WO2015115805A1 - Nouveau dérivé 2-phénylbenzofuranne ou sel pharmaceutiquement acceptable associé, son procédé de production et composition pharmaceutique de prévention ou de traitement d'une maladie inflammatoire comprenant un tel composé utilisé comme principe actif - Google Patents

Nouveau dérivé 2-phénylbenzofuranne ou sel pharmaceutiquement acceptable associé, son procédé de production et composition pharmaceutique de prévention ou de traitement d'une maladie inflammatoire comprenant un tel composé utilisé comme principe actif Download PDF

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WO2015115805A1
WO2015115805A1 PCT/KR2015/000922 KR2015000922W WO2015115805A1 WO 2015115805 A1 WO2015115805 A1 WO 2015115805A1 KR 2015000922 W KR2015000922 W KR 2015000922W WO 2015115805 A1 WO2015115805 A1 WO 2015115805A1
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formula
compound represented
methoxy
aromatich
derivative
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PCT/KR2015/000922
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English (en)
Korean (ko)
Inventor
이경
오세량
안경섭
권옥경
김두영
류형원
김정희
허학진
Original Assignee
한국생명공학연구원
동국대학교 산학협력단
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Priority to JP2016549075A priority Critical patent/JP6343013B2/ja
Priority to CN201580006393.XA priority patent/CN106536497A/zh
Priority to EP15743007.5A priority patent/EP3101014B1/fr
Priority claimed from KR1020150013199A external-priority patent/KR101722571B1/ko
Publication of WO2015115805A1 publication Critical patent/WO2015115805A1/fr
Priority to US15/221,025 priority patent/US20160332980A1/en
Priority to US15/449,465 priority patent/US10053443B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • Novel 2-phenylbenzofuran derivative or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for preventing or treating inflammatory disease comprising the same as an active ingredient
  • the present invention relates to a novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same as an active ingredient.
  • Inflammation is the body's defense against external physical and chemical stimuli, bacteria, bears, viruses, and allergens. Inflammatory reactions are part of innate immune reactions, and like other animals, human innate immune reactions begin by recognizing and attacking non-sel f via macrophage-specific patterns on the cell surface. do. Inflammation reactions result in the accumulation of plasma at the site of inflammation, diluting the toxicity of bacteria, increased blood flow, and accompanying symptoms such as hemorrhage, pain, edema, and fever. These inflammatory reactions involve a variety of biochemical phenomena, especially cyclooxygenase (COX), which is associated with the biosynthesis of nitric oxide synthase (NOS) and various prostaglandins. It is known as a medium.
  • COX cyclooxygenase
  • NOS nitric oxide synthase
  • the N0S is composed of three isomers, such as calcium endogenous toxins such as eNOS (endothelial N0S), nNOS (neuropolyphosphate), and LPS (l ipopolysaccharide), IL-1 ⁇ , and TNF-.
  • eNOS endothelial N0S
  • nNOS neuroropolyphosphate
  • LPS l ipopolysaccharide
  • IL-1 ⁇ IL-1 ⁇
  • TNF- TNF-.
  • iNOS inducible NOS
  • cytokines such as ⁇ , IL-6, IL-8, IL-12
  • Nitric oxide (N0) produced by eNOS or nNOS plays an important role in maintaining the homeostasis of the body by performing various physiological reactions related to blood pressure control, neurotransmitter, learning, memory, etc.
  • N0 is known to be involved in various inflammatory diseases such as arthritis, sepsis, rejection of tissue transplantation, autoimmune diseases, and death of neurons (Non-Patent Documents 1 and 2) of cell walls of gram-negat ive bacteria.
  • LPS LPS
  • macrophages Once activated by LPS, macrophages secrete cytokines, chidocaine, and N0, which are precursors of inflammation, which can even lead to cancerous activity.
  • Cytokines, chemokines, and nitric oxide (N0) are overexpressed by the same mediator of inflammation, resulting in various diseases such as sepsis, rheumatoid arthritis, and autoimmune diabetes. appear.
