KR101248295B1 - A novel chromene derivative compounds, a method of preparing the same and a composition including the same - Google Patents

Abstract

The present invention relates to a novel chromene derivative compound, a preparation method thereof and a composition for preventing or treating dementia comprising the same. The chromene derivative compound of the present invention can be usefully used for the prevention and treatment of dementia by improving memory loss.

Description

A novel chromene derivative compounds, a method of preparing the same and a composition including the same}

The present invention relates to novel chromene derivative compounds, methods for their preparation and compositions comprising them.

Dementia is a pathological phenomenon that should be distinguished from normal aging, and it can be attributed to Alzheimer's dementia, vascular dementia, other alcoholism, trauma, and aftereffects of Parkinson's disease. Are distinguished.

The pathogenesis of Alzheimer's dementia is not well known, but the decrease in acetylcholine function in the central nervous system is most common. Therefore, acetylcholine precursors or drugs that inhibit the degradation of acetylcholine are used to treat the brain. Treatments that increase acetylcholine levels have been used. Therefore, acetylcholinesterase (hereinafter referred to as 'AChE') inhibitors alone or in combination with existing cholinesterase inhibitors are used as therapeutic agents, and representative drugs include tacrine and donepezil. ), Rivastigmine, galantamine, and the like.

Vascular dementia is caused mostly by damage to the brain cells due to insufficient blood supply to various parts of the brain due to cerebral vascular arteriosclerosis.

Vascular dementia and Alzheimer's dementia have different causes, but the same is true in that memory damage occurs.

Therefore, the inventors of the present invention, while researching to develop an effective therapeutic agent for the prevention or treatment of dementia, have synthesized novel chromium derivative compounds, and these compounds effectively improve memory loss and are excellent in preventing or treating dementia. After confirming the effect, the present invention was completed.

It is an object of the present invention to provide novel chromen derivative compounds.

Another object of the present invention is to provide a method for producing a novel chromene derivative compound.

Still another object of the present invention is to provide a composition for preventing or treating dementia, comprising the novel chromene derivative compound.

The present invention provides a chromene derivative compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ to R ₃ are independently straight or branched C ₁ to C ₄ alkoxy or hydroxy,

R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy; NHSO ₂ R ₆ , wherein R ₆ is substituted or unsubstituted phenyl; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl;

X is O or S,

If X is O, R ₁ is straight or branched C ₁ to C ₄ alkoxy and R ₄ and R ₅ are H, then at least one of R ₂ and R ₃ is hydroxy,

If X is O, R ₁ is hydroxy and R ₄ and R ₅ are H, then R ₃ is straight or branched C ₁ to C ₄ alkoxy.

In the present invention, the chromium derivative compound represented by Chemical Formula 1 is wherein R ₁ to R ₃ are methoxy or hydroxy and R ₄ and R ₅ are independently H; Floro; Chloro; methyl; Methoxy; Nitro; Amino; Dimethylamino; Diethylamino, phenyl; Phenoxy; Methylsulfanyl; Methylbenzenesulfonamido; Benzenesulfonamido; Nitrobenzenesulfonamido; Or florobenzenesulfonamido.

In the chromium derivative compound represented by Chemical Formula 1 of the present invention, R ₁ and R ₃ may be hydroxy, and R ₂ may be methoxy. Alternatively, the chromate derivative compound represented by Chemical Formula 1 may be all R ₁ to R ₃ methoxy. Alternatively, in the chromate derivative compound represented by Chemical Formula 1, R ₁ to R ₃ may be all hydroxy. Alternatively, the chromium derivative compound represented by Chemical Formula 1 may be R ₁ and hydroxy, and R ₂ and R ₃ may be methoxy.

The chromene derivative compound represented by Chemical Formula 1 of the present invention may be preferably the following compound;

1) 5-hydroxy-6,7-dimethoxy-2-phenyl-chromen-4-one,

2) 2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-one,

3) 2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

4) 2- (2,4-difluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

5) 2- (2-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

6) 2- (3-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

7) 5,7-dihydroxy-6-methoxy-2- (4-methylsulfanyl-phenyl) -chromen-4-one,

8) 2- (3,4-dichloro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

9) 2- (4-dimethylamino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

10) 5,7-dihydroxy-6-methoxy-2- (4-nitro-phenyl) -chromen-4-one,

11) 2- (4-amino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

12) 5,7-dihydroxy-6-methoxy-2- (4-phenoxy-phenyl) -chromen-4-one,

13) 2- (biphenyl-4-yl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

14) 2- (4-diethylamino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,

15) N- [4- (5,7-dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4-nitro-benzenesulfonamide,

16) N- [4- (5,7-dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4-methyl-benzenesulfonamide,

17) N- [4- (5,7-dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -benzenesulfonamide,

18) N- [4- (5,7-dihydroxy-6methoxy-4-oxo-4H-chromen-2yl) -phenyl] -4-fluoro-benzenesulfonamide,

19) 2- (4-fluoro-phenyl) -5,6,7-trihydroxy-chromen-4-one,

20) 2- (4-fluoro-phenyl) -5-hydroxy-6,7-dimethoxy-chromen-4-one,

21) 5,6,7-trimethoxy-2-phenyl-chromen-4-thione,

22) 5,6,7-trihydroxy-2-phenyl-chromen-4-thione,

23) 5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-thione,

24) 2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-thione,

25) 2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,

26) 2- (2,4-difluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,

27) 2- (2-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,

28) 2- (3-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,

29) 5,7-dihydroxy-6-methoxy-2- (4-methylsulfanyl-phenyl) -chromen-4-thione,

30) 2- (3,4-dichloro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,

31) 2- (4-dimethylamino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,

32) 2- (4-fluoro-phenyl) -5,6,7-trihydroxy-chromen-4-thione or

33) 2- (4-fluoro-phenyl) -5-hydroxy-6,7-dimethoxy-chromen-4-thione.

