KR102242658B1 - A substituted indole derivatives, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient - Google Patents

A substituted indole derivatives, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient Download PDF

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KR102242658B1
KR102242658B1 KR1020190105905A KR20190105905A KR102242658B1 KR 102242658 B1 KR102242658 B1 KR 102242658B1 KR 1020190105905 A KR1020190105905 A KR 1020190105905A KR 20190105905 A KR20190105905 A KR 20190105905A KR 102242658 B1 KR102242658 B1 KR 102242658B1
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cancer
dichlorophenyl
methyl
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indol
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전라옥
류재하
김효진
이화
김윤정
최용성
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숙명여자대학교산학협력단
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Abstract

치환된 인돌 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 PPARα, PPARγ 및 PPARδ 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것으로, 상기 치환된 인돌 유도체는 PPARα, PPARγ 및 PPARδ를 활성화 시키는 능력이 우수하므로, PPAR 효능제로써 대사성 질환, 심혈관계 질환, 암 또는 염증등의 PPARα, PPARγ 및 PPARδ 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있고, 종양성장 억제효과가 우수한 바, 암의 치료에 유용하게 사용할 수 있다.A substituted indole derivative, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of diseases related to PPARα, PPARγ and PPARδ comprising the same as an active ingredient, wherein the substituted indole derivative has the ability to activate PPARα, PPARγ and PPARδ. As a PPAR agonist, it can be usefully used to prevent or treat PPARα, PPARγ, and PPARδ related diseases such as metabolic diseases, cardiovascular diseases, cancer or inflammation, and has excellent tumor growth inhibitory effect, so it is useful for the treatment of cancer. Can be used.

Description

치환된 인돌 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 PPARα, PPARγ 및 PPARδ 관련 질환의 예방 또는 치료용 약학적 조성물{A substituted indole derivatives, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient}A substituted indole derivatives, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient}

치환된 인돌 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 PPARα, PPARγ 및 PPARδ 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.It relates to a substituted indole derivative, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of diseases related to PPARα, PPARγ and PPARδ comprising the same as an active ingredient.

퍼옥시좀 증식자-활성화 수용체(peroxisome proliferator-activated receptor, PPAR)는 핵 수용체 수퍼패밀리(nuclear receptor superfamily)에 속하는 전사 인자이다. PPAR-α, -γ 및 -δ(β)로 지정된 세 가지 아형의 PPAR이 있으며, 각각 특징적인 조직 분포를 보이며 지질 대사 및 에너지 균형의 유지에 중요한 역할을 한다.Peroxisome proliferator-activated receptor (PPAR) is a transcription factor belonging to the nuclear receptor superfamily. There are three subtypes of PPAR, designated as PPAR-α, -γ and -δ(β), each showing a characteristic tissue distribution and playing an important role in lipid metabolism and maintenance of energy balance.

PPARs는 포도당과 지질 대사 및 에너지 항상성을 조절하는 여러 유전자의 조절에 결정적인 역할을 하며, 구체적으로, 리간드와 결합하여 활성화된 PPAR는 레티노이드 엑스 수용체(RXR)와 결합하여 이형결합체(heterodimer)를 구성하고 PPAR 응답 유전자서열(PPRE)에 결합함으로써 지질대사 및 항상성 유지에 관여하는 표적유전자들의 발현을 조절한다. PPAR 응답 유전자서열(PPRE)은 acyl-CoA 산화효소(AOX), 간 내 지방산 결합단백 (L-FABP), 아포지질단백 C-III(apo C-III) 또는 지질단백 리파아제(LPL)와 같이 지질이나 지단백의 대사와 관련된 단백질을 코딩하는 유전자의 프로모터 부위에서 확인된 바 있으며, 이는 PPAR이 지방 생성 및 지질 항상성 유지에 중추적으로 작용함을 암시한다. PPARs play a crucial role in the regulation of several genes that regulate glucose and lipid metabolism and energy homeostasis. Specifically, PPARs activated by binding to ligands form heterodimers by binding to retinoid X receptors (RXR). By binding to the PPAR response gene sequence (PPRE), it regulates the expression of target genes involved in lipid metabolism and maintenance of homeostasis. The PPAR response gene sequence (PPRE) is a lipid such as acyl-CoA oxidase (AOX), fatty acid-binding protein in the liver (L-FABP), apolipoprotein C-III (apo C-III), or lipoprotein lipase (LPL). It has been identified at the promoter region of a gene encoding a protein related to the metabolism of or lipoprotein, suggesting that PPAR plays a pivotal role in adipogenesis and maintenance of lipid homeostasis.

따라서 PPAR은 고중성지방혈증(hypertriglyceridemia)과 제2형 당뇨병 치료효과, 지질항상성 유지 등을 목적으로 하는 치료제 개발의 중요한 타겟이다. 한편, PPAR은 항염증 인자들의 유리 및 염증관련 유전자들의 발현을 조절함으로써 항염증작용을 발휘하여 항암, 항염증제 개발의 타겟이기도 하다.Therefore, PPAR is an important target for the development of therapeutics for the purpose of treating hypertriglyceridemia, type 2 diabetes, and maintaining lipid homeostasis. On the other hand, PPAR is also a target for the development of anti-cancer and anti-inflammatory drugs by exerting anti-inflammatory effects by regulating the release of anti-inflammatory factors and expression of inflammation-related genes.

PPARα는 주로 간이나 신장 등에서 발현되어 지방산의 산화와 에너지 항상성과 관련된 유전자를 조절하는 역할을 한다. PPARα 활성화는 1)지방산의 이화를 증가시켜 중성지방 생합성을 감소시키고, 2)표적장기에서 직접적으로 지질단백리파아제의 발현을 증가시키고, 3)저밀도 지질단백(LDL)저해제인 아포지질단백 C-III 발현을 감소시킴으로써 최종적으로 혈중 중성지방농도를 낮추고, 혈청 중 저밀도 지질단백농도를 감소시킨다. 또한, PPARα 리간드는 간에서 아포지질단백 A-I, A-II의 합성을 증가시킴으로써 혈청 고밀도 지질단백 농도를 증가시킨다. 고지질증 치료제인 피브레이트 계열 약물은 잘 알려진 PPARα 효능제이다. 그러나 일부 PPARα 효능제의 경우, 설치류의 간에서 퍼옥시좀 증식(peroxisome proliferation)으로 인한 발암성이 보고되기도 하였다.PPARα is mainly expressed in the liver and kidneys, and plays a role in regulating genes related to the oxidation of fatty acids and energy homeostasis. PPARα activation 1) increases the catabolism of fatty acids to reduce triglyceride biosynthesis, 2) increases the expression of lipoprotein lipase directly in the target organ, and 3) apolipoprotein C-III, a low-density lipoprotein (LDL) inhibitor. By reducing the expression, the concentration of triglycerides in the blood is finally lowered, and the concentration of low-density lipoproteins in the serum is reduced. In addition, PPARα ligand increases the concentration of high-density lipoproteins in serum by increasing the synthesis of apolipoproteins A-I and A-II in the liver. The fibrate-based drug, which is a treatment for hyperlipidemia, is a well-known PPARα agonist. However, some PPARα agonists have been reported to have carcinogenicity due to peroxisome proliferation in the liver of rodents.

PPARγ는 주로 지방세포에서 발현하고, 지방세포의 분화와 형성, 당대사, 인슐린감수성 및 지질의 저장에 있어서 핵심적인 역할을 수행한다. 현재 제2형 당뇨병 치료제로서 판매되고 있는 티아졸리딘디온(TZD) 계열 약물은 대표적인 PPARγ 효능제로서 로시글리타존(Avandia, Glaxo-Smith Kline)과 피오글리타존(Actos, Takeda)이 이에 속한다. 그러나 티아졸리딘디온(TZD) 계열 약물의 부작용으로 지방세포 분화에 따른 체중증가, PPARγ 활성화에 따른 체액저류, 골절 증가, 울혈성심부전, 심근경색 등이 있으며, 특히 심혈관질환자에의 투여는 금기시되고 있다.PPARγ is mainly expressed in adipocytes and plays a key role in adipocyte differentiation and formation, glucose metabolism, insulin sensitivity, and storage of lipids. Thiazolidinedione (TZD) series drugs currently sold as type 2 diabetes treatments include rosiglitazone (Avandia, Glaxo-Smith Kline) and pioglitazone (Actos, Takeda) as representative PPARγ agonists. However, side effects of thiazolidinedione (TZD) drugs include weight gain due to adipocyte differentiation, fluid retention due to PPARγ activation, increased fractures, congestive heart failure, and myocardial infarction. Has become.

PPARδ는 생체 내 대부분의 조직에서 다양하게 발현되며 선택적인 리간드가 알려지지 않아서 발견 후 10여 년 동안 그 역할이 잘 밝혀지지 않았다. 그러나 최근 PPARδ에 대한 유전자 수준의 연구 및 선택적인 리간드의 도출로 지방산의 산화와 글루코오스를 조절하고 인슐린 민감성과 HDL 콜레스테롤을 증가시키는 역할이 보고되면서 대사성 질환 치료제 개발을 위한 가능성이 높은 타겟으로 인식되고 있다. PPARδ 효능제는 이상지질혈증(dyslipidemia), 비만 및 인슐린 저항성을 개선하는데 활용될 수 있다.PPARδ is expressed in various ways in most tissues in vivo, and its role has not been well elucidated for about 10 years after discovery because the selective ligand is not known. However, it is recognized as a high potential target for the development of metabolic disease therapeutics, as it has recently been reported to regulate fatty acid oxidation and glucose, and to increase insulin sensitivity and HDL cholesterol through gene-level studies of PPARδ and derivation of selective ligands. . PPARδ agonists can be used to improve dyslipidemia, obesity and insulin resistance.

현재, PPARα 또는 PPARγ 작용물질은 각각 지질대사 개선 및 인슐린 민감성의 향상을 통한 고지혈증 및 당뇨치료제로 피브레이트 계열 및 티아졸리딘디온 계열 약물이 개발되어 사용되고 있으나, 최근 확인된 각종 부작용으로 인해 PPARα/γ 이중효능제, PPARγ/δ 이중효능제, PPARγ 활성조절제, PPARγ 부분효능제 및 PPARδ 효능제 개발이 해결방안으로서 모색되고 있다.Currently, PPARα or PPARγ agonist has been developed and used as a treatment for hyperlipidemia and diabetes through improvement of lipid metabolism and insulin sensitivity, respectively. Development of dual agonists, PPARγ/δ dual agonists, PPARγ activity modulators, PPARγ partial agonists, and PPARδ agonists are being sought as solutions.

이 중, PPARα/γ 이중효능제는 티아졸리딘디온 계열의 PPARγ 효능제에서 나타나는 체중증가의 부작용을 해결할 수 있는 좋은 대안으로 검토되었다. 대표적인 화합물군으로 글리타잘(glitazar)계열의 라가글리타잘(ragaglitazar), 테사글리타잘(tesaglitazar), 파르글리타잘(farglitazar) 등이 있으며, 이들은 당뇨치료제로 연구 개발이 진행되었다. 그러나 임상 2상, 3상에 진입한 글리타잘 계열 화합물에서 지질/당대사의 개선을 통한 당뇨병치료 및 대사성증후군 개선 효과는 우수하나 설치류에서의 발암성, 골수조직으로의 지방질침윤, 백혈구감소 등의 부작용이 보고되었다. 최근 효능 및 독성에 대한 고려에서 우수한 양상을 보였던 아스트라제네카의 갈리다(테사글리타잘)도 3상 시험 과정에서 신장기능 손상의 부작용이 발견되어 개발이 중단되었다. 이와 같이 PPARα/γ에 대해 이중효능제로 작용하는 글리타잘 계열의 부작용은 구조의 특이성에 기반한 것일 수 있다는 제안과 함께 다양한 구조의 화합물에 대해 약물후보물질로서의 가능성이 검토되고 있다.Among them, the PPARα/γ dual agonist was reviewed as a good alternative to solve the side effects of weight gain in thiazolidinedione-based PPARγ agonists. Representative groups of compounds include the glitazar family of ragaglitazar, tesaglitazar, and farglitazar, and these have been researched and developed as diabetes treatments. However, the glitazal compounds that entered the phase 2 and 3 clinical trials have excellent effects on diabetes treatment and metabolic syndrome through improvement of lipid/glucose metabolism, but carcinogenicity in rodents, fat infiltration into bone marrow tissue, reduction of leukocytes, etc. Side effects have been reported. AstraZeneca's Galida (Tesaglitazal), which recently showed an excellent aspect in consideration of efficacy and toxicity, was also discontinued due to a side effect of renal impairment in the phase 3 test. As described above, the possibility of a compound of various structures as a drug candidate is being investigated along with the suggestion that the side effects of the Glitazal family acting as a dual agonist against PPARα/γ may be based on the specificity of the structure.

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:28-40Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:28-40

본 발명의 일 목적은 치환된 인돌 유도체, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.One object of the present invention is to provide a substituted indole derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 상기 치환된 인돌 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the substituted indole derivative.

본 발명의 다른 목적은 상기 치환된 인돌 유도체, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나이상의 PPAR 수용체의 활성과 관련된 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to treat diseases related to the activity of one or more PPAR receptors selected from the group consisting of PPARα, PPARγ and PPARδ containing the substituted indole derivative, optical isomer thereof, or pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for prevention or treatment.

