WO2016195361A1 - Novel benzylidene dihydroindenone derivative, and composition for preventing or treating inflammatory bowel disease, containing same - Google Patents

Abstract

The present invention provides: a novel benzylidene dihydroindenone derivative; and a composition for preventing or treating inflammatory bowel disease, containing the same. The benzylidene dihydroindenone derivative maintains the thickness of the small intestine and the length of the large intestine to be like the normal states thereof and has excellent inflammation inhibitory activity in the large intestine, thereby being useful in the prevention or treatment of inflammatory bowel disease.

Description

Novel benzylidene dihydro indenone derivatives and compositions for the prevention or treatment of inflammatory bowel disease containing the same

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.

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.

SUMMARY OF THE INVENTION 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.

In order to achieve the above object, 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-α. 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.

<Formula 1>

In the formula,

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 is 1 or 2.

In one embodiment of the present invention, Y is a hydroxy group, X and X 'may each independently be a hydrogen, a hydroxy group, a methoxy group or a chloro group. In another embodiment of the invention, 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.

In one embodiment of the 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.

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. In particular, 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.

1 is a group administered with the benzylidene dihydro indenon compound of the code name TI-1-78 1 mg / kg, 10 mg / kg in the inflammatory bowel disease-induced animal model, respectively. It is a result of a measurement.

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.

5 is a group of animals administered with the benzylidene dihydro indenone compound of the code name TI-1-188 10 mg / kg, 30 mg / kg in inflammatory bowel disease induction animal model group, inflammatory bowel disease induction animal model This is the result of checking the thickness of the small intestine and the length of the large intestine.

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.

8 is a group administered with 25 mg / kg of benzylidene dihydroindenone compound of code names TI-1-78 and TI-1-188 in an inflammatory bowel disease-induced animal model to determine the weight of 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.

12 is a group of administration of 10 mg / kg, 30 mg / kg of benzylidene dihydroindenone compound of code name TI-1-162 in inflammatory bowel disease-induced animal model to determine the weight of experimental animals One result.

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.

In the present specification, "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:

<Formula 1>

In the formula,

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 is 1 or 2.

In one embodiment of the present invention, Y is a hydroxy group, X and X 'may each independently be a hydrogen, a hydroxy group, a methoxy group or a chloro group.

In another embodiment of the invention, Z is carbon (C) and n can be 2. In this case, the compound of Formula 1 has a structure of Formula 1a.

<Formula 1a>

In the formula, X, X ', and Y are as defined above.

Preferably, 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:

2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

4-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

5-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

5-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

5-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

6-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

6-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

7-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

7-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

7-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

6-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one;

7-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one;

2- (4-chlorobenzylidene) -6-hydroxy-2,3-dihydro-1H-inden-1-one;

2- (4-chlorobenzylidene) -7-hydroxy-2,3-dihydro-1H-inden-1-one;

2- (2-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one;

2- (3-Chlorobenzylidene) -5-hydroxy-2,3-dihydro-1 H-inden-l-one:

2- (4-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one); And

2- (3-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one.

More preferably, 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:

2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one; And

2- (3-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one.

Especially preferably, 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.

As the salts, 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.

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. 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. 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.

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.

Accordingly, 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.

In one embodiment, 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.

In the pharmaceutical composition of the present invention, 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. However, 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. 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.

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. In addition, the beverage may contain various flavors or natural carbohydrates and the like as additional components, as in the usual beverage. Furthermore, 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.

In the food composition of the present invention, 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.

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.

Reagents and Materials

All reagents were purchased from Aldrich Chemical Co., Junsei or other chemical company and used without further purification steps. Thin layer chromatography (TLC) and column chromatography (CC) used products (Kieselgel 60 F ₂₅₄ ; Merck) and silica gel (Kieselgel 60, 230-400 mesh, Merck), respectively. 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.

<General method for preparing compound 3-29 (R = ae, R ₁ = fn)>

Indenon 1 (R = ae) was reacted with 9 aryl aldehyde 2 (R ₁ = fn) and EtOH (method A) in the presence of aqueous NaOH or EtOH solvent (Method B) in the presence of SOCl ₂ for 1-12 h. Reaction was carried out to give a precipitate of compound 3-29 (R = ae, R ₁ = fn).

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.

In the reaction where no precipitation occurs, the reaction mixture is extracted with ethyl acetate and washed with water and brine. The obtained organic layer is dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure and purified by silica gel chromatography (eluent; ethyl acetate / n -hexane) to give solid 3-29 in 28.8-99.7% yield. (MR.Jayapal and NY Sreedhar Synthesis and Characterization Of 4-hydroxy Chalcones By Aldol Condensation Using SOCl ₂ / EtOH Int J Curr Pharm Res , 2 2010), 60-62)

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. The chemical shift of the olefin protons (= CH-) is hidden in the E isomer of the compound and appears downfield (> 7 ppm) compared to the Z isomer (<7 ppm). 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.

