KR20240006143A - Composition for preventing or treating parkinson's disease comprising novel compounds - Google Patents

Abstract

The present invention relates to the use of a novel compound to prevent, improve or treat Parkinson's disease, and the novel compound showed an effect of inhibiting synuclein aggregation in a mouse model of Parkinson's disease (PD). As a result of histological analysis, it was confirmed that the loss of dopaminergic neurons was blocked by treatment with the novel compound. In conclusion, the new compound can be usefully used in the development of a treatment for Parkinson's disease.

Description

Composition for preventing or treating parkinson's disease comprising novel compounds}

The present invention relates to a composition for preventing or treating Parkinson's disease containing a novel compound.

Parkinson's disease is a degenerative neurological disease that gradually increases with aging, and is caused by a decrease in dopamine neurons in the midbrain dopamine pathway, which is responsible for motor functions. Therefore, the main symptoms include movement disorders such as muscle stiffness and tremors of the extremities.

The exact cause of Parkinson's disease is unknown, but it is believed to be related to environmental factors caused by neurotoxins such as pesticides, genetic factors, mitochondrial dysfunction, and aging. Genetic factors are known to be associated with gene mutations such as alpha-synuclein, Parkin, PINK-1, UCH-L1, and DJ-1. Currently, there are many drugs that alleviate the symptoms of Parkinson's disease, but no drugs that can prevent the progression of the disease have yet been reported, and chronic use of drugs carries a high risk of causing side effects that weaken the mind and body.

Drugs for the treatment of Parkinson's disease include L-dopa preparations, dopamine receptor agonists, anticholinergic drugs, and Eldepryl. However, most of these drugs do not treat the cause but rather control symptoms and require continuous medication. Long-term administration of these drugs causes problems with drug side effects. For example, anticholinergic drugs have limitations in continuously administering them to elderly patients because they may cause abnormalities in the autonomic nervous system or mental function. In addition, in the case of L-dopa preparations, the effectiveness gradually decreases when taken over a long period of time, and side effects such as twisting of the body or abnormal movement of hands and feet occur on their own. In addition, surgical treatments such as nerve stimulation using high frequency, that is, high-frequency destruction surgery or deep brain stimulation, are also performed, but they have the problem of requiring invasive surgery and high costs.

Therefore, the etiology of Parkinson's disease is not accurately known, and treatment methods are mainly used to improve symptoms rather than fundamental treatment. Therefore, there is an urgent need to develop new, more effective treatments for the prevention and treatment of Parkinson's disease.

PCT International Publication Patent WO 2008/109521 (published on September 12, 2008)

Accordingly, the purpose of the present invention is to provide a use for preventing, improving or treating Parkinson's disease containing a novel compound.

To achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating Parkinson's disease containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

In Formula 1,

This is a single bond or double bond,

n is an integer from 0 to 1,

X is CH or N,

R ¹ and R ² may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy.

In addition, the present invention provides a health functional food composition for preventing or improving Parkinson's disease containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to the use of a novel compound to prevent, improve or treat Parkinson's disease. The PRG-A compound, a novel compound, showed an effect of inhibiting synuclein aggregation in a Parkinson's disease (PD) mouse model. Histological analysis confirmed that the loss of dopaminergic neurons was blocked by PRG-A compound treatment. In conclusion, PRG-A compounds can be useful in the development of treatments for Parkinson's disease.

Figure 1 shows the results showing that PRG-A compound reduces MT-synuclein aggregation. A. The results show that the PRG-A compound reduces the insoluble form of MT-synuclein. B. Results show that PRG-A-04 inhibits MT-synuclein aggregation in a dose-dependent manner. C. Results show that PRG-A compound abolishes synuclein aggregation in SK-N-SH cells overexpressing Syn-A30P.
Figure 2 shows the results confirming the in vivo effect of the PRG-A compound in a Parkinson's disease (PD) mouse model. A. A schematic diagram of the PRG-A compound (PRG-A-03, PRG-A-04) administration experiment is shown. B. This is the result of measuring dopaminergic neuron loss in the Syn-A53T Tg mouse model. C. Results show that PRG-A-03 inhibits high expression of synuclein and phosphorylation of Tau in brain tissue of Syn-A53T Tg. D. Results show that PRG-A-04 protects against dopaminergic neuron loss in Syn-A53T Tg mice.
Figure 3 shows the toxic effects of PRG-A compound.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating Parkinson's disease, comprising a compound represented by the following formula (1), a hydrate thereof, or a salt thereof.

