WO2012102560A2 - Nouveau dérivé de 4-0-méthylhonokiol et composition contenant ce dérivé en tant que principe actif pour traiter des maladies inflammatoires - Google Patents

Nouveau dérivé de 4-0-méthylhonokiol et composition contenant ce dérivé en tant que principe actif pour traiter des maladies inflammatoires Download PDF

Info

Publication number
WO2012102560A2
WO2012102560A2 PCT/KR2012/000616 KR2012000616W WO2012102560A2 WO 2012102560 A2 WO2012102560 A2 WO 2012102560A2 KR 2012000616 W KR2012000616 W KR 2012000616W WO 2012102560 A2 WO2012102560 A2 WO 2012102560A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
derivative
alkenyl
added
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2012/000616
Other languages
English (en)
Korean (ko)
Other versions
WO2012102560A3 (fr
Inventor
한상배
정재경
곽영신
서승용
이기호
송석길
홍진태
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hyundai Bioland Co Ltd
Original Assignee
Bioland Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bioland Ltd filed Critical Bioland Ltd
Publication of WO2012102560A2 publication Critical patent/WO2012102560A2/fr
Publication of WO2012102560A3 publication Critical patent/WO2012102560A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • C07C43/205—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
    • C07C43/2055—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 containing more than one ether bond
    • 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
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/28—Ethers with hydroxy compounds containing oxirane rings

