KR101172153B1 - A composition for treating attention deficit/hyperactivity disorder - Google Patents

Abstract

The present invention relates to a composition for treating attention deficit hyperactivity disorder comprising a novel chromene compound. The composition of the present invention can be usefully used in the treatment of attention deficit hyperactivity disorder to suppress the impulse while improving overaction and attention deficit.

Description

A composition for treating attention deficit / hyperactivity disorder

The present invention relates to a composition for treating attention deficit hyperactivity disorder (ADHD).

Attention Deficit and Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children before and after school, with attention deficit, hyperactivity, and impulsivity being the main symptoms. This lack of attention and hyperactivity are accompanied by various psychosocial disorders, including children's learning disabilities, and have been reported to cause adolescent misconduct, deviant behavior, and drug abuse and crime in adulthood (YB Lee, JS). Shin, Korean journal of family social work, pp 129-157, 2000, GD Kewley, British Medical Journal, 23 , pp 1594-1596. 1998, LB Silver, Attention-deficit hyperactivity disorder, Washington, DC .: American Psychiatry Press, Inc. 1992).

Genetic factors that contribute to ADHD (RA Barkley.Attention deficit hyperactivity disorder: A handbook of diagnosis and treatment.New York: Guilford Press. 1990), biochemical factors seen as reactions to lead levels and fast foods in food additives (G . David, J. Neal, Abnormal Psychology . John Wilry & Sons. 1976), see opinion that there is a problem to select an appropriate stimulus delivered to the brain (yihyosin, research emotional learning disorders. 16), environmental factors, namely parents and children He also mentioned relationships with parents, social status of parents, smoking of mothers during pregnancy, and alcohol abuse, but there are still many discussions about the causes (H. Mang, H. Chung, The Journal of Elementary Education. 18 , pp 243-). 277, 2005). However, neurobiological factors are considered to be more important than social psychological factors. Accordingly, research on drug treatment and biological factors of the disease is being actively conducted. In particular, it is suggested that the biological factor is a non-uniform disease group caused by the abnormalities of the various brain regions responsible for high cognitive function rather than the development of a single nervous system (Y. Frank, SG Pavlakis, Pediatric Neurology . 25) . , pp278-287, 2001, Bung-Yeon Kim, Dong-Soo Lee, Soo-Chul Cho. Neuropsychiatric Medicine , 39 , pp412-423, 2000). Structural and functional brain imaging studies in children with ADHD up to date indicate that pathophysiology of ADHD is generally associated with dysfunction of the fronto-striatal tract and methylphenidate (MP). Drug effects are known to be associated with functional changes in the dopamine system in this region (MH Teicher, CM Anderson et al., Nat. Med. 6 , pp470-473, 2000, JB Schweitzer, DO Lee et al. , Neuropsychopharmacology 28 , pp967-973. 2003, EY Oh, I. Hwang et al., J. Korean Soc. Biol. Ther.Psychiatri . 9 , pp169-180, 2003).

The most commonly used drug for the treatment of ADHD is the central nervous system stimulant. Ritalin, methylphen, etc. containing methylphenidate is used in Korea. These drugs are known to have short-term effects on attention deficit, hyperactivity and impulse relief, but the long-term effects have not been validated (S. Kim, D. Ahn, Y. Lee, J. Korean Neuropsychiatr. Assoc. 4 , pp683-699, 1998).

Therefore, the inventors of the present invention, while studying to develop an effective therapeutic agent for the treatment of ADHD, synthesized new chromene compounds, and found that these compounds have an ADHD therapeutic effect and completed the present invention.

It is an object of the present invention to provide compositions which exhibit good ADHD therapeutic effects.

The present invention provides a composition for treating ADHD comprising a chromium derivative compound represented by the following Chemical Formula 1 and 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; Linear 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 hydroxy and R ₄ and R ₅ are H, then R ₃ is straight or branched C ₁ to C ₄ alkoxy.

In the composition of 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. Preferably R ₁ and R ₃ are hydroxy and R ₂ is methoxy and R ₄ and R ₅ may be independently H or phenoxy.

