KR20200137164A - 2.6-diarylbenzo[d]oxaoles as MAO-B inhibitors and pharmaceutical composition comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a 2,6-diarylbenzoxazole derivative for inhibiting MAO-B represented by structural formula 1 and a pharmaceutical composition for inhibiting MAO-B comprising the same as an active component. Accordingly, the 2,6-diarylbenzoxazole derivative for inhibiting MAO-B activity and the pharmaceutical composition for inhibiting MAO-B comprising the same as the active component of the present invention are reversible and selectively acting on MAO-B to inhibit MAO-B, thereby being able to exhibit pharmaceutical activity in metabolic diseases such as obesity as well as degenerative brain diseases such as depression, Alzheimer′s disease, and Parkinson′s disease.

Description

2,6-diarylbenzooxazole derivatives for inhibiting MAO-B and pharmaceutical compositions for inhibiting MAO-B containing the same as an active ingredient{2.6-diarylbenzo[d]oxaoles as MAO-B inhibitors and pharmaceutical composition comprising the same as an active ingredient}

The present invention relates to a 2,6-diarylbenzoxazole derivative for inhibiting MAO-B and a pharmaceutical composition for inhibiting MAO-B comprising the same as an active ingredient, and more particularly, to a central nervous system by acting as an MAO-B inhibitor. It relates to a 2,6-diarylbenzoxazole derivative showing pharmaceutical activity in diseases and metabolic diseases, and a pharmaceutical composition for inhibiting MAO-B comprising the same as an active ingredient.

Monoamine oxidase (MAO) is an enzyme containing flavin that reacts oxidative deamination of neurotransmitters such as dopamine, serotonin, adrenaline, and noradrenaline, and non-bioactive amines. There are two types of MAO, MAO-A and MAO-B, which are expressed from other genes.

MAO-A shows a higher binding affinity to serotonin, adrenaline, and noradrenaline, and MAO-B makes deamination reactions well for phenylethylamine and tyramine. In addition, dopamine is oxidized by both MAO-A and MAO-B. MAO-B is widely distributed in several organs including the brain, and the activity of MAO-B has been investigated to increase with age, and it has been reported that the activity is particularly high in the brain of Alzheimer's disease patients. In addition, it was found that the expression was high in reactive astrocytes around senile plaques. Oxidative deamination of primary amines by MAO produces by-products such as ammonia, aldehydes, and hydrogen peroxide, which are known to be toxic, so that if MAO-B is selectively inhibited, it will be possible to cure Alzheimer's disease and Parkinson's disease. The logic was established. With age, degenerative diseases caused by Alzheimer's disease and Parkinson's disease are known to be due to oxidative stress caused by hydrogen peroxide due to increased MAO activity, and MAO-B inhibitors reduce oxygen radical formation and are useful monoamines in the brain. It may have an effect of increasing the amount of.

In addition, in brain diseases including Alzheimer's disease and brain injury, MAO-B promotes the metabolic process of putrescine in reactive astrocytes, resulting in the production of excess GABA. GABA, as a representative inhibitory neurotransmitter, is known to be secreted from reactive astrocytes, inhibiting neuronal activity and causing memory impairment in Alzheimer's disease. Therefore, MAO-B inhibitors act as inhibitors of GABA production by astrocytes and have the effect of restoring nerve signal transduction and brain function.

In the case of irreversible MAO inhibitors such as selegiline, a serious side effect called hypertensive crisis is called hypertensive crisis due to tyramine, the substrate of MAO-B in food, if you are taking a prescription and taking a lot of foods such as cheese. In contrast, reversible and selective MAO inhibitors are known to have fewer side effects.

Therefore, it is reversible and selective to MAO-B, has a good pharmacokinetic profile, has good ADME (absorption, distribution, metabolism, and excretion), and is effective not only for degenerative brain diseases such as depression, Alzheimer's disease, and Parkinson's disease, but also metabolic diseases such as obesity. There is still a need for finding MAO-B inhibitors.

Korean Patent Registration No. 10-0561251

An object of the present invention is to solve the above problems, by inhibiting MAO-B activity by acting reversibly and selectively on MAO-B, pharmaceuticals for metabolic diseases such as obesity as well as degenerative brain diseases such as depression, Alzheimer's disease and Parkinson's disease It is to provide a 2,6-diarylbenzoxazole derivative showing appropriate activity and a pharmaceutical composition for inhibiting MAO-B activity comprising the same as an active ingredient.

According to one aspect of the invention,

A 2,6-diarylbenzooxazole derivative for inhibiting MAO-B represented by the following structural formula 1 is provided.

[Structural Formula 1]

In structural formula 1,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Structural Formula 1 may be represented by the following Structural Formula 2 or Structural Formula 3.

[Structural Formula 2]

[Structural Formula 3]

In structural formulas 1 and 2,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Preferably, in the structural formulas 1 and 2,

Any one of R ¹ and R ² may be a hydrogen atom, and the other may be a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

More preferably, in the structural formulas 1 and 2,

Any one of R ¹ and R ² may be a hydrogen atom, and the other may be a fluoro group, a chloro group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C4 alkoxy group.

Structural Formula 1 may be represented by the following Structural Formula 4 or Structural Formula 5.

