 1.52-1.40 (m, 2H), 0.85-0.80 (t, J= 7.41Hz) 1H -NMR (300MHZ, DMSO) δ 7.7 (br, 1H), 7.44-7.28 (m, 6H) 7.22-7.18 (d, J= 8.61Hz, 2H), 6.97-6.93 (d, J= 8.61Hz, 2H), 5.08 (s, 2H), 4.54 (br, 2H), 3.33 (s, 2H), 1.52-1.40 (m, 2H), 0.85-0.80 (t, J= 7.41Hz)
실시예 4. 1-(4-벤질옥시-벤질)-3-부틸-thiourea (3) 제조Example 4. Preparation of 1-(4-benzyloxy-benzyl)-3-butyl-thiourea (3)
상기 실시예 2와 같은 방법으로 부틸아민을 사용하여 백색 고체(173.0mg, 0.53mmol)를 얻었다(수율: 91%).In the same manner as in Example 2, butylamine was used to obtain a white solid (173.0mg, 0.53mmol) (yield: 91%).
1H-NMR (300MHZ, DMSO) δ7.67 (br, 1H), 7.43-7.28 (m, 6H) 7.21-7.18 (d, J= 2H), 6.96-6.93 (d, J=8.58, 2H), 5.07 (s, 2H), 4.54 (br, 2H), 3.35 (s, 2H), 1.48-1.38 (m, 2H), 1.31-1.22 (m, 2H), 0.88-0.83 (t, J=7.23, 3H) 1H -NMR (300MHZ, DMSO) δ7.67 (br, 1H), 7.43-7.28 (m, 6H) 7.21-7.18 (d, J= 2H), 6.96-6.93 (d, J=8.58, 2H), 5.07 (s, 2H), 4.54 (br, 2H), 3.35 (s, 2H), 1.48-1.38 (m, 2H), 1.31-1.22 (m, 2H), 0.88-0.83 (t, J=7.23, 3H )
실시예 5. Example 5. terttert -부틸-(4-벤질옥시-벤질-카바모싸이오일)-글라이시네이트 (4) 제조-Butyl-(4-benzyloxy-benzyl-carbamothioyl)-glycinate (4) preparation
상기 실시예 2와 같은 방법으로 글리이신-tert-부틸이스터-클로라이드를 사용하여 백색 고체(376.3mg, 0.97mmol)를 얻었다(수율: 83%).In the same manner as in Example 2, glycine-tert-butyl ester-chloride was used to obtain a white solid (376.3 mg, 0.97 mmol) (yield: 83%).
1H-NMR (300MHZ, DMSO) δ 8.10 (br, 1H), 7.57 (br, 1H) 7.43-7.28 (m, 5H), 7.22-7.19 (d, J=8.43Hz, 2H), 5.08 (s, 2H), 4.56 (br, 2H), 4.10-4.03 (d, J = 5.13Hz, 2H), 1.40 (s, 9H) 1H -NMR (300MHZ, DMSO) δ 8.10 (br, 1H), 7.57 (br, 1H) 7.43-7.28 (m, 5H), 7.22-7.19 (d, J=8.43Hz, 2H), 5.08 (s, 2H), 4.56 (br, 2H), 4.10-4.03 (d, J = 5.13Hz, 2H), 1.40 (s, 9H)
실시예 6. ((4-벤질옥시)-벤질-카바노싸이오닐)-글라이신 (5) 제조Example 6. Preparation of ((4-benzyloxy)-benzyl-carbanothionyl)-glycine (5)
상기 실시예 2와 같은 방법으로 글라이신과 다이메틸포름아마이드 용매를 사용하여백색 고체(121.7mg, 0.35mmol)를 얻었다(수율: 82%).In the same manner as in Example 2, a white solid (121.7mg, 0.35mmol) was obtained using glycine and dimethylformamide solvent (yield: 82%).
1H-NMR (300MHZ, DMSO) δ8.07 (s, 1H), 7.53(s, 1H) 7.40-7.26 (m, 5H), 7.18 (d, J = 8.7Hz, 2H), 6.92 (d, J = 8.7Hz, 2H), 4.53 (br, 2H), 4.12 (br, 2H) 1H -NMR (300MHZ, DMSO) δ8.07 (s, 1H), 7.53 (s, 1H) 7.40-7.26 (m, 5H), 7.18 (d, J = 8.7Hz, 2H), 6.92 (d, J = 8.7Hz, 2H), 4.53 (br, 2H), 4.12 (br, 2H)
실시예 7. 1-(4-벤질옥시-벤질)-3-(2-하이드록시에틸)-thiourea (6) 제조Example 7. Preparation of 1-(4-benzyloxy-benzyl)-3-(2-hydroxyethyl)-thiourea (6)
반응식 1과 같이 에탄올아민 염산염(122.2mg, 1.253mmol)에 디에틸이써(Diethyl ether) 용매 하에 TEA(TriEthylAmine, 0.131ml, 0.94mmol)을 넣은 후, 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠(160mg, 0.627mmol)을 넣은 후 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인한 후, 에틸아세테이트와 1M 염산수용액으로 두 번 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하여 백색 고체(160.9mg, 0.51mmol)를 얻었다(수율: 82%).As shown in
1H-NMR (300MHZ, CD3OD) δ 7.84(br, 1H), 7.44-7.28(m, 6H), 7.22-7.19(d, J = 8.43Hz, 2H), 7.00-6.96(d, J = 12.81Hz, 2H), 5.08(s, 2H), 4.77 (br, 1H), 4.55(br, 2H), 3.46(br, 4H) 1H -NMR (300MHZ, CD3OD) δ 7.84 (br, 1H), 7.44-7.28 (m, 6H), 7.22-7.19 (d, J = 8.43Hz, 2H), 7.00-6.96 (d, J = 12.81Hz , 2H), 5.08(s, 2H), 4.77 (br, 1H), 4.55(br, 2H), 3.46(br, 4H)
실시예 8. 1-(2-아미노에틸)-3-(4-벤질옥시-벤질)-thiourea (7) 제조Example 8. Preparation of 1-(2-aminoethyl)-3-(4-benzyloxy-benzyl)-thiourea (7)
반응식 1과 같이 에틸렌다이아민(0.16ml, 2.35mmol)에 디에틸이써 용매를 넣은 후, 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠 (150mg, 0.59mmol)을 넣은 후 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인한 후, 에틸아세테이트와 물로 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하였다. 여과된 유기층을 헥산 용매를 통해 고체화한 후 이를 여과하여 백색 고체(109mg, 0.35mmol)를 얻었다(수율: 60%).As shown in
1H-NMR (300 MHz, DMSO) δ 7.44-7.30 (m, 6H), 7.22-7.19 (d, J = 8.25Hz, 2H), 6.96-6.93 (d, J = 8.25Hz, 2H), 5.07 (s, 2H), 4.55 (br, 2H), 3.30 (br, 2H), 5.04 (s, 2H), 4.53 (br, 2H), 3.25 (br, 2H), 2.66 (br, 2H), 2.49 (s, 2H) 1 H-NMR (300 MHz, DMSO) δ 7.44-7.30 (m, 6H), 7.22-7.19 (d, J = 8.25 Hz, 2H), 6.96-6.93 (d, J = 8.25 Hz, 2H), 5.07 ( s, 2H), 4.55 (br, 2H), 3.30 (br, 2H), 5.04 (s, 2H), 4.53 (br, 2H), 3.25 (br, 2H), 2.66 (br, 2H), 2.49 (s , 2H)
실시예 9. 1-(4-벤질옥시-벤질)-3-(2-디메틸아미노-에틸)-thiourea (8) 제조Example 9. Preparation of 1-(4-benzyloxy-benzyl)-3-(2-dimethylamino-ethyl)-thiourea (8)
반응식 1과 같이 N,N-디메틸에틸렌다이아민(0.17ml, 1.56mmol)에 메틸렌 클로라이드 용매를 넣은 후, 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠 (200mg, 0.78mmol)을 넣은 후 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인 후, 에틸아세테이트와 물로 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하였다. 여과된 유기층을 헥산 용매를 통해 고체화한 후 이를 여과하여 백색 고체(233mg, 0.65mmol)를 얻었다(수율: 83%).As shown in
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J=7.52Hz,2H),7.36-7.34(t,J=7.64Hz,2H),7.30-7.29(t,J = 6.52 Hz, 1H), 7.24-7.22 (t, J = 8.48 Hz, 2H), 6.92-6.90 (d, J = 8.64 Hz, 2H), 6.37 (br, 1H), 5.05 (br, 1H), 5.04 (s, 2H), 4.53 (br, 2H), 3.25 (br, 2H), 2.38-2.37 (t, J = 4.92, 2H), 1.96 (br, 6H) 1H -NMR (800 MHz, CDCl 3 )δ 7.40-7.39(d,J=7.52Hz,2H),7.36-7.34(t,J=7.64Hz,2H),7.30-7.29(t,J=6.52 Hz, 1H), 7.24–7.22 (t, J = 8.48 Hz, 2H), 6.92–6.90 (d, J = 8.64 Hz, 2H), 6.37 (br, 1H), 5.05 (br, 1H), 5.04 (s) , 2H), 4.53 (br, 2H), 3.25 (br, 2H), 2.38–2.37 (t, J = 4.92, 2H), 1.96 (br, 6H)
실시예 10. 1-(4-벤질옥시-벤질)-3-(2-디메틸아미노-에틸)-urea (9) 제조Example 10. Preparation of 1-(4-benzyloxy-benzyl)-3-(2-dimethylamino-ethyl)-urea (9)
[반응식 2][Scheme 2]
반응식 2와 같이 4-(벤질옥시-페닐)-메탄아민 염산염(400mg, 1.60mmol)을 아르곤 치환된 상태에서 다이메틸포름아마이드 용매 하에서 카모닐다이이미다졸(357mg, 3.52mmol)과 TEA(TriEthylAmine, 0.49mL, 1.38mmol)를 넣은 후 교반하였다. TLC 상에 기질이 없어짐을 확인 후, 별도의 여과 과정 없이 다음 반응의 반응물로 사용하였다.As shown in
위의 반응에서 생성된 1-(벤질옥시)-4-(아이소사이아나토메틸)-벤젠을 아르곤 치환된 상태에서 다이메틸포름아마이도 용매 하에서 N,N-디메틸에틸렌다이아민 (0.35mL, 3.2mmol)과 TEA(TriEthylAmine, 0.67mL, 4.80mmol)를 넣은 후 교반하였다. TLC 상에 기질이 없어짐을 확인 후, 에틸아세테이트와 물로 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하였다. 여과된 유기층을 헥산 용매를 통해 고체화한 후 이를 여과하여 백색 고체(86.8mg, 0.65mmol)를 얻었다(수율: 17%).1-(benzyloxy)-4-(isocyanatomethyl)-benzene produced in the above reaction was substituted with argon in a state of dimethylformamide under a solvent of N,N-dimethylethylenediamine (0.35mL, 3.2 mL). mmol) and TEA (TriEthylAmine, 0.67mL, 4.80mmol) were added and stirred. After confirming that the substrate was gone on TLC, extraction was performed with ethyl acetate and water, and the organic layer was washed with brine and filtered with magnesium sulfate. The filtered organic layer was solidified using a hexane solvent and filtered to obtain a white solid (86.8mg, 0.65mmol) (yield: 17%).
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J = 7.12 Hz, 2H), 7.36-7.34 (t, J = 7.64 Hz, 2H), 7.30-7.29 (t, J = 7.36 Hz, 1H), 7.20-7.19 (d, J = 8.64 Hz, 2H), 6.90-6.89 (d, J = 8.56 Hz, 2H), 5.03 (s, 2H), 4.28-4.26 (d, J = 5.52 Hz, 2H), 3.24-3.22 (dd, J 1 = 10.96 Hz, J 2 = 5.28 Hz, 2H), 2.42-2.41 (t, J = 5.6 Hz, 2H), 2.18 (s, J = 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.40-7.39 (d, J = 7.12 Hz, 2H), 7.36-7.34 (t, J = 7.64 Hz, 2H), 7.30-7.29 (t, J = 7.36 Hz, 1H), 7.20–7.19 (d, J = 8.64 Hz, 2H), 6.90–6.89 (d, J = 8.56 Hz, 2H), 5.03 (s, 2H), 4.28–4.26 (d, J = 5.52 Hz) , 2H), 3.24-3.22 (dd, J 1 = 10.96 Hz, J 2 = 5.28 Hz, 2H), 2.42-2.41 (t, J = 5.6 Hz, 2H), 2.18 (s, J = 6H)
실시예 11. 1-(4-벤질옥시-벤질)-3-(3-디메틸아미노-프로필) thiourea (10) 제조Example 11. Preparation of 1-(4-benzyloxy-benzyl)-3-(3-dimethylamino-propyl) thiourea (10)
상기 실시예 9와 같은 방법으로 3-디메틸아미노-1-프로필아민을 사용하여 흰색 고체(249mg, 0.69mmol)를 얻었다(수율: 89%).In the same manner as in Example 9, 3-dimethylamino-1-propylamine was used to obtain a white solid (249mg, 0.69mmol) (yield: 89%).
