KR100847780B1 - 2-ethoxypropionic acid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and agent of prevention and treatment for diabetes containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a 2-ethoxypropionic acid derivative represented by the following Chemical Formula 1, 2 or 3, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and an agent for preventing and treating diabetes containing the same as an active ingredient, 2-ethoxypropionic acid derivatives or pharmaceutically acceptable salts thereof may act usefully in preventing and treating diabetes more effectively by double acting on peroxisome proliferator-activated receptor (PPAR) α or γ receptors.

<Formula 1> <Formula 2> <Formula 3>

(In the above Chemical Formulas 1 to 3, X, Z, n, R ¹ and R ² are as defined in the specification)

2-ethoxypropionic acid, diabetes mellitus, PPAR

Description

2-ethoxypropionic acid derivatives or pharmaceutically acceptable salts thereof, preparation method about and agent of prevention and treatment for diabetes containing the same as an active ingredient}

The present invention relates to a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and an agent for preventing and treating diabetes containing the same as an active ingredient.

Diabetes is largely classified into insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes). Type 1 diabetes develops extreme hyperglycemia due to decreased insulin production due to damage or dysfunction of pancreatic beta cells, often leading to ketosis or ketoacidosis. Type 2 diabetes is known to be caused by insulin resistance, which is manifested by insulin secretion disorders, increased endogenous glucose production in the liver, and decreased glucose availability in peripheral insulin sensitive tissues. In either case, relative insulin deficiency occurs.

Diabetes has been recognized as a representative disease among many cultural diseases that are prevalent today with the development of modern civilization. In recent years, the incidence of diabetes mellitus has increased in Korea, and more than 5% of the total population has been reported as a diabetic patient. As one of the 10 leading causes of death worldwide, the seriousness and sequelae of the condition, If it lasts for a long time, in addition to an increase in blood glucose, blood lipid concentrations increase, causing cardiovascular diseases such as arteriosclerosis and coronary heart disease, diabetic kidney and retinal diseases, etc., which is a serious human problem. Therefore, the development of the therapeutic agent is urgently needed.

On the other hand, the peroxisome proliferator-activated receptor (hereinafter referred to as "PPAR") is a receptor included in the nuclear hormone receptor class and is a transcription factor acting by a ligand. The PPAR receptors exist in three isoforms, PPARα, PPARγ and PPARδ, which are known to be encoded by different genes (Motojima K, Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Cell Struct Funct . 1993 Oct. 18 (5), 267-277).

Different isoforms of PPAR receptors have different tissue distributions and regulate different physiological functions. PPAR receptors play an important role in the regulation of many genes in many aspects, and the products of these genes are critically involved directly or indirectly in lipid and carbohydrate metabolism. For example, it is known that the PPARα receptor plays an important role in fatty acid catabolism or lipid protein metabolism in the liver, and PPARγ plays a crucial role in regulating adipocyte differentiation. These PPARα / γ receptors are also involved in the regulation of many other physiological processes not directly related to carbohydrate or lipid metabolism. The activity of these PPARα / γ receptors can be modulated by various fatty acids, fatty acid derivatives and synthetic compounds with varying amounts.

Recently, various studies have been conducted to combine the aforementioned PPARα and PPARγ with diabetes treatment. In particular, PPARα, which is involved in maintaining homeostasis of fat metabolism through fatty acid degradation, and PPARγ as a target receptor for TZD (thiazolidinedione) -based drugs that reduce insulin resistance to treat diabetes, have attracted much attention. Type 2 diabetes, which is caused by increased insulin resistance and a decreased role of pancreatic β cells, is known to increase the risk of metabolic disorders associated with fat metabolism in patients (Porte, D. Jr., et. al., Science 1996 , 27, 699-700).

Therefore, the development of a substance capable of acting not only on PPARα but also on PPARγ, that is, PPARα / γ dual agent, has great potential as a new concept of diabetes treatment (Sauerberg, P., et. Al, J. Med . Chem. 2002 , 45, 789-804; Etgen, GJ, et.al., Diabetes 2002 , 51, 1083-1087; Henke, BR, J. Med . Chem . 2004 , 47, 4118-4127; Brooks, DA, et. Al., J. Med . Chem . 2001 , 44, 2061-2064; Lohray, BB, et. Al., J. Med . Chem . 2001 , 44, 2675-2678; Ebdrup, S., et al., J. Med . Chem . 2003 , 46, 1306-1317; Xu, Y., et. al., J. Med . Chem . 2004 , 47, 2422-2425; Koyama, H., et. al. ., J. Med Chem 2004, 47 , 3255-3263;.. Takamura, M., et al, Bioorg Med Chem 2004, 12, 2419-2439;...... Murakami, K., et al,. Diabetes 1998, 47, 1841-1847;. ... Liu, KG, et al, Bioorg Med Chem Lett 2001, 11, 2385-2388;...... Willson, TM, et al, J. Med Chem 2000 , 43, 527-550).

Accordingly, the present inventors perform molecular structure modeling to find a compound that acts as a PPAR α / γ dual agent to improve diabetes and through this, designs and synthesizes a 2-ethoxypropionic acid derivative having a new structure to complete the present invention. It was.

It is an object of the present invention to provide a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention to provide a method for producing the 2-ethoxypropionic acid derivative.

Still another object of the present invention is to provide a preventive and therapeutic agent for diabetes containing the 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and an agent for preventing and treating diabetes containing the same as an active ingredient.

It will be described in detail below.

First, the present invention provides a 2-ethoxypropionic acid derivative represented by the following Chemical Formula 1, 2 or 3.

In Chemical Formula 1, 2 or 3,

X is hydrogen; halogen; C ₁ -C ₄ alkyl which may be unsubstituted or substituted with one or more substituents; C ₅ -C ₇ aryl which may be unsubstituted or substituted with one or more substituents; Hydroxy; C ₁ to C ₅ alkoxy which may be unsubstituted or substituted with one or more substituents; Or C ₁ to C ₅ alkylsulfonyl which may be unsubstituted or substituted with one or more substituents, wherein X may be substituted at any one or two or more of the ortho, meta or para positions of the aromatic ring,

,

또는

이고, 상기 Z는 방향족 고리의 메타 또는 파라 위치에 치환될 수 있으며,Z is

,

or

Z may be substituted in the meta or para position of the aromatic ring,

인 경우 1 내지 5의 정수이고, 상기 Z가

인 경우 0 내지 5의 정수이고, Z가

인 경우 0 내지 5의 정수이며,n is the Z

Is an integer of 1 to 5, wherein Z is

When is an integer of 0 to 5, Z is

Is an integer from 0 to 5,

R ¹ and R ² are each hydrogen or C ₁ -C ₄ alkyl which may be unsubstituted or substituted with one or more substituents.

Preferably,

X is hydrogen; Fluoro; Chloro; Bromo; Iodo; t-butyl; Trifluoromethyl; Phenyl; Hydroxy; Methoxy; Trifluoromethoxy; Or methanesulfonyloxy, wherein X is substituted at any one or two or more of the ortho, meta or para positions of the aromatic ring,

,

또는

이고, 상기 Z는 방향족 고리의 메타 또는 파라 위치에 치환될 수 있으며,Z is

,

or

Z may be substituted in the meta or para position of the aromatic ring,

인 경우 1 내지 3의 정수이고, 상기 Z가

인 경우 0 내지 2의 정수이고, Z가

인 경우 0이며,n is the Z

Is an integer of 1 to 3, wherein Z is

When is an integer of 0 to 2, Z is

If is 0,

R ¹ and R ² Are hydrogen, methyl or ethyl, respectively.

In Chemical Formula 1, 2 or 3 according to the present invention,

"Alkyl" includes straight-chain or branched alkyl, wherein "when X, R ₁ or R ₂ is substituted with one or more substituents" independently or optionally halogen; C ₁ -C ₁₀ alkyl; C ₁ -C ₁₀ haloalkyl; C ₁ -C ₁₀ heteroalkyl; C ₃ -C ₇ cycloalkyl; 5 to 10 membered heterocycloalkyl; C ₅ -C ₇ aryl; 5 to 10 membered heteroaryl; C ₅ -C ₇ aryl C ₁ -C ₁₀ alkyl; 5 to 10 membered heteroaryl C ₁ to C ₁₀ alkyl; Hydroxy; C ₁ -C ₁₀ alkoxy; C ₃ -C ₇ cycloalkyloxy; 5-10 membered heterocyclo C ₁ -C ₁₀ alkyloxy; C ₅ -C ₇ aryloxy; 5 to 10 membered heteroaryloxy; C ₁ -C ₁₀ alkoxy C ₁ -C ₁₀ alkyl; C ₁ -C ₁₀ alkoxyC ₅ -C ₇ aryl; C ₁ -C ₁₀ alkoxyheteroaryl; C ₅ -C ₇ aryl C ₁ -C ₁₀ alkyloxy; Amino; C ₁ -C ₁₀ alkylamino; Acylamino; C ₅ -C ₇ arylamino; Amino C ₁ -C ₁₀ alkyl; Sulfonyl; C ₁ -C ₁₀ alkylsulfonyl; C ₅ -C ₇ arylsulfonyl; C ₅ -C ₇ arylsulfinyl; Aminosulfonyl; Cyano; C ₁ -C ₁₀ alkylcyano; C ₅ -C ₇ arylcyano; Cyano C ₁ -C ₁₀ alkyl; Means can be substituted with a substituent, such as cyano C ₅ ~ C ₇ aryl.

Preferred examples of the ethoxypropionic acid derivatives of the general formula (1), (2) or (3) according to the present invention are as follows.

rac- 3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - ethoxy-3- (3- (4,5-dihydro-5-phenyl-isoxazole-3-yl) phenyl) 2-propionic acid;

(S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

ethoxy-3- (4- (5- (4-methanesulfonyloxy-phenyl) -4,5-dihydro-isoxazole-3-yl) phenyl) propionic acid in 2 - rac;

(S) -2-ethoxy-3- (3- (5- (4-methanesulfonyloxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-methanesulfonyloxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

ethoxy-3- (4- (5- (4-trifluoromethyl-phenyl) -4,5-dihydro-isoxazole-3-yl) phenyl) propionic acid in 2 - rac;

(S) -2-ethoxy-3- (3- (5- (4-trifluoromethylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-trifluoromethylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid;

rac - ethoxy-3- (3- (4,5-dihydro-5-phenethyl-isoxazole-3-yl) phenyl) 2-propionic acid;

(S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenethylisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenethylisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid;

rac - 3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid;

(S) -3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid;

(R) -3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac - 2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid;

rac - 3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(S) -3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

(R) -3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid;

rac -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid;

(S) -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid;

(R) -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid.

The 2-ethoxypropionic acid derivatives of Formula 1, 2 or 3 according to the present invention include pharmaceutically acceptable salts thereof, hydrates and solvates that can be prepared therefrom.

As used in the present invention, when referring to a compound of the formula (1), (2) or (3), it is to be understood to include their pharmaceutically acceptable salts. Such pharmaceutically acceptable salts can be prepared by methods of preparing commonly used salts.

The 'pharmaceutically acceptable salts' refer to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc and the like. Especially ammonium, calcium, magnesium, potassium or sodium salts are preferred. Solid salts may exist in one or more crystal structures and may also exist in hydrate form. Salts derived from pharmaceutically acceptable non-toxic organic bases are primary, secondary or tertiary amines, substituted amines including naturally substituted amines, amine rings, or arginine, betaine, caffeine, choline, N, N '-Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, Such as hydravamin, isopropylamine, lysine, methylglucamine, popoline, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. Basic ion exchange resins.

When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. The acid is acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muk Acids, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid or tartaric acid are particularly preferred.

A hydrate of a compound of Formula 1, 2 or 3 of the present invention or a pharmaceutically acceptable salt thereof may be understood to comprise a stoichiometric or nonstoichiometric amount of water bound by noncovalent intermolecular forces. The hydrate may contain 1 equivalent or more, typically 1-5 equivalents of water. Such hydrates can be prepared by crystallizing a compound of formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

It can be understood that the solvates of the compounds of formula (1), (2) or (3) of the present invention, or pharmaceutically acceptable salts thereof, contain stoichiometric or nonstoichiometric amounts of solvent that are bound by non-covalent intermolecular forces. Preferred as the solvent include solvents which are volatile, non-toxic or suitable for administration to humans.

In order to achieve the other object of the present invention, the present invention provides a method for producing a 2-ethoxypropionic acid derivative of the formula (1), (2) or (3).

First, the present invention is represented by the following Scheme 1,

Coupling an optically separated compound of formula 4 (S) or formula 4 (R) as a starting material and a compound of formula 5 having a substituent of X in the presence of a base or an acid (step 1); And

After de-esterifying the coupling product (6 (S) or 6 (R)) prepared in step 1 in the presence of a base, acidification by addition of an acid (step 2) Provided is a method of preparing 2-ethoxypropionic acid derivative ( Preparation 1 ).

(Where X and n are as defined in Formulas 1 to 3, and the compounds of Formulas 2a and 3a are included in the 2-ethoxypropionic acid derivatives of the present invention)

Hereinafter, the manufacturing method 1 will be described in detail step by step.

Step 1

First, step 1 of Scheme 1 according to the present invention comprises a compound (5) having optically separated compound (4 (S)) or compound (4 (R)) and various substituents X as a starting material in the presence of a base or an acid. After dissolving in a suitable organic solvent, it is heated to reflux to prepare a coupling product of compound (6 (S)) or compound (6 (R)).

The starting material (4 (S) or 4 (R)) is a commercially available 3-acetylbenzonitrile ketone group protection reaction, nitrile group reduction reaction, acrylated, as shown in Preparation Example 1 to be described later Compound 19 prepared by carrying out the reaction, ketone group deprotection reaction and the like can be prepared by separating in optically pure form by the same method as Preparation Example 2.

Compound (5) having various substituents X reacting with the starting material (4 (S) or 4 (R)) is a commercially available aldehyde compound (30) having various substituents X, as shown in Preparation Example 4 below. ) Is converted to the alcohol compound (31), and then, an appropriate leaving group is introduced, a substitution reaction with hydrazine and addition of hydrochloric acid can be used in the form of a salt.

Preferably, the compound (5) includes O-benzylhydroxylamine hydrochloride, O- (4-fluorobenzyl) hydroxylamine hydrochloride, O- (4-chlorobenzyl) hydroxylamine hydrochloride, O- (4-bromobenzyl) hydroxylamine hydrochloride, O- (4-iodobenzyl) hydroxylamine hydrochloride, O- (4- (t-butyldimethylsilyloxy) benzyl) hydroxylamine hydrochloride, O- (4-methanesulfonyloxybenzyl) hydroxylamine hydrochloride, O- (4-methoxybenzyl) hydroxylamine hydrochloride, O- (4-trifluoromethylbenzyl) hydroxylamine hydrochloride, O -(4-tbutylbenzyl) hydroxylamine hydrochloride, O- (4-trifluoromethoxybenzyl) hydroxylamine hydrochloride, O- (phenethyl) hydroxylamine hydrochloride, O- (phenylpropoxy) Hyde Hydroxylyl hydrochloride and the like can be used.

Dichloromethane, chloroform, pyridine and the like may be used as the reaction solvent in step 1, pyridine, triethylamine, diisopropylethylamine, etc. may be used as a base, and acetic acid, paratoluenesulfonic acid, etc. may be used as the acid. It may be used, the coupling reaction is preferably performed for about 3 to 12 hours in the temperature range of 70 ~ 80 ℃.

Step 2

Step 2 according to the present invention is subjected to a de-esterification reaction by reacting the coupling product (6 (S) or 6 (R)) prepared in step 1 with a base in a suitable solvent, and then acidified by the addition of acid This step is to prepare a 2-ethoxypropionic acid derivative of formula (2) or (3).

As the base used in the deesterification reaction, a base such as lithium hydroxide (LiOH.H ₂ O), sodium hydroxide (NaOH.H ₂ O), or the like may be used. Preferably, lithium hydroxide is used. Can be used.

As the solvent for the de-esterification reaction, a single solvent of THF, water or methanol, or a mixed solvent of any one or both of these may be used, and preferably a mixed solvent of all of them (THF / water / methanol) Can be used in the ratio of 3: 1: 1.

The deesterification reaction is preferably carried out at room temperature for 2 to 12 hours.

In addition, the acidification reaction may be carried out by adding 2 N hydrochloric acid solution to the reaction solution after the de-esterification reaction to some extent, the de-esterification reaction is terminated by the addition of the hydrochloric acid solution.