[Structural Formula 4]

[Structural Formula 5]

In structural formulas 4 and 5,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Preferably, in the structural formulas 4 and 5,

R ¹ is a hydroxy group,

R ² may be a halogen group.

More preferably, in the structural formulas 4 and 5,

R ¹ is a hydroxy group,

R ² may be a fluoro group or a chloro group.

Most preferably, the 2,6-diarylbenzooxazole derivative represented by the structural formula 1 may be any one selected from the following compounds 1 to 18.

According to another aspect of the present invention,

A method of preparing a 2,6-diarylbenzoxazole derivative for inhibiting MAO-B represented by the following Scheme 1 is provided.

[Scheme 1]

In Scheme 1,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

은 하기 반응식 2에 따라 제조될 수 있다.The above in Scheme 1

Can be prepared according to Scheme 2 below.

[Scheme 2]

In Scheme 2,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

According to another aspect of the present invention,

There is provided a pharmaceutical composition for inhibiting MAO-B comprising a 2,6-diarylbenzooxazole derivative represented by the following structural formula 1 or a pharmaceutically acceptable salt thereof.

[Structural Formula 1]

In structural formula 1,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Structural Formula 1 may be represented by the following Structural Formula 2 or Structural Formula 3.

[Structural Formula 2]

[Structural Formula 3]

In structural formulas 1 and 2,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Preferably, in the structural formulas 1 and 2,

Any one of R ¹ and R ² may be a hydrogen atom, and the other may be a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

More preferably, in the structural formulas 1 and 2,

Any one of R ¹ and R ² may be a hydrogen atom, and the other may be a fluoro group, a chloro group, a hydroxy group, an acetyl group, or a C1 to C4 alkoxy group.

According to another aspect of the present invention,

The structural formula 1 is provided with a pharmaceutical composition for inhibiting MAO-B, characterized in that represented by the following structural formula 4 or structural formula 5.

[Structural Formula 4]

[Structural Formula 5]

In structural formulas 4 and 5,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Preferably, in the structural formulas 4 and 5,

R ¹ is a hydroxy group,

R ² may be a halogen group.

More preferably, in the structural formulas 4 and 5,

R ¹ is a hydroxy group,

R ² may be a fluoro group or a chloro group.

Most preferably, the 2,6-diarylbenzooxazole derivative represented by the structural formula 1 may be any one selected from the following compounds 1 to 18.

The pharmaceutical composition for inhibiting MAO-B may exhibit reversible and selective activity to MAO-B.

The pharmaceutical composition for inhibiting MAO-B may be used for preventing or treating degenerative brain diseases or metabolic diseases.

The degenerative brain disease or metabolic disease may be any one selected from depression, Alzheimer's disease, Parkinson's disease, and obesity.

The 2,6-diarylbenzoxazole derivative for inhibiting MAO-B activity of the present invention and the pharmaceutical composition for inhibiting MAO-B activity comprising the same as an active ingredient reversibly and selectively act on MAO-B to increase MAO-B activity. By inhibiting, it can exhibit pharmacological activity in metabolic diseases such as obesity as well as degenerative brain diseases such as depression, Alzheimer's disease and Parkinson's disease.

1 shows the results of an MPP+ induced neurocytotoxicity experiment according to Experimental Example 3.

The present invention is intended to illustrate specific embodiments and to be described in detail in the detailed description, since various transformations may be applied and various embodiments may be provided. However, this is not intended to limit the present invention to a specific embodiment, it is to be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.

The "substituted" means that at least one hydrogen atom is deuterium, a C1 to C30 alkyl group, a C3 to C30 cycloalkyl group, a C2 to C30 heterocycloalkyl group, a C1 to C30 halogenated alkyl group, C6 to C30 aryl group, C1 to C30 heteroaryl group, C1 to C30 alkoxy group, C3 to C30 cycloalkoxy group, C1 to C30 heterocycloalkoxy group, C2 to C30 alkenyl group, C2 to C30 alkynyl group, C6 to C30 aryloxy group, C1 to C30 heteroaryloxy group, silyloxy Group (-OSiH ₃ ), -OSiR ¹ H ₂ (R ¹ is a C1 to C30 alkyl group or C6 to C30 aryl group), -OSiR ¹ R ² H (R ¹ and R ² are each independently a C1 to C30 alkyl group or C6 To C30 aryl group), -OSiR ¹ R ² R ³ , (R ¹ , R ² , and R ³ are each independently C1 to C30 alkyl group or C6 to C30 aryl group), C1 to C30 acyl group, C2 to C30 acyl Oxy group, C2 to C30 heteroaryloxy group, C1 to C30 sulfonyl group, C1 to C30 alkylthiol group, C3 to C30 cycloalkylthiol group, C1 to C30 heterocycloalkylthiol group, C6 to C30 arylthiol group, C1 to C30 heteroarylthiol group, C1 to C30 phosphate amide group, silyl group (SiR ¹ R ² R ³ ₎ (R ¹ , R ² , and R ³ are each independently a hydrogen atom, C1 to C30 alkyl group or C6 to C30 aryl group ), an amine group (-NRR') (wherein R and R'are each independently a hydrogen atom, a substituent selected from the group consisting of a C1 to C30 alkyl group, and a C6 to C30 aryl group), a carboxyl group, a halogen group, It means substituted with a substituent selected from the group consisting of a cyano group, a nitro group, an azo group, and a hydroxy group.

