WO2013118949A1 - Phenyl derivatives or pharmaceutically acceptable salts thereof, method for preparing same, and composition comprising same as active ingredients for preventing, improving or treating diseases related to vascular endothelial cells or diabetes - Google Patents

Abstract

The present invention relates to phenyl derivatives or to the pharmaceutically acceptable salts thereof, to a method for preparing same, and to a composition comprising same as active ingredients for preventing, improving or treating diseases related to vascular endothelial cells such as diabetes and diabetic complications. The phenyl derivatives according to the present invention may effectively regulate glucose use, have excellent effects in inhibiting the production of advanced glycation end-product which is a causing factor in diabetic complications, have superior effects in treating (preventing) the pathological widening of the diameter of a vitreous body vessel by hyperglycemia in an animal model (zebra fish), prevent a destruction of a blood-retinal barrier in a diabetic retinopathy-induced animal model (SD rat), increase occludin, which is a protein constituting a tight junction, and significantly reduce pathologically-increased vascular endothelial growth factors. Therefore, the phenyl derivatives of the present invention may be effectively used as a composition for preventing, improving or treating diseases related to vascular endothelial cells, such as diabetes and diabetic complications.

Description

 【Specification】

 Title of the Invention

Phenyl derivative or a pharmaceutically acceptable salt, its preparation method and the ^"vascular endothelial cell-related disease, or prevention of diabetes mellitus containing as an active ingredient, improving or value ryoyong composition

TECHNICAL FIELD

 Phenyl derivatives or pharmaceutically acceptable salts thereof, a process for their preparation, and a composition for preventing, ameliorating or treating a vascular endothelial cell-related disease or diabetes comprising the same as an active ingredient.

BACKGROUND ART [0002]

Diabetes is one of the most important geriatric diseases in the world, and Korea accounts for 10% of diabetes mellitus, now more than 240 million people globally, and in 2025 it will increase to 380 million worldwide, % Reported in the United States Medical Association (JAMA) in 2009 that it will develop in Asia. In particular, the onset of diabetes mellitus has been brought to the middle age, and it has become impossible to avoid complications due to prolonged life expectancy. In general, after 10 to 20 years of diabetes, almost all organs in the body are damaged, leading to diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, And endothelial cell-related diseases such as osteoporosis. Chronic diabetic nephropathy is the most important cause of hemodialysis treatment and end-stage renal failure. Diabetic heart disease causes sudden death without warning, diabetic retinopathy and retinopathy cause blindness and eventually death . In the United States, the cause of blindness in the age group of 25 to 74 years old is diabetes, and after 15 or 20 years after the onset of diabetes, 60% lead to blindness iein R., 1996, Annu. Rev. Public. Health. 66: 366-78). These prevalence rates are increasing (Sharkey TP, 1971, J. Am. Diet Ass. 58: 528). In the case of Korea, according to analysis of the 2006 to 2010 NHS data, the number of elderly diabetics increased rapidly due to aging, resulting in a 54% increase in medical expenses, reaching 203.5 billion KRW. In all age groups, the rate of diabetic complications increased, rather than diabetes. In the 40-50 age group, the rate of peripheral circulation disorder diabetes complication was 6.5 times higher than that of diabetic patients and 2.2 times higher in diabetic retinopathy patients. Words The cost of hypertension complications of diabetes complications increased from 54 billion won in 2006 to 80 billion won in 2010, increasing by 54.4% from 32.7 billion won to 30 billion won in 2010 (Joongang Daily, August 29, 2011). This is because the average life expectancy is increasing and the number of older patients with diabetes is increasing. This indicates how important it is to take precautions to prevent diabetic patients from developing diabetic complications. In the United States, diabetes is the cause of blindness in the 25- to 74-year-old age group, and 60% of blindness after 15 or 20 years of diabetes develops blindness. Therefore, even if the duration of complications in diabetic patients is delayed by 5 or 10 years, the quality of life of patients and their families will be different, and will have a major impact on national finances. Glucose metabolism is crucial to maintaining cell homeostasis. When glucose is increased more than necessary by the secretion of insulin influx of glucose in the blood into the cells it was stored in a tissue, such as muscle and liver in the form of glycogen, and is low when the hydrolysis to release glucose into the ^blood, respond appropriately do. Glucose uptake is the first step in glucose metabolism, and abnormalities in the regulation of glucose in certain tissues due to the abnormal function of the genes and proteins of insulin and insulin receptor glucose transport (GULT) in pathological conditions, leading to the onset of diabetes do. Therefore, when glucose uptake is properly controlled, it is treated at an early stage of diabetes. In addition, typical factors causing diabetic complications due to chronic hyperglycemia are as follows.

 In the long-term hyperglycemic environment, the non-enzymatic glycation of progesterone results in excessive production of the final glycation product, and the resulting final glycation product is irreversibly bound to the protein or lipid, or the final glycation end product (RAGE) And Hwang Woong are abnormally activated and abnormal genes of the related genes are transformed into diabetic complications in various parts of the body.

 The nonenzymatic glycation of protein is the result of the condensation reaction of the amino acid groups such as protein lysine residues and reducing sugars without enzymatic action, glycation endproducts, AGEs) are generated.

That is, the non-enzymatic glycosylation reaction of a protein is (1) an amino acid such as a lysine residue of a protein The aldehyde or ketone of the loop and the reducing sugar forms a nucleophilic addition reaction without enzymatic action to form a schiff base, which is an early stage product, and the Schiff base and adjacent ketoamine adducts are condensed with each other to form a reversible the possibly continued steps to ^"early glycosylation products of polycyclic generate the (2) high blood glucose condition is reversible, perhaps, it has a rearrangement (rearrangement) (Amador i) an early glycosylation product of the type without decomposition screen is the final per-irreversible product The product is produced. And the resulting final glycation products are cross-linked or cross-linked with proteins or lipids to produce irreversible glycated proteins or glycated lipids. In contrast to the somewhat reversible amyotrophic early glycation products, the final glycation products are irreversible reaction products, and once formed, they are not degraded even when blood glucose is normalized, and during the survival period of the protein or lipid bound to the final glycation end, (Vinson, JA et al., 1996, J. Nutritinal Biochemistry 1 559-663; Smith, PR et al., 1992), which is an unusual change in the structure and function of tissues, Eur. J. Biochem., 210: 729-739). For example, glycated albumin, one of the final glycation products produced by the reaction of glucose with various proteins, is an important factor in causing chronic diabetic nephropathy. Glycated albumin is more easily injected into the ganglion cells than normal albumin without glycosylation, and high glucose stimulates mesangial cells to increase the synthesis of extracellular matrix. Overgrowth of glycosylated albumin and increased extracellular matrix cause fibrosis of the glomerulus. Such a mechanism would continue to damage and receive the shrine, leading to the stage of extreme treatment such as hemodialysis or organ transplantation. In addition, it has been reported that collagen in arterial wall due to chronic diabetes mellitus and basement membrane protein in glomeruli are accumulated in tissues by binding with the final glycation products (Brownlee, M., et al., 1986, Sciences, 232, 1629 -1632). Thus, glycosylation occurs in proteins such as basement membrane, plasma albumin, lens protein, fibrin, and collagen by non-enzymatic protein glycosylation reaction, and the resulting final glycated product abnormally changes the structure and function of the tissue to cause diabetic retinopathy Diabetic cataract, diabetic nephropathy, diabetic heart disease, diabetic osteoporosis, diabetic cancer, and diabetic neuropathy. Thus, it has been found that inhibiting the formation of the final glycation end product is very important for delaying, preventing or treating the onset of diabetic complications (Brownlee, M., et al., 1988, N Engl. 1315-1321). Currently, aminoguanidine, known as a protein glycosylation inhibitor, is a nucleophilic hydrazine that binds to the lipid product to prevent cross-linking with the protein, thereby inhibiting the production of the final glycosylated product and delaying its progression to complications Edelstein, D. et al., 1992, Diabetes, 41, 26-29). Aminoguanidine was the most promising synthetic drug for the prevention and treatment of diabetic complications, but it was stopped until the third phase of clinical trials. Diabetic retinopathy leads to vitreous hemorrhage due to chronic retinal hypoxia, ischemia, and vascular permeability, resulting in macular edema or atypical neovascularization leading to proliferative diabetic retinopathy (Aiello LP, 1998, Diabetes Care 21: 143-156). Several factors are involved in this process, most notably the neovascularization factor, a neovascular growth factor known as a vascular permeability factor, plays an important role. Diabetic retinopathy and early changes cause the expression of neovascular growth factor, resulting in a decrease in tight junction proteins such as occludin, resulting in the breakdown of the blood-retinal barrier, the physical barrier of the retina, (Wang et al., 2001, Am. J. Physiol. Heart. Circ.Physiol. 280: H434-40).

 Although there is no drug that has been shown to prevent or inhibit the progression of diabetic retinopathy, many researchers have been interested in inhibition of various growth factors involved in angiogenesis during the development of retinopathy.

 Currently, diabetic retinopathy is treated by laser therapy and vitrectomy. Most of the treatments are surgical, and drug therapy is still in development. However, these surgical treatments cause side effects, and after a period of time, they become more severe ophthalmic diseases. '

Recently, the drug therapy in vitreous cavity, which is a drug therapy, has been performed as a primary or additional treatment for diabetic retinopathy. Intravitreal drug injection The effect is direct and relatively fast.

^■ Research and development of new angiostatic agents have been actively conducted as representative drugs. Steroids inhibit the growth of blood vessel growth factors such as neovascular growth factors that increase vascular permeability, and inhibit arachinoic acid pathway (Sutter FK, 2004, Ophthalmology, 111: 20449), which inhibits the production of prostaglandin and stabilizes the blood retinal barrier.

Recently, intravitreal injection of anti-angiogenic growth factor (anti-VEGF), such as Avastin (bevacizumab), not only reduces macular edema caused by central retinal vein occlusion, but also causes proliferative diabetic retinopathy (Avery RL, 2006, Ophthalmology, 113: 363-72, Spaide RF, 2006, Retina, 26: 275-8, Iturralde D., 2006, Retina, 2 & 279) have been reported to reduce vascular permeability and fibrovascular proliferation -U). However, Avastin has received FDA approval as an anticancer drug, but ophthalmologically it has not been approved by the FDA, and the effects of the drug with steroids do not last for months, and some may require cataracts and glaucoma, have. _t as diabetic complications, a therapeutic agent to date, but wherein been studied variously to one to the material, such as neovascular growth factor, a situation still insufficient up. ^■ The present inventors have found that while trying to research to develop a vascular endothelial cell-related disease or treatment of diabetes, including complications of diabetes, was prepared the phenyl derivatives, other the group compounds in vivo (in vitro) and animal studies (in The present invention has been accomplished based on the findings that the present invention is accomplished by activating glucose uptake rate in vivo and inhibiting the production of final glycosylated products and treating or preventing diabetic complications such as diabetic retinopathy.

DETAILED DESCRIPTION OF THE INVENTION

 [Technical Problem]

 It is an object of the present invention to provide a novel phenyl derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for producing the phenyl derivative. Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating vascular endothelial cell-related diseases containing the phenyl derivative or a pharmaceutically acceptable salt thereof as an active ingredient To provide a composition.

 Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetes comprising the phenyl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

 It is still another object of the present invention to provide a health food composition for preventing or ameliorating vascular endothelial cell-related diseases containing the phenyl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

 Another object of the present invention is to provide a health food composition for preventing or ameliorating diabetes comprising the phenyl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[Technical Solution]

In order to achieve the above object,

A pharmaceutically acceptable salt thereof: < RTI ID = 0.0 >

 [Chemical Formula 1]

(In the formula 1,

R ¹ , R ² and R ³ are as defined herein.