<Scheme 1>

Example 1 Synthesis of (E) -2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (3)

Method A was reacted with 1-indenone (1a, 3.96 g, 30 mmol) and salicylaldehyde (2f, 3.14 mL, 30 mmol) in 1.25 N NaOH in a yield of 6.85 g (28.99 mmol, 96.6%). A solid was obtained.

R _f (ethyl acetate / n -hexane 1: 3, v / v): 0.23; mp 203.4-204.9 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H, = CH-), 7.69 (d, J = 7.55 Hz, 1H, indeno H-7), 7.61-7.56 (m, 2H, indeno H-4, H-5), 7.48 (d, J = 7.82 Hz, 1H, phenyl H-6), 7.41 (t, J = 5.4 Hz, 1H, indeno H-6), 6.93 (t, J = 7.35 Hz, 1H, phenyl H-4), 6.45 (d, J = 8.5 Hz, 1H, phenyl H-3), 6.20 (t, J = 7.25 Hz, 1H, phenyl H-5), 3.93 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.72, 172.46, 150.09, 139.72, 134.23, 134.01, 132.80, 130.65, 127.93, 127.29, 127.14, 123.60, 123.47, 121.66, 111.56, 33.30.

Example 2. Synthesis of (E) -2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (4)

Method A Method 1-indenone (1a, 3.96 g, 30 mmol) and 3-hydroxybenzaldehyde (2g, 3.66 g, 30 mmol) were reacted in 1.25 N NaOH to 4.81 g (20.33 mmol, 67.8%). Yield yielded a yellow solid.

R _f (ethyl acetate / n -hexane 1: 3, v / v): 0.21; mp 264.8-265.4 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.72 (d, J = 7.55 Hz, 1H, indeno H-7), 7.63 (t, J = 7.50 Hz, 1H, indeno H-5), 7.56 (d , J = 7.75 Hz, 1H, indeno H-4) 7.42 (t, J = 7.32 Hz, 1H, indeno H-6), 7.35 (s, 1H, = CH-), 7.12 (t, J = 7.72 Hz, 1H, phenyl H-5), 7.01 (s, 1H, phenyl H-2), 6.82 (d, J = 7.45 Hz, 1H, phenyl H-4), 6.69 (d, J = 7.85 Hz, 1H, phenyl H -6), 3.88 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.78, 164.81, 150.25, 137.67, 135.73, 135.18, 134.91, 133.92, 129.81, 127.88, 126.93, 123.75, 119.91, 119.11, 117.93. 32.25.

Example 3. Synthesis of (E) -2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (5)

Method A reacted 1-indenone (1a, 2.64 g, 20 mmol) with 4-hydroxybenzaldehyde (2h, 2.44 g, 20 mmol) in 1.25 N NaOH to give 2.93 g (12.39 mmol, 61.9%). Yield yielded a light green solid.

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.30; mp 235.4-236.0 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H, phenyl 4-OH), 7.75 (d, J = 7.27 Hz, 1H, indeno H-7), 7.67-7.60 (m, 4H, phenyl H-2, H-6, indeno H-4, H-5), 7.46-7.42 (m, 2H, = CH-, indeno H-6), 6.88 (d, J = 8.35 Hz, 2H, phenyl H -3, H-5), 4.04 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 194.11, 160.30, 150.66, 138.45, 135.36, 134.22, 133.87 (2C), 132.40, 128.45, 127.47, 126.85, 124.28, 116.90 (2C), 32.83.

Example 4 Synthesis of (E) -4-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (6)

Method A Method 4-hydroxy-1-indenone (1b, 0.074 g, 0.5 mmol) was reacted with salicyaldehyde (2f, 0.052 mL, 0.5 mmol) in 5N NaOH 55 mg (0.22 mmol, 43.6%) A dark orange solid was obtained in the yield of.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.26; mp 277.6-279.1 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.27 (s, 1H, indeno 4-OH), 10.09 (s, 1H, phenyl 2-OH), 7.91 (s, 1H, = CH-), 7.72 ( d, J = 7.95 Hz, phenyl H-6), 7.32-7.21 (m, 3H, indeno H-6, H-7, phenyl H-4), 7.06 (d, J = 7.52 Hz, 1H, indeno H- 5), 6.96-6.90 (m, 2H, phenyl H-5, H-3), 3.86 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.78, 157.76, 154.84, 139.20, 136.37, 133.54, 131.53, 129.63, 129.08, 127.56, 121.88, 120.29, 119.55, 116.00, 114.18, 29.08.

Example 5 Synthesis of (E) -4-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (7)

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.