In addition, two adjacent substituents among the substituents may be fused to form a saturated or unsaturated ring.

In addition, the range of carbon number of the alkyl group or aryl group in the "substituted or unsubstituted C1 to C30 alkyl group" or "substituted or unsubstituted C6 to C30 aryl group" etc. is unsubstituted without considering the portion where the substituent is substituted It refers to the total number of carbon atoms constituting the alkyl moiety or the aryl moiety when viewed as being formed. For example, a phenyl group in which a butyl group is substituted in the para position corresponds to an aryl group having 6 carbon atoms substituted with a butyl group having 4 carbon atoms.

In addition, the range of carbon number of the fused aryl group in the "substituted or unsubstituted C6 to C30 fused aryl group", etc., is fused and additionally formed when viewed as unsubstituted without considering the substituted portion of the substituent. It means the total number of carbon atoms constituting the aryl moiety.

In the present specification, unless otherwise defined, "hetero" means that one functional group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S and P, and the rest are carbon.

In the present specification, unless otherwise defined, "a combination thereof" means that two or more substituents are bonded with a linking group or two or more substituents are condensed and bonded.

In the present specification, "hydrogen" refers to singlet hydrogen, dihydrogen, or tritium unless otherwise defined.

In the present specification, "alkyl (alkyl) group" refers to an aliphatic hydrocarbon group unless otherwise defined.

The alkyl group may be a "saturated alkyl group" that does not contain any double bonds or triple bonds.

The alkyl group may be an "unsaturated alkyl group" including at least one double bond or triple bond.

The alkyl group, whether saturated or unsaturated, can be branched, straight-chain or cyclic.

The alkyl group may be a C1 to C30 alkyl group. More specifically, it may be a C1 to C20 alkyl group, a C1 to C10 alkyl group, or a C1 to C6 alkyl group.

For example, a C1 to C4 alkyl group has 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. It indicates that it is selected from the group consisting of.

For specific examples, the alkyl group is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, ethenyl group, propenyl group, butenyl group, cyclopropyl group, cyclo It means a butyl group, a cyclopentyl group, a cyclohexyl group, etc.

“Amine group” includes an amino group, an arylamine group, an alkylamine group, an arylalkylamine group, or an alkylarylamine group, and may be represented by -NRR', wherein R and R'are each independently a hydrogen atom , A C1 to C30 alkyl group, and a C6 to C30 aryl group.

“Cycloalkyl groups” include monocyclic or fused ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) functional groups.

"Heterocycloalkyl group" means that the cycloalkyl group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S, and P, and the remainder is carbon. When the heterocycloalkyl group is a fused ring, at least one ring among the fused rings may contain 1 to 4 hetero atoms.

"Aromatic group" refers to a functional group in which all elements of a functional group in the form of a ring have a p-orbital, and these p-orbitals form a conjugation. Specific examples include an aryl group and a heteroaryl group.

“Aryl groups” include monocyclic or fused ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) functional groups.

"Heteroaryl group" means that the aryl group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S and P, and the remainder is carbon. When the heteroaryl group is a fused ring, at least one ring among the fused rings may contain 1 to 4 hetero atoms.

In the aryl group and the heteroaryl group, the number of ring atoms is the sum of the number of carbon atoms and the number of non-carbon atoms.

When used in combination such as "alkylaryl group" or "arylalkyl group", the terms of each of the alkyl and aryl mentioned above have the meanings and contents indicated above.

The term "arylalkyl group" refers to an aryl substituted alkyl radical such as benzyl and is included in the alkyl group.

The term "alkylaryl group" refers to an alkyl substituted aryl radical and is included in an aryl group.

Meanwhile, in the present specification, the term "included as an active ingredient" means including an amount sufficient to achieve the efficacy or activity of a 2,6-diarylbenzoxazole derivative or a pharmaceutically acceptable salt thereof. For example, the 2,6-diarylbenzoxazole derivative or a pharmaceutically acceptable salt thereof may be used in a concentration of 10 to 1500 μg/ml, preferably 100 to 1000 μg/ml, but the scope of the present invention Is not limited thereto, and the upper limit of the quantity of the 2,6-diarylbenzooxazole derivative contained in the pharmaceutical composition of the present invention may be selected and implemented within an appropriate range by a person skilled in the art.

Hereinafter, the 2,6-diarylbenzooxazole derivative for inhibiting MAO-B of the present invention will be described.

The 2,6-diarylbenzooxazole derivative for inhibiting MAO-B of the present invention is represented by the following structural formula 1.

[Structural Formula 1]

In structural formula 1,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Preferably, Structural Formula 1 may be represented by the following Structural Formula 2 or Structural Formula 3.

[Structural Formula 2]

[Structural Formula 3]

In structural formulas 1 and 2,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

More preferably, in the structural formulas 1 and 2, any one of R ¹ and R ² is a hydrogen atom, and the other is a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. I can.

Even more preferably, any one of R ¹ and R ² may be a hydrogen atom, and the other may be a fluoro group, a chloro group, a hydroxy group, an acetyl group, or a C1 to C4 alkoxy group.

As another embodiment, Structural Formula 1 may be represented by the following Structural Formula 4 or Structural Formula 5.

