WO2016056726A1 - Composition comprising indeno pyridium-derived compound as active ingredient for preventing or treating inflammatory bowel diseases - Google Patents

Abstract

The present invention relates to a novel indeno pyridium-derived compound and a method for producing same, the novel compound according to the present invention superbly maintaining the thickness of the small intestine and length of the large intestine as in a normal state, and effectively inhibiting the inflammation of the large intestine, and thus the present invention can be effectively used as a pharmaceutical composition to prevent or treat inflammatory bowel diseases.

Description

Inflammatory growth disease prevention or treatment composition comprising an indeno pyridinium derivative compound as an active ingredient

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.

Conventionally, the incidence of ulcerative colitis and Crohn's disease has been known to be high in Westerners, but the number of patients has increased rapidly in the East, including Korea, due to changes in lifestyles such as eating habits. Nevertheless, due to unclear reasons, fundamental treatments have not yet been established. Therefore, there is a situation in which drugs are used to delay and alleviate the progression of symptoms and to maintain such a condition for as long as possible. As the drug for the popular therapy, aminosalicylic acid preparations, adrenocortical steroids, immunosuppressants, TNF-α monoclonal antibodies and the like are mainly used, but various side effects have been reported. For example, 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-α monoclonal antibody, was used to treat Crohn's patients after receiving approval from the US FDA in 1998 to treat Crohn's disease, but it also has side effects such as pancreacytosis, drug-induced lupus, and hepatitis B / TB reactivation. Is appearing. 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.

Therefore, there is an urgent need for the development of a new inflammatory bowel disease treatment that is superior in efficacy, safe and has fewer side effects than the currently used inflammatory bowel disease treatment.

Accordingly, 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.

Thus, 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) methyl) pyridine-1-ium chloride (6f), 4-((4-methoxy-1-oxo-1 H-indene-2 (3-H) -ylidene) methyl) pyridine-1-ium chloride (6 g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -yly Den) methyl) pyridine-1-ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1a -Indene-2 (3-H) -ylidene) methyl) pyridine-1-ium chloride (6i) of an inflammatory growth disease comprising at least one compound selected from the group consisting of pharmaceutically acceptable salts thereof as an active ingredient It is to provide a pharmaceutical composition for prophylaxis or treatment.

It is also an object of the present invention to provide 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-Im 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-1-ium chloride (6f), 4-((4-methoxy-1-oxo- 1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H)- Ilidene) methyl) pyridin-1-ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1H It is to provide a health functional food for inhibiting inflammatory growth disease comprising as an active ingredient at least one compound selected from the group consisting of inden-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6i). .

In order to achieve the above object, 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) pyridine-1-ium chloride (6f), 4-((4-methoxy-1-oxo-1H) -Inden-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene ) Methyl) pyridine-1-ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1H-indene-2 ( 3H) -Ilidene) methyl) pyridine-1-ium chloride (6i) A pharmaceutical for the prevention or treatment of inflammatory bowel disease comprising at least one compound selected from the group consisting of pharmaceutically acceptable salts thereof or a pharmaceutically acceptable salt thereof as an active ingredient To provide a composition.

In one embodiment of the present invention, the composition may have the effect of maintaining the thickness of the small intestine and the length of the large intestine as normal.

In one embodiment of the invention, the composition may inhibit or reduce the expression of TNF-a.

In one embodiment of the present invention, 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.

Furthermore, 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) pyridine-1-ium chloride (6f), 4-((4-methoxy-1-oxo-1H-) Inden-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) Methyl) pyridine-1-ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1H-indene- It provides a health functional food for inhibiting inflammatory bowel disease comprising at least one compound selected from the group consisting of 2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6i) as an active ingredient.

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.

1 is a result showing the synthesis method of a novel indeno pyridinium derivative compound of the present invention.

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.

Compounds of the present invention are novel compounds that have not been found previously, and novel indeno pyridinium derivative compounds having the structure of formula (1), isomers thereof and pharmacologically acceptable salts thereof:

[Formula 1]

Wherein 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.