[Formula 1]

In Formula 1,

This is a single bond or double bond,

n is an integer from 0 to 1,

X is CH or N,

R ¹ and R ² may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy.

Preferably, the compound is When this ^{is a} single bond, n is 1, , but is not limited to this.

Preferably, the compound is When ^this double bond, n is an integer of 0 to ¹ , It may be selected from (C1-C4) alkylcarboxy, but is not limited thereto.

Preferably, the compound may be a compound represented by the following formula (2).

[Formula 2]

In Formula 2,

n is an integer from 0 to 1,

R ¹ ′ and R ² ′ may each be the same or different and may be selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy. Selected.

The compound represented by Formula 1 or Formula 2 may be named PRG-A compound.

More preferably, the compound is (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(4-hydroxy-3-methoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g ]chromen-7-yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate; PRG-A-01], (S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H ,6H-pyrano[3,2-g]chromen-2-one[(S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl -7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one; PRG-A-02], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-( 4-hydroxy-3-methoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7 -yl 3-(4-hydroxy-3-methoxyphenyl)propanoate; SNU-C4], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3,4-dimethoxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3,4-dimethoxyphenyl)acrylate; SNU-C5], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(3,4 -Dimethoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(3 ,4-dimethoxyphenyl)propanoate; SNU-C7], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(Pyridin-4-yl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(pyridin-4-yl)acrylate; SNU-C9], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3-hydroxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(3-hydroxyphenyl)acrylate; SNU-C10], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl(E)-3 -(4-fluorophenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(4-fluorophenyl)acrylate; PRG-A-03], (S,E)-7-((3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano [3,2-g]chromen-2-one[(S,E)-7-((3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H, 6H-pyrano[3,2-g]chromen-2-one; SNU-C13], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3-acetoxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(3-acetoxyphenyl)acrylate; SNU-C14], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4- Acetoxy-3-methoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4-acetoxy-3-methoxyphenyl)propanoate; SNU-C15], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(4-acetoxy-3-methoxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen- 7-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate; SNU-C17], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3,4-difluorophenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7- yl (E)-3-(3,4-difluorophenyl)acrylate; SNU-C18] and (S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H- Pyrano[3,2-g]chromen-2-one[(S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8 -dihydro-2H,6H-pyrano[3,2-g]chromen-2-one; PRG-A-04], but is not limited thereto.

More preferably, the pharmaceutical composition can inhibit synuclein aggregation and loss of dopaminergic neurons.

The pharmaceutical composition of the present invention can be prepared using pharmaceutically suitable and physiologically acceptable auxiliaries in addition to the active ingredients, and the auxiliaries include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, and glidants. Alternatively, solubilizers such as flavoring agents may be used. For administration, the pharmaceutical composition of the present invention can be preferably formulated as a pharmaceutical composition containing one or more pharmaceutically acceptable carriers in addition to the active ingredient. Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.

The pharmaceutical preparation form of the pharmaceutical composition of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and sustained-release preparations of the active compound. You can. The pharmaceutical composition of the present invention can be administered in any conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. It can be administered. The effective amount of the active ingredient of the pharmaceutical composition of the present invention refers to the amount required for the prevention or treatment of disease. Therefore, the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form and the patient's age, weight, general health condition, gender and diet, administration time, administration route and composition. It can be adjusted depending on a variety of factors, including secretion rate, duration of treatment, and concurrent medications. It is not limited thereto, but for example, in the case of adults, when administered once or several times a day, the composition of the present invention can be administered at a dose of 0.01 ng/kg to 10 g/kg when administered once or several times a day. .

In addition, the present invention provides a health functional food composition for preventing or improving Parkinson's disease, comprising a compound represented by the following formula (1), a hydrate thereof, or a salt thereof.

[Formula 1]

In Formula 1,

This is a single bond or double bond,

n is an integer from 0 to 1,

X is CH or N,

R ¹ and R ² may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy.

Preferably, the compound is When this ^{is a} single bond, n is 1, , but is not limited to this.

Preferably, the compound is When ^this double bond, n is an integer of 0 to ¹ , It may be selected from C1~C4)alkylcarboxy, but is not limited thereto.

Preferably, the compound may be a compound represented by the following formula (2).

[Formula 2]

In Formula 2,

n is an integer from 0 to 1,

R ¹ ′ and R ² ′ may each be the same or different and may be selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy. Selected.

