WO2016056726A1 - Composition comprenant un composé dérivé d'indéno pyridinium en tant que principe actif pour prévenir ou traiter des maladies intestinales inflammatoires - Google Patents

Composition comprenant un composé dérivé d'indéno pyridinium en tant que principe actif pour prévenir ou traiter des maladies intestinales inflammatoires Download PDF

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WO2016056726A1
WO2016056726A1 PCT/KR2015/005354 KR2015005354W WO2016056726A1 WO 2016056726 A1 WO2016056726 A1 WO 2016056726A1 KR 2015005354 W KR2015005354 W KR 2015005354W WO 2016056726 A1 WO2016056726 A1 WO 2016056726A1
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oxo
methyl
ylidene
pyridine
indene
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PCT/KR2015/005354
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English (en)
Korean (ko)
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이응석
김정애
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영남대학교 산학협력단
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system

Definitions

  • the present invention relates to a composition for preventing or treating inflammatory growth disease comprising an indeno pyridinium derivative compound as an active ingredient.
  • Inflammatory bowel disease is a disease that causes chronic inflammation of the intestine and can be divided into ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease in which mucous membranes (erosions) or ulcers are continuously formed on the colon's mucosa, and bloody stools, mucosal stools, diarrhea and abdominal pain occur. In severe cases, systemic symptoms such as fever, weight loss, and anemia appear. In addition, Crohn's disease is a condition in which lesions such as ulcers occur discontinuously in any part of the digestive tract from the mouth to the anus. In addition to abdominal pain, diarrhea and bloody stools, in severe cases, fever, weight loss, general boredom, and anemia Symptoms appear.
  • 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.
  • 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, is used for oral administration, enema, suppositories, intravenous injections, etc., but side effects such as femoral head necrosis due to gastric ulcer and long-term use are strong.
  • Infliximab a TNF- ⁇ monoclonal antibody
  • TNF Tumor Necrosis Factor
  • the present inventors have shown that the indeno pyridinium derivative compound maintains the thickness of the small intestine and the length of the large intestine as the normal state, and has the activity of inhibiting or reducing the activity of TNF-a, thereby preventing or treating inflammatory bowel disease. After confirming that it can be used to complete the present invention.
  • the object of the present invention is 4-((1-oxo-lH-indene-2 (3-h) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy-1 Oxo-lH-indene-2 (3-h) -ylidene) methyl) pyridine-1-ium chloride (6b), 4-((4-hydroxy-l-oxo-lH-indene-2 (3) H) -ylidene) methyl) pyridine-1-ium chloride (6c), 4-((6-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1 -Ium chloride (6d), 4-((6-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6e), 4-(( 6-isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene)
  • the present invention provides a novel indeno pyridinium derivative compound, an isomer thereof and a pharmacologically acceptable salt thereof.
  • the present invention also provides 4-((1-oxo-lH-indene-2 (3-h) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy-1- Oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6b), 4-((4-hydroxy-1-oxo-1H-indene-2 (3H) ) -Ylidene) methyl) pyridine-1-ium chloride (6c), 4-((6-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1- Ium chloride (6d), 4-((6-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6e), 4-((6 Isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl)
  • the composition may have the effect of maintaining the thickness of the small intestine and the length of the large intestine as normal.
  • the composition may inhibit or reduce the expression of TNF-a.
  • 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 present invention provides 4-((1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy-1-oxo -1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6b), 4-((4-hydroxy-1-oxo-1H-indene-2 (3H) -Ylidene) methyl) pyridine-1-ium chloride (6c), 4-((6-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium Chloride (6d), 4-((6-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6e), 4-((6- Isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyr
  • the present invention relates to a novel indeno pyridinium derivative compound and a preparation method thereof, the novel compound of the present invention is excellent in the effect of maintaining the thickness of the small intestine and the length of the large intestine as normal state, inflammation to the large intestine It is excellent in the effect of inhibiting can be usefully used as a pharmaceutical composition that can prevent or treat inflammatory bowel disease.
  • Figure 2 is a result confirming the degree of inflammation inhibition of the novel indeno pyridinium derivative compounds of the present invention in inflammatory growth disease in vitro model.
  • 3a and 3b is a result of confirming the thickness of the small intestine and the length of the large intestine by dividing the experimental animals into the group of the inflammatory bowel disease-induced animal model group, the inflammatory bowel disease-induced animal model group administered the new compound of the present invention.
