WO2013118949A1 - Dérivés de phényle ou sels pharmaceutiquement acceptables de ceux-ci, leurs procédés de préparation, et composition les comprenant comme principes actifs pour prévenir, améliorer ou traiter des maladies associées aux cellules endothéliales vasculaires ou le diabète - Google Patents

Dérivés de phényle ou sels pharmaceutiquement acceptables de ceux-ci, leurs procédés de préparation, et composition les comprenant comme principes actifs pour prévenir, améliorer ou traiter des maladies associées aux cellules endothéliales vasculaires ou le diabète Download PDF

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WO2013118949A1
WO2013118949A1 PCT/KR2012/004805 KR2012004805W WO2013118949A1 WO 2013118949 A1 WO2013118949 A1 WO 2013118949A1 KR 2012004805 W KR2012004805 W KR 2012004805W WO 2013118949 A1 WO2013118949 A1 WO 2013118949A1
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formula
group
diabetic
compound
methoxybiphenyl
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PCT/KR2012/004805
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English (en)
Korean (ko)
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김진숙
김정현
김찬식
김영숙
손은진
정동호
이윤미
정승현
이유리
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한국한의학연구원
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Priority claimed from KR20120064882A external-priority patent/KR101403488B1/ko
Publication of WO2013118949A1 publication Critical patent/WO2013118949A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/04—Phenol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring

Definitions

  • 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.
  • 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.
  • JAMA United States Medical Association
  • 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.
  • endothelial cell-related diseases such as osteoporosis.
  • Diabetic heart disease causes sudden death without warning, diabetic retinopathy and retinopathy cause blindness and eventually death .
  • 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).
  • 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.
  • 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.
  • 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.
  • the resulting final glycation products are cross-linked or cross-linked with proteins or lipids to produce irreversible glycated proteins or glycated lipids.
  • 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.
  • 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.
  • aminoguanidine known as a protein glycosylation inhibitor
  • 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).
  • 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. '
  • 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.
  • 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.
  • anti-VEGF anti-angiogenic growth factor
  • Avastin bevacizumab
  • 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.
  • 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.
  • 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.
  • R 1 , R 2 and R 3 are as defined herein.
  • 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.
  • the present invention relates to a phenyl derivative of the above formula (1) or a pharmaceutically acceptable salt thereof
  • 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.
  • 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. ⁇
  • FIG. 1 is a graph showing the glucose control effect of the compound prepared in Example 1 of the present invention.
  • FIG. 2 is a graph showing the glucose control effect of the compound prepared in Example 2 of the present invention.
  • FIG. 3 is a graph showing the glucose control effect of the compound prepared in Example 4 of the present invention.
  • 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. 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. 8 is a diagram showing changes in the vitreous blood vessels of the shins.
  • Example 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.
  • Example 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.
  • Example 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.
  • Example 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.
  • Example 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. 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. 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. 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.
  • Example 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.
  • the present invention provides a phenyl derivative of the general formula (I) or a pharmaceutically acceptable salt thereof. '
  • 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 galactosy
  • heterocycloalkyl group comprises at least one heteroatom selected from the group consisting of N, O and S.
  • heteroatom selected from the group consisting of N, O and S.
  • R < 1 &gt 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;
  • Morpholinomethyl Morpholinoethyl; Methylcarbonyl; Ethylcarbonyl; Propylcarbonyl; Butylcarbonyl; Aminomethylcarbonyl; Aminoethylcarbonyl; Aminopropylcarbonyl; Aminobutylcarbonyl;
  • 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 &gt 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;
  • R 3 is hydrogen; Or a glucosyl group.
  • the phenyl derivative represented by the above formula (1) is more specifically exemplified as follows.
  • 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, but are not limited to, but are not limited to, but are not limited to, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Benzoate, carboxybenzoate, phthalate, terephthalate, benzene sulphate But
  • 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.
  • 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.
  • the metal salt it is preferable for the metal salt to produce sodium, potassium or calcium salt.
  • 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
  • step 2 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).
  • 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.
  • the step 1 is a step of introducing a substituent R 2 into the compound of the formula (2).
  • the compound having R 2 substituent is reacted in the presence of a base to obtain the compound of formula (3) .
  • 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.
  • the phase may be carried out within the boiling range of the solvent to the solvent, preferably at room temperature.
  • 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.
  • 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.
  • active metal catalyst such as Raney nickel and palladium-activated carbon widely used in reduction reaction.
  • 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.
  • 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.
  • the reaction temperature is not particularly limited, but can be performed within a range of room temperature to the boiling point of the solvent.
  • 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).
  • 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.
  • 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.
  • 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).
  • the step 1 is a step of introducing the R 1 substituent in the compound of formula (4).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • active metal catalyst such as Raney nickel, palladium and activated carbon widely used in the reduction reaction.
  • a catalyst such as activated carbon, alumina, silica or the like supported with palladium of 5-10% by weight may be used.
  • palladium supported on activated carbon may be used.
  • 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.
  • 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).
  • 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.
  • 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.
  • step 2 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).
  • R 3 is as defined in Formula 1, and the compound of Formula 1C is a phenyl derivative of Formula 1.
  • 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).
  • 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.
  • 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).
  • 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.
  • an active metal catalyst such as Raney nickel, palladium-activated carbon, etc. widely used in reduction reaction Pressure reaction.
  • 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.
  • the reaction temperature is not particularly limited, but can be performed within a range of room temperature to the boiling point of the solvent.
  • the compound of formula (7) is dissolved in methane, palladium-carbon is added in a catalytic amount, and hydrogen is added and stirred.
  • 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.
  • 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 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)
  • 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).
  • 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. .
  • 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.
  • 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.
  • 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, cal oftenum 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.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as rib oil, and injectable ester such as ethyl oleate.
  • 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.
  • 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.
  • 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
  • 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).
  • 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)
  • 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).
  • 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.
  • 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 .
  • 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 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.
  • 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.
  • the phenyl derivatives of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
  • 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.
  • step 1 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 ⁇ 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.
  • 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).
  • 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).
  • Step 1 Preparation of 3'-methoxy-5 '- (2-morpholinoeoxy) biphenyl-3,4-diol
  • 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.
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. ,
  • Example 1 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.
  • 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.
  • 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 ⁇ , 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 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • mice mesangial cells mouse mesangial cell
  • 10 4 cells / well cells / well
  • 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 ⁇ M 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.
  • the culture was sucked, and 200 ⁇ cell-based assay buffer (Cayman, USA) was added. (400 > g).
  • the cell-based assay complete solution was suctioned, and 100 ⁇ l of the cell-based assay complete solution was added to each well.
  • 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 40-503 ⁇ 4> 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. ≪ 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.
  • BSA bovine serum albumin
  • H 7.4 bovine serum albumin
  • BSA bovine serum albumin
  • a liquid in which 0.2 M fructose and 0.2 M glucose were mixed was used.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Tg transgenic zebrafish
  • 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.
  • 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 ⁇ M.
  • 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.
  • 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.
  • n represents the number of individuals of the zebrafish.
  • 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.
  • the compound according to the embodiment of the present invention treats or prevents pathological symptoms of blood vessels due to hyperglycemia.
  • 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.
  • 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.
  • SOP Standard Operation Procedures
  • IACUC Institutional Animal Care and Use Co ich ittee
  • the diabetic group was prepared by administering 20 mg / m < 2 > 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] .
  • normal groups without any treatment were prepared.
  • 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.
  • 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.
  • 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.
  • a homogenization buffer pH 7.6
  • the attached proteins were immunoblotted with the antibody to be quantified and developed using an enhanced-chemilluminecence (ECU) solution.
  • ECU enhanced-chemilluminecence
  • the degree of protein expression was then measured using a scion image analysis program The results are shown in the following table.
  • 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.
  • the diabetic group is inferior to the normal group.
  • the neovascular growth factor was markedly increased, but O.
  • 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 ⁇ M and 150 ⁇ M.
  • AGE-BSA AGE-BSA
  • 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 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.
  • Talc 10 rag The above ingredients are mixed and filled into airtight bags to make powders.
  • Magnesium stearate 2 nig According to a conventional capsule preparation method, the above ingredients are mixed and filled into 3 ⁇ 4 latino capsules to prepare capsules.
  • 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. .
  • Vitamin C 10 mg
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.