R_f (ethyl acetate /n-hexane 1: 1, v / v): 0.26; mp 278.4.4-280.1 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H, indeno 4-OH), 9.73 (s, 1H, phenyl 3-OH), 7.41 (s, 1H, = CH-), 7.33- 7.24 (m, 3H, indeno H-6, H-7, phenyl H-5), 7.21-7.18 (m, 2H, phenyl H-6, H-4), 7.09 (d, J = 7.45 Hz, indeno H -5), 6.85 (d, J = 7.6 Hz, 1H, phenyl H-2), 3.88 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.89, 157.95, 155.06, 139.14, 136.58, 136.32, 135.07, 133.28, 130.30, 129.34, 122.50, 120.62, 117.37, 116.95, 114.38, 29.40.

Example 6 Synthesis of (E) -4-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (8)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.20; mp 280.6-281.3 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H, indeno 4-OH), 10.09 (s, 1H, phenyl 4-OH), 7.64 (d, J = 8.52 Hz, 2H, phenyl H -2, H-6), 7.43 (s, 1H, = CH-), 7.31-7.19 (m, 2H, indeno H-6, H-7), 7.06 (d, J = 7.47 Hz, 1H, indeno H -5), 6.89 (d, J = 8.45 Hz, 2H, phenyl H-3, H-5), 3.84 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.82, 159.66, 155.01, 139.53, 136.31, 133.62 (2C), 133.25, 131.80, 129.24, 126.29, 120.34, 116.33 (2C), 114.28, 29.38.

Example 7.Synthesis of (E) -5-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (9)

Method A Method 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) and salicylaldehyde (2f, 0.052 mL, 0.5 mmol) were reacted in 5N NaOH in 85 mg (0.34 mmol, 67.5%). To yield a yellow solid.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.18; mp 248.6-249.8 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.71 (s, 1H, = CH-), 7.61 (d, J = 7.80 Hz, 1H, phenyl H-6), 7.42 (d, J = 8.4 Hz, 1H, indeno H-7), 7.13 (t, J = 7.35 Hz, 1H, phenyl H-4), 6.89 (d, J = 8.10 Hz, 1H, indeno H-4), 6.79 (t, J = 7.37 Hz , 1H, phenyl H-5), 6.57-6.50 (m, 2H, phenyl H-3, indeno H-6), 3.92 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 190.76, 173.13, 159.23, 153.82, 136.12, 130.89, 130.00, 126.36, 125.60, 124.74, 123.64, 119.62, 119.13, 116.91, 113.54, 32.59.

Example 8 Synthesis of (E) -5-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (10)

Method B Method 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) and 3-hydroxybenzaldehyde (2g, 0.061 g, 0.5 mmol) were reacted in SOCl ₂ to give 125 mg (0.49 mmol, 99.5%) to give a dark orange solid.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.17; mp 299.4-300.6 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 8.37 Hz, 1H, indeno H-7), 7.30 (s, 1H, = CH-), 7.26 (d, J = 7.8 Hz, 1H, phenyl H-5), 7.16-7.13 (m, 2H, phenyl H-4, H-6), 6.95 (s, 1H, indeno H-4), 6.87-6.81 (m, 2H, indeno H-6 , phenyl H-2), 3.96 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 192.16, 164.83, 158.51, 153.74, 137.09, 136.50, 131.96, 130.67, 130.05, 126.52, 122.44, 117.55, 117.48, 117.00, 112.76, 32.66.

Example 9.Synthesis of (E) -5-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (11)

Method B Method 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) and 4-hydroxybenzaldehyde (2h, 0.061 g, 0.5 mmol) were reacted in SOCl ₂ to give 125 mg (0.49 mmol, 99.4%) to give a pale yellow solid.

R _f (ethyl acetate / n -hexane 2: 1, v / v): 0.30; mp 289.1-291.4 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.61-7.56 (m, 3H, phenyl H-2, H-6, indeno H-7), 7.32 (s, 1H, = CH-), 6.95 (s , 1H, indeno H-4), 6.88 (d, J = 8.35 Hz, 2H, phenyl H-3, H-5), 6.83-6.82 (m, 1H, indeno H-6), 3.92 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 192.27, 164.53, 159.89, 153.50, 133.32 (2C), 133.18, 132.23, 130.34, 126.98, 126.27, 116.79 (3C), 112.75, 32.66.