The compound represented by Formula 1 or Formula 2 may be named PRG-A compound.

More preferably, the compound is (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(4-hydroxy-3-methoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g ]chromen-7-yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate; PRG-A-01], (S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H ,6H-pyrano[3,2-g]chromen-2-one[(S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl -7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one; PRG-A-02], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-( 4-hydroxy-3-methoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7 -yl 3-(4-hydroxy-3-methoxyphenyl)propanoate; SNU-C4], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3,4-dimethoxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3,4-dimethoxyphenyl)acrylate; SNU-C5], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(3,4 -Dimethoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(3 ,4-dimethoxyphenyl)propanoate; SNU-C7], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(Pyridin-4-yl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(pyridin-4-yl)acrylate; SNU-C9], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3-hydroxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(3-hydroxyphenyl)acrylate; SNU-C10], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl(E)-3 -(4-fluorophenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(4-fluorophenyl)acrylate; PRG-A-03], (S,E)-7-((3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano [3,2-g]chromen-2-one[(S,E)-7-((3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H, 6H-pyrano[3,2-g]chromen-2-one; SNU-C13], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3-acetoxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(3-acetoxyphenyl)acrylate; SNU-C14], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4- Acetoxy-3-methoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4-acetoxy-3-methoxyphenyl)propanoate; SNU-C15], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(4-acetoxy-3-methoxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen- 7-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate; SNU-C17], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3 -(3,4-difluorophenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7- yl (E)-3-(3,4-difluorophenyl)acrylate; SNU-C18] and (S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H- Pyrano[3,2-g]chromen-2-one[(S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8 -dihydro-2H,6H-pyrano[3,2-g]chromen-2-one; PRG-A-04], but is not limited thereto.

The health functional food composition of the present invention may further include one or more additives selected from the group consisting of organic acids, phosphates, antioxidants, lactose casein, dextrin, glucose, sugar, and sorbitol. The organic acid may be, but is not limited to, citric acid, humalic acid, adipic acid, lactic acid, or malic acid, and the phosphate may be, but not limited to, sodium phosphate, potassium phosphate, acid pyrophosphate, or polyphosphate (polyphosphate), and may be an antioxidant. The agent may be, but is not limited to, a natural antioxidant such as polyphenol, catechin, alpha-tocopherol, rosemary extract, licorice extract, chitosan, tannic acid, or phytic acid.

In another embodiment of the present invention, the health functional food contains, in addition to the active ingredients, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants, and thickening agents (cheese, chocolate, etc.) ), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Additionally, the food composition according to an embodiment of the present invention may contain pulp for the production of natural fruit juice, fruit juice beverage, and vegetable beverage.

According to one embodiment of the present invention, the formulation of the health functional food is not limited thereto, but may be in the form of solid, powder, granule, tablet, capsule, liquid, or beverage.

In addition, the above health functional foods are, but are not limited to, confectionery, sugar, ice cream products, dairy products, meat products, fish products, tofu or jelly, edible oils and fats, noodles, tea foods, beverages, special nutritional foods, health supplements, and seasoning foods. , ice, ginseng products, kimchi pickles, raisins, fruits, vegetables, dried fruits or vegetables, cut products, fruit juice, vegetable juice, mixed juices thereof, chips, noodles, processed livestock food, processed seafood, It can be used in the production of foods such as dairy foods, fermented milk foods, pulse foods, grain foods, microbially fermented foods, confectionery and bakery products, seasonings, processed meats, acidic beverages, licorice, and herbs.

Hereinafter, the present invention will be described in detail through examples to aid understanding. However, the following examples only illustrate the content of the present invention and the scope of the present invention is not limited to the following examples. Examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

< Experiment example >

The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present invention.

1. Compound and mouse preparation

1) Compound

The chemical structures and NMR data of the compounds used in the present invention are as follows.