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J = 7.52 Hz, 2H), 7.36-7.35 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.32 Hz, 1H), 7.24 (d, J = 9.54 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.07 (s, 2H), 4.56 (br.s, 2H), 3.43 (br.s, 2H), 2.34 (br.s, 2H), 1.97 (br.s, 6H) 1.78 (br.s, 2H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.40-7.39 (d, J = 7.52 Hz, 2H), 7.36-7.35 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.32 Hz, 1H), 7.24 (d, J = 9.54 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.07 (s, 2H), 4.56 (br.s, 2H), 3.43 (br.s, 2H) ), 2.34 (br.s, 2H), 1.97 (br.s, 6H) 1.78 (br.s, 2H)
실시예 12. 1-(4-벤질옥시-벤질)-3-(4-디메틸아미노-부틸)-thiourea (11) 제조Example 12. Preparation of 1-(4-benzyloxy-benzyl)-3-(4-dimethylamino-butyl)-thiourea (11)
상기 실시예 9와 같은 방법으로 N,N-디메틸-1,4-부탄다이아민을 사용하여 흰색 고체(276mg, 0.74mmol)를 얻었다(수율: 95%).A white solid (276mg, 0.74mmol) was obtained using N,N -dimethyl-1,4-butanediamine in the same manner as in Example 9 (yield: 95%).
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J = 7.2 Hz, 2H), 7.36-7.35 (t, J = 7.64 Hz, 2H), 7.30-7.29 (t, J = 7.32 Hz, 1H), 7.22-7.19 (d, J = 8.56 Hz, 2H), 6.92-6.90 (d, J = 8.64 Hz, 2H), 6.42 (br, 1H), 5.03 (s, 2H), 4.60 (br, 2H), 3.36 (br, 2H), 2.28-2.27 (t, J = 6.6 Hz, 2H), 2.13 (s, 6H), 1.63-1.61 (m, 2H), 1.53-1.50 (m, 2H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.40-7.39 (d, J = 7.2 Hz, 2H), 7.36-7.35 (t, J = 7.64 Hz, 2H), 7.30-7.29 (t, J = 7.32 Hz, 1H), 7.22-7.19 (d, J = 8.56 Hz, 2H), 6.92-6.90 (d, J = 8.64 Hz, 2H), 6.42 (br, 1H), 5.03 (s, 2H), 4.60 (br , 2H), 3.36 (br, 2H), 2.28–2.27 (t, J = 6.6 Hz, 2H), 2.13 (s, 6H), 1.63–1.61 (m, 2H), 1.53–1.50 (m, 2H)
실시예 13. 1-((4-벤질옥시-벤질)-3-(2-디에틸아미노-에틸))-thiourea (12) 제조Example 13. Preparation of 1-((4-benzyloxy-benzyl)-3-(2-diethylamino-ethyl))-thiourea (12)
상기 실시예 9와 같은 방법으로 N,N-디에틸에틸렌다이아민을 사용하여 백색 고체(262mg, 0.71mmol)를 얻었다(수율: 90%).A white solid (262mg, 0.71mmol) was obtained using N,N -diethylethylenediamine in the same manner as in Example 9 (yield: 90%).
1H-NMR (800 MHz, CDCl3)δ10.15(br.s,1H),7.40-7.39(d,J = 7.52 Hz, 2H), 7.36-7.34 (t, J = 7.64 Hz, 2H), 7.30-7.29 (t, J = 7.32 Hz, 2H), 7.25-7.24 (d, J = 5.2 Hz, 2H), 6.29 (br.s, 1H), 5.04 (s, 2H), 4.60 (br.s, 2H), 3.26 (br.s, 2H), 2.50 (s, 2H), 2.34 (s, 4H), 0.80 (s, 6H) 1H -NMR (800 MHz, CDCl 3 )δ 10.15 (br.s, 1H), 7.40-7.39 (d, J = 7.52 Hz, 2H), 7.36-7.34 (t, J = 7.64 Hz, 2H), 7.30-7.29 (t, J = 7.32 Hz, 2H), 7.25-7.24 (d, J = 5.2 Hz, 2H), 6.29 (br.s, 1H), 5.04 (s, 2H), 4.60 (br.s, 2H), 3.26 (br.s, 2H), 2.50 (s, 2H), 2.34 (s, 4H), 0.80 (s, 6H)
실시예 14. 1-(4-벤질옥시-벤질)-3-(2-디메틸아미노에틸)-thiourea (13) 제조Example 14. Preparation of 1-(4-benzyloxy-benzyl)-3-(2-dimethylaminoethyl)-thiourea (13)
상기 실시예 9와 같은 방법으로 2-클로로에틸아민 염산염과 TEA(TriEthylAmine)을 사용하여 백색 고체(249mg, 0.73mmol)를 얻었다(수율: 83%).In the same manner as in Example 9, 2-chloroethylamine hydrochloride and TEA (Triethylamine) were used to obtain a white solid (249mg, 0.73mmol) (yield: 83%).
1H-NMR (800 MHz, CDCl3)δ10.1(br,H) 7.40-7.39 (d, J = 7.2 Hz, 2H), 7.36-7.34 (t, J = 7.6 Hz, 2H), 7.30-7.28 (t, J = 7.32 Hz, 1H), 7.25-7.24 (d, J = 8.48 Hz, 2H), 6.91-6.90 (d, J = 8.56Hz, 2H), 6.40 (br, 1H), 5.04 (s, 2H), 4.68 (br, 2H), 3.27 (br, 2H), 2.40-2.39 (t, J = 4.88 Hz, 2H), 2.30 (br, 4H), 1.24 (br, 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 10.1(br,H) 7.40-7.39 (d, J = 7.2 Hz, 2H), 7.36-7.34 (t, J = 7.6 Hz, 2H), 7.30-7.28 (t, J = 7.32 Hz, 1H), 7.25–7.24 (d, J = 8.48 Hz, 2H), 6.91–6.90 (d, J = 8.56 Hz, 2H), 6.40 (br, 1H), 5.04 (s, 2H), 4.68 (br, 2H), 3.27 (br, 2H), 2.40-2.39 (t, J = 4.88 Hz, 2H), 2.30 (br, 4H), 1.24 (br, 6H)
실시예 15. 1-(4-벤질옥시-벤질)-3-(2-모르폴리노에틸)-thiourea (14) 제조Example 15. Preparation of 1-(4-benzyloxy-benzyl)-3-(2-morpholinoethyl)-thiourea (14)
상기 실시예 9와 같은 방법으로 4-(2-아미노에틸)-모르폴린을 사용하여 백색 고체(251mg, 0.65mmol)를 얻었다(수율: 83%).In the same manner as in Example 9, 4-(2-aminoethyl)-morpholine was used to obtain a white solid (251 mg, 0.65 mmol) (yield: 83%).
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J = 7.6 Hz, 2H), 7.36-7.35 (t, J = 7.6 Hz, 2H), 7.31-7.29 (t, J = 7.28 Hz, 1H), 7.25-7.24 (t, J = 8 Hz, 2H), 6.93-6.91 (d, J = 8.64 Hz, 2H), 6.37 (br.s, 1H), 5.04 (s, 2H), 4.59 (br.s, 2H), 3.39 (br.s, 6H), 2.46-2.45 (t, J = 5.16 Hz, 2H), 2.34 (s, 4H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.40-7.39 (d, J = 7.6 Hz, 2H), 7.36-7.35 (t, J = 7.6 Hz, 2H), 7.31-7.29 (t, J = 7.28 Hz, 1H), 7.25–7.24 (t, J = 8 Hz, 2H), 6.93–6.91 (d, J = 8.64 Hz, 2H), 6.37 (br.s, 1H), 5.04 (s, 2H), 4.59 (br.s, 2H), 3.39 (br.s, 6H), 2.46-2.45 (t, J = 5.16 Hz, 2H), 2.34 (s, 4H)
실시예 16. 1-(4-벤질옥시-벤질)-3-페닐-thiourea(15) 제조Example 16. Preparation of 1-(4-benzyloxy-benzyl)-3-phenyl-thiourea (15)
상기 실시예 2와 같은 방법으로 아닐린과 디에틸이써 용매를 사용하여 흰색 고체(258.6mg, 0.74mmol)를 얻었다(수율: 95%).In the same manner as in Example 2, a white solid (258.6 mg, 0.74 mmol) was obtained using aniline and diethyl ether as solvents (yield: 95%).
1H-NMR (300MHZ, DMSO) δ9.54(br, 1H), 8.07(br, 1H), 7.44-7.25(m, 11H), 7.12-7.07(t, J = 7.32Hz, 1H), 6.99-6.95(d, J = 8.58Hz, 2H), 5.08(s, 2H), 4.65-4.63(d, J = 5.31Hz, 2H) 1H -NMR (300MHZ, DMSO) δ9.54 (br, 1H), 8.07 (br, 1H), 7.44-7.25 (m, 11H), 7.12-7.07 (t, J = 7.32Hz, 1H), 6.99- 6.95(d, J = 8.58Hz, 2H), 5.08(s, 2H), 4.65-4.63(d, J = 5.31Hz, 2H)
실시예 17. 1-(4-벤질옥시-벤질)-3-(4-디메틸아미노-페닐)-thiourea (16) 제조Example 17. Preparation of 1-(4-benzyloxy-benzyl)-3-(4-dimethylamino-phenyl)-thiourea (16)
상기 실시예 2와 같은 방법으로 N,N-디메틸-p-페닐렌다이아민을 사용하여 갈색 고체(132mg, 0.34mmol)를 얻었다(수율: 43%).A brown solid (132mg, 0.34mmol) was obtained using N,N -dimethyl- p -phenylenediamine in the same manner as in Example 2 (yield: 43%).
1H-NMR (800 MHz, CDCl3)δ7.47(s,1H),7.39-7.38(d,J = 7.2 Hz, 2H), 7.36-7.34 (t, J = 7.6 Hz, 2H), 7.30-7.29 (t, J = 7.28 Hz, 1H), 7.18-7.16 (d, J = 8.64 Hz, 2H), 7.02-7.01 (d, J = 8.88 Hz, 2H), 6.89-6.88 (d, J = 8.64 Hz, 2H), 6.65-6.62 (d, J = 8.96 Hz, 2H), 5.97 (br, 1H), 5.01 (s, 2H), 4.76-4.75 (d, J = 5.52 Hz, 2H), 2.93 (s, 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.47(s, 1H), 7.39-7.38 (d, J = 7.2 Hz, 2H), 7.36-7.34 (t, J = 7.6 Hz, 2H), 7.30- 7.29 (t, J = 7.28 Hz, 1H), 7.18–7.16 (d, J = 8.64 Hz, 2H), 7.02–7.01 (d, J = 8.88 Hz, 2H), 6.89–6.88 (d, J = 8.64 Hz) , 2H), 6.65–6.62 (d, J = 8.96 Hz, 2H), 5.97 (br, 1H), 5.01 (s, 2H), 4.76–4.75 (d, J = 5.52 Hz, 2H), 2.93 (s, 6H)
실시예 18. 1-(4-벤질옥시-벤질)-3-(3-디메틸아미노-페닐)-thiourea (17) 제조Example 18. Preparation of 1-(4-benzyloxy-benzyl)-3-(3-dimethylamino-phenyl)-thiourea (17)
상기 실시예 9와 같은 방법으로 N,N-디메틸-1,3-페닐렌다이아민을 사용하여 흰색 고체(171mg, 0.44mmol)를 얻었다(수율: 56%).A white solid (171mg, 0.44mmol) was obtained using N,N -dimethyl-1,3-phenylenediamine in the same manner as in Example 9 (yield: 56%).
