KR101812626B1

KR101812626B1 - (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

Info

Publication number: KR101812626B1
Application number: KR1020150141844A
Authority: KR
Inventors: 전라옥; 류재하; 김효진; 이화
Original assignee: 숙명여자대학교산학협력단
Priority date: 2015-10-08
Filing date: 2015-10-08
Publication date: 2018-01-30
Also published as: KR20170042185A

Abstract

(Phenoxy) alkoxy-1 H-indole derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for the prophylaxis or treatment of PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient. INDUSTRIAL APPLICABILITY The 3-phenoxypropoxy-1H-indole derivative according to the present invention has excellent ability to activate PPARα, PPARγ and PPARδ. Therefore, PPARα, PPARα, and PPARα, which are metabolic diseases, cardiovascular diseases, PPARy and PPAR [delta] -related diseases.

Description

(Phenoxy) alkoxy-1H-indole derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating PPARα, PPARγ and PPARδ- &Lt; / RTI > 1H-indole derivatives or pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions for use in preventing or treating PPAR ?, PPAR? And PPAR?

(Phenoxy) alkoxy-1 H-indole derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for the prophylaxis or treatment of PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, such as steroid receptors, retinoid receptors, thyroid receptors, etc., and are activated by ligands to regulate the expression of specific genes to be. PPAR has three types of isotypes of α, β / δ, and γ, each of which has a distinctive tissue distribution and plays an important role in maintaining lipid metabolism and energy balance.

The ligand-activated PPAR binds to the retinoid X receptor (RXR) to form a heterodimer and binds to the PPAR response gene sequence (PPRE) to regulate the expression of target genes involved in lipid metabolism and homeostasis . The PPAR response gene sequence (PPRE) has been shown to be involved in lipolytic activities such as acyl-CoA oxidase (AOX), hepatic fatty acid binding protein (L-FABP), apolipoprotein C-III (apoC-III) or lipoprotein lipase Or in the promoter region of a gene encoding a protein associated with the metabolism of lipoprotein, suggesting that PPAR is central to lipogenesis and lipid homeostasis.

Therefore, PPAR is an important target for the development of therapeutic agents for hypertriglyceridemia, the treatment of type 2 diabetes, and maintenance of lipid homeostasis. PPAR, on the other hand, is a target of development of anti-cancer and anti-inflammatory drugs by exhibiting anti-inflammatory action by controlling the expression of free and inflammatory genes of anti-inflammatory factors.

PPARα is mainly expressed in the liver and kidney, and plays a role in regulating genes related to oxidation and energy homeostasis of fatty acids. PPARα activation increases lipid peroxidation by decreasing triglyceride biosynthesis by increasing fatty acid catabolism, 2) increasing the expression of lipid protein lipase directly in the target organs, and 3) decreasing apolipoprotein C-III By decreasing the expression, the blood triglyceride concentration is finally lowered and the concentration of low density lipoprotein in the serum is decreased. In addition, the PPARa ligand increases serum high density lipoprotein concentration by increasing the synthesis of the apolipoproteins A-I and A-II in the liver. Fibrate-based drugs, a remedy for hyperlipemia, are well-known PPARα agonists. However, some PPARa agonists have been reported to be carcinogenic due to peroxisome proliferation in the liver of rodents (see Non-Patent Document 1).

PPARγ is mainly expressed in adipocytes and plays a key role in the differentiation and formation of adipocytes, glucose metabolism, insulin sensitivity and lipid storage. Currently, the thiazolidinedione (TZD) family of drugs that are marketed as type 2 diabetes medicines include rosiglitazone (Avandia, Glaxo-Smith Kline) and pioglitazone (Actos, Takeda) as representative PPARγ agonists. However, side effects of thiazolidinedione (TZD) -based drugs include weight gain due to adipocyte differentiation, body fluid retention due to PPARgamma activation, increased fracture, congestive heart failure, and myocardial infarction (see Non-Patent Document 2) Administration to patients is contraindicated.

PPARδ is expressed in many tissues in vivo, and its selective ligand is not known and its role has not been well known for over 10 years after its discovery. However, recent research on gene level for PPAR δ and selective ligand derivation have been reported to control fatty acid oxidation and glucose and to increase insulin sensitivity and HDL cholesterol, and thus it is recognized as a potential target for the development of a therapeutic agent for metabolic diseases . PPARδ agonists can be used to improve dyslipidemia, obesity and insulin resistance.

Currently, PPARa or PPARgamma agonists have been developed and used as fibrates and thiazolidinedione drugs based on the improvement of lipid metabolism and insulin sensitivity, respectively. However, recently, The development of dual agonists, PPARγ / δ dual agonists, PPARγ activity modulators, PPARγ partial agonists and PPARδ agonists has been sought as a solution.

Of these, the PPARα / γ dual agonists have been considered as a good alternative to the side effects of weight gain in the thiazolidinedione-based PPARγ agonists. Representative compounds include the glitazar series ragaglitazar, tesaglitazar, and farglitazar, which have been developed as diabetic agents. However, in the clinical phase 2 and phase 3, the glutathione-based compounds have an excellent effect of treating diabetes and improving the metabolic syndrome through improvement of the lipid / polysaccharide ratio, but the carcinogenicity in rodents, lipid infiltration into bone marrow tissues, Side effects have been reported. Galida (Tessaglitazal) in AstraZeneca, which has been recently considered to have excellent efficacy and toxicity considerations, was also stopped due to the adverse effects of renal damage in the phase III trials. As such, the potential for side effects of glitazenil acting as a dual agonist for PPARa / gamma may be based on the specificity of the structure, and the potential for drug candidates for various structures of compounds is being investigated.

Recently, it has been reported that compounds showing excellent activity against PPARγ or PPARα / γ in indole compounds (see Non-Patent Document 3-7). The indole-based compounds reduce hyperglycemia and hyperinsulinemia by controlling glucose in animal experiments (see Non-Patent Document 8), unlike the thiazolidinedione-based complete agonists, do not cause cardiac hypertrophy, (See Non-Patent Document 9).

Accordingly, the present inventors have found that the (phenoxy) alkoxy-1H-indole derivatives and pharmaceutically acceptable salts thereof according to the present invention exhibit excellent activities against PPAR ?, PPAR? And PPAR ?, and thus, as a PPAR agonist, , PPAR [alpha], PPAR [gamma] and PPAR [delta] -related diseases such as cardiovascular disease, cancer, inflammation and the like, and completed the present invention.

Issemann and Green, 1990 Meier, Kraenzlin et al., 2008 Dropinski, Akiyama et al., 2005 Henke, Adkison et al., 1999 Dong, Zhang et al., 2006 Kuhn, Hilpert et al., 2006 Acton, Black et al., 2005 Berger, Petro et al., 2003 Liu, Black et al., 2005

It is an object of the present invention to provide a (phenoxy) alkoxy-1H-indole derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for producing the above (phenoxy) alkoxy-1H-indole derivatives.

Still another object of the present invention is to provide a pharmaceutical composition for the prophylaxis or treatment of PPARa, PPARgamma and PPARδ related diseases containing the (phenoxy) alkoxy-1H-indole derivative or a pharmaceutically acceptable salt thereof as an active ingredient will be.

Another object of the present invention is to provide a health functional food composition for preventing or ameliorating metabolic diseases, cardiovascular diseases, cancer and inflammation containing the (phenoxy) alkoxy-1H-indole derivative or a pharmaceutically acceptable salt thereof as an active ingredient .

In order to achieve the above object,

The present invention provides a compound represented by the following formula (1): < EMI ID =

[Chemical Formula 1]

In Formula 1,

R ¹ and R ² are each independently hydrogen; halogen; A straight or branched C _1- ₅ alkyl, or C _1-5 alkoxy sulfonyloxy; Unsubstituted or substituted straight or branched C _6- ₈ aryl C ₁ _- ₃ alkoxy; Or a heteroaryl group of the unsubstituted straight or branched chain of 5 to 8 ring atoms including the N atom one or more C ₁ _-3 alkoxy, and said substituted straight-chain or branched C ₈ _6- aryl C ₁ _- ₃ alkoxy group substituted with a _6- C ₈ radicals can be optionally substituted with one or more substituents selected from the group consisting of C _1- ₃ alkyl, halogen and linear or branched, with the proviso that, at least one of R ¹ and R ² are hydrogen;

R ³ is hydrogen; Unsubstituted or substituted allyl; Or unsubstituted heteroaryl group of C ₁ to C ₈ aryl _6- C ₁ _-3 alkyl, or N atoms in the unsubstituted linear or branched 5-8 atoms, including at least _1-3 alkyl, and wherein substituted is a halogen and straight-chain allyl or It may be substituted with one or more substituents selected from the group consisting of C _1- ₃ alkyl and the side chain;

R ⁴ is hydrogen or linear or branched C _1- ₅ alkyl; And

n is an integer of 2-4.

Also, as shown in the following Reaction Scheme 1,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1): < EMI ID =

[Reaction Scheme 1]

In the above Reaction Scheme 1,

L ¹ is halogen, mesylate (-OMs), tosylate (-OTs), bromosylate (-OBs) or nosylate (-ONs); And

R ¹ , R ² , R ³ , R ⁴ and n are the same as defined in the above formula (1).