(S)-8,8- dimethyl -2- oxo -7,8- dihydro - 2H,6H - pyrano[3,2-g]chromen -7- yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate(PRG-A-01)

^1H NMR (acetone-d ₆ , 400MHz)

δ ppm 7.843(d, J=9.6Hz, 1H), 7.616(d, J=16.0Hz, 1H), 7.424(s, 1H), 7.357(s, 1H), 7.123(dd, J=2.0, 8.0Hz) , 1H), 6.851(d, J=8.4Hz, 1H), 6.740(s, 1H), 6.387(d, J=15.6Hz, 1H), 6.198(d, J=9.6Hz, 1H), 5.221(t , J=4.6Hz, 1H), 3.895(s, 3H), 3.321(dd, J=4.6, 17.2Hz, 1H), 2.963(dd, J=4.4, 17.6Hz, 1H), 1.421(s, 3H) , 1.413(s, 3H); MS(m/z) 423 (M+H) ⁺

(S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g] chromen-2-one (PRG-A-02)

^1H NMR: EW15731-164-P1D4 (400 MHz, CDCl ₃ )

δ 7.58 (d, J = 12 Hz, 1H), 7.16 (s, 1H), 6.90 - 6.86 (m, 3H), 6.78 (s, 1H), 6.51 (d, J =16 Hz, 1H), 6.22 ( d, J = 8.0 Hz, 1H), 6.14 - 6.10 (m, 1H), 5.65 (s, 1H), 4.32 - 4.30 (m, 1H), 4.22 - 4.20 (m, 1H), 3.91 (s, 3H) , 3.61 - 3.58 (m, 1H), 3.11 - 3.05 (m, 1H), 3.89 - 3.87 (m, 1H), 1.43 (s, 3H), 1.36 (s, 3H).

(S)-8,8- dimethyl -2- oxo -7,8- dihydro - 2H,6H - pyrano[3,2-g]chromen -7- yl (E)-3-(4-fluorophenyl)acrylate ( PRG -A-03)

^1H NMR (CD ₂ Cl ₂ , 400MHz): δ ppm 7.66 - 7.55 (m, 2H), 7.55 - 7.46 (m, 2H), 7.18 (s, 1H), 7.11 - 7.01 (m, 2H), 6.76 ( s, 1H), 6.35 (d, J = 16.0 Hz, 1H), 6.16 (d, J = 9.5 Hz, 1H), 5.17 (app.t, J = 4.7 Hz, 1H), 3.23 (ddd, J = 17.3 , 4.8, 1.2 Hz, 1H), 2.92 (dd, J = 17.3, 4.7 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 3H).

( S,E )-7-((3-(3- methoxy -4- nitrophenyl ) allyl )oxy)-8,8- dimethyl -7,8- dihydr o-2H,6H-pyrano[3,2-g]chromen-2-one (PRG-A-04)

^1H NMR (CDCl ₃ , 400MHz): δ ppm 7.85 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 9.5 Hz, 1H), 7.16 (s, 1H), 7.05 - 6.97 (m, 2H) ), 6.78 (s, 1H), 6.60 (app.dt, J = 15.9, 1.7 Hz, 1H), 6.40 (app.dt, J = 15.9, 5.5 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 4.39 (ddd, J = 13.6, 5.4, 1.7 Hz, 1H), 4.24 (ddd, J = 13.4, 5.5, 1.6 Hz, 1H), 3.97 (s, 3H), 3.59 (dd, J = 7.1, 4.9 Hz, 1H), 3.11 (dd, J = 16.7, 4.9 Hz, 1H), 2.87 (dd, J = 16.7, 7.2 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H).

( S,E )-7-((3-(4- fluorophenyl ) allyl )oxy)-8,8- dimethyl -7,8- dihydro - 2H,6H -pyrano[3,2-g]chromen-2-one ( SNU -C13)

^1H NMR (CDCl ₃ , 400MHz): δ ppm 7.57 (d, J = 9.5 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.16 (s, 1H), 7.06 - 6.93 (m, 2H), 6.77 (s, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.25 - 6.13 (m, 2H), 4.33 (ddd, J = 12.8, 5.8, 1.5 Hz, 1H), 4.19 (ddd, J = 12.8) , 6.3, 1.4 Hz, 1H), 3.58 (dd, J = 7.4, 5.0 Hz, 1H), 3.08 (dd, J = 16.4, 5.0 Hz, 1H), 2.85 (ddd, J = 16.4, 7.4, 1.1 Hz, 1H), 1.42 (s, 3H), 1.35 (s, 3H).

(S)-8,8- dimethyl -2- oxo -7,8- dihydro - 2H,6H - pyrano[3,2-g]chromen -7- yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate ( SNU -C17)

^1H NMR (CD ₂ Cl ₂ , 600MHz): δ ppm 7.67 - 7.56 (m, 2H), 7.21 (s, 1H), 7.14 - 7.09 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H) , 6.78 (s, 1H), 6.41 (d, J = 16.0 Hz, 1H), 6.19 (d, J = 9.5 Hz, 1H), 5.20 (app.t, J = 4.7 Hz, 1H), 3.82 (s, 3H), 3.26 (ddd, J = 17.3, 4.8, 1.2 Hz, 1H), 2.95 (dd, J = 17.3, 4.5 Hz, 1H), 2.27 (s, 3H), 1.43 (s, 3H), 1.38 (s) , 3H).