In the composition of the present invention, the chromate derivative compound represented by Formula 1 is preferably 5,7-dihydroxy-6-methoxy-2- (4-phenoxy-phenyl) -chromen-4-one Or 5,7-dihydroxy-6-methoxy-2- (3-phenoxy-phenyl) -chromen-4-one.

In the composition of the present invention, the pharmaceutically acceptable salt of the chromium derivative compound represented by Chemical Formula 1 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 the present invention, the chromium derivative compound represented by Chemical Formula 1 may be prepared by a method 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,

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), 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, a compound in which the OH group of the compound represented by Chemical Formula 4 is protected by the benzyl group is reacted with acetic acid and hydrochloric acid. By replacing the following benzyl group with H, the compound represented by the formula (4) can be prepared.

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 dimethyl 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.

In the composition of the present invention, a compound in which R ₁ 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.

In the composition of the present invention, a compound in which 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.

In the composition of the present invention, a compound in which 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.

In the composition of the present invention, the compound in which X is S of the chromate derivative compound represented by Formula 1 may be prepared by reacting the chromate derivative 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 Chemical Formula 7 may be prepared by reacting the compound represented by 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 present invention provides a method for treating ADHD by administering a composition comprising an effective amount of a chromium derivative compound represented by Formula 1 to a mammal including a human in need of ADHD treatment.

The present invention provides a use of a composition comprising a chromene derivative compound represented by Chemical Formula 1 in the preparation of a pharmaceutical preparation for treating ADHD.

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 or 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 or lubricants additionally. 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), and the dosage is based on the weight, age, sex, health condition, diet, time of administration, The range varies depending on 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 composition of the present invention has a therapeutic effect on ADHD by inhibiting hyperactivity, attention deficit and impulse. Therefore, it can solve psychosocial disorders including children's learning disabilities, and prevent adolescent misconduct, deviant behavior, and adult substance abuse and crime in adulthood.

1 is a diagram showing the effect of inhibiting dopamine transporter activity of the composition according to the present invention.
2 and 3 is a view showing the effect of improving the excess behavior of the composition according to the present invention.
4 and 5 is a view showing the attention deficit improvement effect of the composition according to the present invention.
6 and 7 is a view showing the impulse inhibiting effect of the composition according to the present invention.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

In addition, the reagents and solvents mentioned below are purchased from Sigma-Aldrich Korea, Alfa Aesar, Tokyo Chemical incorporation, unless otherwise specified, and the ¹ H-NMR data is measured by Bruker's FT-NMR 300 MHz machine. The melting point (mp) is measured by Fisher's IA-900.

Example 1 Preparation of 5,7-Dihydroxy-6-methoxy-2- (3-phenoxy-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 3-phenoxybenzaldehyde 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 obtain 1- (6-hydroxy-2,3,4-trimethoxyphenyl) -3- (3-phenoxy-phenyl) -2-propene 1-one was obtained.

After dissolving 6.57 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 tiosulfate 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- (3-phenoxy-phenyl) -chromen-4-one.

A solution of 2.5 g of 5,6,7-trimethoxy-2- (3-phenoxy-phenyl) -chromen-4-one mixed with acetic acid and 48% by weight aqueous bromic acid solution in a volume ratio of 2: 1 After dissolving in 52 mL, 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- (3-phenoxy-phenyl) -chromen-4-one. .

mp = 162 ~ 164 ° C

¹ H-NMR (300 MHz, DMSO): δ 12.47 (s, 1H), 8.80 (s, 1H), 7.87-7.90 (d, 1H, J = 7.7 Hz), 7.81 (s, 1H), 7.55-7.61 (t, 1H, J = 8.0 Hz), 7.41-7.47 (t, 2H, J = 7.9 Hz), 7.17-7.21 (m, 2H), 7.07-7.09 (d, 2H, J = 7.9 Hz), 7.01 ( s, 1H), 6.96 (s, 1H), 3.92 (s, 3H)