  • the control of macrophage-mediated inflammatory reactions can be an important substance in treating these inflammatory diseases. Therefore, a substance that inhibits overexpression of the above-described mediators of inflammation can be developed as a therapeutic agent for inflammatory diseases. Accordingly, the present inventors have been trying to develop compounds that exhibit the inhibitory effect of nitric oxide (NO), interleukin-6 (11-6) and tumor necrosis factor (TNF-alpha) on macrophages.
  • NO nitric oxide
  • TNF-alpha tumor necrosis factor
  • Another object of the present invention is to provide a method for preparing the 2-phenylbenzofuran derivative.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing the novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention to provide a health food composition for the prevention or improvement of inflammatory diseases containing the novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof:
  • R 2 and R 3 are independently hydrogen or hydroxy, halogen, unsubstituted or substituted with one or more halogen of straight or branched chain d- 6 alkyl, straight or branched chain d- 6 alkoxy and one or more straight or branched chain 1 type selected from the group consisting of amino substituted with d- 6 alkyl;
  • R 5 is hydroxy or straight or branched dealkoxy.
  • the present invention also provides a method for preparing the 2-phenylbenzofuran derivative.
  • the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases containing the novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • another object of the present invention provides a health food composition for preventing or ameliorating an inflammatory disease containing the novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Novel 2-phenylbenzofuran derivatives or pharmaceutically acceptable salts thereof according to the present invention have excellent effects of inhibiting NO, IL-6 and TNF-alpha induced by macrophages, thus preventing or treating inflammatory diseases. It can be usefully used as a pharmaceutical composition.
  • the present invention provides a 2-phenylbenzofuran derivative represented by the following Chemical Formula 1 or Chemical Formula 2 or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 are independently hydrogen or hydroxy, halogen, unsubstituted or substituted straight chain or branched Cl-6 alkyl, straight chain or branched 6 alkoxy and at least one straight chain or branched d One selected from the group consisting of amino substituted with 6 alkyl;
  • R 5 is hydroxy or straight or branched Ci-6 alkoxy.
  • R 1 , R 2 and R 3 are independently straight or branched chain d- 4 alkyl substituted with hydrogen, hydroxy, chlorine, fluorine, unsubstituted or one or more halogens, straight chain or branched d-4 alkoxy and It is preferably one species selected from the group consisting of amino substituted with one or more linear or branched alkyl, independently hydrogen, hydroxy, chlorine, fluorine, trifluoromethyl, methoxy, ethoxy, dimethylamino and diethyl It is more preferable that it is 1 type chosen from the group which consists of amino.
  • R 5 is preferably one selected from the group consisting of hydroxy, methoxy and ethoxy.
  • 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 are as follows:
  • Acid addition salts formed by pharmaceutically acceptable free acids are useful as salts, which can be used in the form of pharmaceutically acceptable salts.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Eight video obtained from organic acids such as aromatic acids, non-toxic organic acids such 'as aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid maleic acid, gluconic acid, methanesulfonic acid, 4-toluene sulfonic acid framework, tartaric eu fumaric acid.
  • organic acids such as aromatic acids, non-toxic organic acids such 'as aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid maleic acid, gluconic acid, methanesulfonic acid, 4-toluene sulfonic acid framework, tartaric eu fumaric acid.
  • pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate monohydrogen phosphate, dihydrogen phosphate, metaphosphate pyr
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, 2—phenylbenzofuran derivative represented by Formula 1 or Formula 2 may be methane, ethanol, acetone, dichloromethane, acetonitrile It is prepared by dissolving in a organic solvent such as and the like, adding precipitated organic or inorganic acid, and filtering and drying the precipitate. The solvent and the excess acid may be distilled under reduced pressure, dried and crystallized in an organic solvent to prepare. Bases can also be used to make pharmaceutically acceptable metal salts.