[Structural Formula 4]

[Structural Formula 5]

In structural formulas 4 and 5,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Preferably, in Structural Formulas 4 and 5, R ¹ may be a hydroxy group, and R ² may be a halogen group.

More preferably, in the above structural formulas 4 and 5, R ¹ may be a hydroxy group, and R ² may be a fluoro group or a chloro group.

Most preferably, the 2,6-diarylbenzoxazole derivative represented by Structural Formula 1 may be any one selected from Compounds 1 to 18 below.

Hereinafter, a method for preparing a 2,6-diarylbenzoxazole derivative for inhibiting MAO-B represented by the following Scheme 1 of the present invention will be described.

[Scheme 1]

In Scheme 1,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Here, the final product, the 2,6-diarylbenzoxazole derivative, may be represented by Structural Formula 1 as described for the 2,6-diarylbenzoxazole derivative for MAO-B inhibition, and Structural Formulas 2 to 5 described above. It may be a compound represented by any one of them, and specific details will be referred to the above description.

은 하기 반응식 2에 따라 제조될 수 있다.The above in Scheme 1

Can be prepared according to Scheme 2 below.

[Scheme 2]

In Scheme 2,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

Hereinafter, the pharmaceutical composition for inhibiting MAO-B of the present invention will be described.

The pharmaceutical composition for inhibiting MAO-B of the present invention comprises a 2,6-diarylbenzoxazole derivative represented by the following structural formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Structural Formula 1]

In structural formula 1,

R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group.

The description of the 2,6-diarylbenzoxazole derivative represented by Structural Formula 1 is the same as described above, so the detailed information will be referred to that part.

The pharmaceutical composition for inhibiting MAO-B is characterized in that it exhibits reversible and selective activity to MAO-B.

The pharmaceutical composition for inhibiting MAO-B may be used for preventing or treating degenerative brain diseases or metabolic diseases.

The degenerative brain disease or metabolic disease may be any one selected from depression, Alzheimer's disease, Parkinson's disease, and obesity.

The pharmaceutical composition of the present invention may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant includes excipients, disintegrants, sweeteners, binders, coating agents, expanding agents, lubricants, lubricants. Agents or flavoring agents can be used.

For administration, the pharmaceutical composition may include one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients, and may be preferably formulated into a pharmaceutical composition.

The formulation form of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops, or injectable solutions. For example, for formulation in the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders are, but are not limited to, natural sugars such as starch, gelatin, glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, lacquercanth or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

As acceptable pharmaceutical carriers for compositions formulated as liquid solutions, sterilization and biocompatible, saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added as necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.

The pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., preferably oral administration.

A suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, mode of administration, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate and response sensitivity of the patient, and is usually As a result, a skilled physician can easily determine and prescribe an effective dosage for the desired treatment or prevention. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-10 g/kg.

The pharmaceutical composition of the present invention may be prepared in a unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient, or may be prepared by placing it in a multi-dose container. At this time, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or a stabilizer.

[ Example ]

Manufacturing example 1: 1 4- Formylphenylacetate Produce

In the reaction vessel, 4-hydroxybenzaldehyde (2 g, 16.4 mmol) was dissolved in ethyl acetate, triethylamine (2.28 mL, 16.4 mmol) was added at 0°C, and acetyl chloride (1.17 mL, 16.4 mmol) was added. It was stirred at room temperature for 5 hours. After completion of the reaction, the mixed solution was filtered and the filtrate was concentrated under reduced pressure to obtain 1.94 g (11.8 mmol, 72%) of the title compound.

¹ H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.75 (dt, 1H, J =1.2/7.6), 7.62 (t, 1H, J =1.8Hz), 7.55 (t, 1H, J = 7.8Hz), 7.38-7.35 (m, 1H), 2.33 (s, 3H).

Manufacturing example 2: 4-(6- Bromobenzo[d]oxazole -2 days) Phenylacetate

In a reaction vessel, 4-formylphenylacetate (0.670 g, 4.08 mmol) and 5-bromo-2-aminophenol (0.77 g, 4.08 mmol) were dissolved in methanol, stirred at 65° C. for 12 hours, condensed under reduced pressure, and concentrated. Was dissolved in dichloromethane and DDQ (0.93 g, 4.07 mmol) was added. After stirring at room temperature for 30 minutes, dichloromethane was added, washed with supersaturated sodium carbonate, and extracted. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and condensed under reduced pressure. The concentrate was separated by silica gel column chromatography (Hexane: Ethyl acetate = 4: 1) to obtain 0.77 g (2.32 mmol, 55%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (dt, 1H, J =1.2/7.7 Hz), 7.97 (t, 1H, J =1.8 Hz), 7.75 (d, J =1.6 Hz), 7.54 (t , 1H, J =8 Hz), 7.49 (dd, 1H, J =4/8 Hz), 7.30-7.26 (m, 1H), 2.35 (s, 3H).