Definitions

  • Novel 4—0-methylhonokiol derivatives and compositions for treating inflammatory diseases comprising the same as active ingredients
  • the present invention relates to a novel 4-0-methylhonokiol derivative and a composition for treating inflammatory diseases comprising the same as an active ingredient.
  • 4-0- methyl hono kiol is 3 ', 5-diallyl-4' - a generic name of a meteuk fertilization-phenyl-2, has been recently isolated from Magnolia species (Magnolia species), an annular oxygenation enzyme Inhibitors have anti-inflammatory effects, as well as a very useful report of improving memory impairment:: Substance (1, 2).
  • Korean Patent Registration No. 10-932962, Korean Patent Publication No. 2009-94916, and Korean Patent Publication No. 2008 ⁇ 104760 disclose the results of ... by Magnolia officinalis Rehd. Et Wils. It is disclosed that 4-0-methylhonokiol extracted from stems and leaves can be used for the treatment of amyloid-related diseases, prevention of hair loss and the promotion of hair growth, and skin whitening.
  • the main biologically active compounds that have been used in medicine and belong to Magnolia are biphenyl-neolignan's compounds such as honokiol j (magnolol) and obovatol (2 ). Fascinatingly, 4—0-methylhonokiol is a Honoki or other variety. The anti-inflammatory activity was higher than that of one Honokiol analogue, with an IC50 value of 0,06 ⁇ for C0X-2 (3). In addition, 4-0-methylhonokiol has recently been shown to exhibit neuroaffinity and memory enhancing activity (4).
  • the present inventors have made extensive efforts to develop derivative compounds having more improved activity of methylhonokiol compounds known to have various physiological activities such as anti-inflammatory and anti-dementia efficacy.
  • the present invention was completed by synthesizing various derivatives of methyl honokiol and experimentally confirming that they have anti-inflammatory activity that inhibits the activity of C0X-2 (Cyclooxigenase-2).
  • an object of the present invention is to provide a novel methyl honokiol derivative.
  • Another object of the present invention is to provide a composition for treating inflammatory diseases comprising the novel methylhonoki derivative as an active ingredient.
  • the present invention provides a methyl honokiol derivative compound represented by the following formula (1), (2) or (3)
  • 3 ⁇ 4 is H, dC 7 alkyl, C 2 -C 7 alkenyl, — C0 (C3 ⁇ 4) n C3 ⁇ 4, or
  • R 2 is H, or halo
  • R 3 and R 4 are each independently CrC? Alkyl, C 2 -C 7 alkenyl, dC 7 hydroxyalkyl, or C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, (C 3 -C 8 heterocycloalkyl) CC 7 alkyl;
  • ⁇ 2i> and 3 ⁇ 4 are each independently H, dC 6 alkyl, C 2 -C 6 alkenyl, C 6 -C 10 aryl,
  • ⁇ 25> 3 ⁇ 4 is dC? Alkyl, C 2 -C 7 alkenyl, or halo;
  • R 2 is dC 7 alkyl, C 2 -C 7 alkenyl, or dC 7 hydroxyalkyl
  • 3 ⁇ 4 is d— C 7 alkyl, or C 2 -C 7 alkenyl
  • R 2 is dC 7 alkyl, C 2 -C 7 alkenyl, C 3 -C 8 cycloalkyl, or (C 3 -C 8 cycloalkyl
  • CC 7 alkyl According to a preferred embodiment of the present invention, in Formula 1, 3 ⁇ 4 is H, d-Csal
  • R 3 and R 4 are each independently dC 5 alkyl, C 2 _C 5 al
  • 3 ⁇ 4 is d-
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group having a specified carbon number, for example, "d-Cgalkyl '' is a straight chain n- Propyl groups as well as branched isopropyl groups, and “d-alkyl” includes ⁇ -butyl, isobutyl and t-butyl.
  • hydroxyalkyl 'means an alkyl group in which at least one hydrogen atom of the alkyl group as defined above is substituted with a hydroxy group.
  • alkenyl refers to a straight or branched chain saturated hydrocarbon group having a specified carbon number having at least one double bond, for example, ethenyl, propenyl, isopropenyl, butenyl, Isobutenyl, t-butenyl, n-pentenyl, n-nuxenyl and the like.
  • halo means fluoro (F), chloro (C1), bromo (Br) or iodo (I).
  • cycloalkyl ' means a non-aromatic saturated monocyclic, fused bicyclic or crosslinked polycyclic ring hydrocarbon group containing the specified number of ring carbon atoms.
  • C 3 —C 6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclonucleus.
  • cycloalkyl alkyl means an alkyl group wherein at least one hydrogen atom of the alkyl group as defined above is substituted with a cycloalkyl group.
  • heterocycloalkyl alkyl refers to an alkyl group wherein at least one hydrogen atom of the alkyl group as defined above is substituted with a heterocycloalkyl group.
  • aryl 1 refers to an aromatic hydrocarbon group.
  • a "C 6 -C 10 aryl” group refers to phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl and tetrahydronaphthyl. Include.
  • haloaryl means an aryl group in which at least one of the hydrogen atoms of the aryl group is substituted with a halo group.
  • aryl alkyl means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is substituted with an aryl group as defined above.
  • (c 6 -c 14 aryl) d-alkyl refers to benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2 ⁇ phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, and the like. Include.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a methyl honokiol derivative represented by the formula (1), (2) or (3) as an active ingredient. do.
  • the present invention provides a functional food composition for improving an inflammatory disease comprising a methyl honokiol derivative represented by Formula 1, Formula 2 or Formula 3 as an active ingredient.
  • the methyl honokiol derivative of the present invention has excellent anti-inflammatory activity by inhibiting the activity of C0X-2 (Cyclooxigenase-2), as demonstrated in one specific example of the present invention.
  • Methyl honokiol derivatives can be used as active ingredients in the treatment, prevention or amelioration of inflammatory diseases.