  • 2—phenylbenzofuran derivative represented by Formula 1 or Formula 2 may be methane, ethanol, acetone, dichloromethane, acetonitrile It is prepared by dissolving in a organic solvent such as and the like, adding precipitated organic or inorganic acid, and filtering and drying the precipitate. The solvent and the excess acid may be distilled under reduced pressure, dried and crystallized in an organic solvent to prepare. Bases can also be used
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the compound salt at no cost, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate). Furthermore, the present invention includes not only 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof, but also solvates, hydrates, and the like that can be prepared therefrom. In addition, the present invention provides a method for preparing the 2-phenylbenzofuran derivative represented by the formula (1) or (2). Preparation 1:
  • a process for preparing the derivative of Formula 1 according to claim 1 comprising the step of obtaining a compound represented by the formula la by reducing reaction in the presence of sodium borohydride.
  • Step 1 is performed by reacting the compound represented by the formula (3) with Sonogashira and cyclization in the presence of the compound represented by the formula (4), a palladium / charcoal catalyst, and a base. It is a step of obtaining the compound represented by.
  • the Sonogashira Banung is a reaction to form a carbon-carbon bond by replacing halogen with Alkyne using palladium catalyst in organic synthesis.
  • the cyclized reaction means a reaction in which the hydroxyl group of the compound represented by Formula 3 is added to the alkyne substituted via the sonogashira reaction.
  • the palladium catalyst used in the Sonogashira reaction in step 1 can be used without particular limitation as long as it is commonly used in Sonogashira reaction, palladium charcoal (Pd / C), tetrakistriphenylphosphine palladium (Pd (PPh 3 ) 4 ), bistriphenylpalladium dichloride (PdCl 2 (PPh 3 ) 2 ),
  • the base of step 1 is triethylamine, ⁇ , ⁇ -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, L-prlinol Equivalent or excessive amounts of organic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like can be used.
  • organic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like can be used.
  • the solvent of step 1 is water, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methane, ethanol, propane, butanol, dimethylformamide (DMF), Dimethyl sulfoxide (DMS0), acetonitrile, and the like are preferably used alone or in combination, and more preferably water is used.
  • step 2 is a step of obtaining a compound represented by the formula la by reducing the compound represented by the formula (5) obtained in the step 1.
  • Step 2 is a step of reducing the aldehyde group of the compound represented by the formula (5) to convert the alcohol group.
  • the reagent for reducing the aldehyde can be used without limitation as long as it is a reagent capable of reducing the aldehyde, sodium borohydride (NaBH 4 ), lithium aluminum hydride (Li A1H 4 ), etc. It is preferable to use sodium borohydride (NaBH 4 ).
  • the solvent of step 2 is tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methane, ethanol, propanol, butanol, dimethylformamide (DMF), dimethyl sulfoxide It is preferable to use (DMS0), acetonitrile, etc. individually or in mixture, and it is more preferable to use tetrahydrofuran.
  • step 2 may be performed at 0 ° C to below the boiling point of the solvent.
  • the present invention is as shown in the following reaction formula 2 Reacting the compound represented by the formula (5) with methyltriphenylphosphine halide and removing the water under a base catalyst to obtain the compound represented by the formula (6); And
  • Claim 1 comprising the step of obtaining a compound represented by the formula (lb) by boron hydride reaction using borane or diborane and an oxide reaction using hydrogen peroxide obtained in step 1 (step 2); Provided are methods for preparing the derivatives of 1:
  • Step 1 is a step of obtaining a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 5 with methyltriphenylphosphine halide and removing it under a base catalyst.
  • the aldehyde group of the compound represented by Formula 5 is reacted with methyltriphenylphosphine halide, and water is removed under a base catalyst to obtain a compound represented by Formula 6 including a vinyl group.
  • the methyl triphenyl phosphine halide is preferably used iodide methyl triphenyl phosphine (CH 3 PPh 3 I).
  • sodium hydride potassium hydride, lithium hydride, cesium hydride and the like as the base of step 1, more preferably to use sodium hydride.
  • step 1 it is preferable to use dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like as the solvent of step 1.
  • step 2 is a step of obtaining a compound represented by the formula lb by boron hydride reaction and oxidative reaction of the compound represented by the formula (6) obtained in the step 1.