Example 1: compound 1 synthesis

In the reaction vessel, 6-bromo-3-(3-fluorophenyl)benzo[d]oxazole (0.20 g, 0.68 mmol), (4-hydroxyphenyl) boronic acid (0.11 g, 0.82 mmol), Pd (PPh ₃ ) ₄ (0.08 g, 0.007 mmol) is dissolved in 10 mL of DMSO. A solution prepared by dissolving Na ₂ CO ₃ (0.11 g, 1.03 mmol) in a small amount of water was added to the reaction vessel, followed by stirring at 90° C. for 12 hours. After completion of the reaction, the mixed solution was filtered through Celite, and distilled water was added to the filtrate to extract ethyl acetate. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and condensed under reduced pressure. The concentrate was separated by silica gel column chromatography (Hexane: Ethyl acetate = 3: 2) to obtain 0.17 g of the target compound, 4-(2-(4-fluorophenyl)benzo[d]oxazol-6-yl)phenol. (0.56 mmol, 81%) was obtained.

¹ H NMR (400 MHz, DMSO) δ 9.67 (Broad s, 1H), 8.28-8.25 (m, 2H), 7.98 (d, 1H, J =1.2 Hz), 7.81 (d, 1H, J = 8.4 Hz) , 7.65 (dd, 1H, J = 1.6 /8.4Hz), 7.60 (dd, 2H, J = 2 /6.4 Hz), 7.50-7.46 (m, 2H), 6.89 (dd, 2H, J = 1.6 /6.4Hz ).

Example 2: compound 2 synthesis

The final compound 4-(2-(4-chlorophenyl)benzo[d]oxazol-6-yl)phenol (120 mg, 0.37 mmol, 59%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (dd, 2H, J =2/6.8), 7.78 (d, 1H, J =8.4 Hz), 7.72 (d, 1H, J =1.2Hz), 7.57- 7.51 (m, 5H), 6.95 (dd, 2H, J =2/6.8 Hz)

Example 3: Synthesis of compound 3

The final compound 4-(2-(3-fluorophenyl)benzo[d]oxazol-6-yl)phenol (57 mg, 0.19 mmol, 38%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 8.07 (d, 1H, J =8 Hz), 8.01 (s,1H), 7.96 (d, 1H, J = 9.6 Hz), 7.85 ( d, 1H, J =8.4 Hz), 7.73-7.67 (m, 2H), 7.62 (d, 2H, J = 8.4Hz), 7.54-7.52 (m, 1H), 6.90 (d, 2H, J =8.4Hz) ).

Example 4: Synthesis of compound 4

The final compound 4-(2-(3-chlorophenyl)benzo[d]oxazol-6-yl)phenol (150 mg, 0.46 mmol, 29%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.68 (Broad s, 1H), 8.18 (d, 2H, J =7.6 Hz), 8.01 (d,1H, J =1.2Hz), 7.86 (d, 1H, J = 8.4 Hz), 7.75-7.67 (m, 3H), 7.61 (d, 2H, J = 8.4 Hz), 6.90 (d, 2H, J =8.8 Hz).

Example 5: compound 5 synthesis

The final compound 4-(2-(4-methoxyphenyl)benzo[d]oxazol-6-yl)phenol (116 mg, 0.36 mmol, 56%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.65 (Broad s, 1H), 8.16 (d, 2H, J =8.8 Hz), 7.95 (d,1H, J =1.2Hz), 7.76 (d, 1H, J = 2.4), 7.63-7.59 (m, 3H), 7.19 (d, 2H, J = 9.2 Hz), 6.89 (d, 2H, J =8.4 Hz), 3.89 (s, 3H).

Example 6: compound 6 synthesis

The final compound 4-(2-(3-methoxyphenyl)benzo[d]oxazol-6-yl)phenol (150 mg, 0.47 mmol, 29%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 8.00 (s, 1H), 7.82 (t, 1H, J =8.6 Hz), 7.72 (s,1H), 7.66 (dd, 1H, J = 2.2 / 9Hz), 7.61 ( d, 2H, J = 8.8Hz), 7.56 (t, 1H, J = 8Hz), 7.23 (dd, 1H, J = 2.4 / 8.4Hz), 6.90 (d, 2H, J =8.4Hz), 3.90 (s, 3H).

Example 7: compound 7 synthesis

The final compound 4,4'-(benzo[d]oxazole-2,6-diyl)diphenol (40 mg, 0.13 mmol, 19%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, MeOD) δ 8.11-8.08 (m, 2H), 8.89 (d, 1H, J =1.2 Hz), 7.68 (d,1H, J =8.4Hz), 7.59 (dd, 1H, J = 1.4/8.2Hz), 7.54 (t, 2H, J =4.2Hz), 6.98 (dd, 2H, J = 2/8Hz), 6.91 (d, 2H, J =8.4Hz).

Example 8: compound 8 synthesis

The final compound 3-(6-(4-hydroxyphenyl)benzo[d]oxazol-2-yl)phenol (159 mg, 0.52 mmol, 51%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.73 (t, 2H, J =6.8 Hz), 7.67 (s, 1H), 7.63 (dd, 1H, J = 1.4/8.2 Hz), 7.56 (d, 2H, J =8.8 Hz), 7.41 (t, 1H, J = 7.8 Hz), 7.04 (dd, 1H, J =2.4/8 Hz), 6.92 (d, 2H, J = 8.4 Hz).

Example 9: Synthesis of compound 9

The final compound 2-chloro-4-(6-(4-hydroxyphenyl)benzo[d]oxazol-2-yl)phenol (117 mg, 0.35 mmol, 51%) was prepared in the same manner as for obtaining compound 1. Got it.