In the chromate derivative compound represented by Chemical Formula 1 of the present invention, a pharmaceutically acceptable salt means a pharmaceutically acceptable free acid, and inorganic and organic acids may be used. For example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid , Maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, kalutuuronic acid, emboic acid, glutamic acid, Aspartic acid or the like can be used. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid.

In addition, the present invention provides a method for preparing a chromate derivative compound represented by the following formula (1) comprising the following steps:

a) synthesizing the compound represented by the following Chemical Formula 4 by reacting the acetophenone compound represented by the following Chemical Formula 2 with an aldehyde compound represented by the following Chemical Formula 3 in the presence of a base; And

b) preparing a compound represented by Chemical Formula 5 by reacting the compound represented by Chemical Formula 4 with iodine, bromine or selenium oxide.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

In Chemical Formulas 1 to 5

R ₁ to R ₃ are independently straight or branched C ₁ to C ₄ alkoxy or hydroxy,

R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy; NHSO ₂ R ₆ , wherein R ₆ is substituted or unsubstituted phenyl; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl;

X is O or S,

If X is O, R ₁ is straight or branched C ₁ to C ₄ alkoxy and R ₄ and R ₅ are H, then at least one of R ₂ and R ₃ is hydroxy,

When X is O, R ₁ is hydroxy and R ₄ and R ₅ are H, then R ₃ is straight or branched C ₁ to C ₄ alkoxy,

Ra, Rb and Rc are independently straight or branched C ₁ to C ₄ alkyl.

In step a) of the preparation method, the acetophenone compound represented by Formula 2 and the aldehyde compound represented by Formula 3 used as starting materials and reactants can be easily purchased and used as commercially available materials, or known Can be prepared and used directly.

In step a) of the above production method, an organic base or an inorganic base may be used. For example, as the organic base, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, N, N-dimethylaniline, 2, 6 It is preferable to use a general tertiary organic base such as -lutidine, pyridine and the like, and as the inorganic base, potassium hydroxide, sodium hydroxide or sodium hydride can be used. These may be used alone or in combination.

In step a) or b) of the production method, the reaction solvent is alcohol, such as methanol, ethanol, isopropanol, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, N-methyl Pyrrolidinone, acetone, water. These may be used alone or in combination.

When R ₄ of the aldehyde compound represented by Formula 3 in the preparation method is nitro, the method may further include protecting the OH group of the acetophenone compound represented by Formula 2 with a benzyl group. That is, H of the OH group of the acetophenone compound represented by Formula 2 may be substituted with a benzyl group. For example, the acetophenone compound represented by Formula 2 may be reacted with benzyl chloride to protect the OH group of the acetophenone compound with a benzyl group.

A compound in which the OH group of the compound represented by Chemical Formula 4 is protected by a benzyl group is prepared by the reaction of the hydroxy-protected acetophenone compound protected by the benzyl group with the aldehyde compound represented by Chemical Formula 3 wherein R ₄ is nitro. When the benzyl group serving as the protecting group is substituted with H, the compound represented by Chemical Formula 4 may be synthesized. For example, the hydroxyl group of the compound represented by Formula 4 may be deprotected by reacting a compound in which the OH group of the compound represented by Formula 4 is protected with a benzyl group with acetic acid and hydrochloric acid to replace the following benzyl group with H.

The compound in which the R ₄ is amino in the chromate derivative compound represented by Formula 1 may be prepared by reacting the chromate derivative compound represented by Formula 1 wherein R ₄ is nitro with sodium thiosulfate.

In the chromium derivative compound represented by Chemical Formula 1, R ₄ is NHSO ₂ R ₆ The compound represented by sulfonamido may be prepared by reacting the chromate derivative compound represented by Chemical Formula 1, wherein R ₄ is amino, with the sulfonyl halide compound represented by Chemical Formula 6.

[Formula 6]

In Formula 6,

R ₆ is substituted or unsubstituted phenyl,

Y is chloro; Bromo; Or iodo.

When iodine is used in step b) in the preparation method, the compound represented by Chemical Formula 4 may be dissolved and used in Dimail sulfoxide (DMSO). When bromine is used in step b), the reaction may be carried out in the presence of a base. The base is, for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, N, N-dimethylaniline, 2,6 -Lutidine, pyridine, and the like. These may be used alone or in combination.

The compound wherein R ₁ and R ₃ of the chromate derivative compound represented by Formula 1 is hydroxy,

The R ₁ It may be prepared by reacting a compound represented by the formula (1) wherein R ₃ is a straight or branched C ₁ to C ₄ alkoxy.

The compound represented by Formula 1 wherein R ₁ to R ₃ is a straight or branched C ₁ to C ₄ alkoxy may be reacted at -10 ° C to 10 ° C. Examples of the Lewis acid include aluminum trichloride (AlCl ₃ ), aluminum tribromide (AlBr ₃ ), and the like. In addition, the reaction may be carried out under a solvent such as acetonitrile.

The compound wherein R ₁ and R ₃ of the chromate derivative compound represented by Formula 1 is hydroxy,

It can be prepared by dissolving the compound represented by the formula (1) wherein R ₁ to R ₃ is a straight or branched C ₁ to C ₄ alkoxy.

The acid may comprise an organic acid or an inorganic acid. The acid is hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, caluturonic acid, emboic acid, glutamic acid, aspartic acid, and the like. These may be used alone or in combination. For example, the acid may be an aqueous solution containing a mixture of acetic acid and bromic acid.