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, cardiovascular diseases, cancer and inflammation, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating a metabolic disease, cardiovascular disease, cancer and inflammation, which comprises the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

INDUSTRIAL APPLICABILITY The (phenoxy) alkoxy-1H-indole derivatives according to the present invention are excellent in the ability to activate PPARα, PPARγ and PPARδ, and therefore can be used as PPAR agonists for the treatment of obesity, diabetes, hyperlipemia, hypertension, hyperinsulinemia, Metabolic diseases such as cholesterolemia, hypertriglyceridemia, Syndrome X, endothelial dysfunction and dyslipidemia; Cardiovascular diseases such as atherosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, and atherosclerosis; Colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibroid tumor, brain tumor, kidney cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, And PPAR? -Related diseases such as cancer and inflammation.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

(In the formula 1,

R ⁴ is hydrogen or linear or branched C _1- ₅ alkyl; And

n is an integer of 2-4.

Preferably,

R ¹ and R ² are each independently hydrogen; Chloro; A straight or branched C _1- ₃ alkyl or C _1- ₃ alkoxy sulfonyloxy; Phenyl unsubstituted or substituted straight or branched chain C ₁ _- ₃ alkoxy; Or unsubstituted pyridinyl the unsubstituted straight or branched chain C ₁ _- ₃ alkoxy, and said substituted phenyl C ₁ _- phenyl substituted in the _3-alkoxy can be optionally substituted with one or more substituents selected from the group consisting of chloro and methyl, Provided that at least one of R < ¹ > and R < ² > is hydrogen;

R ³ is hydrogen; Unsubstituted or substituted allyl; Or unsubstituted phenyl ring of a linear or branched C ₁ _-3 alkyl, or pyridinyl C ₁ _- ₃ alkyl, and the substituted allyl can be optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl and propyl;

R ⁴ is hydrogen or linear or branched C _1- ₃ alkyl; And

n is 2 or 3;

More preferably,

R ¹ and R ² are each independently hydrogen, chloro, methyl,

,

,

or

, With the proviso that at least one of R < ¹ > and R < ² > is hydrogen;

R ³ is hydrogen,

,

or

ego;

R < ⁴ > is hydrogen or methyl; And

n is 2 or 3;

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds:

(1) Methyl 2- (5- (2- (3- (pyridin-3-ylmethoxy) phenoxy) ethoxy) -1 H-indol-3-yl) acetate;

(2) Methyl 2- (1-benzyl-5- (2- (3- (pyridin-3-ylmethoxy) phenoxy) ethoxy) -1H-indol-3-yl) acetate;

(3) 2- (1-Benzyl-5- (2- (3- (pyridin-3-ylmethoxy) phenoxy) ethoxy) -1H-indol-3-yl) acetic acid;

(4) Methyl 2- (5- (2- (3- (4-methylbenzyloxy) phenoxy) ethoxy) -1- (pyridin-3-ylmethyl) -1H-indol-3-yl) acetate;

(5) Synthesis of 2- (5- (2- (3- (4-methylbenzyloxy) phenoxy) ethoxy) -1- (pyridin- ;

(6) Methyl 2- (1-allyl-5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;

(7) 2- (1-Allyl-5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;

(8) Synthesis of 2- (5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1- (3-methylbut- Tic acid;

(9) Methyl 2- (5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;

(10) 2- (5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;

(11) Methyl 2- (1-benzyl-5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;

(12) 2- (1-Benzyl-5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;

(13) Methyl 2- (5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;

(14) 2- (5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;

(15) Methyl 2- (1-benzyl-5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetate;

(16) 2- (1-Benzyl-5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;

(17) Methyl 2- (5- (2- (3- (methoxycarbonylphenoxy) ethoxy) -1H-indol-3-yl) acetate;

(18) 2- (5- (2- (3- (Methoxycarbonyloxy) phenoxy) ethoxy) -1 H-indol-3-yl) acetic acid;

(19) Methyl 2- (5- (2- (m-tolyloxy) ethoxy) -1H-indol-3-yl) acetate;

(20) 2- (5- (2- (m-Tolyloxy) ethoxy) -1H-indol-3-yl) acetic acid;

(21) methyl 2- (1-benzyl-5- (2- (m-tolyloxy) ethoxy) -1H-indol-3-yl) acetate;

(22) 2- (1-Benzyl-5- (2- (m-tolyloxy) ethoxy) -1H-indol-3-yl) acetic acid;

(23) Methyl 2- (5- (2- (3-chlorophenoxy) ethoxy) -1H-indol-3-yl) acetate;

(24) 2- (5- (2- (3-chlorophenoxy) ethoxy) -1H-indol-3-yl) acetic acid;

(25) Methyl 2- (1-benzyl-5- (2- (3-chlorophenoxy) ethoxy) -1H-indol-3-yl) acetate;

(26) 2- (l-Benzyl-5- (2- (3-chlorophenoxy) ethoxy) -lH-indol-3-yl) acetic acid.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

Also, as shown in the following Reaction Scheme 1,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

In the process for preparing the compound represented by the formula (1) according to the present invention, the compound represented by the formula (2) and the compound represented by the formula (3) are reacted to prepare the compound represented by the formula Can be manufactured.

Specifically, the compound represented by the formula (1) can be prepared by reacting -OH of the compound represented by the formula (2) and -L ¹ of the compound represented by the formula (3) in the presence of a base.

The L ¹ is not particularly limited, but is halogen, mesylate (-OMs), tosylate (-OTs), bromosylate (-OBs) or nonsylate (-ONs), preferably mesylate .

Examples of the base include inorganic bases such as cesium carbonate, sodium hydroxide, sodium carbonate, potassium carbonate and sodium hydride; Or organic bases such as N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-anesene (DBU), pyridine and triethylamine; , Which can be used in equivalent or excess, alone or in combination, and it is preferable to use cesium carbonate.

Further, as the reaction solvent which can be used, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, ethyl acetate, water, isopropanol, methanol, ethanol, propanol and butanol Containing lower alcohols; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane and the like; These can be used singly or in combination, and it is preferable to use acetonitrile.

A process for producing a derivative of the compound represented by the formula (1) (a compound represented by the formula (1a), (1b) or (1c)

The compound represented by the formula (1a), (1b) or (1c), which is a derivative of the compound represented by the formula (1)

Reacting a compound represented by the formula (2a) with a compound represented by the formula (3) to obtain a compound represented by the formula (1a) (step 1);

Reacting a compound represented by the formula (1a) obtained in the above step 1 with a compound represented by the formula (4) to obtain a compound represented by the formula (1b) (step 2);

(Step 3) of reacting a compound represented by the formula (1b) obtained in the above step 2 to obtain a compound represented by the formula (1c): < EMI ID =

[Reaction Scheme 2]

In the above Reaction Scheme 2,

X is halogen;

L ¹ is halogen, mesylate (-OMs), tosylate (-OTs), bromosylate (-OBs) or nosylate (-ONs);

R ¹ , R ² , R ³ , R ^3, and n are as defined in Formula 1, with the proviso that R ³ and R ⁴ are not hydrogen;

The compound represented by the formula (2a) is a derivative of the compound represented by the formula (2); And

The compounds represented by the formulas (1a), (1b) and (1c) are derivatives of the compound represented by the formula (1).

Hereinafter, the method for preparing the compound represented by the above formula (1a), (1b) or (1c) according to the present invention will be described in detail.

In the process for preparing a compound represented by the above formula (1a), (1b) or (1c) according to the present invention, the above step 1 is a step for obtaining a compound represented by the formula (1a) by reacting a compound represented by the formula , And a specific production method can be carried out in the same manner as the production method of the above reaction formula 1. [

In step (2), the compound represented by formula (1a) obtained in step (1) is reacted with the compound represented by formula (4) to produce a compound represented by formula (1b) Is obtained.

Specifically, the step of reacting the -NH of the indole of the compound represented by the formula (1a) with the halogen of the compound represented by the formula (4) in the presence of a base to obtain a compound represented by the formula (1b).

Examples of the reaction solvent which can be used include dimethylformamide (DMF), acetonitrile, dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, ethyl acetate, water, isopropanol, methanol, ethanol, propanol and butanol Containing lower alcohols; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane and the like; These may be used singly or in combination, and it is preferable to use dimethylformamide.

In the process for preparing a compound represented by the above formula (1a), (1b) or (1c) according to the present invention, the above step 3 is a step of reacting a compound represented by the formula (1b) obtained in the above step 2 to obtain a compound represented by the formula (1c).

Specifically, the compound represented by Formula 1b is hydrolyzed in the presence of a base to obtain a compound represented by Formula 1c.

Examples of the base include inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and lithium hydroxide; Or organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7- They may be used alone or in combination, and it is preferable to use sodium hydroxide.

Examples of the reaction solvent which can be used include ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, etc. may be used alone or in combination. It is preferable to use tetrahydrofuran, methanol and water in combination.