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

5,7-dihydroxy-6-methoxy-2- (3-phenoxy-phenyl) -chromen-4- of Example 1, except that 4-phenoxybenzaldehyde was used instead of 3-phenoxybenzaldehyde In substantially the same manner as the one, the desired compound 5,7-dihydroxy-6-methoxy-2- (4-phenoxy-phenyl) -chromen-4-one was obtained.

mp = 178-180 ° C

¹ H-NMR (300 MHz, DMSO): δ 12.52 (s, 1 H), 7.93-7.97 (ddd, 2H, J = 8.6 Hz, 1.9 Hz), 7.72-7.75 (ddd, 2H, J = 8.6 Hz, 1.9 Hz), 7.63-7.66 (dd, 2H, J = 7.0 Hz, 1.5 Hz), 7.46-7.52 (ddd, 2H, J = 7.0 Hz, 1.6 Hz, 1.3 Hz), 7.39-7.44 (ddd, 1H, J = 7.1 Hz), 6.71 (s, 1 H), 6.62 (s, 1 H), 4.01 (s, 3 H).

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 the treatment of attention deficit hyperactivity disorder

1. Confirmation of inhibitory effect of dopamine transporter activity

1) Preparation of Buffer

5 mM Tris, 7.5 mM HEPES, 120 mM NaCl, 5.4 mM KCl, 1.2 mM CaCl ₂ , 1.2 mM MgSO ₄ , 1 mM Ascorbic Acid, 5 mM Glucose, and 20 nM Radiolabeled ³ H-dopamine A buffer of pH 7.1 was prepared.

2) Determination of Dopamine Transporter Activity

Chinese hamster ovary cells (Chinese hamster ovary, CHO) were prepared. The cells were incubated for 5 minutes in the buffer prepared in 1). After washing three times with 1 mL of the buffer and treated with 0.5 mL of 1% by weight of SDS, the amount of radiation was measured by a liquid scintillation counter (LSC).

The compound obtained in Example 2 was dissolved in dimethylsulfoxide, and the compound obtained in Example 2 was included at concentrations of 10 ⁻⁸ M, 10 ⁻⁷ M, 10 ^−6.53 M, 10 ⁻⁶ M, and 10 ^−5.53 M After preparing the medium, the Chinese hamster ovary cells (Chinese hamster ovary, CHO) were incubated for 20 minutes in each medium. Thereafter, the cells were further incubated for 5 minutes in the buffer prepared in 1). The cells were washed three times with 1 mL of the buffer and treated with 0.5 mL of 1% by weight of SDS, and then the amount of radiation was measured with a liquid scintillation counter (LSC). The ratio of the radiation amount of the cell line cultured in the medium containing the compound of Example 2 to the radiation amount of the cells cultured only in the buffer is shown in Figure 1 in terms of%.

Instead of the compound of Example 2, methylphenidate or atomoxetine was added in a medium having a concentration of 10 ⁻⁸ M, 10 ⁻⁷ M, 10 ^−6.53 M, 10 ⁻⁶ M, and 10 ^−5.53 M After preparing, the Chinese hamster ovary cells (Chinese hamster ovary, CHO) in each medium was incubated for 20 minutes. Thereafter, the cells were further incubated for 5 minutes in the buffer prepared in 1). The cells were washed three times with 1 mL of the buffer and treated with 0.5 mL of 1% by weight of SDS, and then the amount of radiation was measured with a liquid scintillation counter (LSC). The ratio of the radiation amount of the cells cultured in the medium containing methylphenidate or atomoxetine to the radiation amount of the cells cultured only in the buffer is shown in FIG.

As can be seen in Figure 1, cells cultured in a medium containing the compound of Example 2 has a higher proportion of radiolabeled dopamine than cells cultured in a medium containing the same concentration of methylphenidate or atomoxetine. I wrote it down. Therefore, it was found that the compound of Example 2 more effectively inhibits the activity of the dopamine transporter than methylphenidate or atomoxetine, which is a conventional drug.

2. Experiment to confirm the effect of improving overaction

In order to confirm the effect of the improvement of the excess behavior of the compounds of the present invention, the general motor activity was measured using the ADHD animal model, Spontaneously Hypertensive Rat (SHR).