In the present invention, 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-1-ium chloride (6f), 4-((4-methoxy-1-oxo-1 H-indene-2 (3-H) -ylidene) methyl) pyridine-1-ium chloride (6 g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -yly Den) methyl) pyridine-1-ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1) Chi-inden-2 (3 H) - ylidene) methyl) may be at least one member selected from the group consisting of pyridin-1-ium chloride (6i).

The compounds of the present invention can be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

As 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.

In this case, 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. In this case, as 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. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and 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.

Scheme 1

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.

Accordingly, 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.

As mentioned above, 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) pyridine-1-ium chloride (6f), 4-((4-methoxy-1-oxo -1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -Ylidene) methyl) pyridine-1-ium chloride (6h) and 4-((4-isopropo) May be ylidene) methyl) pyridin-1-ium chloride (at least one selected from the group consisting of 6i) Compound-1-oxo -1 H-inden-2 (3 H).

In the present invention, 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.

Therefore, the composition according to the present invention can be used as a pharmaceutical composition that can prevent or treat inflammatory bowel disease.

* Unless otherwise stated, means to reverse, alleviate, inhibit, or prevent the disease or condition to which the term applies, or one or more symptoms of the disease or condition, As used herein, the term treatment refers to the act of treating when treating is defined as above. Thus, the treatment or therapy of inflammatory bowel disease in mammals may comprise one or more of the following:

(1) inhibits the growth of inflammatory bowel disease, that is, inhibits its development,

(2) preventing the spread of inflammatory bowel disease, ie preventing metastasis,

(3) relieves inflammatory bowel disease.

(4) prevent the recurrence of inflammatory bowel disease, and

(5) Palliating the symptoms of inflammatory bowel disease

The composition for preventing or treating inflammatory bowel disease according to the present invention 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. However, 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.

In addition, "pharmaceutically acceptable" as used herein 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. Examples of such 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. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.

In addition, the 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.

In addition, the 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.

Accordingly, 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.

On the other hand, 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.

As used herein, 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. In addition, in the present invention, 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.) are not limited thereto. The food, beverage or food additives may be prepared by a conventional manufacturing method.

In addition, 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.

In addition, in the present invention, 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.

Furthermore, in addition to the above, 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.

In the food containing the composition for food of the present invention, 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 In the case of a beverage, 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.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Reference Example 1

<1-1> Reagents and Materials

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) were purchased from companies (Burdick and Jackson, USA), and thin-layer chromatography (TLC) and column chromatography (CC) were obtained from products (Kieselgel 60 F254; Merck) and silica gel ( Kieselgel 60, 230-400 mesh, Merck) were used, and the synthetic compounds were UV ultraviolet (both short and long wavelength) in TLC plates. 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 (δ) 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.

<1-2> HPLC analysis

HPLC analysis was used under the following conditions (gradient-controlled HPLC system).

Pump: Shimadzu LC-10AT pumps

Regulator: Shimadzu system controller (SCL-10A VP)

Detector: photo diode array detector (SPD-M10A VP) (using Shimadzu Class VP program).

Sample injection: Inject a sample volume (10 μl) into a column (Waters X-TerraμM 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 (%).

<1-3> ESILC / MS Analysis

ESI LC / MS analysis was performed by instrument (Finnigan LCQ Advantage LC / MS / MS spectrometry) using the program (Xcalibur).

ESI LC / MS analysis showed that LC was injected into a column (Waters Atlantis C18 column (2.1 × 0 mm, 3 μM)) 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.

<Example 1>

General Preparation of Compound (5)

React with the same amount of 4-pyridine carboxyaldehyde (4-Pyridine carboxaldehyle carboxaldehyle) of 1-Indanone 1 (R = ac) or 3 (R ² = di) and in the presence of methanol / ethanol 5 % Aqueous NaOH solution was added dropwise. The reaction was left at 0 ° C. for 1-6 hours, and the compound 5f and 5i reaction mixtures were placed under nitrogen for 48-72 hours and then refluxed at 90-100 ° C. where aluminum oxide was present.

The mixture was washed with cold methanol, filtered, cooled for 30 minutes and dried overnight. If no precipitation occurred, the reaction mixture was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. Further purification was carried out by recrystallization or column chromatography to obtain Compound 5 (R ³ = ai) as a solid in 67.8-99.4% yield.

