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WO2016195361A1 - Nouveau dérivé de benzylidène dihydroindénone, et composition pour prévenir ou traiter une maladie intestinale inflammatoire contenant le dérivé - Google Patents

Nouveau dérivé de benzylidène dihydroindénone, et composition pour prévenir ou traiter une maladie intestinale inflammatoire contenant le dérivé Download PDF

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WO2016195361A1
WO2016195361A1 PCT/KR2016/005735 KR2016005735W WO2016195361A1 WO 2016195361 A1 WO2016195361 A1 WO 2016195361A1 KR 2016005735 W KR2016005735 W KR 2016005735W WO 2016195361 A1 WO2016195361 A1 WO 2016195361A1
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hydroxy
dihydro
inden
indeno
hydroxybenzylidene
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Korean (ko)
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이응석
김정애
정태천
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Research Cooperation Foundation of Yeungnam University
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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
    • C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
    • C07C49/427—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having two rings
    • C07C49/443—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having two rings the condensed ring system containing eight or nine carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/613—Unsaturated compounds containing a keto groups being part of a ring polycyclic
    • C07C49/617—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system
    • C07C49/623—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having two rings
    • C07C49/633—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having two rings the condensed ring system containing eight or nine carbon 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals

Definitions

  • the present invention relates to a novel benzylidene dihydro indenon derivative and a composition for preventing or treating inflammatory bowel disease containing the same.
  • Inflammatory bowel disease is a disease that causes chronic inflammation of the intestine and includes ulcerative colitis and Crohn's disease. Ulcerative colitis and Crohn's disease are both chronic refractory disorders that cause symptoms to temporarily improve and then recur. Although the cause and pathophysiology of inflammatory bowel disease are not clearly known yet, genetic factors, environmental factors such as intestinal bacteria and foods, and immunological factors are thought to be involved in the complex mechanism of development. Despite the rapid increase in the incidence of ulcerative colitis and Crohn's disease, due to unclear reasons, fundamental treatments have not yet been established, and drugs that delay and alleviate the progress of symptoms are being used.
  • aminosalicylic acid preparations As the drug for the popular therapy, aminosalicylic acid preparations, adrenocortical steroids, immunosuppressants, TNF- ⁇ monoclonal antibodies and the like are mainly used, but various side effects have been reported.
  • sulfasalazine which is frequently used as an aminosalicylic acid preparation, has been reported to have side effects such as nausea, vomiting, anorexia, rash, headache, liver failure, white blood cell reduction, abnormal red blood cells, proteinuria, and diarrhea.
  • Prednisolone an corticosteroid
  • enema a corticosteroid
  • suppositories intravenous injections, etc.
  • side effects such as femoral head necrosis due to gastric ulcer and long-term use are strong.
  • Infliximab a TNF- ⁇ monoclonal antibody
  • the US FDA also warns doctors that using Infliximab and other Tumor Necrosis Factor (TNF) inhibitors may increase the risk of lymphoma and other cancers.
  • TNF Tumor Necrosis Factor
  • An object of the present invention is to provide a new inflammatory bowel disease treatment agent which is superior in efficacy, safe and has fewer side effects than the currently used inflammatory bowel disease treatment agent.
  • the present invention provides a novel benzylidene dihydro indenone derivative or a pharmaceutically acceptable salt thereof.
  • the present inventors have found that the benzylidene dihydro indenone derivative or pharmaceutically acceptable salt thereof is inflammatory by elucidating that the small intestine thickness and large intestine length are maintained as normal and have the activity of inhibiting or reducing the activity of TNF- ⁇ . It has been found that it can be used as a prophylactic or therapeutic agent for intestinal diseases.
  • One aspect of the present invention may be a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • X, X ', and Y are each independently hydrogen, hydroxy group, methoxy group, ethoxy group, isopropyloxy group, C 1 -C 6 alkyl group, or halogen,
  • Z is carbon (C), oxygen (O), or sulfur (S),
  • n 1 or 2.