Example 10. Synthesis of (E) -6-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (12)

Method A Method 6-hydroxy-1-indenone (1d, 0.074 g, 0.5 mmol) and salicylaldehyde (2f, 0.052 mL, 0.5 mmol) were reacted in 5N NaOH and 103 mg (0.41 mmol, 81.7%). The yield of yielded a green solid.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.21; mp 234.3-235.3 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 9.91 (br, 2H, indeno 6-OH, phenyl 2-OH), 7.88 (s, 1H, = CH-), 7.68 (d, J = 7.30 Hz, 1H, phenyl H-6), 7.45 (d, J = 8.15, 1H, indeno H-7), 7.25 (t, J = 7.17, 1H, phenyl H-4), 7.11 (dd, J = 8.15, 2.3 Hz , indeno H-4), 7.07-7.06 (m, 1H, indeno H-5), 6.93 (d, J = 7.82 Hz, 1H, indeno H-5), 6.88 (d, J = 7.52 Hz, 1H, phenyl H-3), 3.91 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.49, 157.74, 157.21, 140.87, 138.85, 134.62, 131.38, 129.62, 127.48, 127.27, 123.27, 122.04, 119.50, 116.05, 108.27, 31.21.

Example 11.Synthesis of (E) -6-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (13)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.24; mp 260.1-262.3 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H, indeno 6-OH), 9.75 (s, 1H, phenyl 3-OH), 7.45 (d, J = 8.17 Hz, 1H, indeno H -7), 7.37 (s, 1H, = CH-), 7.27 (t, J = 7.6 Hz, 1H, phenyl H-5), 7.17-7.10 (m, 4H, indeno H-4, H-5, phenyl H-4, H-6), 6.86 (d, J = 8.05 Hz, 1H, phenyl H-2), 3.93 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 194.13, 158.59, 158.10, 141.46, 139.24, 136.87, 136.63, 133.43, 130.69, 128.16, 124.28, 122.65, 117.85, 117.71, 109.04, 32.03.

Example 12.Synthesis of (E) -6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (14)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.26; mp 366.1-368.6 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.03 (br, 1H, phenyl 4-OH), 9.77 (br, 1H, indeno 6-OH), 7.61 (d, J = 7.57 Hz, 1H, phenyl H -2, H-6), 7.46-7.40 (m, 2H, = CH-, indeno H-4), 7.10 (dd, J = 8.15, 2.25 Hz, 1H, indeno H-5), 7.05 (s, 1H, indeno H-7) 6.88 (d, J = 8.5 Hz, 1H, phenyl H-3, H-5), 3.90 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 194.02, 160.11, 157.90, 141.30, 139.67, 133.65 (2C), 133.41 (2C), 128.10, 126.88, 123.77, 116.82 (2C), 108.92, 32.02

Example 13. Synthesis of (E) -7-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (15)

Method A Method 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.

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.30; mp 244.6-245.8 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 9.97 (br, 1H, phenyl 2-OH), 7.83 (s, 1H, = CH-), 7.67 (d, J = 7.35 Hz, 1H, phenyl H- 6), 7.47 (t, J = 7.75 Hz, 1H, indeno H-5), 7.24 (t, J = 7.12 Hz, 1H, 1H, phenyl H-4), 7.01 (d, J = 7.37 Hz, 1H, indeno H-4), 6.95-6.87 (m, 2H, phenyl H-5, indeno H-6), 6.79 (d, J = 8.07 Hz, 1H, phenyl H-3), 3.97 (s, 2H, indeno H -3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.91, 158.34, 157.67, 151.78, 137.28, 134.62, 131.98, 130.31, 127.19, 124.74, 122.73, 120.20, 117.56, 116.73, 114.97, 32.57.

Example 14 Synthesis of (E) -7-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (16)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.29; mp 214.6-215.3 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H, indeno 7-OH), 9.64 (s, 1H, phenyl 3-OH), 7.48 (t, J = 7.55 Hz, 1H, indeno H -5), 7.31 (s, 1H, = CH-), 7.26 (d, J = 7.55 Hz, 1H, phenyl H-5), 7.17-7.14 (m, 2H, indeno H-4, phenyl H-6) , 7.02 (d, J = 7.4 Hz, 1H, phenyl H-4), 6.86-6.79 (m, 2H, indeno H-6, phenyl H-2), 3.99 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.44, 158.51, 157.72, 151.77, 137.41, 136.92, 136.04, 132.48, 130.71, 124.62, 122.61, 117.74, 117.62, 117.49, 115.11, 32.64.

Example 15. Synthesis of (E) -7-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one (17)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.24; mp 230.8-231.7 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H, indeno 7-OH), 10.04 (s, 1H, phenyl 4-OH), 7.59 (d, J = 8.7 Hz, 2H, phenyl H -2, H-6), 7.46 (t, J = 7.8 Hz, 1H, indeno H-5), 7.35 (s, 1H, = CH-), 7.01 (d, J = 7.32 Hz, 1H, indeno H- 4), 6.91 (d, J = 8.62 Hz, 2H, phenyl H-3, H-5), 6.82 (d, J = 8.07 Hz, 1H, indeno H-6), 3.96 (s, 2H, indeno H- 3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.82, 160.17, 157.60, 151.54, 137.05, 133.52 (2C), 132.95, 132.55, 126.73, 124.76, 117.46, 116.84 (2C), 114.94, 32.66.