본 발명의 다른 목적은 상기 치환된 인돌 유도체, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나이상의 PPAR 수용체의 활성과 관련된 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to treat diseases related to the activity of one or more PPAR receptors selected from the group consisting of PPARα, PPARγ and PPARδ containing the substituted indole derivative, optical isomer thereof, or pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a health functional food composition for prevention or improvement.

상기 목적을 달성하기 위하여,To achieve the above object,

본 발명의 일 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염이 제공된다:According to an aspect of the present invention, there is provided a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure 112019088622808-pat00001
Figure 112019088622808-pat00001

(상기 화학식 1에서,(In Chemical Formula 1,

R1은 수소, 직쇄 또는 분지쇄의 카복시C1-6알킬, 알릴 또는 직쇄 또는 분지쇄의 C6-10아릴C1-3알킬이고, 상기 알릴 및 아릴은 각각 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;R 1 is hydrogen, straight or branched carboxy C 1-6 alkyl, allyl or straight or branched C 6-10 arylC 1-3 alkyl, and allyl and aryl are halogen and straight or branched C 1-6 may be substituted with one or more substituents selected from the group consisting of alkyl;

R2는 수소 또는 직쇄 또는 분지쇄의 C6-10아릴C1-3알킬이고, 상기 아릴은 -COOH로 하나이상 치환될 수 있고;R 2 is hydrogen or straight or branched C 6-10 arylC 1-3 alkyl, and the aryl may be one or more substituted with -COOH;

R3은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고;R 3 is hydrogen, halogen or straight or branched C 1-6 alkyl;

m은 0 내지 5의 정수이고; 및m is an integer from 0 to 5; And

n은 1 내지 5의 정수이다).n is an integer from 1 to 5).

본 발명의 다른 측면에 따라, 하기 반응식 1에 나타낸 바와 같이,According to another aspect of the present invention, as shown in Scheme 1 below,

화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법이 제공된다:There is provided a method for preparing a compound represented by Formula 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3:

[반응식 1][Scheme 1]

Figure 112019088622808-pat00002
Figure 112019088622808-pat00002

(상기 반응식 1에서,(In Scheme 1,

R1, R2, R3, m 및 n은 상기 화학식 1에서 정의한 바와 같고; 및R 1 , R 2 , R 3 , m And n is as defined in Chemical Formula 1; And

X는 할로겐이다).X is halogen).

본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, any selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer and inflammation containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for preventing or treating a disease is provided.

본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 개선용 건강기능식품 조성물이 제공된다.According to another aspect of the present invention, any selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer and inflammation containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient A health functional food composition for preventing or improving one of the diseases is provided.

본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 치료 방법이 제공된다.According to another aspect of the present invention, a metabolic disease comprising administering to a subject in need a pharmaceutical composition or a dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, A method of preventing or treating a disease selected from the group consisting of cardiovascular disease, cancer, and inflammation is provided.

본 발명의 다른 측면에 따라, 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도가 제공된다.According to another aspect of the present invention, in the prevention or treatment of any one disease selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer and inflammation, the compound represented by Formula 1 or a pharmaceutically acceptable thereof The use of a pharmaceutical composition or a dietary supplement composition containing a salt is provided.

본 발명에 따른 치환된 인돌 유도체는 PPARα, PPARγ 및 PPARδ를 활성화 시키는 능력이 우수하므로, PPAR 효능제로써 대사성 질환, 심혈관계 질환, 암 또는 염증등의 PPARα, PPARγ 및 PPARδ 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있고, 종양성장 억제효과가 우수한 바, 암의 치료에 유용하게 사용할 수 있다.Since the substituted indole derivative according to the present invention has excellent ability to activate PPARα, PPARγ and PPARδ, it is used as a PPAR agonist to prevent or treat PPARα, PPARγ and PPARδ related diseases such as metabolic diseases, cardiovascular diseases, cancer or inflammation. Since it can be usefully used and has an excellent tumor growth inhibitory effect, it can be usefully used in the treatment of cancer.

도 1은 실험예 2에서 평가한 마우스 체중변화를 나타낸 그래프이다.
도 2는 실험예 2에서 평가한 마우스의 종양크기 변화를 나타낸 그래프이다.
도 3은 실험예 2에서 평가한 마우스의 종양무게 변화를 나타낸 그래프이다.
도 4는 실험예 2에서 확인한 마우스의 종양 사진을 나타낸 사진이다.1 is a graph showing the change in the weight of the mouse evaluated in Experimental Example 2.
2 is a graph showing changes in tumor size of mice evaluated in Experimental Example 2.
3 is a graph showing changes in tumor weight of mice evaluated in Experimental Example 2.
4 is a photograph showing a tumor picture of a mouse confirmed in Experimental Example 2.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명의 일 측면은, 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다.One aspect of the present invention provides a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112019088622808-pat00003
Figure 112019088622808-pat00003

상기 화학식 1에서,In Formula 1,

R1은 수소, 직쇄 또는 분지쇄의 카복시C1-6알킬, 알릴 또는 직쇄 또는 분지쇄의 C6-10아릴C1-3알킬이고, 상기 알릴 및 아릴은 각각 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;R 1 is hydrogen, straight or branched carboxy C 1-6 alkyl, allyl or straight or branched C 6-10 arylC 1-3 alkyl, and allyl and aryl are halogen and straight or branched C 1-6 may be substituted with one or more substituents selected from the group consisting of alkyl;

R2는 수소 또는 직쇄 또는 분지쇄의 C6-10아릴C1-3알킬이고, 상기 아릴은 -COOH로 하나이상 치환될 수 있고;R 2 is hydrogen or straight or branched C 6-10 arylC 1-3 alkyl, and the aryl may be one or more substituted with -COOH;

R3은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고;R 3 is hydrogen, halogen or straight or branched C 1-6 alkyl;

m은 0 내지 5의 정수이고; 및m is an integer from 0 to 5; And

n은 1 내지 5의 정수이다.n is an integer from 1 to 5.

상기 R1은 수소, 직쇄 또는 분지쇄의 카복시C1-3알킬, 알릴 또는 직쇄 또는 분지쇄의 페닐C1-3알킬이고, 상기 알릴 및 페닐은 각각 할로겐 및 직쇄 또는 분지쇄의 C1-4알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;Wherein R 1 is hydrogen, straight or branched carboxy C 1-3 alkyl, allyl or straight or branched phenyl C 1-3 alkyl, and allyl and phenyl are halogen and straight or branched C 1-4, respectively May be substituted with one or more substituents selected from the group consisting of alkyl;

R2는 수소 또는 직쇄 또는 분지쇄의 페닐C1-3알킬이고, 상기 페닐은 -COOH로 하나이상 치환될 수 있고;R 2 is hydrogen or linear or branched phenylC 1-3 alkyl, and the phenyl may be substituted with one or more -COOH;

R3은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-4알킬이고;R 3 is hydrogen, halogen or straight or branched C 1-4 alkyl;

m은 1 내지 3의 정수이고; 및m is an integer from 1 to 3; And

n은 1 내지 3의 정수일 수 있다.n may be an integer of 1 to 3.

또한, 상기 R1은 수소, 카복시C1-2알킬, 알릴 또는 벤질이고, 상기 알릴 및 벤질은 각각 할로겐 및 C1-2알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;Further, R 1 is hydrogen, carboxy C 1-2 alkyl, allyl or benzyl, and allyl and benzyl may each be substituted with one or more substituents selected from the group consisting of halogen and C 1-2 alkyl;

R2는 수소 또는 벤질이고, 상기 벤질은 -COOH로 하나이상 치환될 수 있고;R 2 is hydrogen or benzyl, and the benzyl may be one or more substituted with -COOH;

R3은 수소, 할로겐 또는 C1-2알킬이고;R 3 is hydrogen, halogen or C 1-2 alkyl;

m은 1 또는 2의 정수이고; 및m is an integer of 1 or 2; And

n은 1 또는 2의 정수일 수 있다.n may be an integer of 1 or 2.

또한, R1은 수소, -CH2COOH,

Figure 112019088622808-pat00004
또는 벤질이고;In addition, R 1 is hydrogen, -CH 2 COOH,
Figure 112019088622808-pat00004
Or benzyl;

R2는 수소,

Figure 112019088622808-pat00005
,
Figure 112019088622808-pat00006
또는
Figure 112019088622808-pat00007
이고;R 2 is hydrogen,
Figure 112019088622808-pat00005
,
Figure 112019088622808-pat00006
or
Figure 112019088622808-pat00007
ego;

R3은 수소 또는 할로겐이고;R 3 is hydrogen or halogen;

m은 1 또는 2의 정수이고; 및m is an integer of 1 or 2; And

n은 1일 수 있다.n may be 1.

상기 화학식 1에서, 치환기

Figure 112019088622808-pat00008
은 페닐의 CH에 치환되어 결합될 수 있음을 의미하고, 각 위치에 결합된
Figure 112019088622808-pat00009
는 서로 동일 또는 상이할 수 있다.In Formula 1, a substituent
Figure 112019088622808-pat00008
Means that the CH of phenyl can be substituted and bonded, and
Figure 112019088622808-pat00009
May be the same or different from each other.

본 발명에 따른 상기 화학식 1로 표시되는 화합물의 예로는 하기의 화합물들을 들 수 있다: Examples of the compound represented by Formula 1 according to the present invention include the following compounds:

<1> 2-(5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드;<1> 2-(5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid;

<2> 2-(6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드;<2> 2-(6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid;

<3> 2-(1-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드;<3> 2-(1-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid;

<4> 2-(1-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드;<4> 2-(1-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid;

<5> 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<5> 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<6> 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<6> 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<7> 3-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<7> 3-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<8> 3-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<8> 3-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<9> 4-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<9> 4-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<10> 4-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<10> 4-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<11> 2-((3-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<11> 2-((3-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<12> 2-((3-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;<12> 2-((3-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;

<13> 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸)벤조익 애시드;<13> 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut-2-en-1-yl)-1H- Indol-1-yl)methyl)benzoic acid;

<14> 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸)벤조익 애시드.<14> 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut-2-en-1-yl)-1H- Indol-1-yl)methyl)benzoic acid.

본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid May be prepared by filtration and drying, or may be prepared by distilling a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, and hydrates that may be prepared therefrom.

본 발명의 다른 측면은, 하기 반응식 1에 나타낸 바와 같이,Another aspect of the present invention, as shown in Scheme 1 below,

화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.It provides a method for preparing a compound represented by Formula 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3.

[반응식 1][Scheme 1]

Figure 112019088622808-pat00010
Figure 112019088622808-pat00010

상기 반응식 1에서,In Scheme 1 above,

R1, R2, R3, m 및 n은 상기 화학식 1에서 정의한 바와 같고; 및R 1 , R 2 , R 3 , m And n is as defined in Chemical Formula 1; And

X는 할로겐이다.X is halogen.

이하, 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법을 상세히 설명한다.Hereinafter, a method for preparing the compound represented by Chemical Formula 1 according to the present invention will be described in detail.

상기 반응식 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조하는 단계로, 구체적으로, 화학식 2로 표시되는 화합물의 OH와 화학식 3으로 표시되는 화합물의 할로겐이 반응하여 화학식 1로 표시되는 화합물이 제조되는 단계이다.Reaction Scheme 1 is a step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3, specifically, OH of the compound represented by Formula 2 and the compound represented by Formula 3 This is a step in which the compound represented by Chemical Formula 1 is prepared by reacting the halogen of the compound.

상기 반응식 1은 통상적으로 알려진 할로겐과 OH를 결합시켜 에테르(ether)를 형성할 수 있는 조건이라면 특히 한정되지 않는다.Reaction Scheme 1 is not particularly limited as long as it is a condition capable of forming ether by combining commonly known halogen and OH.

본 발명에서는 염기 존재하에 교반시켜 반응시켰으나, 이는 일례일 뿐, 이에 한정되는 것은 아니다.In the present invention, the reaction was carried out by stirring in the presence of a base, but this is only an example and is not limited thereto.

상기 염기로는 N,N-다이메틸아미노피리딘(DMAP), 피리딘, 트라이에틸아민, N,N-다이이소프로필에틸아민, 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU) 등의 유기염기 또는 세슘카보네이트, 포타슘카보네이트, 수산화포타슘, 수산화리튬, 소듐카보네이트, 소듐바이카보네이트, 수산화소듐, NaH 등의 무기염기가 있으며, 이를 단독 또는 혼합하여, 당량 또는 과량으로 사용할 수 있다.Examples of the base include N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene ( DBU) or an inorganic base such as cesium carbonate, potassium carbonate, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, NaH, etc., and can be used alone or in combination in an equivalent amount or in an excess amount. .

반응 용매는 아이소프로판올, 메탄올, 에탄올, 프로판올 및 부탄올을 포함하는 저급 알코올; 테트라하이드로퓨란(THF); 디옥산; 에틸에테르, 1,2-다이메톡시에탄 등을 포함하는 에테르용매; 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 메틸렌클로라이드, 디클로로에탄, 물, 아세토나젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 에틸아세테이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시크레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트, 아세토나이트릴 등이 있으며, 이를 단독 또는 혼합하여 사용할 수 있다. The reaction solvent is a lower alcohol including isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether and 1,2-dimethoxyethane; Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, water, acetonase sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenyl acetate, phenyl propionate , Phenylbutyrate, Cycrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, acetonite There are reels and the like, and these may be used alone or in combination.