  • step 2 is a step of obtaining a compound represented by the formula lb containing a primary alcohol group after the boron hydride reaction to the alkene group of the compound represented by the formula (6).
  • the boron compound in the boron hydride reaction is preferably used borane (B3 ⁇ 4) or diborane (3 ⁇ 4), it is preferable to use hydrogen peroxide (0 2 ) in the reaction.
  • the base of step 2 may be used an equivalent or excess of inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • step 1 Reacting the compound represented by the formula (5) with a compound represented by the formula (7) under a base catalyst to obtain a compound represented by the formula (8) (step 1);
  • step 3 of reducing the compound represented by formula 9 obtained in step 2 in the presence of sodium borohydride to obtain a compound represented by formula lc do:
  • step 1 is a step of obtaining a compound represented by the formula (8) by reacting the compound represented by the formula (5) with the compound represented by the formula (7).
  • step 2 is a step of obtaining a compound represented by the formula (9) by hydrogenating the compound represented by the formula (8) obtained in the step 1.
  • the hydrogenation reaction can be used without particular limitation as long as the conditions of conventional hydrogenation reaction, it is preferable to carry out by using palladium charcoal in the presence of acid as a catalyst ,
  • tetrahydrofuran 1,2-dimethoxyethane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like are preferably used alone or in combination. It is more preferable to use tetrahydrofuran.
  • step 3 is a step of obtaining a compound represented by Chemical Formula lc by reducing the compound represented by Chemical Formula 9 obtained in Step 2.
  • step 2 Reducing the compound represented by the formula (10) obtained in step 1 in the presence of sodium borohydride to obtain a compound represented by the formula (2a) (step 2); to provide:
  • step 1 is a step c is a compound represented by the formula (10) by hydrogenation of the compound represented by the formula (7).
  • step 1 is a step of obtaining a compound represented by the formula (10) by hydrogenation of the compound represented by the formula (7) by converting the alken group into an alkyl group and simultaneously opening the furan ring of the benzofuran group.
  • Step 2 is a step of obtaining a compound represented by Chemical Formula 2a by reducing the compound represented by Chemical Formula 10 obtained in Step 1.
  • the reaction may be performed similarly to step 2 of the manufacturing method 1.
  • the reaction may be performed by each step, followed by extraction, drying, filtration, and distillation under reduced pressure with an organic solvent, and additionally, may be prepared by performing column chromatography or recrystallization.
  • the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease containing the novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the inflammatory diseases include dermatitis, allergy, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatism, lupus, fibromyalgia (f ibromyalgi a Psoriatic arthritis, osteoarthritis, rheumatoid arthritis; periarthritis, tendonitis, hay, peritonitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, and acute and chronic inflammatory diseases It is characterized in that it is any one selected.
  • the 2-phenylbenzofuran derivative according to the present invention has excellent cell viability and low cytotoxicity (Experimental Example 1), and the inhibition rate of production of nitric oxide (NO) by immune reaction shows 303 ⁇ 4 or more (Experimental Example 2). -1), the effect of inhibiting the production of interleukin-6 (IL-6) by the immune response is excellent (Experimental Example 2-2), and suppresses the production of tumor necrosis factor (TNF-alpha) by the immune response It can be seen that the effect is excellent (Experimental Example 2-3).
  • IL-6 interleukin-6
  • TNF-alpha tumor necrosis factor
  • the 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof according to the present invention can be usefully used as a pharmaceutical composition for preventing or treating inflammatory diseases.
  • the 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, orally and parenterally, during clinical administration. When formulated, it may be prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches and the like, and such solid preparations may include one or more of the formulas of the present invention.
  • 2-phenylbenzofuran derivative represented by 1, or a pharmaceutically acceptable salt thereof may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose or gelatin. have.
  • excipients such as starch, calcium carbonate, sucrose or lactose or gelatin.
  • lubricants such as magnesium stearate, talc and the like may also be used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspending solvent ⁇ ropropylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • suppositories wi tepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin, and the like may be used.