¹ H NMR (400 MHz, DMSO) δ 11.19 (Broad s, 1H), 9.62 (s, 1H), 8.12 (d, 1H, J =2Hz), 8.01 (dd, 1H, J =2/8.4 Hz), 7.94 (d,1H, J =1.6Hz), 7.77 (d, 1H, J = 8.4Hz), 7.64-7.58 (m, 3H), 7.20 (d, 1H, J = 8.4Hz), 6.89 (d, 2H , J = 8.4 Hz).

Example 10: compound 10 synthesis

In the same manner as for obtaining compound 1, the final compound 3-(2-(4-fluorophenyl)benzo[d]oxazol-6-yl)phenol (170 mg, 0.56 mmol, 81%) was obtained.

¹ H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.29-8.26 (m, 2H), 8.00 (s, 1H), 7.86 (d,1H, J =8.4Hz), 7.66 (d, 1H , J = 8.4 Hz), 7.51-7.46 (m, 2H), 7.30 (t, 1H, J =7.8 Hz), 7.18-7.11 (m, 2H), 6.83-6.81 (m, 1H).

Example 11: Synthesis of compound 11

In the same manner as for obtaining compound 1, the final compound 3-(2-(4-chlorophenyl)benzo[d]oxazol-6-yl)phenol (175 mg, 0.54 mmol, 84%) was obtained.

¹ H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.24 (d, 2H, J =8.8Hz), 8.02 (s, 1H), 7.88 (d, 1H, J =8.4Hz), 7.74- 7.67 (m, 3H), 7.31 (t, 1H, J =8Hz), 7.18 (d, 1H, J =8Hz), 7.12 (t, 1H, J =2Hz), 6.82 (dd, 1H, J = 1.6/ 8.0).

Example 12: compound 12 synthesis

The final compound 3-(2-(3-fluorophenyl)benzo[d]oxazol-6-yl)phenol (80 mg, 0.26 mmol, 53%) was obtained in the same manner as for obtaining compound #1.

¹ H NMR (400 MHz, DMSO) δ 9.62 (S, 1H), 8.08 (d, 1H, J =7.6Hz), 8.03 (s, 1H), 7.97 (d,1H, J =9.6Hz), 7.90 ( d, 1H, J =8.4Hz), 7.74-7.68 (m, 1H), 7.56-7.51 (m, 2H), 7.31 (t, 1H, J =8Hz), 7.18 (d, 1H, J =7.6Hz) , 7.13 (t, 1H, J =2Hz), 6.83 (dd, 1H, J =1.6/8Hz).

Example 13: Synthesis of compound 13

The final compound 3-(2-(3-chlorophenyl)benzo[d]oxazol-6-yl)phenol (153 mg, 0.47 mmol, 49%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 8.02 (d, 2H, J =1.2Hz), 7.89 (d, 1H, J =8.4Hz), 7.75-7.66 (m,3H), 7.31 (t, 1H, J = 7.8Hz), 7.18 (d, 2H, J = 8Hz), 7.12 (t, 1H, J = 2Hz), 6.83 (dd, 1H, J = 1.6 / 8Hz).

Example 14: compound 14 synthesis

The final compound 3-(2-(4-methoxyphenyl)benzo[d]oxazol-6-yl)phenol (137 mg, 0.43 mmol, 66%) was obtained in the same manner as for obtaining compound #1.

¹ H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 8.18 (d, 2H, J =9.2Hz), 7.98 (s, 1H), 7.82 (d, 1H, J =8Hz), 7.64 (dd ,1H, J =1.4/8.2Hz), 7.30 (t, 1H, J =7.8Hz), 7.20 (d, 3H, J =8.8Hz), 7.11 (t, 1H, J =2Hz), 6.82-6.80 ( m, 1H), 3.89 (s, 3H).

Example 15: compound 15 synthesis

The final compound 3-(2-(3-methoxyphenyl)benzo[d]oxazol-6-yl)phenol (137 mg, 0.47 mmol, 66%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.02 (d, 1H, J =1.2Hz), 7.88 (d, 1H, J =8.4Hz), 7.83 (d, 1H, J =7.6 Hz), 7.73 (t, 1H , J = 2Hz), 7.67 (dd, 1H, J = 1.6 / 8.4Hz), 7.57 (t, 1H, J = 8Hz), 7.31 (t, 1H, J = 7.8Hz) , 7.24 (dd, 1H, J =2/8.4Hz), 7.18 (d, 1H, J =8Hz), 7.12 (t, 1H, J =1.8Hz), 6.82 (dd, 1H, J =1.8/8.2Hz ), 3.91 (s, 3H).

Example 16: compound 16 synthesis

The final compound 3-(2-(4-hydroxyphenyl)benzo[d]oxazol-6-yl)phenol (125 mg, 0.41 mmol, 69%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.67 (s, 1H), 9.22 (s, 1H), 8.20 (d, 2H, J =7.6Hz), 8.04 (s, 1H), 7.90 (d,1H, J =8.4Hz), 7.43-7.68 (m, 3H), 7.31 (t, 1H, J =8Hz), 7.19 (d, 1H, J =8Hz), 7.12 (t, 1H, J =2Hz), 6.83 (dd , 1H, J =1.6/8Hz).