 Also, the present invention provides a process for preparing the above-mentioned formula 1 and a phenyl derivative. Furthermore, the present invention provides a pharmaceutical composition for preventing or treating vascular endothelial cell-related diseases, which comprises the phenyl derivative of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

 The present invention also provides a pharmaceutical composition for the prevention or treatment of diabetes comprising the phenyl derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention relates to a phenyl derivative of the above formula (1) or a pharmaceutically acceptable salt thereof A health food composition for preventing or ameliorating a vascular endothelial cell-related disease containing a salt as an effective ingredient. ^' ,

 The present invention also provides a health food composition for preventing or ameliorating diabetes comprising the phenyl derivative of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

【Advantageous effect】

 The phenyl derivative according to the present invention can effectively control the glucose utilization rate and is excellent in the effect of inhibiting the production of the final glycation end product which is a causative factor of diabetic complication and is capable of widening the diameter of the vitreous blood vessel of the eye from hyperglycemia in an animal model (zebrafish) Not only does it have excellent therapeutic effects, it also prevents the destruction of the blood retinal barrier in diabetic retinopathy-induced animal models (SD rats), increases the occludin, a protein that constitutes tight seams, And thus can be effectively used as a composition for improving or treating prevention of vascular endothelial cell-related diseases or diabetes including diabetic complications. ᅳ

BRIEF DESCRIPTION OF THE DRAWINGS

 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the glucose control effect of the compound prepared in Example 1 of the present invention. FIG.

 FIG. 2 is a graph showing the glucose control effect of the compound prepared in Example 2 of the present invention. FIG.

 FIG. 3 is a graph showing the glucose control effect of the compound prepared in Example 4 of the present invention. FIG.

 FIG. 4 is a graph showing the effect of the compound prepared in Example 10 of the present invention on glucose regulation.

 FIG. 5 is a graph showing the glucose control effect of the compound prepared in Example 14 of the present invention. FIG.

 FIG. 6 is a graph showing the effect of the compound prepared in Example 15 of the present invention on the glucose uptake regulation effect. FIG. ᅳ

Figure 7 shows that when the compound prepared in Example 1 of the present invention was treated, Fig. 8 is a diagram showing changes in the vitreous blood vessels of the shins.

 8 is a graph showing changes in the diameter of vitreous blood vessels of zebrafish when the compound prepared in Example 1 of the present invention is treated.

 9 is a graph showing changes in vitreous blood vessels of zebrafish when the compound prepared in Example 13 of the present invention is treated.

 10 is a graph showing changes in the diameter of the vitreous vessel of zebrafish when the compound prepared in Example 13 of the present invention is treated.

 11 is a graph showing changes in vitreous blood vessels of zebrafish when the compound prepared in Example 15 of the present invention is treated.

Figure 12 is the case after treatment with the compound prepared in Example 15 of the invention shown is a graphical analysis of the change in the glass body of the vessel diameter _zebrafish:

 FIG. 13 is a graph showing changes in vitreous blood vessels of zebrafish treated with the compound ol prepared in Example 21 of the present invention. FIG.

 14 is a graph showing changes in the diameter of the vitreous vessel of zebrafish when the compound prepared in Example 21 of the present invention is treated.

 FIG. 15 is a diagram showing retinal vasculature in a crab-type urinary animal model when the compound prepared in Example 23 of the present invention is treated. FIG.

 FIG. 16 is a graph showing changes in the amount of occludin expression in the retinal blood vessels of the type 2 diabetic animal model when the compound prepared in Example 23 of the present invention is treated. FIG.

 17 is a graph showing changes in the expression level of angiogenic factors in the retinal blood vessels of the second type urea animal model when the compound prepared in Example 23 of the present invention is treated.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail. The present invention provides a phenyl derivative of the general formula (I) or a pharmaceutically acceptable salt thereof. ^'

(1)

In the formula 1,

R ¹ , R ² and R ³ are independently hydrogen; d-Cs linear or branched alkyl group; An amino group substituted with an unsubstituted or Ci-C ₄ linear or branched alkyl; A d-straight or branched alkyl group substituted with 5 to 6-membered heterocycloalkyl; An amino linear or branched dC ₄ alkylcarbonyl group; dC ₄ straight or branched chain alkyl carbonyl group; A carbonyl group substituted with 5 to 6 membered heterocycloalkyl substituted with 5 to 6 membered heterocycloalkyl; C ₅ -C ₆ aryl carbonyl group, ·, Ci-C ₄ straight or branched chain alkyl oxy carbonyl group; dC ₄ straight or branched chain alkoxycarbonyl straight or branched chain alkyl carbonyl group; A phosphono group (-PO (OH) ₂ ), a glucosyl group; A galactosyl group; A rhamnoyl group; Thiazole; Arabinosyl group; Or a glucuronic acid group,

 Wherein said heterocycloalkyl group comprises at least one heteroatom selected from the group consisting of N, O and S. Preferably,

R < ¹ > is hydrogen; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; tert-butyl; Pentyl; Isopentyl; A nuclear core; Isohexyl; Heptyl; Isoheptyl; Octyl; Isooctyl; Dimethylaminomethyl; Dimethylaminoethyl; Dimethylaminopropyl; Dimethylaminobutyl; Diethylaminomethyl; Diethylaminoethyl; Diethylaminopropyl; Diethylaminobutyl; morpholinomethyl; Morpholinoethyl; 1- (1,4'-bipiperidin-1'-yl) carbonyl; Or a phosphono group,

R ² is hydrogen; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; tert-butyl; Pentyl; ^' Isopentyl; A nuclear core; Isohexyl; Heptyl; Isoheptyl; Octyl; Isooctyl;

Dimethylaminomethyl; Dimethylaminoethyl; Dimethylaminopropyl; Dimethylaminobutyl;

Diethylaminomethyl; Diethylaminoethyl; Diethylaminopropyl; Diethylaminobutyl;

Morpholinomethyl; Morpholinoethyl; Methylcarbonyl; Ethylcarbonyl; Propylcarbonyl; Butylcarbonyl; Aminomethylcarbonyl; Aminoethylcarbonyl; Aminopropylcarbonyl; Aminobutylcarbonyl;

Phenylcarbonyl; 1- (1,4'-bipiperidin-1'-yl) carbonyl; Methyloxycarbonylmethylcarbonyl; Methyloxycarbonylethylcarbonyl; Ethyloxycarbonylmethylcarbonyl; Ethyloxycarbonylethylcarbonyl; Methyloxycarbonyl; Ethyloxycarbonyl; Propyloxycarbonyl; Butyloxycarbonyl; Or a phosphono group,

R ³ is hydrogen; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; tert-butyl; Pentyl; Isopentyl; A nuclear core; Isohexyl; Heptyl; Isoheptyl; Octyl; Isooctyl; A glucosyl group; A galactosyl group; A rhamnoyl group; Gypsum; Arabinosyl group; Or a glucuronic acid group. More preferably,

R < ¹ > is hydrogen; methyl; ethyl; Isopropyl; Pentyl; Isopentyl; Dimethylaminoethyl; Morpholinoethyl; 1- (1,4'-bipiperidin-1'-yl) carbonyl; Or a phosphono group,

R ² is hydrogen; methyl; ethyl; Isopropyl; Pentyl; Isopentyl; Dimethylaminoethyl; Morpholinoethyl; Methylcarbonyl; Aminomethylcarbonyl; Phenylcarbonyl;

1 (1,4'-bipiperidinyl) carbonyl; Ethyloxycarbonylethylcarbonyl;

Ethyloxycarbonyl; Or a phosphono group,

R ³ is hydrogen; Or a glucosyl group. The phenyl derivative represented by the above formula (1) is more specifically exemplified as follows.

 (1) 3 ', 4 ' hydroxy-5-me ectivebiphenyl-3-yl acetate;

 (2) Synthesis of 3'-meroxy-5'- (2-morpholinoethoxy) biphenyl-3,4-dihydrochloride

 (3) 3 '-( pentyloxy) z5 '-mecicobiphenyl-3,4-di;

 (4) a 3'-benzyl-5'-methicobiphenyl-3, 4'-diol;

 (5) 3 '(isopentyloxy) ᅳ 5' -methoxybiphenyl-3,4-diol;

 (6) 3'-isopropoxy-5'-methoxybiphenyl-3,4-diol;

 (7) 3 ', 4 ' -dihydroxybenzoic acid 5-methicobiphenyl-3-yl 2-aminoacetate hydrochloride;

 (8) 3 '- [2- (Dimethylamino) ethoxy] -5'-methoxybiphenyl-3,4-diol hydrochloride;

 (9) 3 ', 4'-dihydroxy-5-mehoxybiphenyl-3-ylethylcarbonate;

(10) 3 ', 4'-dihydroxy-5-megestiviphenyl-3-yl benzoate; (11) 3 ', 4'-dihydroxy-5'-methicycibiphenyl-3-yl 1,4'-bipiperidine-1'-carboxylate;

 (12) 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-yl dihydrogen phosphate;

(13) 3 ', 4 ' -dihydroxyziphenylcarbiphenyl-3-ylethyl succinate;

 (14) 4,5'-Dimethoxybiphenyl-3,3'-dodecyl;

 (15) 4-eroxy ' 5 ' -methyloxybiphenyl-3,3 '-di;

 (16) 5'-methoxy-4- (pentyloxy) biphenyl-3,3'-di;

 (17) 4- (isopentyloxy) ᅳ 5'-methoxybiphenyl-3,3'-diol;

 (18) 4? Isopropoxy-5 '-methoxybiphenyl-3,3'-dyes;

 (19) 4- [2- (dimethylamino) ethoxy] -5'-methoxybiphenyl-3,3'-diol hydrochloride;

20 5'-blind-4- (2-molpeul Reno a particular city) biphenyl-3,3 '- dayieul hydrochloric _fried;',, ^'

 (21) 3,3'-dihydroxy-5'-methoxybiphenyl-4-yl 1,4'-bipiperidine-1'-carboxylate;

 (22) Synthesis of 3,3'-dihydroxy-5'-methoxybiphenyl-4-ylidenehydrogenphosphate

^• e - ᄆ J

(23) 4-hydroxy-3 ', 5'-dimethoxy-isoquinoline-(eu 1, ^1'-biphenyl) -3-0-β-Ε) - glucoside. The preferred structures of the phenyl derivatives represented by Formula 1 according to the present invention are shown in Table 1 below.

 [Table 1]

S08 ^ 00 / iT0ia¾ / X3d 61-68H / C10Z OAV

ει

S08f00 / iT0ZMM / 13d 6f68ll / £ l0Σ: OAV

The derivatives of formula (I) of the present invention can be used in the form of pharmaceutically acceptable salts, and as salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, alkane video obtained from the maleate, aromatic acids, aliphatic and aromatic sulfonic acids with non-toxic organic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-reulru ^\ enseol acid, tartaric acid, fumaric acid, and organic acids such as . Such pharmaceutically non-toxic salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate methaphosphate pyrophosphate, chloride, But are not limited to, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Benzoate, carboxybenzoate, phthalate, terephthalate, benzene sulphate Butyrate, glycolate, maleate, tartrate, maleate, maleate, maleate, maleate, maleate, maleate, maleate, maleate, maleate, maleate, maleate, Methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate. .