1) Preparation of experimental animals

The experimental animals were purchased from Hallim Experiment Animal Co., Ltd. (Hwaseong, Korea) and ADHD animal model 4 weeks old male congenital hypertension (SHR) and normal animals 4 weeks old male male Wistar Kyoto Rat (WKY). It was used for experiment after breeding for 7 days under the environment of temperature of about 23 ± 2 ℃, humidity of about 55 ± 10% and contrast cycle of 12 hours while freely ingesting water and feed.

2) Test substance administration

Congenital hypertension and normal animals were divided into six groups, respectively, and the compound of Example 1, the compound of Example 2, or methylphenidate (Hwanin Pharmaceutical Co., Ltd., Anseong, Korea) were administered at the doses shown in Table 1 below. One group (non-drug group) administered nothing. Ten animals were used for each experimental group.

[Table 1]

For each group, the compound of Example 1, the compound of Example 2 and methylphenidate were administered orally once 30 minutes before the behavioral observation. The compound of Example 1 and the compound of Example 2 were suspended and used in 10 wt% of Tween 80, and methylphenidate was dissolved in water.

3) Observation of general motor activity

The animals used in the experiment the day before the experiment were subjected to adaptive training at least once for 5 minutes for the test box to be used in the experiment.

On the day of the experiment, the test substance was administered as in 2), and after 30 minutes had elapsed from the test substance administration, the test animal was placed in the center of the test box, and the moving distance and the total travel time of the test animal were measured for about 20 minutes. The behavior of the test animals was recorded and monitored using a EthoVision system (Noldus IT b.v., The Netherlands), which is a computerized device, and then the distance and total travel time of the test animals were computerized. The results for the group injected with the compound of Example 1 is shown in Figure 2, the results for the group injected with the compound of Example 2 is shown in Figure 3.

2 and 3, MP denotes a methylphenidate administration group, SHR means congenital hypertension animals, which are ADHD animal models, and WKY means normal animals. 2 and 3, the longer the travel time and the longer the distance, the greater the general exercise activity, that is, the greater the excess action.

As can be seen in Figures 2 and 3, the group administered with the compounds of Examples 1 and 2 in congenital hypertension animals had less travel distance and travel time compared to the drug non-administered group and the methylphenidate administration group. From this it can be seen that the compounds of Examples 1 and 2 can improve the hyperactivity caused by ADHD.

3. Experiment to confirm the effect of improving attention deficit

The Y-maze test was performed using the ADHD animal model, spontaneously Hypertensive Rat (SHR), to confirm the effect of improving attention deficit of the compounds of the present invention.

1) Administration of test animal and test substance

Experimental animal preparation and test substance administration were carried out substantially the same as the experiment to confirm the effect of improving hyperactivity.

2) measuring attention deficit

The animals used in the experiment the day before the test were subjected to adaptive training at least once for 5 minutes for the Y-maze to be used in the experiment. The Y-maze has three branches, each branch is 42 cm long, 3 cm wide, 12 cm high, and the angle of the three arms is 120 degrees and is made of black polyvinyl resin.

On the day of the experiment, the test animals were administered to each of the groups and after 30 minutes from the administration of the test materials, the test animals were placed in one of three Y-mazes. Branches containing the experimental animals were recorded while allowing the experimental animals to move freely for about 8 minutes. At this time, only the case where the tail was completely entered was recorded as a branch containing the experimental animal.

One point was awarded for three different branches in turn (actual alternation). The alteration behavior was defined as the case that entered three branches in turn and converted to% by the following equation.

% Change behavior = 100 × actual alternation / maximum alternation

(Maximum change: Total number of admissions-2)

The results for the group injected with the compound of Example 1 is shown in Figure 4, the results for the group injected with the compound of Example 2 is shown in Figure 5. 4 and 5, MP represents a methylphenidate administration group, SHR means a congenital hypertension animal, which is an ADHD animal model, and WKY means a normal animal. 4 and 5, the smaller the change behavioral power, the more severe the attention deficit.