Example 17: compound 17 synthesis

The final compound 3,3'-(benzo[d]oxazole-2,6-diyl)diphenol (148 mg, 0.49 mmol, 74%) was obtained in the same manner as for obtaining compound 1.

¹ H NMR (400 MHz, DMSO) δ 9.99 (Broad s, 1H), 9.61 (Broad s, 1H), 8.01 (d, 1H, J =1.2Hz), 8.85 (d, 1H, J =8.4Hz), 7.68-7.62 (m,3H), 7.44 (t, 1H, J =7.8Hz), 7.33 (t, 1H, J =7.8Hz), 7.18 (d, 1H, J =8Hz), 7.12 (t, 1H, J =1.8 Hz), 7.06-7.03 (m, 1H), 6.83-6.80 (m, 1H).

Example 18: compound 18 synthesis

Final compound 2-chloro-4-(6-(3-hydroxyphenyl)benzo[d]oxazol-2-yl)phenol (117 mg, 0.35 mmol, 51%) by the same method as the method of obtaining compound 1 Got it.

¹ H NMR (400 MHz, DMSO) δ 11.22 (Broad s, 1H), 9.60 (s, 1H), 8.14 (d, 1H, J =2Hz), 8.03 (dd, 1H, J =2/8.4Hz), 7.97 (d,1H, J =1.6Hz), 7.81 (d, 1H, J =8.4Hz), 7.64 (dd, 1H, J =1.6/8.4Hz), 7.30 (t, 1H, J =8Hz), 7.21 -7.16 (m, 2H), 7.11 (d, 1H, J = 7.8 Hz), 6.81 (dd, 1H, J =1.8/7.8 Hz).

[ Test example ]

Test example One: MAO -B inhibition test

Human recombinant MAO-B enzyme made from insect cells was obtained from Sigma-Aldrich. Benzylamine-hydrochloric acid (Sigma) was used as a substrate for the enzyme. Sodium phosphate buffer (0.05 M, pH 7.4) was used as a solvent in all enzymatic reactions. The final volume of the enzymatic reaction is 200 μl, and each reaction solution contains benzylamine-hydrochloric acid, samples of various concentrations (0.01 μM-100 μM), and 1% DMSO as a joint solvent. The potential effect of the sample on hMAO-B activity was measured through the formation of hydrogen peroxide from benzylamine, and the AmplexRed® MAO assay kit from Invitrogen was used.

Briefly, 0.1 mL sodium phosphate buffer (0.05 M, 7.4 pH) containing various concentrations of samples (new compounds or reference inhibitors) and appropriate amounts of recombinant hMAO-B (0.5 μl, 71 U/mg) contained in a 96-well plate. Is incubated at 37° C. for 1 hour. After the incubation time, the reaction is initiated by adding 200 μM of AmplexRed® reagent, 1 U/mL of mustard radish peroxidase, and 1 mM benzylamine-hydrochloric acid. The production of resorupine, which is a result of the production of hydrogen peroxide, was quantified by TECAN's multi detection microplate fluorescence reader (absorbance, 570 nm) at 37°C based on its fluorescence.

At the same time, control experiments were conducted using appropriately diluted excipients instead of samples. In addition, the degree to which the activity of a sample can be modified by non-enzymatic inhibition, such as directly reacting with the AmplexRed® reagent, can be determined by treating only the sample and the AmplexRed® reagent in sodium phosphate buffer.

The specific fluorescence absorbance value obtained as a final result is calculated by subtracting the background activity value, that is, the value measured by the reaction product containing sodium phosphate buffer instead of the hMAO-B enzyme.

The results of% inhibition and IC ₅₀ (nM) at 10 mM concentration for MAO-B enzyme of the novel compound according to the present invention are shown in Table 1 below.

Experimental compound IC ₅₀ (nM) Compound 1 353 Compound 2 3,868 Compound 3 184 Compound 4 923 Compound 5 6,614 Compound 6 403 Compound 7 182 Compound 8 338 Compound 9 305 Compound 10 661 Compound 11 6,427 Compound 12 682 Compound 13 2,124 Compound 14 4,698 Compound 15 1,710 Compound 16 1,946 Compound 17 1,695 Compound 18 404

Experimental example 2: MAO -B inhibitor reversibility test

In order to determine whether the MAO-B inhibitor inhibitory ability is reversible or not, a MAO-B inhibitor reversibility experiment was conducted. After washing out the MAO-B% inhibition of the 1 mM compound and the compound attached to MAO-B, it was confirmed by comparing the MAO-B% inhibition of the 1 mM compound measured again. The washing stem was washed with 4 HEPES buffers and 2 phosphate buffers using a centrifugation-ultrafiltration method, and MAO-B was recovered to measure the% inhibitor of the 1 mM compound.

The results of the MAO-B reversibility test for the two selected compounds, Compound 3 and Compound 7 are shown in Table 2 below.

Inhibitor % inhibition
before washout ^a % inhibition
after washout ^a Reversibility Compound 3 84.25 49.22 reversible Compound 7 85.74 79.47 reversible Selegiline 100 0 irreversible Safinamide 94.93 87.27 reversible

Experimental example 3: MPP + Induction Neurotoxicity Experiment

Place the SH-SY5Y cells on a 384 well plate with 4000 cells per well, and grow them in a growth medium for one day. In order to see the compound recover from the neurocytotoxicity induced by MPP+, the compound and DMSO were treated at 1 mM and 10 mM concentrations, respectively, and after 2 hours, 5 mM MPP+ was treated and neurocytotoxicity was observed for 48 hours. To induce. Cell viability was measured by CellTiter-Glo® luminescence Cell viability assay, which determines the number of living cells through ATP quantification, and luminescence was measured by FlexStation3.