Preparation Method 1 of the starting material derivative (compound represented by Formula 2a or 2b) of the compound represented by Formula 2

The compound represented by the formula (2a) or (2b), which is a derivative of the compound represented by the formula (2), which is the starting material of the reaction scheme 1,

Reacting a compound represented by the formula (11) with a compound represented by the formula (12) and oxidizing the compound to obtain a compound represented by the formula (5) (step 1);

Reacting a compound represented by the formula (14) to obtain a compound represented by the formula (13) (step 2);

Reacting the compound represented by the formula (5) obtained in the above step 1 with the compound represented by the formula (13) obtained in the step 2 to obtain a compound represented by the formula (6) (step 3);

Reacting the compound of Formula 6 obtained in Step 3 to obtain the compound of Formula 2a (Step 4);

(Step 5) of reacting the compound represented by the formula (2a) obtained in the above step 4 with the compound represented by the formula (4) to obtain the compound represented by the formula (2b):

[Reaction Scheme 3]

In Scheme 3,

X is halogen;

L ³ is C _1- ₅ alkyl, straight or branched;

R ² and R ³ are as defined in Formula 1, with the proviso that R ³ and R ⁴ are not hydrogen;

The compounds represented by formulas (2a) and (2b) are derivatives of the compound represented by formula (2).

Hereinafter, the method for preparing the compound represented by the above formula (2a) or (2b) according to the present invention will be described in detail.

In step (1), the compound represented by formula (11) is reacted with a compound represented by formula (12) and then oxidized to obtain a compound represented by formula (5) .

Specifically, the compound represented by Formula 11 reacts with the compound represented by Formula 12 to form an alcohol compound, and the resulting alcohol compound is oxidized to obtain an aldehyde compound represented by Formula 5.

At this time, the reagents usable in the oxidation include, but are not limited to, a chromium-base such as Collins reagent (CrO ₃ .Py ₂ ), PDC (pyridinium diclomate), PCC (pyridinium chlorochromate) Chromium-based reagents can be used, and PCC is preferably used.

In the process for preparing a compound represented by the above formula (2a) or (2b) according to the present invention, the above step 2 is a step for obtaining a compound represented by the formula (13) by reacting a compound represented by the formula (14).

Specifically, the compound represented by the formula (14) is reacted with NaNO ₂ , hydrogen halide and SnCl ₂ to obtain a hydrazine compound represented by the formula (13).

In the process for producing the compound represented by the above formula (2a) or (2b) according to the present invention, the above step 3 is a step for reacting the compound represented by the formula (5) obtained in the above step 1 with the compound represented by the formula (13) 6 is obtained.

Specifically, an aldehyde of the compound represented by the formula (5) and a hydrazine of the compound represented by the formula (13) are reacted to obtain an indole compound represented by the formula (6) through a cyclization reaction.

In the method for preparing a compound represented by the above formula (2a) or (2b) according to the present invention, the above step 4 is a step for obtaining a compound represented by the formula (2a) by reacting the compound represented by the formula (6) obtained in the above step 3.

Specifically, L ³ of the compound represented by the formula (6) is removed under an acid condition to obtain an alcohol compound represented by the formula (2a).

The acid may be a Lewis acid such as AlCl ₃ , TiCl ₄ or FeCl ₃ , hydrogen halide, sulfuric acid, trifluoroacetic acid or the like, preferably AlCl ₃ .

In step (5), the compound represented by formula (2a) obtained in step (4) is reacted with the compound represented by formula (4) to obtain the compound represented by formula (2b) , And a specific production method can be carried out in the same manner as the production method of step 2 of the above reaction formula 2. [

Preparation method 2 of starting material (compound represented by formula (3a)) 2

The compound of Formula 3, which is the starting material of Reaction Scheme 1,

Reacting a compound represented by the formula (7) with a compound represented by the formula (8) to obtain a compound represented by the formula (9) (step 1); And

(Step 2) of reacting a compound represented by the formula (9) obtained in the above step 1 with a compound represented by the formula (10) to obtain a compound represented by the formula (3a): < EMI ID =

[Reaction Scheme 4]

In Scheme 4,

X is halogen;

L ² is Mesyl, Tosyl, Brosyl or Nosyl; And

R ¹ , R ^2, and n are as defined in Formula 1; And

The compound represented by the formula (3a) is a derivative of the compound represented by the formula (3).

Hereinafter, a method for preparing the compound represented by Formula 3a according to the present invention will be described in detail.

In step (1), the compound represented by formula (7) is reacted with a compound represented by formula (8) to obtain a compound represented by formula (9).

Specifically, the step of reacting the -OH of the compound represented by the formula (7) with the halogen of the compound represented by the formula (6) in the presence of a base to obtain an ether compound represented by the formula (9).

Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium carbonate and sodium hydride; Or organic bases such as N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-anesene (DBU), pyridine and triethylamine; , Which can be used in equivalent or excess, alone or in combination, and it is preferable to use potassium carbonate.

Examples of the reaction solvent which can be used include dimethylformamide (DMF), acetonitrile, dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, ethyl acetate, water, isopropanol, methanol, ethanol, propanol and butanol Containing lower alcohols; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane and the like; These can be used singly or in combination, and it is preferable to use dimethylformamide.

In the method for preparing the compound represented by the above formula (3a) according to the present invention, the above step 2 is a step of reacting the compound represented by the formula (9) obtained in the above step 1 with the compound represented by the formula (10) .

Specifically, the step of reacting the -OH of the compound represented by the formula (9) with the halogen of the compound represented by the formula (10) in the presence of a base to obtain a compound represented by the formula (3a).

At this time, L ² is a leaving group, and is not particularly limited, but includes Mesyl, Tosyl, Brosyl, Nosyl and the like, preferably mesyl.

Examples of the base include organic bases such as pyridine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU) and triethylamine; Or an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium carbonate, sodium hydride and the like, which can be used in equivalent or excess, alone or in combination, and it is preferable to use pyridine.

Examples of the reaction solvent which can be used include dimethylformamide (DMF), acetonitrile, dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, ethyl acetate, water, isopropanol, methanol, ethanol, propanol and butanol Containing lower alcohols; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane and the like; These can be used singly or in combination.

Specifically, the metabolic diseases include obesity, diabetes, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, syndrome X, endothelial dysfunction, dyslipidemia can do.

In addition, the cardiovascular diseases may include atherosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, atherosclerosis and the like.

Further, the cancer may be selected from the group consisting of renal cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastasis, skin cancer, bladder cancer, Fibrotic tumors, brain tumors, and the like.

As a result of evaluating the PPAR?, PPAR? And PPAR? Activation capacities of the compound represented by Formula 1 according to the present invention, it can be seen that the compounds according to the present invention activate PPAR ?, PPAR? And PPAR ?. In particular, the compounds of Examples 7 and 8 exhibited a% Max value of 100 or more, and were found to activate PPARγ and PPARδ at the same time (see Experimental Example 1).

Therefore, the compound represented by the formula (1) according to the present invention has an excellent ability to activate PPAR?, PPAR? And PPAR?, And therefore, it can be used as a PPAR agonist for obesity, diabetes, hyperlipemia, hypertension, hyperinsulinemia, fatty liver, hyperlipemia, , Hypertriglyceridemia, metabolic syndrome (Syndrome X), endothelial dysfunction, dyslipidemia; Cardiovascular diseases such as atherosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, and atherosclerosis; Colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibroid tumor, brain tumor, kidney cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, And PPAR? -Related diseases such as cancer and inflammation.

In the pharmaceutical composition according to the present invention, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally in various formulations at the time of clinical administration. In the case of formulation, For example, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.

The pharmaceutical composition containing the compound represented by Formula 1 or its pharmaceutically acceptable salt according to the present invention as an active ingredient may be administered parenterally, and parenteral administration may be carried out by subcutaneous injection, intravenous injection, intramuscular injection, It depends on the injection method.

In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dosage of the pharmaceutical composition containing the compound of formula (I) of the present invention or its pharmaceutically acceptable salt as an active ingredient in the human body depends on the age, body weight, sex, dosage form, health condition and disease And is typically 0.1-1000 mg / day, preferably 1-500 mg / day, based on adult patients weighing 70 Kg, and may be administered at a physician or pharmacist's discretion It may be administered once to several times a day at intervals of time.

Furthermore, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient can be used alone or in combination with other agents such as surgery, hormone therapy, chemotherapy And methods using biological response modifiers.

Herein, the metabolic diseases include obesity, diabetes, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Syndrome X, endothelial dysfunction, dyslipidemia The cardiovascular disease may include atherosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, atherosclerosis, etc. The cancer may be kidney cancer, bladder cancer, liver cancer, Cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibroid tumor, brain tumor and the like.

The compound of formula (I) according to the present invention is a health functional food composition for preventing or ameliorating metabolic diseases, cardiovascular diseases, cancer and inflammation by acting as an agonist of PPARα, PPARγ and PPARδ, And the like.

The compound represented by the formula (1) according to the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term ingestion intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

In addition, the health functional beverage composition of the present invention has no particular limitation on other components other than the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavoring agents or natural carbohydrates as additional components such as ordinary beverages have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of said natural carbohydrate is generally about 1-20 g, preferably about 5-12 g, per 100 g of the composition of the present invention.