  • the dosage of the 2-phenylbenzofuran derivative represented by Chemical Formula 1 or Chemical Formula 2 of the present invention or a pharmaceutically acceptable salt thereof to the human body may be age, weight, sex, dosage form, health condition and disease level of the patient. Based on an adult patient weighing 70 Kg, typically 0.1-1000 mg / day, preferably 1-500 mg / day, and at the discretion of the doctor or pharmacist It may be administered once or several times a day at intervals.
  • the pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, chemotherapy and biological response modifiers for the prevention or treatment of inflammatory diseases.
  • the present invention also provides a health food composition for preventing or ameliorating an inflammatory disease containing a novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the inflammatory diseases include dermatitis, allergy, atopy, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus, fibromyalgia (f ibromyalgi a ), Psoriatic arthritis osteoarthritis, rheumatoid arthritis, periarthritis, tendonitis, hay, peritonitis, myositis, hepatitis, cystitis, nephritis, Sj ogren's syndrome, multiple sclerosis, and acute and chronic inflammatory diseases It is characterized in that it is any one selected.
  • the 2-phenylbenzofuran derivative according to the present invention has excellent cell viability and low cytotoxicity (Experimental Example 1), and the inhibition rate of nitrogen monoxide ( ⁇ 0) production by immunoreaction is 30% or more (experimental) Example 2-1), the effect of inhibiting the production of interleukin-6 IL-6) by immune reaction is excellent (Experimental Example 2-2), It can be seen that the effect of inhibiting the production of tumor necrosis factor (TNF-alpha) is excellent (Experimental Example 2-3).
  • the 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof may be usefully used as a health food composition for improving prevention of inflammatory diseases containing as an active ingredient.
  • a health food composition for improving prevention of inflammatory diseases containing as an active ingredient.
  • foods to which the above substances can be added include dairy products, including drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, 3 ⁇ 4, ice cream , Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, etc., and includes all the health functional foods in the ordinary sense.
  • the 2-phenylbenzofuran derivative represented by Formula 1 or Formula 2 according to the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the combined amount of the active ingredient can be suitably determined depending on the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added from 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose dung; And sugars such as conventional sugars such as polysaccharides such as textulin, cyclodextrin, and the like, and xylyl, sorbitol, erythritol and the like.
  • natural flavoring agents tautin, stevia extract (e.g., rebaudioside A, glycyrzin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • 2-phenylbenzofuran derivatives include flavors and neutralizers such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof. And organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • the 2-phenylbenzofuran derivative of the present invention may contain fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.
  • the compound of Table 1 was prepared by the same method as Preparation Example 1 below.
  • the compound of Table 2 was prepared by the same method as Sezo Example 19.
  • the compound of Table 3 was prepared in the same manner as in Preparation Example 37.
  • a white sec solid phase was prepared in the same manner as in Preparation Example 55, except that methyl-3— (7-methoxy-2-P-ylylbenzofuran-5-yl) propanoate obtained in Preparation Example 40 was used.
  • the desired compound (291.2 mg, 96.5%) was obtained.
  • a white solid phase was prepared in the same manner as in Preparation Example 55, except that methyl-3- (7-methoxy-2-m-ylylbenzofuran-5-yl) propanoate obtained in Preparation Example 39 was used. The desired compound (28.3 mg, 67%) was obtained.
  • the compound of Table 4 was prepared by the same method as Example 1 below.
  • Example 1 Methyl 3- (2- (3) obtained from 3- [2- (3,4-dimethoxyphenyl) -7-methoxybenzofuran-5-yl] propane-1- in Preparation Example 27 , 4-Dimethoxyphenyl)-Lithium aluminum hydride dissolved in tetrahydrofuran in a mixed solution of methoxybenzofuran-5-yl] propanoate (57 mg, 0.15 ⁇ l) in tetrahydrofuran (5 mL) (2.0M, 0.15 mL, 0.31 ⁇ l) was slowly added dropwise at 0 ° C.
  • Example 14 2 ′ (3,4-dimethoxyphenethyl) -4- (3-hydroxypropyl) -6-methoxyphenol Methyl-3- (3- (3,4) obtained in Preparation Example 55 above.
