KR20240006144A - Composition for preventing or treating Alzheimer's disease comprising novel compounds - Google Patents

Abstract

The present invention relates to the use of a novel compound to prevent, improve, or treat Alzheimer's disease, and the novel compound showed an effect of inhibiting tau protein aggregation. In addition, it was confirmed that presenilin 1 was reduced by treatment with the novel compound. In conclusion, the novel compound can be useful in the development of a treatment for Alzheimer's disease.

Description

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

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

Alzheimer's disease (AD) is a disease that causes gradual decline in memory, behavior, language, and visuospatial abilities. In the brains of patients with Alzheimer's disease, plaque formation due to amyloid beta is observed, and intracellular neurofibrillary tangles are made up of paired helical filaments (PHFs) containing a hyperphosphorylated form of tau. ) has the characteristic of accumulating. This causes degenerative atrophy throughout the brain tissue and causes various symptoms as described above.

In Alzheimer's disease, the lack of neurotransmitters such as acetylcholine is the most important indicator, and restoring this is becoming one of the treatment goals for Alzheimer's disease.

Parasympathetic drugs for Alzheimer's disease can be divided into muscarinic agonists or nicotine agonists, cholinesterase inhibitors (ChEIs), and drugs that indirectly regulate acetylcholine release. Among these, many drugs have been developed and used as ChEIs, including tacrine, physostigmine, donepezil, rivastigmin, and memantin.

Second-generation drugs, such as donepezil and rivastigmin, have a longer duration of action and are more stable than first-generation drugs, such as tacrine, and have high blood-brain barrier (BBB) permeability, resulting in lower concentrations in the central nervous system. tends to be high. While first-generation drugs non-selectively inhibit AChE, butyrylcholinesterase, and other peripheral cholinesterases, some new drugs are known to have high selectivity for AChE, reducing the incidence of peripheral side effects. It is known that the mechanism of action of these drugs is to increase the concentration of ACh within the synapse by inhibiting the breakdown of acetylcholine (ACh).

Since these conventional treatments for Alzheimer's disease have serious side effects due to long-term use, there is a need to develop new drugs that have similar or better pharmacological efficacy and fewer side effects than the conventional drugs.

Republic of Korea Patent Publication No. 10-2010-0009415 (published on January 27, 2010)

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

In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating Alzheimer'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 Alzheimer'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 Alzheimer's disease, and the novel compound, PRG-A compound, showed an effect of inhibiting tau protein aggregation. In addition, it was confirmed that presenilin 1 was decreased by treatment with PRG-A compound. In conclusion, the PRG-A compound can be useful in the development of a treatment for Alzheimer's disease.

Figure 1 shows the effect of PRG-A compound in preventing tau entanglement. A and B. Tau aggregation induced by Tau-WT and MT overexpression results in removal by compound (PRG-A-01~04)DP. C. PRG-A compound shows results in alleviating abnormal tubulin formation caused by Tau-MT overexpression.
Figure 2 shows the effect of PRG-A compound in eliminating presenilin aggregation. A and B. Presenilin-1 (PS1) aggregation induced by PS-1 overexpression is shown to be reduced by compounds (PRG-A-01 and PRG-A-02). C. PRG-A compound inhibits PS1 aggregation in a dose-dependent manner.
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 Alzheimer'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 the aggregation of tau protein and presenilin 1.

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 Alzheimer'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, (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, dried grapes, 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 preparation

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-dihydro-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. Cell culture and reagents

HEK293 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) and maintained in DMEM liquid medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO ₂ . 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.

3. Western 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. HA (sc-7392) and GFP (green fluorescent protein; sc-8036) were purchased from Santa Cruz biotechnology (Santa Cruz, CA, USA). Actin antibody (66009-1-lg) and α-tubulin antibody (66240-1-lg) were obtained from Proteintech (Rosemont, IL, USA). Anti-TH antibody (NB300-109) was purchased from Novus Biologicals (CO, USA). As secondary antibodies, HRP-conjugated goat anti-mouse, goat anti-rabbit, and mouse anti-goat antibodies (Pierce, Thermo Fisher Scientific, Inc., Rockford, IL, USA) were used. 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.

4. 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 HA (diluted 1:500 in blocking solution) 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).

5. Transfection of vectors

GFP-Tau (WT; #46904, P301L; #46908) was purchased from Addgene (Cambridge, MA, USA). 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.

6. 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 confirm the effect of the PRG-A compound on tau tangle, the present inventors transfected HEK293 cells with an indicator vector (Tau-WT, Tau-P301L) and then incubated the selected compound (5 μM) for 24 hours. processed for a while. Cells were harvested with TNN buffer and centrifuged at 14000 rpm for 30 min, and the pellet (insoluble) and supernatant (soluble) were separated (Figure 1A and B). Transfected mutant tau (P301L) also recovered insoluble fractions due to aggregation (Figure 1A). However, treatment with PRG-A-01 and PRG-A-02 clearly reduced the insoluble mutant tau fraction (Figure 1A). Additionally, similar effects were observed by treatment with PRG-A-04 (Figure 1B). Additionally, cells were transfected with Tau-P301L vector for 24 hours. After incubation, cells were treated with PRG-A compound (5 μM) for 24 hours. Cells were fixed with 4% PFA and subjected to immunofluorescence using α-tubulin antibody (white arrow, strong Tau intensity) (Figure 1C). As a result, the abnormal arrangement of tubulin (yellow arrow) and the aggregation of mutant Tau (white arrow) were normalized or dissolved by the PRG-A compound (Figure 1C). The compound Chem-001 (decursinol) showed a minimal effect on inhibiting Tau aggregation.

<Example 2>

Additionally, mutations in presenilin 1 (PS1) are known to be associated with Alzheimer's disease (AD). Therefore, to determine the effect of PRG-A compound on PS1 expression and localization, cells were transfected with PS1-HA or PS1-GFP vector for 24 h. After incubation, cells were treated with PRG-A compound (5 μM) for 24 hours. Cells were fixed with 4% PFA and stained with HA antibodies (green) and ER (red) to monitor PS1 inclusions (white arrows, strong intensity for PS1) (Figure 2A and B). Ectopically expressed PS1 formed aggregates in the cytoplasm (Figure 2A and B). In contrast, PRG-A-cargo was able to dissolve PS1 aggregates in IF staining (Figure 2A and B). To confirm the effect of PRG-A compounds on inhibiting PS1 aggregation, SK-N-SH cells were transfected with an indicator vector (PS1-HA), and then selected compounds (PRG-A-01 and PRG-A-02) were added to the cells. Treated for 24 hours. SDS-PAGE was performed using HA antibody (Figure 2C). In fact, oligomeric PS1 was reduced by treatment with PRG-A compound (Figure 2C). Considering these results, it can be seen that the PRG-A compound is also useful for preventing or treating Alzheimer's disease.

<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 Alzheimer's disease (AD) 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 Alzheimer'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 Alzheimer'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 Alzheimer'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 Alzheimer'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 Alzheimer'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 Alzheimer's disease according to claim 1, wherein the pharmaceutical composition inhibits the aggregation of tau protein and presenilin 1. A health functional food composition for preventing or improving Alzheimer'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 Alzheimer'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 Alzheimer'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 Alzheimer'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 Alzheimer'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.