In addition, in addition to the above, the compound represented by the formula (1) according to the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese, Acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compound represented by formula (1) of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

Hereinafter, examples and experimental examples of the present invention will be described in detail.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Manufacturing example 1> methyl 2- (5- Hydroxy -1H-indol-3-yl) acetate

step 1: 4 - Oxo butyric Acid methyl Manufacture of Esters

Γ-butyrolactone (5.00 g, 58.67 mmol) was dissolved in distilled methanol (30 mL), and then triethylamine (29.7 g, 293.37 mmol) was added dropwise at room temperature in a nitrogen-purged round flask. The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure to obtain crude (crude, crude compound) methyl [gamma] -hydroxyester, which was dissolved in 80 mL of distilled dichloromethane. PCC (18.9 g, 87.68 mmol) . The reaction solution was stirred at room temperature for 1.5 hours and then 200 mL of ethyl ether was added. The reaction solution is filtered through a pad of celite and washed with ethyl ether. The residue was concentrated under reduced pressure to give 4-oxobutylic acid methyl ester (3.40 g, 29.27 mmol, 50%) as a clear liquid by performing column chromatography (eluent: n-hexane / ethyl acetate = 2: 1 v / ).

¹ H NMR (400 MHz, CDCl ₃ )? 9.82 (1H, s), 3.70 (3H, s), 2.82 (2H, t, J = 6.8 Hz), 2.64 (2H, t, J = 6.8 Hz);

^{_{13 C NMR (100MHz, CDCl 3}} ) δ 199.8, 172.3, 51.3, 38.0, 25.8;

IR (neat, cm- ¹ ) 2956, 1737, 1439, 1210, 1164.

Step 2: (4- Methoxyphenyl ) Hydrazine Produce

P-anisidine (4.93 g, 40 mmol) in water (12 mL) and conc. After dissolving in HCl (12 mL), a solution of sodium nitrite (3.3 g, 46.40 mmol) in water (10 mL) was added dropwise at -5 ° C over 15 min. After the reaction solution was stirred for 1.5 hours, conc. HCl (25 mL) of SnCl ₂ (16.00 g, 84.40 mmol) was slowly added dropwise. The resulting pink solid was stirred at 0 < 0 > C for 30 min and then filtered. The obtained residue was washed with water (20 mL), ethanol (12 mL) and ethyl ether (50 mL) and then reduced in pressure to obtain 5.40 g of (4-methoxyphenyl) hydrazine as a pale pink solid.

¹ H NMR (400 MHz, D ₂ O)? 6.94 (2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 3.64 (3H, s).

Step 3: methyl 2- (5- Methoxy -1H-indol-3-yl) acetate

(4-methoxyphenyl) hydrazine (5.60 g, 38.93 mmol) obtained in the above step 2 was added to an aqueous 10% phosphoric acid solution (50 mL) and then dissolved by heating at 60 ° C. In another round flask, the 4-oxobutylic acid methyl ester (4.53 g, 32.44 mmol) obtained in step 1 above was dissolved in 50 mL of toluene. The hydrazine solution was added to the 4-oxobutylic acid solution and stirred at 90 占 폚 for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate (20 mL) was slowly added dropwise thereto and diluted with ethyl acetate. The mixed solution was put in a separating funnel to separate the organic solution layer, and the aqueous solution layer was extracted with ethyl acetate. The organic layer was mixed solution was washed with water and brine, dried over anhydrous magnesium sulfate (MgSO _4), filtered and concentrated in vacuo. The obtained residue was subjected to column chromatography (eluent: n-hexane / ethyl acetate = 2: 1 v / v) to obtain pale yellow liquid methyl 2- (5-methoxy- 2.3 g, 1.96 mmol, 32%). The extracted aqueous solution layer was washed with water and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The obtained brown solid was added with chloroform and then filtered to obtain methyl 2- (5-methoxy-1H-indol-3-yl) acetate (400 mg, 9%) as an ivory solid.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.22 (1H, d, J = 8.4 Hz), 7.12 (1H, s), 7.00 (1H, d, J = 2.4 Hz), 6.76 (1H, dd, J = 8.4, 2.4 Hz), 3.81 (3H, s), 3.73 (2H, s), 3.68 (3H, s);

¹³ C NMR (100 MHz, CDCl ₃ )? 172.5, 154.1, 131.2, 127.6, 123.8, 112.4, 111.9, 108.0, 100.6, 63.7, 55.9, 31.2;

IR (neat, cm- ¹ ) 3399, 2996, 2952, 1736, 1488, 1439, 1217, 1163.

Step 4: methyl 2- (5- Hydroxy -1H-indol-3-yl) acetate

Methyl 2- (5-methoxy-1H-indol-3-yl) acetate (1.67 g, 7.60 mmol) was dissolved in distilled dichloromethane (60 mL) in a nitrogen-purged round bottom flask. AlCl ₃ (5.07 g, 38.02 mmol) was slowly added dropwise to the solution at 0 ° C and stirred for 30 minutes, and then ethanethiol (2.82 mL, 38.02 mmol) was added dropwise. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, water is slowly added dropwise at 0 ° C, and sodium bicarbonate aqueous solution is added to neutralize. Extracting the mixture with dichloromethane, the combined organic extracts were washed with water and brine, anhydrous magnesium sulfate (MgSO ₄₎ dried, filtered and concentrated in vacuo. The obtained residue was subjected to column chromatography (eluent: n-hexane / ethyl acetate = 3: 2 v / v) to obtain a pale yellow liquid of methyl 2- (5-methoxy-1H-indol-3-yl) acetate 1.12 g, 5.48 mmol, 72%).

¹ H NMR (400 MHz, CDCl ₃ )? 7.82 (NH, s); (1H, dd, J = 8.8, 2.4 Hz), 7.16 (1H, d, J = 4.83 (2 H, s), 3.66 (3 H, s);

¹³ C NMR (100 MHz, CDCl ₃ ) 隆 174.9, 151.3, 132.8, 129.2, 125.5, 112.8, 112.5, 107.7, 103.6, 52.3, 31.9;

IR (neat, cm ^-1 ) 3398, 2924, 2853, 1715, 1628, 1436, 1360, 1203;

FAB-MS m / z 205.1 (M ^< ^{+ &} gt ^; ).

< Example 1> methyl 2- (5- (2- (3- (Pyridin-3- Ylmethoxy ) Phenoxy ) Ethoxy ) -1H-indol-3-yl) acetate

(Cs ₂ CO ₃ , 1.2 eq.) And 2- (3- (pyridin-3-ylmethoxy) phenoxy) -1,2,3,4-tetrahydroisoquinoline ) Acetic anhydride (0.5 M) of ethyl methanesulfonate (1.1 eq.) Was refluxed for 2 hours. The reaction mixture was cooled, diluted and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, anhydrous magnesium sulfate (MgSO ₄₎ dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain the desired compound in 80% yield.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.67 (1H, s), 8.58 (1H, d, J = 4.8 Hz), 8.35 (NH, br s), 7.76 (1H, dd, J = 8.0, 1.6 Hz (1H, m), 7.31 (1H, dd, J = 8.0, 4.8 Hz), 7.22 (1H, d, J = 8.8 Hz), 7.20 (2H, s), 3.68 (2H, s), 3.68 (2H, d, J = ).

< Example 2> methyl 2- (1- benzyl -5- (2- (3- (pyridin-3- Ylmethoxy ) Phenoxy ) Ethoxy ) -1H-indol-3-yl) acetate

A mixture of methyl 2- (5- (2- (3- (pyridin-3-ylmethoxy) phenoxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 1 and cesium carbonate Benzyl chloride (1.5 eq.) Was added to anhydrous dimethylformamide (DMF, 0.5 M) and refluxed overnight at 100 < 0 > C. The reaction mixture was diluted and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, anhydrous magnesium sulfate (MgSO ₄₎ dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain the desired compound in 70% yield.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.67 (1H, s), 8.58 (1H, d, J = 4.4 Hz), 7.77 (1H, d, J = 7.6 Hz), 7.31 (1H, dd, J = 7.6, 4.4 Hz), 7.20 (1H, t, J = 8.4 Hz), 7.10-7.33 (8H, m), 6.88 (1H, dd, J = 8.8, 2.4 Hz), 6.58-6.62 5.24 (2H, s), 5.04 (2H, s), 4.34 (4H, m), 3.74 (2H, s), 3.69 (3H, s).

< Example 3 > 2- (1- benzyl -5- (2- (3- (pyridin-3- Ylmethoxy ) Phenoxy ) Ethoxy ) -1H-indol-3-yl) acetic acid

Yl) acetate (30.50 mg) obtained in Example 2, and methyl 2- (1-benzyl-5- (2- (3- (pyridin- Was added sodium hydroxide (1.5 eq.) In a mixture of tetrahydrofuran / methanol / water (1 mL, 2: 1: 1 v / v / v) and stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with 1N HCl aqueous solution and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, anhydrous magnesium sulfate (MgSO ₄₎ dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol = 1: 1: 0.2 or chloroform / methanol = 10: 1) to obtain the desired compound in 80% yield.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.73 (1H, s), 8.51 (1H, br s), 7.78 (1H, d, J = 7.6 Hz), 7.06-7.32 (10H, m), 6.85 (1H (d, J = 8.4 Hz), 6.51-6.57 (3H, m), 5.20 (2H, s), 5.07 s);

IR (KBr pellet, cm ^-1 ) 3436, 2925, 1708, 1600, 1490, 1157.