본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is any one selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer, and inflammation containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of phosphorus disease.

이때, 상기 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환은 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나 이상인 수용체의 활성과 관련된 것일 수 있다.At this time, any one disease selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer and inflammation may be related to the activity of one or more receptors selected from the group consisting of PPARα, PPARγ, and PPARδ.

또한, 화합물은 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나 이상인 수용체를 활성화시킬 수 있다.In addition, the compound can activate one or more receptors selected from the group consisting of PPARα, PPARγ and PPARδ.

상기 대사성 질환은 비만, 당뇨병, 비알콜성 지방간 질환, 고지혈증, 고혈압, 고인슐린혈증, 지방간, 고요산혈증, 고콜레스테롤혈증, 고중성지방혈증, 대사증후군(Syndrome X), 내피기능장애 및 이상지질혈증으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The metabolic diseases are obesity, diabetes, non-alcoholic fatty liver disease, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), endothelial dysfunction and dyslipidemia. It may be any one selected from the group consisting of.

상기 심혈관계 질환은 동맥경화, 심부전, 심근경색, 고혈압, 혈전증, 응집전 상태(Precoagulant state) 및 아테롬성 경화증으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The cardiovascular disease may be any one selected from the group consisting of arteriosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, and atherosclerosis.

상기 암은 신장암, 방광암, 간암, 흉선암, 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The cancer is kidney cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrous It may be any one selected from the group consisting of tumors and brain tumors.

본 발명에 따른 화학식 1로 표시되는 화합물은 PPARα, PPARγ 및 PPARδ를 활성화 시키는 능력이 우수하고(실험예 1 참조), 종양성장 억제효과가 우수하다(실험예 2 참조). The compound represented by Formula 1 according to the present invention has excellent ability to activate PPARα, PPARγ and PPARδ (see Experimental Example 1), and excellent tumor growth inhibitory effect (see Experimental Example 2).

따라서, 본 발명에 따른 화학식 1로 표시되는 화합물은 PPARα, PPARγ 및 PPARδ를 활성화 시키는 능력이 우수하므로, PPAR 효능제로써 대사성 질환, 심혈관계 질환, 암 또는 염증등의 PPARα, PPARγ 및 PPARδ 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있고, 종양성장 억제효과가 우수한 바, 암의 치료에 유용하게 사용할 수 있다.Therefore, the compound represented by Formula 1 according to the present invention has excellent ability to activate PPARα, PPARγ, and PPARδ, and thus, PPARα, PPARγ, and PPARδ related diseases such as metabolic diseases, cardiovascular diseases, cancer or inflammation as a PPAR agonist It can be usefully used for prevention or treatment, and has an excellent tumor growth inhibitory effect, so it can be usefully used in the treatment of cancer.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc., but may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with. The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing and granulation. It can be formulated according to the method of painting or coating.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (such as silica, talc, stearic acid and magnesium or calcium salts thereof and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another aspect of the present invention is any one selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer, and inflammation containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a health functional food composition for the prevention or improvement of phosphorus disease.

이때, 상기 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환은 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나 이상인 수용체의 활성과 관련된 것일 수 있다.At this time, any one disease selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer and inflammation may be related to the activity of one or more receptors selected from the group consisting of PPARα, PPARγ, and PPARδ.

또한, 화합물은 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나 이상인 수용체를 활성화시킬 수 있다.In addition, the compound can activate one or more receptors selected from the group consisting of PPARα, PPARγ and PPARδ.

상기 대사성 질환은 비만, 당뇨병, 비알콜성 지방간 질환, 고지혈증, 고혈압, 고인슐린혈증, 지방간, 고요산혈증, 고콜레스테롤혈증, 고중성지방혈증, 대사증후군(Syndrome X), 내피기능장애 및 이상지질혈증으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The metabolic diseases are obesity, diabetes, non-alcoholic fatty liver disease, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), endothelial dysfunction and dyslipidemia. It may be any one selected from the group consisting of.

상기 심혈관계 질환은 동맥경화, 심부전, 심근경색, 고혈압, 혈전증, 응집전 상태(Precoagulant state) 및 아테롬성 경화증으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The cardiovascular disease may be any one selected from the group consisting of arteriosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, and atherosclerosis.

상기 암은 신장암, 방광암, 간암, 흉선암, 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The cancer is kidney cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrous It may be any one selected from the group consisting of tumors and brain tumors.

본 발명에 따른 화학식 1로 표시되는 화합물은, PPARα, PPARγ 및 PPARδ를 활성화 시키는 능력이 우수하므로, 대사성 질환, 심혈관계 질환, 암 또는 염증등의 PPARα, PPARγ 및 PPARδ 관련 질환의 예방 또는 개선용 건강기능식품 조성물로 식품, 음료 등의 건강기능보조 식품에 첨가할 수 있다.Since the compound represented by Formula 1 according to the present invention has excellent ability to activate PPARα, PPARγ and PPARδ, health for the prevention or improvement of PPARα, PPARγ and PPARδ related diseases such as metabolic diseases, cardiovascular diseases, cancer or inflammation As a functional food composition, it can be added to health functional foods such as foods and beverages.

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by Formula 1 according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount above the above range.

또한, 본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages. have. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

나아가, 상기 외에 본 발명에 따른 화학식 1로 표시되는 화합은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 화학식 1로 표시되는 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. Further, in addition to the above, the compound represented by Chemical Formula 1 according to the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pects. Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages.

본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention is a metabolic disease, cardiovascular disease comprising the step of administering to a subject in need a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a method for preventing or treating any one disease selected from the group consisting of related diseases, cancer, and inflammation.

본 발명의 다른 측면은, 대사성 질환, 심혈관계 질환, 암 및 염증으로 이루어지는 군으로부터 선택되는 어느 하나인 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도를 제공한다.Another aspect of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of any one disease selected from the group consisting of metabolic diseases, cardiovascular diseases, cancer and inflammation. It provides the use of a pharmaceutical composition or a health functional food composition containing.

이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and experimental examples.

단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following Examples and Experimental Examples.

<제조예 1> 2-클로로-<Production Example 1> 2-chloro- NN -(2,4-디클로로페닐)아세트아마이드의 제조-(2,4-dichlorophenyl)acetamide preparation

Figure 112019088622808-pat00011
Figure 112019088622808-pat00011

트리클로로아민 (1.1 equiv.)을 2,4-클로로아닐린의 CH2Cl2 (0.5 M)에 첨가하고, 상온에서 30분간 교반시켰다. 반응 혼합물을 0 ℃까지 냉각시키고, 온도를 유지하면서 클로로아세틸 클로라이드 (1.2 equiv.)를 적하첨가하였다. 반응 종료 후, 반응 혼합물에 물을 첨가하여 퀀칭하였다. 유기층을 분리하고, 물로 세번 세척하였다. 이후, 소금물(brine) 및 MgSO4로 건조하고, 여과한 후, 진공하에 농축하엿다. 잔여물을 실리카 겔 컬럼 크로마토그래피 (n-hexane:EtOAc (5:1))를 사용하여 정제하여 정량적인 수율로 목적 화합물을 얻었다.Trichloroamine (1.1 equiv. ) was added to CH 2 Cl 2 (0.5 M) of 2,4-chloroaniline, and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C., and chloroacetyl chloride (1.2 equiv.) was added dropwise while maintaining the temperature. After completion of the reaction, water was added to the reaction mixture, followed by quenching. The organic layer was separated and washed three times with water. Thereafter, it was dried over brine and MgSO 4 , filtered, and then concentrated under vacuum. The residue was purified using silica gel column chromatography ( n- hexane:EtOAc (5:1)) to obtain the target compound in a quantitative yield.

1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 8.8, 2.4 Hz, 1H), 4.23 (s, 2H); 13C NMR (100 MHz, CDCl3) δ164.0, 132.5, 130.2, 129.1, 128.1, 124.1, 122.0, 43.2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 8.8, 2.4 Hz, 1H), 4.23 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.0, 132.5, 130.2, 129.1, 128.1, 124.1, 122.0, 43.2.

<실시예 1> 2-(5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조<Example 1> Preparation of 2-(5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid

Figure 112019088622808-pat00012
Figure 112019088622808-pat00012

단계 1: 메틸 2-(5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트의 제조Step 1: Preparation of methyl 2-(5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetate

메틸 2-(5-하이드록시-1H-인돌-3-일)아세테이트를 무수 MeCN (0.5 M)에 용해시키고, Cs2CO3 (1.5 equiv.)를 첨가하여 상온에서 30분간 교반시켰다. 반응 혼합물에 상기 제조예 1에서 제조한 화합물 (1.2 equiv.)을 첨가하고, 반응이 종료될 때 까지 교반시켰다. 이 후, 반응 혼합물을 물로 희석시키고, EtOAc로 추출하였다. 합친 유기 추출물을 물 및 소금물(brine)으로 세척하고, 무수 MgSO4로 건조하여 여과한 후, 감압하에 농축하였다. 잔여물을 실리카 겔 컬럼 크로마토그래피 (용리액: n-hexane 및 EtOAc)를 사용하여 정제하여 메틸 2-(5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트를 얻었다.Methyl 2-(5-hydroxy-1H-indol-3-yl)acetate was dissolved in anhydrous MeCN (0.5 M), Cs 2 CO 3 (1.5 equiv.) was added, followed by stirring at room temperature for 30 minutes. The compound (1.2 equiv.) prepared in Preparation Example 1 was added to the reaction mixture, and the mixture was stirred until the reaction was completed. After this time, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous MgSO 4 , filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (eluent: n- hexane and EtOAc) to obtain methyl 2-(5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)- 1 H -indol-3-yl)acetate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.10 (s, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.3 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.8, 2.4 Hz, 1H), 4.70 (s, 2H), 3.75 (d, J = 0.5 Hz, 2H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 167.2, 151.7, 132.9, 132.3, 129.6, 129.0, 128.1, 127.9, 124.6, 123.9, 122.1, 112.7, 112.5, 108.7, 103.1, 68.9, 52.2, 31.3. 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.10 (s, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.3 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.8, 2.4 Hz, 1H), 4.70 (s, 2H), 3.75 (d, J = 0.5 Hz, 2H), 3.70 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 172.4, 167.2, 151.7, 132.9, 132.3, 129.6, 129.0, 128.1, 127.9, 124.6, 123.9, 122.1, 112.7, 112.5, 108.7, 103.1, 68.9, 52.2, 31.3.

단계 2: 2-(5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조Step 2: Preparation of 2-(5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetic acid

상기 단계 1에서 얻은 화합물의 THF/MeOH/H2O (1 M, 2:1:1 v/v/v)에 LiOH·H2O (1.5 equiv.)를 첨가하고 상온에서 교반시켰다. 반응 종결 후, 상기 반응 혼합물을 감압하에 농축하고, 1N HCl 용액으로 산성화한 후, EtOAc로 추출하였다. 합친 유기 추출물을 물 및 소금물(brine)으로 세척하고, 무수 MgSO4로 건조하여 여과한 후, 감압하에 농축하였다. 잔여물을 실리카 겔 컬럼 크로마토그래피 (용리액: CHCl3 및 MeOH)를 사용하여 정제하여 목적 화합물을 얻었다. LiOH·H 2 O (1.5 equiv.) was added to THF/MeOH/H 2 O (1 M, 2:1:1 v/v/v) of the compound obtained in step 1 and stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, acidified with 1N HCl solution, and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous MgSO 4 , filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (eluent: CHCl 3 and MeOH) to obtain the title compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.14 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.8, 2.3 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.19 (s, 2H), 6.94 (dd, J = 8.6, 2.3 Hz, 1H), 4.73 (s, 2H), 3.71 (s, 2H); HRMS(ESI): m/z 391.0263 [M-H]- (calcd for C18H13Cl2N2O4 = 391.0258). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.14 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.8, 2.3 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.19 (s, 2H), 6.94 (dd, J = 8.6, 2.3 Hz, 1H), 4.73 (s, 2H), 3.71 (s, 2H); HRMS (ESI): m/z 391.0263 [MH] - (calcd for C 18 H 13 Cl 2 N 2 O 4 = 391.0258).

<실시예 2> 2-(6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조<Example 2> Preparation of 2-(6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid

Figure 112019088622808-pat00013
Figure 112019088622808-pat00013

단계 1: 메틸 2-(6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트의 제조Step 1: Preparation of methyl 2-(6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-(6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트를 얻었다.Methyl 2-(6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl) by performing a method similar to step 1 of Example 1 above I got the acetate.