  • the inflammatory disease is atopic dermatitis, encephilitis, inflammatory enteritis, chronic obstructive pulmonary disease, pneumonia shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthrosis , Arthritis, inflammatory osteolysis, chronic inflammatory diseases caused by chronic viruses or bacterial infections, colitis, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, reactive arthritis, osteoarthritis, psoriasis, balls Blood, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericardium , Cystic fibrosis, Hashimoto thyroiditis, Graves' disease, leprosy, syphilis, Lyme disease
  • Lyme Borrel iosis, Angio-Botelosis, Tuberculosis, Sarcoidosis, Lupus, Discus lupus, Alma Lupus, Lupus nephritis, Systemic lupus lupus, Macular degeneration, Uveitis, Irritable bowel syndrome, Crossie's disease, Sjogren's syndrome, fibromyalgia, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, myalgia encephalomyelitis, muscular dystrophy Attention deficit hyperactivity disorder.
  • the inflammatory disease may be treated, prevented or improved by anti-inflammatory activity. It is well known in the art that the anti-inflammatory activity can be induced by inhibiting the activity of C0X-2 (Cyclooxigenase-2) or by inhibiting the production of PGFla (Seibert K, Masferrer JL., Receptor. 1994 Spring 4 (1): 17-23; AK Black, et al., Br J Clin Pharmacol. 1982 March 13 (3): 351-354; Koh-ichi Yuhki, et a 1., J / 3 ⁇ 4T December 2004 vol .311 no.3: 1218-1224).
  • the pharmaceutical composition of the present invention may comprise (a) a pharmaceutically effective amount of a methyl honokiol derivative represented by Formula 1, Formula 2, or Formula 3; And (b) it may be provided in the form of a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a pharmaceutically acceptable carrier. :
  • compositions of the present invention are conventionally used in the preparation of lactose, dextrose, sucrose, sorbbi, manna, starch, acacia rubber, calcium phosphate, Alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methylhydroxy benzoate, propylhydroxybenzoate, talc, stearate magnesium and Including but not limited to mineral oils.
  • the pharmaceutical compositions of the present invention may further comprise lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. in addition to the above components. ed., 1995).
  • Suitable dosages (pharmaceutically effective amounts) of the pharmaceutical compositions of the present invention may be formulated by the method of administration, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and reaction of the patient. It can be prescribed in various ways by factors such as gender.
  • the oral dosage of the pharmaceutical composition of the present invention is preferably 0.001-100 mg / kg (body weight) per day.
  • the pharmaceutical compositions of the present invention can be administered orally or parenterally, and when administered parenterally, intravenous, subcutaneous, intramuscular, intraperitoneal, transdermal Or by administration.
  • the route of administration of the pharmaceutical composition of the present invention is determined according to the type of the disease to be applied.
  • the concentration of the active ingredient in the pharmaceutical composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the period of time, etc., and is not limited to a specific range of concentration.
  • the pharmaceutical composition of the present invention may be formulated using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those skilled in the art. It may be prepared in unit dose form or incorporated into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or an aqueous medium, or may be in the form of axes, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer.
  • the present invention provides a functional food composition for improving an inflammatory disease comprising a methyl hono keol derivative represented by Formula 1, Formula 2, or Formula 3 as an active ingredient.
  • the functional food composition of the present invention includes ingredients that are commonly added during food production, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings.
  • a flavoring agent or a natural carbohydrate may be included as an additional ingredient in addition to the methyl honokiol derivative as an active ingredient.
  • natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); Dissaccharides (eg maltose, sucrose, etc.); oligosaccharide; Polysaccharides (eg dex: lean, cyclotextin, etc.); And sugar alcohols (e.g., Xili, Sorbi, Eritri, etc.).
  • natural flavoring agents e.g. taumartin, stevia extract, etc.
  • synthetic flavorings e.g. saccharin, aspartame, etc.
  • the present invention is the claim 1 or claim
  • the present invention is the claim 1 or claim
  • a method of treating or preventing inflammatory diseases including administering a pharmaceutically effective amount of the methyl honokiol derivative compound according to item 2.
  • the present invention provides a novel methyl honokiol derivative compound.
  • the novel methyl honokiol derivative of the present invention is a C0X-2 in RAW 264.7 macrophages. It showed anti-inflammatory activity by inhibiting the activity of.
  • novel methyl honokiol derivatives of the present invention can be developed as drugs for the treatment or prevention of inflammatory diseases
  • Methyl honokiol (1.0 eq) was dissolved in anhydrous THF under a nitrogen stream, and then isopropalma magnesium chloride (2,0 M solution in diethyl ether, 1.2 eq) was added at -78 ° C. Stirred at ⁇ 78 ° C. for 30 minutes and then further stirred at room temperature for about 10 minutes. After stirring for 10 minutes, DCD ⁇ (0.8 eq) was added, followed by reaction for 2 hours. After the reaction was completed, the mixture was washed with aqueous NH 4 C1 and extracted three times with ethyl acetate.