< Example 4> methyl 2- (5- (2- (3- (4- Methylbenzyloxy ) Phenoxy ) Ethoxy ) -1- (pyridin-3-ylmethyl) -1H-indol-3-yl) acetate

Step 1: methyl 2- (5- (2- (3- (4- Methylbenzyloxy ) Phenoxy ) Ethoxy ) -1H-indol-3-yl) acetate

(5- (2- (3- (4-methylpiperazin-1-ylmethyl) -1H-pyrazole-3- Benzyloxy) phenoxy) ethoxy) -1 H-indol-3-yl) acetate.

Step 2: methyl 2- (5- (2- (3- (4- Methylbenzyloxy ) Phenoxy ) Ethoxy ) -1- (pyridin-3- Yl methyl ) -1H-indol-3-yl) acetate

Using the methyl 2- (5- (2- (3- (4-methylbenzyloxy) phenoxy) ethoxy) -1H-indol-3-yl) acetate obtained in the step 1 and 3- (chloromethyl) , The target compound was obtained.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.41 (1H, d, J = 5.2 Hz), 8.39 (1H, s), 7.44 (1H, d, J = 7.6 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.25 (1H, dd, J = 7.6, 5.2 Hz), 7.16-7.20 (4H, m), 7.11 (2H, s), 4.32 (4H, m), 3.61 (2H, s), 2.36 (3H, , s).

< Example 5 > 2- (5- (2- (3- (4- Methylbenzyloxy ) Phenoxy ) Ethoxy ) -1- (pyridin-3- Yl methyl ) -1H-indol-3-yl) acetic acid Acid's Produce

To a solution of methyl 2- (5- (2- (3- (4-methylbenzyloxy) phenoxy) ethoxy) -1- (pyridin- ) Acetate was used as the starting material, the objective compound was obtained.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.37 (1H, d, J = 4.4 Hz), 8.34 (1H, s), 7.46 (1H, d, J = 8.0 Hz), 7.25-7.26 (3H, m ), 7.18 (1H, s), 7.10-7.16 (5H, m), 6.83 (1H, d, J = 8.8 Hz), 6.52-6.56 s), 4.24 (4H, m), 3.72 (2H, d, J = 2.0 Hz), 3.65 (3H, s), 2.30 (3H, s);

IR (neat, cm- ¹ ) 2920, 1590, 1488, 1262, 1178, 1153.

< Example 6> methyl 2- (l-Allyl-5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

Step 1: methyl 2- (5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

(5- (3- (3- (4-chlorobenzyloxy) phenoxy) propylmethanesulfonate was used in the same manner as in Example 1, Benzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate.

Step 2: methyl 2- (l-Allyl-5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

The same procedure as in Example 1 was used, except that methyl 2- (5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Step 1 and allyl bromide were used. 2, the target compound was obtained.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.34 (4H, s), 7.17-7.29 (2H, m), 7.05 (1H, d, J = 6.4 Hz), 6.94-7.00 (1H, m), 6.86 ( D, J = 8.8 Hz), 6.55 (3H, s), 5.97 (1H, m), 5.18 (1H, d, J = 9.2 Hz), 5.09 2H), 4.64 (2H, s), 4.18 (4H, m), 3.71 (2H, s), 3.69 (3H, s), 2.27 (2H, s).

< Example 7> 2- (1-Allyl-5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetic acid

Except that methyl 2- (1-allyl-5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetate obtained in Example 6 was used The objective compound was obtained by carrying out the same method as in Example 3.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.33 (4H, s), 7.16 (1H, d, J = 8.8 Hz), 7.16 (1H, dd, J = 9.2, 7.6 Hz), 7.04-7.05 (2H, (1H, m), 6.86 (1H, dd, J = 8.8,2.4Hz), 6.52-6.55 (3H, m), 5.95 (2H, t, J = 6.0 Hz), 3.73 (2H, d, J = , < / RTI > s), 2.25 (2H, m);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.3, 160.2, 159.7, 135.5, 133.4, 129.9, 128.8, 128.7, 128.0, 127.5, 117.4, 112.6, 110.7, 110.5, 107.3, 107.0, 101.9, 101.8, 69.1, 65.2 , 64.7, 48.9, 34.9, 29.4;

IR (neat, cm- ¹ ) 3083, 2927, 2877, 1708, 1601, 1491, 1152;

HRMS-ESI [M + H] ⁺ calcd for C ₂₉ H ₂₈ ClNO ₅ : 506.1729, found: 506.1737.

< Example 8 2- (5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1- (3- Methyl boot 2-enyl) -1H-indol-3-yl) acetic acid Acid's Produce

Step 1: methyl 2- (5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1- (3- Methyl boot -2-enyl) -1H-indol-3-yl) acetate

(3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Step 1 of Example 6 and 1-chloro- -Methylbut-2-ene was used in place of methyl 2- (5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1- (3-methylbut-2-enyl) -1H-indol-3-yl) acetate.

step 2: 2 - (5- (3- (3- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1- (3- Methyl boot 2-enyl) -1H-indol-3-yl) acetic acid

To a solution of methyl 2- (5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1- (3-methylbut- Yl) acetate was used as the starting material to obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.35 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.11-7.18 (2H, m), 7.06 (1H, d, (1H, m), 4.97 (2H, s), 6.97 (1H, s) (2H, t, J = 6.0 Hz), 4.65 (2H, d, J = 6.8 Hz), 4.18 1.81 (3 H, s), 1.74 (3 H, s);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 177.5, 160.2, 159.7, 53.2, 136.3, 135.5, 133.6, 131.6, 128.8, 128.7, 128.1, 127.1, 119.9, 112.5, 110.4, 107.3, 107.0, 105.5, , 69.1, 65.3, 64.8, 44.2, 31.1, 29.4, 25.6, 18.0;

IR (neat, cm- ¹ ) 2925, 1708, 1600, 1491, 1151;

HRMS-ESI [M + H] ⁺ calcd for C ₃₁ H ₃₂ ClNO ₅ : 534.2042, found: 534.2042.

< Example 9> methyl 2- (5- (3- (4- (4- Methylbenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

The procedure of Example 1 was repeated except for using 3- (4- (4-methylbenzyloxy) phenoxy) propylmethanesulfonate to obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.03 (NH, br s), 7.29 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz), 7.16-7.19 (1H, m ), 7.06 (1H, d, J = 2.0 Hz), 6.83-6.90 (4H, m), 4.95 (2H, s), 4.18 (2H, dd, J = J = 6.0 Hz), 3.71 (2H, s), 3.68 (3H, s), 2.34 (3H, s), 2.24 (2H, m);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.6, 153.4, 153.2, 153.0, 137.6, 134.2, 134.0, 132.2, 131.3, 129.2, 127.6, 123.9, 115.8, 115.4, 112.9, 111.9, 108.0, 101.8, 70.6, 65.4 , 65.3, 52.0, 31.2, 29.6, 21.2;

IR (neat, cm ^-1 ) 3414, 2950, 2873, 1733, 1507, 1228, 1208.

< Example 10. Preparation of 2- (5- (3- (4- (4- Methylbenzyloxy ) Phenoxy ) Propoxy ) -LH-indol-3-yl) Acetic Acid's Produce

Example 3 was repeated except that methyl 2- (5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Example 9 was used. The objective compound was obtained by carrying out the same production method.

^{1 H NMR (400 MHz, CDCl} 3 + CD 3 OD) δ 7.30 (2H, d, J = 8.0 Hz), 7.26 (1H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.0 Hz) , 7.15 (1H, s), 7.09 (1H, d, J = 2.4 Hz), 6.85-6.91 (4H, m), 6.82 (1H, dd, J = = 6.4, 6.0 Hz), 4.15 (2H, dd, J = 6.0,5.6 Hz), 3.70 (2H, s), 2.35 (3H, s), 2.24 (2H, m);

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD) δ 174.8, 153.2, 153.0, 152.9, 137.6, 134.1, 131.4, 129.1, 127.6, 124.0, 115.8, 115.4, 112.6, 111.9, 107.7, 101.8, 70.6, 65.4 , 65.3, 31.0, 29.5, 21.0;

IR (KBr pellet, cm ^-1 ) 3454, 2933, 2880, 1509, 1241, 1193, 1066, 824;

HRMS-ESI [M + H] ⁺ calcd for C ₂₇ H ₂₇ NO ₅ : 446.1962, found: 446.1976.