In addition, the present invention is represented by the following scheme 2,

Coupling a compound of Formula 8, which is a starting material, to a compound of Formula 8 having a substituent of X in the presence of sodium hypochlorite (step 1);

De-esterifying the coupling product of Formula 9 prepared in step 1 in the presence of a base, and then acidifying by adding an acid (step 2);

Converting the compound of Formula 10 prepared in step 2 into a diastereomer, and then separating each of the diastereomers (step 3);

A mixture of compound (12 (S)) or compound (12 (R)) by hydrolyzing an amide group by adding an acid to a solvent in which the diastereomer (11 (S) or 11 (R)) separated in step 3 is dissolved. Obtaining a mixture of (step 4);

Reacting the mixture of the compound (12 (S)) or the mixture of the compound (12 (R)) hydrolyzed in step 4 with an alcohol in the presence of trimethylsilylchloride for esterification (step 5); And

De-esterified compound (13 (S)) or compound (13 (R)) esterified in step 5 in the presence of a base, and then acidified by the addition of an acid 2 Provided is a method (manufacturing method 2) of preparing an ethoxypropionic acid derivative.

(In the above scheme, X and n are as defined in Formulas 1-3, Formula 2b and Formula 3b are included in the 2-ethoxypropionic acid derivative of the present invention)

Hereinafter, the preparation method 2 will be described in detail step by step.

Step 1

First, Step 1 of Scheme 2 according to the present invention dissolves the styrene derivative of Formula 8 having various substituents X and the starting compound of Formula 7 in the presence of sodium hypochlorite in a suitable organic solvent, and then stirred at room temperature for a certain time. It is a step of preparing a coupling product of compound (9).

As the starting material (7) is shown in Preparation Example 3 to be described later, commercially available isophthalaldehyde (24) acrylate reaction, aldehyde group protection reaction, reduction reaction, aldehyde group deboration reaction, jade It may be prepared by carrying out the deepening reaction.

Compound (8) having various substituents X reacting with the starting material (7) is reacted with normal butyllithium by commercially available aldehyde compound (30) having various substituents X, as shown in Preparation Example 5 to be described later You can use what you have obtained.

Preferably, the compound (8) having the substituent X is styrene, 4-fluorostyrene, 3-chlorostyrene, 4-chlorostyrene, 4-bromostyrene, 4-iodostyrene, 4-methanesulfonyloxy Styrene, 4-methoxystyrene, 4-trifluoromethylstyrene, 4-t-butylstyrene, 1-allylbenzene, 1- (but-3-enyl) benzene, phenylacetylene and the like can be used.

The sodium hypochlorite serves as a halogenating agent of oxime in the coupling reaction.

Dichloromethane, chloroform, ethanol and the like may be used as the reaction solvent of step 1, and the coupling reaction is preferably performed at room temperature for 2 to 5 hours.

Step 2

In step 2 according to the present invention, the coupling product (9) prepared in step 1 is reacted with a base in a suitable solvent to perform a deesterification reaction, and then an acid is added to carry out an acidification reaction to give a compound (10) To prepare.

As the base used in the deesterification reaction, a base such as lithium hydroxide (LiOH.H ₂ O), sodium hydroxide (NaOH.H ₂ O), or the like may be used. Preferably, lithium hydroxide is used. Can be used.

As the solvent for the de-esterification reaction, a single solvent of THF, water or methanol, or a mixed solvent of any one or both of these may be used, and preferably a mixed solvent of all of them (THF / water / methanol) Can be used in the ratio of 3: 1: 1.

The deesterification reaction is preferably carried out at room temperature for 1 to 12 hours.

In addition, the acidification reaction may be carried out by adding 2 N hydrochloric acid solution to the reaction solution after the de-esterification reaction to some extent, the de-esterification reaction is terminated by the addition of the hydrochloric acid solution.

Step 3

Step 3 according to the present invention converts the compound (10) obtained in step 2 to the diastereoisomer into the compound (11 (S)) and the compound (11 (R)) using a reagent, and then converts them into their respective diastereomers. Separation into isomers.

The diastereomer synthesis method may be any method commonly known in the art without particular limitation, and such diastereomer is preferably N- (3-dimethylaminopropyl) -N'-ethyl as the conversion reagent. Carbodiimide hydrochloride (EDCI), R-(-)-2-phenylglycinol and 1-hydroxybenzotriazole hydrate (HOBT) were mixed and reacted, followed by addition of diisopropylethylamine at 0 ° C. After addition, it can manufacture by raising a temperature and making it react for about 12 hours. The diastereomers thus prepared may be separated into respective diastereomers by performing column chromatography through filtration and concentration steps.

Step 4

In step 4 according to the present invention, the concentration of the compound (12 (S)) in which the amide group is hydrolyzed by adding an acid to a solvent in which each diastereomer (11 (S) or 11 (R)) separated in step 3 is dissolved This step is to obtain a mixture or a concentrated mixture of compound (12 (R)).

The solvent may be a mixed solvent of dioxane / water, and preferably dioxane / water (10: 1).

The reaction is carried out by heating to reflux for 6 hours or more at 100 ℃, the concentrated mixture can be obtained by cooling the reaction solution to room temperature to complete the reaction, and then concentrated under reduced pressure.

Step 5

In step 5 according to the present invention, the concentrated mixture of the compound (12 (S)) or the concentrated mixture of the compound (12 (R)) hydrolyzed in step 4 is dissolved in alcohol and esters are added by adding trimethylsilyl chloride. This step is to perform the reaction.

Methanol, ethanol, and the like may be used as the alcohol, and the reaction is preferably performed by refluxing the reaction solution at 70 ° C. for 3 hours or more.

The trimethylsilyl chloride reacts with compound (12 (S)) or compound (12 (R)), and then the alcohol forms an ester bond with compound (12 (S)) or compound (12 (R)). To act as a leaving machine.

Step 6

Step 6 according to the present invention is subjected to a deesterification reaction by reacting the ester compound (13 (S) or 13 (R)) obtained in step 5 with a base, followed by acidification by adding an acid to the formula (2) Or preparing a 2-ethoxypropionic acid derivative of Formula 3.

The deesterification reaction and acidification reaction of step 6 may be carried out in the same manner as in step 2.

Furthermore, the present invention general formula (2) or in the preparation of 1-ethoxy-2-propionic acid derivative having an optically active substance of formula (3), the pure form of the compound (19) producing a starting material in Preparation 1, the optically according to Preparation Example 2 according to accept, without going through the process and performing a first manufacturing method or second production method of separating into, by performing only the steps 1 and 2, a method for producing a ethoxypropionate derivative in racemic form of formula 2 (Preparation method 3 ).

The present invention provides a prophylactic and therapeutic agent for diabetes containing the 2-ethoxypropionic acid derivative represented by Chemical Formulas 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

Peroxisome proliferator-activated receptors ("PPARs") are receptors included in the class of nuclear hormone receptors, which are transcription factors acting by ligands. The PPAR receptors exist in three isoforms, PPARα, PPARγ and PPARδ, which are known to be encoded by different genes. In particular, many studies have been reported on PPARα as a target receptor for PPARα, which is involved in maintaining homeostasis of fat metabolism through fatty acid degradation, and TZD (thiazolidinedione) family of drugs that reduce insulin resistance and treat diabetes. (Martin, G., et. Al., Atherosclerosis 1998 , 137 (Suppl.) S75-S80; Rosen, ED, et.al., J. Biol . Chem . 2001 , 276, 37731-37734; Lehmann, JM, et.al J. Biol . Chem . 1995 , 270, 12953-12956; Hulin, B., et. Al., Curr. Pharm . Des. 1996 , 2, 85-102; Ibrahimi, A., et. Al., Mol Pharmacol 1994, 46, 1070-1076; .. Brown, PJ, et al, J. Med Chem 1999, 42, 3785-3788;...... Chilcott, J., Clin Ther 2001, 23, 1792- 1823; Boyle, PJ, et. Al., Clin. Ther . 2002 , 24 (3), 378-396). Type 2 diabetes, which is caused by increased insulin resistance and a decreased role of pancreatic β cells, is known to increase the risk of metabolic disorders associated with fat metabolism in patients. Therefore, not only a substance that acts on PPARα but also a substance that can act on PPARγ, that is, a PPARα / γ dual agent, may be usefully used as a new concept for treating diabetes.

EC ₅₀ measurement of human PPARγ for 2-ethoxypropionic acid derivatives according to the present invention shows that it is used as a hypoglycemic agent in diabetic patients but exhibits superior or equivalent level of pharmacological activity than rosiglitazone having side effects of weight gain or edema. In addition, EC ₅₀ measurements on PPARα showed significantly better pharmacological activity than gemfibrozil, which can be used as a therapeutic agent for lipid metabolic disorders in diabetic patients. This is a result confirming that the derivative of the present invention can be used as a therapeutic agent for lipid metabolic disorders that have a blood sugar lowering effect of rosiglitazone and also have no improvement effect with rosiglitazone and also reduce weight gain and edema, which are side effects of rosiglitazone. It can be done (see Experimental Example 1 and Table 1).

In vivo experiments in type 2 diabetic mice (db / db mouse) showed better hypoglycemic effects at the same or lower doses than the previously developed PPARα / γ dual agonist, muraglita, and body weight as a side effect. The increase could confirm little result. This confirms that the derivative of the present invention has a superior hypoglycemic effect than the conventional PPARα / γ dual agonist while the side effect can be used as a therapeutic agent for less diabetes (see Experimental Example 2 and Table 2).

Therefore, the pharmaceutical composition containing a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for preventing and treating diabetes as well as preventing and treating diabetes.

Prophylactic and therapeutic agents containing 2-ethoxypropionic acid derivatives of the general formula (1), (2) or (3) according to the present invention as active ingredients can be used in the form of general pharmaceutical preparations. That is, the 2-ethoxypropionic acid derivatives of the present invention can be administered in various formulations, oral and parenteral, in actual clinical administration. In addition, when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used.

Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like. Such solid preparations include at least one excipient, for example, starch, in the 2-ethoxypropionic acid derivatives of Formulas 1 to 3 , Calcium carbonate (calcium carbonate), sucrose (sucrose) or lactose (lactose), gelatin and the like are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

In addition, liquid preparations for oral administration include suspending agents, liquid solutions, emulsions, and syrups, and various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. This may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

In addition, the dosage or dosage of the pharmaceutical composition containing the 2-ethoxypropionic acid derivative of the present invention as an active ingredient is determined by the weight, age, sex, health status, diet, administration time, administration method, excretion rate and disease of the patient. The range varies depending on the severity, and when taken, it is preferable to take 20 to 200 mg once or several times a day for adults.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

Preparation Example 1 Preparation of Ethyl 3- (3-acetylphenyl) -2-ethoxypropionate (19)

<Scheme 3>

Step 1: Preparation of 3- (2-methyl-1,3-dioxolan-2-yl) benzonitrile (15)

As shown in Scheme 3, commercially available 3-acetylbenzonitrile (14) (2 g, 13.78 mmol), ethylene glycol (1.54 ml, 27.56 mmol) and 4-toluenesulfonic acid (263 mg, 1.38 mmol) ) Was put into the reactor, a heating reflux apparatus connected with a Dean-stark apparatus was prepared, and benzene (50 ml) was added at room temperature, and then heated to reflux for 4 hours. The reaction was cooled to room temperature to terminate the reaction, concentrated under reduced pressure to remove benzene, and then the residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (15) (2.446 g, yield 94%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.77 (t, 1H, J = 1.61 Hz), 7.70 (td, 1H, J = 1.56, 7.88 Hz), 7.57 (td, 1H, J = 1.45, 7.70 Hz) , 7.43 (t, 1H, J = 7.83 Hz), 4.07-4.02 (m, 2H), 3.76-3.71 (m, 2H), 1.61 (s, 3H)

Step 2: Preparation of 3- (2-methyl-1,3-dioxolan-2-yl) benzaldehyde (16)

3- (2-methyl-1,3-dioxolan-2-yl) benzonitrile (15) (2.398 g, 12.67 mmol) obtained in step 1 was added to a reactor, and after argon substitution, anhydrous CH ₂ Cl ₂ (45 ml) was added. After cooling the reactor to −40 ° C., diisopropylbutylaluminum hydride (DIBAL-H) (1 M solution, 19.01 ml, 19.01 mmol) was slowly added dropwise and stirred for 3 hours. Methanol (0.5 ml) was added dropwise to the reaction solution to terminate the reaction, acidified with 2N hydrochloric acid, and the temperature of the reactor was gradually raised to room temperature and stirred for 1 hour. The reaction solution was diluted with CH ₂ Cl ₂ , washed with Rochelle's solution, saturated brine, and the filtrate was dried over anhydrous magnesium sulfate and filtered. The concentrated compound under reduced pressure was subjected to column chromatography with ethyl acetate: hexane (1:10) to obtain the title compound (16) (2.068 g, yield 85%).

¹ H-NMR (300 MHz, CDCl ₃ ) 10.01 (s, 1H), 7.99 (t, 1H, J = 1.74 Hz), 7.81 (td, 1H, J = 1.47, 7.61 Hz), 7.74 (td, 1H, J = 1.46, 7.70 Hz), 7.50 (t, 1H, J = 7.70 Hz), 4.08-4.03 (m, 2H), 3.78-3.74 (m, 2H), 1.65 (s, 3H)

Step 3: Preparation of ethyl 2-ethoxy-3- (3- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (17)

3- (2-methyl-1,3-dioxolan-2-yl) benzaldehyde (16) (10.220 g, 53.17 mmol) and ethoxy ethoxycarbonylmethyl-triphenylphosphonium chloride obtained in step 2 ( 27.363 g, 63.80 mmol) were placed in a reactor and substituted with argon inside, followed by addition of anhydrous CH ₂ Cl ₂ (100 ml). After the reactor was cooled to 0 ° C., tetramethylguanidine (10.01 ml, 79.76 mmol) was slowly added dropwise to the reaction solution, and the temperature was raised to room temperature and stirred for 12 hours. The reaction solution was diluted with CH ₂ Cl ₂ , washed with saturated sodium bicarbonate solution and saturated brine, and the filtrate was dried over anhydrous magnesium sulfate and filtered. The concentrated compound under reduced pressure was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (17) (14.963 g, yield 92%).

¹ H-NMR (E / Z mixture of isomer, 300 MHz, CDCl ₃ ) 7.89 (bs, 1H), 7.73-7.71 (m, 1H), 7.50-7.30 (m, 2H), 6.98 (s, 1H), 4.28 (q, 2H, J = 7.08 Hz), 4.05-3.96 (m, 4H), 3.78-3.73 (m, 2H), 1.64 (s, 1H), 1.38 (t, 3H, J = 7.14 Hz), 1.35 (t, 3H, J = 7.14 Hz)

Step 4: Preparation of ethyl 2-ethoxy-3- (3- (2-methyl-1,3-dioxolan-2-yl) phenyl) propionate (18)

Ethyl 2-ethoxy-3- (3- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (17) (14.960 g, 48.83 mmol) obtained in step 3 was added to the reactor. Methanol (100 ml) was added. 10% palladium / activated carbon was added to the reaction solution, and the inside was replaced with hydrogen, followed by stirring at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate and filtered through celite, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (18) (14.970 g, yield 99%).

¹ H-NMR (400 MHz, CDCl ₃₎ 7.35-7.31 (m, 2H), 7.24 (t, 1H, J = 7.6 Hz), 7.17-7.15 (m, 2H), 4.15 (q, 2H, J = 7.2 Hz), 4.03-3.98 (m, 3H), 3.76-3.73 (m, 2H), 3.61-3.57 (m, 1H), 3.34-3.30 (m, 1H), 3.00 (d, 2H, J = 6.8 Hz) , 1.62 (s, 3H), 1.21 (t, 3H, J = 7.2 Hz), 1.13 (t, 3H, J = 7.0 Hz)

Step 5: Preparation of ethyl 3- (3-acetylphenyl) -2-ethoxypropionate (19)

Ethyl 2-ethoxy-3- (3- (2-methyl-1,3-dioxolan-2-yl) phenyl) propionate (18) (14.970 g, 48.55 mmol) obtained in step 4 was added to the reactor. And THF (80 ml) was added. 2 N hydrochloric acid (40.78 ml) was added to the reaction solution, followed by stirring for 3 hours while heating to reflux at 65 ° C. After cooling to room temperature, saturated sodium bicarbonate solution was added to terminate the reaction and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (19) (10.540 g, yield 82%).