1H-NMR (800 MHz, CDCl3)δ7.65(s,1H),7.39-7.38(d,J = 7.52 Hz, 2H), 7.36-7.35 (t, J = 7.6 Hz, 2H), 7.31-7.29 (t, J = 7.28 Hz, 1H), 7.21-7.20 (d, J = 8.56 Hz, 2H), 7.19-7.17 (t, J = 8.08 Hz, 1H), 6.90-6.89 (d, J = 8.64 Hz, 2H), 6.55-6.54 (dd, J 1 = 8.4, J 2 = 2.78, 1H), 6.45-6.44 (d, J = 7.6 Hz, 1H), 6.40 (s, 1H), 6.37 (br, 1H), 5.02 (s,2H), 4.78-4.77 (d, J = 5.36 Hz, 2H), 2.87 (s, 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.65(s, 1H), 7.39-7.38 (d, J = 7.52 Hz, 2H), 7.36-7.35 (t, J = 7.6 Hz, 2H), 7.31- 7.29 (t, J = 7.28 Hz, 1H), 7.21–7.20 (d, J = 8.56 Hz, 2H), 7.19–7.17 (t, J = 8.08 Hz, 1H), 6.90–6.89 (d, J = 8.64 Hz) , 2H), 6.55–6.54 (dd, J 1 = 8.4, J 2 = 2.78, 1H), 6.45–6.44 (d, J = 7.6 Hz, 1H), 6.40 (s, 1H), 6.37 (br, 1H) , 5.02 (s, 2H), 4.78-4.77 (d, J = 5.36 Hz, 2H), 2.87 (s, 6H)
실시에 19. 1-벤질-3-(4-벤질옥시-벤질) -thiourea (18) 제조Example 19. Preparation of 1-benzyl-3-(4-benzyloxy-benzyl)-thiourea (18)
상기 실시예 9와 같은 방법으로 벤질아민 염산염과 TEA(TriEthylAmine)을 사용하여 백색 고체(161mg, 0.44mmol)를 얻었다(수율: 70%).A white solid (161mg, 0.44mmol) was obtained using benzylamine hydrochloride and TEA (TriEthylAmine) in the same manner as in Example 9 (yield: 70%).
1H-NMR (300MHZ, DMSO) δ 6.64(d, J = 2.2 Hz, 2H), 6.36-6.34(t, J = 2.2 Hz, 2H), 4.62(s, 2H), 3.74(s, 6H), 2.94(s, 3H) 1H -NMR (300MHZ, DMSO) δ 6.64 (d, J = 2.2 Hz, 2H), 6.36-6.34 (t, J = 2.2 Hz, 2H), 4.62 (s, 2H), 3.74 (s, 6H), 2.94(s, 3H)
실시예 20. 1-(4-벤질옥시-벤질)-3-(4-디메틸아미노-벤질)-thiourea (19) 제조Example 20. Preparation of 1-(4-benzyloxy-benzyl)-3-(4-dimethylamino-benzyl)-thiourea (19)
상기 실시예 9와 같은 방법으로 4-디메틸아미노-벤질아민 염산염과 TEA(TriEthylAmine)을 사용하여 백색 고체(257mg, 0.63mmol)를 얻었다(수율: 81%).In the same manner as in Example 9, 4-dimethylamino-benzylamine hydrochloride and TEA (Triethylamine) were used to obtain a white solid (257mg, 0.63mmol) (yield: 81%).
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J = 7.52 Hz, 2H), 7.37-7.35 (t, J = 7.6 Hz, 2H), 7.31-7.29 (t, J = 7.28 Hz, 1H), 7.13-7.12 (d, J = 8.4 Hz, 2H), 7.09-7.08 (d, J = 8.56 Hz, 2H), 6.89-6.88 (d, J = 8.64 Hz, 2H), 6.64-6.63 (d, J = 8.56 Hz, 2H), 5.91 (br, 1H), 5.03 (s, 2H), 4.52 (br, 2H), 4.42 (br, 2H), 2.91 (s, 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.40-7.39 (d, J = 7.52 Hz, 2H), 7.37-7.35 (t, J = 7.6 Hz, 2H), 7.31-7.29 (t, J = 7.28 Hz, 1H), 7.13–7.12 (d, J = 8.4 Hz, 2H), 7.09–7.08 (d, J = 8.56 Hz, 2H), 6.89–6.88 (d, J = 8.64 Hz, 2H), 6.64–6.63 (d, J = 8.56 Hz, 2H), 5.91 (br, 1H), 5.03 (s, 2H), 4.52 (br, 2H), 4.42 (br, 2H), 2.91 (s, 6H)
실시예 21. 1-(4-벤질옥시-벤질)-3-(3-디메틸아미노-벤질)-thiourea (20) 제조Example 21. Preparation of 1-(4-benzyloxy-benzyl)-3-(3-dimethylamino-benzyl)-thiourea (20)
상기 실시예 9와 같은 방법으로 N-(3-아미노메틸-페닐)-N,N-디메틸아민 염산염과 TEA(TriEthylAmine)을 사용하여 백색 고체(197mg, 0.49mmol)를 얻었다(수율: 62%).In the same manner as in Example 9, N-(3-aminomethyl-phenyl)-N,N-dimethylamine hydrochloride and TEA (Triethylamine) were used to obtain a white solid (197mg, 0.49mmol) (yield: 62%) .
1H-NMR (800 MHz, CDCl3)δ7.40-7.39(d,J = 7.2 Hz, 2H), 7.37-7.35 (t, J = 6.68 Hz, 2H), 7.31-7.30 (t, J = 7.28 Hz, 1H), 7.15-7.14 (t, J = 7.84 Hz, 2H), 7.12-7.11 (d, J = 8.16 Hz, 1H), 6.88-6.87 (d, J = 8.56 Hz, 2H), 6.62-6.61 (dd, J 1 = 8.32 Hz, J 2 = 2.78 Hz, 1H), 6.56 (a, 1H), 6.55-6.54 (d, J = 7.52 Hz, 1H), 6.08 (br, 1H), 5.96 (br, 1H), 5.02 (s, 2H), 4.53 (br, 2H), 4.49 (br, 2H), 2.89 (s, 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.40-7.39 (d, J = 7.2 Hz, 2H), 7.37-7.35 (t, J = 6.68 Hz, 2H), 7.31-7.30 (t, J = 7.28 Hz, 1H), 7.15–7.14 (t, J = 7.84 Hz, 2H), 7.12–7.11 (d, J = 8.16 Hz, 1H), 6.88–6.87 (d, J = 8.56 Hz, 2H), 6.62–6.61 (dd, J 1 = 8.32 Hz, J 2 = 2.78 Hz, 1H), 6.56 (a, 1H), 6.55-6.54 (d, J = 7.52 Hz, 1H), 6.08 (br, 1H), 5.96 (br, 1H), 5.02 (s, 2H), 4.53 (br, 2H), 4.49 (br, 2H), 2.89 (s, 6H)
실시예 22. 1-(3, 4-디하이드록시-벤질)-3-메틸-thiourea (21) 제조방법Example 22. Method for preparing 1-(3,4-dihydroxy-benzyl)-3-methyl-thiourea (21)
[반응식 3][Scheme 3]
반응식 3과 같이 5-클로로-2-나이트로아닐린(1000mg, 5.79mmol)을 Dimethylforamide 용매 하에서 포타슘 카보네이트(4805mg, 34.8mmol)를 넣은 후, 디메틸아민 염산염(784mg, 17.4mmol)을 넣고 교반하였다. TLC 상에 기질이 없어짐을 확인한 후, 용매를 날리고 에틸아세테이트와 물을 이용하여 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과한 후, 여과된 유기층을 실리카 컬럼을 통해 분리하며 노란색 고체(661.5mg, 3.65mmol)를 얻었다(수율: 63%).As shown in
위의 반응에서 얻은 물질인 N,N-디메틸-4-나이트로벤젠-1,3-다이아민(100mg, 0.55mmol)을 아르곤 치환된 상태에서 에틸아세테이트와 메탄올 용매 하에서 Pd/C(Palladium on carbon, 5.87mg, 0.055mmol)과 소듐보로하이드라이드(52mg, 1.38mmol)를 넣은 후 교반하였다. TLC 상에 기질이 없어짐을 확인 후, 용매를 날리고 Celite로 여과한 후 유기층을 별도의 여과 과정 없이 다음 반응의 반응물로 사용하였다. N,N -dimethyl-4-nitrobenzene-1,3-diamine (100mg, 0.55mmol), the material obtained from the above reaction, was substituted with argon in ethyl acetate and methanol solvent to Pd/C (Palladium on carbon). , 5.87mg, 0.055mmol) and sodium borohydride (52mg, 1.38mmol) were added and stirred. After confirming that the substrate was gone on TLC, the solvent was blown off and filtered with Celite, and the organic layer was used as a reactant for the next reaction without a separate filtration process.
Celite로 여과한 물질인 N,N-디메틸벤젠-1,2,4-트리아민(167mg, 1.10mmol)을 다이클로로메탄 용매 하에 1-(벤질옥시)-4-(아이소싸이오사이아나토메틸)-벤젠(141mg, 0.55mmol)을 넣어 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인한 후, 디클로로메탄과 물로 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하였다. 여과된 유기층을 헥산 용매를 통해 고체화한 후 이를 여과하여 백색 고체(203mg, 0.50mmol)를 얻었다(수율: 90%). N,N -dimethylbenzene-1,2,4-triamine (167mg, 1.10mmol), a material filtered through Celite, was mixed with 1-(benzyloxy)-4-(isothiocyanatomethyl) under dichloromethane solvent. )-benzene (141mg, 0.55mmol) was added and stirred. After confirming the disappearance of the substrate on thin layer chromatography (TLC), extraction was performed with dichloromethane and water, and the organic layer was washed with brine and filtered with magnesium sulfate. The filtered organic layer was solidified using a hexane solvent and filtered to obtain a white solid (203 mg, 0.50 mmol) (yield: 90%).
헥산으로 고체화한 물질인 1-(2-아미노-4-디메틸아미노-페닐_-3-(4-벤질옥시-벤질)thiourea(50mg, 0.12mmol)를 에탄올과 디클로로메탄 용매 하에서 산화수은(53mg, 0.12mmol)과 황(0.79mg, 0.025mmol)을 넣고 교반하였다. TLC(Thin layer chromatography) 상에 기질이 없어짐을 확인 후, 용매를 날리고 디클로로메탄과 물로 추출한 후 유기층을 브라인으로 씻어주고 황산마그네슘으로 여과하였다. 여과된 유기층을 실리카 컬럼을 통해 분리하며 갈색 고체(36mg, 0.097mmol)를 얻었다(수율: 79%).Mercury oxide (53 mg, 0.12 mmol) and sulfur (0.79mg, 0.025mmol) were added and stirred.After confirming that the substrate was gone on TLC (Thin layer), the solvent was blown off, extracted with dichloromethane and water, and the organic layer was washed with brine and filtered with magnesium sulfate. The filtered organic layer was separated through a silica column to obtain a brown solid (36mg, 0.097mmol) (yield: 79%).
1H-NMR (800 MHz, CDCl3)δ7.39-7.38(d,J = 7.44 Hz, 2H), 7.36-7.34 (t, J = 7.6 Hz, 2H), 7.30-7.28 (t, J = 7.28 Hz, 1H), 7.24-7.22 (d, J = 8.96 Hz, 2H), 7.09 (br, 1H), 6.90-6.89 (d, J = 2.72 Hz, 2H) 6.73 (br, 1H), 6.58 (br, 1H), 5.01 (s, 2H), 4.45 (br, 2H), 2.86 (br, 6H) 1 H-NMR (800 MHz, CDCl 3 )δ 7.39-7.38 (d, J = 7.44 Hz, 2H), 7.36-7.34 (t, J = 7.6 Hz, 2H), 7.30-7.28 (t, J = 7.28 Hz, 1H), 7.24-7.22 (d, J = 8.96 Hz, 2H), 7.09 (br, 1H), 6.90-6.89 (d, J = 2.72 Hz, 2H) 6.73 (br, 1H), 6.58 (br, 1H), 5.01 (s, 2H), 4.45 (br, 2H), 2.86 (br, 6H)
[실험예 - 생물학적 효능 검사][Experimental Example - Biological Efficacy Test]
실험예 1. Thiourea계 신규화합물들이 RORα의 전사활성에 미치는 효과 확인Experimental Example 1. Confirmation of the effect of Thiourea-based novel compounds on the transcriptional activity of RORα
Chang liver 세포(CCL-13)는 ATCC(American Type Culture Collection)로부터 구입하였다. Chang liver 세포(2.5 x 104세포/웰)를 24-웰 배양 플레이트에 분주하고, 10% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤 동안 배양하였다. Chang liver 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후, PolyFect(QIAGEN)를 이용하여 세포를 RORE-tk-Luc 리포터 플라스미드(50 ng), RORα 발현 벡터(10 ng)로 형질전환시켰다. 형질 전환 24시간 후, thiourea계 신규화합물들(20 μM), 또는 JC1-40 대조군을 처리하였다. 처리한 지 18시간 후, 루시퍼라아제 활성을 Analytical luminescence luminometer를 이용하여 측정하였다. 형질전환 효율을 확인하기 위하여, 200ng의 β-galactosidase(β-gal) 발현 벡터의 활성을 이용하여 루시퍼라아제 활성을 표준화하였다. 이에 대한 결과는 표 1에 나타내었으며, 표 1을 도식화하여 도 2에 나타내었다.Chang liver cells (CCL-13) were purchased from American Type Culture Collection (ATCC). Chang liver cells (2.5 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air. After culturing, the cells were transformed with the RORE-tk-Luc reporter plasmid (50 ng) and the RORa expression vector (10 ng) using PolyFect (QIAGEN). 24 hours after transformation, thiourea-based novel compounds (20 μM) or JC1-40 control were treated. Eighteen hours after treatment, luciferase activity was measured using an Analytical luminescence luminometer. To confirm the transformation efficiency, luciferase activity was normalized using the activity of 200 ng of β-galactosidase (β-gal) expression vector. The results for this are shown in Table 1, and Table 1 is schematized and shown in FIG. 2.