Example 16 Synthesis of (E) -4-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one (18)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.18; mp 262.3-262.9 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H, indeno 4-OH), 9.39 (s, 1H, phenyl 3-OH), 7.37 (s, 1H, = CH-), 7.32- 7.18 (m, 4H, indeno H-6, H-7, phenyl H-2, H-6) 7.08-7.01 (m, 2H, phenyl H-5, indeno H-5), 3.83 (s, 5H, indeno H-3, phenyl 4-OCH ₃ ).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.89, 155.05, 149.94, 146.99, 139.49, 136.42, 133.69, 132.61, 129.33, 128.04, 124.49, 120.44, 116.97, 114.37, 112.52, 55.94, 29.38.

Example 17. Synthesis of (E) -5-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one (19)

Method B reacted 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) with 3-hydroxy-4-methoxy-benzaldehyde (2i, 0.076 g, 0.5 mmol) in SOCl ₂ A yield of 124 mg (0.43 mmol, 87.3%) gave a light brown solid.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.30; mp 316.4-317.7 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H, indeno 5-OH), 9.27 (s, 1H, phenyl 3-OH), 7.60 (d, J = 8.25 Hz, 1H, indeno H -7), 7.26 (s, 1H, = CH-), 7.18-7.15 (m, 2H, phenyl H-2, H-6), 7.01 (d, J = 8.02 Hz, 1H, phenyl H-5), 6.94 (s, 1H, indeno H-4), 6.83 (d, J = 7.92 Hz, 1H, indeno H-6), 3.92 (s, 2H, indeno H-3), 3.81 (s, 3H, phenyl 4- OCH ₃ ).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 191.67, 163.85, 153.06, 149.62, 146.67, 133.39, 131.66, 129.72, 128.20, 125.84, 123.18, 116.98, 116.22, 112.46, 112.08, 56.47, 32.08.

Example 18.Synthesis of (E) -6-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one (20)

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.

R _f (ethyl acetate / n -hexane 1: 1, v / v): 0.29; mp 251.2-252.4 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.46 (d, J = 8.22 Hz, 1H, indeno H-7), 7.34 (s, 1H, = CH-), 7.21-7.19 (m, 2H, phenyl H-2, H-6), 7.11 (dd, J = 8.2, 2.27 Hz, 1H, indeno H-4), 7.05-7.01 (m, 2H, indeno H-5, phenyl H-5), 3.89 (s , 2H, indeno H-3), 3.81 (s, 3H, phenyl 4-OCH ₃ ).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 194.11, 157.93, 150.38, 147.49, 141.37, 139.58, 134.17, 133.81, 128.61, 128.23, 124.74, 123.94, 117.67, 113.03, 108.92, 56.46, 32.02

Example 19. Synthesis of (E) -7-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one (21)

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.

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.19; mp 208.4-208.9 ℃

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H, indeno 7-OH), 9.31 (s, 1H, phenyl 3-OH), 7.47 (t, J = 7.75 Hz, 1H, indeno H -5), 7.28 (s, 1H, = CH-), 7.20-7.17 (m, 2H, phenyl H-2, H-6), 7.04-7.0 (m. 2H, indeno H-4, phenyl H-5 ), 3.94 (s, 2H, indeno H-3), 3.81 (s, 3H, phenyl 4-OCH ₃ ).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.10, 157.02, 151.09, 149.68, 146.89, 136.67, 132.90, 132.32, 128.04, 124.19, 124.02, 117.06, 117.00, 114.46, 112.45, 55.88, 32.07.

Example 20.Synthesis of (E) -2- (4-chlorobenzylidene) -2,3-dihydro-1H-inden-1-one (22)

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.

R _f (ethyl acetate / n -hexane 1: 7, v / v): 0.23; mp 191.8-193.7 ℃

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.80-7.73 (m, 3H, phenyl H-2, H-6, indeno H-7), 7.70-7.63 (m, 2H, indeno H-4, H -5), 7.55 (s, 1H, = CH-), 7.52-7.43 (m, 3H, phenyl H-3, H-5, indeno H-6), 4.08 (s, 2H, indeno H-3).

Example 21.Synthesis of (E) -2- (4-chlorobenzylidene) -6-hydroxy-2,3-dihydro-1H-inden-1-one (23)

Method B Method 92 mg (0.34 mmol, 68.1) of 6-hydroxy-1-indenone (1d, 0.074 g, 0.5 mmol) with 4-chlorobenzaldehyde (2l, 0.07 g, 0.5 mmol) in SOCl ₂ Yield) yielded an orange solid.