<Example 2>

General Preparation of Compound (6)

Compound 5 (R ³ = ai) obtained by the method of Example 1 was dissolved in acetone, and hydrochloric acid was added dropwise until precipitation occurred. It was then filtered until precipitation. If no precipitate occurred, the solvent was evaporated to dryness with the aid of a rotary evaporator to obtain a pure solid compound, yielding 9 compounds of 6 (R ³ = ai) synthesized in 62.7-96.9% yield (see Figure 1). .

<2-1>  4-((1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a)

0.79 g (3.07 mmol, 62.7%) of white creamy solid phase 4-((1- 1) having the following physical properties by using 5a (1.08 g, 4.9 mmol) and acetone (30 mL) was prepared in the same manner as in the general synthesis method. Oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a) was obtained.

R _f (ethylacetate / n-hexane 2: 1, v / v): 0.25; mp 229.6-230.2 ° C., purity by HPLC: 100%, MS (ESI): [MH ⁺ ]: 222.1

¹ H NMR (250 MHz, DMSO- d ₆ ) 8.93 (d, J = 6.37 Hz, 2H, pyridine H-2, H-6), 8.24 (d, J = 6.30 Hz, 2H, pyridine H-3, H -5), 7.58-7.6 (m, 4H, = CH-, indeno H-4, H-5, H-7), 7.51 (t, J = 7.22, 1 H, indeno H-6), 4.27 (s, 2H, indenoH-3).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.16, 150.51, 149.96, 144.02, 143.58, 136.68, 136.23, 128.38, 127.78, 127.00, 124.39, 32.04.

<2-2> 4-((6-hydroxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6b)

0.45 g (1.64 mmol, 96.9%) of the yellow solid phase 4-((6-hydroxy) having the following physical properties using 5b (0.4 g, 1.69 mmol) and acetone (40 mL) using the same method as the general synthesis method. -1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6b) was obtained.

R _f (ethylacetate / n-hexane2: 1, v / v): 0.13; mp 265.8-266.9 ° C., purity by HPLC: 100%, MS (ESI): [M−H ⁺ ]: 238.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ8.81 (d, J = 6.42 Hz, 2H, pyridine H-2, H-6), 8.51 (d, J = 6.47 Hz, 2H, pyridineH-3, H-5), 7.50-7.46 (m, 2H, = CH-, indenoH-4), 7.18 (dd, J = 8.22, 2.45 Hz, 1H, indenoH-5), 7.11-7.10 (m, 1H, indenoH-) 7), 4.07 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.08, 157.74, 149.40, 144.61, 144.19, 141.29, 137.97, 127.83, 127.62, 126.74, 124.84, 108.65, 31.27.

<2-3> 4-((4-hydroxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6c)

0.36 g (1.33 mmol, 79.2%) of the light yellow solid having the following physical properties using 5c (0.4 g, 1.69 mmol) and acetone (80 mL) using the same method as in the above general synthesis. Roxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6c) was obtained.

R _f (ethylacetate / n-hexane2: 1, v / v): 0.13; mp 259.2-262.8 ° C, purity by HPLC: 97.5%, MS (ESI): [M−H ⁺ ]: 238.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ10.26 (s, 1H, indeno4-OH), 8.88 (d, J = 5.27Hz, 2H, pyridineH-2, H-6), 8.12 (d, J = 5.40Hz, 2H, pyridineH-3, H-5), 7.58 (s, 1H, = CH-), 7.37-7.26 (m, 2H, indenoH-6, H-7), 7.16 (d, J = 7.35 Hz, 1H, indenoH-5), 4.05 (s, 2H, indenoH-3).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.03, 154.83, 146.24, 141.94, 138.15, 136.48, 129.25, 128.43, 125.54, 121.09, 114.34, 28.80

<2-4> 4-((6-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6d)

0.22 g (0.78 mmol, 81.2%) of the yellow solid phase 4-((6-methoxy) having the following physical properties using 5d (0.24 g, 0.96 mmol) and acetone (20 mL) using the same method as the general synthesis method. -1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6d) was obtained.