표 1 및 도 2에 나타난 바와 같이, thiourea계 신규화합물들 중에서 8번(ODH-08) 및 13번 화합물이 JC1-40보다 현저히 높은 RORα의 전사활성 증가 효과를 나타내었다. As shown in Table 1 and FIG. 2, among the new thiourea compounds, compounds No. 8 (ODH-08) and No. 13 exhibited significantly higher RORα transcriptional activity increasing effect than JC1-40.
8번 및 13번 화합물 외에도 9, 12, 16, 17, 19, 및 20번 화합물의 경우 JC1-40보다 우수한 RORα의 전사활성 증가 효과를 나타내었다.In addition to
실험예 2. ODH-08 농도에 따른 RORα 전사활성에 미치는 효과 확인Experimental Example 2. Confirmation of effect on RORα transcriptional activity according to ODH-08 concentration
Chang liver 세포(1.25 x 104세포/웰)를 24-웰 배양 플레이트에 분주하고, 10% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤 동안 배양하였다. Chang liver 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지시켰다. 배양 후, PolyFect(QIAGEN)를 이용하여 RORE-Luc 리포터(50 ng)와 RORα 발현 벡터(10 ng)를 Chang liver 세포에 형질전환 시켰다. 형질전환 24시간 후, Chang liver 세포를 상기 실험예 1에서 관찰된 RORα의 전사활성 효과가 가장 뛰어난 8번 화합물(ODH-08)을 다이메틸설폭시드(DMSO)에 용해시키고 특정 농도(0.5 μM, 2 μM, 10 μM, 20 μM 및 30 μM) 또는 동량의 용매(대조군)로 18시간 동안 처리하였다. 이후 세포 용해물을 수득하고, Analytical luminescence luminometer를 이용하여 루시퍼라아제 활성을 분석하고 결정하였다. β-gal 활성으로 형질전환 효율에 대한 루시퍼라아제 활성을 표준화하였고, 그 결과를 도 3에 나타내었다.Chang liver cells (1.25 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air. After culturing, the RORE-Luc reporter (50 ng) and the RORα expression vector (10 ng) were transfected into Chang liver cells using PolyFect (QIAGEN). 24 hours after transformation, Chang liver cells were dissolved in dimethyl sulfoxide (DMSO) with Compound 8 (ODH-08), which has the highest effect on RORα transcription activity observed in Experimental Example 1, and was dissolved at a specific concentration (0.5 μM, 2 μM, 10 μM, 20 μM and 30 μM) or the same amount of solvent (control) for 18 hours. Cell lysates were then obtained, and luciferase activity was analyzed and determined using an Analytical luminescence luminometer. Luciferase activity was normalized for transformation efficiency with β-gal activity, and the results are shown in FIG. 3 .
도 3에 나타난 바와 같이, RORα의 전사활성은 ODH-08의 농도에 의존적으로 증가하였다. 저농도(0.5 μM 및 2 μM)의 ODH-08에 의해서는 RORα 활성이 미미한 증가를 보였으나, 10-30 μM 범위의 농도로 처리하였을 때는 농도 의존적 활성의 증가 효과를 나타내는 것으로 관찰되었다. As shown in Figure 3, the transcriptional activity of RORα increased in a concentration-dependent manner of ODH-08. Low concentrations (0.5 μM and 2 μM) of ODH-08 showed a slight increase in RORα activity, but treatment with concentrations in the range of 10-30 μM showed a concentration-dependent increase in activity.
실험예 3. ODH-08 이 RORα와 결합하는 부위 예측Experimental Example 3. Prediction of ODH-08 binding site to RORα
ODH-08과 RORα 단백질의 결합 구조를 인 실리코(in silico) 상으로 예측하기 위하여 도킹 시뮬레이션을 수행하였다. 도킹 모델은 Schrodinger Glide v.7.9(force field: OPLS3e) 및 Macromodel v. 12.0 프로그램을 사용하여 RORα 단백질과 ODH-08 간의 수용체-리간드 상호작용을 모델링하였다. 분자 도킹 시뮬레이션을 위해 RORα의 PDB를 RCSB Protein Data Bank에서 다운로드하고 Schrodinger Suite(힘 필드: OPLS3e)를 사용하였고, 리간드 ODH-08의 3D 형태는 OPLS3 힘장에서 최소안정화 하였다. ODH-08과 RORα 단백질의 결합 가능한 구조를 시뮬레이션 하여 최대 1000개의 포즈가 생성되었고, 2D & 3D 뷰로 포즈 분석을 수행하여 그 중 에너지 결과 값이 가장 우수한 결과를 도 4에 나타내었다.Docking simulation was performed to predict the binding structure of ODH-08 and RORa protein in silico. Docking models are Schrodinger Glide v.7.9 (force field: OPLS3e) and Macromodel v. 12.0 program was used to model the receptor-ligand interaction between RORa protein and ODH-08. For molecular docking simulation, the PDB of RORα was downloaded from the RCSB Protein Data Bank and Schrodinger Suite (force field: OPLS3e) was used, and the 3D conformation of the ligand ODH-08 was minimally stabilized in the OPLS3 force field. Up to 1000 poses were generated by simulating the structure capable of binding ODH-08 and RORα protein, and pose analysis was performed with 2D & 3D views, and among them, the best energy results are shown in FIG. 4 .
도 4에 나타난 바와 같이, 알려진 천연 리간드 콜레스테롤 설페이트와 같이 ODH-08은 안정화된 비공유 상호작용을 통해 RORα에 도킹되었다. ODH-08의 벤질옥시벤질기와 Cys323, Ile327, Leu361, Phe 365, Val379, Tyr380, Phe381, Phe391, Leu394로 구성된 친유성 포켓에 소수성 상호작용을 하고 있고 특히, Phe391은 ODH-08의 벤질옥시기(benzyloxy group)와 π-π stacking을 보였다. ODH-08의 3차 디메틸아민 그룹은 Gln289와 H-결합을 하고 있는데, 이는 티오우레아와 아민 그룹 사이의 길이가 길어짐에 따라 ODH-010 또는 ODH-011이 ODH-08보다 활성이 낮다는 결과를 뒷받침한다. 한편, 에틸아민(ODH-012) 및 피페리딘(ODH-013) 그룹은 입체 충돌을 일으키는 Tyr290, Glu329 및 GLn289와의 거리가 가깝기 때문에 디메틸아민 그룹(ODH-08)보다 선호도가 낮다. 티오요소(ODH-08)를 요소(ODH-09)로 대체하는 것은 도킹 모델로 명확하게 설명할 수 없으나, 티오요소는 요소보다 N-H의 pKa가 낮아 산성이 강하여 H-결합이 강하다는 것이 잘 알려져 있다. 두 화합물의 에너지를 비교할 때, ODH-08의 쿨롱에너지가 ODH-09의 쿨롱에너지보다 더 안정적이었다. As shown in Figure 4, like the known natural ligand cholesterol sulfate, ODH-08 was docked to RORa through a stabilized non-covalent interaction. The benzyloxybenzyl group of ODH-08 and Cys323, Ile327, Leu361, Phe 365, Val379, Tyr380, Phe381, Phe391, and Leu394 have hydrophobic interactions in the lipophilic pocket, and in particular, Phe391 has a benzyloxy group of ODH-08 ( benzyloxy group) and π-π stacking. The tertiary dimethylamine group of ODH-08 has an H-bond with Gln289, which means that ODH-010 or ODH-011 has lower activity than ODH-08 as the length between the thiourea and amine groups increases. support On the other hand, the ethylamine (ODH-012) and piperidine (ODH-013) groups are less preferred than the dimethylamine group (ODH-08) because they are close to Tyr290, Glu329, and GLn289, which cause steric collisions. Although the replacement of thiourea (ODH-08) with urea (ODH-09) cannot be clearly explained by the docking model, it is well known that thiourea has a lower pKa of N-H than urea and is more acidic, resulting in stronger H-bonds. there is. When comparing the energies of the two compounds, the Coulomb energy of ODH-08 was more stable than that of ODH-09.
실험예 4. ODH-08 의 농도에 따른 RORα와의 결합력 분석Experimental Example 4. Analysis of binding force with RORα according to the concentration of ODH-08
ODH-08과 RORα 간의 결합력을 확인하기 위하여 표면 플라스몬 공명(surface plasmon resonance, SPR) 실험을 수행하였다. 먼저, RORα 재조합단백질을 생산하기 위하여 pET21a+-GST-RORα-His플라스미드를 B21 세포에 형질전환시킨 후 37℃ LB배지(Luria-Bertani broth)에서 배양하였다. 그후 0.5mM 이소프로필 β-D-1-티오갈락토피라노사이드를 처리하여 6시간 동안 30℃에서 배양하였다. 세포를 용해시킨 뒤 원심분리하여 상등액을 취하였다. 수득한 상등액으로부터 His-tag 친화 크로마토그래피법으로 단백질을 분리 및 정제하였다. 보다 자세하게는, 상등액을 Ni+-NTA수지(Qiagen)로 구성된 컬럼에 통과시키고 50mM 트리스-염화수소(Tris-HCl), 100mM 염화나트륨, 50 mM 이미다졸으로 구성된 용액을 통과시켜 컬럼에 부착하지 않은 단백질을 제거하였다. 이동상의 이미다졸 농도를 250mM에서 500mM으로 증가시키며 목표 단백질을 용리하여 수득하였다. 이후 농축 및 희석과정을 거쳐 137mM 염화나트륨, 2.7mM 염화칼륨, 8.1mM 디소듐포스페이트, 1.8mM 인산이수소칼륨, 0.1% 폴리소베이트20(Sigma Aldrich)으로 구성된 PBS-T 용액으로 용매를 치환하였다. SPR 시스템 장비인 Biacore T200 (Cytiva)에 Series S CM5 sensor chip(Cytiva)을 삽입하고 앞서 정제한 재조합단백질을 고정하였다. 0.1% 다이메틸설폭사이드(DMSO)를 포함하는 PBS-T 용액에 ODH-08을 용해시켜 30μl/min의 속도로 주입하였다. 1-100μM의 범위의 다양한 농도의 ODH-08을 사용하였으며, 이에 대한 결과는 도 5에 나타내었다.In order to confirm the binding force between ODH-08 and RORα, a surface plasmon resonance (SPR) experiment was performed. First, in order to produce RORa recombinant protein, pET21a + -GST-RORa-His plasmid was transformed into B21 cells and cultured in LB medium (Luria-Bertani broth) at 37°C. Thereafter, the cells were treated with 0.5 mM isopropyl β-D-1-thiogalactopyranoside and incubated at 30° C. for 6 hours. After the cells were lysed, the supernatant was collected by centrifugation. Proteins were separated and purified from the obtained supernatant by His-tag affinity chromatography. More specifically, the supernatant was passed through a column composed of Ni + -NTA resin (Qiagen) and passed through a solution composed of 50 mM Tris-HCl, 100 mM sodium chloride, and 50 mM imidazole to remove proteins that did not adhere to the column. Removed. The target protein was eluted while increasing the concentration of imidazole in the mobile phase from 250 mM to 500 mM. After concentration and dilution, the solvent was replaced with a PBS-T solution composed of 137 mM sodium chloride, 2.7 mM potassium chloride, 8.1 mM disodium phosphate, 1.8 mM potassium dihydrogen phosphate, and 0.1% polysorbate 20 (Sigma Aldrich). Series S CM5 sensor chip (Cytiva) was inserted into Biacore T200 (Cytiva), an SPR system equipment, and the previously purified recombinant protein was fixed. ODH-08 was dissolved in a PBS-T solution containing 0.1% dimethyl sulfoxide (DMSO) and injected at a rate of 30 μl/min. Various concentrations of ODH-08 in the range of 1-100 μM were used, and the results are shown in FIG. 5 .
도 5에 나타난 바와 같이, ODH-08은 1-100 μM의 농도범위에서 RORα 단백질과의 결합을 나타내었다. 또한 농도의존적으로 RORα와의 결합 세기도 증가함을 확인하였다.As shown in Figure 5, ODH-08 showed binding to RORa protein in the concentration range of 1-100 μM. In addition, it was confirmed that the binding strength with RORα increased in a concentration-dependent manner.