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.3; mp 243.8-244.6 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H, indeno 6-OH), 7.77 (d, J = 8.45 Hz, 2H, phenyl H-2, H-6), 7.53 (d, J = 8.37 Hz, 2H, phenyl H-3, H-5), 7.47-7.45 (m, 2H, = CH-, indeno H-5), 7.13 (dd, J = 8.2, 2.15 Hz, 1H, indeno H -5), 7.06 (s, 1H, indeno H-7), 3.96 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.54, 174.06, 159.25, 138.49, 137.20, 134.37, 134.14, 132.41 (2C), 130.83, 129.15 (2C), 127.27, 124.46, 108.61, 31.18.

Example 22. Synthesis of (E) -2- (4-chlorobenzylidene) -7-hydroxy-2,3-dihydro-1H-inden-1-one (24)

Method B Method 7-hydroxy-1-indenone (1e, 0.074 g, 0.5 mmol) and 4-chlorobenzaldehyde (2l, 0.07 g, 0.5 mmol) were reacted in SOCl ₂ with 101 mg (0.37 mmol, 74.8 Yield) yielded a red solid.

R _f (ethyl acetate / n -hexane 1: 7, v / v): 0.3; mp 205.9-206.2 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H, indeno 7-OH), 7.76 (d, J = 8.52 Hz, 2H, phenyl H-2, H-6), 7.52 (d, J = 8.4 Hz, 2H, phenyl H-3, H-5), 7.48 (t, J = 7.55 Hz, 1H, indeno H-5), 7.40 (s, 1H, = CH-), 7.02 (d, J = 7.4 Hz, 1H, indeno H-4), 6.79 (d, J = 8.12 Hz, 1H, indeno H-6), 4.01 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 192.47, 157.10, 151.12, 136.87, 136.39, 134.26, 134.04, 132.33 (2C), 130.10, 129.09 (2C), 123.89, 116.78, 114.49, 31.78.

Example 23. Synthesis of (E) -2- (2-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one (25)

Method B Method 5-hydroxy-1-indenone (1c, 0.074 g, 0.5 mmol) and 2-chlorobenzaldehyde (2j, 0.07 g, 0.5 mmol) were reacted in SOCl ₂ to give 102 mg (0.37 mmol, 75.5 Yielded a brown solid.

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.19; mp 291.8-292.7 ℃

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H, indeno 5-OH), 7.90-7.87 (m, 1H, = CH-), 7.67-7.63 (m, 2H, indeno H-7 , phenyl H-3), 7.58-7.55 (m, 1H, phenyl H-6), 7.45-7.39 (m, 2H, phenyl H-4, H-5), 6.93 (s, 1H, indeno H-4) , 6.85 (d, J = 8.4 Hz, 1H, indeno H-6), 3.97 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 191.17, 164.39, 153.48, 138.72, 134.81, 132.96, 130.95, 130.49, 130.16, 129.24, 127.78, 126.26, 126.21, 116.53, 112.12, 31.42.

Example 24. Synthesis of (E) -2- (3-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one (26)

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.

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.21; mp 246.6-247.2 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H, indeno 5-OH), 7.77 (s, 1H, = CH-), 7.69 (d, J = 6.45 Hz, 1H, indeno H- 7), 7.63 (d, J = 8.35 1H, phenyl H-6), 7.53-7.44 (m, 2H, phenyl H-4, H-5), 7.37 (s, 1H, phenyl H-2), 6.96 ( s, 1H, indeno H-4), 6.85 (dd, J = 8.2, 1.52 Hz, 1H, indeno H-6), 4.01 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 191.44, 164.35, 153.40, 137.73, 137.55, 133.88, 130.93, 129.93, 129.57, 129.30, 129.27, 129.18, 126.18, 116.51, 112.20.

Example 25. Synthesis of (E) -2- (4-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one (27)

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%).

R _f (ethyl acetate / n -hexane 1: 2, v / v): 0.21; mp 288.3-289.1 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H, indeno 5-OH), 7.76 (dd, J = 8.45, 1.85 Hz, 2H, phenyl H-2, H-6), 7.63 ( dd, J = 8.35, 1.85 Hz, 1H, indeno H-7), 7.52 (dd, J = 8.52, 2.02 Hz, 2H, phenyl H-3, H-5), 7.39 (s, 1H, = CH-) , 6.94 (s, 1H, indeno H-4), 6.85 (d, J = 8.4 Hz, 1H, indeno H-6), 3.99 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 190.76, 163.57, 152.57, 136.20, 133.58, 133.50, 131.63 (2C), 129.09, 128.69, 128.48 (2C), 125.43, 115.77, 111.44, 31.20.

Example 26.Synthesis of (E) -2-((5-chlorofuran-2-yl) methylene) -2,3-dihydro-1H-inden-1-one (28)

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.