  • Trihosgene (89 mg, 0.3 ⁇ l ol) was added to a dichloromethane solution (1 mL) of methylhonokki (42 mg, 0.15 ⁇ l ol) and pyridine (80 mg, 1 mmol). After stirring for 2 hours at room temperature, glycineamide (glycinamide) (22 mg, 0.3 ⁇ l ol) was added thereto. After stirring for 12 hours at room temperature, the mixture was diluted with dichloromethane and washed with saturated NH 4 C1 and water. After washing with brine, dried over MgS0 4 , filtered and distilled under reduced pressure.
  • Tetrakis (triphenylphosphin ' ) was dissolved in a DMF solution (1 mL) of isoxazole compound (46 mg, 0.16 ⁇ ol) and allyltributyltin (103 mg, 0.31 ⁇ ol) obtained in step 2.
  • e) palladium (0) (10 mg, 7.8 ymol) was added. After stirring at 90 ° C. for 5 hours, cooled to room temperature, diluted with ethyl acetate and washed twice with water. After washing with brine, dried over MgS0 4 , filtered and distilled under reduced pressure.
  • Step 5 Preparation of the derivative 1 compound
  • boron tribromide (1,0 M solution in dichloromethane, 680 U L, 0.68 ⁇ L).
  • boron tribromide (1,0 M solution in dichloromethane, 680 U L, 0.68 ⁇ L).
  • Methanol was added to terminate the reaction.
  • the mixture was stirred at room temperature for 30 minutes, diluted with dichloromethane and washed with water. After washing with brine, dried over MgS0 4 , filtered and distilled under reduced pressure.
  • Column chromatography ethyl acetate : n-
  • NCS 120 mg, 0.9 ⁇ l
  • a chloroform solution (2 mL) of the product aldoxime compound (164 mg, 0.76 ⁇ l ol) of Preparation Example 20 at 0 ° C.
  • the reaction solution was poured into ice water. Extracted with ethyl acetate, dried over MgS0 4 , concentrated under reduced pressure and chlorooxime
  • Step 1-2
  • Step 2-2
  • reaction solution was poured into a cold 1N-NH 4 0H aqueous solution to terminate the reaction (to prevent explosion during drying of the remaining CuN 3 ). ). Extracted with ethyl acetate, washed with brine, dried over MgS0 4 , filtered and distilled under reduced pressure. Into the flask for the next reaction, Methanol (1 mL) and K 2 CO 3 (15 mg, 0.1 ⁇ l) were added. The mixture was stirred at 50 ° C for 2 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. After washing with brine, dried over MgS0 4 , filtered and distilled under reduced pressure.
  • RAW 264.7 macrophages were cultured in DMEM medium containing 10% FBS as mouse macrophages.
  • a background tube, a 100% initial active tube with maximum reactivity, and a COX-2 inhibitor tube containing the sample were prepared.
  • the background tube was inactivated C0X-2 enzyme 10 at 100 ° C for 3 minutes, and then added 970 ⁇ react ion buffer and 10 ⁇ heme.
  • the 100% initial activity tube was loaded with 970 ⁇ reaction buffer, 10 / ⁇ heme, and 10 / ⁇ C0X-2.
  • the C0X-2 inhibitor tube was filled with 950 ⁇ reaction strip, 10 / ⁇ heme, 10 ⁇ C0X-2 and 20 ⁇ .
  • the three tubes were reacted for 10 minutes in a 37 ° C water bath, arachidonic acid (10 ⁇ ) was added to the vortex and reacted for 2 minutes in a 37 ° C water bath. Then, 50 M of 1M HC1 was added to stop the reaction, and 100 / ⁇ stannous chloride solution was added thereto, followed by vortexing, and reaction at room temperature for 5 minutes. Samples were prepared and the samples of the three tubes, tracer and antiserum were placed in wells of 50 ⁇ each and reacted for 18 hours at room temperature. After the reaction, the reaction was washed five times, and Ellman's regent in each well was darkened and reacted. When the absorbance value of the reference value is between 0.3 and 0.8 at 412 ⁇ , the value was measured and analyzed.
  • RAW 264.7 macrophages dendritic cells were lysed in DMEM medium containing 10% FBS and plated at 1 ⁇ 10 6 cells per well in 96 well plates. LPS of 1 yg / ⁇ and samples were treated by concentration. After incubation for 24 hours after sample processing, the supernatant was recovered and used for the experiment. Each well was added with supernatant, tracer, and antiserum (50) and reacted for 18 hours at 4 ° C. After the reaction, the reaction was washed five times, and 200 ⁇ l of Ellman's regent was added to each well, darkened, and reacted. When the absorbance value of the reference value was between 0.3 and 1.0 at 412 nm, the value was analyzed.
  • the methyl honokiol derivative of the present invention exhibited cytotoxicity with an IC 50 of 20-100 ⁇ . In addition, while having a similar IC 50 value, it inhibited the NO production of macrophage (macrophage). This means that derivatives are cytotoxic to macrophages but do not inhibit NO production at low concentrations (see Table 4), but cytotoxicity .
  • the present invention provides a novel methyl honokiol derivative and a composition for the treatment, prevention or improvement of an inflammatory disease comprising the same as an active ingredient.
  • the methyl honokiol derivatives of the present invention exhibit very excellent anti-inflammatory activity by inhibiting the activity of C0X-2 (Cyclooxigenase-2). Therefore, methyl honoki derivative of the present invention can be developed as an active ingredient of a therapeutic agent for various inflammatory diseases and health functional food for improving inflammatory diseases.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un nouveau dérivé de méthylhonokiol et une composition contenant ce dérivé en tant que principe actif pour traiter, prévenir ou atténuer des maladies inflammatoires. Ce dérivé de méthylhonokiol permet d'inhiber les activités de la COX-2(Cyclooxigénase-2), ce qui permet d'assurer des activités anti-inflammatoires. Ainsi, ce dérivé de méthylhonokiol peut être développé en tant qu'agent thérapeutique pour des maladies anti-inflammatoires variées et en tant que principe actif d'aliments fonctionnels.
PCT/KR2012/000616 2011-01-26 2012-01-26 Nouveau dérivé de 4-0-méthylhonokiol et composition contenant ce dérivé en tant que principe actif pour traiter des maladies inflammatoires Ceased WO2012102560A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020110007844A KR101386068B1 (ko) 2011-01-26 2011-01-26 신규한 4-ｏ-메틸호노키올 유도체 및 이를 유효성분으로 포함하는 염증질환 치료용 조성물
KR10-2011-0007844 2011-01-26