¹ H-NMR (300 MHz, CDCl ₃₎ 7.84-7.80 (m, 2H), 7.45 (d, 1H, J = 7.50 Hz), 7.37 (t, 1H, J = 7.50 Hz), 4.17 (q, 2H, J = 7.14 Hz), 4.00 (dd, 1H, J = 7.77, 5.40 Hz), 3.66-3.56 (m, 1H), 3.36-3.26 (m, 1H), 3.11-2.98 (m, 2H), 2.58 (s , 1H), 1.22 (t, 3H, J = 7.14 Hz), 1.13 (t, 3H, J = 6.96 Hz)

Production Example 2 to (S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) and (R) -methyl 3- (3-acetylphenyl) -2- Preparation of Toxypropionate (4 (R))

<Scheme 4>

Step 1: Preparation of 3- (3-acetylphenyl) -2-ethoxypropionic acid (20)

As shown in Scheme 2, ethyl 3- (3-acetylphenyl) -2-ethoxypropionate (19) obtained in Preparation Example 1 (2.040 g, 7.72 mmol) and LiOH.H ₂ O (970 mg, 23.16 mmol) was added to the reactor, and THF / water / methanol (3: 1: 1) (50 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction by adding 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (20) (1.810 g, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.85-7.81 (m, 2H), 7.47-7.36 (m, 2H), 4.09 (dd, 1H, J = 7.88, 4.22 Hz), 3.67-3.57 (m, 1H ), 3.46-3.36 (m, 1H), 3.18 (dd, 1H, J = 14.1, 4.20 Hz), 3.06 (dd, 1H, J = 14.1, 7.86 Hz), 2.59 (s, 3H), 1.15 (t, 3H, J = 7.05 Hz)

Step 2: (2S) -3- (3-acetylphenyl) -2-ethoxy-N-((R) -2-hydroxy-1-phenylethyl) propaneamide (21 (S)) and (2R) Preparation of 3- (3-acetylphenyl) -2-ethoxy-N-((R) -2-hydroxy-1-phenylethyl) propaneamide (21 (R))

3- (3-acetylphenyl) -2-ethoxypropionic acid (20) obtained in step 1 (9.970 g, 42.20 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) (8.899 g, 46.42 mmol), (R)-(-)-2-phenylglycinol (6.368 g, 46.42 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (6.273 g, 46.42 mmol ) Was placed in a reactor, and after argon substitution, anhydrous CH ₂ Cl ₂ (120 ml) was added. After the reactor was cooled to 0 ° C., diisopropylethylamine (8.09 ml, 46.42 mmol) was slowly added dropwise, and the reaction solution was heated to room temperature and stirred for 12 hours. The reaction was terminated by addition of saturated ammonium chloride solution, then diluted with CH ₂ Cl ₂ and washed with water. Next, after drying with anhydrous magnesium sulfate and filtration, the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (2: 1) to give the target compound (21 (S)) (4.604 g, 31% yield) and (21 (R)) (4.259 g, yield 28). %) Respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.85-7.82 (m, 2H), 7.47-7.06 (m, 7H), 5.00-4.94 (m, 1H), 4.00 (dd, 1H, J = 6.60, 4.02 Hz ), 3.73-3.63 (m, 2H), 3.48 (q, 2H, J = 6.90 Hz), 3.21 (dd, 1H, J = 14.1, 3.84 Hz), 3.06 (dd, 1H, J = 13.9, 6.57 Hz) , 2.59 (s, 3H), 1.11 (t, 3H, J = 7.05 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.80-7.75 (m, 2H), 7.39-7.17 (m, 5H), 7.02-6.99 (m, 2H), 5.01-4.96 (m, 1H), 4.04 (dd , 1H, J = 6.59, 3.86 Hz, 3.83 (d, 2H, J = 4.95 Hz), 3.63-3.48 (m, 2H), 3.16 (dd, 1H, J = 14.1, 3.84 Hz), 3.00 (dd, 1H, J = 14.1, 6.78 Hz), 2.46 (s, 3H), 1.18 (t, 3H, J = 6.96 Hz)

Step 3: (S) -3- (3-acetylphenyl) -2-ethoxypropionic acid (22 (S)) and (R) -3- (3-acetylphenyl) -2-ethoxypropionic acid (22 (R) Manufacture of))

(2S) -3- (3-acetylphenyl) -2-ethoxy-N-((R) -2-hydroxy-1-phenylethyl) propaneamide (21 (S)) obtained in step 2 (4.604) g, 12.95 mmol) was added to the reactor and 1,4-Dioxane / water (10: 1) (55 ml) was added and concentrated sulfuric acid (5 ml) was slowly added dropwise. The reaction solution was heated to reflux for 8 hours at 100 ℃, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a concentrated mixture (3.917 g) of the target compound (22 (S)).

Further, (2R) -3- (3-acetylphenyl) -2-ethoxy-N-((R) -2-hydroxy-1-phenylethyl) propaneamide (21 (R)) obtained in step 2 ( 4.259 g, 11.98 mmol) was added to the reactor and 1,4-Dioxane / water (10: 1) (55 ml) was added, followed by slowly dropwise addition of concentrated sulfuric acid (5 ml). The reaction solution was heated to reflux for 8 hours at 100 ℃, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a concentrated mixture (3.678 g) of the target compound (22 (R)).

Step 4: (S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) and (R) -methyl 3- (3-acetylphenyl) -2-ethoxyprop Preparation of Cypionate (4 (R))

The mixture (3.917 g) of (S) -3- (3-acetylphenyl) -2-ethoxypropionic acid (22 (S)) obtained in step 3 was added to the reactor, and methanol (50 ml) was added thereto. Methyl silyl chloride (4.93 ml, 38.85 mmol) was slowly added dropwise. The reaction solution was heated to reflux at 70 ° C. for 4 hours, and then saturated sodium bicarbonate solution was added to terminate the reaction. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (4 (S)) (2.374 g, two-step yield 73%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.83-7.80 (m, 2H), 7.45-7.34 (m, 2H), 4.02 (dd, 1H, J = 7.88, 5.12 Hz), 3.71 (s, 3H), 3.65-3.55 (m, 1H), 3.35-3.25 (m, 1H), 3.11-2.98 (m, 2H), 2.58 (s, 3H), 1.13 (t, 3H, J = 6.96 Hz)

The mixture (3.678 g) of (R) -3- (3-acetylphenyl) -2-ethoxypropionic acid (4 (R)) obtained in step 3 was added to the reactor, and methanol (50 ml) was added thereto. Methyl silyl chloride (4.56 ml, 35.94 mmol) was slowly added dropwise. The reaction solution was heated to reflux at 70 ° C. for 4 hours, and then saturated sodium bicarbonate solution was added to terminate the reaction. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the title compound (4 (R)) (2.157 g, 72% yield in two steps).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.83-7.80 (m, 2H), 7.45-7.34 (m, 2H), 4.02 (dd, 1H, J = 7.88, 5.12 Hz), 3.71 (s, 3H), 3.65-3.55 (m, 1H), 3.35-3.25 (m, 1H), 3.11- 2.98 (m, 2H), 2.58 (s, 3H), 1.13 (t, 3H, J = 7.05 Hz)

Preparation Example 3 Preparation of Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7)

Scheme 5

(Step 1) Preparation of ethyl 2-ethoxy-3- (3-formylphenyl) acrylate (25)

As shown in Scheme 5, commercially available isophthalaldehyde (24) (2.858 g, 21.31 mmol) and ethoxy ethoxycarbonylmethyl-triphenylphosphonium chloride (8.226 g, 19.18 mmol) were added to the reactor. After argon replacement, anhydrous CH 2 Cl 2 (40 ml) was added thereto. After the reactor was cooled to 0 ° C., tetramethylguanidine (4.01 ml, 31.97 mmol) was slowly added dropwise, and the reaction solution was heated to room temperature and stirred for 12 hours. The reaction solution was diluted with CH ₂ Cl ₂ , washed with saturated sodium hydrogen carbonate solution and saturated brine, and the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (25) (4.033 g, yield 85%).

¹ H-NMR (300 MHz, CDCl ₃ ) 10.01 (s, 1H), 8.29 (s, 1H), 8.01 (d, 1H, J = 7.68 Hz), 7.81 (d, 1H, J = 7.50 Hz), 7.51 (t, 1H, J = 7.68 Hz), 6.98 (s, 1H), 4.30 (q, 2H, J = 7.14 Hz), 4.05 (q, 2H, J = 6.96 Hz), 1.37 (t, 3H, J = 6.96 Hz), 1.37 (t, 3H, J = 6.96 Hz)

Step 2: Preparation of ethyl 3- (3- (1,3-dioxolan-2-yl) phenyl) -2-ethoxyacrylate (26)

Ethyl 2-ethoxy-3- (3-formylphenyl) acrylate (25) obtained in step 1 (4.033 g, 16.24 mmol), ethylene glycol (1.81 ml, 32.48 mmol), and 4-toluenesulfonic acid (308 mg , 1.62 mmol) was added to the reactor, and a heating reflux apparatus having a Dean-stark device connected thereto was prepared, benzene (50 ml) was added at room temperature, and heated to reflux for 12 hours. The reaction solution was cooled to room temperature to terminate the reaction, concentrated under reduced pressure to remove benzene, and the residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and water. Next, the mixture was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a concentrated mixture (4.750 g) of the target compound (26).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.89 (s, 1H), 7.80-7.76 (m, 1H), 7.42-7.33 (m, 2H), 6.98 (s, 1H), 4.28 (q, 2H, J = 7.14 Hz), 4.16-4.00 (m, 4H), 3.98 (q, 2H, J = 7.14 Hz), 1.35 (t, 3H, J = 6.96 Hz), 1.35 (t, 3H, J = 6.96 Hz)

Step 3: Preparation of ethyl 3- (3- (1,3-dioxolan-2-yl) phenyl) -2-ethoxypropionate (27)

A mixture (4.750 g, 48.83 mmol) of ethyl 3- (3- (1,3-dioxolan-2-yl) phenyl) -2-ethoxyacrylate (26) obtained in step 2 was added to a reactor and THF ( 35 ml) was added. A catalytic amount of 10% palladium / activated carbon was added, and the inside was replaced with hydrogen, followed by stirring at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate and filtered through celite, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (27) (4.735 g, two-step yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.76-7.73 (m, 1H), 7.53-7.41 (m, 1H), 7.35-7.18 (m, 2H), 5.77 (s, 1H), 4.20-3.96 (m , 6H), 3.72 (s, 1H), 3.64-3.53 (m, 1H), 3.35-3.25 (m, 1H), 3.09-2.94 (m, 2H), 1.20 (t, 3H, J = 6.96 Hz), 1.13 (t, 3H, J = 6.96 Hz)

(Step 4) Preparation of ethyl 2-ethoxy-3- (3-formylphenyl) propionate (28)

Ethyl 3- (3- (1,3-dioxolan-2-yl) phenyl) -2-ethoxypropionate (27) (4.735 g, 16.09 mmol) obtained in step 3 was added to the reactor and THF (25 ml). ) Was added. 2 N hydrochloric acid (5 ml) was added, followed by stirring for 1 hour while heating to reflux at 65 ° C. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was added to terminate the reaction and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (28) (3.043 g, yield 75%).

¹ H-NMR (300 MHz, CDCl ₃ ) 9.98 (s, 1H), 7.76-7.73 (m, 2H), 7.53-7.41 (m, 2H), 4.16 (q, 2H, J = 6.96 Hz), 4.04- 3.99 (m, 1H), 3.67-3.57 (m, 1H), 3.37-3.27 (m, 1H), 3.13-3.01 (m, 2H), 1.22 (t, 3H, J = 6.96 Hz), 1.13 (t, 3H, J = 6.96 Hz)

Step 5: Preparation of ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7)

Ethyl 2-ethoxy-3- (3-formylphenyl) propionate (28) (3.043 g, 12.16 mmol) and hydroxylamine hydrochloride (1.014 g, 14.59 mmol) obtained in step 4 were added to a reactor and pyridine (25 ml) was added. It was stirred for 5 hours while heating to reflux at 75 ℃. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (7) (3.136 g, yield 97%).

¹ H-NMR (300 MHz, CDCl ₃ ) 8.10 (s, 1H), 7.96-7.42 (m, 2H), 7.32-7.27 (m, 1H), 4.15 (q, 2H, J = 6.96 Hz), 4.02- 3.97 (m, 1H), 3.65-3.55 (m, 1H), 3.37-3.27 (m, 1H), 3.07-2.94 (m, 2H), 1.20 (t, 3H, J = 6.96 Hz), 1.13 (t, 3H, J = 6.96 Hz)

Preparation Example 4 Preparation of O-benzyl-hydroxylamine hydrochloride derivatives (5)

<Scheme 6>

(Wherein X and n are as defined in Chemical Formulas 1 to 3)

Step 1: Preparation of Benzyl Alcohol Derivative (31)

As shown in Scheme 6, commercially available benzaldehyde 30 was placed in a reactor and methanol was added. After the reactor was cooled to 0 ° C., sodium borohydride (1.1 equivalents) was slowly added, and the temperature of the reaction solution was raised to room temperature and stirred for 1 to 2 hours. 2N hydrochloric acid was added to the reaction solution to terminate the reaction, and concentrated under reduced pressure. The residue was diluted with diethyl ether and washed with water, and the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (31) (yield 85 to 99%).

Step 2: Preparation of 2- (benzyloxy) isoindolin-1,3-dione derivatives (32)

Benzyl alcohol (31), triphenylphosphine (1.1 equivalents) and N-hydroxyphthalimide (1.1 equivalents) obtained in step 1 were added to a reactor, argon was substituted therein, anhydrous THF was injected, and the reactor was zero. After cooling to 占 폚, diethylazodicarboxylate (DEAD) (1.2 equiv) was slowly added dropwise. The temperature of the reaction solution was raised to room temperature and stirred for 2-12 hours. Water was added to the reaction solution to terminate the reaction, concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (32) (yield 90 to 99%).

Step 3: Preparation of O-benzyl-hydroxylamine hydrochloride derivatives (5)

2- (benzyloxy) isoindolin-1,3-dione derivatives 32 obtained in step 2 were added to the reactor, acetonitrile was added, and hydrazine (1.1 equiv) was slowly added dropwise. The reaction solution was stirred at room temperature for 10 minutes to 1 hour. The reaction solution was filtered to remove solid precipitate, and diethyl ether and hydrochloric acid were added to the filtrate to obtain the target compound (5) (yield 10 to 99%) in the salt state.

Preparation Example 5 Preparation of Styrene Derivative (8)

Scheme 7

(Wherein X and n are as defined in Chemical Formulas 1 to 3)

Methyltriphenylphosphonium bromide (1.5 equivalents) was added to the reactor, argon was substituted for the inside, anhydrous THF was injected, and normal butyllithium (1.6 M solution, 1.3 equivalents) was slowly added dropwise. After raising the temperature of the reaction solution to room temperature and stirring for 2 hours, benzaldehyde 30, a starting material of Preparation Example 4, was dissolved in anhydrous THF and added to the reactor through a cannula. The reaction solution was stirred at room temperature for 1-2 hours, and the reaction was terminated by addition of saturated ammonium chloride solution and concentrated under reduced pressure. The residue was diluted with diethyl ether and washed with water, and the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1:10) to obtain the target compound (8) (yield 40 to 90%).

Example 1 (S) -3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid (2-1) and (R) -3- (3- ( (E) -1-Benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid (3-1)

Step 1: (S) -methyl 3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionate and (R) -methyl 3- (3-((E) Preparation of -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionate

(S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (33 mg, 0.132 mmol) and O-benzylhydroxylamine hydrochloride (25) obtained in Preparation Example 2 mg, 0.158 mmol) was added to the reactor and pyridine (3 ml) was added. It was stirred for 5 hours while heating to reflux at 75 ℃. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the (S) -oriented compound (34 mg, yield 72%).

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (46 mg, 0.184 mmol) and O-benzylhydroxylamine hydrochloride (35) obtained in Preparation Example 2 mg, 0.221 mmol) was added to the reactor and pyridine (3 ml) was added. The reaction solution was stirred for 1 hour while heating to reflux at 75 ℃. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the above-mentioned (R) -oriented compound (50 mg, yield 74%).