실험예 5. ODH-08 의 선택적 RORα 전사활성 조절 확인Experimental Example 5. Confirmation of the regulation of selective RORα transcriptional activity of ODH-08
Chang liver 세포 (1.25 x 104세포/웰)를 24-웰 배양 플레이트에 분주하고, 10% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤 동안 배양하였다. Chang liver 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후, PolyFect(QIAGEN)를 이용하여 Gal4-tk-Luc 리포터(50 ng)와 RORα, RORβ 및 RORγ 발현 벡터(10 ng)를 Chang liver 세포에 형질전환시켰다. 형질전환 24시간 후, ODH-08 20μM 또는 동량의 용매(대조군)로 18시간 동안 처리하였다. 이후 세포 용해물을 수득하고, Analytical luminescence luminomete를 이용하여 루시퍼라아제 활성을 분석하고 결정하였다. β-gal 활성으로 형질전환 효율에 대한 루시퍼라아제 활성을 표준화하였고, 그 결과를 도 6a에 나타내었다. Chang liver cells (1.25 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air. After culturing, the Gal4- tk -Luc reporter (50 ng) and RORα, RORβ and RORγ expression vectors (10 ng) were transfected into Chang liver cells using PolyFect (QIAGEN). 24 hours after transformation, treatment was performed with 20 μM ODH-08 or the same amount of solvent (control) for 18 hours. Cell lysates were then obtained, and luciferase activity was analyzed and determined using an Analytical luminescence luminomete. Luciferase activity was normalized for transformation efficiency by β-gal activity, and the results are shown in FIG. 6A.
도 6a에 나타난 바와 같이, ODH-08 은 RORβ 및 RORγ의 전사활성은 증가시키지 않으며, RORα 전사활성만을 선택적으로 증가시키는 것을 확인하였다.As shown in Figure 6a, it was confirmed that ODH-08 selectively increased only RORα transcriptional activity without increasing the transcriptional activity of RORβ and RORγ.
또한, Chang liver 세포(1.25 x 104세포/웰)를 24-웰 배양 플레이트에 분주하고, 10% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤 동안 배양하였다. Chang liver 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후, PolyFect(QIAGEN)를 이용하여 Gal4-tk-Luc 리포터 (50 ng)와 PPARα, PPARδ, PPARγ 및 LXRα 발현 벡터(10 ng)를 Chang liver 세포에 형질전환시켰다. 형질전환 24시간 후, ODH-08 20μM, WY-14643 20μM, GW501516 20μM, troglitazone 20μM 또는 GW3965 20μM를 세포에 18시간 동안 처리하였다. 이후 세포 용해물을 수득하고, Analytical luminescence luminometer를 이용하여 루시퍼라아제 활성을 분석하고 결정하였다. β-gal 활성으로 형질전환 효율에 대한 루시퍼라아제 활성을 표준화하였고, 그 결과를 도 6b에 나타내었다. In addition, Chang liver cells (1.25 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air. After culturing, the Gal4- tk -Luc reporter (50 ng) and PPARα, PPARδ, PPARγ, and LXRα expression vectors (10 ng) were transfected into Chang liver cells using PolyFect (QIAGEN). 24 hours after transfection, cells were treated with 20 μM of ODH-08, 20 μM of WY-14643, 20 μM of GW501516, 20 μM of troglitazone or 20 μM of GW3965 for 18 hours. Cell lysates were then obtained, and luciferase activity was analyzed and determined using an Analytical luminescence luminometer. Luciferase activity was normalized for transformation efficiency by β-gal activity, and the results are shown in FIG. 6B.
도 6b에 나타난 바와 같이, ODH-08은 PARα, PPARδ, PPARγ 및 LXRα 전사활성에 대해서는 유의미한 증가 효과를 보이지 않았다.As shown in Figure 6b, ODH-08 did not show a significant increase effect on PARα, PPARδ, PPARγ and LXRα transcriptional activities.
실험예 6. ODH-08가 간세포 내의 지질 축적에 미치는 효과 확인Experimental Example 6. Confirmation of the effect of ODH-08 on lipid accumulation in hepatocytes
HepG2 세포(2.5 x 105세포/웰)를 6웰 디쉬에 분주하고, 10% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤 동안 배양하였다. HepG2 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후, HepG2 세포에 20μM의 ODH-08 또는 동량의 용매(대조군)를, 지질 생성 유도 물질로서 0.4 mM의 올레익산과 0.2 mM의 팔미트산을 2:1 비율로 섞은 지방산(free fatty acid, FFA) 믹스처(1M의 올레익산(oleic acid)과 50mM의 팔미트산은 1% fatty acid-free bovine serum albumin(BSA)이 포함된 배지에 섞어 최종 농도로 희석하여 사용함)와 함께 20시간 동안 처리하였다. 지방산 믹스처를 처리하지 않은 세포에는 1% fatty acid-free BSA가 포함된 배지와 동량의 용매를 처리하였다. 20시간 후, 세포를 1μg/ml의 나일 레드로 15분간 상온에서 염색하여 현미경으로 관찰하였다. 중성지방 (트리글리세라이드, triglyceride) 농도는 EnzyChromTM Triglyceride Assay Kit (BioAssay Systems)을 이용하여 570nm에서 흡광도를 측정한 후 단백질 양으로 표준화하였다. 그 결과를 도 7a 및 도 7b에 나타내었다.HepG2 cells (2.5 x 10 5 cells/well) were seeded into 6-well dishes and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). HepG2 cells were maintained at 37° C. in a humidified thermostat with 5% CO 2 and 95% air. After culturing, 20 μM of ODH-08 or the same amount of solvent (control) was added to HepG2 cells, and 0.4 mM of oleic acid and 0.2 mM of palmitic acid were mixed at a ratio of 2:1 as lipid production inducers (free fatty acid, FFA) Mixer (1M oleic acid and 50mM palmitic acid are mixed in a medium containing 1% fatty acid-free bovine serum albumin (BSA) and diluted to the final concentration) for 20 hours. did Cells not treated with the fatty acid mixture were treated with the same amount of solvent as the medium containing 1% fatty acid-free BSA. After 20 hours, the cells were stained with 1 μg/ml of Nile Red for 15 minutes at room temperature and observed under a microscope. The concentration of triglyceride (triglyceride) was normalized to the amount of protein after measuring the absorbance at 570 nm using the EnzyChrom™ Triglyceride Assay Kit (BioAssay Systems). The results are shown in Figures 7a and 7b.
도 7a 및 도 7b에 나타난 바와 같이, ODH-08 를 지방산과 함께 처리하였을 때, 지방산만 처리하였을 때보다 간세포 내의 지질의 축적이 유의하게 감소함을 확인하였다. 이는 ODH-08이 간에서의 지질 축적 억제 효과가 우수함을 나타낸다.As shown in Figures 7a and 7b, when ODH-08 was treated with fatty acids, it was confirmed that lipid accumulation in hepatocytes was significantly reduced compared to when only fatty acids were treated. This indicates that ODH-08 has an excellent effect of inhibiting lipid accumulation in the liver.
실험예 7. ODH-08가 쿠퍼세포의 극성 조절에 미치는 효과 확인Experimental Example 7. Confirmation of the effect of ODH-08 on the polarity regulation of Kupffer cells
ODH-08의 처리가 간 상주 대식세포인 쿠퍼세포의 극성 조절에 미치는 영향을 확인하였다. 먼저, 마우스로부터 분리한 복강 대식세포(peritoneal macrophage)에 ODH-08 또는 JC1-40를 처리하여 극성 표지인자들의 발현 변화를 확인하였다. 구체적으로, 마우스를 마취하고 개복한 다음, 복강에 한 마리 당 삼투 인산완충생리식염수 3ml를 넣어주었다. 2분 동안 복강 내 인산완충생리식염수를 흔들어준 후 주사기를 이용하여 인산완충생리식염수를 재취득해 복강 대식세포(peritoneal macrophage)를 수득하였다. 분리한 세포들은 24웰 배양접시에 분주(5 x 104세포/웰)하였다. 다이메틸설폭시드에 용해시킨 ODH-08 20 μM과 JC1-40 20 μM 또는 동량의 용매(대조군)를 처리하고, 지질다당류(LPS) 5ng/ml 또는 인터루킨-4(IL-4) 20ng/ml을 각각 처리하여 24시간 동안 배양하였다. 지질다당류(LPS)와 인터루킨-4(IL-4)를 처리하지 않은 세포에는 동량의 3차 멸균증류수를 처리하였다. 배양 시에는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후 RNeasy Micro Kit(QIAGEN)를 사용하여 mRNA를 추출하였다. 역전사 중합효소 연쇄반응(RT-PCR)을 이용하여 추출한 mRNA로부터 cDNA를 합성하였다. 이후 실시간 중합효소 연쇄반응(qRT-PCR)을 이용하여 M1 표지인자인 인터루킨1b(IL-1b), 인터루킨6(IL-6), 및 CD80, M2 표지인자인 인터루킨10(IL-10), 아르지네이스1(Arg1), 및 CD206의 cDNA 양을 증폭 및 측정하였다. 보다 자세하게는, M-MLV reverse transcriptase(Invitrogen)를 이용하여 mRNA-M-MLV 혼합물을 제조하고 thermal cycler를 이용하여 역전사 중합효소 연쇄반응을 전개하였다. 그 후 ABI StepOnePlus Real-Time PCR system(Applied Biosystems)을 이용하여 실시간 중합효소 연쇄반응을 수행하였다. 그 결과는 도 8a 및 도 8b에 나타내었다.The effect of ODH-08 treatment on the polarity regulation of Kupffer cells, which are liver resident macrophages, was confirmed. First, ODH-08 or JC1-40 was treated with peritoneal macrophages isolated from mice to confirm changes in expression of polarity markers. Specifically, after the mice were anesthetized and laparotomy, 3 ml of osmotic phosphate buffered saline per mouse was put into the abdominal cavity. After shaking the intraperitoneal phosphate-buffered saline for 2 minutes, the phosphate-buffered saline was reacquired using a syringe to obtain peritoneal macrophages. The separated cells were dispensed (5 x 10 4 cells/well) in a 24-well culture dish. 20 μM of ODH-08 dissolved in dimethyl sulfoxide and 20 μM of JC1-40 or the same amount of solvent (control group) were treated, and 5 ng/ml of lipopolysaccharide (LPS) or 20 ng/ml of interleukin-4 (IL-4) was added. Each treatment was incubated for 24 hours. Cells not treated with lipopolysaccharide (LPS) and interleukin-4 (IL-4) were treated with the same amount of tertiary sterile distilled water. During cultivation, it was maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air. After incubation, mRNA was extracted using RNeasy Micro Kit (QIAGEN). cDNA was synthesized from the extracted mRNA using reverse transcription polymerase chain reaction (RT-PCR). Then, using real-time polymerase chain reaction (qRT-PCR), M1 markers interleukin 1b (IL-1b), interleukin 6 (IL-6), and CD80, M2 markers interleukin 10 (IL-10), AR The amounts of genease 1 (Arg1) and CD206 cDNA were amplified and measured. More specifically, an mRNA-M-MLV mixture was prepared using M-MLV reverse transcriptase (Invitrogen) and a reverse transcription polymerase chain reaction was developed using a thermal cycler. Then, real-time polymerase chain reaction was performed using an ABI StepOnePlus Real-Time PCR system (Applied Biosystems). The results are shown in Figures 8a and 8b.
도 8a에 나타난 바와 같이, 지질다당류(LPS) 처리로 인하여 대식세포 M1 표지인자들의 발현이 증가하였으며, ODH-08 처리에 의하여 그 발현이 현저히 감소하였다. As shown in Figure 8a, the expression of macrophage M1 markers increased due to lipopolysaccharide (LPS) treatment, and the expression significantly decreased by ODH-08 treatment.
도 8b에 나타난 바와 같이, 인터루킨4(IL-4) 처리로 인하여 대식세포 M2 표지인자들의 발현이 증가하였으며, ODH-08 처리에 의하여 그 발현이 더욱 증가하였다. As shown in FIG. 8B, treatment with interleukin 4 (IL-4) increased the expression of macrophage M2 markers, and treatment with ODH-08 further increased their expression.
상기 결과들을 종합하여, 대식세포에의 ODH-08 처리가 M1 표지인자들의 발현을 감소시키고, M2 표지인자들의 발현을 증가시키는 것을 확인하였으며, 이를 통하여 대식세포에의 ODH-08 처리가 M1에서 M2로의 극성 변화에 영향을 미친다는 것을 확인할 수 있었다.Summarizing the above results, it was confirmed that ODH-08 treatment of macrophages decreased the expression of M1 markers and increased the expression of M2 markers. It was confirmed that it affects the polarity change of Rho.