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Filtration, and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying or crystallization in an organic solvent. In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkaline metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. Further, the silver salt obtained by counteracting the salt with an alkali metal or an alkaline earth metal salt with a suitable salt (such as silver nitrate). The present invention also includes all possible solvates, hydrates, and the like, which can be prepared therefrom, as well as the phenyl derivatives of Formula 1 and pharmaceutically acceptable salts thereof. The present invention also provides a process for preparing the phenyl derivative of formula (1). Recipe 1

 As shown in the following Equation 1,

 Tripping the compound of formula (2) to obtain the compound of formula (3) (step 1); And a step of repelling the compound of formula (3) prepared in step 1 above in the presence of hydrogen gas to obtain a compound of formula (1A) (step 2).

 [Reaction Scheme 1]

 1A

(In the above Reaction Scheme 1,

The substituent R ² is the same as defined in Formula 1, and the compound of Formula 1A is a phenyl derivative of Formula 1. In the production method 1 according to the present invention, the step 1 is a step of introducing a substituent R ² into the compound of the formula (2). After the compound of formula (2) is dissolved in an organic solvent, the compound having R ² substituent is reacted in the presence of a base to obtain the compound of formula (3) . At this time, as the organic solvent which can be used, at least one solvent selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran, diethyl ether and the like can be used as a solvent which does not affect the reaction, Acetonitrile can be used. The base may be at least one selected from the group consisting of sodium hydride, potassium hydride, sodium eroxides and pyridine, preferably pyridine. Further, However, the phase may be carried out within the boiling range of the solvent to the solvent, preferably at room temperature. Specifically, the compound of formula (2) is added to acetonitrile, the base is added, and the mixture is stirred for 2 to 3 hours. After completion of the reaction, column chromatography is performed to obtain the compound of formula (3). Step 2 is a step of performing a hydrogen reduction reaction on the compound of Formula 3 prepared in Step 1 to obtain the compound of Formula 1A.

 At this time, the compound of formula (2) prepared in step 1 is dissolved in methanol, and hydrogen gas is used in the presence of a small amount of active metal catalyst to carry out the reaction using a pressurized reaction mixture. After completion of the reaction, palladium is removed by filtration under reduced pressure to obtain the compound represented by the formula (1A).

The hydrogen reduction reaction used in this reaction is performed by pressurization reaction using hydrogen gas in the presence of a small amount of active metal catalyst such as Raney nickel and palladium-activated carbon widely used in reduction reaction. Here, as the anti-Hwang catalyst, a reducing catalyst in which 5-10 wt% of bradadium is supported on a support such as activated carbon, alumina, or silica can be used, preferably palladium supported on activated carbon. In this case, the use of methane as an organic solvent that does not adversely influence the banung, ethanol, 2-propanol, _isobutanol,. Butanol, dichloromethane, chloroform, tetrahydrofuran The reaction may be carried out using diethyl ether, ethyl acetate or the like, and preferably, a solvent in which methane and ethyl acetate are mixed. In addition, the reaction temperature is not particularly limited, but can be performed within a range of room temperature to the boiling point of the solvent. Specifically, the compound of formula (2) is dissolved in methane, palladium-carbon is added in a catalytic amount, and hydrogen is added and stirred. After completion of the reaction, palladium is removed by filtration under reduced pressure to obtain the compound represented by the formula (1A). If necessary, the compound of the formula (1A) may be dissolved in an organic solvent and then added with a hydrochloric acid solution to form a salt, but the present invention is not limited thereto. At this time, as the organic solvent which can be used, at least one solvent selected from the group consisting of methane, ethane, acetonitrile, tetrahydrofuran, diethyl ether and the like can be used as a solvent which does not affect the reaction Acetonitrile can be used. Recipe 2

^' Further, as shown in Reaction Scheme 2 below,

Tripping the compound of formula 4 to obtain the compound of formula 5 (step 1); And banung to a compound of formula (5) prepared in Step 1 in a hydrogen gas exists, it is possible to manufacture a phenyl derivative of formula (I), including compounds come obtaining step (step 2) of the formula 1B: ^'

[HanWoong2] ^.

(In the above equation 2,

The substituent R ¹ is as defined in the above formula (1), and the compound of the above formula is a phenyl derivative of the formula (1). - In the ^"production method 2 of the present invention, the step 1 is a step of introducing the R ¹ substituent in the compound of formula (4). After the compound of formula (4) is dissolved in an organic solvent, a compound having an R ² substituent may be subjected to a reaction in the presence of a base to obtain a compound of formula (5). At this time, the organic solvent which can be used is a solvent which does not affect the reaction, that is, methane, ethane, acetonitrile, tetrahydrofuran or diethyl ether. , And acetonitrile can be preferably used. The base may be at least one selected from the group consisting of sodium hydride, potassium hydride, sodium eroxides, and pyridine, preferably pyridine. Further, the reaction temperature is not particularly limited, but may be performed within a range of room temperature to the boiling point of the solvent, and preferably at room temperature. Specifically, the compound of formula (4) is added to acetone, followed by addition of a base, stirring for 2-3 hours, termination of the reaction, and column chromatography to obtain the compound of formula (5). Step 2 is a step of performing a hydrogen reduction reaction on the compound of Chemical Formula 5 prepared in Step 1 to obtain a compound represented by Chemical Formula 1B. ^\

 At this time, the compound of Chemical Formula 5 prepared in Step 1 is dissolved in methanol, and hydrogen gas is used in the presence of a small amount of an active metal catalyst to perform the reaction using a pressurized reaction mixture. After completion of the reaction, palladium is removed by filtration under reduced pressure to obtain the compound represented by the formula (1B).

The hydrogen reduction reaction used in this reaction is performed by hydrogen gas in the presence of a small amount of active metal catalyst such as Raney nickel, palladium and activated carbon widely used in the reduction reaction. As the anti-catalyst, a catalyst such as activated carbon, alumina, silica or the like supported with palladium of 5-10% by weight may be used. Preferably, palladium supported on activated carbon may be used. Examples of usable organic solvents include methane, ethane, 2-propane, isobutane, butane, dichloromethane, chloroform, tetrahydrofuran, diethyl ether or ethyl acetate, which do not adversely affect the reaction. Can be used to carry out the reaction, and preferably a solvent of methanol and ethyl acetate can be used. The compound of formula (5) is dissolved in methane, palladium-carbon is then added in a catalytic amount, and hydrogen And the mixture is stirred. After completion of the reaction, palladium is removed by filtration under reduced pressure to obtain a compound represented by the formula (1B). If desired, the compound of formula (1B) may be dissolved in an organic solvent and then added with a hydrochloric acid solution to form a salt, but the present invention is not limited thereto. At this time, as the organic solvent which can be used, at least one selected from the group consisting of methanol, ethane, acetonitrile, tetrahydrofuran, diethyl ether and the like can be used as a solvent which does not affect the reaction, Acetonitrile can be used. Recipe 3

 Further, as shown in the following equation (3)

 Tripping the compound of formula 6 to obtain the compound of formula 7 (step 1); And isolating the compound of formula (VII) prepared in step (1) in the presence of hydrogen gas to obtain a compound of formula (1C) (step 2).

 [Hanwoong 3]

(In the above equation 3,

R ³ is as defined in Formula 1, and the compound of Formula 1C is a phenyl derivative of Formula 1.

In the production method 3 according to the present invention, the step 1 is a step of introducing a substituent R ³ into the compound of the formula (6). The compound of formula (6) may be dissolved in an organic solvent, and then the compound having an R ³ substituent may be subjected to a reaction in the presence of a base to obtain a compound of formula (7). At this time, as the organic solvent which can be used, at least one selected from the group consisting of methanol, ethane, acetonitrile, tetrahydrofuran, diethyl ether and the like can be used as a solvent which does not affect the reaction, Acetonitrile can be used. The base may be at least one kind selected from the group consisting of sodium hydride, potassium hydride, sodium ericonide, pyridine, and the like, preferably pyridine. Furthermore, the antistatic silver salt is not particularly limited, but may be carried out at a temperature ranging from room temperature to a boiling point of the solvent, and preferably at room temperature. Specifically, after the compound of formula (6) is added to acetone, the base is added, and the mixture is stirred for 2-3 hours. After completion of the reaction, column chromatography is conducted to obtain the compound of formula (7). Step 2 is a step of performing a hydrogen reduction reaction on the compound of formula (7) prepared in step 1 to obtain a compound represented by formula (1C).

 At this time, the compound of Chemical Formula 7 prepared in Step 1 is dissolved in methanol, and hydrogen gas is used in the presence of a small amount of an active metal catalyst to perform the reaction using a pressurized reaction. After completion of the reaction, palladium is removed by filtration under reduced pressure to obtain a compound represented by the formula (1C).

The hydrogen reduction reaction used in this reaction is carried out using hydrogen gas in the presence of a small amount of an active metal catalyst such as Raney nickel, palladium-activated carbon, etc. widely used in reduction reaction Pressure reaction. As the reaction catalyst, there can be used a reducing catalyst in which 5-10 wt% of palladium is supported on a support such as activated carbon, alumina or silica, preferably palladium supported on activated carbon.

. The organic solvent that can be used herein is methanol, ethane, 2-propanol, isobutane, butanol, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, etc., , Preferably a coalescing solvent of methane and ethyl acetate. In addition, the reaction temperature is not particularly limited, but can be performed within a range of room temperature to the boiling point of the solvent. Specifically, the compound of formula (7) is dissolved in methane, palladium-carbon is added in a catalytic amount, and hydrogen is added and stirred. After the completion of the reaction, palladium is removed by filtration under reduced pressure to obtain a compound represented by the formula (1C). If necessary, the compound of the formula (1C) is dissolved in an organic solvent and then a hydrochloric acid solution is added thereto. But is not limited thereto. At this time, as the organic solvent which can be used, at least one selected from the group consisting of methanol, ethane, acetonitrile, tetrahydrofuran, diethyl ether and the like can be used as a solvent which does not affect the reaction, Acetonitrile can be used. ^{"Furthermore,} the present invention provides a vascular endothelial cell-related diseases, the prevention or treatment a pharmaceutical composition comprising a phenyl derivative or a pharmaceutically acceptable salt thereof of formula (I) as an active ingredient.

The endothelial cell-related diseases include diabetic complications and the like. Examples of the diabetic complications include diabetic retinopathy, diabetic cataract diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic cancer, Diabetic atherosclerosis, and the like. The present invention also relates to a phenyl derivative of the above formula (1) or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating diabetes containing an effective salt as an active ingredient is provided. The phenyl derivative of formula (1) according to the present invention activates abnormal glucose control ability which causes diabetes and significantly inhibits the absorption (see Experimental Example 1), and the phenyl derivative of the formula (1) As a result of the measurement of the production inhibitory effect, it was proved that the test group treated with the compound according to the present invention was more excellent in efficacy than aminoguanidine, which is known as a conventional end glycocalyx production inhibitor (see Experimental Example 2) (Tokuda H. et al., 2005, < RTI ID = 0.0 >

53rd GA Congress joint with SIF, P076), a pharmaceutical composition for preventing, ameliorating or treating diabetic cancer (see Experimental Example 2).

 In addition, the compound according to the present invention has an effect of treating (preventing) the diameter of the eye glass body that is pathologically enlarged due to hyperglycemia to a normal level again (see Experimental Example 3) In order to confirm the therapeutic effect on retinas induced by retinopathy, blood retinal barrier was destroyed in the animal test (in vivo) and in the group in which diabetic retinopathy was induced, but the test treated with the compound according to the present invention The group has the effect of preventing the destruction of the blood retinal barrier, increasing the amount of ecludine, the protein that constitutes the dense seam, and significantly reducing the pathologically increased neovascular growth factor (see Experimental Example 4).

^• Thus, the phenyl derivatives according to the present invention may be useful as endothelial cell-related diseases, or the prevention or treatment of a pharmaceutical composition for diabetes, including complications of diabetes. The composition comprising the phenyl derivative of the present invention preferably comprises 0.1 to 50% by weight of the composition based on the total weight of the composition, but is not limited thereto. ^"The compositions of the present invention may further comprise a suitable carrier, and ended the dilution agent to be typically used in the manufacture of a medicament. .

The composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method have. May be included in the composition of the present invention. Examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbic, mannitol, xyli, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, chitosan phosphate, calcium silicate, Rosin, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared by using a commonly used filler, an extender, a binder, a wetting agent, a disintegrating agent, a surfactant, etc., a chelating agent or an excipient. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one or more excipients such as starch, calciuneum carbonate, Sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as rib oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao bean, laurea bean, glycerol gelatin and the like can be used. The composition of the present invention may be administered orally or parenterally, and any parenteral administration method may be used.

 The preferred dosage of the composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art.

 The compositions of the present invention may be used alone or in combination with methods using surgery, radiotherapy, hormone therapy, chemotherapy and biological antagonists. Furthermore, the present invention provides a health food composition for preventing or ameliorating a vascular endothelial cell-related disease containing the phenyl derivative of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the vascular endothelial cell-related diseases include diabetic complications and the like, Urine complications include diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic cancer, diabetic atherosclerosis, and the like. The present invention also provides a health food composition for preventing or ameliorating diabetes, comprising the phenyl derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The phenyl derivative of the formula (1) according to the present invention activates abnormal glucose-regulating ability to cause diabetes and significantly inhibits the absorption (see Experimental Example 1), and the phenyl derivative of the formula As a result of the measurement of the production inhibitory effect, it was proved that the test group treated with the compound according to the present invention was more excellent in efficacy than the aminoguanidine known as the conventional end glycocalyx production inhibitor (see Experimental Example 2) (Tokuda H. et al., 2005, Book 53 Abstract 53rd GA Congress of SIF, P076), and can be usefully used in health food compositions for the prevention or improvement of diabetic cancer Experimental Example 2).

 In addition, the phenyl derivative of formula (I) according to the present invention not only exhibits the effect of treating (preventing) the eye of the vitreous body widely enlarged due to hyperglycemia at a normal level (see Experimental Example 3) In order to confirm the therapeutic effect on the retinas induced by diabetic retinopathy, in vivo experiments were carried out. In the group in which diabetic retinopathy induced, the blood retinal barrier was destroyed. However, The test group treated with the derivatives has the effect of preventing destruction of the retinal barrier of the retinal pigment epithelium, increasing the amount of occludin, a protein that constitutes tight seams, and significantly reducing pathologically increased neovascular growth factors 4).

 Accordingly, the phenyl derivative of formula (I) according to the present invention can be effectively used as a health food composition for preventing or ameliorating vascular endothelial cell-related diseases or diabetes, including diabetic complications. The composition according to the present invention may be added to a health supplement such as food or drink for the purpose of preventing or ameliorating vascular endothelial cell-related diseases or diabetes including diabetic complications.

- There are no particular restrictions on the type of food. In the formula Examples of products include dairy products, including syrups, sausages, bread, biscuits, rice cakes, candies, snacks, confectionery, pizza, ramen, other noodles, gums and ice cream, dairy products, various sour drinks, alcoholic beverages and vitamin complex dairy products Dairy products, etc., and includes all the health functional foods in ordinary wami.

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

 The intestine functional beverage composition of the present invention is not particularly limited to other components other than those containing the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages . Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xyli, sorbic acid, erythritol and the like. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the composition of the present invention.

 In addition to the above, the phenyl derivative represented by Chemical Formula (1) of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate, etc.) Salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the phenyl derivatives of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

These components may be used independently or in combination. The ratio of such additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the phenyl derivative of the present invention. In addition, the present invention provides a method for preventing or treating diabetic vascular endothelial cell-related diseases, comprising the step of administering the phenyl derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof .

 The endothelial cell-related diseases include diabetic complications, and the diabetic complications include diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic cancer , Diabetic atherosclerosis, and the like.

DETAILED DESCRIPTION OF THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to Production Examples, Examples and Experimental Examples.

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

PREPARATION EXAMPLE 1 Preparation of 1- (benzyloxy) -3-iodo-5-

 Step 1: Preparation of 3-amino-5-methoxyphenol

(5.0 g, 32.64 mol) was dissolved in methyl-2-pyrrolidinone (25 ml), and sodium thiomide (4.6 g, 65.28 mmol) was added thereto at 0 ^° C. The whole was slowly added and stirred at 140 ^° C for 1.5 hours. After cooling to room temperature, the reaction was terminated with a saturated aqueous solution of potassium hydrogen phosphate and extracted with ethyl acetate. The organic solvent layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 1: 1) to give the title compound (2.9 g, Off-white solid.

^{1 H-NMR (400 MHz,} CDC1 3) δ 5.84 (s, 2H), 5.80 (s, 1H), 4.81 (br, 1H), 3.72 (s, 3H), 3.68 (br, 2H) ' Step 2: Preparation of 3-iodo-5-methoxyphenol

The compound prepared in step 1 (2.6 g, 18.68 mmol. ) And then added to water (26 ml) concentrated sulfuric acid solution (3.0 ml, 56.05睡ol) and sodium nitrite (1.5 g, 22.42 mmol) aqueous solution of -5 ^° to C. The mixture was slowly added dropwise and stirred for 30 minutes. An aqueous solution of diethyl ether (26 ml) and potassium iodide (12.4 g, 74.74 mmol) was added thereto at the same temperature, and the mixture was further stirred at room temperature for 4 hours. Extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic solvent layer was dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 4: 1) to give the title compound (2.7 g, yield 58%, red solid). ,

 (T, 1.8 Hz, 1H), 6.80 (t, 7-1.8 Hz, 1H), 6.35 (t, J = 1.8 Hz, 1H), 4.83 3.75 (s, 3H) Step 3: Preparation of 1- (benzyloxy) -3-iodo-5-

The compound (2.7 g, 10.80 mmol) prepared in Step 2 was dissolved in acetone (50 ml), and then potassium carbonate (2. ² g, 16.20 睡 ol) and benzyl bromide (1.9 ml, 16.20 瞧 ol) And refluxed for 7 hours. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 1: 1) to obtain the title compound (3.2 g, yield: 86.4%, colorless oil).

 J = 1.8 Hz, 1H), 6.87 (t, J = 1.8 Hz, 1H), 6.48 (t, J = 2.2 Hz, , ≪ / RTI > 1H), 5.00 (s, 2H), 3.75 (s,

PREPARATION EXAMPLE 2 Preparation of 3, 4-bis (benzyloxy) phenylboronic acid

Step 1: Preparation of 1, 2-bis (benzyloxy) benzene

(10.0 g, 0.09 mol) was dissolved in acetone (80 ml). Potassium carbonate (37.7 g, 0.27 mol) and benzyl bromide (32.4 ml, 0.27 mol) were added in the flask and refluxed overnight. After cooling to room temperature, the reaction mixture was cooled with cold ice water, filtered and dried to obtain the title compound (19.0 g, yield: 72%, white solid).

¾-NMR (400 MHz, CDC1 3) δ 7.48-7.46 (m, 4H), 7.39-7.30 (m, 6H), 6.97-6.94 (m, 2H), 6.92-6.88 (m, 2H) Step 2: ( Preparation of 4-bromo-1,2-phenylene) bis (oxy) bis (methylene) dibenzene

The compound (17.0 g, 0.06 mol) obtained in the above step 1 was dissolved in carbon tetrachloride (70 ml), and then bromosuccinimide (12.5 g, 0.07 mol) was added thereto and refluxed for 1.5 hours. The residue was extracted with dichloromethane and washed with aqueous 1N sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure, followed by filtration and drying under methane to obtain the title compound (12.4 g, yield 57%, white solid).

 (D, J = 8.6 Hz, 2.2 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H) J = 8.8 Hz, 1H) Step 3: Preparation of 3, 4-bis (benzyloxy) phenylboronic acid

The compound (1.0 g, 2.71 mol) prepared in the above step 2 was dissolved in tetrahydrofuran (10 ml) and then a 2.571 / n-butyllithium nucleic acid solution (1.6 ml, 4.06 ol ol) was slowly added dropwise at -78 ^° C And stirred for 1 hour. To the reaction mixture was added triisopropyl borate (1.6 ml, 6.77 隱₀ 1) was added at the same temperature and slowly warmed to room temperature and further stirred for 5 hours. 3 aqueous solution (40 ml), the reaction mixture was extracted with ethyl acetate, and washed with a saturated aqueous solution of sodium chloride. The organic solvent layer was dried over anhydrous sodium sulfate. The solvent was then concentrated under reduced pressure, and the residue was purified by recrystallization in dichloromethane and petroleum ether to obtain the title compound (0.46 g, yield: 51.4%, white solid).

 -NMR (400 thym, CDCl3). 2H), 7.53-7.47 (m, 4H), 7.41-7.29 (m, 6H), 7.04 (d, J = 7.6 Hz,

PREPARATION EXAMPLE 3 Preparation of 3 ', 4'-bis (benzyloxy) -5-methoxybiphenyl ᅳ 3 ᅳ

 The compound (90 mg, 0.36 mmol) obtained in the above Step 2 of Preparation Example 1 was dissolved in ethanol and then treated with boronic acid (100 mg, 0.3 ol ol), barium hydroxide octahydrate (140 mg, 0.45 mmol) and palladium (Π) acetate (7 mg, 0.036 thymol) in that order, and the mixture was stirred at room temperature for 2 hours. After filtration through celite, the mixture was extracted with ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic solvent layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 5: 1) to obtain the desired compound (73 mg, yield: 59% ≪ / RTI >

_{-NMR (400 MHz, CDC1 3)} δ 7.48-7.45 (m, 4H), 7.39-7.31 (m, 6H), 7.15-7.14 (m, 1H), 7.08-7.06 (m, 1H), 6.98-6.96 ( 2H), 6.36-6.35 (m, 1H), 5.21-5.19 (m, 4H), 5.02 (s,

: Preparation Example 4> Preparation of 2- (benzyloxy) -4-bromophenol

(3.2 g, 27.24 mmol) and potassium carbonate (4.1 g, 29.97 mmol) were dissolved in acetone (20 ml) and then benzyl bromide (3.2 mL, 27.24 mmol) I was surprised. The reaction was then quenched with water and extracted with ethyl acetate After drying with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 ml), acetic acid (0.81 ml, 14.28 ol ol) and bromine (0.4 ml, 7.79 mmol) were added, respectively, and the mixture was stirred at room temperature for 1 hour. The reaction was terminated with water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 5: 1) to obtain the desired compound (5.2 g, yield: 62%, colorless liquid).

¾-NMR (400 MHz, CDC1 3) δ 7.42-7.34 (m, 5H), 7.06 (s, 1H), 7.02 (d, J-8.8Hz, 1H), 6.83 (d, J = 8.3Hz, 1H) , 5.07 (s, 2 H)

PREPARATION EXAMPLE 5 Preparation of 3 (benzyloxy) -5-mexylphenylboronic acid

The compound (3.7 g, 10.84 mmol) prepared in the step 3 of Preparation Example 1 was dissolved in dry tetrahydrofuran (30 ml), the temperature was lowered to -78 ^° C, and a 2.5M n-butyllithium nucleic acid solution ml, 23.86 mmol) was slowly added dropwise and the mixture was stirred for 2 hours. Triisopropyl borate (3.75 ml, 16.27 mmol) was added to the reaction mixture at the same temperature, and the mixture was slowly warmed to room temperature and further stirred for 3 hours. The solvent was evaporated under reduced pressure, and 1N aqueous sodium hydroxide solution (28 ml) was added thereto. The mixture was stirred for 10 minutes. Then, impurities were removed with dichloromethane (10 ml) and acidified with concentrated hydrochloric acid. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 5: 1) to obtain the desired compound (1.1 g, yield: 39%, yellow Liquid).