A compound wherein R ₁ to R ₃ of the chromate derivative compound represented by Formula 1 is hydroxy,

The compound represented by the formula (1) wherein R ₁ to R ₃ is a straight or branched C ₁ to C ₄ alkoxy may be prepared by reacting with tribromoborane.

The compound in which X is S of the chromium derivative compound represented by Formula 1 may be prepared by reacting the compound represented by Formula 1 wherein X is O with Lawson reagent. That is, by reacting with Lawson's reagent, carbonyl may be substituted with thionyl. For example, the compound represented by the following Chemical Formula 7 may be prepared by reacting the compound represented by the following Chemical Formula 5 with Lawson's reagent.

[Formula 7]

In Chemical Formula 7

R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy; NHSO ₂ R ₆ , wherein R ₆ is substituted or unsubstituted phenyl; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl,

Ra, Rb and Rc are independently straight or branched C ₁ to C ₄ alkyl.

The chromene derivative compound represented by Chemical Formula 1 of the present invention has no toxicity or side effects. For example, the chromene derivative compound represented by Chemical Formula 1 of the present invention does not cause side effects such as convulsions in mammals including humans.

The present invention provides a composition for preventing or treating dementia, comprising a chromium derivative compound represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Formula 1,

R ₁ to R ₃ are independently straight or branched C ₁ to C ₄ alkoxy or hydroxy,

R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy; NHSO ₂ R ₆ , wherein R ₆ is substituted or unsubstituted phenyl; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl,

X is O or S,

If X is O and R ₁ is hydroxy and R ₄ and R ₅ are H, then R ₃ is straight or branched C ₁ to C ₄ alkoxy.

Here, the pharmaceutically acceptable salts are substantially the same as described above.

The present invention provides a method for preventing or treating dementia by administering an effective amount of the chromium derivative compound represented by Formula 1 to a mammal including a human in need of preventing or treating dementia.

The present invention provides a use of the chromene derivative compound represented by Chemical Formula 1 in the preparation of a pharmaceutical preparation for the prevention or treatment of dementia.

In the present invention, dementia may be Alzheimer's dementia or vascular dementia.

In the present invention, the composition comprising the chromene derivative compound represented by Formula 1 has no toxicity and side effects. For example, the composition does not cause side effects such as spasm when administered to mammals, including humans.

The composition of the present invention may further include one or more active ingredients exhibiting the same or similar functions in addition to the chromene derivative compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The composition of the present invention may further comprise one or more pharmaceutically acceptable carriers for administration in addition to the above components. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, and antioxidants, buffers, bacteriostatic agents, and the like. Other conventional additives can be added. The compositions of the present invention may also be formulated into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions, etc., with the addition of diluents, dispersants, surfactants, binders, and lubricants. Further, the composition of the present invention can be formulated according to each disease or component using appropriate methods in the art or methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex, health status, The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dosage of the chromene derivative compound represented by Chemical Formula 1 of the present invention is about 1 to 500 mg / kg, preferably 2.5 to 250 mg / kg, and may be administered once to several times a day.

The composition of the present invention can be used alone or in combination with methods using surgery, hormonal therapy, drug therapy or biological response modifiers for the prevention or treatment of dementia.

The novel chromene derivative compounds of the present invention and their pharmaceutically acceptable salts can effectively improve memory loss, thus exhibiting a prophylactic or therapeutic effect of dementia, including Alzheimer's dementia and vascular dementia.

1 to 12 are diagrams showing the results of passive avoidance experiments for mice administered a composition containing a chromene derivative compound represented by the formula (1) according to the present invention.

Hereinafter, preferred examples and examples of the present invention are presented to facilitate understanding of the present invention. However, the following Production Examples and Examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the Production Examples and Examples.

The reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, Alfa Aesar, Tokyo Chmical incorporation, unless otherwise noted. ¹ H-NMR data were measured on Bruker's FT-NMR 300 MHz machine, Mass Data is measured with Autospec M363 series MASS machine and melting point (mp) is measured with Fisher's IA-900.

Preparation Example 1 Preparation of 5,6,7-trimethoxy-2-phenyl-chromen-4-one

One equivalent of 2-hydroxy-4,5,6-trimethoxy acetophenone (5.40 g) and three equivalents of potassium hydroxide (4.02 g) were dissolved in 24 mL of methanol, followed by addition of one equivalent of benzaldehyde (2.43 mL) at room temperature. The reaction was stirred for 24 hours. After the reaction was completed, 3% (w / v%) aqueous hydrochloric acid solution was slowly added dropwise. The solid produced at this time was filtered, washed with methanol and dried to give 1- (6-hydroxy-2,3,4-trimethoxyphenyl) -3-phenyl-2-propen-1-one. .

After dissolving 5.03 g of the solid obtained in 80 mL of dimethyl sulfoxide (DMSO), 0.1 equivalent (0.41 g) of iodine was added based on the obtained solid, followed by stirring at 100 ° C. for 10 hours. After the solution was cooled to room temperature, a saturated aqueous solution of sodium thiosulfate was slowly added dropwise until the solution turned colorless. The resulting solid was filtered and recrystallized with methanol to give the target compound 5,6,7-trimethoxy-2-phenyl-chromen-4-one.

mp = 153 ~ 155 ℃

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.86-7.89 (m, 2H), 7.48-7.52 (m, 3H), 6.82 (s, 1H), 6.68 (s, 1H), 3.99 (s, 3H ), 3.98 (s, 3H), 3.93 (s, 3H)

Preparation Example 2 Preparation of 5,6,7-trihydroxy-2-phenyl-chromen-4-one

One equivalent of 2-hydroxy-4,5,6-trimethoxy acetophenone (5.40 g) and three equivalents of potassium hydroxide (4.02 g) were dissolved in 24 mL of methanol, followed by addition of one equivalent of benzaldehyde (2.43 mL) at room temperature. The reaction was stirred for 24 hours. After the reaction was completed, 3% (w / v%) aqueous hydrochloric acid solution was slowly added dropwise. The solid produced at this time was filtered, washed with methanol and dried to give 1- (6-hydroxy-2,3,4-trimethoxyphenyl) -3-phenyl-2-propen-1-one. .