  • Y is a hydroxy group
  • X and X ' may each independently be a hydrogen, a hydroxy group, a methoxy group or a chloro group.
  • Z is carbon (C) and n can be 2.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing or treating inflammatory bowel disease, which comprises a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the inflammatory bowel disease may be selected from the group consisting of Crohn's disease, intestinal lesions associated with Behcet's disease, ulcerative colitis, hemorrhagic rectal ulcer and ileal cystitis.
  • Another aspect of the present invention provides a food composition for improving inflammatory bowel disease comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Benzylidene dihydro indenone derivatives according to the present invention can be usefully applied to the prevention or treatment of inflammatory bowel disease.
  • the benzylidene dihydro indenone derivative according to the present invention maintains the thickness of the small intestine and the length of the large intestine as in a normal state, and has an excellent anti-inflammatory activity in the large intestine.
  • 2 is a group of animals administered with 1 mg / kg and 10 mg / kg of benzylidene dihydroindenone compound having code name TI-1-78 in inflammatory bowel disease-induced animal model group and inflammatory bowel disease-induced animal model, respectively. This is the result of checking the thickness of the small intestine and the length of the large intestine.
  • Figure 3 is a group administered to the benzylidene dihydro indenon compound of the code name TI-1-78 1 mg / kg, 10 mg / kg in inflammatory bowel disease induction animal model to determine the weight of the colon of the experimental animals It is a result of a measurement.
  • Figure 4 is a group administered to the benzylidene dihydro indenon compound of the code name TI-1-78 1 mg / kg, 10 mg / kg in inflammatory bowel disease induction animal model to determine the MPO activity of the experimental animals It is a result of a measurement.
  • Figure 6 is a group administered to the benzylidene dihydro indenon compound of the code name TI-1-188 10 mg / kg, 30 mg / kg in inflammatory bowel disease induction animal model to determine the weight of the experimental animals One result.
  • Figure 7 is a group administered to the benzylidene dihydro indenon compound of the code name TI-1-188 10 mg / kg, 30 mg / kg in inflammatory bowel disease-induced animal model to determine the weight of the colon of the experimental animals It is a result of a measurement.
  • 9 is a colonic weight of the experimental animals by dividing the experimental animals into a group administered with 25 mg / kg of benzylidene dihydro indenone compound of code names TI-1-78 and TI-1-188 in an inflammatory bowel disease-induced animal model Is the result of measurement.
  • 10 is a group of animals treated with 25 mg / kg of benzylidene dihydroindenone compound having code names TI-1-78 and TI-1-188 in an inflammatory bowel disease-induced animal model group and an inflammatory bowel disease-induced animal model. This is the result of checking the thickness of the small intestine and the length of the large intestine.
  • 11 is a group of animals administered with 10 mg / kg and 30 mg / kg of benzylidene dihydroindenone compound having code name TI-1-162 to inflammatory bowel disease-induced animal model group and inflammatory bowel disease-induced animal model. This is the result of checking the thickness of the small intestine and the length of the large intestine.
  • Figure 13 is a group administered to the benzylidene dihydro indenon compound of the code name TI-1-162 10 mg / kg, 30 mg / kg in inflammatory bowel disease-induced animal model to determine the weight of the colon of the experimental animals It is a result of a measurement.
  • inflammatory bowel disease refers to chronic inflammation of unknown cause occurring in the intestine, and generally refers to ulcerative colitis and Crohn's disease, which are idiopathic inflammatory bowel diseases, but enteric Behcet's disease is relatively common in Korea. It can be said. In a broad sense, it refers to infectious enteritis such as bacterial, viral, amoeba, and tuberculosis enteritis, and inflammatory diseases occurring in all intestines such as ischemic enteritis and radiation enteritis.
  • the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
  • X, X ', and Y are each independently hydrogen, hydroxy group, methoxy group, ethoxy group, isopropyloxy group, C 1 -C 6 alkyl group, or halogen,
  • Z is carbon (C), oxygen (O), or sulfur (S),
  • n 1 or 2.