  • Figures 4a and 4b is a result of measuring the weight of the experimental animals by dividing the experimental animals into groups of the inflammatory bowel disease-induced animal model group, inflammatory bowel disease-induced animal model group administered the new compound of the present invention.
  • Figures 5a and 5b is a result of measuring the colon weight of the experimental animals by dividing the experimental animals into groups of the inflammatory bowel disease-induced animal model group, inflammatory bowel disease-induced animal model group administered the new compound of the present invention.
  • the present invention relates to novel indeno pyridinium derivative compounds, isomers thereof and pharmacologically acceptable salts thereof.
  • R 1 and R 2 are each independently one or more substituents selected from the group consisting of a hydrogen atom, a hydroxy group, a methoxy group, an ethoxy group, an isopropyloxy group, a C 1 -C 6 lower alkyl group, a halogen atom and a carboxylic acid.
  • the compound is 4-((1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy-1 Oxo-lH-indene-2 (3-h) -ylidene) methyl) pyridine-1-ium chloride (6b), 4-((4-hydroxy-l-oxo-lH-indene-2 (3) H) -ylidene) methyl) pyridine-1-ium chloride (6c), 4-((6-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1 -Ium chloride (6d), 4-((6-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6e), 4-(( 6-isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine
  • the compounds of the present invention can be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.
  • salts are acid addition salts formed with pharmaceutically acceptable free acids.
  • 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.
  • Alkali metal or alkaline earth metal salts are 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.
  • Another object of the present invention is a method for preparing a compound of the present invention, can be prepared by a synthetic method known in the art, can be chemically synthesized by the method shown in the following schemes, but is not limited only to these examples no.
  • the inventors of the present invention are excellent in the effect of maintaining the thickness of the small intestine and the length of the large intestine as the normal state, and the effect of effectively inhibiting the inflammation of the large intestine inflammatory growth diseases and Crohn's disease It was found to be suitable for use as a composition for prophylaxis or treatment.
  • the present invention relates to a pharmaceutical composition for preventing or treating inflammatory bowel disease, which comprises an indeno pyridinium derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound is 4-((1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy -1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6b), 4-((4-hydroxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6c), 4-((6-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine -1-ium chloride (6d), 4-((6-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6e), 4- ((6-Isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl)
  • the "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 entero Behcet's disease is relatively common in Korea. can do. In a broad sense, it is a collective term for infectious enteritis such as bacterial, viral, amoeba, and tuberculosis, and inflammatory diseases occurring in all intestines such as ischemic bowel disease and radiation enteritis.
  • composition according to the present invention can be used as a pharmaceutical composition that can prevent or treat inflammatory bowel disease.
  • the term treatment refers to the act of treating when treating is defined as above.
  • the treatment or therapy of inflammatory bowel disease in mammals may comprise one or more of the following:
  • composition for preventing or treating inflammatory bowel disease may include a pharmaceutically effective amount of a compound represented by Formula 1 or a salt thereof alone or may include one or more pharmaceutically acceptable carriers, excipients or diluents. have.
  • the pharmaceutically effective amount herein refers to an amount sufficient to prevent, ameliorate and treat the symptoms of inflammatory bowel disease.
  • the pharmaceutically effective amount of the indeno pyridinium derivative compound or salt thereof according to the present invention is 0.5 to 100 mg / day / kg body weight, preferably 0.5 to 5 mg / day / kg body weight.
  • the pharmaceutically 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.
  • pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction, such as gastrointestinal disorders, dizziness, or the like when administered to a human.
  • 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 can provide a medicament for the prevention or treatment of inflammatory bowel disease, which comprises an indeno pyridinium derivative compound or a composition containing a salt thereof as an active ingredient, and the present invention further provides an indeno pyridinium derivative compound Or it may provide a composition for treating inflammatory bowel disease comprising a salt thereof as an active ingredient.