After dissolving 5.03 g of the solid obtained in 80 mL of dimethyl sulfoxide (DMSO), 0.1 equivalent (0.41 g) of iodine was added based on the obtained solid, followed by stirring at 100 ° C. for 10 hours. After cooling the solution to room temperature, a saturated aqueous solution of sodium thiosulfate was slowly added dropwise until the solution turned colorless. The solid produced at this time was filtered, washed with methanol and dried to prepare 5,6,7-trimethoxy-2-phenyl-chromen-4-one.

0.15 g of the 5,6,7-trimethoxy-2-phenyl-chromen-4-one was dissolved in 7.5 mL of anhydrous chloroform, cooled to 0 ° C., and 2.3 mL of 1M tribromoborane dissolved in chloroform. Was dropped. The solution was stirred at room temperature for 1 hour and then allowed to react for 24 hours under heated reflux conditions. Thereafter, the solution was cooled to room temperature and excess tribromo borane was removed while methanol was slowly added dropwise. Thereafter, the resulting solid was concentrated under reduced pressure, washed with water and recrystallized to obtain 5,6,7-trihydroxy-2-phenyl-chromen-4-one as a target compound.

mp = 263 ~ 265 ℃

¹ H-NMR (300 MHz, DMSO): δ 12.67 (s, 1H), 10.59 (s, 1H), 8.86 (s, 1H), 8.06-8.08 (m, 2H), 7.54-7.64 (m, 3H) , 6.94 (s, 1H), 6.64 (s, 1H)

Example 1 Preparation of 5-hydroxy-6,7-dimethoxy-2-phenyl-chromen-4-one

One equivalent of 2-hydroxy-4,5,6-trimethoxy acetophenone (5.40 g) and three equivalents of potassium hydroxide (4.02 g) were dissolved in 24 mL of methanol, followed by addition of one equivalent of benzaldehyde (2.43 mL) at room temperature. The reaction was stirred for 24 hours. After the reaction was completed, 3% (w / v%) aqueous hydrochloric acid solution was slowly added dropwise. The solid produced at this time was filtered, washed with methanol and dried to give 1- (6-hydroxy-2,3,4-trimethoxyphenyl) -3-phenyl-2-propen-1-one. .

After dissolving 5.03 g of the solid obtained in 80 mL of dimethyl sulfoxide (DMSO), 0.1 equivalent (0.41 g) of iodine was added based on the obtained solid, followed by stirring at 100 ° C. for 10 hours. After cooling the solution to room temperature, a saturated aqueous solution of sodium thiosulfate was slowly added dropwise until the solution turned colorless. The solid produced at this time was filtered, washed with methanol and dried to prepare 5,6,7-trimethoxy-2-phenyl-chromen-4-one.

1 equivalent (0.50 g) of the 5,6,7-trimethoxy-2-phenyl-chromen-4-one was dissolved in 16 mL of acetonitrile and cooled to about 0 ° C. using ice, followed by anhydrous aluminum trichloride 5 Equivalent weight (1.09 g) was added and reacted for 4 hours under heating reflux conditions. After completion of the reaction, the solution was concentrated under reduced pressure to remove acetonitrile, and the obtained solid was dissolved in 40 mL of a solution in which chloroform and 3N hydrochloric acid aqueous solution were mixed at a volume ratio of 2: 1, and then maintained under heating and reflux for 40 minutes. Thereafter, the organic layer was separated, excess water was removed with anhydrous magnesium sulfate, and concentrated under reduced pressure. The solid obtained at this time was washed again with methanol and dried again to obtain 5-hydroxy-6,7-dimethoxy-2-phenyl-chromen-4-one as the target compound.

mp = 159 ° C

1 H-NMR (300 MHz, CDCl ₃ ): δ 12.69 (s, 1H), 7.87-7.91 (m, 2H), 7.49-7.59 (m, 3H), 6.67 (s, 1H), 6.57 (s, 1H) , 3.98 (s, 1 H), 3.93 (s, 1 H).

Example 2 Preparation of 2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-one

Except for using 4-fluorobenzaldehyde instead of benzaldehyde, 2- (4) as a target compound in substantially the same manner as 5,6,7-trimethoxy-2-phenyl-chromen-4-one of Preparation Example 1 -Fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-one was obtained.

mp = 173-175 ° C

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.86-7.91 (dd, 2H, J = 5.2 Hz, 8.8 Hz) 7.18-7.23 (t, 2H, J = 8.8 Hz), 6.81 (s, 1H), 6.62 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.93 (s, 3H)

Example 3 Preparation of 2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one

After dissolving 1 equivalent (1.0 g) of 2-hydroxy-4,5,6-trimethoxy acetophenone and 3 equivalents of potassium hydroxide (0.74 g) in 4.5 mL of methanol, 1 equivalent of 4-fluorobenzaldehyde (0.48 mL) Was added and stirred at room temperature for 24 hours to react. After the reaction was completed, 3% (w / v%) aqueous hydrochloric acid solution was slowly added dropwise. The solid produced at this time was filtered, washed with methanol and dried to obtain 3- (4-fluoro-phenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) -2-propene. 1-one was obtained.

After dissolving 1.22 g of the solid obtained in 18 mL of dimethyl sulfoxide (DMSO), 0.1 equivalent (0.1 g) of iodine was added based on the obtained solid, followed by stirring at 100 ° C. for 10 hours. After cooling the solution to room temperature, a saturated aqueous solution of sodium thiosulfate was slowly added dropwise until the solution turned colorless. The resulting solid was filtered, washed with methanol and dried to afford 2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-one.