  • Y is a hydroxy group
  • X and X ' may each independently be a hydrogen, a hydroxy group, a methoxy group or a chloro group.
  • Z is carbon (C) and n can be 2.
  • the compound of Formula 1 has a structure of Formula 1a.
  • X, X ', and Y are as defined above.
  • the compound of the present invention may be a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound of the present invention may be a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound of the present invention may be 6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can be prepared with pharmaceutically acceptable salts and / or solvates according to methods conventional in the art.
  • Acid addition salts formed by pharmaceutically acceptable free acid are useful.
  • Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol (eg, glycol monomethyl ether) in the mole can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equal molar amounts of the compound and the acid or alcohol (eg, glycol monomethyl ether) in the mole can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • organic acids and inorganic acids may be used as the organic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid , Vanic acid, hydroiodic acid and the like can be used.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of this invention include salts of acidic or basic groups which may be present in the compound, unless otherwise indicated.
  • pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate succinate citrate, tartrate, lactate, mandelate methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, which are prepared by methods or processes for preparing salts known in the art. Can be.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be usefully used for the prevention or treatment of inflammatory bowel disease by maintaining the thickness of the small intestine and the length of the large intestine as a normal state and having an excellent anti-inflammatory activity in the large intestine. It has been found by the present invention that it can.
  • the present invention provides a pharmaceutical composition for preventing or treating inflammatory bowel disease, which comprises a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the inflammatory bowel disease may be selected from the group consisting of Crohn's disease, intestinal lesions associated with Behcet's disease, ulcerative colitis, hemorrhagic rectal ulcer and ileal cystitis.
  • the therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be 0.5 to 100 mg / day / kg body weight, preferably 0.5 to 5 mg / day / kg body weight have.
  • the therapeutically effective amount may be appropriately changed depending on the extent of symptoms of inflammatory bowel disease, the age, weight, health condition, sex, route of administration, and duration of treatment of the patient.
  • the pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable carriers, excipients or diluents in addition to the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • composition for preventing or treating inflammatory bowel disease according to the present invention can be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, the dosage of the active ingredient is the route of administration, age, sex of the patient According to the present invention, the composition for preventing or treating inflammatory bowel disease according to the present invention may be appropriately selected according to various factors such as the weight, the severity of the patient, and the like. It can be administered in parallel.
  • the present invention also provides a food composition for improving inflammatory bowel disease comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the food composition according to the present invention may be in the form of a functional food composition or a beverage, but is not limited thereto.
  • the functional food may include food acceptable food additives, and may further include appropriate carriers, excipients and diluents commonly used in the manufacture of functional foods.
  • the beverage may contain various flavors or natural carbohydrates and the like as additional components, as in the usual beverage.
  • the food composition of the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and salts thereof , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, and the components may be used independently or in combination.
  • nutrients vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and salts thereof , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, and the components may be used independently or in combination.
  • the compound of Formula 1 or a salt thereof may be contained in an amount useful for improving inflammatory bowel disease, for example, in the range of 0.001% to 10% by weight based on the total weight of the composition. It may be, but is not limited thereto.
  • Method A Compounds 3-6, 9, 12, 15, 22, 28, and 29 were obtained by Aldol condensation reaction (Method A). For example, 1-indenone (1a, 3.96 g, 30 mmol) is reacted with salicylaldehyde (2f, 3.14 mL, 30 mmol) in ethanol solvent (30 mL) and 5N NaOH (5 mL) is added dropwise. Stir at room temperature for 2 hours. Then add water and carry out the reaction for 6 hours to obtain a reaction precipitate. The mixture was filtered, washed with water and washed with cold methanol to obtain a red solid.