The results of the effect on MPP+ induced neurocytotoxicity of the two selected compounds, Compound 3 and Compound 7, are shown in FIG. 1. According to this, it was confirmed that the group treated with 5 mM MPP and 10 μM of Compound 3 or 7 together showed resilience to neurocytotoxicity.

Claims (21)

2,6-diarylbenzoxazole derivatives for inhibiting MAO-B represented by the following structural formula 1;
[Structural Formula 1]

In structural formula 1,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 1,
The structural formula 1 is a 2,6-diarylbenzoxazole derivative, characterized in that represented by the following structural formula 2 or structural formula 3;
[Structural Formula 2]

[Structural Formula 3]

In structural formulas 1 and 2,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 2,
In the above structural formulas 1 and 2,
Any one of R ¹ and R ² is a hydrogen atom, and the other is a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group, characterized in that 2,6-diarylbenzooxazole derivative. The method of claim 3,
In the above structural formulas 1 and 2,
Any one of R ¹ and R ² is a hydrogen atom, and the other is a fluoro group, a chloro group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C4 alkoxy group. Rylbenzoxazole derivatives. The method of claim 1,
Structural Formula 1 is a 2,6-diarylbenzoxazole derivative, characterized in that represented by the following Structural Formula 4 or 5;
[Structural Formula 4]

[Structural Formula 5]

In structural formulas 4 and 5,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 5,
In the above structural formulas 4 and 5,
R ¹ is a hydroxy group,
R ² is a 2,6-diarylbenzoxazole derivative, characterized in that a halogen group. The method of claim 6,
In the above structural formulas 4 and 5,
R ¹ is a hydroxy group,
R ² is a 2,6-diarylbenzoxazole derivative, which is a fluoro group or a chloro group. The method of claim 1,
The 2,6-diarylbenzoxazole derivative represented by Structural Formula 1 is a 2,6-diarylbenzoxazole derivative, which is any one selected from the following compounds 1 to 18.

Method for producing a 2,6-diarylbenzoxazole derivative for inhibiting MAO-B represented by the following Scheme 1;
[Scheme 1]

In Scheme 1,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 9,
The above in Scheme 1

Is a method for producing a 2,6-diarylbenzooxazole derivative for inhibiting MAO-B, characterized in that prepared according to the following Scheme 2;
[Scheme 2]

In Scheme 2,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. A pharmaceutical composition for inhibiting MAO-B comprising a 2,6-diarylbenzoxazole derivative represented by the following structural formula 1 or a pharmaceutically acceptable salt thereof.
[Structural Formula 1]

In structural formula 1,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 11,
The structural formula 1 is a pharmaceutical composition for inhibiting MAO-B, characterized in that represented by the following structural formula 2 or structural formula 3;
[Structural Formula 2]

[Structural Formula 3]

In structural formulas 1 and 2,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 11,
In the above structural formulas 1 and 2,
Any one of R ¹ and R ² is a hydrogen atom, and the other is a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. A pharmaceutical composition for inhibiting MAO-B. The method of claim 13,
In the above structural formulas 1 and 2,
Any one of R ¹ and R ² is a hydrogen atom, and the other is a fluoro group, a chloro group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C4 alkoxy group, characterized in that for inhibiting MAO-B Pharmaceutical composition. The method of claim 11,
The structural formula 1 is a pharmaceutical composition for inhibiting MAO-B, characterized in that represented by the following structural formula 4 or 5;
[Structural Formula 4]

[Structural Formula 5]

In structural formulas 4 and 5,
R ¹ and R ² are different from each other, and each independently a hydrogen atom, a halogen group, a hydroxy group, an acetyl group, or a substituted or unsubstituted C1 to C10 alkoxy group. The method of claim 15,
In the above structural formulas 4 and 5,
R ¹ is a hydroxy group,
R ² is a pharmaceutical composition for inhibiting MAO-B, characterized in that a halogen group. The method of claim 16,
In the above structural formulas 4 and 5,
R ¹ is a hydroxy group,
R ² is a pharmaceutical composition for inhibiting MAO-B, characterized in that a fluoro group or a chloro group. The method of claim 11,
The 2,6-diarylbenzoxazole derivative represented by Structural Formula 1 is a pharmaceutical composition for inhibiting MAO-B, characterized in that any one selected from the following compounds 1 to 18.

The method of claim 11,
The pharmaceutical composition for inhibiting MAO-B is a pharmaceutical composition for inhibiting MAO-B, characterized in that it exhibits a reversible and selective activity to MAO-B. The method of claim 11,
The pharmaceutical composition for inhibiting MAO-B is a pharmaceutical composition for inhibiting MAO-B, characterized in that for preventing or treating degenerative brain diseases or metabolic diseases. The method of claim 20,
The degenerative brain disease or metabolic disease is a pharmaceutical composition for inhibiting MAO-B, characterized in that any one selected from depression, Alzheimer's disease, Parkinson's disease, and obesity.

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