 1H NMR (400 MHz, CDCl3) δ 7.50-7.32 (s, 1H), 6.93 (s, 1H) , 3H)

PREPARATION EXAMPLE 6 Preparation of 3,3'-bis (benzyloxy) -5'-methicobiphenyl-4

(9 mg, 2 mol%) of tetrakis (triphenylphosphine) palladium (130 mg, 0.46 mole) prepared in Preparation Example 5 and the compound prepared in Preparation Example 4 (100 mg, 0.38 mol) ) Was dissolved in 1, 2-dimethoxyethane (5 ml), 2N aqueous sodium carbonate solution (0.6 ml) was added, and the mixture was stirred at 70 ^° C for one day. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 5: 1) to obtain the desired compound (70 mg, reaction yield: 37%, yellow liquid).

_{-NMR (400 MHz, CDC1 3)} δ 7.46-7.34 (m, 5H), 7.12-7.09 (m, 2H), 6.99 (d, J = 8.3Hz, 1H), 6.72 (s, 1H), 6.65 (s 2H), 5.08 (s, 3H), 2.28 (s, 2H)

Example 1 Preparation of 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-yl acetate Step 1: Preparation of 3', 4'- bis (benzyloxy) 3-yl acetate

Acetic anhydride (3 ml) was added to the compound prepared in Preparation Example 3 (50 mg, 0.12 mmol), pyridine (1 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, uracil (10 ml) was added and concentrated to obtain the desired compound (51 mg, yield: 93%, yellow liquid). ¬ eu應R (400腿z, CDC1 3) δ 7.48-7.45 (m, 4H), 7.39-7.31 (m, 6Η), 7.15-7.14 (m, 1H), 7.09-7.07 (m, 1H), 6.99 (M, 1H), 6.82 (s, 3H), 6.96 (m, , 2.31 (s, 3H) Step 2: Preparation of 3 ', 4'-dihydroxy-5-megestiviphenyl-3-yl acetate

 The compound obtained in the above step 1 (51 mg, 0.11 mmol) was dissolved in methane (5 ml), palladium carbon black (51 mg) was added at room temperature, and the mixture was stirred under hydrogen gas for 10 hours. After confirming the completion of the reaction, the palladium-carbon was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 3: 1) to obtain the desired compound (16 mg, yield 53% ).

 3H), 6.57-6.55 (m, IH), 3.80 (s, 3H), 6.70-6. 2.32 (s, 3H) ᅳ

Example 2 Preparation of 3'-mehroxy-5 '- (2-morpholinoeoxy) biphenyl-3,4-diol hydrochloride

 Step 1: Preparation of 3'-methoxy-5 '- (2-morpholinoeoxy) biphenyl-3,4-diol

The compound (50 mg, 0.12 mmol) prepared in Preparation Example 3 was dissolved in acetonitrile (10 ml), potassium carbonate (50 mg, 0.36 mmol) and 4- (2-chloroethyl) It was added and then the tarpaulins (27 mg, 0.15 mraol) was heated overnight at 60 ^° C. After completion of the reaction, the reaction mixture was extracted with a saturated aqueous sodium bicarbonate solution and ethyl acetate, and purified by column chromatography (nucleic acid: ethyl acetate The compound thus obtained was dissolved in methane (5 ml), palladium-carbon (50 mg) was added at room temperature, and the mixture was stirred under hydrogen gas for 10 hours. After completion of the reaction, the palladium-carbon was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 3: 1) to obtain the desired compound (26 mg, yield: .

 (M, 2H), 6.60 (s, 1H), 6.48 (s, 1H), 6.34-6.33 2H), 3.80-3.75 (m, 7H), 2.88 (t, J = 5.6Hz, 2H), 2.7-2.68 (m, 4H). Step 2: Preparation of 3'-methoxy-5'- (2-morpholinoethoxy) biphenyl-3,4-diol hydrochloride

The compound (26 mg, 0.08 mmol) prepared in the above step 1 was dissolved in dioxane (3 ml), 4M hydrochloric acid dioxane solution (0.5 ml) was added at 0 ^° C, and the mixture was stirred at room temperature for 10 hours. The solvent was concentrated under reduced pressure, washed with ethyl acetate, and then dried to obtain the desired compound (26 mg, yield: 91%, yellow oil).

^{: H-NMR (400 MHz,} DMS0-d 6) δ 10.59 (br, 1Η), 9.13 (s, 1H), 8.99 (s, 1H), 7.03 (ITI, 1H), 6.95-6.93 (m, 1H) 2H), 3.79 (br, 2H), 3.79-3.75 (m, 5H), 3.57 (m, 2H), 6.81-6.79 -3.50 (m, 4 H), 3.22 (br, 2 H)

Example 3 Preparation of 3'- (pentyloxy) -5'-methoxybiphenyl-3,4-di

The target compound (12.9 mg) was prepared in the same manner as in Example 1, except that pentane was used instead of acetic anhydride in Step 1 of Example 1.

 - Anon (400 MHz, CDCl3); J = 4.2 Hz, 1H), 6.66-6. 64 (m, 2H), 6.43-6.42 (m, 1H) (M, 2H), 5.39 (br, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 1.81-1.78 = 6.8 Hz, 3H), 6.59-6.58 (m, IH), 5.20-5.19 (m, 4H), 3.82 (s,

<Example 4> ₃ '- _eu-ethoxy-5' - Preparation of methoxy-biphenyl-3, 4-diol

The objective compound (22.5 mg) was prepared in the same manner as in Example 1, except that ethane was used instead of acetic anhydride in Step 1 of Example 1. .

¾-NM (400 MHz, CDCI 3) δ 7.09 (d, J = 2.0Hz, 1H), 7.03 (dd, J = 8.2Hz, 2.2Hz, 1H), 6.90 (d, J = 8.4Hz, 1H), 2H), 6.42 (t, J = 2.2 Hz, 1H), 5.32 (br, 2H), 4.06 (qt, J = 6.8 Hz, 2H), 3.82 , J = 7.2 Hz, 3H)

Example 5 Preparation of 3 '- (isopentyloxy) -5'-methoxybiphenyl-3,4-di

The objective compound (16.1 mg) was prepared in the same manner as in Example 1, except that isopentane was used in place of acetic anhydride in Step 1 of Example 1.

 7.03 (d, J = 5.2 Hz, 1 H), 7.03 (d, J =

2H), 6.43-6.42 (m, 1H), 5.47 (br, 2H)

2H), 3.83 (s, 3H), 1.83 (m, 1H), 1.71-1.66 .98-0.96 (m, 6H)

Example 6 Preparation of 3'-isopropoxy-5'-methoxybiphenyl-3,4-diol

The target compound (10.5 mg) was prepared in the same manner as in Example 1, except that isopropanol was used instead of acetic anhydride in Step 1 of Example 1.

 (M, 2H), 6.42-7.00 (m, 1H), 6.90 (d, J = 3H), 1.36-1.34 (m, 6H), 6.82 (m, IH)

Example 7 Preparation of 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-yl 2-aminoacetate hydrochloride

The objective compound (10.5 mg) was prepared in the same manner as in Example 2, except that aminoacetic acid was used instead of 4- (2-chloroethyl) morpholine in the step 1 of Example 2. [

 1H NMR (400 MHz, CD 3 OD)? 7.02-7.00 (m, 2H), 6.95-6.92 (m, 2H), 6.83-6.81 2H), 3.84 (s, 3H)

Example 8 Synthesis of 3 '- [2- (dimethylamino) ethoxy] -5'-methoxybiphenyl-3,4-diol hydrochloride

. The objective compound (7.2 mg) was prepared in the same manner as in Example 2, except that 2- (dimethylamino) ethanol was used in place of 4 (2-chloroethyl) morpholine in the step 1 of Example 2. [

(400 MHz, CD30D); (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.76-6.73 (m, 2H), 6.51 (t, J = 2.4Hz, 1H ), 4.38 (t, J = 4.8Hz, 2H), 3.82 (. s, 3H), 3.60-3.58 (m, 2H), 2.99 (s, 6H)

Example 9 Preparation of 3 '4'-dihydroxy-5-mehoxybiphenyl-3-ylethylcarbonate

The objective compound (19.5 mg) was prepared in the same manner as in Example 1, except that ethyl hydrogen carbonate was used instead of acetic anhydride in the step 1 of Example 1.

¾-NMR (400 MHz, CDC1 3) δ 7.02 (d, J = 2.4Hz, 1H), 6.96 (dd, J = 8.2Hz, 2.2Hz, 1H), 6.91-6.90 (m, 2H), 6.86 (d J = 8.0 Hz, 1H), 6.66 (t, J = 2.0 Hz, 1H), 5.56 (br, 2H), 4.34 (qt, J = 6.8 Hz, 2H) , J = 7.2 Hz, 3H)

Example 10: Preparation of 3 '4'-dihydroxy-5-mehoxybiphenyl-3-yl benzoate

The target compound (15.3 g) was prepared in the same manner as in Example 1, except that benzoic acid was used instead of acetic anhydride in the step 1 of Example 1. _,

_{-NMR (400 MHz, CDC1 3)} δ 8.23-8.21 (m, 2H), 7.67-7.64 (m, 1H), 7.55-7.51 (m, 2H), 7.08-7.07 (m, 1H), 7.02-7.00 ( 2H), 3.85 (s, 3H), 3.60 (s, 3H)

Example 11 Preparation of 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-yl 1,4'-bipiperidine-1'-carboxylate

The procedure of Example 1 was repeated except that 1, 4'-bipiperidine-1'-carboxylic acid C-bipiperidine-1'-carboxylic acid was used instead of acetic anhydride in Step 1 of Example 1 The objective compound (11.4 mg) was prepared.

 (400 females, CDCl3 + CD3OD); (d, J = 8.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.96 ), 6.84 (m, 1H), 6.57 (t, J = 2.0 Hz, 1H), 4.40-4.34 (m, 2H), 3.82 (s, 3H), 2.97-2.64 m, 2H), 1.69 (m, 4H), 1.60 (m, 2H)

Example 12 Preparation of 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-yl dihydrogenphosphate

The objective compound (7.4 mg) was prepared in the same manner as in Example 1, except that phosphoric acid was used in place of acetic anhydride in Step 1 of Example 1.

(D, J = 8.4, 1H), 6.87 ( _s, 1H), 6.81 (d, J = H), 6.70 (s, 1 H), 3.82 (s, 3 H)

Example 13 Preparation of 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-ylethylsuccinate

 Except that 4-ethoxy-4-oxobutanoic acid was used instead of acetic anhydride in the step 1 of Example 1, the title compound (18.1 mg) .

¾-NMR (400 MHz, CDC1 3) δ 7.05 (d, J = 2.0Hz, 1H), 6.97 (dd, J = 7.8Hz, 2.2Hz, 1H), 6.90-6.86 (m, 2H), 6.82 (s J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.90 (t, J = 6.6Hz, 1H), 6.58 , 2H), 2.75 (1, J = 6.6 Hz, 2H), 1.27 (t, J = 7.4 Hz,

Example 14 Preparation of 4,5'-dimeroxybiphenyl-3,3'-di

Step 1: Preparation of 3,3'-bis (benzyloxy) -4,5'-dimethoxybiphenyl

The compound (38 mg, 0.09 mmol) prepared in Preparation Example 6 and potassium carbonate (25 mg, 0.18 ol ol) were dissolved in acetone (5 niL) and then iodomethane (7 μΐ, 0.11 mmol) at 50 ^° C and stirred for one day. The reaction mixture was terminated with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 5: 1) to obtain the desired compound (28 mg, yield: 71%, colorless liquid).