(S)-8,8- dimethyl -2- oxo -7,8- dihydro - 2H,6H - pyrano[3,2-g]chromen -7- yl (E)-3-(3,4-difluorophenyl)acrylate (SNU-C18)

^1H NMR (CDCl ₃ , 400MHz): δ ppm 7.62 - 7.53 (m, 2H), 7.32 (ddd, J = 11.1, 7.6, 2.2 Hz, 1H), 7.24 - 7.11 (m, 3H), 6.83 (s, 1H), 6.33 (d, J = 16.0, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.19 (app.t, J = 4.7 Hz, 1H), 3.25 (ddd, J = 17.4, 4.8, 1.1 Hz, 1H), 2.93 (dd, J = 17.4, 4.5 Hz, 1H), 1.43 (s, 3H), 1.39 (s, 3H).

(7S)-(+)-3-(2- Furanyl )-acrylic acid, 8,8- dimethyl -2- oxo -6,7- dihydro -2H,8H-pyrano[3,2-g]chromen-7-yl-ester (SLC-B050)

¹ H NMR (400 MHz, CDCl ₃ ): δH 7.64 (1H, s, H-6'), 7.58 (1H, d, J = 9.6 Hz, H-4), 7.56 (1H, d, J = 16.0 Hz) , H-3'), 7.41(1H, d, J = 1.6Hz, H-7'), 7.17(1H, s, H-5), 6.82(1H, s, H-10), 6.55(1H, d, J = 1.6Hz, H-8'), 6.23(1H, d, J = 9.6Hz, H-3), 6.13(1H, d, J = 16.0Hz, H-2'), 5.17(1H, t, J = 4.4Hz, H-7), 3.23(1H, dd, J = 4.4, 17.6Hz, H-6a), 2.92(1H, dd, J = 4.4, 17.6Hz, H-6b), 1.42( 3H, s, CH3-8), 1.38(3H, s, CH3-8).

2) Mice

Experiments were conducted in an Association for Laboratory Animal Care Assessment and Certification approved facility in accordance with the animal policy approved by Pusan National University. B6.Cg-Tg(Prnp-SNCAA53T)/J mice were obtained from Jackson Laboratory (Stock No: 006823). All mice were maintained under temperature- and light-controlled conditions (20-23°C, 12-hour light/dark cycle) and provided with autoclaved food and water.

2. In vivo medication and tissue analysis

Syn ^{A53T - Tg} mice were administered vehicle (DMSO), PRG-A-03, and PRG-A-04 intraperitoneally twice a week for 24 to 26 weeks in 24-week-old mice. Control mice were treated under identical conditions. Mice at 48 to 52 weeks of age were sacrificed for histological analysis. After cardiac perfusion with 4% paraformaldehyde, the brain was dissected and embedded in paraffin blocks according to standard tissue processing procedures. Embedded tissues (cervical and lumbar regions of the spinal cord) were cut into 5㎛ pieces using a tissue slicer (Leica microtome) and transferred to adhesive-coated slides (Marienfeld laboratory glassware, Germany). For pathological and histological analysis of Syn ^{A53T - Tg} mice, after deparaffinization and rehydration, immunohistochemistry (IHC) using a dopaminergic neuron marker (Tyrosine Hydroxylase) was performed. To monitor dopaminergic neurons by immunofluorescence (IF), dissected brains were embedded in agarose holders and sectioned with a vibratome. Thinly sliced tissues were treated with blocking solution (normal donkey serum diluted 1:500 in 0.1% Triton X-100 PBS) for 1 hour. Cells were incubated with anti-TH antibody (diluted 1:500) overnight at 4°C. Finally, cells were incubated with FITC-conjugated secondary antibodies for 2 hours at 4°C. The cells were washed three times with PBS, and then the coverslip was mounted using a mounting solution (H-5501, Vector Laboratories) and analyzed under a fluorescence microscope (Zeiss).