1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.42 (d, J = 8.9 Hz, 1H), 8.24 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.7, 2.5 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 4.63 (s, 2H), 3.76 (s, 2H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 167.0, 153.8, 136.6, 132.7, 129.6, 129.0, 128.0, 123.8, 123.02, 122.97, 122.0, 120.1, 110.0, 108.5, 96.3, 68.4, 52.2, 31.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.42 (d, J = 8.9 Hz, 1H), 8.24 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.7, 2.5 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H) , 6.84 (d, J = 2.0 Hz, 1H), 4.63 (s, 2H), 3.76 (s, 2H), 3.71 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 172.7, 167.0, 153.8, 136.6, 132.7, 129.6, 129.0, 128.0, 123.8, 123.02, 122.97, 122.0, 120.1, 110.0, 108.5, 96.3, 68.4, 52.2, 31.2.

단계 2: 2-(6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조Step 2: Preparation of 2-(6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.20 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.7, 2.3 Hz, 1H), 4.70 (s, 2H), 3.65 (s, 2H); HRMS(ESI): m/z 391.0256 [M-H]- (calcd for C18H13Cl2N2O4 = 391.0258). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.20 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.7, 2.3 Hz, 1H), 4.70 (s, 2H), 3.65 (s, 2H); HRMS (ESI): m/z 391.0256 [MH] - (calcd for C 18 H 13 Cl 2 N 2 O 4 = 391.0258).

<실시예 3> 2-(1-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조<Example 3> Preparation of 2-(1-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid

Figure 112019088622808-pat00014
Figure 112019088622808-pat00014

단계 1: 메틸 2-(1-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트의 제조Step 1: Preparation of methyl 2-(1-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-(1-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트를 얻었다.Methyl 2-(1-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indole- 3-day) acetate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.32-7.24 (m, 4H), 7.18 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 7.12-7.09 (m, 2H), 6.92 (dd, J = 8.9, 2.5 Hz, 1H), 5.26 (s, 2H), 4.69 (s, 2H), 3.74 (d, J = 0.6 Hz, 2H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 167.2, 151.6, 137.3, 132.9, 132.8, 129.5, 128.98, 128.95, 128.6, 128.5, 128.1, 127.9, 126.9, 123.8, 122.1, 112.4, 111.2, 107.4, 103.4, 68.9, 52.2, 50.5, 31.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.11 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.32-7.24 (m, 4H) , 7.18 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 7.12-7.09 (m, 2H), 6.92 (dd, J = 8.9, 2.5 Hz, 1H), 5.26 (s, 2H), 4.69 (s, 2H), 3.74 (d, J = 0.6 Hz, 2H), 3.70 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 172.4, 167.2, 151.6, 137.3, 132.9, 132.8, 129.5, 128.98, 128.95, 128.6, 128.5, 128.1, 127.9, 126.9, 123.8, 122.1, 112.4, 111.2, 107.4, 103.4 , 68.9, 52.2, 50.5, 31.2.

단계 2: 2-(1-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조Step 2: Preparation of 2-(1-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.34 (d, J = 8.9 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.31-7.26 (m, 2H), 7.24-7.18 (m, 3H), 7.13 (d, J = 6.6 Hz, 2H), 6.94 (dd, J = 9.2, 2.2 Hz, 1H), 5.30 (s, 2H), 4.72 (s, 2H), 3.74 (s, 2H); HRMS(ESI): m/z 481.0724 [M-H]- (calcd for C25H19Cl2N2O4 = 481.0727). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.34 (d, J = 8.9 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.31-7.26 (m, 2H), 7.24-7.18 (m, 3H), 7.13 (d, J = 6.6 Hz, 2H), 6.94 (dd, J = 9.2, 2.2 Hz, 1H ), 5.30 (s, 2H), 4.72 (s, 2H), 3.74 (s, 2H); HRMS (ESI): m/z 481.0724 [MH] - (calcd for C 25 H 19 Cl 2 N 2 O 4 =481.0727).

<실시예 4> 2-(1-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조<Example 4> Preparation of 2-(1-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid

Figure 112019088622808-pat00015
Figure 112019088622808-pat00015

단계 1: 메틸 2-(1-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트의 제조Step 1: Preparation of 2-methyl acetate (1-benzyl-6- (2-indol-3-yl - ((2,4-dichlorophenyl) amino) -2-oxo-ethoxy) -1 H a)

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-(1-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세테이트를 얻었다.Methyl 2-(1-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indole- 3-day) acetate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.31-7.22 (m, 4H), 7.13-7.08 (m, 2H), 7.06 (s, 1H), 6.87 (dd, J = 8.6, 2.3 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 5.22 (s, 2H), 4.61 (s, 2H), 3.75 (s, 2H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 166.9, 153.8, 137.0, 132.8, 129.6, 129.0, 128.0, 127.9, 127.2, 126.9, 123.9, 123.8, 122.1, 120.5, 109.6, 107.8, 95.3, 68.5, 52.2, 50.3, 31.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 2.4 Hz , 1H), 7.31-7.22 (m, 4H), 7.13-7.08 (m, 2H), 7.06 (s, 1H), 6.87 (dd, J = 8.6, 2.3 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 5.22 (s, 2H), 4.61 (s, 2H), 3.75 (s, 2H), 3.70 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 172.5, 166.9, 153.8, 137.0, 132.8, 129.6, 129.0, 128.0, 127.9, 127.2, 126.9, 123.9, 123.8, 122.1, 120.5, 109.6, 107.8, 95.3, 68.5, 52.2 , 50.3, 31.2.

단계 2: 2-(1-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드의 제조Step 2: Preparation of 2-(1-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-3-yl)acetic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.25 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.28-7.21 (m, 3H), 7.16-7.11 (m, 3H), 6.89 (dd, J = 8.7, 2.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 5.29 (s, 2H), 4.66 (s, 2H), 3.74 (s, 2H); HRMS(ESI): m/z 481.0726 [M-H]- (calcd for C25H19Cl2N2O4 = 481.0727). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.25 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H) , 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.28-7.21 (m, 3H), 7.16-7.11 (m, 3H), 6.89 (dd, J = 8.7, 2.0 Hz, 1H), 6.84 (d , J = 2.0 Hz, 1H), 5.29 (s, 2H), 4.66 (s, 2H), 3.74 (s, 2H); HRMS (ESI): m/z 481.0726 [MH] - (calcd for C 25 H 19 Cl 2 N 2 O 4 =481.0727).

<실시예 5> 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 5> Preparation of 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00016
Figure 112019088622808-pat00016

단계 1: 메틸 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조에이트의 제조Step 1: Preparation of methyl 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조에이트를 얻었다.Methyl 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl by performing a method similar to step 1 of Example 1 above. )Methyl)benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.12-7.98 (m, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.33-7.29 (m, 2H), 7.28-7.25 (m, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.17-7.12 (m, 2H), 6.90 (dd, J = 8.9, 2.4 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 6.48-6.44 (m, 1H), 5.76 (s, 2H), 4.68 (s, 2H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 151.6, 140.1, 133.1, 132.9, 132.7, 131.2, 130.1, 129.1, 129.0, 128.1, 127.8, 127.4, 127.1, 123.8, 122.1, 121.0, 112.2, 111.0, 104.9, 101.8, 95.9, 68.9, 52.4, 49.0. 1 H NMR (400 MHz, CDCl 3 ) δ 9.11 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.12-7.98 (m, 1H), 7.39 (d, J = 2.3 Hz, 1H) , 7.33-7.29 (m, 2H), 7.28-7.25 (m, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.17-7.12 (m, 2H), 6.90 (dd, J = 8.9, 2.4 Hz , 1H), 6.54 (d, J = 3.0 Hz, 1H), 6.48-6.44 (m, 1H), 5.76 (s, 2H), 4.68 (s, 2H), 3.94 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.2, 151.6, 140.1, 133.1, 132.9, 132.7, 131.2, 130.1, 129.1, 129.0, 128.1, 127.8, 127.4, 127.1, 123.8, 122.1, 121.0, 112.2, 111.0, 104.9 , 101.8, 95.9, 68.9, 52.4, 49.0.

단계 2: 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드Step 2: 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.38 (d, J = 8.9 Hz, 1H), 8.03-7.99 (m, 1H), 7.42-7.39 (m, 1H), 7.28 (dd, J = 8.9, 2.4 Hz, 1H), 7.24-7.20 (m, 2H), 7.19 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 3.1 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 6.42-6.38 (m, 1H), 5.75 (s, 2H), 4.66 (s, 2H); HRMS(ESI): m/z 467.0549 [M-H]- (calcd for C24H17Cl2N2O4 = 467.0571). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.38 (d, J = 8.9 Hz, 1H), 8.03-7.99 (m, 1H), 7.42-7.39 (m, 1H), 7.28 (dd, J = 8.9, 2.4 Hz, 1H), 7.24-7.20 (m, 2H), 7.19 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 3.1 Hz, 1H), 7.10 (d, J = 8.9 Hz , 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 6.42-6.38 (m, 1H), 5.75 (s, 2H), 4.66 (s, 2H); HRMS (ESI): m/z 467.0549 [MH] - (calcd for C 24 H 17 Cl 2 N 2 O 4 =467.0571).

<실시예 6> 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 6> Preparation of 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00017
Figure 112019088622808-pat00017

단계 1: 메틸 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Preparation of methyl 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다Methyl 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl by performing a method similar to step 1 of Example 1 above. )Methyl) to obtain benzoate

1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.07-8.02 (m, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.30-7.26 (m, 2H), 7.25-7.22 (m, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 6.55 (dd, J = 3.2, 0.7 Hz, 1H), 6.49-6.44 (m, 1H), 5.73 (s, 2H), 4.59 (s, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 153.6, 139.8, 136.9, 133.0, 132.8, 131.2, 129.5, 128.9, 128.7, 128.0, 127.8, 127.4, 127.0, 124.4, 123.8, 122.2, 122.0, 109.9, 102.0, 95.2, 68.5, 52.4, 48.8. 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.07-8.02 (m, 1H), 7.59 (d, J = 8.6 Hz, 1H) , 7.36 (d, J = 2.4 Hz, 1H), 7.30-7.26 (m, 2H), 7.25-7.22 (m, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.88 (dd, J = 8.6 , 2.3 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 6.55 (dd, J = 3.2, 0.7 Hz, 1H), 6.49-6.44 (m, 1H), 5.73 (s, 2H), 4.59 (s, 2H), 3.95 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.9, 153.6, 139.8, 136.9, 133.0, 132.8, 131.2, 129.5, 128.9, 128.7, 128.0, 127.8, 127.4, 127.0, 124.4, 123.8, 122.2, 122.0, 109.9, 102.0 , 95.2, 68.5, 52.4, 48.8.

단계 2: 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: Preparation of 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.32 (d, J = 8.9 Hz, 1H), 8.09-8.05 (m, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 0.7 Hz, 1H), 7.30-7.25 (m, 3H), 7.13 (d, J = 3.1 Hz, 1H), 6.89 (dd, J = 8.6, 2.2 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 6.52-6.48 (m, 1H), 5.77 (s, 2H), 4.63 (s, 2H); HRMS(ESI): m/z 467.0550 [M-H]- (calcd for C24H17Cl2N2O4 = 467.0571). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.32 (d, J = 8.9 Hz, 1H), 8.09-8.05 (m, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.41 ( d, J = 2.4 Hz, 1H), 7.39 (d, J = 0.7 Hz, 1H), 7.30-7.25 (m, 3H), 7.13 (d, J = 3.1 Hz, 1H), 6.89 (dd, J = 8.6 , 2.2 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 6.52-6.48 (m, 1H), 5.77 (s, 2H), 4.63 (s , 2H); HRMS (ESI): m/z 467.0550 [MH] - (calcd for C 24 H 17 Cl 2 N 2 O 4 =467.0571).

<실시예 7> 3-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 7> Preparation of 3-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00018
Figure 112019088622808-pat00018

단계 1: 메틸 3-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Preparation of methyl 3-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 3-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 3-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl by performing a method similar to step 1 of Example 1 above. )Methyl) benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.45 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.25 (dd, J = 8.9, 2.3 Hz, 1H), 7.21-7.13 (m, 4H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 5.32 (s, 2H), 4.66 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 151.5, 137.8, 132.7, 132.3, 131.1, 130.7, 129.4, 129.3, 129.2, 128.99 128.95, 128.8, 127.92, 127.88, 123.6, 121.9, 112.0, 110.7, 104.9, 101.8, 68.7, 52.2, 50.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (s, 1H), 8.45 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.25 (dd, J = 8.9, 2.3 Hz, 1H), 7.21-7.13 (m, 4H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 5.32 (s, 2H), 4.66 (s, 2H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.0, 151.5, 137.8, 132.7, 132.3, 131.1, 130.7, 129.4, 129.3, 129.2, 128.99 128.95, 128.8, 127.92, 127.88, 123.6, 121.9, 112.0, 110.7, 104.9, 101.8, 68.7, 52.2, 50.1.

단계 2: 3-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: Preparation of 3-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.37 (d, J = 8.8 Hz, 1H), 7.99-7.90 (m, 3H), 7.44 (d, J = 2.3 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.24-7.20 (m, 4H), 6.93 (dd, J = 8.9, 2.6 Hz, 1H), 6.51 (d, J = 3.2 Hz, 1H), 5.38 (s, 2H), 4.70 (s, 2H); HRMS(ESI): m/z 467.0558 [M-H]- (calcd for C24H17Cl2N2O4 = 467.0571). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.37 (d, J = 8.8 Hz, 1H), 7.99-7.90 (m, 3H), 7.44 (d, J = 2.3 Hz, 1H), 7.36 ( t, J = 7.6 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.24-7.20 (m, 4H), 6.93 (dd, J = 8.9, 2.6 Hz, 1H), 6.51 (d , J = 3.2 Hz, 1H), 5.38 (s, 2H), 4.70 (s, 2H); HRMS (ESI): m/z 467.0558 [MH] - (calcd for C 24 H 17 Cl 2 N 2 O 4 =467.0571).