36 mL solution of 0.5 g of 2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-one mixed with acetic acid and 48% by weight of bromic acid in a volume ratio of 2: 1 After dissolving in, it was stirred for 5 hours under heating and reflux conditions. After cooling the mixture solution to room temperature, ice water was slowly added dropwise. The resulting solid was filtered, washed with methanol and dried to afford the desired compound 2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one. .

mp = 255 ~ 257 ℃

¹ H-NMR (300 MHz, DMSO): δ 12.49 (s, 1H), 8.79 (s, 1H), 8.16-8.21 (dd, 2H, J = 5.4 Hz, 8.9 Hz), 7.41-7.47 (t, 2H , J = 8.9 Hz), 7.01 (s, 1H), 6.97 (s, 1H), 3.93 (s, 3H)

<Examples 4 to 12>

2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen- of Example 3, except that the aldehyde compounds shown in Table 1 were used instead of 4-fluorobenzaldehyde The desired compounds described in Table 1 were synthesized in substantially the same manner as 4-ones.

Table 1 below shows the names of the compounds prepared in Examples 4 to 12, the names of the aldehyde compounds used, the NMR results and the melting points of the target compounds.

[Table 1]

Example 13 Preparation of 5,7-Dihydroxy-6-methoxy-2- (4-nitro-phenyl) -chromen-4-one

One equivalent of 2-hydroxy-4,5,6-trimethoxy acetophenone (4.36 g) and four equivalents of calcium hydroxide (4.33 g) were dissolved in 95 mL of dimethylformamide. 3.4 mL of benzyl chloride was added to the solution and heated to reflux for 1-2 hours. After the reaction was completed, the solution was cooled to room temperature and 2N aqueous hydrochloric acid solution was added. Extracted with dichloromethane and the organic layer was separated. Water was removed from the organic layer using anhydrous magnesium sulfate and filtered to give 2-benzyloxy-4,5,6-trimethoxyacetophenone in which the hydroxy group was protected with a benzyl group.

After dissolving 1 equivalent (3.35 g) of 2-benzyloxy-4,5,6-trimethoxyacetophenone and 4 equivalents of potassium hydroxide (2.4 g) in which a hydroxyl group was protected with a benzyl group, 4-ditro-benzaldehyde 1 Equivalent weight (1.6 g) was added and the reaction was stirred for 2 hours at room temperature. After the reaction was completed, 3% (w / v%) aqueous hydrochloric acid solution was slowly added dropwise. The solid produced at this time was filtered, washed with methanol and dried to obtain 1- (6-benzyloxy-2,3,4-trimethoxyphenyl) -3- (4-nitro-phenyl) -2-propene- 1-one was obtained.

2.2 g of the solid thus obtained was dissolved in 45 mL of acetic acid, and 15 mL of concentrated hydrochloric acid was added thereto, followed by heating to reflux for 30 minutes to 1 hour. After cooling the solution to room temperature, ice was added. The solid produced at this time was filtered and washed with methanol to deprotect the benzyl group protecting the hydroxy group. 1- (6-hydroxy-2,3,4-trimethoxyphenyl) -3- (4-nitro- Phenyl) -2-propen-1-one was obtained.

After dissolving 1.50 g of the solid obtained in 20 mL of dimethyl sulfoxide (DMSO), 0.1 equivalent (0.11 g) of iodine was added based on the obtained solid, followed by stirring at 100 ° C. for 10 hours. After cooling the solution to room temperature, a saturated aqueous solution of sodium thiosulfate was slowly added dropwise until the solution turned colorless. The resulting solid was filtered, washed with methanol and dried to give 5,6,7-trimethoxy-2- (4-nitro-phenyl) -chromen-4-one.

1.35 g of the 5,6,7-trimethoxy-2- (4-nitro-phenyl) -chromen-4-one was added to 50 mL of a solution in which acetic acid and 48% by weight bromic acid were mixed in a volume ratio of 2: 1. After dissolving, the mixture was stirred for 5 hours under heating and reflux conditions. After cooling the mixture solution to room temperature, ice water was slowly added dropwise. The resulting solid was filtered, washed with methanol and dried to give the desired compound 5,7-dihydroxy-6-methoxy-2- (4-nitro-phenyl) -chromen-4-one.

mp:> 300 ° C

¹ H-NMR (300 MHz, DMSO): δ 12.31 (s, 1H), 8.94 (s, 1H,), 8.36-8.38 (d, 4H, J = 3.4 Hz), 7.17 (s, 1H), 6.99 ( s, 1 H), 3.94 (s, 3 H)

Example 14 Preparation of 2- (4-amino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one

3.25 g of 5,7-dihydroxy-6-methoxy-2- (4-nitro-phenyl) -chromen-4-one and 17.19 g of sodium thiosulfate were dissolved in a solution containing 100 mL of acetone and 50 mL of water. Heated to reflux for 2 hours. The solution was cooled to room temperature, distilled under reduced pressure to remove acetone, and the resulting solid was filtered and washed with methanol to give 2- (4-amino-phenyl) -5,7-dihydroxy-6-meth as the target compound. Obtained oxy-chromen-4-one.

mp: 245 ~ 247 ℃

¹ H-NMR (300 MHz, DMSO): δ 12.78 (s, 1 H), 8.72 (s, 1 H), 7.80-7.77 (d, 2H, J = 8.7 Hz), 6.87 (s, 1H), 6.66-6.69 (d, 2H), 6.65 (s, 1H), 6.06 (s, 2H), 3.90 (s, 3H)

Example 15 N- [4- (5,7-Dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4-nitro-benzenesulfonamide