  • Example 15 4- (3-hydroxypropyl) -2-methoxy-6- (3-methylphenethyl) phenol Methyl obtained in Preparation Example 56 instead of methyl-3- (3- (3,4-dimethoxyphenethyl) -4-hydroxy-5-hydroxyphenyl) propanoate in Example 14;
  • the target compound (246 mg, 92.5%) was obtained by the same method as Example 14 except for using (4-hydroxy-3-methoxy-5 (3-methylphenethyl) phenyl) propanoate. Got it. ⁇
  • Example 14 methyl-3-((3- (3,4-dimethoxyphenethyl) -4-hydroxy-5-methoxyphenyl) propanoate instead of methyl-3- (
  • the desired compound as a white solid (79.7 mg, 67.3 «in the same manner as in Example 14 except that 4-hydroxy-3-methoxy ⁇ 5- (4-methylphenethyl) phenyl) propanoate was used Got.
  • Example 19 (7-Methoxy-2- (4-methoxy-2-methylphenyl) benzofuran-5-yl) methane was replaced with 2- (3,4-dimethoxyphenyl) -gramme in Example 18.
  • 7-methoxy-2- (4-methoxy ⁇ 2-methylphenyl) benzofuran-5carbaldehyde (O obtained in Preparation Example 2 instead of oxybenzofuran-5 carbaldehyde (O.lg, 0.32 mmol) .lg, 0.35 ⁇ l ol) was carried out in the same manner as in Example 18, to obtain the title compound (89 mg, 88.6%) as a white solid.
  • reaction product was extracted with ethyl acetate and brine.
  • the organic insects were separated, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example 22 The above preparation in place of 3- (2- (4- (tert-butyldimethylsiloxy) -3-methoxyphenyl) -7-methoxybenzofuranyl 5-al) propane-1- in Example 22
  • Example 22 Example was used except that 3- (2- (3,4-vice (talt-butyldimethylsilyloxy) phenyl) -7-methoxybenzofuranyl 5-yl) propane-1- obtained in Example 64 was used.
  • the title compound (70 mg, 74.5%) was obtained in the same manner as the 22.
  • Example 65 The above preparation instead of 3- (2- (4- (tert-butyldimethylsiloxy) -3-methoxyphenyl) -7-methoxybenzofuran-5-yl) propane-1- in Example 22 Except for the use of 3- (2- (4- (tert-butyldimethylsilyloxy) -3,5-dimethoxyphenyl) -gramoxybenzofuran-5-yl) propan-1-ol obtained in Example 65 was carried out in the same manner as in Example 22 to obtain the target compound (80 mg, 74.8%).
  • Methyl -3 '(2- (3,4-dimethoxyphenyl)-hydroxybenzofuran-5yl) propanoate (56 mg, 0.16 ⁇ ol) prepared in Preparation Example 68 was prepared by tetrahydrofuran ( Lithium aluminum hydride (2.0M, 0.15 mL, 0.31 mmol) dissolved in tetrahydrofuran was slowly added dropwise at 0 ° C. to a mixed solution dissolved in 5 mL) and stirred until thin layer chromatography confirmed the completion of reaction. When the reaction was completed, 10% hydrochloric acid was added dropwise and added with ethyl acetate and brine.
  • Lithium aluminum hydride 2.0M, 0.15 mL, 0.31 mmol
  • DMEM Dulbecco's modified Eagle medium; Wei gene, Korea
  • FBS Fetal Bovine Serum
  • 2 mM glutamine penicillin (100 unit / O and streptomycin (100 g / m £)
  • penicillin 100 unit / O
  • streptomycin 100 g / m £
  • 5 mg / n MTT 3- (4,5-dimethylthiazol-2-yl) —2,5-diphenyl
  • Tetrazolium bromide Amresco, OH, USA
  • the absorbance was measured at the wavelength of 570 nm, and the negative control group received 0.2% of DMS0 from which the sample was prepared.
  • the absorbance of the negative control group was used as 100% and the ratio was calculated as cell viability and is shown in Table 6 below.