실험예 8. ODH-08가 간 성상세포에서 섬유화 유전자 발현에 미치는 효과 확인Experimental Example 8. Confirmation of the effect of ODH-08 on fibrosis gene expression in hepatic stellate cells
간 성상세포 Lx-2(3 x 105세포/웰)를 60-㎠ 디쉬에 분주하고, 2% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤동안 배양하였다. Lx-2 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후, Lx-2 세포에 TGFβ1 5ng/ml와 ODH-08 화합물을 특정 농도(5μM, 10μM, 20μM 및 30μM) 또는 동량의 용매(대조군)로 18시간 동안 처리하였다. TGFβ1를 처리하지 않은 세포에는 0.5% BSA가 포함된 동량의 인산완충생리식염수(Phosphate-buffered saline, PBS)를 처리하였다. 처리 후 웨스턴 블롯팅 분석법으로 단백질의 발현을 분석하였다. 즉, 시험물질의 처리 후 50mM NaCl, 50mM Tris(pH 7.4), 5mM EDTA, 1% NP-40 및 프로테아제 억제제를 포함하는 용해 완충액을 사용하여 얼음 위에서 30분 동안 Lx-2 세포를 파괴하고, 원심분리하여 전체 세포 용해액을 얻었다. 전체 세포 용해액으로부터 얻은 20-30μg 단백질을 7-9% SDS-PAGE(sodium dodecylsulfate-polyacrylamide gel electrophoresis) 하고, 폴리비닐리덴 디플루오리드 막(Millipore, Bedford, MA, USA)에 전이시켰다. 0.1% Tween-20을 포함하는 PBS 내의 5% 또는 10%(w/v) 비지방 건조 밀크로 차단을 실시하고, COL1A1(Santa Cruz Biotechnology), α-SMA(Abcam), COL1A2(Santa Cruz Biotechnology), Hsp60(Abcam)에 대한 특정 항체와 반응시켰다. HRP(horseradish peroxidase)-접합 2차 항체(Zymed Lab)를 이용하여, 면역반응성 단백질을 Amersham ECL Western Blotting Detection Reagents로 검출하였다. 단백질 농도는 BCA (bicinchoninic acid) (Pierce) 분석으로 정량화하였고, Hsp60의 발현을 대조군으로 모니터링하였다. Hepatic stellate cells Lx-2 (3 x 10 5 cells/well) were dispensed into a 60-
한편, RNA 추출을 위해 EASY BLUE(Intron, Korea)로 용해하고, 이소프로판올 분획과 에탄올 침전을 이용하였다. 각 RNA 샘플을 가지고 cRNA를 합성하였고 특정 유전자의 cDNA를 증폭시키는 올리고머를 사용하였으며 18s rRNA의 발현을 대조군으로 모니터링하였다. 보다 자세하게는, M-MLV reverse transcriptase(Invitrogen)를 이용하여 mRNA-M-MLV 혼합물을 제조하고 thermal cycler를 이용하여 역전사 중합효소 연쇄반응을 전개하였다. 그 후 ABI StepOnePlus Real-Time PCR system(Applied Biosystems)을 이용하여 실시간 중합효소 연쇄반응을 수행하였다. Meanwhile, RNA was dissolved with EASY BLUE (Intron, Korea) for extraction, and isopropanol fractionation and ethanol precipitation were used. cRNA was synthesized with each RNA sample, an oligomer amplifying the cDNA of a specific gene was used, and the expression of 18s rRNA was monitored as a control. More specifically, an mRNA-M-MLV mixture was prepared using M-MLV reverse transcriptase (Invitrogen) and a reverse transcription polymerase chain reaction was developed using a thermal cycler. Then, real-time polymerase chain reaction was performed using an ABI StepOnePlus Real-Time PCR system (Applied Biosystems).
도 9a에 나타난 바와 같이, TGFβ1에 의해 증가되었던 Pro-COL1A1, α-SMA 단백질의 발현이 ODH-08에 의해 농도의존적으로 감소되는 것을 관찰하였다.As shown in Figure 9a, it was observed that the expression of Pro-COL1A1 and α-SMA proteins, which were increased by TGFβ1, were decreased by ODH-08 in a concentration-dependent manner.
또한, 도 9b에 나타난 바와 같이, TGFβ1에 의해 증가되었던 α-SMA, COL1A1, TGFβ1의 mRNA 발현이 ODH-08에 의해 농도의존적으로 감소되는 것을 관찰하였다.In addition, as shown in FIG. 9B, it was observed that the mRNA expressions of α-SMA, COL1A1, and TGFβ1, which were increased by TGFβ1, were decreased by ODH-08 in a concentration-dependent manner.
따라서, ODH-08이 간 성상세포에서 섬유화 유전자의 발현을 억제함에 따라, 간 섬유증과 같은 대사성 간 질환에 효과가 있음을 확인하였다.Therefore, it was confirmed that ODH-08 suppresses the expression of fibrosis genes in hepatic stellate cells, and thus has an effect on metabolic liver diseases such as liver fibrosis.
실험예 9. ODH-08가 간 성상세포주에서 SMAD 전사활성에 미치는 효과 확인Experimental Example 9. Confirmation of the effect of ODH-08 on SMAD transcriptional activity in hepatic stellate cell lines
TGF-β는 간성상세포의 가장 강력한 섬유화 촉진 사이토카인이며 간성상세포 자체가 TGF-β의 주 생산원으로 type I, III, IV collagen을 포함한 세포외기질의 생성을 촉진시킨다. TGF-β는 type II receptor와 결합하여 type I receptor를 인산화시키고 이는 곧 Smad2와 Smad3와 접촉하여 이들을 인산화시킨다. 이후 Smad2와 Smad3의 결합체는 Smad4와 결합하여 핵 내로 이동하여 목표유전자의 전사를 조절한다. 이러한 TGF-β와 Smad 신호전달을 통해 콜라겐 α1과 α2의 전사가 촉진됨에 따라 콜라겐의 생성을 증가시키게 된다. 따라서 Smad 신호 네트워크의 조절은 간 성상세포의 활성화 제어를 통한 간섬유화 질환을 치료할 수 있는 대표적인 약물작용점으로 간주되고 있다. TGF-β is the most potent fibrosis-promoting cytokine of hepatic stellate cells, and hepatic stellate cells themselves are the main producer of TGF-β, promoting the production of extracellular matrix including type I, III, and IV collagen. TGF-β binds to the type II receptor and phosphorylates the type I receptor, which then contacts and phosphorylates Smad2 and Smad3. Then, the complex of Smad2 and Smad3 binds to Smad4 and moves into the nucleus to regulate transcription of the target gene. As the transcription of collagen α1 and α2 is promoted through such TGF-β and Smad signaling, the production of collagen is increased. Therefore, regulation of the Smad signaling network is regarded as a representative drug action point that can treat hepatic fibrotic disease through the activation control of hepatic stellate cells.
간 성상세포 Lx-2(2.5 x 104세포/웰)를 24-웰 배양 플레이트에 분주하고, 2% FBS(fetal bovine serum)를 함유하는 DMEM(Dulbecco's modified Eagle's medium) 배지에서 하룻밤 동안 배양하였다. Lx-2 세포는 5% CO2 및 95% 공기를 갖는 함습 항온기에서 37℃로 유지하였다. 배양 후, X-tremeGENE HP DNA transfection reagent(Roche, Mannheim, Germany)을 이용하여 SMAD cignal 리포터(20 ng)를 단독으로 또는 RORα 발현 벡터(10 ng)와 함께 Lx-2 세포에 형질전환시켰다. 형질전환 24시간 후, Lx-2 세포에 TGFβ1 5ng/ml와 특정 농도(10μM, 20μM)의 ODH-08 또는 Obeticholic acid(OCA, 양성 대조군) 또는 동량의 용매(대조군)를 18시간 동안 처리하였다. TGFβ1를 처리하지 않은 세포에는 0.5% BSA가 포함된 동량의 PBS를 처리하였다. 이후 세포 용해물을 수득하고, Analytical luminescence luminometer를 이용하여 루시퍼라아제 활성을 분석하고 결정하였다. β-gal 활성으로 형질전환 효율에 대한 루시퍼라아제 활성을 표준화하였고, Hepatic stellate cells Lx-2 (2.5 x 10 4 cells/well) were seeded into a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 2% fetal bovine serum (FBS). Lx-2 cells were maintained at 37° C. in a humidified thermostat with 5% CO 2 and 95% air. After culturing, Lx-2 cells were transfected with the SMAD cignal reporter (20 ng) alone or together with the RORα expression vector (10 ng) using X-tremeGENE HP DNA transfection reagent (Roche, Mannheim, Germany). 24 hours after transfection, Lx-2 cells were treated with 5 ng/ml of TGFβ1 and specific concentrations (10 μM, 20 μM) of ODH-08 or Obeticholic acid (OCA, positive control) or the same amount of solvent (control) for 18 hours. Cells not treated with TGFβ1 were treated with the same amount of PBS containing 0.5% BSA. Cell lysates were then obtained, and luciferase activity was analyzed and determined using an Analytical luminescence luminometer. Luciferase activity was normalized for transformation efficiency with β-gal activity,
도 10b에 나타난 바와 같이, TGFβ1에 의해 증가되었던 SMAD signal 리포터 전사 활성은 ODH-08의 농도에 의존적으로 감소하였다.As shown in FIG. 10b, the SMAD signal reporter transcriptional activity, which was increased by TGFβ1, decreased in a concentration-dependent manner of ODH-08.
또한, 도 10a의 OCA와 비교해서 ODH-08이 보다 우수한 SMAD 억제 활성을 나타냄을 확인하였다.In addition, it was confirmed that ODH-08 showed better SMAD inhibitory activity compared to OCA of FIG. 10a.
실험예 10. ODH-08가 식이 유도 간 섬유화 동물 모델에서 간 손상 억제에 미치는 효과 확인Experimental Example 10. Confirmation of the effect of ODH-08 on inhibition of liver damage in animal models of diet-induced liver fibrosis
ODH-08의 투여와 간 손상 억제와의 연관관계를 확인하기 위하여, 식이 유도 간 섬유화 동물 모델을 이용하여 실험을 진행하였다. 먼저, 7주령 C57BL/6 마우스 수컷을 실온 및 습도가 조절되는 환경에 1주일 간 적응시키고, 서양식 식이(무수버터(anhydrous butter) 유래 지방 38 kcal%, 옥수수유 유래 지방 2 kcal%, 콜레스테롤0.15% 함유)를 21주간 제공하여 비알콜성 지방간염을 유도하였다. In order to confirm the relationship between administration of ODH-08 and inhibition of liver damage, an experiment was conducted using an animal model of diet-induced liver fibrosis. First, 7-week-old male C57BL/6 mice were acclimatized to a room temperature and humidity-controlled environment for 1 week, and fed with a Western-style diet (38 kcal% fat from anhydrous butter, 2 kcal% fat from corn oil, 0.15% cholesterol). containing) for 21 weeks to induce non-alcoholic steatohepatitis.
식이 시작 16주째부터 ODH-08을 10 mg/kg 농도로 5주간 1일 1회 경구 투여하였다. 자세하게는, 0.5% 카복시메틸셀룰로스(CMC)를 포함하는 멸균수에 최종 농도에 부합하는 양의 ODH-08을 칭량하여 첨가한 후 막자사발을 이용하여 고르게 현탁화시켜 약물을 제조하였다. 개별 마우스 개체의 투여량을 계산하고, 존데를 사용하여 경구 투여하였다. 대조군에는 0.5% 카복시메틸셀룰로스를 포함하는 멸균수를 동일한 방법으로 투여하였다. 21주간의 식이가 종료되고 마우스들을 마취하여 개복, 간 하대정맥에서 채혈한 다음, 간을 적출하여 무게를 칭량한 후 일부는4% 파라포름알데하이드 용액을 이용하여 고정하였으며, 나머지는 -70℃에 동결하였다. 채취한 혈액은 상온(15-25℃)에서 2시간 동안 혈액응고반응을 진행시킨 뒤 같은 온도에서 10분간 13000rpm 속도로 원심분리하여 상등액을 취하였다. 간독성 표지인자인 AST(aspartate aminotransferase)와 알라닌 아미노전달효소(ALT)는 Fuji DRI-CHEM 3500s serum biochemistry analyzer(Fuji film)를 이용하여 측정하였다. From the 16th week of the diet, ODH-08 was orally administered at a concentration of 10 mg/kg once a day for 5 weeks. Specifically, a drug was prepared by weighing and adding an amount of ODH-08 corresponding to the final concentration to sterile water containing 0.5% carboxymethylcellulose (CMC) and then evenly suspending the mixture using a mortar and pestle. Doses for individual mouse subjects were calculated and administered orally using a sonde. Sterile water containing 0.5% carboxymethylcellulose was administered to the control group in the same manner. After the 21-week diet was completed, the mice were anesthetized openly and blood was collected from the inferior vena cava of the liver, and then the liver was removed, weighed, and some were fixed using a 4% paraformaldehyde solution, and the rest were stored at -70 ° C. frozen. The collected blood was subjected to coagulation at room temperature (15-25 ° C) for 2 hours, and then centrifuged at 13000 rpm for 10 minutes at the same temperature to obtain the supernatant. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are hepatotoxicity markers, were measured using a Fuji DRI-CHEM 3500s serum biochemistry analyzer (Fuji film).