1 equivalent (0.9 g) of 2- (4-amino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one of Example 14 was diluted with 14 mL of dichloromethane and 7.5 mL of NaHCO _3. It was dissolved in saturated aqueous solution and then cooled to 0 ° C. Two equivalents of 4-nitro-benzenesulfonyl chloride (1.1 g) was slowly added to the solution, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with dichloromethane and the organic layer was separated. Water was removed from the organic layer using anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The solid produced at this time was recrystallized with methanol to give the title compound N- [4- (5,7-dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4- Nitro-benzenesulfonamide was obtained.

mp = 254-255 ° C

¹ H-NMR (300 MHz, DMSO): δ 13.57 (s, 1H), 8.47-8.50 (d, 2H, J = 8.7 Hz), 8.23-8.26 (d, 2H, J = 8.7 Hz), 7.81-7.84 (d, 2H, J = 8.6Hz), 6.97 (s, 1H), 6.77 (s, 1H), 6.67-6.69 (d, 2H, J = 8.6Hz), 6.20 (s, 1H), 3.68 (s, 3H)

<Examples 16 to 18>

N- [4- (5,7-dihydroxy-6-methoxy-4-oxo of Example 15, except that the sulfonylchloride compounds shown in Table 2 were used instead of 4-nitro-benzenesulfonylchloride The desired compounds described in Table 2 were obtained in substantially the same manner as -4H-chromen-2-yl) -phenyl] -4-nitro-benzenesulfonamide.

Table 2 shows the names of the compounds prepared in Examples 16 to 18, the names of the aldehyde compounds used, and the NMR results.

[Table 2]

Example 19 Preparation of 2- (4-fluoro-phenyl) -5,6,7-trihydroxy-chromen-4-one

Except for using 4-fluorobenzaldehyde instead of benzaldehyde, 2- (4) as the target compound in substantially the same manner as in 5,6,7-trihydroxy-2-phenyl-chromen-4-one of Preparation Example 2. -Fluoro-phenyl) -5,6,7-trihydroxy-chromen-4-one was obtained.

mp = 292-294 ° C

¹ H-NMR (300 MHz, DMSO): 1 H-NMR (300 MHz, DMSO): δ 12.64 (s, 1H), 10.62 (s, 1H), 8.85 (s, 1H), 8.13-8.17 (dd, 2H , J = 5.4 Hz, 8.8 Hz), 7.39-7.45 (t, 2H, J = 8.8 Hz), 6.93 (s, 1H), 6.64 (s, 1H)

Example 20 Preparation of 2- (4-fluoro-phenyl) -5-hydroxy-6,7-dimethoxy-chromen-4-one

2- (4- in substantially the same manner as 5-hydroxy-6,7-dimethoxy-2-phenyl-chromen-4-one of Example 1, except that 4-fluorobenzaldehyde was used instead of benzaldehyde. Floro-phenyl) -5-hydroxy-6,7-dimethoxy-chromen-4-one was obtained.

mp = 192 ~ 194 ℃

¹ H-NMR (300 MHz, DMSO): δ 12.74 (s, 1H), 8.15-8.20 (dd, 2H, J = 5.3 Hz, 9.0 Hz), 7.38-7.44 (t, 2H, J = 8.8 Hz), 7.01 (s, 1H), 6.94 (s, 1H), 3.94 (s, 3H), 3.76 (s, 3H)

Example 21 Preparation of 5,6,7-Trimethoxy-2-phenyl-chromen-4-thione

0.7 equivalent (0.18 g) of Lawson's reagent and 1 equivalent (0.2 g) of 5,6,7-trimethoxy-2-phenyl-chromen-4-one of Preparation Example 1 were dissolved in 5 mL of toluene, followed by heating. It stirred for 4 hours under reflux conditions. The solution was then cooled to room temperature and concentrated under reduced pressure to remove toluene from the solution. The solid obtained at this time was recrystallized from a solution containing methanol and chloromethane in a volume ratio of 1: 1 to obtain the target compound 5,6,7-trimethoxy-2-phenyl-chromen-4-thione.

mp = 100 ~ 103 ℃

Mass (M +) = 328

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.91-7.95 (m, 2H), 7.60 (s, 1H), 7.47-7.56 (m, 3H), 6.83 (s, 1H), 4.01 (s, 3H ), 3.95 (s, 3H), 3.93 (s, 3H)

Example 22 Preparation of 5,7-Dihydroxy-6-methoxy-2-phenyl-chromen-4-thione

0.5 g of 5,6,7-trimethoxy-2-phenyl-chromen-4-one of Preparation Example 1 was dissolved in 37.5 mL of a solution in which acetic acid and 48% by weight bromic acid were mixed in a volume ratio of 2: 1. Then, the mixture was stirred for 5 hours under heating and reflux conditions. After the mixture was cooled to room temperature, ice water was slowly added dropwise. The resulting solid was filtered, washed with methanol and dried to give 5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-one.

0.7 equivalents (0.2 g) of Lawson's reagent and 1 equivalent (0.2 g) of 5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-one were dissolved in 3.5 mL of toluene. Stirred under heated reflux conditions for 4 hours. The solution was then cooled to room temperature and concentrated under reduced pressure to remove toluene from the solution. The solid obtained at this time was recrystallized from a solution containing methanol and chloromethane in a volume ratio of 1: 1 to obtain the target compound 5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-thione. It was.

mp = 211-213 ° C

Mass (M +) = 300

¹ H-NMR (300 MHz, CDCl ₃ ): δ 13.66 (s, 1H), 7.93-7.96 (dd, 2H, J = 1.2 Hz, 8.1 Hz), 7.51 to 7.58 (m, 3H), 7.46 (s, 1H), 6.67 (s, 1H), 4.04 (s, 3H)

<Examples 23 to 33>

Instead of 5,6,7-trimethoxy-2-phenyl-chromen-4-one of Preparation Example 1 to the compounds synthesized in Preparation Examples 2, 2 to 9, 19 and 20 Each of the target compounds shown in Table 2 was synthesized in substantially the same manner as in Example 21 except for the use.