R _f (ethyl acetate / n -hexane 1: 7, v / v): 0.20; mp 140.1-140.7 ° C

¹ H NMR (250 MHz, CDCl ₃ ) δ 7.86 (d, J = 7.44652 Hz, 1H, indeno H-7), 7.62-7.52 (m, 2H, indeno H-5, H-4), 7.39 (t, J = 6.92 Hz, 1H, indeno H-6), 7.30 (s, 1H, = CH-), 6.71 (d, J = 3.47 Hz, 1H, chlorofuryl H-3), 6.32 (d, J = 3.4 Hz, 1H, chlorofuryl H-4), 3.99 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, CDCl ₃ ) δ 193.75, 151.79, 149.68, 139.85, 138.29, 134.58, 132.90, 127.52, 126.21, 124.24, 118.85, 118.38, 109.52, 32.20.

Example 27. Synthesis of (E) -2-((5-chlorothiophen-2-yl) methylene) -2,3-dihydro-1H-inden-1-one (29)

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.

R _f (ethyl acetate / n -hexane 1: 7, v / v): 0.23; mp 163.8-164.6 ℃

¹ H NMR (250 MHz, CDCl ₃ ) δ 7.87 (d, J = 7.57 Hz, 1H, indeno H-7), 7.72 (s, 1H, = CH-), 7.62 (t, J = 7.70 Hz, 1H, indeno H-5), 7.54 (d, J = 7.35 Hz, 1H, indeno H-4), 7.42 (t, J = 7.02 Hz, 1H, indeno H-6), 7.20 (d, J = 3.95 Hz, 1H , chlorothienyl H-3), 7.99 (d, J = 3.95 Hz, 1H, chlorothienyl H-4), 3.85 (s, 2H, indeno H-3).

¹³ C NMR (62.5 MHz, CDCl ₃ ) δ 193.46, 148.77, 138.64, 138.36, 135.30, 134.66, 132.82, 132.40, 127.74, 127.43, 126.21, 126.01, 124.34, 32.10.

Example 28. Synthesis of ( E ) -2- (3-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one (30)

A mixture of compound 4 (0.35 g, 1.48 mmol), methyl iodide (1.84 mL, 29.6 mmol), and potassium carbonate (1.02 g, 7.4 mmol) in tetrahydrofuran (8 mL) was added at 30 ^° C. Stirred for 24 h. The mixture was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and dried to yield a light yellow solid in a yield of 0.37 g (1.47 mmol, 99.8%).

R _f (ethyl acetate / n -hexane 1: 7, v / v): 0.23; mp 149.8-150.6 ° C

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.78 (d, J = 7.6 Hz, 1H, indeno H-7), 7.74-7.66 (m, 2H, indeno H-5, H-4), 7.51- 7.42 (m, 2H, phenyl H-5, = CH-, indeno H-6), 7.37-7.32 (m, 2H, phenyl H-2, H-6), 7.03 (d, J = 6.67 Hz, 1H, phenyl H-4), 4.12 (s, 2H, indeno H-3), 3.29 (s, 3H, phenyl 3-OCH ₃ ).

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 193.46, 159.69, 150.23, 137.31, 136.36, 135.49, 135.07, 132.92, 130.14, 127.83, 126.85, 123.74, 123.19, 116.01, 115.82, 55.37, 31.99.

TABLE 1a Code Names, Yields and Melting Points of Prepared Compounds

TABLE 1b Code Name, Yield and Melting Point of Prepared Compounds

TABLE 1c Codename, Yield and Melting Point of Prepared Compounds

Experimental Example 1. Evaluation of Inflammatory Inhibitory Activity in Inflammatory Bowel Disease Model

In order to determine whether the compound of the present invention inhibits inflammation in inflammatory bowel disease in vitro model, the experiment was conducted as follows.

First, 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.

For the experiment, cells were dispensed into plastic cell culture wells containing serum containing medium and attached for 24 hours. After that, 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. 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 µM. 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 inflammation activated in IBD.

The results of measuring the inhibitory activity of the compounds of the present invention in the in vitro model of inflammatory bowel disease are shown in Table 2 below.

	% inhibition (Mean) ± S.E.M
5-ASA	52.9 ± 1.8
TI-1-76	62.2 ± 9.2
TI-1-78	44.2 ± 11.5
TI-1-88	73.4 ± 17.4
TI-1-154	30.3 ± 14.5
TI-1-155	6.1 ± 17.1
TI-1-156	-1.7 ± 23.3
TI-1-157	32.1 ± 12.0
TI-1-158	50.2 ± 12.1
TI-1-159	45.4 ± 14.7
TI-1-160	71.3 ± 3.4
TI-1-161	62.7 ± 5.8
TI-1-162	80.3 ± 4.8
TI-1-163	67.9 ± 3.3
TI-1-164	60.5 ± 2.3
TI-1-165	69.8 ± 6.7
TI-1-166	0.19 ± 17.5
TI-1-167	-2.520 ± 9.2
TI-1-168	12.0 ± 27.5
TI-1-169	35.1 ± 1.1
TI-1-133	-6.1 ± 17.4
TI-1-152	-8.9 ± 9.2
TI-1-153	5.7 ± 27.4
TI-1-186	67.9 ± 3.5
TI-1-187	78.4 ± 6.7

As can be seen from the results of Table 2, the compound of the present invention effectively inhibited the inflammatory response of HT-29 cells induced by TNF-α.