Publications (2)

Publication Number Publication Date
WO2012102560A2 true WO2012102560A2 (fr) 2012-08-02
WO2012102560A3 WO2012102560A3 (fr) 2012-10-18

Family

ID=46581294

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2012/000616 Ceased WO2012102560A2 (fr) 2011-01-26 2012-01-26 Nouveau dérivé de 4-0-méthylhonokiol et composition contenant ce dérivé en tant que principe actif pour traiter des maladies inflammatoires

Country Status (2)

Country Link
KR (1) KR101386068B1 (fr)
WO (1) WO2012102560A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9486419B2 (en) 2013-04-17 2016-11-08 Ariel-University Research And Development Company CB2 receptor ligands for the treatment of psychiatric disorders
CN113999191A (zh) * 2021-11-25 2022-02-01 大连理工大学 一种含活性酯侧基新型生物基环氧树脂及其制备方法
WO2025247160A1 (fr) * 2024-05-27 2025-12-04 上海植瑞新成医药科技有限公司 Dérivé d'honokiol, son procédé de préparation et son utilisation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101941221B1 (ko) * 2017-12-14 2019-01-22 (주)솔빛피앤에프 노근 추출물을 유효성분으로 하는 황반변성 예방, 개선 또는 치료용 조성물
WO2023182871A1 (fr) * 2022-03-25 2023-09-28 바스테라 주식회사 Dérivé de 3-phénylisoxazole et composition pharmaceutique pour prévenir ou traiter une maladie oculaire le contenant en tant que principe actif
WO2025116596A1 (fr) * 2023-11-29 2025-06-05 가천대학교 산학협력단 Nouveau composé et composition pour la prévention ou le traitement de maladies oculaires le contenant