Table 2 below shows the names of the target compounds prepared in Examples 23 to 33, the names of the compounds synthesized in the preparations or examples used in the synthesis of the target compounds, and the NMR results.

[Table 3]

Hereinafter, preferred experimental examples are presented to help understand the present invention. However, the following experimental examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the experimental examples.

Experimental Example Confirmation of Dementia Treatment Efficacy

In order to confirm the efficacy of the dementia treatment of the compound of the present invention, a passive avoidance experiment using a forgetfulness model induced by scopolamine was performed.

1) Preparation of experimental animals

Six-week-old ICR rats (Orient Co., Ltd., Korea) from 26g to 28g are allowed to freely ingest water and feed, under a temperature of 23 ± 2 ℃, 55 ± 10% humidity, and 12 hours of contrast cycle. The animals were adapted for daily use and then used for experiments.

2) Preparing the device to be used for the experiment

For the passive avoidance experiment was prepared a passive avoidance response measuring apparatus. The passive avoidance reaction measuring apparatus is divided into two spaces of a first space and a second space, and a guillotine-type entrance is formed between the two spaces, and the first and second spaces are connected through the entrance. The first space was kept bright with illumination and the second space was dark. The bottom of the second space, which is kept dark, is provided with a lattice, and when the animal moves to the dark space, an electric shock of 0.5 mA flows through the bottom of the grid for 3 seconds.

3) Manual evasion experiment on ICR rat

Manual Evasion Experiment 1

Learning was performed on the ICR mice prepared in 1). After the rat is placed in the first space that is kept bright, after about 20 seconds of search time has elapsed, the time to move to the second space where the rat is kept dark by opening a guillotine-type doorway (latency time, delay time). ) Was measured. Mice that did not migrate to the second space, which remained dark until 40 seconds after opening the guillotine-type doorway, were excluded from the experiment.

After 24 hours from the learning, the selected mice were classified into drug administration groups 1 to 3, control 1 and control 2. After preparing the composition by suspending the compound of Preparation Example 1 in Tween 80 (Sigma-Aldrich Chemistry Co., USA), the effective amount of the compound of Preparation Example 1 was 2.5mg / Kg, 5mg / Kg and 10mg / Kg Each of the compositions was administered to the drug administration groups 1 to 3. 10 mL / Kg of 10 wt% of Tween 80 was administered to Control 1 and Control 2. About 30 minutes after the composition comprising the compound of Preparation Example 1 and Tween 80, scopolamine dissolved in distilled water was administered to the drug administration groups 1 to 3 and the control group 2 at a dose of about 1 mg / Kg. The number of animals used in the control group 1, the control group 2 and the drug administration groups 1 to 3 is 10 each.

About 30 minutes after the scopolamine administration, the mice of the drug administration groups 1 to 3, the control group 1 and the control group 2 were respectively placed in the first space kept bright in the passive evacuation measuring device. After about 20 seconds of exploration time, the guillotine-type doorway was opened, and the delay time for all four rounds to move to the second space where the rat was kept dark through the doorway was measured up to 300 seconds. 1 is shown. The experimental results were statistically analyzed using ANOVA (one way analysis of variance). When significance was recognized, the significance test was performed at p <0.05 level using Student-Newman-Keuls Test.

Manual Evasion Experiment 2-12

Manual avoidance experiments 2 to 12 were carried out in substantially the same manner as passive avoidance experiment 1 except that other compounds prepared in Examples were used instead of the compound prepared in Preparation Example 1. However, in the case of passive avoidance experiment 12 using the compound of Example 31, the drug administration group was separated into five groups of 1 to 5 and the effective amount of the compound obtained in Example 31 was 0.625 mg / Kg, 1.25 mg / Kg, 2.5 To the mg / Kg, 5 mg / Kg and 10 mg / Kg was administered a composition comprising the compound of Example 31 in the dosing groups 1 to 5, respectively. Table 4 summarizes the compounds used in each passive avoidance experiment, the results of each passive avoidance experiment 2 to 12 are shown in Figures 2 to 12, respectively.

[Table 4]

As can be seen in Figures 1 to 12, it was found that the compounds of the present invention can improve memory loss caused by scopolamine. Thus, it was found that the compounds of the present invention can prevent or treat dementia causing memory loss symptoms.

Claims (11)