R _f (ethylacetate / n-hexane2: 1, v / v): 0.22; mp259.8-261.2 ° C, puritybyHPLC: 99.3%, MS (ESI): [MH ⁺ ]: 252.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ8.87 (d, J = 6.30Hz, 2H, pyridineH-2, H-6), 8.14 (d, J = 6.37Hz, 2H, pyridineH-3, H -5), 7.61-7.57 (m, 2H, = CH-, indenoH-4), 7.35 (dd, J = 8.35,2.55Hz, 1H, indenoH-5), 7.27 (s, 1H, indenoH-7), 4.15 (s, 2H, indenoH-3), 3.82 (s, 3H, indeno-6-OCH ₃ ).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.13,160.18,145.05,144.14,143.30,138.11,128.21,128.05,126.63,125.01,106.23,55.96,31.39.

<2-5> 4-((6-Ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6e)

0.65 g (2.12 mmol, 76.9%) of the yellow solid phase 4-((6-ethoxy) having the following physical properties using 5e (0.75 g, 2.8 mmol) and acetone (25 mL) using the same method as the general synthesis method. -1-oxo-lH-indene-2 (3-h) -ylidene) methyl) pyridine-1-ium chloride (6e) was obtained.

R _f (ethylacetate / n-hexane 2: 1, v / v): 0.26; mp 234.4-235.7 ° C., purity by HPLC: 98.3%, MS (ESI): [MH ⁺ ]: 266.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ8.90 (d, J = 5.92Hz, 2H, pyridineH-2, H-6), 8.19 (d, J = 5.95Hz, 2H, pyridineH-3, H -5), 7.59-7.56 (m, 2H, = CH-, indenoH-4), 7.32 (d, J = 8.32 Hz, 1H, indenoH-5), 7.23 (s, 1H, indenoH-7), 4.14 ( s, 2H, indenoH-3), 4.09 (q, J = 6.97 Hz, 2H, indeno-6-OC H 2CH ₃ ), 1.33 (t, J = 6.90 Hz, 3H, indeno-6-OCH ₂ C H ₃ ).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ192.96, 158.85, 148.91, 144.67, 144.15, 143.04, 138.00, 127.98, 127.94, 126.58, 125.15, 106.68, 63.92, 31.29, 14.73.

<2-6> 4-((6-isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6f)

5f (0.34 g, 1.1 mmol) and acetone (15 mL) were used to form 0.28 g (0.9 mmol, 82%) of the yellow solid 4-((6-isopro). Foxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6f) was obtained.

R _f (ethylacetate / n-hexane 2: 1, v / v): 0.28; mp212.9-213.7 ° C., puritybyHPLC: 100%, MS (ESI): [MH ⁺ ]: 280.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ8.87 (d, J = 6.50Hz, 2H, pyridineH-2, H-6), 8.12 (d, J = 6.60Hz, 2H, pyridineH-3, H -5), 7.59-7.56 (m, 2H, = CH-, indenoH-4), 7.31 (dd, J = 8.30, 2.52 Hz, 1H, indenoH-5), 7.25 (s, 1H, indenoH-7), 4.71 (sep, J = 6.02 Hz, 1H, indeno-6-OCH (CH ₃ ) ₂ ), 4.14 (s, 2H, indenoH-3), 1.27 (d, J = 5.97 Hz, 6H, indeno-6-OCH (CH3) ₂ ).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ192.52, 157.28, 149.88, 144.88, 142.84, 142.48, 137.51, 127.67, 127.12, 126.67, 125.76, 107.48, 69.62, 30.90, 21.43.

<2-7> 4-((4-methoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6 g)

0.34 g (1.17 mmol, 71.6%) of light yellow solid having the following physical properties using 5 g (0.41 g, 1.63 mmol) and acetone (110 mL) using the same method as in the above general synthesis. Toxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6 g) was obtained.