  • the present invention can provide a food composition that can improve or prevent the symptoms of inflammatory bowel disease containing indeno pyridinium derivative compounds or salts thereof as an active ingredient, the composition for food according to the present invention Food, which is effective in improving or preventing the symptoms of inflammatory bowel disease, for example, it can be easily utilized as a main ingredient, side ingredients, food additives, functional food or beverage of food.
  • the food means a natural product or processed product containing one or more nutrients, and preferably means a state in which it can be directly eaten through a certain processing process, and as a general meaning, food It includes all food additives, functional foods and drinks.
  • Foods to which the food composition according to the present invention may be added include, for example, various foods, beverages, gums, teas, vitamin complexes, functional foods, and the like.
  • food includes special nutritional products (e.g., formulated milk, young, infant food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g. ramen, noodles, etc.), bread, health supplements, seasonings.
  • Foods e.g. soy sauce, miso, red pepper paste, mixed soy sauce
  • sauces confectionery (e.g. snacks), candy, chocolates, gums, ice creams, dairy products (e.g.
  • fermented milk, cheese, etc. other processed foods
  • kimchi, Pickled foods various kimchi, pickles, etc.
  • beverages e.g., fruit drinks, vegetable drinks, soy milk, fermented beverages, etc.
  • natural seasonings e.g. ramen soup, etc.
  • the food, beverage or food additives may be prepared by a conventional manufacturing method.
  • the functional food is a biological defense rhythm control, disease prevention and recovery of a food group or a food composition that has added value to the food by using physical, biochemical, biotechnological techniques, etc. to function and express the function of the food for a specific purpose. It means a food that is designed and processed to fully express the body regulatory function related to the living body, specifically, it may be a health functional food.
  • 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 drink refers to a generic term for drinking to quench thirst or enjoy a taste and includes a functional drink.
  • the beverage contains, as an essential ingredient, a composition for improving or preventing the symptoms of the immune disease as an essential ingredient, and there are no special limitations on the other ingredients, and as a further beverage, contains various flavors or natural carbohydrates as additional ingredients. can do.
  • foods containing a food composition for improving or preventing symptoms of inflammatory bowel disease of the present invention include various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, Colorants and fillers (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • the components may be used independently or in combination.
  • the amount of the composition according to the present invention may comprise from 0.001% to 90% by weight of the total food weight, preferably from 0.1% to 40% by weight
  • the amount of the composition according to the present invention may comprise from 0.001% to 90% by weight of the total food weight, preferably from 0.1% to 40% by weight
  • it may be included in a ratio of 0.001g to 2g, preferably 0.01g to 0.1g based on 100ml, in the case of long-term intake for health and hygiene purposes or health control purposes It may be less than the above range, and the active ingredient is not limited to the above range because it may be used in an amount above the above range because there is no problem in terms of safety.
  • the compound was used as starting material and reagents were purchased from the company (Aldrich Chemical Co., Junsei or other chemical company) and used without further purification steps.
  • Solvents HPLC grade acetonitrile (ACN) and methanol
  • TLC thin-layer chromatography
  • CC column chromatography
  • NMR spectra were obtained from the company (Bruker AMX 250; 250 MHz, FT: 1H NMR and 62.5 MHz: 13C NMR) and the chemical shifts ( ⁇ ) were calculated from TMS in ppm and coupling constants (J) hertz (Hz). )). Melting points were recorded on open capillary tubes using an electrothermal 1A 9100 digital melting point apparatus and were not calibrated.
  • HPLC analysis was used under the following conditions (gradient-controlled HPLC system).
  • Detector photo diode array detector (SPD-M10A VP) (using Shimadzu Class VP program).
  • Sample injection Inject a sample volume (10 ⁇ l) into a column (Waters X-Terra ⁇ M reverse-phase C18 column (4.6 ⁇ 50 mm) and flow (1) into B 100-60% of A for 15 minutes (2) A Medium B was flowed by gradient dilution at a flow rate (1.0 mL / min) for 15 minutes (254 nm UV detection) (mobile phase A: double diluted with 20 mM ammonium formate (AF) and B was 90% ACN in water) Double diluted to 20 mM AF in.) Purity of the compound is expressed as (%).
  • ESI LC / MS analysis showed that LC was injected into a column (Waters Atlantis C18 column (2.1 ⁇ 0 mm, 3 ⁇ M)) with (1) 100% distilled water (A) and (2) 100% ACN (B).
  • the mobile phase was composed of 10% B and the linear composition was changed to 90% B after 5 minutes in the programmed sequence and 10% B after 15 minutes. Spent as spilled.
  • MS ionization conditions are as follows: Sheath gas flow rate: 70 arb, aux gas flow rate: 20 arb, I spray voltage: 4.5 KV, capillary temperature 215 ° C, column temperature 40 ° C, capillary voltage: 21 V, tube lens offset: 10 V. Retention time is in minutes.