3. Cell culture and reagents

SK-N-SH cells were purchased from Korean Cell Line Bank (KCLB, Seoul, South Korea) and maintained in MEM medium containing 10% fetal bovine serum, 1% antibiotics, 25mM HEPES, and 300 mg/L L-Glu. . Human fibroblasts (9-year-old female) were obtained from Coridll Cell Repositories (New Jersey, USA) and maintained in EMEM containing 15% FBS, 2mM glutamine with 26mM HEPES without antibiotics.

4. western blot ( wetern blot analysis

Protein extraction from cells using RIPA buffer [50 mM Tris-Cl, pH 7.5, 150 mM NaCl, 1% NP-40, 0.1% SDS, and 10% sodium deoxycholate] for SDS-PAGE. did. Samples were separated via SDS-PAGE and transferred to PVDF membranes. Blotted membranes were blocked with 3% skim milk containing TBST buffer for 1 h and incubated with specific antibodies. Reacted antibodies were detected by ECL and X-ray film exposure. The antibody used in this experiment was pan-Syn (GTX112799), purchased from Genetex (California, USA). Actin antibody (66009-1-lg) and α-tubulin antibody (66240-1-lg) were obtained from Proteintech (Rosemont, IL, USA). Anti-FLAG (Sigma; F3165) was purchased from Sigma Aldrich (St, Louis, MO, USA), and HRP-conjugated goat anti-mouse, goat anti-rabbit, and mouse anti-goat antibodies (Pierce, Thermo Fisher) were used as secondary antibodies. Scientific, Inc., Rockford, IL, USA)] was used. FLAG-Syn-WT and MT vectors were transfected in SK-N-SH cells for 24 hours. After incubation, cells were harvested with TNN buffer (50mM Tris-Cl, pH 7.5, 150mM NaCl, 0.3% NP-40), centrifuged at 14000rpm for 30min, and pellet (insoluble) and supernatant (soluble) were separated. . Input indicated whole cell lysate (WCL) harvested with RIPA buffer. Actin was used as a loading control.

5. Immunofluorescence dyeing( immunofluorescence staining)

Cells on the coverslip were washed with PBS, fixed with 4% paraformaldehyde (PFA) for 30 minutes at room temperature, and then permeabilized in 0.1% Triton X-100/PBS for 10 minutes. After cells were treated with blocking solution (3% anti-human antibody diluted 1:500 in PBS) for 1 h, cells were incubated with anti-FLAG (diluted 1:400) overnight at 4°C. Finally, cells were incubated with FITC and rhodamine-conjugated secondary antibodies for 6 hours at 4°C. Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI), and endoplasmic reticulum (ER) was stained using ER-Tracker Red dye for 10 minutes. Cells were washed three times with PBS, then coverslips were mounted with mounting solution (H-5501; Vector Laboratories (Burlingame, CA, USA)) and analyzed by fluorescence microscopy (Zeiss).

6. Transfection of vector ( Transfection of vectors)

FLAG-Syn (WT, A30P and A53T) vectors were provided by Dr. Purchased from Seol (Wonkwang University Korea). Transfection was performed using Jet-PEI reagent (JetPEI; Polyplus transfection, New York, NY, USA) according to the manufacturer's protocol. Briefly, the vector was mixed with JetPEI reagent in 150mM NaCl buffer, and then the mixture was incubated for 15 minutes. The mixture was added to the cells in serum-free medium for 4 hours. After incubation, cells were replaced with culture medium supplemented with 10% FBS.

7. Measurement of cell viability

To examine cell viability, cells were treated with a chemical (PRG-A compound) for 48 hours. Then, cells were incubated with 0.5 mg/ml MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution (475989; Merck, Darmstadt, Germany) at 37°C for 4 h. It was incubated for a while. After removing the excess solution and washing with PBS, the precipitated material was dissolved in 200 ㎕ of DMSO and quantified by measuring the absorbance at 540 nm.