<실시예 8> 3-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 8> Preparation of 3-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00019
Figure 112019088622808-pat00019

단계 1: 메틸 3-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Preparation of methyl 3-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 3-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 3-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl by performing a method similar to step 1 of Example 1 above. )Methyl) benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.24 (dd, J = 8.9, 2.4 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.86 (dd, J = 8.6, 2.3 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 3.2, 0.8 Hz, 1H), 5.29 (s, 2H), 4.60 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 153.6, 137.6, 136.6, 132.7, 131.2, 130.9, 129.5, 129.10, 129.09, 128.9, 128.2, 128.03, 127.99, 124.5, 123.7, 122.3, 122.0, 109.8, 102.2, 95.1, 68.5, 52.3, 50.0. 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.24 (dd, J = 8.9, 2.4 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.86 (dd, J = 8.6, 2.3 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 3.2, 0.8 Hz, 1H), 5.29 (s, 2H), 4.60 (s, 2H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.8, 153.6, 137.6, 136.6, 132.7, 131.2, 130.9, 129.5, 129.10, 129.09, 128.9, 128.2, 128.03, 127.99, 124.5, 123.7, 122.3, 122.0, 109.8, 102.2 , 95.1, 68.5, 52.3, 50.0.

단계 2: 3-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: Preparation of 3-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.25 (d, J = 8.8 Hz, 1H), 7.94-7.87 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.28 (s, 1H), 7.26 (dd, J = 8.8, 2.4 Hz, 1H), 7.20-7.15 (m, 1H), 7.10 (d, J = 2.7 Hz, 1H), 6.86 (dd, J = 8.6, 2.2 Hz, 1H), 6.82 (s, 1H), 6.48 (d, J = 3.1 Hz, 1H), 5.28 (s, 2H), 4.63 (s, 2H); HRMS(ESI): m/z 467.0557 [M-H]- (calcd for C24H17Cl2N2O4 = 467.0571). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.25 (d, J = 8.8 Hz, 1H), 7.94-7.87 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.42- 7.38 (m, 1H), 7.28 (s, 1H), 7.26 (dd, J = 8.8, 2.4 Hz, 1H), 7.20-7.15 (m, 1H), 7.10 (d, J = 2.7 Hz, 1H), 6.86 (dd, J = 8.6, 2.2 Hz, 1H), 6.82 (s, 1H), 6.48 (d, J = 3.1 Hz, 1H), 5.28 (s, 2H), 4.63 (s, 2H); HRMS (ESI): m/z 467.0557 [MH] - (calcd for C 24 H 17 Cl 2 N 2 O 4 =467.0571).

<실시예 9> 4-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 9> Preparation of 4-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00020
Figure 112019088622808-pat00020

단계 1: 메틸 4-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Preparation of methyl 4-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 4-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 4-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl by performing a similar method to Step 1 of Example 1 above. )Methyl) benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 8.7, 2.1 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 3.1 Hz, 1H), 7.15-7.10 (m, 3H), 6.91 (dd, J = 8.9, 2.4 Hz, 1H), 6.53 (d, J = 3.1 Hz, 1H), 5.36 (s, 2H), 4.68 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 151.7, 142.6, 132.9, 132.5, 130.3, 129.8, 129.7, 129.5, 129.3, 129.0, 128.1, 126.6, 123.8, 122.1, 120.0, 112.3, 110.9, 105.1, 102.0, 68.8, 52.3, 50.3. 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (s, 1H), 8.46 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 2.4 Hz , 1H), 7.27 (dd, J = 8.7, 2.1 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 3.1 Hz, 1H), 7.15-7.10 (m, 3H) , 6.91 (dd, J = 8.9, 2.4 Hz, 1H), 6.53 (d, J = 3.1 Hz, 1H), 5.36 (s, 2H), 4.68 (s, 2H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.2, 151.7, 142.6, 132.9, 132.5, 130.3, 129.8, 129.7, 129.5, 129.3, 129.0, 128.1, 126.6, 123.8, 122.1, 120.0, 112.3, 110.9, 105.1, 102.0 , 68.8, 52.3, 50.3.

단계 2: 4-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: Preparation of 4-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.17 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 7.20-7.16 (m, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.89 (dd, J = 8.9, 2.2 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 5.39 (s, 2H), 4.68 (s, 2H); HRMS(ESI): m/z 467.0545 [M-H]- (calcd for C24H17Cl2N2O4 = 467.0571). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.17 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 2.4 Hz, 1H) , 7.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 7.20-7.16 (m, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.89 ( dd, J = 8.9, 2.2 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 5.39 (s, 2H), 4.68 (s, 2H); HRMS (ESI): m/z 467.0545 [MH] - (calcd for C 24 H 17 Cl 2 N 2 O 4 =467.0571).

<실시예 10> 4-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 10> Preparation of 4-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00021
Figure 112019088622808-pat00021

단계 1: 메틸 4-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Preparation of methyl 4-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 4-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 4-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl by performing a method similar to step 1 of Example 1 above. )Methyl) benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 9.1, 2.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 3.2 Hz, 1H), 6.87 (dd, J = 8.6, 2.2 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.54 (d, J = 3.1 Hz, 1H), 5.32 (s, 2H), 4.60 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 153.7, 142.3, 136.7, 132.7, 130.3, 129.8, 129.6, 128.9, 128.3, 128.0, 126.6, 124.5, 123.7, 122.3, 122.0, 109.9, 102.3, 95.0, 68.5, 52.3, 50.1. 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.6 Hz , 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 9.1, 2.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 3.2 Hz , 1H), 6.87 (dd, J = 8.6, 2.2 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.54 (d, J = 3.1 Hz, 1H), 5.32 (s, 2H), 4.60 (s, 2H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.8, 153.7, 142.3, 136.7, 132.7, 130.3, 129.8, 129.6, 128.9, 128.3, 128.0, 126.6, 124.5, 123.7, 122.3, 122.0, 109.9, 102.3, 95.0, 68.5 , 52.3, 50.1.

단계 2: 4-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: Preparation of 4-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 9.06 (s, 1H), 8.33 (dd, J = 8.9, 3.1 Hz, 1H), 7.96 (d, J = 8 Hz, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 8.8, 2.3 Hz, 1H), 7.16-7.11 (m, 3H), 6.89 (dd, J = 8.6, 2.2 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 5.36 (s, 2H), 4.64 (s, 2H); HRMS(ESI): m/z 467.0549 [M-H]- (calcd for C24H17Cl2N2O4 = 467.0571). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 9.06 (s, 1H), 8.33 (dd, J = 8.9, 3.1 Hz, 1H), 7.96 (d, J = 8 Hz, 2H), 7.59 ( d, J = 8.6 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 8.8, 2.3 Hz, 1H), 7.16-7.11 (m, 3H), 6.89 (dd, J = 8.6, 2.2 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 5.36 (s, 2H), 4.64 (s, 2H); HRMS (ESI): m/z 467.0549 [MH] - (calcd for C 24 H 17 Cl 2 N 2 O 4 =467.0571).

<실시예 11> 2-((3-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 11> 2-((3-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid Manufacture of

Figure 112019088622808-pat00022
Figure 112019088622808-pat00022

단계 1: 메틸 2-((3-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Methyl 2 - ((3-benzyl-5- (2 - ((2,4-a-dichlorophenyl) amino) -2-oxo-ethoxy) -1 H-indol-1-yl) methyl) benzoate Produce

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-((3-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 2-((3-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indole by performing a method similar to step 1 of Example 1 above. -1-yl)methyl) benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.07-7.99 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.36-7.22 (m, 7H), 7.20-7.14 (m, 1H), 7.09 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.91-6.84 (m, 2H), 6.52-6.46 (m, 1H), 5.70 (s, 2H), 4.62 (s, 2H), 4.10 (s, 2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 167.2, 151.3, 141.0, 140.3, 133.3, 133.0, 132.9, 131.1, 129.5, 129.0, 128.7, 128.52, 128.48, 128.42, 128.0, 127.8, 127.3, 127.0, 126.1, 123.8, 122.1, 114.9, 112.1, 111.0, 103.6, 68.9, 52.3, 48.8, 31.7. 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.07-7.99 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H) , 7.36-7.22 (m, 7H), 7.20-7.14 (m, 1H), 7.09 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.91-6.84 (m, 2H) ), 6.52-6.46 (m, 1H), 5.70 (s, 2H), 4.62 (s, 2H), 4.10 (s, 2H), 3.92 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.5, 167.2, 151.3, 141.0, 140.3, 133.3, 133.0, 132.9, 131.1, 129.5, 129.0, 128.7, 128.52, 128.48, 128.42, 128.0, 127.8, 127.3, 127.0, 126.1 , 123.8, 122.1, 114.9, 112.1, 111.0, 103.6, 68.9, 52.3, 48.8, 31.7.

단계 2: 2-((3-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: 2 - ((3-benzyl-5- (2 - ((a 2,4-dichlorophenyl) amino) -2-oxo-ethoxy) -1 H-indol-1-yl) methyl) benzoic acid in Produce

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, (CD3)2SO) δ 9.59 (s, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.31-7.19 (m, 6H), 7.14 (d, J = 6.7 Hz, 1H), 7.10 (s, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 5.72 (s, 2H), 4.71 (s, 2H), 4.03 (s, 2H); HRMS(ESI): m/z 557.1010 [M-H]- (calcd for C31H23Cl2N2O4 = 557.1040). 1 H NMR (400 MHz, (CD 3 ) 2 SO) δ 9.59 (s, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.31-7.19 (m, 6H), 7.14 (d, J = 6.7 Hz, 1H), 7.10 ( s, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 5.72 (s, 2H), 4.71 (s, 2H), 4.03 (s, 2H); HRMS (ESI): m/z 557.1010 [MH] - (calcd for C 31 H 23 Cl 2 N 2 O 4 =557.1040).

<실시예 12> 2-((3-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 12> 2-((3-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid Manufacture of

Figure 112019088622808-pat00023
Figure 112019088622808-pat00023

단계 1: 메틸 2-((3-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Methyl 2 - ((3-Benzyl-6- (2 - ((2,4-a-dichlorophenyl) amino) -2-oxo-ethoxy) -1 H-indol-1-yl) methyl) benzoate Produce

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-((3-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 2-((3-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1 H -indole by performing a method similar to step 1 of Example 1 above. -1-yl)methyl) benzoate was obtained.

1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.06-8.01 (m, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.32-7.22 (m, 7H), 7.22-7.16 (m, 1H), 6.84-6.79 (m, 2H), 6.70 (d, J = 2.0 Hz, 1H), 6.54-6.49 (m, 1H), 5.67 (s, 2H), 4.58 (s, 2H), 4.11 (s, 2H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 166.9, 153.8, 141.2, 140.0, 137.5, 133.0, 132.8, 131.2, 129.6, 129.0, 128.8, 128.5, 128.0, 127.9, 127.4, 127.04, 126.95, 126.1, 124.0, 123.8, 122.1, 120.7, 115.4, 109.3, 95.3, 68.6, 52.4, 48.7, 31.7. 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.06-8.01 (m, 1H), 7.44 (d, J = 8.6 Hz, 1H) , 7.37 (d, J = 2.3 Hz, 1H), 7.32-7.22 (m, 7H), 7.22-7.16 (m, 1H), 6.84-6.79 (m, 2H), 6.70 (d, J = 2.0 Hz, 1H ), 6.54-6.49 (m, 1H), 5.67 (s, 2H), 4.58 (s, 2H), 4.11 (s, 2H), 3.94 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.5, 166.9, 153.8, 141.2, 140.0, 137.5, 133.0, 132.8, 131.2, 129.6, 129.0, 128.8, 128.5, 128.0, 127.9, 127.4, 127.04, 126.95, 126.1, 124.0 , 123.8, 122.1, 120.7, 115.4, 109.3, 95.3, 68.6, 52.4, 48.7, 31.7.

단계 2: 2-((3-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: 2 - ((3-Benzyl-6- (2 - ((a 2,4-dichlorophenyl) amino) -2-oxo-ethoxy) -1 H-indol-1-yl) methyl) benzoic acid in Produce

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, (CD3)2SO) δ 10.43 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H), 7.38 (dd, J = 8.7, 2.2 Hz, 1H), 7.30-7.20 (m, 6H), 7.17-7.10 (m, 2H), 7.09-7.00 (m, 2H), 6.70 (d, J = 6.5 Hz, 1H), 6.66 (dd, J = 8.5, 1.8 Hz, 1H), 5.66 (s, 2H), 4.74 (s, 2H), 3.99 (s, 2H); HRMS(ESI): m/z 557.1010 [M-H]- (calcd for C31H23Cl2N2O4 = 557.1040). 1 H NMR (400 MHz, (CD 3 ) 2 SO) δ 10.43 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H), 7.38 (dd, J = 8.7, 2.2 Hz, 1H), 7.30-7.20 (m, 6H), 7.17-7.10 (m, 2H), 7.09-7.00 (m, 2H), 6.70 (d, J = 6.5 Hz, 1H), 6.66 (dd, J = 8.5, 1.8 Hz, 1H), 5.66 (s, 2H), 4.74 (s, 2H), 3.99 (s, 2H); HRMS (ESI): m/z 557.1010 [MH] - (calcd for C 31 H 23 Cl 2 N 2 O 4 =557.1040).