도 11a에 나타난 바와 같이, 서양식 식이만을 제공한 마우스(WD)의 간 무게는 대조군(CD)에 비해 현저히 증가되었으나, 서양식 식이에 ODH-08을 투여한 마우스 실험군(WD+ODH-08)의 간 무게는 서양식 식이만을 제공한 마우스 실험군(WD)에 비하여 유의하게 감소하였다. As shown in Figure 11a, the weight of the liver of mice (WD) fed only Western diet was significantly increased compared to that of the control group (CD), but the liver weight of mice experimental group (WD + ODH-08) administered with ODH-08 to Western diet The weight was significantly decreased compared to the mouse experimental group (WD) provided only with Western diet.
또한, 도 11b에 나타난 바와 같이, 서양식 식이를 제공한 마우스 실험군(WD)의 AST와 ALT 혈중 농도는 대조군(CD)에 비해 크게 증가되어 있었으나 서양식 식이와 함께 ODH-08을 투여한 마우스 실험군(WD+ODH-08)의 혈중 농도는 두 가지 모두 WD에 비하여 현저히 감소됨을 확인하였다.In addition, as shown in FIG. 11b, the AST and ALT blood concentrations of the mouse experimental group (WD) fed with the Western-style diet were significantly increased compared to those of the control group (CD), but the experimental group of mice fed with ODH-08 with the Western-style diet (WD +ODH-08) was confirmed to be significantly reduced compared to both WD.
종합하면, 서양식 식이로 유도된 간 손상이 ODH-08에 의하여 유의하게 개선된 것을 확인하였으며, 이를 통하여 ODH-08의 간 손상 억제 효과를 확인할 수 있었다.In summary, it was confirmed that liver damage induced by Western-style diet was significantly improved by ODH-08, and through this, the liver damage inhibitory effect of ODH-08 could be confirmed.
실험예 11. ODH-08 가 식이 유도 간 섬유화 동물 모델에서 섬유화 억제에 미치는 효과 확인Experimental Example 11. Confirmation of the effect of ODH-08 on inhibition of fibrosis in animal models of diet-induced liver fibrosis
11-1. 간 조직의 섬유화 진행 확인11-1. Confirmation of the progression of fibrosis in liver tissue
ODH-08이 섬유화 억제에 미치는 영향을 확인하기 위하여, 실험예 10의 동물 모델에서 섬유화 진행 정도를 확인하였다. 앞서 실험예 10에서 고정화한 조직은 세척, 탈석회화(decalcification), 탈수화를 거쳐 최종적으로 파라핀 블록으로 제작되었다. 제작된 파라핀 블록을 3㎛ 두께로 절단하여 절편을 제작한 후 60℃의 가열 블록(heating block)에서 45분간의 탈파라핀화 과정을 수행하였다. 이후 자일렌(xylene) 용액으로 5분간 세척을 3회 수행하였고, 100% 에탄올(ethanol)에 3 분씩 3회, 95% 에탄올에 2분씩 2회, 70% 에탄올에 2분씩 2회, 증류수로 2분씩 2회 담가두어 수화(hydration)시켰다. 수화 과정을 마친 파라핀 절편을 1% 헤마톡실린 용액에 30초 동안 담가 염색한 후에 증류수로 1회 세척하고, 다시 0.25% 염화수소(HCl)에서 1초 반응시킨 후에 증류수로 1회 세척하였다. 그리고 헤마톡실린의 매염제인 10% 리튬카보네이트를 2-4초간 반응시킨 후에 증류수로 세척하였다. 이후 에오신을 2초간 처리하여 세포질을 염색한 뒤에 95% 에탄올과 100% 에탄올을 이용하여 순차적으로 최종 탈수화 및 투명화 단계를 수행하였다. 투명화된 절편을 봉입(mounting)하여 광학현미경으로 관찰하고 사진을 획득하여 간 조직 내의 지방 축적 상태를 관찰하였다. 그 결과는 도 12a에 나타내었다.In order to confirm the effect of ODH-08 on fibrosis inhibition, the degree of fibrosis progression was confirmed in the animal model of Experimental Example 10. The tissues previously fixed in Experimental Example 10 were finally made into paraffin blocks through washing, decalcification, and dehydration. The prepared paraffin block was cut to a thickness of 3 μm to make a slice, and then a deparaffinization process was performed for 45 minutes in a heating block at 60 ° C. Thereafter, washing was performed three times for 5 minutes with a xylene solution, 3 times for 3 minutes in 100% ethanol, 2 times for 2 minutes in 95% ethanol, 2 times for 2 minutes in 70% ethanol, and 2 times with distilled water. It was hydrated by soaking twice per minute. After hydration, the paraffin sections were immersed in 1% hematoxylin solution for 30 seconds, washed once with distilled water, reacted with 0.25% hydrogen chloride (HCl) for 1 second, and washed once with distilled water. Then, 10% lithium carbonate, a mordant for hematoxylin, was reacted for 2-4 seconds, and then washed with distilled water. Thereafter, eosin was treated for 2 seconds to stain the cytoplasm, and then final dehydration and clearing steps were sequentially performed using 95% ethanol and 100% ethanol. The cleared section was mounted, observed under an optical microscope, and a photograph was obtained to observe the state of fat accumulation in the liver tissue. The results are shown in Figure 12a.
도 12a에 나타난 바와 같이, 서양식 식이와 ODH-08을 함께 투여한 실험군(WD+ODH-08)에서는 간 조직 내에 지방 축적, 간세포의 풍선 확장 및 풍선 변성 현상이 WD에서보다 현저히 완화된 것을 확인하였다.As shown in Figure 12a, in the experimental group (WD + ODH-08) administered with Western diet and ODH-08, fat accumulation in liver tissue, balloon expansion of hepatocytes, and balloon degeneration were significantly alleviated compared to WD. .
11-2. 콜라겐 침착 정도 확인11-2. Check the degree of collagen deposition
파라핀 블록을 다시 3㎛의 두께로 잘라 절편을 제작한 후에 간 조직 내의 콜라겐 침착 정도를 확인하였다. 콜라겐 침착 정도는 시리우스 레드(Sirius red) 염색을 통해 확인하였다. 그 결과는 도 12b에 나타내었다.After the paraffin block was cut again to a thickness of 3 μm to prepare a section, the degree of collagen deposition in the liver tissue was confirmed. The degree of collagen deposition was confirmed by Sirius red staining. The results are shown in Figure 12b.
도 12b에 나타난 바와 같이, 서양식 식이를 제공한 실험군(WD)에서는 콜라겐 축적이 증가되었다. 반면 서양식 식이와 함께 ODH-08을 투여한 실험군(WD+ODH-08)에서는 콜라겐 축적이 현저히 감소된 것을 확인하였다.As shown in Figure 12b, the collagen accumulation was increased in the experimental group (WD) provided with a Western-style diet. On the other hand, in the experimental group (WD+ODH-08) administered with ODH-08 along with Western-style diet, it was confirmed that collagen accumulation was significantly reduced.
11-3. 간 섬유화 관련 단백질의 발현 확인11-3. Identification of the expression of liver fibrosis-related proteins
동결한 마우스 간 조직 중 일부를 단백질 분해효소 저해제와 인산가수분해효소 저해제를 포함하는 용해 완충액에 넣고 TissueLyser II(QIAGEN)을 이용하여 용해화하였다. 원심분리하여 상등액을 취함으로써 간 조직 단백질을 분리하였다. 이후 웨스턴 블롯팅을 통하여 섬유화 표지인자인 pro-COL1A1과 α-SMA 단백질 발현 변화를 확인하였다. 웨스턴 블롯팅은 실험예 4와 동일한 방법으로 진행하였으며, 항체로는 anti-COL1A1(Santa Cruz), anti-αSMA(Abcam), anti-HSP60(Abcam)을 이용하였다. 그 결과는 도 12c에 나타내었다.A portion of the frozen mouse liver tissue was placed in a lysis buffer containing a protease inhibitor and a phosphatase inhibitor and solubilized using TissueLyser II (QIAGEN). Liver tissue proteins were isolated by taking the supernatant by centrifugation. Then, changes in the expression of pro-COL1A1 and α-SMA proteins, which are markers of fibrosis, were confirmed through Western blotting. Western blotting was performed in the same manner as in Experimental Example 4, and anti-COL1A1 (Santa Cruz), anti-αSMA (Abcam), and anti-HSP60 (Abcam) were used as antibodies. The results are shown in Figure 12c.
도 12c에 나타난 바와 같이, 서양식 식이를 제공한 실험군(WD)에서는 섬유화 표지인자인 pro-COL1A1과 α-SMA의 단백질 발현이 크게 증가하였지만, ODH-08을 함께 투여한 실험군(WD+ODH-08)에서는 그 양이 현저히 감소하였다.As shown in FIG. 12c, in the experimental group (WD) fed with a Western-style diet, the protein expression of pro-COL1A1 and α-SMA, which are fibrosis markers, increased significantly, but in the experimental group administered with ODH-08 (WD + ODH-08 ), the amount was significantly reduced.
11-4. 간 섬유화 관련 유전자의 발현 확인11-4. Identification of the expression of liver fibrosis-related genes
섬유화 표지인자들의 mRNA 발현량을 측정하기 위하여 마우스 간 조직으로부터 mRNA를 분리하였다. 동결한 간 조직 일부를 easy-BLUE(iNtRON biotechnology)에 넣고 TissueLyser II(QIAGEN)을 이용하여 용해화하였다. 200μl 클로로포름을 처리하여 원심분리 후 RNA를 포함하는 상등액을 취하였다. 상등액과 동량의 70% 에탄올을 처리한 뒤 RNeasy Mini Kit(QIAGEN)을 이용하여 RNA를 추출하였다. 추출한 mRNA로부터 cDNA를 역전사 중합효소 연쇄반응(RT-PCR)을 이용하여 합성하였으며 실시간 중합효소연쇄반응(qRT-PCR)을 이용하여 증폭하여 측정하였다. 역전사 중합효소 연쇄반응과 실시간 중합효소연쇄반응은 실험예 7과 동일한 방법으로 진행하였다. 그 결과는 도 12d에 나타내었다.In order to measure the mRNA expression level of fibrosis markers, mRNA was isolated from mouse liver tissue. A portion of frozen liver tissue was placed in easy-BLUE (iNtRON biotechnology) and solubilized using TissueLyser II (QIAGEN). After treatment with 200 μl chloroform and centrifugation, the supernatant containing RNA was taken. After treatment with the same amount of 70% ethanol as the supernatant, RNA was extracted using RNeasy Mini Kit (QIAGEN). cDNA was synthesized from the extracted mRNA using reverse transcription polymerase chain reaction (RT-PCR), and amplified and measured using real-time polymerase chain reaction (qRT-PCR). Reverse transcription polymerase chain reaction and real-time polymerase chain reaction were performed in the same manner as in Experimental Example 7. The results are shown in Figure 12d.
도 12d에 나타난 바와 같이, 섬유화 표지인자인 α-SMA, COL1A1, COL1A2, COL3A1, MMP2, TIMP1의 mRNA 발현이 모두 서양식 식이를 제공한 실험군(WD)에서 증가하였으며, 서양식 식이와 ODH-08을 함께 투여한 실험군(WD+ODH-08)에서는 그 발현량이 현저히 감소하였음을 확인하였다.As shown in FIG. 12d, the mRNA expression of α-SMA, COL1A1, COL1A2, COL3A1, MMP2, and TIMP1, which are fibrosis markers, all increased in the experimental group (WD) fed a Western diet, and Western diet and ODH-08 together In the administered experimental group (WD+ODH-08), it was confirmed that the expression level was significantly reduced.
상기 결과들을 종합하여, 서양식 식이로 유도된 간 섬유화가 ODH-08 에 의하여 유의하게 개선된 것을 확인하였으며, 이를 통하여 ODH-08의 간 섬유화 억제 효과를 확인할 수 있었다.Summarizing the above results, it was confirmed that liver fibrosis induced by a Western-style diet was significantly improved by ODH-08, and through this, the liver fibrosis inhibitory effect of ODH-08 could be confirmed.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.