< Example 1>

To determine the effect of the PRG-A compound on alpha-synuclein aggregation, the present inventors transfected the FLAG-Syn-A30P vector in SK-N-SH cells for 24 hours. After incubation, cells were treated with compounds (5 μM) for 24 hours. As a result, a large portion of the ectopically expressed mutant alpha-synuclein (Syn-A30P) was recovered as an insoluble fraction (Figure 1A). However, treatment with PRG-A compound clearly reduced synuclein aggregation (Figure 1A). Additionally, SK-N-SH cells were transfected with an instruction vector (MT-Syn) for 24 hours and then treated with PRG-A-04 for 24 hours. Cells were then harvested with TNN buffer (50mM Tris-Cl, pH 7.5, 150mM NaCl, 0.3% NP-40), centrifuged at 14000 rpm for 30 min, and the pellet (insoluble) and supernatant (soluble) were separated. . Actin was used as a loading control (Figure 1B). Similar effects were observed in experiments with another synuclein mutant (Syn-A53T) (Figure 1B), where PRG-A-04 was able to reduce insoluble synuclein in a dose-dependent manner. To confirm this, immunofluorescence staining was performed with Syn-Ab. Cells were transfected with Syn-A53T vector for 24 hours. After incubation, cells were treated with PRG-A compound (5 μM) for 24 hours and fixed with 4% PFA. Aggregated synuclein (white arrow) was solubilized by treatment with PRG-A compound (Figure 1C). Synuclein expression was observed under a fluorescence microscope with a pan-Syn antibody (white arrow; strong intensity of Syn). Chem-001 (decursinol) showed a marginal effect on inhibition of synuclein aggregation.

< Example 2>

To investigate the in vivo effects of PRG-A compounds, 20 mg/kg or 40 mg/kg of PRG-A compounds (PRG-A-03, PRG-A-04) were injected intraperitoneally from 24-week-old mice for 24 to 26 weeks. For histological analysis, mice were sacrificed and brain tissue was dissected at 48-49 weeks of age (Figure 2A). Tyrosine Hydroxylase (TH) staining was used to identify dopaminergic neurons in the substantia nigra (SN) ( Fig. 2B ). Dopaminergic neuron marker (Tyrosine Hydroxylase, TH) is maintained in mice injected with PRG-A-03. Representative images are shown at 10x magnification and inset image (yellow box) at 20x (Figure 2B). Compound treatment can block the loss of dopaminergic neurons (Figure 2B). Additionally, mutant Syn expression was reduced in brain tissue (Figure 2C). Additionally, the dissected brain was embedded in an agarose holder and cut with a vibratome. Thinly sliced tissue was stained with TH antibody (Figure 2D). As a result, similar results were obtained by treatment with PRG-A-04, which prevented the loss of dopaminergic neurons in the SN by IF staining with TH ( Figure 2D ). These results indicated that PRG-A compounds could not only block synuclein (Syn) aggregation but also protect against neuronal loss in Parkinson's disease (PD).

< Example 3>

Finally, to determine the toxicity of the PRG-A compound, normal human fibroblasts and neuroblastoma cells (SK-N-SH) were cultured with each compound for 48 hours, and cell survival rate was measured through MTT assay. The effect on survival rate on neuronal cells and normal fibroblasts was confirmed (Figure 3). PRG-A-01, 02 04 compounds showed no cytotoxic effect in normal human fibroblasts. PRG-A-03 compound showed low effect on cell viability at high doses (50 and 100 μM). In summary, since the new compound does not show toxicity up to 50 μM in normal cells, the side effects of the new compound are not expected to be serious.

In conclusion, the novel compound can be used to treat Parkinson's disease (PD) without serious side effects.

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (11)

Pharmaceutical composition for preventing or treating Parkinson's disease comprising a compound represented by the following formula (1), a hydrate thereof, or a salt thereof:
[Formula 1]

In Formula 1,
This is a single bond or double bond,
n is an integer from 0 to 1,
X is CH or N,
R ¹ and R ² may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy. The method of claim 1, wherein the compound is When this ^{is a} single bond, n is 1, A pharmaceutical composition for preventing or treating Parkinson's disease. The method of claim 1, wherein the compound is When ^this double bond, n is an integer of 0 to ¹ , A pharmaceutical composition for preventing or treating Parkinson's disease, characterized in that it is selected from (C1-C4) alkyl carboxy. The method of claim 1, wherein the compound is (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl ( E)-3-(4-hydroxy-3-methoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2- g]chromen-7-yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate], (S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl ) Oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one[(S,E)-7-((3-( 4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one], (S)-8, 8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4-hydroxy-3-methoxyphenyl)propano ate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4-hydroxy-3-methoxyphenyl) propanoate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-( 3,4-dimethoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(3,4-dimethoxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen- 7-yl 3-(3,4-dimethoxyphenyl)propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g] chromen-7-yl 3-(3,4-dimethoxyphenyl)propanoate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g ]chromen-7-yl (E)-3-(pyridin-4-yl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3 ,2-g]chromen-7-yl (E)-3-(pyridin-4-yl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H -Pyrano[3,2-g]chromen-7-yl (E)-3-(3-hydroxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8- dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3-hydroxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8 -dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl(E)-3-(4-fluorophenyl)acrylate[(S)-8,8-dimethyl-2 -oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(4-fluorophenyl)acrylate], (S,E)-7-(( 3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one[(S, E)-7-((3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3-ace Toxyphenyl) acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-( 3-acetoxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-( 4-acetoxy-3-methoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7 -yl 3-(4-acetoxy-3-methoxyphenyl)propanoate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g] Chromen-7-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H -pyrano[3,2-g]chromen-7-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8- dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3,4-difluorophenyl)acrylate[(S)-8,8-dimethyl -2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3,4-difluorophenyl)acrylate] and (S,E)- 7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen- 2-one[(S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3, A pharmaceutical composition for preventing or treating Parkinson's disease, characterized in that it is selected from the group consisting of [2-g]chromen-2-one]. The pharmaceutical composition for preventing or treating Parkinson's disease according to claim 1, wherein the compound is represented by the following formula (2):
[Formula 2]