<실시예 13> 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 13> 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut-2-en-1-yl)- Preparation of 1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00024
Figure 112019088622808-pat00024

단계 1: 메틸 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Methyl 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut-2-en-1-yl)-1 Preparation of H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut- 2-en-1-yl)-1 H -indol-1-yl)methyl) benzoate was obtained.

1H NMR (500 MHz, CDCl3) δ 9.01 (s, 1H), 8.40 (d, J = 8.9 Hz, 1H), 8.06-8.02 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.31-7.28 (m, 2H), 7.24 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.6, 2.2 Hz, 1H), 6.83 (s, 1H), 6.69 (d, J = 2.2 Hz, 1H), 6.52-6.48 (m, 1H), 5.67 (s, 2H), 5.45-5.40 (m, 1H), 4.60 (s, 2H), 3.96 (s, 3H), 3.45 (d, J = 6.8 Hz, 2H), 1.77 (s, 3H), 1.75 (s, 3H); 13C NMR (125 MHz, CDCl3)

Figure 112019088622808-pat00025
167.4, 166.9, 153.7, 140.1, 137.4, 132.9, 132.7, 132.1, 131.1, 129.4, 128.9, 127.9, 127.7, 127.2, 126.9, 125.7, 123.9, 123.7, 122.9, 122.0, 120.4, 115.7, 108.9, 95.2, 68.5, 52.2, 48.5, 25.7, 24.1, 17.8. 1 H NMR (500 MHz, CDCl 3 ) δ 9.01 (s, 1H), 8.40 (d, J = 8.9 Hz, 1H), 8.06-8.02 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H) , 7.38 (d, J = 2.3 Hz, 1H), 7.31-7.28 (m, 2H), 7.24 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.6, 2.2 Hz, 1H), 6.83 ( s, 1H), 6.69 (d, J = 2.2 Hz, 1H), 6.52-6.48 (m, 1H), 5.67 (s, 2H), 5.45-5.40 (m, 1H), 4.60 (s, 2H), 3.96 (s, 3H), 3.45 (d, J = 6.8 Hz, 2H), 1.77 (s, 3H), 1.75 (s, 3H); 13 C NMR (125 MHz, CDCl 3 )
Figure 112019088622808-pat00025
167.4, 166.9, 153.7, 140.1, 137.4, 132.9, 132.7, 132.1, 131.1, 129.4, 128.9, 127.9, 127.7, 127.2, 126.9, 125.7, 123.9, 123.7, 122.9, 122.0, 120.4, 115.7, 108.9, 95.2, 68.5, 52.2, 48.5, 25.7, 24.1, 17.8.

단계 2: 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: 2 - ((5- (2 - ((2,4-dichlorophenyl) amino) -2-oxo-ethoxy) -3- (3-methyl-2-boot-en-1-yl) -1 H -Preparation of indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.33 (1H, d, J = 8.8 Hz), 8.09 (1H, dd, J =5.6, 3.6 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.31-7.25 (3H, m), 6.88-6.85 (2H, m), 6.75 (1H, d, J = 2.0 Hz), 6.50 (1H, dd, J = 5.6, 3.2 Hz), 5.70 (2H, s), 5.43 (1H, t, J = 7.2 Hz), 4.62 (2H, s), 3.46 (2H, d, J = 6.8 Hz), 1.77 (3H, s), 1.76 (3H, s); HRMS(ESI): m/z 535.1178 [M-H]- (calcd for C29H25Cl2N2O4 = 535.1197). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.33 (1H, d, J = 8.8 Hz), 8.09 (1H, dd, J =5.6, 3.6 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.31-7.25 (3H, m), 6.88-6.85 (2H, m), 6.75 (1H, d, J = 2.0 Hz), 6.50 (1H, dd , J = 5.6, 3.2 Hz), 5.70 (2H, s), 5.43 (1H, t, J = 7.2 Hz), 4.62 (2H, s), 3.46 (2H, d, J = 6.8 Hz), 1.77 (3H , s), 1.76 (3H, s); HRMS (ESI): m/z 535.1178 [MH] - (calcd for C 29 H 25 Cl 2 N 2 O 4 =535.1197).

<실시예 14> 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸)벤조익 애시드의 제조<Example 14> 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut-2-en-1-yl)- Preparation of 1H-indol-1-yl)methyl)benzoic acid

Figure 112019088622808-pat00026
Figure 112019088622808-pat00026

단계 1: 메틸 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸) 벤조에이트의 제조Step 1: Methyl 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut-2-en-1-yl)-1 Preparation of H -indol-1-yl)methyl) benzoate

상기 실시예 1의 단계 1과 유사한 방법을 수행하여 메틸 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸) 벤조에이트를 얻었다.Methyl 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-3-(3-methylbut- 2-en-1-yl)-1 H -indol-1-yl)methyl) benzoate was obtained.

1H NMR (500 MHz, CDCl3) δ 9.13 (s, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.07-8.01 (m, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.31 (dt, J = 6.1, 4.1 Hz, 2H), 7.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 6.50-6.46 (m, 1H), 5.70 (s, 2H), 5.43-5.38 (m, 1H), 4.70 (s, 2H), 3.95 (s, 3H), 3.44 (d, J = 7.0 Hz, 2H), 1.78 (s, 3H), 1.75 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.5, 167.2, 151.1, 140.4, 133.2, 132.9, 132.8, 132.2, 131.0, 129.4, 128.9, 128.4, 127.9, 127.7, 127.3, 127.2, 127.0, 123.7, 122.8, 122.0, 115.2, 111.9, 110.8, 103.4, 68.9, 52.2, 48.6, 25.7, 24.1, 17.9. 1 H NMR (500 MHz, CDCl 3 ) δ 9.13 (s, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.07-8.01 (m, 1H), 7.41 (d, J = 2.3 Hz, 1H) , 7.31 (dt, J = 6.1, 4.1 Hz, 2H), 7.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 6.50-6.46 (m, 1H), 5.70 (s, 2H), 5.43-5.38 (m, 1H), 4.70 (s, 2H), 3.95 (s, 3H), 3.44 (d, J = 7.0 Hz, 2H), 1.78 (s, 3H), 1.75 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.5, 167.2, 151.1, 140.4, 133.2, 132.9, 132.8, 132.2, 131.0, 129.4, 128.9, 128.4, 127.9, 127.7, 127.3, 127.2, 127.0, 123.7, 122.8, 122.0 , 115.2, 111.9, 110.8, 103.4, 68.9, 52.2, 48.6, 25.7, 24.1, 17.9.

단계 2: 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-3-(3-메틸부트-2-엔-1-일)-1H-인돌-1-일)메틸)벤조익 애시드의 제조Step 2: 2 - ((6- (2 - ((2,4-dichlorophenyl) amino) -2-oxo-ethoxy) -3- (3-methyl-2-boot-en-1-yl) -1 H -Preparation of indol-1-yl)methyl)benzoic acid

상기 실시예 1의 단계 2와 유사한 방법을 수행하여 목적화합물을 얻었다.A method similar to step 2 of Example 1 was performed to obtain the target compound.

1H NMR (400 MHz, CDCl3/CD3OD) δ 8.31 (1H, d, J = 8.8 Hz), 8.08-8.05 (1H, m), 7.55 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 2.4 Hz), 7.31-7.26 (3H, m), 6.89-6.86 (2H, m), 6.78 (1H, d, J = 2.0 Hz), 6.52-6.49 (1H, m), 5.71 (2H, s), 5.44 (1H, t, J = 7.2 Hz), 4.64 (2H, s), 3.47 (2H, d, J = 7.2 Hz), 1.78 (3H, s), 1.77 (3H, s); HRMS(ESI): m/z 535.1177 [M-H]- (calcd for C29H25Cl2N2O4 = 535.1197). 1 H NMR (400 MHz, CDCl 3 /CD 3 OD) δ 8.31 (1H, d, J = 8.8 Hz), 8.08-8.05 (1H, m), 7.55 (1H, d, J = 8.4 Hz), 7.42 ( 1H, d, J = 2.4 Hz), 7.31-7.26 (3H, m), 6.89-6.86 (2H, m), 6.78 (1H, d, J = 2.0 Hz), 6.52-6.49 (1H, m), 5.71 (2H, s), 5.44 (1H, t, J = 7.2 Hz), 4.64 (2H, s), 3.47 (2H, d, J = 7.2 Hz), 1.78 (3H, s), 1.77 (3H, s) ; HRMS (ESI): m/z 535.1177 [MH] - (calcd for C 29 H 25 Cl 2 N 2 O 4 =535.1197).

상기 실시예 1 내지 15의 화학구조를 하기 표 1에 정리하여 나타내었다.The chemical structures of Examples 1 to 15 are summarized and shown in Table 1 below.

실시예Example 화학구조Chemical structure 실시예Example 화학구조Chemical structure 1One

Figure 112019088622808-pat00027
Figure 112019088622808-pat00027
22
Figure 112019088622808-pat00028
Figure 112019088622808-pat00028
 33
Figure 112019088622808-pat00029
Figure 112019088622808-pat00029
 44
Figure 112019088622808-pat00030
Figure 112019088622808-pat00030
 55
Figure 112019088622808-pat00031
Figure 112019088622808-pat00031
 66
Figure 112019088622808-pat00032
Figure 112019088622808-pat00032
 77
Figure 112019088622808-pat00033
Figure 112019088622808-pat00033
 88
Figure 112019088622808-pat00034
Figure 112019088622808-pat00034
 99
Figure 112019088622808-pat00035
Figure 112019088622808-pat00035
 1010
Figure 112019088622808-pat00036
Figure 112019088622808-pat00036
 1111
Figure 112019088622808-pat00037
Figure 112019088622808-pat00037
 1212
Figure 112019088622808-pat00038
Figure 112019088622808-pat00038
 1313
Figure 112019088622808-pat00039
Figure 112019088622808-pat00039
 1414
Figure 112019088622808-pat00040
Figure 112019088622808-pat00040

<실험예 1> 화학식 1로 표시되는 화합물의 PPARα, PPARγ 및 PPARδ 활성화 능력 평가<Experimental Example 1> Evaluation of PPARα, PPARγ, and PPARδ activation ability of the compound represented by Formula 1

본 발명에 따른 화학식 1로 표시되는 화합물의 PPAR에 대한 활성화를 평가하기 위하여, 하기와 같은 실험을 수행하였다.In order to evaluate the activation of the compound represented by Formula 1 according to the present invention to PPAR, the following experiment was performed.

신장세포 CV-1 세포를 5% 이산화탄소, 37 ℃ 조건에서 10% 송아지 혈청 (FBS)을 포함한 DMEM 배양액으로 배양하였으며, 본 실험에 사용하기 위해 48 웰 플레이트에 웰 당 1.5×105개의 세포를 접종하고 24시간 동안 배양하였다. 루시퍼라제(luciferase) 활성을 가진 리포터 DNA(tk-PPREx3-luc)와 PPARα(pCMX-mPPARa), PPARδ(pCMX-mPPARd), PPARγ(pCMX-mPPARg) 각각의 플라스미드 DNA를 Lipofectamine LTX 시약 및 PLUS 시약을 이용하여 37 ℃에서 6 시간 동안 형질전환하였다. 상기 형질 전환율을 정규화(nomalization)하기 위하여, β-갈락토시데이즈(β-galactosidase) 플라스미드를 같이 형질전환하였다. DMSO를 용매로 30 μM 농도로 제조한 상기 실시예 화합물을 배양액을 이용하여 0.001, 0.01, 0.1, 1 및 10 μM의 농도로 희석하여 세포배양계에 400 μL씩 처리하여 40시간 동안 배양한 후, 배양액을 제거하고, 세포용해 완충액 50 μL를 가하여 20분 동안 진탕하면서 세포를 용해시켰다. 세포용해액 20 μL와 루시퍼레이즈 에세이시약 50 μL를 가하여 발광값을 발광계(luminometer)를 이용하여 측정하였다. 상기 세포용해에서 루시퍼레이즈의 활성은 루시퍼레이즈 assay system(Promega Corp., Madison, WI)을 사용하여 측정하였고, β-갈락토시데이즈의 활성은 ELISA plate reader를 사용하여 410nm에서의 흡광도로 측정하였다. 상기 데이터는 β-갈락토시데이즈 활성으로 나눈 상대적인 루시퍼레이즈 활성으로 나타내었다. 음성대조군으로는 0.1% DMSO를 사용하였으며, 양성대조군으로 PPARα 효능제 GW7647를 1 μM, PPARγ 효능제 로지글리타존(rosiglitazone)을 1 μM, PPARδ 효능제 GW0742를 0.1 μM씩 각각 사용하였다. 실험결과는 양성대조군의 최대값에 대한 시료의 값을 상대적으로 표현한 % Max 값으로 표시하였으며, 이를 하기 표 2에 나타내었다. 상기 % Max 값은 하기 수학식 1에 의해 계산된 값이다. Renal cells CV-1 cells were cultured in DMEM culture medium containing 10% calf serum (FBS) at 37°C and 5% carbon dioxide, and 1.5×10 5 cells per well were inoculated into 48 well plates for use in this experiment. And incubated for 24 hours. Reporter DNA with luciferase activity (tk-PPREx3-luc), PPARα (pCMX-mPPARa), PPARδ (pCMX-mPPARd), and PPARγ (pCMX-mPPARg) plasmid DNA were each prepared with Lipofectamine LTX reagent and PLUS reagent. And transformed at 37° C. for 6 hours. In order to normalize the transformation rate, a β-galactosidase plasmid was transformed together. The Example compound prepared in DMSO at a concentration of 30 μM as a solvent was diluted to a concentration of 0.001, 0.01, 0.1, 1 and 10 μM using a culture solution, treated with 400 μL each in a cell culture system, and incubated for 40 hours, The culture solution was removed, 50 μL of cell lysis buffer was added, and the cells were lysed while shaking for 20 minutes. 20 μL of cell lysate and 50 μL of luciferase assay reagent were added, and the luminescence value was measured using a luminometer. The activity of luciferase in the cytolysis was measured using a luciferase assay system (Promega Corp., Madison, WI), and the activity of β-galactosidase was measured by absorbance at 410 nm using an ELISA plate reader. . The data are presented as relative luciferase activity divided by β-galactosidase activity. 0.1% DMSO was used as the negative control group, 1 μM of the PPARα agonist GW7647, 1 μM of the PPARγ agonist rosiglitazone, and 0.1 μM of the PPARδ agonist GW0742 were used, respectively. The experimental results were expressed as% Max values, which relatively expressed the values of the samples with respect to the maximum values of the positive control group, which are shown in Table 2 below. The% Max value is a value calculated by Equation 1 below.