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Abstract

La présente invention concerne des dérivés de phényle ou leurs sels pharmaceutiquement acceptables, un procédé pour leur préparation et une composition les comprenant comme principes actifs pour prévenir, améliorer ou traiter des maladies associées aux cellules endothéliales vasculaires telles que le diabète et les complications diabétiques. Les dérivés de phényle selon la présente invention peuvent réguler efficacement l'utilisation de glucose, ont d'excellents effets dans l'inhibition de la production de produit final de glycation avancée qui est un facteur causal dans les complications diabétiques, ont des effets supérieurs dans le traitement (la prévention) de l'élargissement pathologique du diamètre d'un récipient de corps vitré par hyperglycémie chez un modèle animal (poisson zèbre), préviennent une destruction d'une barrière hémato-rétinienne dans un modèle animal à rétinopathie diabétique induite (rat SD), augmentent l'occludine, qui est une protéine constituant une jonction serrée et réduisent significativement des facteurs de croissance de l'endothélium vasculaire augmentés pathologiquement. Par conséquent, les dérivés de phényle de la présente invention peuvent être utilisés efficacement comme composition pour prévenir, améliorer ou traiter des maladies associées aux cellules endothéliales vasculaires telles que le diabète et les complications diabétiques.
PCT/KR2012/004805 2012-02-08 2012-06-18 Dérivés de phényle ou sels pharmaceutiquement acceptables de ceux-ci, leurs procédés de préparation, et composition les comprenant comme principes actifs pour prévenir, améliorer ou traiter des maladies associées aux cellules endothéliales vasculaires ou le diabète WO2013118949A1 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2012021013A2 (fr) * 2010-08-11 2012-02-16 한국한의학연구원 Nouveau composé de biphényle ou sel pharmaceutiquement acceptable de celui-ci, procédé de préparation du nouveau composé de biphényle ou du sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci comme ingrédient actif pour prévenir ou traiter les complications du diabète

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012021013A2 (fr) * 2010-08-11 2012-02-16 한국한의학연구원 Nouveau composé de biphényle ou sel pharmaceutiquement acceptable de celui-ci, procédé de préparation du nouveau composé de biphényle ou du sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci comme ingrédient actif pour prévenir ou traiter les complications du diabète

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CERVELLATI, RINADO ET AL.: "Polyphenols from Polygala spp. and Their Antioxidant Activity", CHEMISTRY & BIODIVERSITY, vol. 1, 2004, pages 415 - 425 *
LEBEUF, RAPHAEL ET AL.: "Birch Reductive Alkylation of Biaryls: Scope and Limitations", J. ORG. CHEM., vol. 74, 2009, pages 6469 - 6478 *
LEBEUF, RAPHAEL ET AL.: "Preparation of (3,5-dimethoxy-1-phenylcyclohexa-2,5-dienyl)- acetonitrile through Birch reductive alkylation (BRA)", ORG. SYNTH., vol. 86, 2009, pages 1 - 10 *
LEBEUF, RAPHAEL ET AL.: "Regioselectivity of Birch Reductive Alkylation of Biaryls", ORGANIC LETTERS, vol. 7, 2005, pages 4557 - 4560 *

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