R _f (ethylacetate / n-hexane2: 1, v / v): 0.29; mp239.5-240.3 ° C., purity by HPLC: 98%, MS (ESI): [MH ⁺ ]: 252.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ8.88 (d, J = 6.42Hz, 2H, pyridineH-2, H-6), 8.20 (d, J = 6.07Hz, 2H, pyridineH-3, H -5), 7.60 (s, 1H, = CH-), 7.49 (t, J = 7.67 Hz, 1H, indenoH-6), 7.41-7.33 (m, 2H, indenoH-5, H-7), 4.07 ( s, 2H, indenoH-3), 3.91 (s, 3H, indeno-4-OCH ₃ ),

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.06, 156.64, 149.30, 144.05, 143.22, 138.44, 137.96, 130.04, 128.14, 126.75, 117.08, 115.71, 55.81, 28.91.

<2-8> 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6h)

0.83 g (2.75 mmol, 74.9%) of yellow solid 4-((4-ethoxy) having the following physical properties using 5h (0.97 g, 3.67 mmol) and acetone (25 mL) using the same method as the general synthesis method above -1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6h) was obtained.

R _f (ethylacetate / n-hexane2: 1, v / v): 0.34; mp224.2-225.4 ° C, puritybyHPLC: 100%, MS (ESI): [MH ⁺ ]: 266.1

¹ H NMR (250 MHz, DMSO- d ₆ ) δ8.90 (d, J = 6.50Hz, 2H, pyridineH-2, H-6), 8.21 (d, J = 6.50Hz, 2H, pyridineH-3, H -5), 7.60 (s, 1H, = CH-), 7.47 (t, J = 7.65Hz, 1H, indenoH-6), 7.39-7.32 (m, 2H, indenoH-5, H-7), 4.18 ( q, J = 6.95 Hz, 2H, indeno-4-OC H 2CH ₃ ), 4.06 (s, 2H, indenoH-3), 1.39 (t, J = 6.95 Hz, 3H, indeno-4-OCH ₂ C H ₃ ),

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.28, 156.11, 149.77, 144.14, 144.02, 143.55, 138.72, 138.21, 130.19, 128.30, 127.00, 126.95, 118.08, 115.80, 64.17, 29.00, 14.97

<2-9> 4-((4-isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6i)

0.51 g (1.83 mmol, 82.9%) of the yellow solid phase 4-((4-isopro) having the following physical properties using 5i (0.61 g, 1.95 mmol) and acetone (20 mL) using the same method as the general synthesis method. Posi-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6i) was obtained.

R _f (ethylacetate / n-hexane2: 1, v / v): 0.41; mp164.9-165.8 ° C., purity by HPLC: 100%, MS (ESI): [MH ⁺ ]: 280.0

^a1 H NMR (250 MHz, DMSO- d ₆ ) δ8.90 (d, J = 6.37Hz, 2H, pyridineH-2, H-6), 8.17 (d, J = 6.42Hz, 2H, pyridineH-3, H -5), 7.60 (s, 1H, = CH-), 7.46 (t, J = 7.70 Hz, 1H, indenoH-6), 7.38-7.36 (m, 2H, indenoH-5, H-7), 4.78 ( sep, J = 6.02 Hz, 1H, indeno-4-OC H (CH ₃ ) ₂ ), 4.03 (s, 2H, indenoH-3), 1.34 (d, J = 6.04 Hz, 6H, indeno-4-OCH ( C H 3) ₂ ),

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ193.16, 155.15, 150.08, 143.77, 143.34, 139.35, 138.32, 130.02, 128.01, 127.11, 119.33, 115.65, 70.47, 28.96, 22.11.

For reference, 4-((6-hydroxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6b) of the present invention was named 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-2-47, 4-((4-methoxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6g) TI-2-48, 4-((4-ethoxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6h) is TI-2-49, 4- ( (4-isopropoxy-1-oxo-1H-inden-2 (3H) -ylidene) methyl) pyridin-1-ium chloride (6i) was named TI-2-50.

Experimental Example 1

Inhibitory Activity of Novel Compounds of the Invention in an In Vitro Model of Inflammatory Growth Disease

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.

First, 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. 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.

Cells were passaged weekly using Dulbecco's phosphate buffered saline (D-PBS) containing 0.25% trypsin and 1% EDTA. Culture medium was changed every two days. After growing confluent, it was subcultured in a 1: 5 ratio.

For the experiment, cells were dispensed into plastic cell culture wells containing serum containing medium and attached for 24 hours. Then all experiments were performed in serum free conditions.