Looking at Figures 4 and 5, the group of the compound of Example 1 and Example 2 was found to be higher than the non-drug group or MP administration group. That is, it can be seen that the compounds of Examples and Example 2 may improve attention deficit.

4. Impulse Inhibitory Effect Confirmation Experiment

1) Administration of test animal and test substance

Experimental animal preparation and test substance administration were carried out substantially the same as the experiment to confirm the effect of improving hyperactivity.

2) Test device preparation

An impulse measuring device was prepared to measure impulsiveness. The impulsivity measuring device is sequentially divided into a first space, a second space, and a third space. The first space corresponds to a safe area, the second space corresponds to an intermediate obstacle area, and the third space corresponds to a water supply area. In the impulsivity measuring device, the third space may be reached from the first space through the second space, and thus water may be consumed in the water supply region of the third space only through the intermediate obstacle area, which is the second space.

The intermediate obstacle area, which is the second space, is divided into an electric region in which electricity flows and a radio region in which no electricity flows, and the normal drinking water is placed in a water supply region of a third space connected to the electric region, Salt water was placed in the water supply region of the connected third space.

3) impulse measurement

The animals were subjected to adaptive training for 30 minutes on the impulse measuring device three days before the experiment.

The animals were administered with a 1 mL / 100 g dose of 5 wt% aqueous NaCl solution on the day of the experiment without watering for 36 hours before the experiment. After 10 minutes, the test substance was administered to each of the groups, and 30 minutes after the test substance was administered, the test animal was placed in a safety area, which is the first space of the impulse measuring device, and the intermediate disorder was the second space for 1 hour. The number of area passages was measured.

The results for the group injected with the compound of Example 1 is shown in Figure 6, the results for the group injected with the compound of Example 2 is shown in Figure 7. 6 and 7, MP represents methylphenidate administration group, SHR means congenital hypertensive animal model of ADHD animal, and WKY means normal animal. 6 and 7 shows that the impulse is stronger as the number of times of passing through the intermediate obstacle region, which is the second space, is higher.

As can be seen in Figures 6 and 7, the group administered with the compounds of Examples 1 and 2 in the congenital hypertension animals had a smaller number of times of passing through the intermediate impaired region of the second space than the non-drug group. That is, it can be seen that the compounds of Examples 1 and 2 can suppress the impulse caused by ADHD.

Claims (11)

A pharmaceutical composition for treating attention deficit hyperactivity disorder comprising a compound represented by the following 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; Substituted or unsubstituted phenyl; Or substituted or unsubstituted phenoxy, wherein at least one of R ₄ and R ₅ is substituted or unsubstituted phenyl; Or substituted or unsubstituted phenoxy,
X is O. The method of claim 1,
Wherein R ₁ and R ₃ is hydroxy and R ₂ is methoxy, characterized in that attention deficit hyperactivity disorder treatment pharmaceutical composition. The method of claim 1,
R ₁ to R ₃ are independently methoxy or hydroxy,
R ₄ and R ₅ are independently H; Phenyl; Or phenoxy, wherein at least one of R ₄ and R ₅ is phenyl or phenoxy for treating attention deficit hyperactivity disorder. The compound of claim 1, wherein
5,7-dihydroxy-6-methoxy-2- (4-phenoxy-phenyl) -chromen-4-one, or
5,7-dihydroxy-6-methoxy-2- (3-phenoxy-phenyl) -chromen-4-one pharmaceutical composition for the treatment of attention deficit hyperactivity disorder characterized in that. The compound of claim 1, wherein
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;
b) 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 Chemical Formula 5; And
c) A pharmaceutical composition for treating attention deficit hyperactivity disorder, which is prepared by a method comprising the step of dissolving a compound represented by the formula (5) in an acid and heating.
[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; Substituted or unsubstituted phenyl; Or substituted or unsubstituted phenoxy, wherein at least one of R ₄ and R ₅ is substituted or unsubstituted phenyl; Or substituted or unsubstituted phenoxy,
X is O,
Ra, Rb and Rc are independently straight or branched C ₁ to C ₄ alkyl. delete delete delete delete delete delete

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