¹ H-NMR (400 MHz, CDCl ₃ )? 7.48-7.34 (m, 5H), 7.12-7.09 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H) 2H), 3.92 (s, 3H), 3.80 (s, 3H) Step 2: Preparation of 4, 5'- Lt; / RTI &gt; biphenyl-3,3 &apos; -diol

The compound (28 mg, 0.07 mmol) prepared in the above step 1 was dissolved in methane (5 ml), palladium-carbon (6 mg) was added thereto at room temperature, and the mixture was stirred under hydrogen gas for 3 hours. After completion of the reaction, palladium-carbon was removed by salting out and the residue was purified by vacuum column chromatography (nucleic acid: ethyl acetate = 1: 1) to obtain the desired compound (14 mg, yield 87% ᅳ red liquid).

¾-NMR (400 MHz, CD 3 0D) δ 7.02 ~ 7.00 (m, 2Η), 6.95 (d. J = 8.0Hz, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 6.29 (s , &Lt; / RTI &gt; 1H), 3.87 (s, 3H), 3.78

Example 15 Preparation of 4-epi-Si-5'-mechsibibhenyl-3,3'-di

The target compound (11.1 mg) was prepared in the same manner as in Example 14, except that iodoethane was used in place of iodomethane in the step 1 of Example 14.

Eu丽R (400 MHz, CD3OD) δ 7.03-7.00 (m, 2H), 6.98 (d. J = 8.3Hz, 1H), 6.56 (s, 1H) (6.55 (s, 1H), 6.29 (s, 1H ), 4.11 (q, J = 7.3, 6.8 Hz, 2H), 3.78 (s,

Example 16: Preparation of 5'-methoxy-4- (pentyloxy) biphenyl-3,3'-di

The target compound (15.1 _mg ) was prepared in the same manner as in Example 14 except that iodomethane was replaced by iodopentane in the step 1 of Example 14. [

 1H), 6.55 (s, IH), 6.29 (s, IH), 6.59 (d, J = ), 4.04 (t, J = 7.5 Hz, 2H), 3.78 (s, 3H), 1.84-1.79 (m, 2H), 1.50-1.38 (m, 4H), 0.95

Example 17 Preparation of 4- (isopentyloxy) -5'-methoxybiphenyl-3,3'-di

 The objective compound (12.5 mg) was prepared in the same manner as in Example 14, except that iodomethane was used instead of iodomethane in the step 1 of Example 14.

2H), 6.98 (d, J = 8.2 Hz, 1 H), 7.23 (d, (T, J = 7.3 Hz, 2H), 3.78 (s, 1H)

1.88-1.85 (m, 1H), 1.74-1.69 (m, 2H), 0.99-0.97 (m, 6H)

Example 18: Preparation of 4-isopropoxy-5'-methoxybiphenyl-3,3'-di

In Step 1 of Example 14 was the iodo in the ^example, produced the desired compound (16.3 mg) in the same manner as 14, except that Fig iodo instead of methane using isopropanol.

¾-NMR (400 MHz, CD 3 0D) δ 7.03-6.93 (m, 3Η), 6.57 (s, 1H),, 6.56 (s, 1H), 6.30 (s, 1H), 4.61-4.56 (m, 1H ), 3.78 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H)

Example 19 Synthesis of 4- [2- (dimethylamino) ethoxy] -5'-methicobiphenyl-3,3'-diol hydrochloride

In the same manner as in Example 14 except that 2-iodo-N, N-dimethylethanamine was used instead of iodomethane in the step 1 of Example 14, Compound (10.1 mg).

(D, J = 6.4 Hz, 2H), 6.28 (s, 1H), 7.03-7.01 (m, 3H), 6.53 ^{1H), 4.32 '(t,} J = 4.8Hz, 2H), 3.74 (s, 3H), 3.52 (br, 2H), 2.86 (s, 3H)

Example 20 Preparation of 5'-methoxy-4- (2-morpholinoethoxy) biphenyl-3,3'-diol into hydrochloride

The objective compound (10.3) was obtained in the same manner as in Example 14, except that 4- (2-iodoethyl) morpholine was used in place of iodomethane in the step 1 of Example 14. mg).

-NMR (400 MHz, DMS0-d 6); (m, 2H), 6.29 (s, 1H), 4.37 (br, 1H), 9.10 2H), 3.39-3.38 (m, 2H), 3.22-3.19 (m, 2H), 4.01-3.84 (m, 4H)

Example 21 Preparation of 3,3'-dihydroxy-5 '"methoxybiphenyl-4-yl 1,4'-bipiperidine-1'-carboxylate

Except that 1,4'-bipiperidine-1'-carbonyl iodide (l, 4'-t) ipiperidine-l'-carbonyl iodide was used instead of iodomethane in Step 1 of Example 14 , The target compound (10.5 mg) was prepared in the same manner as in Example 14.

 (M, 2H), 6.36-6.31 (m, 1H), 4.49-4.31 (m, 2H) (m, 2H), 3.79-3.78 (m, 3H), 3.35-2.95 (m, 9H), 2.13-1.64

Example 22 Preparation of 3,3'-dihydroxy-5'-methoxybiphenyl-4-yl dihydrogen phosphate

The target compound (17.5 mg) was prepared in the same manner as in Example 14, except that phosphor iodide acid was used in place of iodomethane in the step 1 of Example 14.

-賺(400 MHz, CDsOD) δ 7.47-6.93 (m, 3H), 6.59- 6.57 (m, '2H), 6.34-6.30 (m, 1H), 3.79 (s, 3H)

Example 23 Preparation of 4-hydroxy-3 ', 5' -dimethoxy (1,1, -biphenyl) -3-0-? -D-glucoside)

The leaves were extracted with ethanol (12 L), filtered and concentrated to obtain an ethanol extract. A portion of the ethane extract was suspended in distilled water and sequenced with n-nucleic acid, EtOAc and n-BuOH to finally separate n-nucleic acid fractions, EtOAc fractions and n-BuOH fractions.

 Among the above solvent fractions, the EtOAc-soluble fraction having the highest inhibitory effect on the formation of AGEs was subjected to column chromatography (chloroform: methanol = 40: 1: 0: 1 (v / v)) and column chromatography with Sephadex LH2 : Water = 1: 1-1: 0 (v / v)) was performed to obtain a new biphenyl glucoside.

 HRESIMS: 407.1349 [Μ-ΗΓ;

(1H, d, J = 8.4, 2.1 Hz, H-6), 6.86 1H, d, J = M, 2.4 Hz, H-5 '), 6.70 (1H, d, J = Hl "), 3.91 (1H, dd, J = 12.0, 1.8Hz, H-6"), 3.8K6H, s, 0CH 3), 3.72 (1H, dd, J = 12.0, 5.4Hz, H-6 ") , 3.59-3.34 (4H, m, H-2 " / 3 " / 4 &apos; 75 &quot;);

^{13 C-NMR (75MHz, CD} 3 0D) 162.7 (C-3 '/ 5'), 148.8 (02), 147.1 (03),

(C-1), 134.4 (C-1), 123.5 (c-6), 117.8 (c-2), 117.6 -5 "), 77.8 (c- 3"), 75.1 (c-2 "), 71.6 (c-4 '62.7 (c-6"), 55.9 (0CH 3)

<Experimental Example 1> Effect of glucose uptake control

 In order to analyze the effect of the compounds of Examples 1, 2, 4, 10, 14 and 15 of the present invention on the ability to regulate glucose uptake in human mouse mesangial cell lines, the following experiment was conducted.

Specifically, seeded into 96-well ^culture, the plate (96 well black, clear bottom culture plate, Corning, USA) mouse mesangial cells (mouse mesangial cell) for each 3> 10 ⁴ cells / well (cells / well) in (seeding ), And cultured in an incubator at 37 ^° C and 5% CO ₂ for 24 hours. A 100-ml serum (glucose-free culture medium, Gibco, USA), 150 g / ml 2-NBDG 2, 4, 10, 14, and 15 compounds at 10 μM concentration were added to each well, followed by incubation for 10 minutes with each of the compounds of Examples 1, 2, 4, 10, 14 and 15. Next, after centrifugation (400 g) for 5 minutes at room temperature, the culture was sucked, and 200 ≠ cell-based assay buffer (Cayman, USA) was added. (400 > g). Subsequently, the cell-based assay complete solution was suctioned, and 100 μl of the cell-based assay complete solution was added to each well. The reaction solution was applied to each well using a multiplate detector (Bio-TEK, Synergy HT, USA) i ss i on = 485/535 nm) to determine the glucose uptake inhibition efficacy.

The glucose utilization capacity of the compounds of Examples 1, 2, 4, 10, 14 and 15 is shown in FIGS. 1, 2, 3, 4, 5 and 6, respectively. As shown in FIGS. 1-6, all of the compounds of Examples 1, 2, 4, 10, 14, and 15 of the present invention exhibited an effect of about 40-50¾> glucose utilization. Accordingly, the phenyl derivatives of formula (I) according to the present invention are excellent in the ability to regulate blood glucose, and consequently can be used to treat, prevent or ameliorate diabetes and further diabetic complications. &Lt; Experimental Example 2 > Evaluation of inhibitory effect on final glycation end product formation

 The amount of final glycation end product is an indicator of diabetic complication and an index of evaluation of therapeutic efficacy. In this experiment, in order to measure the inhibitory effect of the compounds of Examples 1-21 and 23 of the present invention on the production of the final glycation products, binding of fructose and glucose to bovine serum albumin (BSA) And aminoguanidine, which is known to be highly effective in inhibiting endogenous glycoconjugates, was used as a positive control.

Specifically, BSA was added to 50 mM phosphate buffer (H 7.4) to a concentration of 10 mg / ml using bovine serum albumin (BSA: Sigma, USA) as a protein source . As the party member, a liquid in which 0.2 M fructose and 0.2 M glucose were mixed was used. To the prepared BSA solution, fructose and glucose were added, and the compounds of Examples 1-21 and 23 were prepared at the concentrations shown in Table 2 below (all compounds were dissolved in DMSO and then 15% tween 80 was added, The total DMSO content was 0.2%), which was added to the BSA and sugar solutions, and then cultured at 37 ^° C for 7 days.

 At this time, 0.02% sodium azide was added as an antibacterial agent. The control group was a culture of BSA and saccharide mixed solution, and the blank group of the test group and the control group was not cultured after each preparation. On the other hand, aminoguanidine was used as a positive control, which is an index that can compare excellent efficacy. All cultures decreased the error as much as possible by preparing more than one.

After 7 days, the content of final glycation products in each culture was analyzed and the results are shown. Advanced glycation end product is tinged fluorescence, Brown may have a ligand that can be recognized as well as have the will physicochemical properties can be cross-linked ^"membrane receptors. The amount of the final glycation end product with this property was determined by a microplate reader (Excite at ion: 350 nm, Emission: 450 nm), and the degree of its inhibition was analyzed (Vinson, JA et al. J. Nutr. Biochem., 7: 659-663, 1996), and the production inhibition rate was calculated by the following equation (1).

As a positive control group, aminoguanidine was used at the concentrations shown in the following Table 2, and aminoguanidine was dissolved in distilled water for 7 days by the method described above. After 7 days, the amount of the final glycation products produced in the culture was measured by Microplate reader (Excitation at ion: 350 nm, Emission: 450 nm). That Are shown in Table 2 below.