  • the 2-phenylbenzofuran derivative according to the present invention has excellent cell viability (%) at 10 ⁇ , which has low effect on macrophages and thus is inflammatory due to low cytotoxicity It can be usefully used as a pharmaceutical composition for the prevention or treatment of diseases.
  • Raw2 64.7 was inoculated in the same medium as Experimental Example 1 at a cell concentration of 1 ⁇ 10 5 per well of a 96 well plate, and the cells were attached at 5% CO 2 and 37 ° C. for 4 hours. After incubation for one more hour, inflammation-induced macrophages (LPS) were incubated at a final concentration of 500 ng / for a further 24 hours.
  • LPS inflammation-induced macrophages
  • the 2-phenylbenzofuran derivatives according to the present invention exhibit a nitrogen monoxide production inhibition rate of 30% or more, and thus have an excellent effect of inhibiting the production of nitrogen monoxide (NO). It can be usefully used as a pharmaceutical composition for the prevention or treatment of inflammatory diseases.
  • Raw 264.7 was dispensed in the same manner as in Experimental Example 2-1, and IL-6 contained in the supernatant treated with the concentration of each sample was analyzed by enzyme immunoassay (IL-6 ELISA kit, BD
  • the supernatant diluted 10-fold was dispensed into a 96 well plate to which IL-6 antibody was attached and attached for 2 hours, and the excess supernatant was washed with the washing solution.
  • the excess antibody was washed, the reaction was developed using a TMB substrate, the reaction was stopped with sulfuric acid solution, and the absorbance was measured at 450 nm. .
  • the amount of IL-6 in the supernatant was quantified according to the standard curve prepared using standard IL-6 in the kit.
  • IL-6 production inhibition rate is shown in Table 8 by calculating the sample concentration that inhibits the production of IL-6 to 50% of the LPS treated group. Table 8
  • TNF-alpha Tumor necrosis factor
  • TNF-alpha EL ISA kit R & D Systems, USA.
  • the supernatant 100-fold dilution was dispensed in a 96-well plate to which the TNF-alpha antibody is attached and attached for 2 hours, and the excess supernatant was washed with the washing solution.
  • the excess antibody was washed, the color reaction was performed using a TMB substrate, the reaction was stopped with sulfuric acid solution, and the absorbance was measured at 450 nm.
  • the amount of TNF-alpha in the supernatant was quantified according to the standard curve prepared using the standard TNF-alpha in the kit.
  • the inhibition rate of TNF-alpha production was shown in Table 9 by calculating the sample concentration that inhibits the production of TNF-alpha by 50% in the LPS-treated group.
  • E 15 ⁇ E ⁇ 17 It can be usefully used as a pharmaceutical composition for the prevention or treatment of diseases.
  • a derivative represented by the formula (1) or (2) 100 nig Corn starch 100 nig Lactose 100 nig Magnesium stearate 2 nig
  • the capsules were prepared by layering on gelatin capsules according to a conventional method for preparing capsules.
  • Vitamin B2 0. 15 nig
  • Vitamin B6 0.5 nig
  • composition ratio of the above-mentioned vitamin and mineral mixtures is a composition which is relatively suitable for health foods in a preferred embodiment, but may be modified arbitrarily, and the above ingredients may be mixed according to a conventional health food manufacturing method.
  • Granules are prepared and can be used to prepare health food compositions according to conventional methods.
  • composition ratio is a composition that is relatively suitable for a preferred beverage in a preferred embodiment, the compounding ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau dérivé 2-phénylbenzofuranne ou un sel pharmaceutiquement acceptable associé, son procédé de production et une composition pharmaceutique permettant de prévenir ou de traiter une maladie inflammatoire comprenant un tel composé utilisé comme principe actif, et le nouveau dérivé 2-phénylbenzofuranne ou le sel pharmaceutiquement acceptable associé selon la présente invention est remarquablement efficace dans la suppression de NO, d'IL-6 et de TNF-alpha dus aux macrophages, et peut par conséquent être utilisé de manière avantageuse dans une composition pharmaceutique permettant de prévenir ou de traiter une maladie inflammatoire.