Step 2: (S) -3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid (2-1) and (R) -3- (3-((E ) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid (3-1)

(S) -methyl 3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionate (102 mg, 0.276 mmol) obtained in step 1 and LiOH.H ₂ O (35 mg, 0.828 mmol) was added to the reactor, THF / water / methanol (3: 1: 1) (10 ml) was added, followed by stirring at room temperature for 12 hours. After completion of the reaction by adding 2N hydrochloric acid to the reaction solution, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2-1) (94 mg, 99% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.42-7.21 (m, 7H), 5.22 (s, 2H), 4.08 (dd, 1H, J = 7.86, 4.02 Hz), 3.62-3.52 (m, 1H), 3.47-3.37 (m, 1H), 3.15 (dd, 1H, J = 14.1, 4.02 Hz), 2.99 (dd, 1H, J = 14.1, 7.88 Hz), 2.24 (s, 3H), 1.14 (t, 3H, J = 7.05 Hz)

(R) -methyl 3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionate (50 mg, 0.135 mmol) obtained in step 1 above and LiOH.H ₂ O (17 mg, 0.405 mmol) was added to the reactor, and THF / water / methanol (3: 1: 1) (10 ml) was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction by adding 2N hydrochloric acid to the reaction solution, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The target compound (3-1) (46 mg, yield 99%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.42-7.25 (m, 7H), 5.22 (s, 2H), 4.07 (dd, 1H, J = 8.06, 4.04 Hz), 3.64-3.54 (m, 1H), 3.45-3.35 (m, 1H), 3.14 (dd, 1H, J = 14.1, 4.02 Hz), 3.00 (dd, 1H, J = 14.0, 8.13 Hz), 2.24 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

Example 2 (S) -3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxy cipropionic acid (2-2) and (R)- Preparation of 3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-2)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (40 mg, 0.160 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-fluorobenzyl) hydroxylamine hydrochloride (34 mg, 0.192 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2 in the same manner as in step 1 of Example 1 (reaction time 4 hours) -Ethoxypropionate (32 mg, yield 54%) was obtained. The obtained compound (28 mg, 0.075 mmol) and LiOH.H ₂ O (7 mg, 0.150 mmol) were added to the reactor, and the target compound (2-2) was prepared in the same manner as in the step 2 of Example 1 (reaction time 12 hours). (27 mg, yield 99%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.49 (m, 2H), 7.39-7.21 (m, 4H), 7.06-7.00 (m, 2H), 5.17 (s, 2H), 4.08 (dd, 1H) , J = 7.89, 4.02 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.14 (dd, 1H, J = 14.1, 4.02 Hz), 3.00 (dd, 1H, J = 14.2 , 7.97 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J = 7.05 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (54 mg, 0.216 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-fluorobenzyl) hydroxylamine hydrochloride (46 mg, 0.259 mmol) was added to the reactor and pyridine (3 ml) was added. Then (R) -methyl 3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl)-in the same manner as in Step 1 of Example 1 (reaction time 8 hours). 2-Ethoxypropionate (40 mg, yield 50%) was obtained. The obtained compound (40 mg, 0.107 mmol) and LiOH.H ₂ O (13 mg, 0.321 mmol) were added to the reactor, and the target compound (3-2) was obtained in the same manner as in the step 2 of Example 1 (reaction time 12 hours). (33 mg, yield 87%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.48 (m, 2H), 7.39-7.22 (m, 4H), 7.06-7.00 (m, 2H), 5.17 (s, 2H), 4.07 (dd, 1H) , J = 8.07, 4.02 Hz), 3.64-3.54 (m, 1H), 3.45-3.35 (m, 1H), 3.14 (dd, 1H, J = 14.0, 4.11 Hz), 3.00 (dd, 1H, J = 14.1 , 8.07 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J = 6.95 Hz)

Example 3 (S) -3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-3) and (R) -3 Preparation of-(3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-3)

(S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (51 mg, 0.204 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-Chlorobenzyl) hydroxylamine hydrochloride (40 mg, 0.204 mmol) was added to the reactor and pyridine (3 ml) was added. Then (S) -methyl 3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 9 hours). Ethoxypropionate (19 mg, yield 24%) was obtained. The obtained compound (19 mg, 0.048 mmol) and LiOH.H ₂ O (6 mg, 0.144 mmol) were added to the reactor, and the target compound (2-3) was obtained in the same manner as in the step 2 of Example 1 (reaction time 5 hours). (16 mg, yield 89%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ): 7.51-7.47 (m, 2H), 7.35-7.22 (m, 6H), 5.18 (s, 2H), 4.07 (dd, 1H, J = 8.06, 4.04 Hz) , 3.64-3.54 (m, 1H), 3.45-3.35 (m, 1H), 3.14 (dd, 1H, J = 14.1, 4.04 Hz), 3.00 (dd, 1H, J = 14.1, 8.04 Hz), 2.23 (s , 3H), 1.14 (t, 3H, J = 6.96 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (46 mg, 0.184 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-Chlorobenzyl) hydroxylamine hydrochloride (35 mg, 0.259 mmol) was added to the reactor and pyridine (3 ml) was added. Then, (R) -methyl 3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 9 hours). Ethoxypropionate (15 mg, 21% yield) was obtained. The obtained compound (15 mg, 0.038 mmol) and LiOH.H ₂ O (5 mg, 0.114 mmol) were added to the reactor, and the target compound (3-3) was obtained in the same manner as in the step 2 of Example 1 (reaction time 5 hours). (14 mg, yield 94%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ): 7.51-7.48 (m, 2H), 7.35-7.25 (m, 6H), 5.18 (s, 2H), 4.07 (dd, 1H, J = 7.77, 3.93 Hz) , 3.61-3.53 (m, 1H), 3.46-3.38 (m, 1H), 3.14 (dd, 1H, J = 14.1, 4.20 Hz), 3.00 (dd, 1H, J = 14.1, 7.86 Hz), 2.23 (s , 3H), 1.14 (t, 3H, J = 6.96 Hz)

Example 4 (S) -3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-4) and (R)- Preparation of 3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-4)

(S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (55 mg, 0.220 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-bromobenzyl) hydroxylamine hydrochloride (63 mg, 0.264 mmol) was added to the reactor and pyridine (3 ml) was added. Subsequently, (S) -methyl 3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2 in the same manner as in Step 1 of Example 1 (reaction time 4 hours) -Ethoxypropionate (56 mg, yield 59%) was obtained. The obtained compound (56 mg, 0.129 mmol) and LiOH.H ₂ O (16 mg, 0.387 mmol) were added to the reactor, and the target compound (2-4) was obtained in the same manner as in the step 2 of Example 1 (reaction time 4 hours). (52 mg, yield 96%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.50-7.45 (m, 4H), 7.30-7.21 (m, 4H), 5.16 (s, 2H), 4.07 (dd, 1H, J = 7.86, 4.02 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.14 (dd, 1H, J = 14.0, 4.13 Hz), 3.00 (dd, 1H, J = 14.1, 7.86 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (52 mg, 0.208 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-bromobenzyl) hydroxylamine hydrochloride (60 mg, 0.250 mmol) was added to the reactor and pyridine (3 ml) was added. Then, (R) -methyl 3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2 in the same manner as in step 1 of Example 1 (reaction time 4 hours) -Ethoxypropionate (57 mg, yield 63%) was obtained. The obtained compound (57 mg, 0.131 mmol) and LiOH.H ₂ O (16 mg, 0.393 mmol) were added to the reactor, and the target compound (3-4) was prepared in the same manner as in the step 2 of Example 1 (reaction time 4 hours). (52 mg, yield 95%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.50-7.45 (m, 4H), 7.30-7.25 (m, 4H), 5.16 (s, 2H), 4.08 (dd, 1H, J = 7.80, 4.11 Hz), 3.60-3.52 (m, 1H), 3.47-3.39 (m, 1H), 3.15 (dd, 1H, J = 14.1, 3.84 Hz), 3.00 (dd, 1H, J = 14.1, 7.86 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J = 7.05 Hz)

Example 5 (S) -3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-5) and (R)- Preparation of 3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-5)

(S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (58 mg, 0.233 mmol) obtained in Preparation Example 2 and O- obtained in the same manner as in Preparation Example 4. (4-iodobenzyl) hydroxylamine hydrochloride (80 mg, 0.280 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2 in the same manner as in step 1 of Example 1 (reaction time 6 hours) -Ethoxypropionate (99 mg, yield 88%) was obtained. The obtained compound (41 mg, 0.085 mmol) and LiOH.H ₂ O (7 mg, 0.170 mmol) were added to the reactor, and the target compound (2-5) was prepared in the same manner as in Example 2 (Step 2). ) (39 mg, yield 98%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.68-7.65 (m, 2H), 7.51-7.48 (m, 2H), 7.34-7.22 (m, 2H), 7.15-7.12 (m, 2H), 5.15 (s , 2H), 4.06 (dd, 1H, J = 7.89, 4.02 Hz), 3.64-3.54 (m, 1H), 3.45-3.35 (m, 1H), 3.13 (dd, 1H, J = 13.9, 4.04 Hz), 2.99 (dd, 1H, J = 14.1, 7.88 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (26 mg, 0.103 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-iodobenzyl) hydroxylamine hydrochloride (35 mg, 0.123 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2 in the same manner as in Step 1 of Example 1 (reaction time 12 hours) -Ethoxypropionate (20 mg, yield 41%) was obtained. The obtained compound (19 mg, 0.039 mmol) and LiOH.H ₂ O (5 mg, 0.117 mmol) were added to the reactor, and the target compound (3-5) was prepared in the same manner as in Example 2 step 2 (reaction time 3 hours). ) (15 mg, yield 83%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.68-7.13 (m, 8H), 5.15 (s, 2H), 4.09 (br m, 1H), 3.57 (br m, 1H), 3.43 (br m, 1H) , 3.16-3.13 (br m, 1 H), 3.00 (br m, 1 H), 2.23 (s, 3 H), 1.14 (t, 3 H, J = 6.50 Hz)

Example 6 (S) -3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-6) and (R)- Preparation of 3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-6)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (76 mg, 0.303 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4- (t-butyldimethylsilyloxy) benzyl) hydroxylamine hydrochloride (105 mg, 0.363 mmol) was added to the reactor and pyridine (3 ml) was added. (S) -Methyl 3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 3 hours) Toxypropionate (98 mg, yield 67%) was obtained. The obtained compound (98 mg, 0.202 mmol) and LiOH.H ₂ O (25 mg, 0.606 mmol) were added to the reactor, and the target compound (2-6) was obtained in the same manner as in the step 2 of Example 1 (reaction time 4 hours). ) (72 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.49 (m, 2H), 7.31-7.19 (m, 4H), 6.82-6.79 (m, 2H), 5.13 (s, 2H), 4.08 (dd, 1H) , J = 7.89, 4.02 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.14 (dd, 1H, J = 13.9, 4.02 Hz), 3.00 (dd, 1H, J = 14.0 , 7.97 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J = 7.04 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (23 mg, 0.092 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4- (t-butyldimethylsilyloxy) benzyl) hydroxylamine hydrochloride (32 mg, 0.110 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2 in the same manner as in Step 1 of Example 1 (reaction time 3 hours) -Ethoxypropionate (28 mg, yield 64%) was obtained. The obtained compound (28 mg, 0.057 mmol) and LiOH.H ₂ O (7 mg, 0.171 mmol) were added to the reactor, and the target compound (3-6) was prepared in the same manner as in Example 2 (Step 2). ) (18 mg, yield 90%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.49 (m, 2H), 7.31-7.20 (m, 4H), 6.82-6.79 (m, 2H), 5.13 (s, 2H), 4.08 (dd, 1H) , J = 7.98, 3.93 Hz), 3.60-3.52 (m, 1H), 3.48-3.38 (m, 1H), 3.15 (dd, 1H, J = 14.1, 3.86 Hz), 3.00 (dd, 1H, J = 14.0 , 7.79 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J = 6.96 Hz)

Example 7 (S) -3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-7) and (R Preparation of) -3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-7)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (40 mg, 0.160 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-Methanesulfonyloxybenzyl) hydroxylamine hydrochloride (49 mg, 0.192 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 3 hours) 2-Ethoxypropionate (40 mg, yield 56%) was obtained. The obtained compound (40 mg, 0.089 mmol) and LiOH.H ₂ O (8 mg, 0.178 mmol) were added to the reactor, and the target compound (2-7) was obtained in the same manner as in Example 2 (Step 2). ) (38 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.43 (m, 4H), 7.30-7.22 (m, 4H), 5.21 (s, 2H), 4.07 (dd, 1H, J = 7.70, 4.22 Hz), 3.63-3.53 (m, 1H), 3.46-3.36 (m, 1H), 3.17-3.11 (m, 4H), 3.00 (dd, 1H, J = 14.1, 7.89 Hz), 2.24 (s, 3H), 1.14 ( t, 3H, J = 7.05 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (33 mg, 0.131 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-methanesulfonyloxybenzyl) hydroxylamine hydrochloride (40 mg, 0.157 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 12 hours) 2-Ethoxypropionate (38 mg, yield 66%) was obtained. The obtained compound (24 mg, 0.053 mmol) and LiOH.H ₂ O (7 mg, 0.156 mmol) were added to the reactor, and the target compound (3-7) was obtained in the same manner as in Example 2 step 2 (reaction time 3 hours). ) (20 mg, yield 87%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.43 (m, 4H), 7.31-7.22 (m, 4H), 5.21 (s, 2H), 4.07 (dd, 1H, J = 7.68, 4.02 Hz), 3.61-3.55 (m, 1H), 3.45-3.40 (m, 1H), 3.17-3.13 (m, 4H), 3.00 (dd, 1H, J = 14.1, 7.70 Hz), 2.24 (s, 3H), 1.14 ( t, 3H, J = 6.87 Hz)

Example 8 (S) -3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-8) and (R)- Preparation of 3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-8)

(S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (46 mg, 0.184 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-methoxybenzyl) hydroxylamine hydrochloride (42 mg, 0.221 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2 in the same manner as in Step 1 of Example 1 (reaction time 6 hours) -Ethoxypropionate (54 mg, yield 76%) was obtained. The obtained compound (46 mg, 0.120 mmol) and LiOH.H ₂ O (10 mg, 0.240 mmol) were added to the reactor. ) (44 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.50 (m, 2H), 7.36-7.21 (m, 4H), 6.90-6.87 (m, 2H), 5.15 (s, 2H), 4.08 (dd, 1H) , J = 8.07, 4.02 Hz), 3.79 (s, 3H), 3.63-3.53 (m, 1H), 3.46-3.36 (m, 1H), 3.14 (dd, 1H, J = 14.1, 4.02 Hz), 3.00 ( dd, 1H, J = 14.1, 8.04 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J = 6.96 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (56 mg, 0.223 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-methoxybenzyl) hydroxylamine hydrochloride (51 mg, 0.267 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2 in the same manner as in Step 1 of Example 1 (reaction time 8 hours) -Ethoxypropionate (41 mg, yield 48%) was obtained. The obtained compound (41 mg, 0.106 mmol) and LiOH.H ₂ O (13 mg, 0.318 mmol) were added to the reactor, and the target compound (3-8) was obtained in the same manner as in Step 2 of Example 1 (reaction time 12 hours). ) (34 mg, yield 87%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.36-7.25 (m, 4H), 6.90-6.87 (m, 2H), 5.15 (s, 2H), 4.09-4.05 (m , 1H), 3.79 (s, 3H), 3.64-3.54 (m, 1H), 3.46-3.36 (m, 1H), 3.14 (dd, 1H, J = 13.9, 3.84 Hz), 3.00 (dd, 1H, J = 14.1, 8.07 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J = 6.96 Hz)

Example 9 (S) -3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-9) and (R Preparation of) -3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-9)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (87 mg, 0.350 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-Trifluoromethylbenzyl) hydroxylamine hydrochloride (119 mg, 0.520 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 6 hours) 2-Ethoxypropionate (111 mg, yield 75%) was obtained. The obtained compound (110 mg, 0.260 mmol) and LiOH.H ₂ O (33 mg, 0.780 mmol) were added to the reactor. ) (96 mg, yield 91%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.61-7.48 (m, 6H), 7.31-7.22 (m, 2H), 5.27 (s, 2H), 4.07 (dd, 1H, J = 7.89, 4.02 Hz), 3.62-3.52 (m, 1H), 3.46-3.36 (m, 1H), 3.14 (dd, 1H, J = 14.1, 4.02 Hz), 3.00 (dd, 1H, J = 14.1, 7.86 Hz), 2.26 (s, 3H), 1.13 (t, 3H, J = 7.04 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (96 mg, 0.380 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-Trifluoromethylbenzyl) hydroxylamine hydrochloride (130 mg, 0.570 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 6 hours) 2-Ethoxypropionate (95 mg, yield 58%) was obtained. The obtained compound (94 mg, 0.220 mmol) and LiOH.H ₂ O (28 mg, 0.660 mmol) were added to the reactor, and the target compound (3-9) was obtained in the same manner as in Example 2 step 2 (reaction time 2 hours). ) (89 mg, yield 98%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.61-7.48 (m, 6H), 7.30-7.22 (m, 2H), 5.26 (s, 2H), 4.07 (dd, 1H, J = 7.97, 4.13 Hz), 3.63-3.53 (m, 1H), 3.45-3.35 (m, 1H), 3.13 (dd, 1H, J = 14.1, 4.02 Hz), 2.99 (dd, 1H, J = 14.2, 7.97 Hz), 2.26 (s, 3H), 1.13 (t, 3H, J = 6.96 Hz)

Example 10 (S) -3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-10) and (R) Preparation of 3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-10)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (49 mg, 0.196 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-t-butylbenzyl) hydroxylamine hydrochloride (51 mg, 0.235 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl)-in the same manner as in Step 1 of Example 1 (reaction time 12 hours) 2-Ethoxypropionate (12 mg, yield 15%) was obtained. The obtained compound (12 mg, 0.029 mmol) and LiOH.H ₂ O (4 mg, 0.087 mmol) were added to the reactor, and the target compound (2-10) was obtained in the same manner as in Step 2 of Example 1 (reaction time 8 hours). ) (12 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.54-7.50 (m, 2H), 7.40-7.22 (m, 6H), 5.20 (s, 2H), 4.08 (dd, 1H, J = 8.06, 4.04 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.15 (dd, 1H, J = 14.2, 3.93 Hz), 2.99 (dd, 1H, J = 14.0, 7.97 Hz), 2.24 (s, 3H), 1.31 (s, 9H), 1.15 (t, 3H, J = 6.95 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (33 mg, 0.132 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-t-butylbenzyl) hydroxylamine hydrochloride (34 mg, 0.158 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl)-in the same manner as in Step 1 of Example 1 (reaction time 12 hours) 2-Ethoxypropionate (5 mg, 9% yield) was obtained. The obtained compound (5 mg, 0.012 mmol) and LiOH.H ₂ O (2 mg, 0.036 mmol) were added to the reactor, and the target compound (3-10) was prepared in the same manner as in Example 2, step 2 (reaction time 8 hours). ) (5 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.54-7.51 (m, 2H), 7.40-7.26 (m, 6H), 5.20 (s, 2H), 4.09 (dd, 1H, J = 7.79, 3.95 Hz), 3.60-3.52 (m, 1H), 3.50-3.41 (m, 1H), 3.16 (dd, 1H, J = 13.9, 3.84 Hz), 3.00 (dd, 1H, J = 14.1, 7.89 Hz), 2.24 (s, 3H), 1.31 (s, 9H), 1.15 (t, 3H, J = 6.96 Hz)