 [Equation 1]

(Fluorescence intensity of sample group) - (fluorescence intensity of sample blank group) Generation inhibition rate (%) = {100- X 100

 (Fluorescence intensity of the control group) - (fluorescence intensity of the blank group of the control group)

[Table 2]

As shown in Table 2, it can be seen that the IC ₅₀ values of all test groups administered with the compound according to the present invention were much better than those of the control group, aminoguanidine (IC ₅₀ value: 1040.7 ± 44.17 μM). Compared with the inhibitory effect on the final glycosylation of aminoguanidine at a concentration of 750 占 ((39.93 占 1.74 占)), most of the compounds according to the examples of the present invention had aminoguanidine Which is more excellent than the final glycation end product. Therefore, the phenyl derivative of formula (I) according to the present invention significantly inhibits the formation of the final glycation end product by inhibiting the binding between the protein and the saccharide. Therefore, the endogenous saccharide- Can be usefully used for the treatment, prophylaxis or amelioration of cell-related diseases.

Experimental Example 3 Zebrafish Effect on Animal Model (Zebrafish) Zebrafish is one of the vertebrate animals and is highly absorbed by human genes and can be quickly confirmed for its efficacy. Also, compared to rodents (2005), Journal of Molecular Endocrinology, (2007), pp. 236-245 (2010)]. In this study, 38, 433-440). On the other hand, when zebrafish was cultured in a hyperglycemic state, various pathophysiological characteristics appeared in the early stages of non-proliferative diabetic retinopathy (NPDR) (Disease Models & Median isms (2010 ) 3, 236-245). In the hyperglycemic state, the retina of the zebrafish is thicker than that of the retina, the surface blood vessels become thicker, the cell junction between the vascular endothelial cells becomes weaker, and the vessel basement membrane becomes thicker. It changes to symptom. In this experiment, it was confirmed that the compounds prepared in Examples 1, 13, 15 and 21 of the present invention had a preventive (therapeutic) effect on diabetic retinopathy using zebrafish induced diabetic retinopathy, which is an example of diabetic complication In order to see, we experimented as follows.

 Specifically, a zebrafish embryo was prepared by crossing male and female transgenic zebrafish (Tg (kdr: EGFP)) expressing a fluorescent protein (green fluorescence protein) specifically in vascular endothelial cells. Next, in the zebrafish embryo prepared above, the embryos expressing fluorescence were selected at 24 hours after the fertilization, and 5 individuals were dispensed into a 24-well plate. A glucose solution at a concentration of 30 mM was added to induce a hyperglycemic environment Respectively. At this time, each of the compounds prepared in Examples 1, 13, 15, and 21 was co-treated with the glucose solution at a concentration of 1-20 μM. In the above hyperglycemic environment, zebrafish was treated for 5 days and then fixed with 4% formaldehyde for one day. Thereafter, the lens is separated from the fixed body, and the change in the diameter of the blood vessel of the hyaloid vasculature is analyzed with a fluorescence microscope.

 In order to compare the changes in blood vessel diameter of the vitreous vessels by the compounds prepared in Examples 1, 13, 15 and 21, the 'hyperglycemic treatment group' without the compound of Example ' Hyperglycemic group (normal group) 'was used as a control group, and the diameter of the blood vessels of the vitreous were also measured.

 The changes in vessel diameter of the vitreous blood vessels according to the compounds prepared in Examples 1, 13, 15 and 21 are shown in Tables 3 and 14 below.

 [Table 3]

Γ ^* Ρ <0.001 VS. HG, ^m P < 0.001 VS. Hyperglycemic untreated group)

In Table 3, n represents the number of individuals of the zebrafish. As shown in Table 3, in the hyperglycemic environment, the vitreous blood vessels were widened, It was found that the treatment group in which the compounds of Examples 1, 13, 15, and 21 were administered at the same time maintained the width of the vitreous body at almost normal level. This means that the compound according to the embodiment of the present invention treats or prevents pathological symptoms of blood vessels due to hyperglycemia. Accordingly, the phenyl derivative of formula (I) according to the present invention has the effect of restoring the diameter of blood vessels of the vitreous body to normal levels in laboratory animals (zebrafish) induced in hyperglycemia, and therefore, the treatment of diabetic retinopathy, Prevention or amelioration.

Experimental Example 4 Effect on diabetic retinopathy-induced diabetic animal model (SD rats) When the compound prepared in Example 23 of the present invention was treated in a diabetic retinopathy-induced diabetic model (SD rats) The following experiment was conducted to evaluate changes in blood vessels, changes in occludin, a tight junction protein in which angiogenic growth factors are expressed, and changes in neovascularization factors. Preparation of experimental animals induced diabetic retinopathy

Sprague Dawley (SD) white rats (6 weeks old) were distributed from BioLink and transferred to a 7 ^' day incubation environment. After dividing into normal, diabetic, and experimental groups, The temperature was maintained at 23 ± 2: 0, the humidity was 40-60%, and the light-dark cycle was maintained for 12 hours. All experiments were performed according to the Standard Operation Procedures (SOP) of the Institutional Animal Care and Use Co ich ittee (IACUC). SD rats were anesthetized with intraperitoneal injections of 5 rag / ^ and 5 mg / kg of zoletile. The diabetic group was prepared by administering 20 mg / m &lt; 2 &gt; BSA-AGE into the vitreous cavity, and the experimental group was prepared by administering 20 mg / ml BSA-AGE and the compound of Example 23 at a concentration of 150 [mu] . In addition, normal groups without any treatment were prepared.

Twenty-four hours after administration of each, an equal amount of Zoletil and Lumpen were intraperitoneally injected, and the heart was secured by opening the abdominal cavity and thoracic cavity. 50 of the fluorescent isocyanate dextran (FT C- The retina was removed from the eyecup and the left eye was incised in a four-pronged radial pattern to remove the left eye. , And observed with a fluorescence microscope. In the case of the right eye, only the retina was separated from the eyeball, and then rapidly frozen in liquid nitrogen and stored at -70 ^° C.

BSA-AGE _.

BSA-AGE is 30 mM glucose (Sigma, St. Louis, MO, USA) and 20 g / ml of bovine serum albumin (BSA, Roche, Germany) to 37 ^° into a sodium phosphate wancheung solution (100 mM, H 7.4) C for 50 days.

After 50 days, BSA-AGE was added to the PD-10 column and dialyzed to remove remaining glucose and pure BSA-AGE alone. The purified BSA-AGE was dispensed and stored at -70 ^° C. Western blot analysis

The retinas stored ^at -70 ^° C were homogenized with a homogenization buffer (pH 7.6), quantitated using lowry principle, and electrophoresed on SDS-PAGE at 30 g each. Proteins transferred to the gels were transferred to membranes at 100V 250mA for 1 hour 30 minutes by fixing the nitrocells to a nitrocellulose membrane.

 The attached proteins were immunoblotted with the antibody to be quantified and developed using an enhanced-chemilluminecence (ECU) solution. The degree of protein expression was then measured using a scion image analysis program The results are shown in the following table.

 1. Changes in retinal vessels

Each group (normal group, diabetic group and experimental group) _. After injection of a fluorescent material (FITC-dextran) into the experimental animals, retinal blood vessels were observed. The results are shown in FIG.

As shown in Fig. 15, no abnormality was observed in the normal group (a), and in the diabetic group (b) in which diabetic retinopathy was caused by 20 μE / mt BSA-AGE, (C): 50 .mu.M, (d): 100 .mu.M, (e): 150 .mu.M) treated with the compound prepared in Example 23 of the present invention, And 100 μM and 150 μM, respectively. In the group treated with 100 μM and 150 μM, it was confirmed that no symptoms were observed at the normal level. 2. Changes in ecludins

 Fig. 16 shows the results of measurement of the change in occludin, a protein that constitutes a tight junction, which is a water-tight barrier to protect the eye.

 As shown in FIG. 16, in the diabetic group, auricide was significantly decreased compared to the normal group, but not in the diarrhea group. Nor). In the group treated with the compound of Example 23 according to the present invention, the concentration of occludin showed a tendency to increase in a concentration-dependent manner. Especially, it was confirmed that the concentration of 100 μM and 150 μM increased significantly . AGE-BSA).

3. Changes in neovascular growth factors

 The results of measuring the changes of the angiogenic growth factors are shown in Fig.

As shown in Fig. 17, the diabetic group is inferior to the normal group. The neovascular growth factor was markedly increased, but O. Nor), the group treated with Example 23 according to the present invention tended to decrease in a concentration-dependent manner, and in particular, it showed a significant decrease at concentrations of 100 μM and 150 μM. AGE-BSA). Accordingly, the phenyl derivative according to the present invention prevents destruction and breakage of the vascular retinal barrier, increases the amount of ecludine, which is a constituent of the gingival seam, and significantly decreases the pathologically increased neovascularization factor, It can be usefully used for the treatment, prevention or improvement of diabetic retinopathy, for example. The results of the above Experimental Examples 1 to 4 show that the phenyl derivative according to the present invention has an excellent effect of inhibiting abnormal glucose absorption due to hyperglycemia and inhibits the binding of protein and sugar, (Zebrafish) in which the diameter of the ocular vitreous body is enlarged due to hyperglycemia, as well as exhibiting an effect of inhibiting the expansion of the diameter of blood vessels. In addition, diabetic complications such as diabetic retinopathy the experimental animals (SD rats) preventing the pathologic blood destruction of the tube retina barrier in and the occlusion ^\ Dean protein constituting the dense joint increases, decreasing the angiogenic growth factors increase the pathological significantly induced , Which is useful for the treatment, prevention or improvement of vascular endothelial cell-related diseases such as diabetes and diabetic complications . Meanwhile, the phenyl derivative represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following are illustrative examples of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

 1-1. Manufacture of Powder

In the present invention,

500 mg

 Lactose 100 mg

 Talc 10 rag The above ingredients are mixed and filled into airtight bags to make powders.

1-2. Manufacture of tablets

 500 mg of the derivative represented by the formula (1) of the present invention

 Corn starch 100 mg

 100 rag

 Lactose

 Magnesium stearate 2 nig After the above ingredients are mixed, tablets are prepared by tableting according to the usual preparation method of tablets.

1-3. Manufacture of Cellulose

In the present invention,

500 mg

 Corn starch 100 rag

 Magnesium stearate 2 nig According to a conventional capsule preparation method, the above ingredients are mixed and filled into ¾ latino capsules to prepare capsules.

1-4. Injection preparation 500 mg of the derivative represented by the formula (1) of the present invention

 Sterile sterilized water for injection

 H modulator q.s. Prepare with the above ingredient content per 1 squf (2 ml) according to the usual injection preparation method.

 Each component was added to the purified water according to the usual preparation method of the liquid and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and then purified water was added thereto. The whole was adjusted to 100 by adding purified water, And sterilized to prepare a liquid. .

&Lt; Formulation Example 2 > Preparation of health food

 The derivative represented by the formula (1) of the present invention, 1000 rag

 Vitamins Accumulation Quantity

 Vitamin A acetate 701 return

 Vitamin E 1.0 mg

 Vitamin 0.13 rag

 0.15 mg of vitamin B2

 Vitamin ΊΒ6 0.5 nig

 Vitamin B12 0.2

 Vitamin C, 10 mg

 Biotin 10

 Nicotinic acid amide 1.7 nig

 Folic acid 50 mg

Calcium pantothenate 0.5 nig Mineral impurities

 1.75 mg of ferrous sulfate

 Zinc oxide 0.82 nig

 Carbonate Magnes 25.3 nig

 Potassium phosphate 15 rag

 Second Phosphate Deer 55 mg

 Potassium citrate 90 mg

 Calcium carbonate 100 mg

 Magnesium Chloride 24.8 mg Although the composition ratio of the above vitamins and minerals is comparatively low, it is not preferable to use a composition suitable for health food as a preferred embodiment. However, After the ingredients are mixed, the granules can be prepared and used in the manufacture of a health food composition according to conventional methods.