<110> SNU R&DB FOUNDATION <120> New Thiourea derivatives as ROR-alpha Activators, and pharmaceutical compositions comprising the same <130> MP21-184 <160> 26 <170> KoPatentIn 3.0 <210> 1 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> IL-1b_F <400> 1 agagcccatc ctctgtgact ca 22 <210> 2 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> IL-1b_R <400> 2 tgcttgggat ccacactctc ca 22 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-6_F <400> 3 gaacaacgat gatgcacttg c 21 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-6_R <400> 4 tccaggtagc tatggtactc c 21 <210> 5 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> CD80_F <400> 5 ccccagaaga ccctcctgat ag 22 <210> 6 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> CD80_R <400> 6 ccgaaggtaa ggctgttgtt tg 22 <210> 7 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> IL-10_F <400> 7 gctcttactg actggcatga g 21 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> IL-10_R <400> 8 cgcagctcta ggagcatgtg 20 <210> 9 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> ARG1_F <400> 9 ctccaagcca aagtccttag ag 22 <210> 10 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> ARG1_R <400> 10 aggagctgtc attagggaca tc 22 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CD206_F <400> 11 caggtgtggg ctcaggtagt 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CD206_R <400> 12 tgtggtgagc tgaaaggtga 20 <210> 13 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> RORalpha_F <400> 13 gatcgctcgt ggcttcagga a 21 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> RORalpha_R <400> 14 tggaggaaaa tggagtcgca ca 22 <210> 15 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> alpha-SMA_F <400> 15 ggcaccactg aaccctaagg 20 <210> 16 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> alpha-SMA_R <400> 16 tctccagagt ccagcacaat 20 <210> 17 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> COL1A1_F <400> 17 gaaacccgag gtatgcttga 20 <210> 18 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> COL1A1_R <400> 18 gaccaggagg accaggaagt 20 <210> 19 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> COL1A2_F <400> 19 agccaaccgt gcttctcag 19 <210> 20 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> COL1A2_R <400> 20 tctcctcatc caggtacgca 20 <210> 21 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> COL3A1_F <400> 21 aaggctgcaa gatggatgct 20 <210> 22 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> COL3A1_R <400> 22 gtgcttacgt gggacagtca 20 <210> 23 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MMP2_F <400> 23 tttgctcggg ccttaaaagt at 22 <210> 24 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MMP2_R <400> 24 ccatcaaatg ggtatccatc tc 22 <210> 25 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> TIMP1_F <400> 25 cttggttccc tggcgtactc 20 <210> 26 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> TIMP1_R <400> 26 acctgatccg tccacaaaca g 21 <110> SNU R&DB Foundation <120> New Thiourea derivatives as ROR-alpha Activators, and pharmaceutical compositions comprising the same <130> MP21-184 <160> 26 <170> KoPatentIn 3.0 <210> 1 <211> 22 <212> DNA <213> artificial sequence <220> <223> IL-1b_F <400> 1 agagcccatc ctctgtgact ca 22 <210> 2 <211> 22 <212> DNA <213> artificial sequence <220> <223> IL-1b_R <400> 2 tgcttgggat ccacactctc ca 22 <210> 3 <211> 21 <212> DNA <213> artificial sequence <220> <223> IL-6_F <400> 3 gaacaacgat gatgcacttg c 21 <210> 4 <211> 21 <212> DNA <213> artificial sequence <220> <223> IL-6_R <400> 4 tccaggtagc tatggtactc c 21 <210> 5 <211> 22 <212> DNA <213> artificial sequence <220> <223> CD80_F <400> 5 ccccagaaga ccctcctgat ag 22 <210> 6 <211> 22 <212> DNA <213> artificial sequence <220> <223> CD80_R <400> 6 ccgaaggtaa ggctgttgtt tg 22 <210> 7 <211> 21 <212> DNA <213> artificial sequence <220> <223> IL-10_F <400> 7 gctcttactg actggcatga g 21 <210> 8 <211> 20 <212> DNA <213> artificial sequence <220> <223> IL-10_R <400> 8 cgcagctcta ggagcatgtg 20 <210> 9 <211> 22 <212> DNA <213> artificial sequence <220> <223> ARG1_F <400> 9 ctccaagcca aagtccttag ag 22 <210> 10 <211> 22 <212> DNA <213> artificial sequence <220> <223> ARG1_R <400> 10 aggagctgtc attagggaca tc 22 <210> 11 <211> 20 <212> DNA <213> artificial sequence <220> <223> CD206_F <400> 11 caggtgtggg ctcaggtagt 20 <210> 12 <211> 20 <212> DNA <213> artificial sequence <220> <223> CD206_R <400> 12 tgtggtgagc tgaaaggtga 20 <210> 13 <211> 21 <212> DNA <213> artificial sequence <220> <223> RORalpha_F <400> 13 gatcgctcgt ggcttcagga a 21 <210> 14 <211> 22 <212> DNA <213> artificial sequence <220> <223> RORalpha_R <400> 14 tggaggaaaa tggagtcgca ca 22 <210> 15 <211> 20 <212> DNA <213> artificial sequence <220> <223> alpha-SMA_F <400> 15 ggcaccactg aaccctaagg 20 <210> 16 <211> 20 <212> DNA <213> artificial sequence <220> <223> alpha-SMA_R <400> 16 tctccagagt ccagcacaat 20 <210> 17 <211> 20 <212> DNA <213> artificial sequence <220> <223> COL1A1_F <400> 17 gaaacccgag gtatgcttga 20 <210> 18 <211> 20 <212> DNA <213> artificial sequence <220> <223> COL1A1_R <400> 18 gaccaggagg accaggaagt 20 <210> 19 <211> 19 <212> DNA <213> artificial sequence <220> <223> COL1A2_F <400> 19 agccaaccgt gcttctcag 19 <210> 20 <211> 20 <212> DNA <213> artificial sequence <220> <223> COL1A2_R <400> 20 tctcctcatc caggtacgca 20 <210> 21 <211> 20 <212> DNA <213> artificial sequence <220> <223> COL3A1_F <400> 21 aaggctgcaa gatggatgct 20 <210> 22 <211> 20 <212> DNA <213> artificial sequence <220> <223> COL3A1_R <400> 22 gtgcttacgt gggacagtca 20 <210> 23 <211> 22 <212> DNA <213> artificial sequence <220> <223> MMP2_F <400> 23 tttgctcggg ccttaaaagt at 22 <210> 24 <211> 22 <212> DNA <213> artificial sequence <220> <223> MMP2_R <400> 24 ccatcaaatg ggtatccatc tc 22 <210> 25 <211> 20 <212> DNA <213> artificial sequence <220> <223> TIMP1_F <400> 25 cttggttccc tggcgtactc 20 <210> 26 <211> 21 <212> DNA <213> artificial sequence <220> <223> TIMP1_R <400> 26 acctgatccg tccacaaaca g 21
Claims (13)
[화학식 1]
상기 화학식 1에서,
X는 C1-C5인 알킬기, 벤질기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C3-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하고;
Y는 수소, 히드록시기, 할로겐, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 시클로알킬기, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고;
Z는 N, O, 또는 S이고;
R1 내지 R4는 각각 독립적으로 수소, C1-C5인 알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이며,
상기 X가 메틸기일 때, Y는 수소가 아니다.
A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
Z is N, O, or S;
R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
When the above X is a methyl group, Y is not hydrogen.
상기 R1 또는 R2가 치환 아릴기 또는 치환 헤테로아릴기인 경우, 방향족 환(aromatic ring)이 C1-C3인 알킬기, C1-C3인 알콕시기, 트리플루오로메틸기 또는 t-부틸기로 치환되는 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
When R 1 or R 2 is a substituted aryl group or a substituted heteroaryl group, an aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or a t-butyl group. Characterized in that it is substituted, a compound or a pharmaceutically acceptable salt thereof.
상기 R3와 R4는 서로 결합하여 치환 또는 비치환 C3-C20 시클로알킬 고리, 치환 또는 비치환 C6-C20 헤테로시클로알킬 고리, 치환 또는 비치환 C6-C20 아릴 고리 또는 치환 또는 비치환 C3-C20 헤테로아릴 고리를 형성하는 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
Wherein R 3 and R 4 are bonded to each other to form a substituted or unsubstituted C 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 6 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted Or a compound or a pharmaceutically acceptable salt thereof, characterized in that it forms an unsubstituted C 3 -C 20 heteroaryl ring.
상기 Y가 치환 아릴기, 또는 치환 헤테로아릴기일 때 방향족 환(aromatic ring)이 C1-C3인 알킬기, C1-C3인 알콕시기, 트리플루오로메틸기 또는 t-부틸기로 치환되는 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
When Y is a substituted aryl group or a substituted heteroaryl group, the aromatic ring is substituted with a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group or a t-butyl group. To, the compound or a pharmaceutically acceptable salt thereof.
상기 X는 C1-C4인 알킬기, 벤질기, 치환 또는 비치환 C6-C10 아릴기, 또는 치환 또는 비치환 C3-C10 헤테로아릴기이거나, Z와 서로 결합하여 치환 또는 비치환 C3-C10 헤테로아릴 고리를 형성하고;
상기 Y는 수소, OR1, CO2R2, NR3R4, 치환 또는 비치환 C3-C20 헤테로시클로알킬기, 치환 또는 비치환 C6-C20 아릴기, 또는 치환 또는 비치환 C3-C20 헤테로아릴기이고;
상기 Z는 N, 또는 S이고;
상기 R1은 수소이고;
상기 R2는 수소 또는 t-부틸기이고;
상기 R3 및 R4는 각각 독립적으로 수소, C1-C5인 알킬기인 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
X is a C 1 -C 4 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted C 3 -C 10 heteroaryl group, or combined with Z to form a substituted or unsubstituted form a C 3 -C 10 heteroaryl ring;
Y is hydrogen, OR 1 , CO 2 R 2 , NR 3 R 4 , a substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 is a heteroaryl group;
wherein Z is N or S;
wherein R 1 is hydrogen;
R 2 is hydrogen or a t-butyl group;
Wherein R 3 and R 4 are each independently hydrogen or a C 1 -C 5 alkyl group, characterized in that, a compound or a pharmaceutically acceptable salt thereof.
상기 화학식 1로 표시되는 화합물은 하기 구조식을 가진 화합물로 이루어진 군으로부터 선택된 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
The compound represented by Formula 1 is characterized in that it is selected from the group consisting of compounds having the following structural formula, a compound or a pharmaceutically acceptable salt thereof.
상기 화학식 1로 표시되는 화합물은 RORα 단백질의 활성화제인 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용가능한 염.
According to claim 1,
A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound represented by Formula 1 is an activator of RORα protein.
A pharmaceutical composition for preventing or treating metabolic or inflammatory diseases, comprising the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 대사성 질환은 인슐린 저항성 증후군, 간섬유증, 지방간, 지방간염, 간경화, 제2형 당뇨병, 고지혈증, 심혈관 질환, 및 동맥경화증으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 약학적 조성물.
According to claim 8,
The metabolic disease is characterized in that at least one selected from the group consisting of insulin resistance syndrome, liver fibrosis, fatty liver, steatohepatitis, liver cirrhosis, type 2 diabetes, hyperlipidemia, cardiovascular disease, and arteriosclerosis, pharmaceutical composition.
상기 대사성 질환은 대사성 간 질환인 것을 특징으로 하는, 약학적 조성물.
According to claim 8,
Characterized in that the metabolic disease is a metabolic liver disease, a pharmaceutical composition.
상기 대사성 질환은 지질 대사 관련 질환인 것을 특징으로 하는, 약학적 조성물.
According to claim 8,
Characterized in that the metabolic disease is a lipid metabolism-related disease, a pharmaceutical composition.
An anti-inflammatory composition comprising the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화합물은 전염증성 사이토카인의 발현 또는 분비 저해, 또는 M2 대식세포의 상향 조절에 의해 염증을 억제하거나 감소시키는 것을 특징으로 하는, 항염 조성물.
According to claim 12,
The anti-inflammatory composition, characterized in that the compound inhibits or reduces inflammation by inhibiting the expression or secretion of pro-inflammatory cytokines, or upregulating M2 macrophages.
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KR20120130733A (en) | 2011-05-23 | 2012-12-03 | 서울대학교산학협력단 | New Thiourea derivatives as ROR Activators, and pharamaceutical compositions containing the same |
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GB9825652D0 (en) * | 1998-11-23 | 1999-01-13 | Celltech Therapeutics Ltd | Chemical compounds |
GB9929988D0 (en) * | 1999-12-17 | 2000-02-09 | Celltech Therapeutics Ltd | Chemical compounds |
NZ544674A (en) * | 2003-07-10 | 2009-03-31 | Achillion Pharmaceuticals Inc | Substituted arylthiourea derivatives useful as inhibitors of viral replication |
KR20160132534A (en) * | 2015-05-11 | 2016-11-21 | 경북대학교병원 | Pharmaceutical composition for prevention or treatment of cancer comprising ror activating regulator |
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KR20120130733A (en) | 2011-05-23 | 2012-12-03 | 서울대학교산학협력단 | New Thiourea derivatives as ROR Activators, and pharamaceutical compositions containing the same |
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