Example 11 (S) -3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-11) and (R Preparation of) -3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-11)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (40 mg, 0.160 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-trifluoromethoxybenzyl) hydroxylamine hydrochloride (47 mg, 0.192 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 12 hours) 2-Ethoxypropionate (59 mg, yield 84%) was obtained. The obtained compound (59 mg, 0.134 mmol) and LiOH.H ₂ O (17 mg, 0.402 mmol) were added to the reactor. ) (57 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.48 (m, 2H), 7.43-7.39 (m, 2H), 7.31-7.17 (m, 4H), 5.21 (s, 2H), 4.07 (dd, 1H) , J = 7.86, 4.02 Hz), 3.63-3.53 (m, 1H), 3.46-3.36 (m, 1H), 3.14 (dd, 1H, J = 13.9, 4.02 Hz), 3.00 (dd, 1H, J = 14.0 , 7.97 Hz), 2.24 (s, 3H), 1.14 (t, 3H, J = 7.05 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (28 mg, 0.112 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 4-trifluoromethoxybenzyl) hydroxylamine hydrochloride (33 mg, 0.134 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 12 hours) 2-Ethoxypropionate (43 mg, yield 88%) was obtained. The obtained compound (43 mg, 0.098 mmol) and LiOH.H ₂ O (12 mg, 0.294 mmol) were added to the reactor, and the target compound (3-11) was obtained by the same method as the step 2 of Example 1 (reaction time 6 hours). ) (41 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ³ ) 7.52-7.49 (m, 2H), 7.43-7.40 (m, 2H), 7.31-7.17 (m, 4H), 5.21 (s, 2H), 4.07 (dd, 1H) , J = 7.79, 4.13 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.14 (dd, 1H, J = 14.0, 3.93 Hz), 3.00 (dd, 1H, J = 14.0 , 7.98 Hz), 2.24 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

Example 12 Preparation of (S) -3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-12)

(S) -methyl 3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionate (48 mg, 0.100) obtained as an intermediate of Example 5. mmol), phenylboronic acid (15 mg, 0.120 mmol) and Pd (PPh ₃ ) ₄ (6 mg, 0.005 mmol) were added to the reactor and argon substituted in the reactor. DME (3 ml) and saturated aqueous sodium hydrogen carbonate solution (0.5 ml) were added, followed by stirring for 12 hours while heating to reflux at 80 ° C. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with CH ₂ Cl ₂ , washed with water, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1:10) to obtain the title compound (2-12) (17 mg, yield 38%). The obtained compound (17 mg, 0.038 mmol) and LiOH.H ₂ O (4 mg, 0.076 mmol) were added to a reactor, THF / water / methanol (3: 1: 1) (10 ml) was added thereto, and the mixture was stirred at room temperature. Stir for hours. After completion of the reaction by adding 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2-12) (16 mg, 99% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.26 (m, 13H), 5.27 (s, 2H), 4.07 (dd, 1H, J = 7.97, 3.95 Hz), 3.63-3.53 (m, 1H), 3.46-3.36 (m, 1H), 3.15 (dd, 1H, J = 14.0, 3.95 Hz), 3.00 (dd, 1H, J = 14.0, 7.97 Hz), 2.26 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

Example 13 (S) -3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid (2-13) and (R) -3- (3- Preparation of ((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid (3-13)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (46 mg, 0.184 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; Phenethyl) hydroxylamine hydrochloride (35 mg, 0.202 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropio by the same method as in step 1 of Example 1 (reaction time 12 hours) Nate (39 mg, yield 57%) was obtained. The obtained compound (39 mg, 0.105 mmol) and LiOH.H ₂ O (13 mg, 0.315 mmol) were added to the reactor, and the target compound (2-13) was prepared in the same manner as in Example 2 (Step 2 of 12 hours). ) (37 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.50 (m, 2H), 7.31-7.18 (m, 6H), 4.39 (t, 2H, J = 6.96 Hz), 4.08 (dd, 1H, J = 7.97 , 3.95 Hz), 3.64-3.54 (m, 1H), 3.48-3.38 (m, 1H), 3.16 (dd, 1H, J = 14.2, 3.93 Hz), 3.06-2.97 (m, 3H), 2.19 (s, 3H), 1.16 (t, 3H, J = 7.04 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (43 mg, 0.172 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; Phenethyl) hydroxylamine hydrochloride (35 mg, 0.202 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropio by the same method as in step 1 of Example 1 (reaction time 12 hours) Nate (35 mg, yield 56%) was obtained. The obtained compound (35 mg, 0.095 mmol) and LiOH.H ₂ O (12 mg, 0.285 mmol) were added to the reactor, and the target compound was reacted in the same manner as in Step 2 of Example 1 (reaction time 12 hours). ) (33 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.31-7.18 (m, 6H), 4.39 (t, 2H, J = 6.95 Hz), 4.08 (dd, 1H, J = 8.06 , 4.04 Hz), 3.64-3.54 (m, 1H), 3.47-3.37 (m, 1H), 3.15 (dd, 1H, J = 14.2, 4.13 Hz), 3.06-2.97 (m, 3H), 2.19 (s, 3H), 1.16 (t, 3H, J = 6.96 Hz)

Example 14 (S) -3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-14) and (R) -3 Preparation of-(3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-14)

(S) -Methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (33 mg, 0.132 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; Phenylpropoxy) hydroxylamine hydrochloride (37 mg, 0.198 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, a compound (45 mg, yield 90%) was obtained by the same method as the step 1 of Example 1 (reaction time 4 hours). The obtained compound (45 mg, 0.117 mmol) and LiOH.H ₂ O (15 mg, 0.351 mmol) were added to the reactor, and the target compound ((S) was prepared in the same manner as in Example 2 (Step 2). -38) (40 mg, 93% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.31-7.14 (m, 6H), 4.20 (t, 2H, J = 6.51 Hz), 4.08 (dd, 1H, J = 7.86 , 4.02 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.15 (dd, 1H, J = 14.1, 4.02 Hz), 3.00 (dd, 1H, J = 14.0, 7.97 Hz) , 2.73 (t, 2H, J = 7.77 Hz), 2.22 (s, 3H), 2.09-1.99 (m, 2H), 1.15 (t, 3H, J = 6.96 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (36 mg, 0.144 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; Phenylpropoxy) hydroxylamine hydrochloride (40 mg, 0.216 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, a compound (45 mg, yield 82%) was obtained by the same method as the step 1 of Example 1 (reaction time 4 hours). The obtained compound (45 mg, 0.117 mmol) and LiOH.H ₂ O (15 mg, 0.351 mmol) were added to the reactor, and the target compound ((R) was prepared in the same manner as in Example 2 (Step 2). -38) (41 mg, yield 95%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.31-7.14 (m, 6H), 4.20 (t, 2H, J = 6.50 Hz), 4.08 (dd, 1H, J = 8.06 , 4.04 Hz), 3.63-3.53 (m, 1H), 3.47-3.36 (m, 1H), 3.15 (dd, 1H, J = 14.0, 3.96 Hz), 3.00 (dd, 1H, J = 14.1, 8.07 Hz) , 2.73 (t, 2H, J = 7.68 Hz), 2.22 (s, 3H), 2.09-1.99 (m, 2H), 1.15 (t, 3H, J = 6.96 Hz)

Example 15 (S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (2-15) and (R) Preparation of 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (3-15)

<Scheme 7a>

Step 1: Preparation of ethyl 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionate 34

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (879 mg, 3.313 mmol) and styrene (33) (0.418 ml, 3.644 mmol) obtained in Preparation Example 3. Into the reactor, CH ₂ Cl ₂ (25 ml) was added, sodium hypochlorite (10-13% solution, 2 ml) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with CH ₂ Cl ₂ , washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (34) (1003 mg, yield 82%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.52 (m, 2H), 7.39-7.29 (m, 7H), 5.72 (dd, 1H, J = 10.9, 8.16 Hz), 4.16 (q, 2H, J = 7.02 Hz), 3.99 (dd, 1H, J = 7.32, 5.67 Hz), 3.76 (ddd, 1H, J = 16.7, 11.0, 0.93 Hz), 3.65-3.55 (m, 1H), 3.36-3.26 (m, 2H), 3.07-2.94 (m, 2H), 1.22 (t, 3H, J = 7.14 Hz), 1.16 (dt, 3H, J = 2.73, 6.96 Hz)

Step 2: Preparation of 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (35)

Ethyl 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionate (34) (993 mg, 2.702 mmol) obtained in step 1 above. And LiOH.H ₂ O (227 mg, 5.404 mmol) were added to the reactor, and THF / water / methanol (3: 1: 1) (50 ml) was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction by adding 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain the target compound (35) (917 mg, 99% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.53 (m, 2H), 7.38-7.27 (m, 7H), 5.73 (dd, 1H, J = 11.0, 8.22 Hz), 4.10 (dd, 1H, J = 7.59, 4.11 Hz), 3.76 (dd, 1H, J = 16.6, 10.9 Hz), 3.65-3.54 (m, 1H), 3.51-3.44 (m, 1H), 3.32 (dd, 1H, J = 16.6, 8.31 Hz), 3.16 (dd, 1H, J = 14.0, 4.13 Hz), 3.02 (dd, 1H, J = 14.4, 7.71 Hz), 1.16 (dt, 3H, J = 2.01, 6.96 Hz)

Step 3: (2S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) -N-((R) -2-hydroxy -1-phenylethyl) propaneamide (36 (S)) and (2R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) Preparation of -N-((R) -2-hydroxy-1-phenylethyl) propaneamide (36 (R))

2-Ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (35) (920 mg, 2.711 mmol) obtained in step 2, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) (572 mg, 2.982 mmol), (R)-(-)-2-phenylglycinol (409 mg, 2.982 mmol) And 1-hydroxybenzotriazole hydrate (HOBT) (403 mg, 2.982 mmol) were placed in a reactor, and after argon substitution, anhydrous CH ₂ Cl ₂ (25 ml) was added. After cooling the reactor to 0 ° C., diisopropylethylamine (0.52 ml, 2.982 mmol) was slowly added dropwise, the temperature was raised to room temperature and stirred for 12 hours. The reaction was terminated by addition of saturated ammonium chloride solution, diluted with CH ₂ Cl ₂ and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (2: 1) to give the target compound (36 (S)) (482 mg, yield 39%) and (36 (R)) (461 mg, yield 37 %) Respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.56 (m, 2H), 7.40-7.26 (m, 9H), 7.17-7.15 (m, 2H), 7.05 (d, 1H, J = 7.14 Hz), 5.73 (dd, 1H, J = 11.0, 8.25 Hz), 5.00-4.93 (m, 1H), 4.01 (dd, 1H, J = 5.96, 4.13 Hz), 3.84-3.75 (m, 1H), 3.71-3.61 ( m, 2H), 3.49 (q, 2H, J = 7.02 Hz), 3.40-3.28 (m, 1H), 3.18 (dd, 1H, J = 14.1, 2.93 Hz), 3.05 (dd, 1H, J = 14.2, 6.14 Hz), 1.16 (dt, 3H, J = 0.66, 7.01 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.60-7.01 (m, 14H), 5.69 (m, 1H), 4.98 (m, 1H), 4.04 (m, 1H), 3.83-3.82 (m, 2H), 3.66-3.45 (m, 3H), 3.24-3.10 (m, 2H), 2.99 (m, 1H), 3.02 (dd, 1H, J = 14.4, 7.71 Hz), 1.18 (dt, 3H, J = 3.84, 6.96 Hz)

Step 4: (S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (37 (S)) and (R)- Preparation of 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (37 (R))

(2S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) -N-((R) -2- obtained in step 3 above Hydroxy-1-phenylethyl) propaneamide (36 (S)) (482 mg, 1.051 mmol) was added to the reactor and 1,4-Dioxane / water (10: 1) (20 ml) was added, followed by concentrated sulfuric acid. (4 ml) was added slowly dropwise. The reaction solution was heated to reflux at 100 ° C for 6 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a concentrated mixture (537 mg) of the target compound (37 (S)).

(2R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) -N-((R) -2- obtained in step 3 above Hydroxy-1-phenylethyl) propaneamide (36 (R)) (461 mg, 1.005 mmol) was added to the reactor and 1,4-Dioxane / water (10: 1) (20 ml) was added, followed by concentrated sulfuric acid. (4 ml) was added slowly dropwise. The reaction solution was heated to reflux at 100 ° C for 6 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a concentrated mixture (493 mg) of the target compound (37 (R)).

Step 5: (S) -Methyl 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionate (38 (S)) and ( Preparation of R) -methyl 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionate (38 (R))

A mixture of (S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (37 (S)) obtained in step 4; 537 mg) was added to the reactor, methanol (15 ml) was added, and trimethylsilyl chloride (0.6 ml, 4.746 mmol) was slowly added dropwise. The reaction solution was heated to reflux at 70 ° C. for 3 hours, and then saturated sodium bicarbonate solution was added to terminate the reaction. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexanoic acid (1: 5) to obtain the target compound (38 (S)) (323 mg, two-step yield 87%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.52 (m, 2H), 7.39-7.26 (m, 7H), 5.72 (dd, 1H, J = 11.0, 8.22 Hz), 4.02 (dd, 1H, J = 7.68, 5.31 Hz), 3.81-3.71 (m, 4H), 3.64-3.54 (m, 1H), 3.36-3.26 (m, 2H), 3.07-2.94 (m, 2H), 1.13 (dt, 3H, J) = 2.81, 7.00 Hz)

A mixture of (R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (37 (R)) obtained in step 4; 493 mg) was added to the reactor, methanol (15 ml) was added, and trimethylsilyl chloride (0.55 ml, 4.359 mmol) was slowly added dropwise. The reaction solution was heated to reflux at 70 ° C. for 3 hours, and then saturated sodium bicarbonate solution was added to terminate the reaction. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated compound was subjected to column chromatography with ethyl acetate: hexane (1: 5) to obtain the target compound (38 (R)) (315 mg, two-step yield 89%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.52 (m, 2H), 7.39-7.26 (m, 7H), 5.72 (dd, 1H, J = 11.0, 8.22 Hz), 4.02 (dd, 1H, J = 7.86, 5.13 Hz), 3.81-3.71 (m, 4H), 3.64- 3.54 (m, 1H), 3.36-3.26 (m, 2H), 3.07-2.94 (m, 2H), 1.13 (dt, 3H, J) = 2.88, 7.01 Hz)

Step 6: (S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (2-15) and (R) -2 Preparation of -ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (3-15)

(S) -methyl 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionate (38 (S)) obtained in step 5 above. (314 mg, 0.889 mmol) and LiOH.H ₂ O (75 mg, 1.778 mmol) were added to the reactor, THF / water / methanol (3: 1: 1) (25 ml) was added, followed by stirring at room temperature for 5 hours. It was. After completion of the reaction by adding 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2-15) (302 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.60-7.53 (m, 2H), 7.37-7.28 (m, 7H), 5.72 (dd, 1H, J = 10.8, 8.25 Hz), 4.08 (dd, 1H, J = 7.70, 4.22 Hz), 3.76 (dd, 1H, J = 16.7, 11.0 Hz), 3.66-3.56 (m, 1H), 3.47-3.40 (m, 1H), 3.32 (dd, 1H, J = 16.7, 8.22 Hz), 3.14 (dd, 1H, J = 14.1, 4.22 Hz), 3.01 (dd, 1H, J = 14.0, 7.77 Hz), 1.15 (dt, 3H, J = 2.21, 6.95 Hz)

(R) -methyl 2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionate (38 (S)) obtained in step 5 above. (304 mg, 0.860 mmol) and LiOH.H ₂ O (73 mg, 1.720 mmol) were added to the reactor, THF / water / methanol (3: 1: 1) (25 ml) was added, followed by stirring at room temperature for 5 hours. It was. After completion of the reaction by adding 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. Next, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (3-15) (292 mg, 99% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.60-7.53 (m, 2H), 7.38-7.31 (m, 7H), 5.73 (dd, 1H, J = 10.8, 8.25 Hz), 4.09 (dd, 1H, J = 7.88, 4.22 Hz), 3.76 (dd, 1H, J = 16.7, 11.0 Hz), 3.66-3.56 (m, 1H), 3.48-3.38 (m, 1H), 3.32 (dd, 1H, J = 16.7, 8.24 Hz), 3.15 (dd, 1H, J = 14.1, 4.04 Hz), 3.01 (dd, 1H, J = 14.2, 7.77 Hz), 1.15 (dt, 3H, J = 2.13, 7.01 Hz)