  • TI-2-9 4-((4-hydroxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6c) is TI-2-11, 4-((6-methoxy- 1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6d) is TI-2-45, 4-((6-ethoxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6e) is TI-2-46, 4-((6-isopropoxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin -1-ium chloride (6f) is TI-2-
  • the present inventors conducted the experiment as follows to find out whether the indenone compound has an inhibitory activity in the in vitro model of the inflammatory growth disease prepared by the compounds of the present invention.
  • the human colon cancer cell line HT-29 cells (American Type Culture Collections, Rockville, Mass., USA) were subjected to RPMI 1640 containing 10% fetal bovine serum (FBS), 1% penicillin / streptomycin and 2 mmol / L glutamine.
  • FBS fetal bovine serum
  • penicillin / streptomycin 1% penicillin / streptomycin
  • 2 mmol / L glutamine 2 mmol / L glutamine.
  • the cell lines were maintained at 37 ° C. under an environment of 95% air and 5% CO 2 .
  • the experiment below used cells of 36 passages or less.
  • D-PBS Dulbecco's phosphate buffered saline
  • Each cell was pretreated with each compound prepared in Example 1 hour before stimulation of TNF- ⁇ .
  • Stock solutions of each compound were prepared with dimethylsulfoxide (DMSO), where the final maximum concentration of DMSO used in the test medium was less than 0.1%.
  • DMSO dimethylsulfoxide
  • 5-aminosalicylic acid 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 inflammatory sequence activated in IBD.
  • In vitro model of Inflammatory Growth Disorders measured the inhibitory activity of Indenone Compounds and found that TNF- ⁇ showed significant inflammatory responses in HT-29 cells.
  • TI-2-9, TI-2-47 , TI-2-11, TI-2-49, TI-2-50 (10 ⁇ M each) was found to be superior to the positive control 5-ASA (20 mM) (see Figure 2).
  • the present inventors conducted the experiment as follows to determine whether the novel compound of the present invention prepared in the above example has a colitis inhibitory effect 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 room temperature 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 consisted of 6 animals in each group, and the average body weight was 180 ⁇ 10 g by means of randomized block design (5 groups (control group, TNBS alone group, TNBS + 5-ASA 100 mg / kg group, TNBS + indenon) 2 compounds 10 mg / kg administration group) was tested.
  • 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. After slowly injecting 0.8 ml of 3% TNBS, the rats were left upside down for 60 seconds to prevent 3% TNBS from leaking into the anus. In the control group, vehicle (50% (v / v) ethanol) was injected in the same manner as the other experimental groups.
  • the comparative test substance was 5-ASA, an active metabolite of sulfasalazine, best known as an IBD treatment, as a positive control.
  • the novel compound of the present invention was found to show a greater weight recovery than the positive control 5-ASA (see Figs. 4a and 4b).
  • the present inventors examined the naked eye after extracting the colon after 5 days of drug administration, the colon of the TNBS-treated rats were observed edema and hyperemia compared to the control group, edema of the appendix and congestion and adhesion phenomenon It was found that this appeared.
  • the positive control group 5-ASA was administered in the amount of 100 mg / kg, and compared with the TNBS alone group, the visual symptom and adhesion between the other organs and colonic hyperemia were significantly suppressed.
  • the inhibitory effect of edema and hyperemia was greater than that of the positive control group 5-ASA, indicating that the novel compounds of the present invention effectively inhibit inflammatory bowel disease. It was found (see FIGS. 3A and 3B).
  • the weight of the colon obtained from the rat colon was significantly increased, and the weight of the intestinal edema was significantly increased in the TNBS-treated group compared to the vehicle-treated control group.
  • the positive control group in the amount of 100 mg / kg, the intestinal weight was significantly reduced compared to the TNBS-treated group, and the group treated with the novel compound of the present invention was similar in weight to the control group. It can be seen that the decrease (see Figs. 5a and 5b).

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  • Polymers & Plastics (AREA)

Abstract

La présente invention concerne un nouveau composé dérivé d'indéno pyridinium et son procédé de fabrication, le nouveau composé maintenant parfaitement l'épaisseur de l'intestin grêle et la grosseur du gros intestin dans un état normal, et réalisant efficacement une inhibition de l'inflammation du gros intestin. Par conséquent, la présente invention peut être efficacement utilisée en tant que composition pharmaceutique pour prévenir ou traiter les maladies inflammatoires de l'intestin.
PCT/KR2015/005354 2014-10-08 2015-05-28 Composition comprenant un composé dérivé d'indéno pyridinium en tant que principe actif pour prévenir ou traiter des maladies intestinales inflammatoires WO2016056726A1 (fr)

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KR1020140135732A KR101712708B1 (ko) 2014-10-08 2014-10-08 인데노 피리디니움 유도체 화합물을 유효성분으로 포함하는 염증성장질환 예방 또는 치료용 조성물
KR10-2014-0135732 2014-10-08

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101732776B1 (ko) 2014-10-08 2017-05-04 영남대학교 산학협력단 신규한 인데노 피리디니움 유도체 화합물 및 이의 제조방법

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