PCT/KR2015/000922 2014-01-28 2015-01-28 Nouveau dérivé 2-phénylbenzofuranne ou sel pharmaceutiquement acceptable associé, son procédé de production et composition pharmaceutique de prévention ou de traitement d'une maladie inflammatoire comprenant un tel composé utilisé comme principe actif WO2015115805A1 (fr)

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JP2016549075A JP6343013B2 (ja) 2014-01-28 2015-01-28 新規２−フェニルベンゾフラン誘導体又はその薬学的に許容される塩、その生産方法、及び炎症性疾患を予防又は治療するための、活性成分としてそれを含む医薬組成物
CN201580006393.XA CN106536497A (zh) 2014-01-28 2015-01-28 新型2‑苯基苯并呋喃衍生物或其药学上可接受的盐、其生产方法、及包括其作为有效成分的用于预防或治疗炎症性疾病的药物组合物
EP15743007.5A EP3101014B1 (fr) 2014-01-28 2015-01-28 Nouveau dérivé 2-phénylbenzofuranne ou sel pharmaceutiquement acceptable associé, son procédé de production et composition pharmaceutique de prévention ou de traitement d'une maladie inflammatoire comprenant un tel composé utilisé comme principe actif
US15/221,025 US20160332980A1 (en) 2014-01-28 2016-07-27 Novel 2-phenylbenzofuran derivative or pharmaceutically acceptable salt thereof, production method for same and pharmaceutical composition for preventing or treating inflammatory disease comprising same as active ingredient
US15/449,465 US10053443B2 (en) 2014-01-28 2017-03-03 2-phenylbenzofuran derivatives, method for preparing the same and use of the same for treating inflammatory disease

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KR20140010224 2014-01-28
KR10-2014-0010224 2014-01-28
KR10-2015-0013199 2015-01-28
KR1020150013199A KR101722571B1 (ko) 2014-01-28 2015-01-28 신규한 2-페닐벤조퓨란 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 염증성 질환의 예방 또는 치료용 약학적 조성물

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US11785598B2 (en) 2017-03-17 2023-10-10 Shanghai Langbo Communication Technology Company Limited Method and device for dynamically adjusting a number of resource elements in uplink control information

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JPH11158067A (ja) * 1997-08-13 1999-06-15 Sankyo Co Ltd セロトニン２受容体拮抗剤
WO2006023778A2 (fr) * 2004-08-20 2006-03-02 The Regents Of The University Of Michigan Petits inhibiteurs moleculaires de membres de la famille des anti-apoptose bcl-2, et utilisations correspondantes

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JPH11158067A (ja) * 1997-08-13 1999-06-15 Sankyo Co Ltd セロトニン２受容体拮抗剤
WO2006023778A2 (fr) * 2004-08-20 2006-03-02 The Regents Of The University Of Michigan Petits inhibiteurs moleculaires de membres de la famille des anti-apoptose bcl-2, et utilisations correspondantes

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H.-Y. SUNG ET AL.: "Chemico-Biological Interactions", NOVEL DANSHEN METHOAYBENZO[B] FURAN DERIVATIVE ANTAGONIZING ADIPOGENIC DIFFERENTIATION AND PRODUCTION OF INFLAMMATORY ADIPOKINES, vol. 188, no. 3, 2010, pages 457 - 466, XP055217744 *
J.-W. HWANG ET AL.: "Bull. Korean Chem. Soc.", FACILE PREPARATION OF 2-ARYLBENZO[B]FURAN MOLECULES AND THEIR ANTI-INFLAMMATORY EFFECTS, vol. 31, no. 4, 2010, pages 965 - 970, XP055217742 *
MONCADE S. ET AL., PHARMACOL. REV., vol. 43, 1991, pages 109
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Publication number Priority date Publication date Assignee Title
US11785598B2 (en) 2017-03-17 2023-10-10 Shanghai Langbo Communication Technology Company Limited Method and device for dynamically adjusting a number of resource elements in uplink control information

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