Example 16 (S) -2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2- 16) and (R) -2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-16) Manufacture

4-fluoro obtained by the method of Preparation Example 5 with ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (225 mg, 0.848 mmol) obtained in Preparation Example 3. Styrene (0.11 ml, 0.933 mmol) was added to the reactor, and the target compound (2-16) (79 mg, 6 step yield 26%) and (3-16) (91) were prepared in the same manner as in steps 1 to 6 of Example 15. mg, 6 steps yield 30%) respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.52 (m, 2H), 7.37-7.28 (m, 4H), 7.08-7.00 (m, 2H), 5.70 (dd, 1H, J = 10.9, 8.31 Hz ), 4.08 (dd, 1H, J = 7.79, 4.31 Hz), 3.75 (dd, 1H, J = 16.7, 10.8 Hz), 3.66-3.56 (m, 1H), 3.48-3.38 (m, 1H), 3.28 ( dd, 1H, J = 16.7, 8.24 Hz, 3.14 (dd, 1H, J = 14.1, 4.20 Hz), 3.02 (dd, 1H, J = 14.0, 7.79 Hz), 1.15 (dt, 3H, J = 2.19, 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.53 (m, 6H), 7.37-7.28 (m, 4H), 7.08-7.01 (m, 2H), 5.70 (dd, 1H, J = 10.9, 8.34 Hz ), 4.08 (dd, 1H, J = 7.61, 4.31 Hz), 3.75 (dd, 1H, J = 16.7, 10.8 Hz), 3.66-3.56 (m, 1H), 3.49-3.38 (m, 1H), 3.28 ( dd, 1H, J = 16.6, 8.33 Hz, 3.14 (dd, 1H, J = 14.0, 4.32 Hz), 3.02 (dd, 1H, J = 14.0, 7.59 Hz), 1.16 (dt, 3H, J = 2.19, 6.96 Hz)

Example 17 (S) -2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2-17 ) And (R) -2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-17)

4-chlorostyrene obtained by the method of Preparation Example 5 with ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (189 mg, 0.714 mmol) obtained in Preparation Example 3. (0.10 ml, 0.785 mmol) was added to the reactor, and the target compound (2-17) (68 mg, 6-step yield 26%) and (3-17) (67 mg) were prepared in the same manner as in steps 1 to 6 of Example 15. , 6-step yield 25%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.57-7.52 (m, 2H), 7.35-7.29 (m, 6H), 5.70 (dd, 1H, J = 11.0, 8.06 Hz), 4.09 (dd, 1H, J = 7.41, 4.32 Hz), 3.76 (dd, 1H, J = 16.7, 11.0 Hz), 3.65-3.55 (m, 1H), 3.51-3.43 (m, 1H), 3.27 (dd, 1H, J = 16.7, 8.24 Hz), 3.15 (dd, 1H, J = 14.1, 4.22 Hz), 3.02 (dd, 1H, J = 14.1, 7.50 Hz), 1.16 (dt, 3H, J = 2.01, 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.56-7.52 (m, 2H), 7.36-7.30 (m, 6H), 5.70 (dd, 1H, J = 10.9, 7.97 Hz), 4.10 (dd, 1H, J = 7.50, 4.20 Hz), 3.76 (dd, 1H, J = 16.6, 11.1 Hz), 3.63-3.55 (m, 1H), 3.49-3.44 (m, 1H), 3.27 (dd, 1H, J = 16.8, 8.15 Hz), 3.15 (dd, 1H, J = 14.0, 4.32 Hz), 3.02 (dd, 1H, J = 14.1, 7.32 Hz), 1.16 (dt, 3H, J = 2.02, 6.97 Hz)

Example 18 (S) -2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2- 18) and (R) -2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-18) Manufacture

4-Bromo obtained by the method of Preparation Example 5 with ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (185 mg, 0.695 mmol) obtained in Preparation Example 3. Styrene (0.10 ml, 0.765 mmol) was added to the reactor, and the target compound (2-18) (77 mg, 6% yield 27%) and ((R) -46) were prepared in the same manner as in steps 1 to 6 of Example 15. (76 mg, 6 steps yield 26%) respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.56-7.47 (m, 4H), 7.36-7.27 (m, 4H), 5.68 (dd, 1H, J = 11.0, 8.07 Hz), 4.10 (dd, 1H, J = 7.32, 4.23 Hz), 3.76 (dd, 1H, J = 16.8, 11.1 Hz), 3.62-3.48 (m, 2H), 3.26 (dd, 1H, J = 16.6, 8.16 Hz), 3.16 (dd, 1H, J = 14.3, 4.05 Hz), 3.02 (dd, 1H, J = 14.2, 7.23 Hz), 1.17 (dt, 3H, J = 1.89, 7.01 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.57-7.47 (m, 4H), 7.36-7.27 (m, 4H), 5.68 (dd, 1H, J = 11.0, 8.07 Hz), 4.10 (dd, 1H, J = 7.43, 4.31 Hz), 3.76 (dd, 1H, J = 16.7, 11.0 Hz), 3.65-3.55 (m, 1H), 3.51-3.43 (m, 1H), 3.26 (dd, 1H, J = 16.7, 8.24 Hz), 3.15 (dd, 1H, J = 14.1, 4.23 Hz), 3.02 (dd, 1H, J = 14.0, 7.41 Hz), 1.16 (dt, 3H, J = 2.08, 7.00 Hz)

Example 19 (S) -2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2- 19) and (R) -2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-19) Manufacture

4-Iodo obtained by the method of Preparation Example 5 with ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (368 mg, 1.390 mmol) obtained in Preparation Example 3. Styrene (352 mg, 1.53 mmol) was added to the reactor, and the target compound (2-19) (85 mg, 6-step yield 13%) and (3-19) (85) were prepared in the same manner as in steps 1 to 6 of Example 15. mg, 6 steps yield 13%) respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.70-7.67 (m, 2H), 7.57-7.51 (m, 2H), 7.35-7.28 (m, 2H), 7.13-7.11 (m, 2H), 5.67 (dd) , 1H, J = 10.9, 7.98 Hz), 4.09 (dd, 1H, J = 7.50, 4.41 Hz), 3.76 (dd, 1H, J = 16.5, 11.0 Hz), 3.65-3.55 (m, 1H), 3.48- 3.42 (m, 1H), 3.26 (dd, 1H, J = 16.7, 8.04 Hz), 3.15 (dd, 1H, J = 14.0, 4.31 Hz), 3.02 (dd, 1H, J = 14.0, 7.62 Hz), 1.16 (dt, 3H, J = 2.07, 7.05 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.70-7.67 (m, 2H), 7.57-7.51 (m, 2H), 7.35-7.28 (m, 2H), 7.13-7.11 (m, 2H), 5.66 (dd) , 1H, J = 11.0, 8.07 Hz, 4.09 (dd, 1H, J = 7.52, 4.22 Hz), 3.76 (dd, 1H, J = 16.7, 11.0 Hz), 3.65-3.55 (m, 1H), 3.50- 3.42 (m, 1H), 3.26 (dd, 1H, J = 16.7, 8.04 Hz), 3.14 (dd, 1H, J = 14.2, 4.29 Hz), 3.02 (dd, 1H, J = 14.2, 7.41 Hz), 1.16 (dt, 3H, J = 2.08, 7.00 Hz)

Example 20 (S) -2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2- 20) and (R) -2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2-21) Manufacture

4- (t obtained by the method of Preparation Example 5 with ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (294 mg, 1.108 mmol) obtained in Preparation Example 3. -Butyldimethylsilyloxy) styrene (286 mg, 1.219 mmol) was added to the reactor, and the target compound (2-20) (69 mg, 6-step yield 18%) was obtained in the same manner as in steps 1 to 6 of Example 15. (3-20) (67 mg, 6 steps yield 17%) were obtained respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.53 (m, 2H), 7.35-7.22 (m, 4H), 6.82-6.80 (m, 2H), 5.65 (dd, 1H, J = 10.8, 8.43 Hz ), 4.08 (dd, 1H, J = 7.70, 4.04 Hz), 3.70 (dd, 1H, J = 16.7, 10.8 Hz), 3.65-3.55 (m, 1H), 3.48-3.38 (m, 1H), 3.29 ( dd, 1H, J = 16.8, 8.42 Hz), 3.14 (dd, 1H, J = 14.0, 4.50 Hz), 3.01 (dd, 1H, J = 14.2, 7.59 Hz), 1.16 (dt, 3H, J = 1.17, 7.05 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.53 (m, 2H), 7.35-7.22 (m, 4H), 6.83-6.80 (m, 2H), 5.65 (dd, 1H, J = 10.7, 8.69 Hz ), 4.09 (dd, 1H, J = 7.50, 4.38 Hz), 3.70 (dd, 1H, J = 16.8, 10.9 Hz), 3.65-3.55 (m, 1H), 3.49-3.41 (m, 1H), 3.29 ( dd, 1H, J = 16.8, 8.51 Hz, 3.14 (dd, 1H, J = 14.0, 4.11 Hz), 3.02 (dd, 1H, J = 13.8, 7.61 Hz), 1.16 (dt, 3H, J = 1.09, 7.04 Hz)

Example 21 (S) -2-Ethoxy-3- (3- (5- (4-methanesulfonyloxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid ( 2-21) and (R) -2-ethoxy-3- (3- (5- (4-methanesulfonyloxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid ( 3-21) Preparation

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (358 mg, 1.350 mmol) obtained in Preparation Example 3 and 4-methanesulfur obtained by the method of Preparation Example 5. Phenyloxystyrene (242 mg, 1.220 mmol) was added to the reactor, and the target compound (2-21) (50 mg, 6% yield 9%) and (3-21) were prepared in the same manner as in steps 1 to 6 of Example 15. (41 mg, 6 steps yield 7%) each.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.52 (m, 2H), 7.45-7.42 (m, 2H), 7.36-7.27 (m, 4H), 5.74 (dd, 1H, J = 10.8, 7.71 Hz ), 4.09 (dd, 1H, J = 7.43, 4.13 Hz), 3.79 (dd, 1H, J = 16.7, 11.0 Hz), 3.66-3.56 (m, 1H), 3.50-3.40 (m, 1H), 3.29 ( dd, 1H, J = 16.7, 7.86 Hz), 3.18-3.13 (m, 4H), 3.02 (dd, 1H, J = 14.2, 7.41 Hz), 1.16 (dt, 3H, J = 1.77, 7.01 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.52 (m, 2H), 7.45-7.42 (m, 2H), 7.36-7.27 (m, 4H), 5.74 (dd, 1H, J = 10.8, 7.89 Hz ), 4.09 (dd, 1H, J = 7.43, 4.13 Hz), 3.79 (dd, 1H, J = 16.7, 11.0 Hz), 3.66-3.56 (m, 1H), 3.51-3.41 (m, 1H), 3.29 ( dd, 1H, J = 16.7, 7.86 Hz), 3.18-3.13 (m, 4H), 3.02 (dd, 1H, J = 14.2, 7.41 Hz), 1.16 (dt, 3H, J = 1.71, 7.01 Hz)

Example 22 (S) -2-Ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2- 22) and (R) -2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-22) Manufacture

4-methoxy obtained by the method of Preparation Example 5 with ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (179 mg, 0.675 mmol) obtained in Preparation Example 3. Styrene (0.1 ml, 0.743 mmol) was added to the reactor, and the target compound (2-22) (45 mg, 6-step yield 18%) and (3-22) (54) were prepared in the same manner as in steps 1 to 6 of Example 15. mg, 6 steps yield 22%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.54 (m, 2H), 7.36-7.28 (m, 4H), 6.90-6.87 (m, 2H), 5.67 (dd, 1H, J = 10.7, 8.70 Hz ), 4.09 (dd, 1H, J = 7.61, 4.31 Hz), 3.79 (s, 3H), 3.70 (dd, 1H, J = 16.6, 10.9 Hz), 3.65-3.55 (m, 1H), 3.51-3.43 ( m, 1H), 3.30 (dd, 1H, J = 16.7, 8.61 Hz), 3.15 (dd, 1H, J = 14.1, 4.23 Hz), 3.02 (dd, 1H, J = 14.2, 7.59 Hz), 1.16 (dt , 3H, J = 1.35, 7.01 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.54 (m, 2H), 7.36-7.29 (m, 4H), 6.91-6.87 (m, 2H), 5.67 (dd, 1H, J = 10.9, 8.70 Hz ), 4.09 (dd, 1H, J = 7.61, 4.31 Hz), 3.79 (s, 3H), 3.70 (dd, 1H, J = 16.7, 10.8 Hz), 3.66-3.55 (m, 1H), 3.50-3.40 ( m, 1H), 3.30 (dd, 1H, J = 16.7, 8.61 Hz), 3.15 (dd, 1H, J = 14.1, 4.20 Hz), 3.02 (dd, 1H, J = 14.2, 7.59 Hz), 1.16 (dt , 3H, J = 1.35, 7.01 Hz)

Example 23 (S) -2-Ethoxy-3- (3- (5- (4-trifluoromethylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2 -23) and (R) -2-ethoxy-3- (3- (5- (4-trifluoromethylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3- Manufacture of 23

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (335 mg, 1.262 mmol) obtained in Preparation Example 3 and 4-trifluoro obtained by the method of Preparation Example 5. Romethyl styrene (238 mg, 1.388 mmol) was added to the reactor, and the target compound (2-23) (81 mg, 6-step yield 16%) and (3-23) were prepared in the same manner as in Steps 1 to 6 of Example 15. (72 mg, 6 steps yield 14%) each.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.64-7.49 (m, 6H), 7.34-7.31 (m, 2H), 5.79 (dd, 1H, J = 11.0, 7.68 Hz), 4.09 (dd, 1H, J = 7.52, 4.22 Hz), 3.82 (dd, 1H, J = 16.8, 11.1 Hz), 3.60-3.58 (m, 1H), 3.48-3.46 (m, 1H), 3.29 (dd, 1H, J = 16.6, 7.79 Hz), 3.14-3.12 (m, 1H), 3.06-3.03 (m, 1H), 1.16 (dt, 3H, J = 3.09, 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.64-7.48 (m, 6H), 7.36-7.31 (m, 2H), 5.78 (dd, 1H, J = 10.8, 7.89 Hz), 4.09 (dd, 1H, J = 7.50, 4.20 Hz), 3.82 (dd, 1H, J = 16.7, 11.2 Hz), 3.63-3.58 (m, 1H), 3.47-3.42 (m, 1H), 3.29 (dd, 1H, J = 16.7, 7.70 Hz), 3.15 (dd, 1H, J = 14.2, 4.11 Hz), 3.02 (dd, 1H, J = 14.4, 7.41 Hz), 1.16 (dt, 3H, J = 3.18, 7.01 Hz)

Example 24 (S) -2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2 -24) and (R) -2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3- Manufacture of 24

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (198 mg, 0.745 mmol) obtained in Preparation Example 3 and 4-t- obtained by the method of Preparation Example 5. Butyl styrene (0.15 ml, 0.819 mmol) was added to the reactor, and the target compound (2-24) (67 mg, 6-step yield 23%) and (3-24) ( 84 mg, 6 steps yield 29%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.54 (m, 2H), 7.40-7.24 (m, 6H), 5.70 (dd, 1H, J = 10.8, 8.40 Hz), 4.10 (dd, 1H, J = 7.50, 4.20 Hz), 3.72 (dd, 1H, J = 16.6, 10.9 Hz), 3.62-3.44 (m, 2H), 3.33 (dd, 1H, J = 16.7, 8.42 Hz), 3.16 (dd, 1H, J = 14.0, 4.32 Hz), 3.02 (dd, 1H, J = 14.0, 7.43 Hz), 1.30 (s, 9H), 1.16 (dt, 3H, J = 1.51, 7.00 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.59-7.54 (m, 2H), 7.40-7.27 (m, 6H), 5.70 (dd, 1H, J = 10.8, 8.61 Hz), 4.10 (dd, 1H, J = 7.50, 4.20 Hz), 3.72 (dd, 1H, J = 16.6, 10.9 Hz), 3.65-3.44 (m, 2H), 3.33 (dd, 1H, J = 16.7, 8.60 Hz), 3.16 (dd, 1H, J = 14.0, 4.13 Hz), 3.02 (dd, 1H, J = 14.0, 7.43 Hz), 1.30 (s, 9H), 1.16 (dt, 3H, J = 1.58, 7.00 Hz)

Example 25 (S) -3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid (2-25) and (R) Preparation of 3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid (3-25)