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101116852B1 (ko) * 2007-05-31 2012-03-06 주식회사 바이오랜드 후박 추출물 또는 이로부터 분리된 ４-ｏ-메틸호노키올을유효성분으로 함유하는 항염, 항알러지 및 주름 개선용조성물
KR100919625B1 (ko) * 2007-08-31 2009-09-30 서울대학교산학협력단 후박 추출물 또는 추출정제물을 포함하는 지방간 질환 예방및 치료용 조성물, 및 추출정제물의 제조방법

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9486419B2 (en) 2013-04-17 2016-11-08 Ariel-University Research And Development Company CB2 receptor ligands for the treatment of psychiatric disorders
CN113999191A (zh) * 2021-11-25 2022-02-01 大连理工大学 一种含活性酯侧基新型生物基环氧树脂及其制备方法
WO2025247160A1 (fr) * 2024-05-27 2025-12-04 上海植瑞新成医药科技有限公司 Dérivé d'honokiol, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
WO2012102560A3 (fr) 2012-10-18
KR20120086538A (ko) 2012-08-03
KR101386068B1 (ko) 2014-04-21

Similar Documents

Publication Publication Date Title
Ko et al. Structure–activity relationship studies on chalcone derivatives: the potent inhibition of chemical mediators release
KR101386068B1 (ko) 신규한 4-ｏ-메틸호노키올 유도체 및 이를 유효성분으로 포함하는 염증질환 치료용 조성물
EP2725018B1 (fr) Dérivé de cinnamamide substitué, son procédé de préparation et son utilisation
KR20140021047A (ko) Ｈｉｖ 단백질 분해 효소 억제제 및 그를 포함하는 약학 조성물
KR101305524B1 (ko) 신규한 4-ｏ-메틸호노키올 유도체를 유효성분으로 포함하는 치매 치료용 조성물
CN107090000A (zh) 一种苯并硼唑7位脂肪酸的衍生物及其制备与药物用途
CN111718352B (zh) 一类化合物及其药学上可接受的盐
KR101466144B1 (ko) 신규한 4-ｏ-메틸호노키올 유도체 및 이를 유효성분으로 포함하는 염증질환 치료용 조성물
CN112592252B (zh) 柏木醇衍生物、其制备方法及其应用
CN113402414A (zh) 一种苯甲酸衍生物及其制法和药物用途
CN105461573A (zh) 一种(s)-n-脱甲基达泊西汀的制备方法
CN104513172B (zh) 含有三氟甲基的酰胺生物碱、制备方法及其药物用途
CN102516066B (zh) Ostopanic acid类似物及制备方法及用途
RU2649406C1 (ru) 3-n-замещенные борнилпропионаты, используемые в качестве ингибиторов вируса марбург
KR101585450B1 (ko) Ｄｅｃｕｒｓｉｎｏｌ 유도체를 포함하는 해열 및 진통제 조성물
JP6848047B2 (ja) スピロインドロンポリエチレングリコールカーボネート系化合物及びその組成物、調製方法及びその使用
CN111592520A (zh) 一类4,5-二取代基胡椒碱衍生物及其制备方法和应用
CN114736252B (zh) 一种连翘苷衍生物及其制备方法和医用用途
KR102906581B1 (ko) 올레아난 신남아미드 유도체 및 이의 제조 방법과 용도
RU2829816C1 (ru) Производное циннамида оленана, способ его получения и применение
CN104974116B (zh) 韧革菌素酰胺类衍生物及其制备方法与应用
RU2697716C1 (ru) Гидрохлорид 1,7,7-триметилбицикло[2.2.1]гептан-2-ил 3-(пиперидин-1-ил)пропионат, используемый в качестве ингибитора вируса Эбола
AU5341198A (en) Substituted propionyl derivatives
KR20130083879A (ko) 신규한 4-ｏ-메틸호노키올 유도체를 유효성분으로 포함하는 치매 치료용 조성물
KR100386318B1 (ko) 오스테놀 유도체를 포함하는 암 예방 및 치료용 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12739382

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12739382

Country of ref document: EP

Kind code of ref document: A2