In Formula 2,
n is an integer from 0 to 1,
R ¹ ′ and R ² ′ may each be the same or different and may be selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy. Selected. The pharmaceutical composition for preventing or treating Parkinson's disease according to claim 1, wherein the pharmaceutical composition inhibits synuclein aggregation and loss of dopaminergic neurons. A health functional food composition for preventing or improving Parkinson's disease comprising a compound represented by the following formula (1), a hydrate thereof, or a salt thereof:
[Formula 1]

In Formula 1,
This is a single bond or double bond,
n is an integer from 0 to 1,
X is CH or N,
R ¹ and R ² may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy. The method of claim 7, wherein the compound is When this ^{is a} single bond, n is 1, A health functional food composition for preventing or improving Parkinson's disease. The method of claim 7, wherein the compound is When ^this double bond, n is an integer of 0 to ¹ , A health functional food composition for preventing or improving Parkinson's disease, characterized in that it is selected from (C1-C4) alkyl carboxy. The method of claim 7, wherein the compound is (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl ( E)-3-(4-hydroxy-3-methoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2- g]chromen-7-yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate], (S,E)-7-((3-(4-hydroxy-3-methoxyphenyl)allyl ) Oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one[(S,E)-7-((3-( 4-hydroxy-3-methoxyphenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one], (S)-8, 8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4-hydroxy-3-methoxyphenyl)propano ate[(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-(4-hydroxy-3-methoxyphenyl) propanoate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-( 3,4-dimethoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E )-3-(3,4-dimethoxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen- 7-yl 3-(3,4-dimethoxyphenyl)propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g] chromen-7-yl 3-(3,4-dimethoxyphenyl)propanoate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g ]chromen-7-yl (E)-3-(pyridin-4-yl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3 ,2-g]chromen-7-yl (E)-3-(pyridin-4-yl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H -Pyrano[3,2-g]chromen-7-yl (E)-3-(3-hydroxyphenyl)acrylate[(S)-8,8-dimethyl-2-oxo-7,8- dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3-hydroxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8 -dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl(E)-3-(4-fluorophenyl)acrylate[(S)-8,8-dimethyl-2 -oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(4-fluorophenyl)acrylate], (S,E)-7-(( 3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one[(S, E)-7-((3-(4-fluorophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3-ace Toxyphenyl) acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-( 3-acetoxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl 3-( 4-acetoxy-3-methoxyphenyl) propanoate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7 -yl 3-(4-acetoxy-3-methoxyphenyl)propanoate], (S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g] Chromen-7-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate [(S)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H -pyrano[3,2-g]chromen-7-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate], (S)-8,8-dimethyl-2-oxo-7,8- dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3,4-difluorophenyl)acrylate[(S)-8,8-dimethyl -2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3,4-difluorophenyl)acrylate] and (S,E)- 7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen- 2-one[(S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3, A health functional food composition for preventing or improving Parkinson's disease, characterized in that it is selected from the group consisting of [2-g]chromen-2-one]. The health functional food composition for preventing or improving Parkinson's disease according to claim 7, wherein the compound is represented by the following formula (2):
[Formula 2]

In Formula 2,
n is an integer from 0 to 1,
R ¹ ′ and R ² ′ may each be the same or different and may be selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano, or (C1~C4)alkylcarboxy. Selected.