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (153 mg, 0.577 mmol) obtained in Preparation Example 3 and 1-allylbenzene obtained by the method of Preparation Example 5. (0.085 ml, 0.635 mmol) was added to the reactor, and the target compound (2-25) (57 mg, 6-step yield 28%) and (3-25) (58 mg) were prepared in the same manner as in steps 1 to 6 of Example 15. , 6-step yield 28%) respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.49 (m, 2H), 7.34-7.24 (m, 7H), 4.98 (m, 1H), 4.08-4.07 (m, 1H), 3.61-3.56 (m , 1H), 3.47-3.44 (m, 1H), 3.29 (dd, 1H, J = 16.7, 10.3 Hz), 3.20-3.12 (m, 2H), 3.07-2.99 (m, 2H), 2.87 (dd, 1H , J = 13.7, 7.32 Hz), 1.15 (t, 3H, J = 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.52-7.49 (m, 2H), 7.33-7.24 (m, 7H), 5.00-4.98 (m, 1H), 4.10-4.06 (m, 1H), 3.62-3.56 (m, 1H), 3.47-3.41 (m, 1H), 3.29 (dd, 1H, J = 16.7, 10.3 Hz), 3.19-3.11 (m, 2H), 3.07-2.99 (m, 2H), 2.87 (dd , 1H, J = 13.8, 7.23 Hz), 1.15 (t, 3H, J = 7.05 Hz)

Example 26 (S) -2-Ethoxy-3- (3- (4,5-dihydro-5-phenethylisoxazol-3-yl) phenyl) propionic acid (2-26) and (R Preparation of) -2-ethoxy-3- (3- (4,5-dihydro-5-phenethylisoxazol-3-yl) phenyl) propionic acid (3-26)

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (347 mg, 1.308 mmol) obtained in Preparation Example 3 and 1- (Boot obtained by the method of Preparation Example 5) -3-enyl) benzene (0.216 ml, 1.439 mmol) was added to the reactor, and the target compound (2-26) (85 mg, 6% yield 18%) and (2) were prepared in the same manner as in steps 1 to 6 of Example 15. -26) (59 mg, 6 steps yield 12%) respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.55-7.51 (m, 2H), 7.34-7.19 (m, 7H), 4.72 (m, 1H), 4.09 (dd, 1H, J = 7.79, 4.13 Hz), 3.63-3.55 (m, 1H), 3.47-3.33 (m, 2H), 3.15 (dd, 1H, J = 14.0, 3.93 Hz), 3.05-2.91 (m, 2H), 2.83-2.74 (m, 2H), 2.11-2.08 (m, 1H), 1.92 (m, 1H), 1.16 (t, 3H, J = 7.05 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.55-7.51 (m, 2H), 7.35-7.16 (m, 7H), 4.75-4.70 (m, 1H), 4.09 (dd, 1H, J = 7.70, 4.22 Hz ), 3.65-3.55 (m, 1H), 3.47-3.33 (m, 2H), 3.15 (dd, 1H, J = 14.1, 4.20 Hz), 3.05-2.91 (m, 2H), 2.83-2.74 (m, 2H) ), 2.16- 2.03 (m, 1H), 1.97-1.92 (m, 1H), 1.16 (t, 3H, J = 6.96 Hz)

Example 27 (S) -2-Ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (2-27) and (R) Preparation of 2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid (3-27)

Ethyl 2-ethoxy-3- (4-benzaldehyde- (E) -oxime) propionate (220 mg, 0.829 mmol) and styrene (0.11 ml, 0.912 mmol) obtained from terephthalaldehyde in the same manner as in Preparation Example 3. To the reactor in the same manner as in Steps 1 to 6 of Example 15 to the target compound (2-27) (23 mg, 6-step yield 8%) and (3-27) (37 mg, 6-step yield 13%) Were obtained respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.63-7.60 (m, 2H), 7.37-7.26 (m, 7H), 5.75-5.69 (m, 1H), 4.11-4.08 (m, 2H), 3.80-3.70 (m, 1H), 3.60-3.40 (m, 1H), 3.35-3.25 (m, 1H), 3.20-2.98 (m, 2H), 1.17 (t, 3H, J = 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.63-7.60 (m, 2H), 7.37-7.26 (m, 7H), 5.75-5.69 (m, 1H), 4.11-4.08 (m, 2H), 3.80-3.70 (m, 1H), 3.60-3.40 (m, 1H), 3.35-3.25 (m, 1H), 3.20-2.98 (m, 2H), 1.17 (t, 3H, J = 6.96 Hz)

Example 28 (S) -3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid (2-28) and (R) Preparation of 3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid (3-28)

Ethyl 2-ethoxy-3- (4-benzaldehyde- (E) -oxime) propionate (184 mg, 0.693 mmol) and 1-allylbenzene (0.1 ml, obtained from terephthalaldehyde in the same manner as in Preparation Example 3 0.762 mmol) was added to the reactor, and the target compound (2-28) (44 mg, 6-step yield 18%) and (3-28) (39 mg, 6-step yield were prepared in the same manner as in Steps 1 to 6 of Example 15. 16%) respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.57-7.55 (m, 2H), 7.33-7.23 (m, 7H), 5.02-4.92 (m, 1H), 4.10-4.06 (m, 1H), 3.65-3.55 (m, 1H), 3.48-3.38 (m, 1H), 3.33-3.24 (m, 1H), 3.19-3.11 (m, 2H), 3.07-2.97 (m, 2H), 2.90-2.83 (m, 1H) , 1.16 (t, 3H, J = 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.57-7.55 (m, 2H), 7.33-7.20 (m, 7H), 5.02-4.92 (m, 1H), 4.10-4.06 (m, 1H), 3.65-3.55 (m, 1H), 3.48-3.38 (m, 1H), 3.33-3.24 (m, 1H), 3.19-3.11 (m, 2H), 3.07-2.97 (m, 2H), 2.90-2.83 (m, 1H) , 1.16 (t, 3H, J = 6.96 Hz)

Example 29 (S) -3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-29) and (R) -3 Preparation of-(3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-29)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (63 mg, 0.252 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 2-chlorobenzyl) hydroxylamine hydrochloride (163 mg, 0.839 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 6 hours). Ethoxypropionate (61 mg, yield 62%) was obtained. The obtained compound (60 mg, 0.154 mmol) and LiOH.H ₂ O (19 mg, 0.462 mmol) were added to the reactor, and the target compound (2-29) was prepared in the same manner as in Example 2 step 2 (reaction time 3 hours). ) (55 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.50 (m, 2H), 7.46-7.43 (m, 1H), 7.38-7.21 (m, 5H), 5.34 (s, 2H), 4.08 (dd, 1H) , J = 7.89, 4.02 Hz), 3.60-3.52 (m, 1H), 3.47-3.39 (m, 1H), 3.15 (dd, 1H, J = 14.3, 4.02 Hz), 2.99 (dd, 1H, J = 14.1 , 7.88 Hz), 2.28 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (45 mg, 0.180 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 2-chlorobenzyl) hydroxylamine hydrochloride (116 mg, 0.599 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 6 hours) Ethoxypropionate (44 mg, yield 63%) was obtained. The obtained compound (44 mg, 0.113 mmol) and LiOH.H ₂ O (14 mg, 0.339 mmol) were added to the reactor, and the target compound was reacted in the same manner as in Step 2 of Example 1 (reaction time 3 hours). ) (43 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.53-7.43 (m, 3H), 7.37-7.22 (m, 5H), 5.34 (s, 2H), 4.07 (dd, 1H, J = 7.89, 4.02 Hz), 3.61-3.55 (m, 1H), 3.43-3.38 (m, 1H), 3.14 (dd, 1H, J = 13.9, 4.02 Hz), 3.00 (dd, 1H, J = 14.2, 8.15 Hz), 2.28 (s, 3H), 1.14 (t, 3H, J = 7.05 Hz)

Example 30 (S) -3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-30) and (R) -3 Preparation of-(3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-30)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (47 mg, 0.188 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 3-Chlorobenzyl) hydroxylamine hydrochloride (73 mg, 0.376 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 6 hours). Ethoxypropionate (37 mg, yield 51%) was obtained. The obtained compound (37 mg, 0.095 mmol) and LiOH.H ₂ O (12 mg, 0.285 mmol) were added to the reactor, and the target compound (2-30) was obtained in the same manner as in Step 2 of Example 1 (reaction time 5 hours). ) (36 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.48 (m, 2H), 7.38 (m, 1H), 7.31-7.24 (m, 5H), 5.18 (s, 2H), 4.07 (dd, 1H, J = 7.79, 4.13 Hz), 3.60-3.55 (m, 1H), 3.45-3.39 (m, 1H), 3.14 (dd, 1H, J = 13.8, 3.75 Hz), 3.00 (dd, 1H, J = 14.4, 7.77 Hz), 2.25 (s, 3H), 1.14 (t, 3H, J = 7.05 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (49 mg, 0.196 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 3-chlorobenzyl) hydroxylamine hydrochloride (76 mg, 0.392 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2- in the same manner as in Step 1 of Example 1 (reaction time 6 hours). Ethoxypropionate (37 mg, yield 48%) was obtained. The obtained compound (36 mg, 0.092 mmol) and LiOH.H ₂ O (12 mg, 0.276 mmol) were added to the reactor, and the target compound (3-30) was obtained by the same method as the step 2 of Example 1 (reaction time 5 hours). ) (37 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.48 (m, 2H), 7.38 (m, 1H), 7.30-7.24 (m, 5H), 5.18 (s, 2H), 4.07 (dd, 1H, J = 7.68, 4.02 Hz), 3.59-3.54 (m, 1H), 3.45-3.43 (m, 1H), 3.18-3.12 (m, 1H), 3.03-2.96 (m, 1H), 2.25 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

Example 31 (S) -2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2-31 ) And (R) -2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-31)

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (298 mg, 1.123 mmol) obtained in Preparation Example 3 and 3-chlorostyrene obtained by the method of Preparation Example 5. (171 mg, 1.234 mmol) was added to the reactor, and the target compound (2-31) (69 mg, 6-step yield 16%) and (3-31) (63 mg were prepared in the same manner as in Steps 1 to 6 of Example 15. , Yields of 6% yield 15%) were obtained, respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.57-7.53 (m, 2H), 7.37-7.23 (m, 6H), 5.70 (dd, 1H, J = 11.2, 8.06 Hz), 4.09 (dd, 1H, J = 7.52, 4.22 Hz), 3.78 (dd, 1H, J = 16.7, 11.2 Hz), 3.63-3.55 (m, 1H), 3.48-3.43 (m, 1H), 3.29 (dd, 1H, J = 16.6, 7.97 Hz), 3.15 (dd, 1H, J = 14.0, 4.13 Hz), 3.02 (dd, 1H, J = 13.9, 7.52 Hz), 1.16 (dt, 3H, J = 2.01, 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.52 (m, 2H), 7.37-7.24 (m, 6H), 5.70 (dd, 1H, J = 11.0, 7.86 Hz), 4.10 (dd, 1H, J) = 7.43, 4.31 Hz), 3.78 (dd, 1H, J = 16.7, 11.2 Hz), 3.63-3.55 (m, 1H), 3.51-3.41 (m, 1H), 3.29 (dd, 1H, J = 16.7, 7.86 Hz), 3.16 (dd, 1H, J = 14.1, 4.20 Hz), 3.02 (dd, 1H, J = 14.2, 7.41 Hz), 1.16 (dt, 3H, J = 2.02, 6.95 Hz)

Example 32 (S) -2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (2-32 ) And (R) -2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid (3-32)

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (300 mg, 1.131 mmol) obtained in Preparation Example 3 and 2-chlorostyrene obtained by the method of Preparation Example 5. (172 mg, 1.241 mmol) was added to the reactor, and the target compound (2-32) (72 mg, 6-step yield 17%) and (3-32) (63 mg) were prepared in the same manner as in Steps 1 to 6 of Example 15. , Yields of 6% yield 15%) were obtained respectively.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.58-7.51 (m, 3H), 7.39-7.20 (m, 5H), 6.01 (dd, 1H, J = 11.1, 6.87 Hz), 4.07 (dd, 1H, J = 7.88, 4.22 Hz), 3.92 (dd, 1H, J = 16.8, 11.2 Hz), 3.65-3.55 (m, 1H), 3.47-3.37 (m, 1H), 3.23-3.10 (m, 2H), 3.01 ( dd, 1H, J = 13.4, 7.82 Hz), 1.16 (dt, 3H, J = 3.30, 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.57-7.52 (m, 3H), 7.39-7.20 (m, 5H), 6.01 (dd, 1H, J = 11.1, 7.05 Hz), 4.07 (dd, 1H, J = 7.88, 4.22 Hz), 3.92 (dd, 1H, J = 16.8, 11.2 Hz), 3.65-3.55 (m, 1H), 3.47-3.37 (m, 1H), 3.23-3.10 (m, 2H), 3.01 ( dd, 1H, J = 14.2, 7.77 Hz), 1.16 (dt, 3H, J = 3.36, 7.05 Hz)

Example 33 (S) -3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (2-33) and (R Preparation of) -3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid (3-33)

(S) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (S)) (28 mg, 0.112 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 2,4-Dichlorobenzyl) hydroxylamine hydrochloride (51 mg, 0.224 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (S) -methyl 3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 7 hours) 2-Ethoxypropionate (10 mg, yield 21%) was obtained. The obtained compound (10 mg, 0.023 mmol) and LiOH.H ₂ O (3 mg, 0.069 mmol) were added to a reactor, and the target compound (2-33) was prepared in the same manner as in Example 2 step 2 (reaction time: 1 hour). ) (10 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.48 (m, 2H), 7.39-7.36 (m, 2H), 7.31-7.21 (m, 3H), 5.28 (s, 2H), 4.08 (dd, 1H) , J = 7.86, 4.02 Hz), 3.60-3.52 (m, 1H), 3.48-3.40 (m, 1H), 3.14 (dd, 1H, J = 14.3, 4.02 Hz), 3.00 (dd, 1H, J = 14.2 , 7.80 Hz), 2.27 (s, 3H), 1.14 (t, 3H, J = 7.04 Hz)

(R) -methyl 3- (3-acetylphenyl) -2-ethoxypropionate (4 (R)) (31 mg, 0.124 mmol) obtained in Preparation Example 2 and O- (obtained by the method of Preparation Example 4; 2,4-Dichlorobenzyl) hydroxylamine hydrochloride (57 mg, 0.248 mmol) was added to the reactor and pyridine (3 ml) was added. Thereafter, (R) -methyl 3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) in the same manner as in step 1 of Example 1 (reaction time 7 hours) 2-Ethoxypropionate (12 mg, yield 22%) was obtained. The obtained compound (12 mg, 0.028 mmol) and LiOH.H ₂ O (4 mg, 0.084 mmol) were added to the reactor, and the target compound was reacted in the same manner as in Step 2 of Example 1 (reaction time: 1 hour). ) (12 mg, yield 99%).

¹ H-NMR (300 MHz, CDCl ₃ ) 7.51-7.48 (m, 2H), 7.39-7.36 (m, 2H), 7.31-7.21 (m, 3H), 5.28 (s, 2H), 4.08 (dd, 1H) , J = 7.70, 4.04 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.14 (dd, 1H, J = 14.0, 4.13 Hz), 3.00 (dd, 1H, J = 14.0 , 7.77 Hz), 2.27 (s, 3H), 1.14 (t, 3H, J = 6.96 Hz)

Example 34 (S) -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid (2-34) and (R) -2-ethoxy-3 Preparation of-(3- (5-phenylisoxazol-3-yl) phenyl) propionic acid (3-34)

Ethyl 2-ethoxy-3- (3-benzaldehyde- (E) -oxime) propionate (7) (500 mg, 1.885 mmol) and phenylacetylene (212 mg, 2.074 mmol) obtained in Preparation Example 3 were reacted. To the target compound (2-34) (19 mg, 6-step yield 3%) and (3-34) (16 mg, 6-step yield 3%) in the same manner as in steps 1-6 of Example 15, respectively. Got it.

¹ H-NMR (300 MHz, CDCl ₃ ) 7.84-7.72 (m, 4H), 7.51-7.33 (m, 5H), 6.81 (s, 1H), 4.14-4.06 (m, 1H), 3.68-3.54 (m , 1H), 3.49-3.39 (m, 1H), 3.23-3.03 (m, 2H), 1.16 (t, 3H, J = 6.96 Hz)

¹ H-NMR (300 MHz, CDCl ₃ ) 7.84-7.72 (m, 4H), 7.51-7.33 (m, 5H), 6.83-6.82 (m, 1H), 4.14-4.06 (m, 1H), 3.67-3.57 (m, 1H), 3.51-3.29 (m, 1H), 3.24-3.03 (m, 2H), 1.17 (t, 3H, J = 6.96 Hz)

Experimental Example 1 Evaluation of Human PPAR Transcription Activation Capacity of Synthetic Derivatives

Experiments were conducted on the extent to which the new ethoxy propionic acid derivatives synthesized according to the method of the present invention induce the transcriptional activation ability of PPAR in a cell.