  • Method B Compounds 7, 8, 10, 11, 13, 14, 16-21, and 23-27 were described by Jayapal et al. [1], (Method B) was prepared by the method described. For example, 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) is added to ethanol (5 mL) followed by the same amount of 3-hydroxybenzaldehyde (2g, 0.061 g, 0.5 mmol). Put it in. Then thionyl chloride (0.054 mL, 0.75 mmol) is added dropwise at room temperature to keep the reaction for 2 hours, precipitation occurs and EtOH is evaporated in a rotary evaporator. Then rinse with cold water and methanol. Finally, a dark orange solid was obtained by spinning and vacuum drying.
  • 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) is added to ethanol (5 mL) followed by the same amount of 3-hydroxybenzaldehyde (2g, 0.061 g,
  • the extracyclic double bond in the compound may be in E (trans) or Z (cis) form.
  • This conformational isomer exhibits a characteristic 1 H chemical shift in the NMR spectrum.
  • 1 H NMR data of compound 3-30 shows E-stereochemistry.
  • the synthetic route is shown in Scheme 1, and physical and chemical property data such as yield and melting point are shown in Table 1.
  • Method B Method 4-hydroxy-1-indenone (1b, 0.074 g, 0.5 mmol) and 3-hydroxybenzaldehyde (2g, 0.061 g, 0.5 mmol) were reacted in SOCl 2 to give 112 mg (0.44 mmol, 92.1%) to give a light brown solid.
  • Method B Method 4-hydroxy-1-indenone (1b, 0.074 g, 0.5 mmol) and 4-hydroxybenzaldehyde (2h, 0.061 g, 0.5 mmol) were reacted in SOCl 2 to 121 mg (0.48 mmol, 96.0%) to give a light brown solid.
  • Method B Method 124 mg (0.49 mmol, 6-hydroxy-1-indenone (1d, 0.074 g, 0.5 mmol) and 3-hydroxybenzaldehyde (2g, 0.061 g, 0.5 mmol) were reacted in SOCl 2 . 98.1%) to give a dark brown solid.
  • Method B was reacted with 6-hydroxy-1-indenone (1d, 0.074 g, 0.5 mmol) and 4-hydroxybenzaldehyde (2h, 0.061 g, 0.5 mmol) in SOCl 2 to give 109 mg (0.43 mmol, 86.6%) to give a dark orange solid.
  • Method A 36 mg (0.14 mmol, 28.8%) reacted with 7-hydroxy-1-indenone (1e, 0.074 g, 0.5 mmol) and salicylaldehyde (2f, 0.052 mL, 0.5 mmol) in 5N NaOH. To yield a yellow solid.
  • Method B Method 7-hydroxy-1-indenone (1e, 0.074 g, 0.5 mmol) and 3-hydroxybenzaldehyde (2g, 0.061 g, 0.5 mmol) were reacted in SOCl 2 to 122 mg (0.48 mmol, 96.8%) to give a dark orange solid.
  • Method B Method 125 mg (0.49 mmol, 7-hydroxy-1-indenone (1e, 0.074 g, 0.5 mmol) and 4-hydroxybenzaldehyde (2h, 0.061 g, 0.5 mmol) were reacted in SOCl 2 . 99.2%) to give a light green solid.
  • Method B was reacted with 4-hydroxy-1-indenone (1b, 0.074 g, 0.5 mmol) and 3-hydroxy-4-methoxy-benzaldehyde (2i, 0.076 g, 0.5 mmol) in SOCl 2 .
  • a yield of 108 mg (0.38 mmol, 76.5%) gave a dark green solid.
  • Method B was reacted with 6-hydroxy-1-indenone (1d, 0.074 g, 0.5 mmol) and 3-hydroxy-4-methoxy-benzaldehyde (2i, 0.076 g, 0.5 mmol) in SOCl 2 A yield of 117 mg (0.41 mmol, 82.9%) yielded a light brown solid.
  • Method B was reacted with 7-hydroxy-1-indenone (1e, 0.074 g, 0.5 mmol) and 3-hydroxy-4-methoxy-benzaldehyde (2i, 0.076 g, 0.5 mmol) in SOCl 2 A yield of 125 mg (0.44 mmol, 88.0%) gave a green solid.