[수학식 1][Equation 1]

% Max = 100×(시료활성-음성대조군활성)/(양성대조군활성-음성대조군활성)% Max = 100 × (Sample activity-negative control activity) / (positive control activity-negative control activity)

% Max% Max % Max% Max % Max% Max 실시예Example mPPAR-α(10 μM)mPPAR-α (10 μM) mPPAR-γ(10 μM)mPPAR-γ (10 μM) mPPAR-δ(10 μM)mPPAR-δ (10 μM) 1One -38.13 ± 0.06-38.13 ± 0.06 5.60 ± 0.145.60 ± 0.14 11.84 ± 0.3511.84 ± 0.35 22 1.12 ± 0.241.12 ± 0.24 8.66 ± 0.238.66 ± 0.23 8.27 ± 0.338.27 ± 0.33 33 21.41 ± 0.2121.41 ± 0.21 31.20 ± 0.3831.20 ± 0.38 44.35 ± 0.7744.35 ± 0.77 44 31.68 ± 0.2231.68 ± 0.22 71.87 ± 0.9171.87 ± 0.91 65.41 ± 0.7065.41 ± 0.70 55 105.08 ± 0.41105.08 ± 0.41 189.21 ± 1.67189.21 ± 1.67 94.86 ± 0.2094.86 ± 0.20 66 51.84 ± 0.2551.84 ± 0.25 74.54 ± 0.9474.54 ± 0.94 86.70 ± 0.5386.70 ± 0.53 77 10.33 ± 0.0710.33 ± 0.07 42.01 ± 0.5242.01 ± 0.52 23.85 ± 0.5123.85 ± 0.51 88 78.15 ± 0.0478.15 ± 0.04 126.55 ± 0.92126.55 ± 0.92 86.09 ± 0.3186.09 ± 0.31 99 -19.98 ± 0.08-19.98 ± 0.08 0.29 ± 0.060.29 ± 0.06 -1.07 ± 0.14-1.07 ± 0.14 1010 -14.44 ± 0.16-14.44 ± 0.16 -0.84 ± 0.16-0.84 ± 0.16 4.87 ± 0.244.87 ± 0.24 1111 23.79 ± 0.1123.79 ± 0.11 93.20 ± 0.5993.20 ± 0.59 75.88 ± 0.3575.88 ± 0.35 1212 7.25 ± 0.127.25 ± 0.12 19.03 ± 0.1319.03 ± 0.13 19.40 ± 0.5419.40 ± 0.54 1313 -5.93 ± 0.14-5.93 ± 0.14 5.10 ± 0.205.10 ± 0.20 8.92 ± 0.488.92 ± 0.48 1414 -2.30 ± 0.19-2.30 ± 0.19 9.55 ± 0.329.55 ± 0.32 22.16 ± 0.5922.16 ± 0.59

상기 표 2에 나타난 바와 같이, As shown in Table 2 above,

본 발명에 따른 실시예 화합물은 PPARα, PPARγ 및 PPARδ를 활성화 시키는 것을 알 수 있다.It can be seen that the example compounds according to the present invention activate PPARα, PPARγ and PPARδ.

구체적으로, 실시예 4 및 11의 화합물은 PPARγ 및 PPARδ에 대하여 50이상의 % Max 값을 나타내어, PPARγ 및 PPARδ를 우수하게 활성화 시키는 것을 확인하였다.Specifically, it was confirmed that the compounds of Examples 4 and 11 exhibited a% Max value of 50 or more for PPARγ and PPARδ, and excellently activated PPARγ and PPARδ.

실시예 5, 6 및 8의 화합물은 PPARα, PPARγ 및 PPARδ 전체에 대하여 50이상의 % Max 값을 나타내어, PPARα, PPARγ 및 PPARδ를 모두 우수하게 활성화 시키는 것을 확인하였다.The compounds of Examples 5, 6 and 8 exhibited a% Max value of 50 or more with respect to all of PPARα, PPARγ and PPARδ, and it was confirmed that all of PPARα, PPARγ and PPARδ were excellently activated.

<실험예 2> 화학식 1로 표시되는 화합물의 함암효과 평가<Experimental Example 2> Evaluation of the anticancer effect of the compound represented by Formula 1

본 발명에 따른 화학식 1로 표시되는 화합물의 함암효과를 평가하기 위하여, 하기와 같은 실험을 수행하였다. 구체적으로, 인체유래 대장암세포주(HT 29)의 nude mouse 이종 이식 동물모델 제작하여, 실시예 5의 화합물 및 비교예로서 PPAR에 결합하여 약효를 나타내는 것으로 잘 알려진 rosiglitazone을 반복 경구 투여하여 항암 약효를 평가하였다. 구체적인 실험방법은 하기와 같다.In order to evaluate the anti-cancer effect of the compound represented by Formula 1 according to the present invention, the following experiment was performed. Specifically, a nude mouse xenograft animal model of human-derived colorectal cancer cell line (HT 29) was produced, and the compound of Example 5 and rosiglitazone, which is well known to have a medicinal effect by binding to PPAR as a comparative example, were repeatedly orally administered to demonstrate anticancer efficacy. Evaluated. The specific experimental method is as follows.

<실험방법><Experiment method>

먼저, 인체유래 대장암 세포주 HT-29(colon cancer cell line)을 사용하였다. 액체 질소 속에서 냉동보관 중이던 암세포를 해동한 후 CO2 incubator(Forma, USA)내에서 온도 37 ℃와 CO2 농도 5%로 맞춰서 배양하였다. 실험동물모델은 특정병원체 부재(SPF)BALB/C 계통 및 암컷 누드 마우스를 Nara Biotech Co.에서 공급받아 사용하였으며, 입수시 주령은 4 주령, 암세포 이식시 주령은 5 주령, 약물투여 개시시 주령은 5 주령이었다. 최종일에 모든 암세포를 수거하여 계수하고 serum free media 를 이용하여 세포 농도를 3×107 cells/ml로 조절 하였다. 조절된 세포 배양액을 마우스당 0.3 ml(9×106 cells/mouse)씩 우측의 견갑부와 흉벽 사이의 액와부위 피하에 주입하여 실험동물 모델을 제작하였다.First, a human-derived colon cancer cell line HT-29 (colon cancer cell line) was used. After thawing cancer cells in liquid nitrogen, they were incubated in a CO 2 incubator (Forma, USA) at a temperature of 37° C. and a CO 2 concentration of 5%. As for the experimental animal model, specific pathogen-free (SPF) BALB/C strain and female nude mice were supplied and used from Nara Biotech Co. I was 5 weeks old. On the last day, all cancer cells were collected and counted, and the cell concentration was adjusted to 3×10 7 cells/ml using serum free media. An experimental animal model was prepared by injecting the controlled cell culture solution into the axillary area between the right shoulder blade and the chest wall at 0.3 ml (9×10 6 cells/mouse) per mouse.

실시예 5 화합물 및 rosiglitazone의 시료에 총 투입용매 volume 의 10%에 해당하는 DMAC(Dimethylacetamide)을 넣어 stock solution을 조제한 뒤 하루 분씩 튜브에 분주 하여 냉동보관 후, 투여당일 튜브 한 개를 꺼내 녹인 다음 총 투입 용매 volume 의 10% 에 해당하는 tween80을 넣고 vortex하였으며, 마지막으로 80% 에 해당하는 주사용 증류수 넣고 vortex하여 최종 30 mg/ml 농도로 조제하였다. 조제된 물질들은 완전히 녹은 상태로 마우스 20 g당 0.2 ml(10 ml/kg)씩 총 14회 매일 반복 경구투여 하였다(days 0-13).Example 5 Dimethylacetamide (DMAC) equivalent to 10% of the total input solvent volume was added to a sample of the compound and rosiglitazone to prepare a stock solution, dispensed into tubes for a day, and stored in a freezer. Tween80 corresponding to 10% of the volume of the input solvent was added and vortexed, and finally, distilled water for injection corresponding to 80% was added and vortexed to obtain a final concentration of 30 mg/ml. The prepared substances were administered orally repeated every 14 times daily at 0.2 ml (10 ml/kg) per 20 g of mice in a completely dissolved state (days 0-13).

<통계학적 검사 방법><Statistical test method>

통계분석은 GraphPad Software사의 GraphPad Prism software를 이용하여 분석하였다. 날짜에 따른 체중 및 종양부피 변화의 경우 two-way ANOVA 후 Bonferroni multiple comparison test를 사용하여 분석하였고, 최종일 종양 무게는 one-way ANOVA 후 Dunnett's multiple comparison test를 사용하여 분석하였다.Statistical analysis was performed using GraphPad Prism software of GraphPad Software. Changes in body weight and tumor volume according to date were analyzed using Bonferroni multiple comparison test after two-way ANOVA, and tumor weight on the last day was analyzed using Dunnett's multiple comparison test after one-way ANOVA.

2-1. 일반증상 및 체중 변화 측정2-1. General symptoms and weight change measurement

HT29 세포 이식 nude mouse에 실시예 5 화합물 및 rosiglitazone을 30 mg/kg 용량으로 반복 경구 투여 시, 독성 정도를 알아보기 위해 투여기간 동안 동물의 일반증상 및 체중 관찰 하였다. 그 결과를 표 3 및 4, 도 1에 나타내었다.When repeated oral administration of the compound of Example 5 and rosiglitazone at a dose of 30 mg/kg to HT29 cell transplanted nude mice, general symptoms and body weight of animals were observed during the administration period to determine the degree of toxicity. The results are shown in Tables 3 and 4 and Fig. 1.

마우스의 일반증상Common symptoms of mice 그룹 (n=5)Group (n=5) 투여량 (mg/kg)Dosage (mg/kg) 임상 증상Clinical symptoms VehicleVehicle 00 이상증상 없음No abnormal symptoms 실시예 5Example 5 3030 이상증상 없음No abnormal symptoms RosiglitazoneRosiglitazone 3030 이상증상 없음No abnormal symptoms

Vehicle: DMAC 10% + Tween80 10% + D.W 80% 투여군Vehicle: DMAC 10% + Tween80 10% + D.W 80% administration group

날짜별 마우스의 체중 변화(%)Change in weight of mice by date (%) 그룹group 투여량Dosage 처리 후, 경과 일자 (Day)After processing, the elapsed date (Day) (n=5)(n=5) (mg/kg)(mg/kg) 00 33 55 77 1010 1212 1414 VehicleVehicle 00 100
±0.0100
±0.0 104.1
±1.7104.1
±1.7 104.7
±2.6104.7
±2.6 102.4
±2.1102.4
±2.1 100.8
±2.0100.8
±2.0 100.7
±1.9100.7
±1.9 102.9
±2.6102.9
±2.6 실시예 5Example 5 3030 100±0.0100±0.0 106.3
±3.0106.3
±3.0 107.9
±2.5107.9
±2.5 106.8
±2.6106.8
±2.6 109
±4.2109
±4.2 108.7
±5.0108.7
±5.0 109.2
±4.3109.2
±4.3 RosiglitazoneRosiglitazone 3030 100±0.0100±0.0 104.7
±2.6104.7
±2.6 104.4
±3.2104.4
±3.2 105.8
±4.0105.8
±4.0 106.1
±3.0106.1
±3.0 105.2
±3.0105.2
±3.0 106.7
±2.6106.7
±2.6

Vehicle: DMAC 10% + Tween80 10% + D.W 80% 투여군Vehicle: DMAC 10% + Tween80 10% + D.W 80% administration group

표 3 및 4, 도 1에 나타난 바와 같이, 모든 투여군에서 시험기간 동안 특이한 일반증상 및 통계적으로 유의한 체중 감소는 관찰되지 않았다. 이로부터, 본 발명의 화합물은 독성을 나타내지 않음을 알 수 있다.As shown in Tables 3 and 4 and Fig. 1, no specific general symptoms and statistically significant weight loss were observed during the test period in all administration groups. From this, it can be seen that the compounds of the present invention do not show toxicity.