< Example 11> methyl 2- (1- benzyl -5- (3- (4- (4- Methylbenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

Example 2 was repeated except that methyl 2- (5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Example 9 was used. The objective compound was obtained by carrying out the same production method.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.29 (2H, d, J = 8.0 Hz), 7.25-7.36 (5H, m), 7.17 (2H, d, J = 8.0 Hz), 7.06-7.12 (3H, m), 6.88 (2H, d, J = 8.8Hz), 6.84 (2H, d, J = 8.8Hz), 6.81-6.84 (2H, d, J = 6.4, 6.0 Hz), 4.12 (2H, t, J = 6.0 Hz), 3.72 (2H, s), 3.69 (3H, s), 2.34 , m);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.5, 162.6, 152.7, 151.0, 137.6, 129.2, 128.7, 128.6, 127.6, 126.8, 126.0, 115.8, 115.4, 112.6, 110.6, 102.1, 100.9, 70.6, 69.8, 65.3 , 52.0, 31.2, 29.6, 26.1, 21.2.

< Example 12> 2- (1- benzyl -5- (3- (4- (4- Methylbenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetic acid Acid's Produce

Except that methyl 2- (1-benzyl-5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Example 11 was used The objective compound was obtained by carrying out the same method as in Example 3.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.34 (2H, d, J = 4.0 Hz), 7.28 (2H, d, J = 7.2 Hz), 7.15-7.23 (5H, m), 7.11 (2H, s) , 6.99 (2H, d, J = 4.0 Hz), 6.84 (2H, d, J = 8.8 Hz) s), 4.91 (2H, s), 4.08 (2H, t, J = 5.6 Hz), 4.04 (2H, t, J = 6.0 Hz), 3.65 2H, m);

^{13 C NMR (100 MHz, CDCl} 3) δ 153.2, 153.0, 137.6, 134.2, 131.8, 129.2, 128.7, 128.5, 128.0, 127.6, 127.0, 126.7, 115.8, 115.4, 112.6, 102.0, 70.6, 65.3, 65.3, 50.1 , 39.3, 29.5, 21.2;

IR (KBr pellet, cm ^-1 ) 3427, 3029, 2931, 1701, 1509, 1230;

HRMS-ESI [M + H] + calcd for C 34 H 33 NO 5: 536.2431, found: 536.2451.

< Example 13> methyl 2- (5- (3- (4- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

The objective compound was obtained by the same method as in Example 1 except for using 3- (4- (4-chlorobenzyloxy) phenoxy) propylmethanesulfonate.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.04 (NH, br s), 7.33 (4H, s), 7.17 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 2.0 Hz), (1H, d, J = 6.4, 6.0 Hz), 3.72 (2H, s) , 3.68 (3 H, s), 2.25 (2 H, m);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.6, 153.4, 152.6, 135.8, 133.6, 131.3, 128.8, 128.7, 127.6, 123.9, 115.8, 112.9, 111.9, 108.0, 101.8, 69.9, 65.3, 52.0, 31.2, 29.6 ;

IR (neat, cm ^-1 ) 3405, 2951, 2874, 1732, 1507, 1227, 1207.

< Example 14 2- (5- (3- (4- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetic acid Acid's Produce

Example 3 was repeated except that methyl 2- (5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Example 13 was used. The objective compound was obtained by carrying out the same production method.

^{1 H NMR (400 MHz, CDCl} 3 + CD 3 OD) δ 7.38 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.26 (1H, d, J = 8.8 Hz) , 7.16 (1H, s), 7.09 (1H, s), 6.89 (4H, s), 6.83 (1H, d, J = 8.8 Hz), 5.00 Hz), 4.16 (2H, t, J = 6.0 Hz), 3.71 (2H, s), 2.25 (2H, m);

^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD) δ 174.9, 153.3, 152.8, 152.5, 135.7, 133.4, 131.5, 128.7, 128.5, 127.4, 124.1, 115.8, 115.4, 112.3, 111.9, 107.4, 101.7, 69.8 , 65.3, 65.2, 31.0, 29.4;

IR (KBr pellet, cm ^-1 ) 3451, 2930, 2882, 1728, 1509, 1241, 1195;

HRMS-ESI [M + H] ⁺ calcd for C ₂₆ H ₂₄ ClNO ₅ : 466.1416, found: 466.1416.

< Example 15> methyl 2- (1- benzyl -5- (3- (4- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetate

Example 2 was repeated except that methyl 2- (5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Example 13 was used. The objective compound was obtained by carrying out the same production method.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.32 (4H, s), 7.22-7.36 (4H, m), 7.07-7.12 (4H, m), 6.81-6.85 (5H, m), 5.21 (2H, s ), 4.94 (2H, s), 4.18 (2H, t, J = 6.0 Hz), 4.12 (2H, t, J = 6.0 Hz), 3.72 , m);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.5, 153.5, 153.3, 152.7, 137.5, 135.8, 133.6, 131.9, 128.8, 128.7, 128.6, 128.5, 128.3, 127.8, 127.6, 126.8, 115.8, 115.5, 112.6, 110.6 , 107.0, 102.1, 69.9, 65.3, 52.0, 50.2, 31.2, 29.6.

< Example 16> 2- (1- benzyl -5- (3- (4- (4- Chlorobenzyloxy ) Phenoxy ) Propoxy ) -1H-indol-3-yl) acetic acid Acid's Produce

Except that the methyl 2- (1-benzyl-5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate obtained in Example 15 was used The objective compound was obtained by carrying out the same method as in Example 3.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.36 (1H, d, J = 8.4 Hz), 7.32 (4H, s), 7.21-7.25 (3H, m), 7.01-7.07 (4H, m), 6.78- Dd, J = 6.0, 5.4 Hz), 3.68 (2H, d, J = 6.0, 5.6 Hz), 6.85 (5H, m) (2 H, s), 2.18 (2 H, m);

¹³ C NMR (100 MHz, CDCl ₃ )? 153.4, 153.3, 152.6, 137.4, 135.8, 133.6, 128.8, 128.7, 127.5, 126.7, 115.8, 115.4, 112.6, 110.6, 105.0, 102.0, 69.9, 65.2, , 29.5;

IR (KBr pellet, cm ^-1 ) 3434, 3030, 2022, 2864, 1704, 1508, 1492, 1231;

HRMS-ESI [M + H] + calcd for C 33 H 30 ClNO 5: 556.1885, found: 556.1886.

< Example 17> methyl 2- (5- (2- (3- ( Methoxylphenyloxy ) Phenoxy ) Ethoxy ) -1H-indol-3-yl) acetate

The procedure of Example 1 was repeated except for using 2- (3- (methoxysulfonyloxy) phenoxy) ethyl methanesulfonate, to thereby obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.09 (NH, br s), 7.31 (1H, t, J = 8.4 Hz), 7.23 (1H, d, J = 8.4 Hz), 7.12 (2H, dd, J = 7.2, 2.0 Hz), 6.88-6.95 (4H, m), 4.31-4.38 (4H, m), 3.74 (2H, s), 3.69 (3H, s), 3.11 (3H, s);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.5, 159.9, 153.0, 150.1, 131.6, 130.4, 127.6, 124.0, 114.2, 13.8, 113.0, 112.0, 108.8, 108.2, 102.3, 67.3, 67.2, 52.0, 37.3, 31.2 ;

IR (neat, cm ^-1 ) 3415, 3024, 2935, 1731, 1484, 1365, 1183, 1124, 967.

< Example 18 2- (5- (2- (3- ( Methoxylphenyloxy ) Phenoxy ) Ethoxy ) -LH-indol-3-yl) Acetic Acid's Produce

The same procedure as in Example 3 was repeated except for using methyl 2- (5- (2- (3- (methoxycarbonyloxy) phenoxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 17. And the desired compound was obtained.

^{1 H NMR (400 MHz, CDCl} 3 + CD 3 OD) δ 7.34 (1H, t, J = 7.6 Hz), 7.28 (1H, d, J = 8.8 Hz), 7.17 (1H, s), 7.13 (1H, m), 3.72 (2H, s), 3.16 (3H, d, J = 2.4 Hz), 6.97 (1H, dd, J = 8.0, 2.0 Hz), 6.87-6.93 , s);

IR (KBr pellet, cm ^-1 ) 3421, 2936, 1703, 1615, 1356, 1212, 1187, 977.

< Example 19> methyl 2- (5- (2- (m- Tolyloxy ) Ethoxy ) -1H-indol-3-yl) acetate

The procedure of Example 1 was repeated except for using 2- (m-tolyloxy) ethylmethanesulfonate to obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.11 (NH, br s), 7.17 (1H, d, J = 8.8 Hz), 7.16 (1H, t, J = 7.2 Hz), 7.10 (1H, d, J M), 3.72 (2H, m, 2H), 7.05 (1H, d, J = 2.0 Hz), 6.89 (1H, dd, J = 8.8, 2.0 Hz), 6.76-6.79 , < / RTI > s), 3.68 (3H, s), 2.32 (3H, s);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.6, 158.7, 153.1, 139.5, 131.6, 129.2, 127.6, 124.1, 121.8, 115.6, 113.1, 112.0, 111.6, 108.0, 102.2, 67.5, 65.6, 52.0, 31.2, 21.5 ;

IR (neat, cm- ¹ ) 3405, 2924, 2873, 1732, 1486, 1261, 1159.