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Chemical Formula 1,
R ₁ to R ₃ are independently straight or branched C ₁ to C ₄ alkoxy or hydroxy,
R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Phenyl; Phenoxy; Methylbenzenesulfonamido; Benzenesulfonamido; Nitrobenzenesulfonamido; Florobenzenesulfonamido; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl,
X is O or S,
If X is O, R ₁ is straight or branched C ₁ to C ₄ alkoxy and R ₄ and R ₅ are H, then at least one of R ₂ and R ₃ is hydroxy,
If X is O, R ₁ is hydroxy and R ₄ and R ₅ are H, then R ₃ is straight or branched C ₂ to C ₄ alkoxy. The method of claim 1,
R ₁ to R ₃ are independently methoxy or hydroxy,
At least one of R ₄ and R ₅ is flow; Chloro; methyl; Methoxy; Nitro; Amino; Dimethylamino; Diethylamino; Phenyl; Phenoxy; Methylsulfanyl; Methylbenzenesulfonamido; Benzenesulfonamido; Nitrobenzenesulfonamido; Or fluorobenzenesulfonamido. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein
2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-one,
2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
2- (2,4-difluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
2- (2-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
2- (3-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
5,7-dihydroxy-6-methoxy-2- (4-methylsulfanyl-phenyl) -chromen-4-one,
2- (3,4-dichloro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
2- (4-dimethylamino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
5,7-dihydroxy-6-methoxy-2- (4-nitro-phenyl) -chromen-4-one,
2- (4-amino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
5,7-dihydroxy-6-methoxy-2- (4-phenoxy-phenyl) -chromen-4-one,
2-biphenyl-4-yl-5,7-dihydroxy-6-methoxy-chromen-4-one,
2- (4-diethylamino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-one,
N- [4- (5,7-Dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4-nitro-benzenesulfonamide,
N- [4- (5,7-Dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4-methyl-benzenesulfonamide,
N- [4- (5,7-Dihydroxy-6-methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -benzenesulfonamide,
N- [4- (5,7-Dihydroxy-6methoxy-4-oxo-4H-chromen-2-yl) -phenyl] -4-fluoro-benzenesulfonamide,
2- (4-fluoro-phenyl) -5,6,7-trihydroxy-chromen-4-one,
2- (4-fluoro-phenyl) -5-hydroxy-6,7-dimethoxy-chromen-4-one,
5,6,7-trimethoxy-2-phenyl-chromen-4-thione,
5,6,7-trihydroxy-2-phenyl-chromen-4-thione,
5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-thione,
2- (4-fluoro-phenyl) -5,6,7-trimethoxy-chromen-4-thione,
2- (4-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,
2- (2,4-difluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,
2- (2-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,
2- (3-fluoro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,
5,7-dihydroxy-6-methoxy-2- (4-methylsulfanyl-phenyl) -chromen-4-thione,
2- (3,4-dichloro-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,
2- (4-dimethylamino-phenyl) -5,7-dihydroxy-6-methoxy-chromen-4-thione,
2- (4-fluoro-phenyl) -5,6,7-trihydroxy-chromen-4-thione, and
2- (4-fluoro-phenyl) -5-hydroxy-6,7-dimethoxy-chromen-4-thione
Compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of. a) synthesizing the compound represented by the following Chemical Formula 4 by reacting the acetophenone compound represented by the following Chemical Formula 2 with an aldehyde compound represented by the following Chemical Formula 3 in the presence of a base; And
b) a method of preparing a compound represented by the following Chemical Formula 1, comprising the step of reacting the compound represented by Chemical Formula 4 with any one selected from the group consisting of iodine, bromine and selenium oxide to prepare a compound represented by the following Chemical Formula 5. :
[Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

In Chemical Formulas 1 to 5
R ₁ to R ₃ are independently straight or branched C ₁ to C ₄ alkoxy or hydroxy,
R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Phenyl; Phenoxy; Methylbenzenesulfonamido; Benzenesulfonamido; Nitrobenzenesulfonamido; Florobenzenesulfonamido; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl,
X is O or S,
If X is O, R ₁ is straight or branched C ₁ to C ₄ alkoxy and R ₄ and R ₅ are H, then at least one of R ₂ and R ₃ is hydroxy,
When X is O, R ₁ is hydroxy, R ₄ and R ₅ are H, then R ₃ is straight or branched C ₁ to C ₄ alkoxy,
Ra, Rb and Rc are independently straight or branched C ₁ to C ₄ alkyl. The compound of claim 4, wherein R ₄ of the compound represented by Formula 1 is amino;
A method for preparing a compound represented by Formula 1, further comprising the step of reacting a compound in which R ₄ of the compound represented by Formula 1 is nitro with sodium thiosulfate. delete The compound of claim 4, wherein R ₁ of the compound represented by Formula 1 is hydroxy,
Preparation of a compound represented by the formula (1) characterized in that it further comprises the step of reacting the compound represented by the formula (1) wherein R ₁ to R ₃ is a straight or branched C ₁ to C ₄ alkoxy Way. The compound of claim 4, wherein R ₁ and R ₃ of the compound represented by Formula 1 are hydroxy,
The compound represented by the formula (1) further comprises the step of dissolving a compound represented by the formula (1) wherein R ₁ to R ₃ is a straight or branched chain alkoxy of C ₁ to C _{4 in} an acid. Manufacturing method. The compound of claim 4, wherein R ₁ to R ₃ of the compound represented by Formula 1 are hydroxy,
The compound represented by the formula (1) further comprising the step of reacting a compound represented by the formula (1) wherein R ₁ to R ₃ is a straight or branched C ₁ to C ₄ alkoxy with tribromoborane Manufacturing method. The compound according to any one of claims 4, 5, and 7 to 9, wherein X of the compound represented by Formula 1 is S,
The method of preparing a compound represented by Chemical Formula 1, further comprising the step of reacting the compound represented by Chemical Formula 1 wherein X is O with Lawson's reagent. A composition for preventing or treating dementia comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
[Formula 1]

In Chemical Formula 1,
R ₁ to R ₃ are independently straight or branched C ₁ to C ₄ alkoxy or hydroxy,
R ₄ and R ₅ are independently H; Floro; Chloro; Bromo; Straight or branched C ₁ to C ₅ alkyl; Nitro; Amino; C ₁ to C ₃ dialkylamino; Straight or branched C ₁ to C ₈ alkoxy; Phenyl; Phenoxy; Methylbenzenesulfonamido; Benzenesulfonamido; Nitrobenzenesulfonamido; Florobenzenesulfonamido; Or SR ₇ , wherein R ₇ is straight or branched C ₁ to C ₅ alkyl,
X is O or S,
If X is O, R ₁ is hydroxy and R ₄ and R ₅ are H, then R ₃ is straight or branched C ₁ to C ₄ alkoxy.

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