  • Method A method yielded 3.81 g (14.9 mmol, 99.7%) by reacting 1-indenone (1a, 1.98 g, 15 mmol) with 4-chlorobenzaldehyde (2l, 2.11 g, 15 mmol) in 1.25 N NaOH. White solid was obtained.
  • Method B Method 112 mg (0.41 mmol, 82.7) was reacted with 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) and 3-chlorobenzaldehyde (2k, 0.07 g, 0.5 mmol) in SOCl 2 . %) To yield a light orange solid.
  • Method B Method 45 mg (0.17 mmol, 33.33) was reacted with 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) and 4-chlorobenzaldehyde (2l, 0.07 g, 0.5 mmol) in SOCl 2 . A dark brown solid was obtained in the yield of%).
  • Method A Method 1-indenone (1a, 0.66 g, 5 mmol) and 5-chloro-2-furalaldehyde (2m, 0.65 g, 5 mmol) were reacted in 1.25 N NaOH to 1.17 g (4.79 mmol, 95.9 %) To a creamy white solid.
  • Method A Method 1-indenone (1a, 0.66 g, 5 mmol) and 5-chloro-2-thiophenecarboxaldehyde (2n, 0.53 mL, 5 mmol) were reacted in 1.25 N NaOH to 1.24 g (4.76 mmol, 95.2%) to give a light orange solid.
  • the human colon cancer cell line HT-29 cells (American Type Culture Collections, Rockville, Mass., USA) were cultured in RPMI 1640 containing 10% fetal bovine serum (FBS), 1% penicillin / streptomycin and 2 mmol / L glutamine. The cell line was maintained at 37 ° C. under 95% air and 5% CO 2 . The experiment below used cells of 36 passages or less. Cells were passaged weekly using Dulbecco's phosphate uffered saline (D-PBS) containing 0.25% trypsin and 1% EDTA. Culture medium was checked every two days. After growing confluent, subcultures were subcultured in a 1: 5 ratio.
  • D-PBS Dulbecco's phosphate uffered saline
  • Each cell was pretreated with each compound prepared in Example 1 hour before stimulation of TNF- ⁇ .
  • a stock solution of each compound was prepared by dissolving in dimethyl sulfoxide (DMSO) at a concentration of 10 mM. The prepared stock solution was treated with each experimental medium so that the treatment concentration of each compound was 10 ⁇ M.
  • Cells treated with the control and TNF- ⁇ alone were pretreated with experimental medium containing 0.1% DMSO. 20 mM 5-aminosalicylic acid (5-ASA) was used as a positive control.
  • the 5-ASA is known to have an effect of inhibiting the inflammation activated in IBD.
  • the compound of the present invention effectively inhibited the inflammatory response of HT-29 cells induced by TNF- ⁇ .
  • the present inventors conducted the experiment as follows to determine whether the compound of the present invention prepared in the above example has an inhibitory effect on colitis in vivo.
  • mice were purchased from Orient Bio Korea for 7-8 weeks old Sprague Dawley species and stabilized with general solid feed for 2 days and used for experiments. Feed and water were freely supplied during the experiment, and the temperature in the cage was maintained at 25 ⁇ 1 °C and relative humidity at 50 ⁇ 10%. Lighting control was controlled by a 12-hour light-dark cycle by an automatic light controller.
  • the experimental group was 6 mice in each group, and the control group, the TNBS alone group, the TNBS + 5-ASA 100 mg / kg administration group, and the TNBS + test compound (randomized block design) so that the average weight was 180 ⁇ 10 g. And compound) to the administration group.
  • Rats fasted for 24 hours were anesthetized with diethyl ether and diluted with 50% (v / v) ethanol in the lumen of the large intestine through the anus using a 1 ml syringe connected to a polyethylene catheter.
  • 0.8 ml of 3% TNBS (2,4,6-trinitrobenzenesulfonic acid) was slowly injected and allowed to stand for 60 seconds with the rat upside down to prevent 3% TNBS from leaking into the anus.