Each cell was pretreated with each compound prepared in Example 1 hour before stimulation of TNF-α. 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%. Cells treated with the control and TNF-α 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 inflammatory sequence activated in IBD.

In vitro model of Inflammatory Growth Disorders measured the inhibitory activity of Indenone Compounds and found that TNF-α showed significant inflammatory responses in HT-29 cells. TI-2-9, TI-2-47 , TI-2-11, TI-2-49, TI-2-50 (10μM each) was found to be superior to the positive control 5-ASA (20 mM) (see Figure 2).

Experimental Example 2

Evaluation of in vivo efficacy evaluation of novel compound colitis inhibition of the present invention in animal models of inflammatory growth diseases induced by TNBS

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.

First, animals 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 ℃ 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.

 To investigate the effect of the drug, 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. The comparative test substance was 5-ASA, an active metabolite of sulfasalazine, best known as an IBD treatment, as a positive control.

 All rats were sacrificed 7 days after TNBS administration. The severity of visual ulcer and colitis was assessed by two investigators who did not participate in the experiment. The large intestine of the rat was extracted, and tissues between 5 and 6 cm from the anus were cut into lengths of 1 cm and used for measuring the intestinal weight and MPO activity of the tissues and performing a biopsy. In addition, all experimental animals were observed the weight change of each rat during fasting and TNBS administration and drug administration using digital mass meter, and the animal experiment was established at Yeungnam University experimental animal center for management and use of experimental animals. It was performed according to the instructions.

In the colitis model that induced inflammation in the intestine using 3% TNBS in rats weighing 180 to 190 g, the weight change was observed every day for 5 days based on the weight before TNBS treatment. Similarly, the vehicle treated control group continued to gain weight and the TNBS group continued to lose weight and recovered slightly from day 5, but the weight was significantly reduced compared to the normal group. The positive control group 5-ASA 100 mg / kg treated group was gradually recovered from the 4th day, the weight was increased compared to the TNBS alone group. Intraperitoneal administration of the new compound of the present invention at a dose of 1 mg / kg after TNBS treatment showed weight loss until day 3, and gradually recovered from day 4 to increase body weight compared to TNBS alone.

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).

In addition, 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. However, in the group treated with the new compound of the present invention in an amount of 10 mg / kg, 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).

In addition, 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. In the group treated with 5-ASA, 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).

Therefore, the above results showed that the novel compounds prepared by the method of the present invention are effective for the treatment of inflammatory diseases.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (5)

4-((1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy-1-oxo-1H- Inden-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) pyridine-1-ium chloride (6f), 4-((4-methoxy-1-oxo-1H-indene-2 ( 3H) -ylidene) methyl) pyridine-1-ium chloride (6 g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine- 1-Ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) Methyl) pyridine-1-ium chloride (6i) A pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising at least one compound selected from the group consisting of or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 1, The composition is a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease, characterized in that it has the effect of maintaining the thickness of the small intestine and the length of the large intestine as in a normal state. The method of claim 1, The composition is a pharmaceutical composition for preventing or treating inflammatory bowel disease, characterized in that to suppress or reduce the expression of TNF-a. The method according to any one of claims 1 to 3, The inflammatory bowel disease is a composition for preventing or treating inflammatory bowel disease, characterized in that selected from the group consisting of Crohn's disease, intestinal lesions associated with Behcet's disease, ulcerative colitis, hemorrhagic rectal ulcer and ileal cystitis. 4-((1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine-1-ium chloride (6a), 4-((6-hydroxy-1-oxo-1H- Inden-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) pyridine-1-ium chloride (6f), 4-((4-methoxy-1-oxo-1H-indene-2 ( 3H) -ylidene) methyl) pyridine-1-ium chloride (6 g), 4-((4-ethoxy-1-oxo-1H-indene-2 (3H) -ylidene) methyl) pyridine- 1-Ium chloride (6h) and 4-((4-isopropoxy-1-oxo-1H-indene-2 (3H) -ylidene) Methyl) pyridine-1-ium chloride (6i) Health functional foods for inhibiting inflammatory growth disease comprising at least one compound selected from the group consisting of as an active ingredient.

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