< Example 20 2- (5- (2- (m- Tolyloxy ) Ethoxy ) -LH-indol-3-yl) Acetic Acid's Produce

The procedure of Example 3 was repeated except for using methyl 2- (5- (2- (m-tolyloxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 19, Compound.

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.24 (1H, d, J = 8.8 Hz), 7.11-7.16 (3H, m), 6.82 (1H, dd, J = 8.8, 2.4 Hz), 6.79 (1H , 6.75 (2H, d, J = 8.0 Hz), 4.27 (4H, m), 3.69 (2H, m), 2.30 (3H, s);

¹³ C NMR (100 MHz, CD ₃ OD) 158.9, 152.6, 139.2, 132.1, 128.8, 127.6, 124.0, 121.3, 115.0, 112.0, 111.5, 111.2, 107.6, 101.7, 67.5, 66.5, 40.0, 20.1;

IR (KBr pellet, cm ^-1 ) 3384, 2926, 1696, 1676, 1594, 1489, 1451, 1267, 1178, 1070, 962;

HRMS-ESI [M + H] + calcd for C 19 H 19 NO 4: 326.1387, found: 326.1388.

< Example 21> methyl 2- (1- benzyl -5- (2- (m- Tolyloxy ) Ethoxy ) -1H-indol-3-yl) acetate

The same procedure as in Example 2 was repeated except for using methyl 2- (5- (2- (m-tolyloxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 19, Compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.08-7.36 (9H, m), 6.88 (1H, dd, J = 8.8 Hz), 6.77-6.79 (3H, m), 5.22 (2H, s), 4.33 ( 4H, m), 3.73 (2H, s), 3.69 (3H, s), 2.32 (3H, s);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.4, 158.7, 153.1, 139.5, 137.5, 132.1, 129.2, 128.8, 128.6, 128.3, 127.9, 127.6, 126.8, 121.8, 115.6, 112.9, 111.6, 110.6, 107.0, 102.5 , 67.5, 66.5, 52.0, 50.2, 31.2, 21.5;

IR (neat, cm ^-1 ) 3032, 2949, 2873, 1737, 1488, 1453, 1260, 1159.

< Example 22 > 2- (1- benzyl -5- (2- (m- Tolyloxy ) Ethoxy ) -LH-indol-3-yl) Acetic Acid's Produce

The same procedure as in Example 3 was repeated except for using methyl 2- (1-benzyl-5- (2- (m-tolyloxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 21 To give the desired compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.34 (1H, d, J = 8.4 Hz), 7.17-7.23 (2H, m), 7.13 (1H, t, J = 8.0 Hz), 6.99-7.06 (5H, m), 6.83 (1H, dd, J = 8.4, 2.0 Hz), 6.70-6.76 (3H, m), 5.08 , < / RTI > s), 2.29 (3H, s);

^{13 C NMR (100 MHz, CDCl} 3) δ 158.7, 153.1, 139.4, 137.4, 131.9, 129.2, 128.7, 128.6, 128.2, 128.1, 127.5, 127.0, 126.7, 121.7, 115.6, 112.9, 111.5, 110.7, 106.6, 102.3 , 67.4, 66.5, 65.3, 50.1, 21.5;

IR (KBr pellet, cm ^-1 ) 3429, 3033, 2948, 2921, 2884, 1707, 1584, 1491, 1232, 1160;

HRMS-ESI [M + H] ⁺ calcd for C ₂₆ H ₂₅ NO ₄ : 416.1856, found: 416.1861.

< Example 23> methyl 2- (5- (2- (3- Chlorophenoxy ) Ethoxy ) -1H-indol-3-yl) acetate

The procedure of Example 1 was repeated except for using 2- (3-chlorophenoxy) ethylmethanesulfonate to obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.10 (NH, br s), 7.22 (1H, d, J = 8.8 Hz), 7.20 (1H, dd, J = 8.4, 8.0 Hz), 7.10 (2H, d (1H, dd, J = 2.0 Hz), 6.93-6.98 (2H, m), 6.89 (1H, dd, J = 8.8,2.4Hz) m), 3.73 (2 H, s), 3.69 (3 H, s);

¹³ C NMR (100 MHz, CDCl ₃ ) 隆 172.5, 159.5, 153.0, 134.8, 131.6, 130.2, 127.6, 124.0, 121.1, 115.1, 113.3, 113.1, 112.0, 108.1, 102.3, 67.3, 67.0. 52.0, 31.2;

IR (neat, cm- ¹ ) 3404, 2950, 2875, 1732, 1594, 1482, 1454, 1249, 1212, 1073.

< Example 24> 2- (5- (2- (3- Chlorophenoxy ) Ethoxy ) -LH-indol-3-yl) Acetic Acid's Produce

The procedure of Example 3 was repeated except for using methyl 2- (5- (2- (3-chlorophenoxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 23 To obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.24 (1H, d, J = 8.8 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.14 (1H, s), 7.00 (1H, t, J = Dd, J = 8.0, 2.0, 0.8 Hz), 6.90 (1H, dd, J = 8.0, 2.4 Hz), 6.81 4H, m), 3.69 (2H, s);

¹³ C NMR (100 MHz, CDCl ₃ )? 159.8, 152.5, 134.5, 132.1, 130.1, 127.6, 124.1, 120.5, 114.6, 112.8, 111.9, 111.6, 107.7, 101.7, 67.3, 67.0, 47.8;

IR (KBr pellet, cm ^-1 ) 3383, 3068, 2949, 2933, 1696, 1675, 1593, 1487, 1453, 1249, 1074, 964;

HRMS-ESI [M + H] + calcd for C 18 H 16 ClNO 4: 346.0841, found: 346.0843.

< Example 25> methyl 2- (1- benzyl -5- (2- (3- Chlorophenoxy ) Ethoxy ) -1H-indol-3-yl) acetate

The same procedure as in Example 2 was repeated except for using methyl 2- (5- (2- (3-chlorophenoxy) ethoxy) -1H-indol-3-yl) acetate obtained in Example 23 To obtain the target compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.24-7.36 (4H, m), 7.19 (1H, t, J = 8.0 Hz), 7.09-7.14 (4H, m), 6.97 (1H, dd, J = 2.4 (2H, s), 3.32 (2H, s), 2.32 (2H, s) , 3.69 (3 H, s);

^{13 C NMR (100 MHz, CDCl} 3) δ 172.4, 159.5, 134.8, 132.1, 130.2, 128.8, 128.2, 127.9, 127.6, 126.8, 121.1, 115.1, 113.3, 112.8, 110.7, 107.0, 102.5, 67.3, 67.0, 52.0 , 50.2, 31.2;

IR (neat, cm ^-1 ) 3031, 2949, 1735, 1594, 1483, 1454, 1249, 1223, 1072, 958.

< Example 26> 2- (1- benzyl -5- (2- (3- Chlorophenoxy ) Ethoxy ) -LH-indol-3-yl) Acetic Manufacture of acid

The same procedure as in Example 3 was repeated except for using methyl 2- (1-benzyl-5- (2- (3-chlorophenoxy) ethoxy) -1 H-indol-3-yl) acetate obtained in Example 25. To give the desired compound.

¹ H NMR (400 MHz, CDCl ₃ )? 7.35 (1H, d, J = 8.4 Hz), 7.22-7.24 (3H, m), 7.15 m), 6.83 (1H, d, J = 8.8 Hz), 6.79 (1H, d, J = 7.2 Hz), 5.13 (2H, s), 4.23 (4H, m), 3.70 (2H, s);

¹³ C NMR (100 MHz, CDCl ₃ )? 159.5, 153.0, 137.4, 134.8, 130.2, 128.7, 128.1, 127.6, 126.7, 121.1, 115.1, 113.2, 112.9, 110.7, 102.3, 37.2, 66.9, 50.1;

IR (KBr pellet, cm-1) 3430, 3028, 2930, 1705, 1596, 1486, 1231, 962;

HRMS-ESI [M + H] ⁺ calcd for C ₂₅ H ₂₂ ClNO ₄ : 436.1310, found: 436.1319.

Table 1 below summarizes the chemical structures of the compounds prepared in Examples 1-26.

Example constitutional formula Example constitutional formula One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

< Experimental Example 1> (phenoxy) alkoxy-1 H-indole derivatives of PPAR?, PPAR? And PPAR?

In order to evaluate the activation of (phenoxy) alkoxy-1 H-indole derivatives according to the present invention against PPAR, the following experiment was conducted.