2-2. 종양크기 변화 평가2-2. Evaluation of tumor size change

암세포 이식 후 군별평균 종양 크기가 52.9 mm3 도달 시부터, 14 일째까지 총 7회 개체별로 vernier caliper를 이용하여 3 방향을 측정한 후, 가로(length)×세로(width)×높이(height)/2의 계산식으로 계산하여, 종양크기(tumor volume)를 측정하였으며, 종양무게도 측정하여 그 결과를 표 5 및 도 2-4에 나타내었다. 또한 저해율을 계산하여 표 6에 나타내었다.After cancer cell transplantation, after the average tumor size of each group reached 52.9 mm 3 , 3 directions were measured using a vernier caliper for a total of 7 times from day 14 to day 14, and then length×width×height/ Calculated by the formula of 2, the tumor volume was measured, and the tumor weight was also measured, and the results are shown in Table 5 and FIGS. 2-4. In addition, the inhibition rate was calculated and shown in Table 6.

종양크기 변화 및 최종일 종양무게Tumor size change and tumor weight on the last day 그룹group 투여량Dosage 종양 크기a Tumor size a 종양
무게tumor
weight (n=5)(n=5) (mg/kg)(mg/kg) 00 33 55 77 1010 1212 1414 (mg)(mg) Vehi
cleVehi
cle 00 0.0
±0.00.0
±0.0 111.4
±21.6111.4
±21.6 237.1
±38.5237.1
±38.5 410.5
±38.1410.5
±38.1 589.8
±52.4589.8
±52.4 786.1
±83.8786.1
±83.8 1267.6
±162.71267.6
±162.7 2353.9
±425.52353.9
±425.5 실시예 5Example 5 3030 0.0
±0.00.0
±0.0 77.1
±18.877.1
±18.8 125.7
±21.5125.7
±21.5 264.0
±40.8* 264.0
±40.8 * 366.4
±62.1* 366.4
±62.1 * 473.9
±36.4* 473.9
±36.4 * 615.5
±80.1* 615.5
±80.1 * 1393.5
±308.3* 1393.5
±308.3 * Rosi
Glita
zoneRosi
Glita
zone 3030 0.0
±0.00.0
±0.0 94.9
±6.094.9
±6.0 197.0
±23.5197.0
±23.5 371.6
±54.3371.6
±54.3 517.1
±51.2517.1
±51.2 695.8
±161.9695.8
±161.9 921.4
±139.0* 921.4
±139.0 * 2055.8
±587.92055.8
±587.9

*: p<0.05 (vs Vehicle)*: p<0.05 (vs Vehicle)

a: △t=Vt-Vo, Vt(측정된 종양 크기), Vo(최초 종양 크기)a: △t=Vt-Vo, Vt (measured tumor size), Vo (initial tumor size)

종양 부피 및 무게 증가 저해율Inhibition rate of tumor volume and weight increase 그룹group 투여량Dosage 종양 부피 저해율(%)Tumor volume inhibition rate (%) 종양무게
저해율(%)Tumor weight
Inhibition rate (%) (n=5)(n=5) (mg/kg)(mg/kg) 3(days)3(days) 55 77 1010 1212 1414 (mg)(mg) 실시예 5Example 5 3030 30.8 b 30.8 b 47.047.0 35.735.7 37.937.9 39.739.7 51.451.4 40.840.8 RosiglitazoneRosiglitazone 3030 14.814.8 16.916.9 9.59.5 12.312.3 11.511.5 27.327.3 12.712.7

b: 저해율 (%, vs Vehicle)b: inhibition rate (%, vs Vehicle)

표 5-6 및 도 2-4에 나타난 바와 같이, 용매대조군(vehicle)과 비교하여 실시예 5 및 rosiglitazone 투여군에서 종양 크기 및 무게가 줄어드는 것을 확인하였다. 구체적으로, 최종일 시점에, 실시예 화합물이 51.4%(p<0.05), rosiglitazone이 27.3%(p<0.05)의 종양크기 감소 효과를 나타내었으며, 본 발명의 실시예 5 화합물이 rosiglitazone보다 약 2배 우수한 효과를 나타낸다. 또한, 최종일 시점에, 실시예 화합물이 40.8%(p<0.05), rosiglitazone이 12.3%(p<0.05)의 종양무게 감소 효과를 나타내었으며, 본 발명의 실시예 5 화합물이 rosiglitazone보다 약 3.3배 우수한 효과를 나타낸다. 이로부터, 본원 발명의 화합물은 종양성장 억제 효과가 우수함을 알 수 있다.As shown in Tables 5-6 and 2-4, it was confirmed that the tumor size and weight were reduced in Example 5 and the rosiglitazone-administered group compared to the solvent control group (vehicle). Specifically, at the time point of the last day, the Example compound showed a tumor size reduction effect of 51.4% (p<0.05) and rosiglitazone 27.3% (p<0.05), and the Example 5 compound of the present invention was about twice that of rosiglitazone. It shows an excellent effect. In addition, at the time point of the last day, the Example compound showed a tumor weight reduction effect of 40.8% (p<0.05) and rosiglitazone 12.3% (p<0.05), and the Example 5 compound of the present invention was about 3.3 times superior to rosiglitazone. Shows the effect. From this, it can be seen that the compound of the present invention has an excellent tumor growth inhibitory effect.

따라서, 본 발명에 따른 치환된 인돌 유도체는 PPARα, PPARγ 및 PPARδ를 활성화 시키는 능력이 우수하므로, PPAR 효능제로써 대사성 질환, 심혈관계 질환, 암 또는 염증등의 PPARα, PPARγ 및 PPARδ 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있고, 종양성장 억제효과가 우수한 바, 암의 치료에 유용하게 사용할 수 있다.Therefore, the substituted indole derivative according to the present invention has excellent ability to activate PPARα, PPARγ, and PPARδ, so as a PPAR agonist, PPARα, PPARγ and PPARδ related diseases such as metabolic diseases, cardiovascular diseases, cancer or inflammation are prevented or Since it can be usefully used for treatment and has excellent tumor growth inhibitory effect, it can be usefully used in the treatment of cancer.

<제제예 1> 산제의 제조<Formulation Example 1> Preparation of powder

화학식 1로 표시되는 유도체 2g2g of derivatives represented by Formula 1

유당 1g1g lactose

상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

<제제예 2> 정제의 제조<Formulation Example 2> Preparation of tablets

화학식 1로 표시되는 유도체 100 ㎎100 mg of derivatives represented by Formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎100 mg lactose

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.

<제제예 3> 캡슐제의 제조<Formulation Example 3> Preparation of capsules

화학식 1로 표시되는 유도체 100 ㎎100 mg of derivatives represented by Formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎100 mg lactose

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above ingredients, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule.

<제제예 4> 주사제의 제조<Formulation Example 4> Preparation of injection

화학식 1로 표시되는 유도체 100 ㎎100 mg of derivatives represented by Formula 1

만니톨 180 ㎎Mannitol 180 mg

Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 ㆍ2H 2 O 26 mg

증류수 2974 ㎎Distilled water 2974 mg

통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to a conventional method for preparing injections, injections were prepared by containing the above ingredients in the indicated amount.

<제제예 5> 건강식품의 제조<Formulation Example 5> Preparation of health food

화학식 1로 표시되는 유도체 500ng500 ng of derivatives represented by Formula 1

비타민 혼합물 적량The right amount of vitamin mixture

비타민 A 아세테이트 70mg 70mg vitamin A acetate

비타민 E 1.0mg1.0mg vitamin E

비타민 0.13mg0.13mg vitamin

비타민 B2 0.15mg0.15mg vitamin B2

비타민 B6 0.5mg0.5mg vitamin B6

비타민 B12 0.2mg0.2mg vitamin B12

비타민 C 10mg10mg vitamin C

비오틴 10mg10mg biotin

니코틴산아미드 1.7mg1.7 mg of nicotinic acid amide

엽산 50mg50mg folic acid

판토텐산 칼슘 0.5mg0.5mg calcium pantothenate

무기질 혼합물 적량Suitable amount of inorganic mixture

황산제1철 1.75mg1.75 mg ferrous sulfate

산화아연 0.82mgZinc oxide 0.82mg

탄산마그네슘 25.3mg25.3mg magnesium carbonate

제1인산칼륨 15mg15 mg of potassium monophosphate

제2인산칼슘 55mgDicalcium Phosphate 55mg

구연산칼륨 90mg90mg potassium citrate

탄산칼슘 100mg100mg calcium carbonate

염화마그네슘 24.8mgMagnesium chloride 24.8mg

상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.The composition ratio of the vitamin and mineral mixture is relatively suitable for health food, but it may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. , Granules can be prepared, and used for preparing health food compositions according to conventional methods.

<제제예 6> 건강음료의 제조<Formulation Example 6> Preparation of health drink

화학식 1로 표시되는 유도체 500ng500 ng of derivatives represented by Formula 1

구연산 1000mg1000mg citric acid

올리고당 100g100g oligosaccharide

매실농축액 2g2g plum concentrate

타우린 1g1 g taurine

정제수를 가하여 전체 900mlTotal 900ml with purified water

통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 음료 조성물 제조에 사용하였다.After mixing the above ingredients according to a conventional health drink manufacturing method, after stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then stored in a refrigerator. It was used in preparation.

상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호 도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.The composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.

Claims (13)

하기 화합물 군으로부터 선택되는 어느 하나의 화합물, 또는 이의 약학적으로 허용가능한 염:
<4> 2-(1-벤질-6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-3-일)아세틱 애시드;
<5> 2-((5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;
<6> 2-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드;
<8> 3-((6-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드; 및
<11> 2-((3-벤질-5-(2-((2,4-디클로로페닐)아미노)-2-옥소에톡시)-1H-인돌-1-일)메틸)벤조익 애시드.
Any one compound selected from the following compound group, or a pharmaceutically acceptable salt thereof:
<4> 2-(1-benzyl-6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-3-yl)acetic acid;
<5> 2-((5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;
<6> 2-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid;
<8> 3-((6-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid; And
<11> 2-((3-benzyl-5-(2-((2,4-dichlorophenyl)amino)-2-oxoethoxy)-1H-indol-1-yl)methyl)benzoic acid.
 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 제1항의 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for the prevention or treatment of cancer containing the compound of claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
 제7항에 있어서,
상기 화합물은 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나 이상인 수용체를 활성화 시키는 것을 특징으로 하는 약학적 조성물.
The method of claim 7,
The compound is a pharmaceutical composition, characterized in that the activation of one or more receptors selected from the group consisting of PPARα, PPARγ and PPARδ.
 제7항에 있어서,
암은 PPARα, PPARγ 및 PPARδ로 이루어지는 군으로부터 선택되는 하나 이상인 수용체의 활성과 관련된 것을 특징으로 하는 약학적 조성물.
The method of claim 7,
Cancer is a pharmaceutical composition, characterized in that associated with the activity of one or more receptors selected from the group consisting of PPARα, PPARγ and PPARδ.
 삭제delete 삭제delete 제7항에 있어서,
상기 암은 신장암, 방광암, 간암, 흉선암, 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 예방 또는 치료용 약학적 조성물.
The method of claim 7,
The cancer is kidney cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrous Preventive or therapeutic pharmaceutical composition, characterized in that any one selected from the group consisting of tumors and brain tumors.
 제1항의 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 개선용 건강기능식품 조성물.A health functional food composition for preventing or improving cancer containing the compound of claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
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WO2001032619A1 (en) 1999-11-03 2001-05-10 Astrazeneca Ab Positive modulators of nicotinic receptor agonists
WO2005016867A2 (en) 2003-08-14 2005-02-24 Smithkline Beecham Corporation Anthranilic acid derivatives and their use as activators of the hm74a receptor

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GB9919411D0 (en) * 1999-08-18 1999-10-20 Zeneca Ltd Chemical compounds
KR101812626B1 (en) * 2015-10-08 2018-01-30 숙명여자대학교산학협력단 (phenoxy)alkoxy-1H-indole derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient

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WO1995001334A1 (en) 1993-06-30 1995-01-12 Pierre Fabre Medicament Arylamine-derived indole compounds as selective 5ht1d and 5ht1b receptor ligands
WO2001032619A1 (en) 1999-11-03 2001-05-10 Astrazeneca Ab Positive modulators of nicotinic receptor agonists
WO2005016867A2 (en) 2003-08-14 2005-02-24 Smithkline Beecham Corporation Anthranilic acid derivatives and their use as activators of the hm74a receptor

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