  • vehicle 50% (v / v) ethanol
  • 24 mg of fasting was administered once daily at a fixed time every day by oral administration of 10 mg / kg for 5 days after the TNBS treatment.
  • Comparative test material used 5-ASA as a positive control.
  • TI-1-78 Compound 4
  • HYI-3-1 is a compound prepared internally for comparison (structure not shown).
  • the vehicle treated control group continued to increase in weight
  • the TNBS group continued to decrease in weight and recovered slightly from day 5, but the weight was significantly reduced compared to the normal group.
  • the group treated with TI-1-78 showed weight loss until day 3, gradually recovered from day 4, and continued to increase in weight (see FIG. 1), and significantly reduced the weight of the large intestine. It can be confirmed (see Fig. 3).
  • each well was washed four times, and 100 ⁇ l of TMB substrate was added to all wells, followed by reaction for 30 minutes under shading, and then 100 ⁇ l of the same amount of stop solution was added thereto. Afterwards, the absorbance was measured at 450 nm, and the MPO activity of the sample was determined using a standard curve prepared as a standard solution.
  • FIGS. 5-10 show the results for TI-1-188 (Compound 30).
  • the macroscopic symptoms of the large intestine and the adhesion between other organs and the congestion of the large intestine in the group administered with TI-1-188 10, 30, 25 mg / kg are also significantly suppressed.
  • 10, 30, 25 mg / kg of TI-1-188 resulted in a continuous increase in weight and a significant reduction in the weight of the colon in FIGS. 7 and 9. I could confirm it.
  • FIG. 11-13 show the results for TI-1-162 (Compound 14).
  • TI-1-162 Compound 14
  • 10-1-30 mg / kg of TI-1-162 resulted in a decrease in weight until day 3, but recovered from day 4 and continued to increase in weight, in the case of 30mg / kg-administered group 5 After days, weight gain was the same as that of normal group.
  • Figure 13 it can be seen that the extraction weight of the colon also significantly reduced.

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  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Mycology (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Nutrition Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau dérivé de benzylidène dihydroindénone; et une composition pour prévenir ou traiter une maladie intestinale inflammatoire contenant le dérivé. Le dérivé de benzylidène dihydroindenone maintient l'épaisseur de l'intestin grêle et la longueur du gros intestin à des états similaires à ses états normaux, et présente une excellente activité d'inhibition d'inflammation dans le gros intestin, étant ainsi utile pour prévenir ou traiter une maladie intestinale inflammatoire.
PCT/KR2016/005735 2015-06-03 2016-05-31 Nouveau dérivé de benzylidène dihydroindénone, et composition pour prévenir ou traiter une maladie intestinale inflammatoire contenant le dérivé Ceased WO2016195361A1 (fr)

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KR1020150078721A KR101734650B1 (ko) 2015-06-03 2015-06-03 신규한 벤질리덴 디하이드로 인덴온계 화합물 및 이를 함유하는 염증성 장질환 치료용 조성물
KR10-2015-0078721 2015-06-03

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CN1099288C (zh) 1994-05-27 2003-01-22 吴羽化学工业株式会社 用于治疗炎性肠疾病的药用组合物

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JP2020533328A (ja) * 2017-09-07 2020-11-19 タイワンジェ ファーマシューティカルズ カンパニー リミテッドＴａｉｗａｎｊ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ． ベンゼン縮合複素環誘導体およびその医薬組成物
JP7296948B2 (ja) 2017-09-07 2023-06-23 ニューソアラ バイオファーマ カンパニー リミテッド ベンゼン縮合複素環誘導体およびその医薬組成物
CN108516929A (zh) * 2018-01-24 2018-09-11 温州医科大学 一种2-亚-(3-甲氧基-4-羟基)-苄基-1-茚酮类似物及应用
CN108516929B (zh) * 2018-01-24 2021-06-18 温州医科大学 一种2-亚-(3-甲氧基-4-羟基)-苄基-1-茚酮类似物及应用

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KR20160142677A (ko) 2016-12-13

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