Experimental Example 2 Evaluation of Efficacy of Colitis Inhibition in Animal Model of TNBS Induced IBD

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.

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 temperature in the cage 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 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. 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. Comparative test material used 5-ASA 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 by 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.

1 to 4 show the results for TI-1-78 (Compound 4). In Figures 1 to 4 HYI-3-1 is a compound prepared internally for comparison (structure not shown). As shown in FIG. 1, the vehicle treated control group continued to increase in weight, and 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. On the other hand, 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). In addition, when the colon was extracted and examined visually, edema and hyperemia were observed in the colon of rats treated with TNBS, and edema, congestion, and adhesion of appendix were observed. On the other hand, in the group treated with the indenon compound of the present invention in an amount of 1 or 10 mg / kg it was confirmed the inhibitory effect of edema and hyperemia (see Figure 2). It can also be seen that MPO activity was significantly reduced (see FIG. 4). Myeloperoxidase (MPO) activity was performed using MPO ELISA kit (Hycult Biotech, HK105). Centrifuge the homogeneously ground intestinal tissue with a homogenizer for 15 minutes and add 100 μl of the prepared supernatant to the wells with the antibodies, and seal it with a cover to prevent air from entering the plate. The reaction was carried out for 1 hour at. After 1 hour after the reaction, the washing buffer was washed four times using the washing buffer was completely removed. After 100 μl of tracer solution was added to each well, the cover was attached and reacted at room temperature for 1 hour, and washed 4 times. Then, the diluted streptavidin-peroxidase solution was added to all wells by 100 μl and the cover was attached and reacted at room temperature for 1 hour. After completion of the reaction, each well was washed four times, and 100 μl of TMB substrate was added to all wells, followed by reaction for 30 minutes under shading, and then 100 μl 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.

5-10 show the results for TI-1-188 (Compound 30). Referring to FIGS. 5 and 10, 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. Could. In addition, in the results of FIGS. 6 and 8, 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.

11-13 show the results for TI-1-162 (Compound 14). Referring to FIG. 11, it was found that the macroscopic symptoms of the large intestine, adhesions between the other organs, and the redness of the large intestine were also significantly suppressed in the group administered with 10-1-30 mg / kg of TI-1-162. Equivalent to that of the 300 mg / kg administered group shows an equivalent level of efficacy. In addition, in the results of FIG. 12, 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. In Figure 13 it can be seen that the extraction weight of the colon also significantly reduced.

Therefore, it can be seen from the above results that the compound according to the present invention can be effectively applied to the treatment of inflammatory bowel disease.

Claims (9)

1. A compound of Formula 1 or a pharmaceutically acceptable salt thereof:

   <Formula 1>

   

   In the formula,

   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 is 1 or 2.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is a hydroxy group, and X and X 'are each independently hydrogen, a hydroxy group, a methoxy group, or a chloro group.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is carbon (C) and n is 2. 4.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

   2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   4-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   5-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   5-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   5-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   6-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   6-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   7-hydroxy-2- (2-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   7-hydroxy-2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   7-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   6-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   7-hydroxy-2- (3-hydroxy-4-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   2- (4-chlorobenzylidene) -6-hydroxy-2,3-dihydro-1H-inden-1-one;

   2- (4-chlorobenzylidene) -7-hydroxy-2,3-dihydro-1H-inden-1-one;

   2- (2-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one;

   2- (3-Chlorobenzylidene) -5-hydroxy-2,3-dihydro-1 H-inden-l-one:

   2- (4-chlorobenzylidene) -5-hydroxy-2,3-dihydro-1H-inden-1-one); And

   2- (3-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one.
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

   2- (3-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one;

   6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one; And

   2- (3-methoxybenzylidene) -2,3-dihydro-1H-inden-1-one.
6. 6-hydroxy-2- (4-hydroxybenzylidene) -2,3-dihydro-1H-inden-1-one or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
8. The method of claim 7, wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease, intestinal lesions associated with Behcet's disease, ulcerative colitis, hemorrhagic rectal ulcer and ileal cystitis. Pharmaceutical composition.
9. A food composition for improving inflammatory bowel disease, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

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