&Lt; Formulation Example 3 > Preparation of health drink

 The derivative represented by the formula (1) of the present invention, 1000 rag

 Citric acid 1000 nig

 100 g per serving

 Plum concentrate 2 g

 Taurine 1 g

 Purified water was added thereto, and the above components were mixed according to a general 900 ml ordinary health drink manufacturing method. After stirring for about 1 hour at 85 ° C, the solution was filtered to obtain a sterilized 21-degree container, And then used for the manufacture of a health beverage composition. Although the above-mentioned composition ratio is prepared by mixing the ingredients suitable for the beverage of the present invention into the preferred embodiment, the blending ratio may be arbitrarily varied depending on the regional and national taste preferences such as the demand level, the demanded country, and the intended use.

&Lt; Formulation Example 4 > Production of other health foods

4-1. Manufacturing of beverages

 5 mg &lt; RTI ID = 0.0 &gt;

 Nicotinic acid amide 10 nig

 Riboflavin sodium 3 nig

 Pyridoxine hydrochloride 2 mg

 30 mg of inosine

 Ortho acid 50 rag

 0.48 to 1.28 mg of the derivative represented by the formula (1) of the present invention

A beverage was prepared using the above-mentioned composition and content by a conventional method.

Chewing gum was prepared using the above-mentioned composition and content by a conventional method

4-3. Manufacture of candy

 Sugar 50-60%

 Starch syrup 39.26-49.66%

In the present invention,

0.24-0.64%

 &Lt; tb &gt; Orange &lt; SEP &gt; 0.1% &lt; tb &gt; &lt; tb &gt; 4-4. Manufacture of flour food products

0.5 to 5 parts by weight of the bead core represented by the formula (1) of the present invention, 100 parts by weight of wheat flour And the bread was used to prepare breads, cakes, cookies, crackers and noodles to prepare foods for health promotion.

4-5. Manufacture of dairy products

 5 to 10 parts by weight of the derivative represented by the formula (1) of the present invention was added to 100 parts by weight of milk, and various dairy products such as butter and ice cream were prepared using the milk.

4-6. Manufacture of wires

 Brown rice, barley, rice, and yulmu were alphalized by a known method, and dried, and the mixture was then pulverized into powder having a particle size of 60 mesh. Black beans, black sesame seeds, and perilla seeds were ground in a known manner and dried, and were then ground to a powder having a mesh size of 60 mesh. The grains and seeds prepared above were mixed with the derivatives represented by formula (I) of the present invention in the following proportions.

 Brown rice 30%

 Yulmu 15%

 Barley 20%

 Perilla 7%

 Black soybeans 7%

 Black sesame 7%

 The derivative 3% of the present invention represented by the formula (1)

 Manure 0.5%

 0.5%

[Industrial applicability]

Phenyl derivatives according to the invention effectively control the glucose utilization rate and excellent the causative factors of advanced glycation end products produce inhibitory effects of complications of diabetes, an animal model (zebrafish) in hyperglycemia in glass body ^vessel, diameter of the eye is widened to pathological (SD rats). In addition, it inhibits the breakdown of the blood retinal barrier and increases the amount of ecludine, a protein in the dense seams, The effect of significantly reducing the neovascular growth factor pathologically Shown since it can be usefully used as a vascular endothelial cell-related ^disease, or diabetic example improving or therapeutic composition comprising the complications of diabetes.

Claims

Claims: What is claimed is: 1. A phenyl derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof: wherein R1, R2 and R3 independently represent hydrogen, a d-C6 straight chain or branched alkyl group; C4 straight or branched chain alkyl group substituted with 5 to 6 membered heterocycloalkyl, amino straight chain or branched chain Cr " C4 alkylcarbonyl group, Ci-C4 linear or branched chain alkyl A C5-C6 arylcarbonyl group, a d-straight chain or branched alkyloxycarbonyl group, a d-C4 linear or branched alkyl group having from 1 to 6 carbon atoms, a carbonyl group substituted with a 5- to 6-membered heterocycloalkyl group, A phosphono group (-PO (OH) 2), a glucosyl group, a galactosyl group, a ramosyl group, a gyrosyl group, an arabinosyl group, or a glucuronic acid group, Here, And the cycloalkyl group includes at least one hetero atom selected from the group consisting of N, O and S. 2. The compound according to claim 1, wherein R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl Isopropyl, isobutyl, tert-butyl, pentyl, isopentyl, isohexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, ; Diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, morpholinomethyl, morpholinoethyl, 1- (1,4'-bipiperidin-1'-yl) carbonyl, or phosphono Isopropyl, butyl, isopentyl, isobutyl, isobutyl, isobutyl, isobutyl, isobutyl, isobutyl, isohexyl, isoheptyl, octyl, isooctyl, dimethylaminomethyl, dimethyl Aminoethyl, dimethylaminopropyl, dimethylaminobutyl, di Aminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, morpholinomethyl, morpholinoethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, aminomethylcarbonyl; Aminoethylcarbonyl; Aminopropylcarbonyl; Aminobutylcarbonyl; Phenylcarbonyl; 1 &lt; / RTI &gt; (1, 4 'carbopiperidin-1' yl) carbonyl; Methyloxycarbonylmethylcarbonyl; Methyloxycarbonylethylcarbonyl; Ethyloxycarbonylmethylcarbonyl; Ethyloxycarbonylethylcarbonyl; Methyloxycarbonyl; Ethyloxycarbonyl; Propyloxycarbonyl; Butyloxycarbonyl; Or a phosphono group, R3 is hydrogen; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; tert-butyl; Pentyl; Isopentyl; A nuclear core; Isohexyl; Heptyl; isoheptyl; Octyl; Isooctyl; A glucosyl group; A galactosyl group; A rhamnoyl group; Gypsum; Arabinosyl group; Or a glucuronic acid group, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein R 1 is hydrogen; methyl; ethyl; Isopropyl; Pentyl; Isopentyl; Dimethylaminoethyl; Morpholinoethyl; 1- (1,4'-bipiperidin-1'-yl) carbonyl; or a phosphono group; R2 is hydrogen; methyl; ethyl; Isopropyl; Pentyl; Isopentyl; Dimethylaminoethyl; Morpholinoethyl; Methylcarbonyl; Aminomethylcarbonyl; Phenylcarbonyl; 1- (1,4'-bipiperidin-1'-yl) carbonyl; Ethyloxycarbonylsethylcarbonyl; Ethyloxycarbonyl; Or a phosphono group; R3 is hydrogen; Or a glucosyl group, or a pharmaceutically acceptable salt thereof. 4. The process according to claim 1, wherein the phenyl derivative of formula (1)

 (1) 3 ', 4'-dihydroxy-5-mehoxybiphenyl-3-yl acetate;

 (2) 3'-Methoxy-5 '- (2-morpholino eroxy) biphenyl-3,4-diol hydrochloride

 (3) 3'- (pentyloxy) -5'-methoxybiphenyl-3,4-diol;

(4) 3'-Eroxy-5'-methoxybiphenyl-3,4-diol;

(5) 3 (isopentyloxy) -5'-methoxybiphenyl-3,4-diol;

 (6) 3 ' -isopropoxy-5 '-methoxybiphenyl-3,4-diol;

 (7) 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-yl 2-aminoacetate hydrochloride;

 (8) 3 '- [2- (Dimethylamino) ethoxy] -5'-methoxybiphenyl-3,4-dihydrochloride;

 (9) 3 ', 4'-dihydroxy-5-megestiviphenyl-3-ylethyl carbonate;

 (10) 3 ', 4'-dihydroxy-5-mehoxybiphenyl-3-yl benzoate;

(11) 3 ¹ , 4'-dihydroxy-5-megestiviphenyl-3-yl 1,4'-bipiperidine-1'-carboxylate;

 (12) 3 ', 4'-dihydroxy-5-megestiviphenyl-3-yl dihydrogen phosphate;

(13) 3 ', 4'-dihydroxy-5-methoxybiphenyl-3-ylethyl succinate;

 (14) 4,5'-dimethoxybigenyl-3,3'-dodiol;

 (15) 4-Ethoxy-5'-methoxybiphenyl-3,3'-di; .

 (16) 5'-methoxy-4- (pentyloxy) biphenyl-3,3'-di;

 (17) 4- (isopentyloxy) -5'-methicobiphenyl-3,3'-diol;

 (18) 4-isopropoxy-5 ' -mecicobiphenyl-3 ' 3 &apos;-di;

 (19) 4- [2- (dimethylamino) ethoxy] -5'-methoxybiphenyl-3,3'-dihydrochloride;

 (20) 5'-Meeroxy-4 '(2-morpholinoEoxy) biphenyl-3,3'-diol hydrochloride; ,

 (21) 3,3'-dihydroxy-5'-methoxybiphenyl-4-yl 1,4'-bipiperidine-1'-carboxylate;

 (22) Synthesis of 3,3'-dihydroxy-5'-methoxybiphenyl-4-yl dihydrogenphosphate

(23) 4-hydroxy-3 ', 5'-dimeroxy- (1,1'-biphenyl) -3-0-? -D-glucoside &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.

[Claim 5]

As shown in the following Equation 1, Tripping the compound of formula (2) to obtain the compound of formula (3) (step 1); And a step (2) of counteracting the compound of formula (3) prepared in step 1 in the presence of hydrogen gas to obtain a compound of formula (1A) (step 2) :

 [Reaction Scheme 1]

(In the above equation 1,

The substituent R &lt; ² &gt; is the same as defined in formula (1) of claim 1).

[Claim 6]

 As shown in the following Equation 2,

 Tripping the compound of formula 4 to obtain the compound of formula 5 (step 1); And a step of unreacting the compound of formula (5) prepared in step 1 above in the presence of hydrogen gas to obtain a compound of formula (1B) (step 2). :

 [Hanwoong2]

 4 5 1B

(In the above Reaction Scheme 2,

R ¹ is as defined in formula (I) of claim 1).

7.

As shown in Scheme 3 below Unreacting the compound of formula 6 to obtain the compound of formula 7 (step 1); And a step of reacting the compound of formula (7) prepared in step 1 with hydrogen gas to obtain a compound of formula (1C) (step 2).

 [Hanwoong 3]

(In the above equation 3,

R &lt; ³ &gt; is as defined in Chemical Formula 1 of claim 1). 8.

 A pharmaceutical composition for the prevention or treatment of vascular endothelial cell-related diseases containing as an active ingredient a phenyl derivative of the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof.

9]

 18. The method of claim 18,

 Wherein said vascular endothelial cell-related disease is diabetic complication. Claim 10

10. The compound of claim 9, wherein ^{1 '} _.

 Wherein said diabetic complication is diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic nephropathy, diabetic heart disease, diabetic osteoporosis, diabetic cancer or diabetic atherosclerosis.

Claim 11.

A pharmaceutical composition for preventing or treating diabetes comprising a phenyl derivative of the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Claim 12

 A health food composition for preventing or ameliorating vascular endothelial cell-related diseases containing a phenyl derivative of the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient

Claim 13

 13. The method of claim 12,

 Wherein said vascular endothelial cell-related diseases are diabetic complications. 14.

14. The method of claim 13, ^'wherein the diabetic complications are diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic nerve disease, diabetic core service members, diabetic osteoporosis, diabetic cancer or diabetic wherein atherosclerotic light Fine &Lt; / RTI &gt;

15. The method of claim 1 ^,

 A health food composition for preventing or ameliorating diabetes comprising a phenyl derivative of formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.