Kidney cells CV-1 cells were cultured in DMEM culture medium containing 5% carbon dioxide and 10% calf serum (FBS) at 37 ° C. For this experiment, 1.5 × 10 ⁵ cells per well were inoculated on a 48-well plate And cultured for 24 hours. Plasmid DNAs of PPARα (pCMX-mPPARa), PPARδ (pCMX-mPPARd) and PPARγ (pCMX-mPPARg) with reporter DNA (tk-PPREx3-luc) with luciferase activity were ligated with Lipofectamine LTX reagent and PLUS reagent Gt; 37 C < / RTI > for 6 hours. In order to normalize the transfection rate, the plasmids were transformed with β-galactosidase plasmids. DMSO as a solvent at a concentration of 30 μM was diluted to a concentration of 0.001, 0.01, 0.1, 1, and 10 μM using the culture medium, and the cells were treated with 400 μL of each of them in a cell culture system for 40 hours, The culture medium was removed, and 50 μL of the cell lysis buffer was added and the cells were lysed while shaking for 20 minutes. 20 μL of the 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 cell lysis was measured using a Luciferase assay system (Promega Corp., Madison, Wis.), And the activity of? -Galactosidase was measured by absorbance at 410 nm using an ELISA plate reader . The data indicated relative luciferase activity divided by? -Galactosidase activity. As a negative control, 0.1% DMSO was used. As a positive control, 1 μM of PPARα agonist GW7647, 1 μM of PPARγ agonist rosiglitazone and 0.1 μM of PPARδ agonist GW0742 were used, respectively. Experimental results are expressed as% Max value representing relative value of the maximum value of the positive control group, and it is shown in Table 2 below. The% Max value is a value calculated by the following equation (1).

[Equation 1]

% Max = 100 x (sample activity - negative control activity) / (positive control activity - negative control activity)

Example
% Max mPPAR? (10? M) mPPAR? (10 μM) mPPAR? (10? M) 3 48.4 30.8 79.5 5 51.7 27.3 89.5 7 35.8 ± 9.0 104.4 ± 4.2 71.1 + - 11.4 8 37.9 ± 6.4 120.1 ± 13.1 65.2 ± 13.0 10 41.2 ± 11.8 91.7 ± 8.4 53.3 ± 15.7 12 18.9 ± 2.1 92.6 ± 9.0 93.6 ± 8.6 14 18.9 ± 9.0 99.4 ± 14.9 89.5 ± 3.8 16 19.0 ± 5.6 83.7 ± 13.0 94.7 ± 11.8 17 4.1 1.4 1.0 18 21.6 NA 5.8 20 21.8 ± 3.2 31.3 ± 4.3 27.9 ± 7.3 22 10.9 ± 4.8 36.5 ± 4.6 13.2 ± 5.7 24 15.5 ± 3.6 16.8 ± 2.4 16.2 ± 8.9 26 15.3 ± 4.3 23.6 ± 3.8 13.7 ± 3.7

In Table 2, NA means not active.

As shown in Table 1,

It can be seen that the example compounds according to the invention activate PPAR [alpha], PPAR [gamma] and PPAR [delta]. The compounds of Examples 3 and 4 exhibited a% Max value of at least 50 with respect to PPAR ?, confirming that PPAR? It was also found that the compounds of Examples 7, 8, 10, 12, 14 and 16 exhibit a% Max value of 50 or more for PPAR gamma and PPAR delta, thereby excellently activating PPAR gamma and PPAR delta simultaneously. 7 and 8 compounds showed PPARγ activation with a% Max value of 100 or more, and they were found to activate PPARγ and PPARδ at the same time.

Therefore, it has excellent ability of activating PPAR?, PPAR? And PPAR? Represented by Chemical Formula 1 according to the present invention. Therefore, it can be used as a PPAR agonist for the treatment of obesity, diabetes, hyperlipemia, hypertension, hyperinsulinemia, fatty liver, hyperlipemia, hypercholesterolemia, Metabolic diseases such as neutropenia, syndrome X, endothelial dysfunction and dyslipidemia; Cardiovascular diseases such as atherosclerosis, heart failure, myocardial infarction, hypertension, thrombosis, precoagulant state, and atherosclerosis; Colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibroid tumor, brain tumor, kidney cancer, bladder cancer, liver cancer, thymus cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, And PPAR? -Related diseases such as cancer and inflammation.

< Formulation example 1> Sanje Produce

2 g of the compound represented by the general formula (1)

Lactose 1g

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example 2> Preparation of tablets

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example 3> Preparation of capsules

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example 4> Preparation of injection

100 mg of the compound represented by the formula (1)

180 mg mannitol

Na ₂ HPO ₄ .2H ₂ O 26 mg

2974 mg of distilled water

According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

&Lt; Formulation Example 5 > Preparation of health food

The compound represented by the formula (1)

Vitamin mixture quantity

Vitamin A acetate 70 mg

Vitamin E 1.0mg

0.13mg of vitamin

0.15 mg of vitamin B2

Vitamin B6 0.5mg

Vitamin B12 0.2mg

Vitamin C 10mg

Biotin 10mg

Nicotinic acid amide 1.7 mg

Folic acid 50mg

Calcium pantothenate 0.5mg

Mineral mixture quantity

1.75 mg ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Calcium phosphate diphosphate 55 mg

Potassium citrate 90mg

Calcium carbonate 100 mg

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

Claims

1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

(Wherein, in Formula 1, any one of R ₁ and R ₂ is hydrogen,
When R ¹ is hydrogen, R ² is an unsubstituted or substituted straight-chain or branched C _6-8 aryl C _1-3 alkoxy, and the substitution of the substituted straight or branched C _6-8 aryl C _1-3 alkoxy The substituted C _6-8 aryl may be substituted with one or more substituents selected from the group consisting of halogen and straight or branched C _1-3 alkyl, and R ³ is hydrogen; Unsubstituted or substituted allyl; Or unsubstituted straight or branched C _6-8 arylC _1-3 alkyl; and said substituted allyl may be substituted with one or more substituents selected from the group consisting of halogen and straight or branched C _1-3 alkyl Have;
When R ² is hydrogen, R ¹ is an unsubstituted or substituted straight-chain or branched C _6-8 aryl C _1-3 alkoxy, the substitution of the substituted straight or branched C _6-8 aryl C _1-3 alkoxy The substituted C _6-8 aryl may be substituted with one or more substituents selected from the group consisting of halogen and C _1-3 alkyl of straight or branched chain and R ³ is unsubstituted or substituted allyl, And straight or branched C _1-3 alkyl; and R < 3 >
R ⁴ is hydrogen or straight or branched C _1-5 alkyl; And
and n is an integer of 2-4.

The method according to claim 1,
When R < ¹ ^> is hydrogen, R < ² ^> is an unsubstituted or substituted straight chain or branched phenyl _C1-3 alkoxy and substituted phenyl of the substituted straight or branched phenyl _C1-3 alkoxy is chloro and methyl And R < ³ > is hydrogen; Unsubstituted or substituted allyl; Or unsubstituted straight or branched C _6-8 arylC _1-3 alkyl; and said substituted allyl may be substituted with one or more substituents selected from the group consisting of methyl, ethyl and propyl;
When R ² is hydrogen, R ¹ is an unsubstituted or substituted straight chain or branched phenyl C _1-3 alkoxy and the substituted phenyl of the substituted straight or branched phenyl C _1-3 alkoxy is chloro and methyl And R ³ is unsubstituted or substituted allyl, said substituted allyl may be substituted with one or more substituents selected from the group consisting of methyl, ethyl and propyl;
R < ⁴ > is hydrogen or straight or branched C _1-3 alkyl; And
and n is 2 or 3. < RTI ID = 0.0 > 25. < / RTI >

The method according to claim 1,
When R < ¹ ^> is hydrogen, R < ^{2 &}

or

, R < ³ > is hydrogen,

,

or

ego;
If R ² is hydrogen, R ¹ is

or

And R < ³ >

or

ego;
R < ⁴ > is hydrogen or methyl; And
and n is 2 or 3. < RTI ID = 0.0 > 25. < / RTI >

The method according to claim 1,
Wherein the compound represented by the formula (1) is any one selected from the group consisting of the following compounds: or a pharmaceutically acceptable salt thereof:
(6) Methyl 2- (1-allyl-5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;
(7) 2- (1-Allyl-5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;
(8) Synthesis of 2- (5- (3- (3- (4-chlorobenzyloxy) phenoxy) propoxy) -1- (3-methylbut- Tic acid;
(9) Methyl 2- (5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;
(10) 2- (5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;
(11) Methyl 2- (1-benzyl-5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;
(12) 2- (1-Benzyl-5- (3- (4- (4-methylbenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;
(13) Methyl 2- (5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1H-indol-3-yl) acetate;
(14) 2- (5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid;
(15) Methyl 2- (1-benzyl-5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetate; And
(16) 2- (l-Benzyl-5- (3- (4- (4-chlorobenzyloxy) phenoxy) propoxy) -1 H-indol-3-yl) acetic acid.

As shown in Scheme 1 below,
A process for preparing a compound represented by the formula (1), comprising the step of reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1)
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
L ¹ is halogen, mesylate (-OMs), tosylate (-OTs), bromosylate (-OBs) or nosylate (-ONs); And
R ¹ , R ² , R ³ , R ⁴ and n are the same as defined in the formula (1).

A pharmaceutical composition for preventing or treating a disease comprising any one selected from the group consisting of obesity, diabetes mellitus and dyslipidemia comprising the compound represented by the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

delete

A health functional food composition for preventing or ameliorating a disease comprising any one selected from the group consisting of obesity, diabetes and dyslipidemia, which comprises the compound represented by the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.