The ligand binding site of the human PPAR receptor was fused with the DNA binding site of Gal4, a yeast transcription factor. Each PPAR chimera was infected with monkey kidney cells (CV-1 cells) as a reporter construct containing 5 copies of the regulatory vector (Promega) pRL-tk and Gal4 DNA binding sites. The test sample was dissolved in DMSO solvent and diluted 1: 1000. The test sample was treated with cells for 7 hours from 0.03 M to 100 M for 7 hours using the dual glucosiferase reagent (Promega). At this time, the degree of luminescence was compared with the control to determine the effective activity. As a comparative substance, rosiglitazone (Comparative Example 1), which is known as a diabetes treatment substance, and gemfibrozil (Comparative Example 2) (provided by Dong-A Pharmaceutical Research Institute), which are used for treating adipose metabolic disease, were used. In the following Table 1 E _max means the pharmacological maximum effect when compared to the control and EC ₅₀ means the compound concentration when showing half the activity of the maximum activity. EC ₅₀ of the compound was determined using nonlinear regression using SigmaPlot 4.0.

Ethoxypropionic acid derivatives Human PPARγ Human PPARα EC ₅₀ (μM) E _max (%) EC ₅₀ (μM) E _max (%) Example 1 2-1 0.121 141 2.91 71 3-1 1.89 135 - 8 Example 2 2-2 0.139 214 5.90 299 3-2 2.77 168 59.0 58 Example 3 2-3 0.028 163 7.22 386 3-3 1.53 134 53.9 119 Example 4 2-4 0.036 160 2.70 150 3-4 1.25 135 34.0 85 Example 5 2-5 0.040 146 0.674 139 3-5 4.90 210 40.8 142 Example 6 2-6 2.94 222 58.8 58 3-6 32.6 138 - 3 Example 7 2-7 1.61 129 13.1 165 3-7 17.2 151 49.4 123 Example 8 2-8 0.175 155 4.06 179 3-8 6.19 152 37.7 88 Example 9 2-9 0.046 135 2.95 185 3-9 2.06 212 32.0 180 Example 10 2-10 0.279 155 12.1 137 3-10 6.77 86 39.1 78 Example 15 2-15 0.220 115 3.99 78 3-15 3.32 54 - 18 Example 16 2-16 1.16 158 24.4 119 3-16 36.8 119 - 0 Example 17 2-17 0.816 167 6.78 125 3-17 27.3 114 59.0 18 Example 18 2-18 0.740 151 4.39 144 3-18 23.5 113 - 36 Example 19 2-19 0.606 161 2.76 162 3-19 13.5 103 34.8 95 Example 20 2-20 38.6 83 - 0 3-20 - 20 - 11 Example 21 2-21 28.1 95 37.4 107 3-21 - 13 - 6 Example 22 2-22 3.19 121 11.3 156 3-22 54.0 61 - 11 Example 24 2-24 2.73 158 3.95 138 3-24 29.7 91 40.4 76 Example 25 2-25 6.98 173 21.6 104 3-25 41.4 102 - 6 Example 26 2-26 1.85 114 3.08 262 3-26 25.1 119 44.5 217 Example 34 2-34 3.29 164 5.60 162 3-34 37.4 106 30.4 48 Comparative Example 1 0.033 100 3.46 56 Comparative Example 2 147.8 79 193.3 100

As shown in Table 1, the EC ₅₀ value for the human PPARγ receptor of the (S) -oriented optical activity derivative of the 2-ethoxypropionic acid derivative in the derivative according to the embodiment of the present invention is in the range of about 0.028 to 38.6 μM In the case of PPARα it was found to have a value in the range of 0.674 ~ 58.8 μM. Although it is used as a hypoglycemic agent in diabetic patients, it has been shown to show better or equivalent pharmacological activity than the rosiglitazone of Comparative Example 1, which has side effects of weight gain or edema, as well as EC ₅₀ measurement of PPARα. It has been shown to exhibit significantly better pharmacological activity than gemfibrozil of Comparative Example 2, which can be used as a therapeutic agent for lipid metabolic disorders.

Therefore, the pharmaceutical composition containing a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for the prevention and treatment of diabetes as well as the treatment of complications thereby.

Experimental Example 2 Evaluation of Mouse Blood Sugar Lowering Effect and Weight Gain

Experiments were conducted on weight gain, in which new derivatives synthesized according to the method of the present invention exhibited a degree and side effects of reducing blood glucose levels in vivo, in the following manner. The purpose of the experiment was to evaluate the hypoglycemic effect of the synthesized derivatives in type 2 diabetic mice (db / db mouse).

Male type 2 diabetic mice (SLC, Japan) having the same age were set to 5 groups after the blood glucose and body weight were measured in advance using the ACCU-CECK Active (Roche) via the tail vein. General feed and water were freely ingested and the drug was orally administered once daily for 5 days. 0.5% methyl cellulose was used as the base, and the experiment was performed according to the standard protocol 50. Blood glucose and body weight were measured on the 5th day. The results were expressed as “mean ± SEM” and the significance between groups was tested by One Way Analysis of Variance and Student-Newman-Keuls.

Ethoxypropionic acid derivatives Dose (mpk) Blood glucose enhancing effect (%) Weight gain Experimental group Control ^* Example 1 3-1 20 23 50 3-1 <control Example 15 2-42 20 27 30 2-42 ≒ Control 3-42 20 3 30 3-42 ≒ control Example 2 2-2 3 61 47 2-2 <control Example 3 2-3 0.3 41 37 2-3 <control 3 60 37 Example 17 2-17 0.3 19 36 2-17 ≤ control 3 42 36  *: Muraglitaza (Dose 3 mpk)

As shown in Table 2, the 2-ethoxypropionic acid derivatives according to the present invention showed an equivalent or superior glycemic-enhancing effect when compared to the control group, and the result of measuring the weight gain was also equal or increased compared to the control group. Appeared to be small. In particular, the (S) -oriented 2-ethoxypropionic acid derivatives (S) -oriented 2-ethoxypropionic acid derivatives showed better blood glucose enhancing effect, the effect was found to be concentration-dependent. Particularly, in the case of 2-3 derivatives, it was found that even at a dose of 1/10 times lower than the control group, the hypoglycemic effect was excellent.

From this, the pharmaceutical composition containing a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for the prevention and treatment of diabetes as well as the treatment of complications thereby.

Examples of preparations for the therapeutic agents of the present invention are illustrated below.

Preparation Example Preparation of Pharmaceutical Formulation for Oral Administration

One. Powder  Produce

2 g of 2-ethoxypropionic acid derivative

1 g lactose

The above ingredients were mixed and filled in airtight cloth to prepare a powder.

2. Preparation of Tablets

100 mg of 2-ethoxypropionic acid derivative

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

3. Preparation of Capsule

100 mg of 2-ethoxypropionic acid derivative

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

4. Preparation of Injectables

10 ug / ml 2-ethoxypropionic acid derivative

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

The 2-ethoxypropionic acid derivative was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection and thoroughly mixed. . The solution was filled into a 5 ml Type I ampoule made of clear glass, dissolved under glass, enclosed under an upper grid of air, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

2-ethoxypropionic acid derivatives or pharmaceutically acceptable salts thereof of the present invention can be usefully used to prevent and treat diabetes more effectively by double acting on the peroxisome proliferator-activated receptor (PPAR) α or γ receptor. .

Claims (8)

2-ethoxypropionic acid derivative represented by Formula 1, 2 or 3 or a pharmaceutically acceptable salt thereof: <Formula 1>

<Formula 2>

<Formula 3>

(In Formula 1, 2 or 3, X is hydrogen; halogen; C ₁ -C ₄ alkyl which may be unsubstituted or substituted with one or more substituents; C ₅ -C ₇ aryl which may be unsubstituted or substituted with one or more substituents; Hydroxy; C ₁ to C ₅ alkoxy which may be unsubstituted or substituted with one or more substituents; And C ₁ to C ₅ alkylsulfonyl which may be unsubstituted or substituted with one or more substituents, wherein X is any one or two or more of the ortho, meta or para positions of the aromatic ring. Can be substituted in position, Z is

,

And

Any one selected from the group consisting of, Z may be substituted at any one of the meta or para position of the aromatic ring, n is the Z

Is an integer of 1 to 5, wherein Z is

When is an integer of 0 to 5, Z is

Is an integer from 0 to 5, R ¹ and R ² are each selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl which may be unsubstituted or substituted with one or more substituents, "Alkyl" includes straight-chain or branched alkyl, "When X, R ₁ or R ₂ is substituted with one or more substituents", independently or optionally, halogen; C ₁ -C ₁₀ alkyl; C ₁ -C ₁₀ haloalkyl; C ₁ -C ₁₀ heteroalkyl; C ₃ -C ₇ cycloalkyl; 5 to 10 membered heterocycloalkyl; C ₅ -C ₇ aryl; 5 to 10 membered heteroaryl; C ₅ -C ₇ aryl C ₁ -C ₁₀ alkyl; 5 to 10 membered heteroaryl C ₁ to C ₁₀ alkyl; Hydroxy; C ₁ -C ₁₀ alkoxy; C ₃ -C ₇ cycloalkyloxy; 5-10 membered heterocyclo C ₁ -C ₁₀ alkyloxy; C ₅ -C ₇ aryloxy; 5 to 10 membered heteroaryloxy; C ₁ -C ₁₀ alkoxy C ₁ -C ₁₀ alkyl; C ₁ -C ₁₀ alkoxyC ₅ -C ₇ aryl; C ₁ -C ₁₀ alkoxyheteroaryl; C ₅ -C ₇ aryl C ₁ -C ₁₀ alkyloxy; Amino; C ₁ -C ₁₀ alkylamino; Acylamino; C ₅ -C ₇ arylamino; Amino C ₁ -C ₁₀ alkyl; Sulfonyl; C ₁ -C ₁₀ alkylsulfonyl; C ₅ -C ₇ arylsulfonyl; C ₅ -C ₇ arylsulfinyl; Aminosulfonyl; Cyano; C ₁ -C ₁₀ alkylcyano; C ₅ -C ₇ arylcyano; Cyano C ₁ -C ₁₀ alkyl; And cyano C ₅ ~ C _{7 It} means that it can be substituted with any substituent selected from the group consisting of aryl.) The compound of claim 1, wherein X is hydrogen; Fluoro; Chloro; Bromo; Iodo; t-butyl; Trifluoromethyl; Phenyl; Hydroxy; Methoxy; Trifluoromethoxy; And it is any one selected from the group consisting of methanesulfonyloxy, wherein X may be substituted at any one or two or more of the ortho, meta or para position of the aromatic ring, Z is

,

And

Any one selected from the group consisting of, Z may be substituted at any one of the meta or para position of the aromatic ring, n is the Z

Is an integer of 1 to 3, wherein Z is

When is an integer of 0 to 2, Z is

If is 0, R ¹ and R ² Is a 2-ethoxypropionic acid derivative or a pharmaceutically acceptable salt thereof, each of which is selected from the group consisting of hydrogen, methyl and ethyl. The method of claim 1, wherein the 2-ethoxypropionic acid derivative of Formula 1, 2 or 3, rac- 3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1-benzyloxyiminoethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-fluorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-bromobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-iodobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-hydroxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-methanesulfonyloxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-methoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-trifluoromethylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-t-butylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxy cipropionic acid; (R) -3- (3-((E) -1- (4-trifluoromethoxybenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (4-phenylbenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1-phenethyloxyiminoethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (3-phenylpropoxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - ethoxy-3- (3- (4,5-dihydro-5-phenyl-isoxazole-3-yl) phenyl) 2-propionic acid; (S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-fluorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-bromophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-iodophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-hydroxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; ethoxy-3- (4- (5- (4-methanesulfonyloxy-phenyl) -4,5-dihydro-isoxazole-3-yl) phenyl) propionic acid in 2 - rac; (S) -2-ethoxy-3- (3- (5- (4-methanesulfonyloxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-methanesulfonyloxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-methoxyphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; ethoxy-3- (4- (5- (4-trifluoromethyl-phenyl) -4,5-dihydro-isoxazole-3-yl) phenyl) propionic acid in 2 - rac; (S) -2-ethoxy-3- (3- (5- (4-trifluoromethylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-trifluoromethylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (4-t-butylphenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid; (S) -3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid; (R) -3- (3- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid; rac - ethoxy-3- (3- (4,5-dihydro-5-phenethyl-isoxazole-3-yl) phenyl) 2-propionic acid; (S) -2-ethoxy-3- (3- (4,5-dihydro-5-phenethylisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (4,5-dihydro-5-phenethylisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (4- (4,5-dihydro-5-phenylisoxazol-3-yl) phenyl) propionic acid; rac - 3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid; (S) -3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid; (R) -3- (4- (5-benzyl-4,5-dihydroisoxazol-3-yl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (2-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (3-chlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac - 2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (3-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; (R) -2-ethoxy-3- (3- (5- (2-chlorophenyl) -4,5-dihydroisoxazol-3-yl) phenyl) propionic acid; rac - 3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (S) -3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; (R) -3- (3-((E) -1- (2,4-dichlorobenzyloxyimino) ethyl) phenyl) -2-ethoxypropionic acid; rac -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid; (S) -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid; And (R) -2-ethoxy-3- (3- (5-phenylisoxazol-3-yl) phenyl) propionic acid 2-ethoxypropionic acid derivative, or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of. As represented by Scheme 1 below, Optically pure compounds of formula 4 (S) or 4 (R) as starting materials and compounds of formula 5 having substituents of X are substituted with a base such as pyridine, triethylamine or diisopropyl, or acetic acid or paratoluenesulfonic acid. Coupling in the presence of the same acid (step 1); And Decoating the coupling product (6 (S) or 6 (R)) prepared in step 1 in the presence of a base such as lithium hydroxide or sodium hydroxide, and then acidifying by adding hydrochloric acid ( Method for producing a 2-ethoxypropionic acid derivative comprising step 2) ( Preparation 1 ): <Scheme 1>

(Wherein X and n are as defined in claim 1, and the compounds of formulas 2a and 3a are included in the 2-ethoxypropionic acid derivatives of the present invention). According to claim 4, wherein the compound of formula 5 having a substituent of X in Step 1 is O-benzylhydroxylamine hydrochloride; O- (4-fluorobenzyl) hydroxylamine hydrochloride; O- (4-chlorobenzyl) hydroxylamine hydrochloride; O- (4-bromobenzyl) hydroxylamine hydrochloride; O- (4-iodobenzyl) hydroxylamine hydrochloride; O- (4- (t-butyldimethylsilyloxy) benzyl) hydroxylamine hydrochloride; O- (4-methanesulfonyloxybenzyl) hydroxylamine hydrochloride; O- (4-methoxybenzyl) hydroxylamine hydrochloride; O- (4-trifluoromethylbenzyl) hydroxylamine hydrochloride; O- (4-tbutylbenzyl) hydroxylamine hydrochloride; O- (4-trifluoromethoxybenzyl) hydroxylamine hydrochloride; O- (phenethyl) hydroxylamine hydrochloride; And O- (phenylpropoxy) hydroxylamine hydrochloride. The method for producing a 2-ethoxypropionic acid derivative, which is selected from the group consisting of As represented by Scheme 2 below, Coupling a compound of Formula 8, which is a starting material, to a compound of Formula 8 having a substituent of X in the presence of sodium hypochlorite (step 1); De-esterifying the coupling product of Formula 9 prepared in step 1 in the presence of a base such as lithium hydroxide or sodium hydroxide, and then acidifying by adding hydrochloric acid (step 2); Converting the compound of Formula 10 prepared in step 2 into a diastereomer, and then separating each of the diastereomers (step 3); A mixture of Compound (12 (S)) or Compound (12 (R) by hydrolyzing an amide group by adding concentrated sulfuric acid to a solvent in which the diastereomer (11 (S) or 11 (R)) separated in step 3 was dissolved. Obtaining a mixture of c) (step 4); Reacting the mixture of the compound (12 (S)) or the mixture of the compound (12 (R)) hydrolyzed in step 4 with an alcohol in the presence of trimethylsilylchloride for esterification (step 5); And Compound (13 (S)) or compound (13 (R)) esterified in step 5 above is de-esterified in the presence of a base such as lithium hydroxide or sodium hydroxide, and then acidified by addition of hydrochloric acid. Method for producing a 2- ethoxypropionic acid derivative comprising the step ( Preparation 2 ): <Scheme 2>

(In the above scheme, X and n are as defined in claim 1, and formulas 2b and 3b are included in the 2-ethoxypropionic acid derivative of the present invention). The compound (8) according to claim 6, wherein the compound (8) having the substituent X in Step 1 is styrene, 4-fluorostyrene, 3-chlorostyrene, 4-chlorostyrene, 4-bromostyrene, 4-iodostyrene, 4 From the group consisting of methanesulfonyloxystyrene, 4-methoxystyrene, 4-trifluoromethylstyrene, 4-t-butylstyrene, 1-allylbenzene, 1- (but-3-enyl) benzene and phenylacetylene Method for producing a 2-ethoxypropionic acid derivative, characterized in that any one selected. An agent for preventing and treating diabetes, comprising the 2-ethoxypropionic acid derivative of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.