Composition for preventing or treating alzheimer's disease, containing novel compound

Abstract

The present invention relates to use of a novel compound for preventing, alleviating or treating Alzheimer's disease, and the novel compound exhibits an inhibitory effect on tau protein aggregation. In addition, it was identified that presenilin 1 was reduced by treatment using the novel compound. Therefore, the novel compound can be effectively used in the development of a therapeutic agent for Alzheimer's disease.

Description

Composition for preventing or treating Alzheimer's disease containing a novel compound

[0001] The present invention relates to a composition for preventing or treating Alzheimer's disease containing a novel compound.

[0002] Alzheimer's disease (AD) is a progressive disorder characterized by the decline of memory, behavior, language, and visuospatial abilities. The brains of patients with AD are characterized by the formation of plaques caused by amyloid beta and the accumulation of intracellular neurofibrillary tangles composed of paired helical filaments (PHFs) containing hyperphosphorylated tau. This leads to degenerative atrophy throughout the brain tissue, triggering various symptoms, as described above.

[0003] In Alzheimer's disease, a deficiency of neurotransmitters such as acetylcholine is the most important indicator, and restoring this is becoming one of the goals of Alzheimer's disease treatment.

[0004] Parasympathetic drugs used in the treatment of Alzheimer's disease can be divided into muscarinic or nicotinic agonists, cholinesterase inhibitors (ChEIs), and drugs that indirectly regulate acetylcholine release. Among these, many ChEIs have been developed and used, including tacrine, physostigmine, donepezil, rivastigmine, and memantine.

[0005] Second-generation drugs, such as donepezil and rivastigmine, have a longer duration of action and are more stable than first-generation drugs such as tacrine. They also have higher blood-brain barrier (BBB) ​​penetration, which tends to result in higher concentrations in the central nervous system. While first-generation drugs nonselectively inhibit acetylcholinesterase (AChE), butyrylcholinesterase (butyrylcholinesterase), and other peripheral cholinesterases, some newer drugs are known to have higher selectivity for AChE, thereby reducing the incidence of peripheral side effects. The mechanism of action of these drugs is known to be due to inhibiting the breakdown of acetylcholine (ACh), thereby increasing ACh concentrations within the synapse.

[0006] These existing treatments for Alzheimer's disease have serious side effects due to long-term use, so there is a need to develop new drugs with similar or better pharmacological effects and fewer side effects.

[0007] Accordingly, the purpose of the present invention is to provide a use for preventing, improving or treating Alzheimer's disease containing a novel compound.

[0008] To solve the above problem, the present invention provides a pharmaceutical composition for preventing or treating Alzheimer's disease, which contains a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0009] [Chemical Formula 1]

[0010]

[0011] In the above chemical formula 1,

[0012] This is a single bond or double bond,

[0013] n is an integer from 0 to 1,

[0014] X is CH or N,

[0015] R 1 and R 2may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

[0016] In addition, the present invention provides a health functional food composition for preventing or improving Alzheimer's disease, which contains a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] The present invention relates to the use of a novel compound for the prevention, improvement, or treatment of Alzheimer's disease. The novel compound, PRG-A, exhibited an inhibitory effect on tau protein aggregation. Furthermore, it was confirmed that presenilin 1 was reduced by treatment with the PRG-A compound. In conclusion, the PRG-A compound can be usefully utilized in the development of a therapeutic agent for Alzheimer's disease.

[0018] Figure 1 shows that PRG-A compounds exhibit anti-tau tangle-inhibiting effects. A and B. Tau aggregation induced by Tau-WT and MT overexpression is eliminated by compounds (PRG-A-01-04). C. PRG-A compounds alleviate abnormal tubulin formation induced by Tau-MT overexpression.

[0019] Figure 2 shows the effect of PRG-A compounds on 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 compounds show the result of inhibiting PS1 aggregation in a dose-dependent manner.

[0020] Figure 3 shows the toxic effects of PRG-A compounds.

[0021] Hereinafter, the present invention will be described in detail.

[0022]

[0023] The present invention provides a pharmaceutical composition for preventing or treating Alzheimer's disease, comprising a compound represented by the following chemical formula 1, a hydrate thereof, or a salt thereof.

[0024] [Chemical Formula 1]

[0025]

[0026] In the above chemical formula 1,

[0027] This is a single bond or double bond,

[0028] n is an integer from 0 to 1,

[0029] X is CH or N,

[0030] R 1 and R 2 may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

[0031] Preferably, the compound is When this is a single bond, n is 1, X is CH, and R 1 and R 2 may be the same or different, and may be selected from (C1~C4)alkoxy, hydroxy, or (C1~C4)alkylcarboxy, but is not limited thereto.

[0032] Preferably, the compound is When this double bond is n, an integer from 0 to 1, X is CH or N, and R 1 and R 2 may be the same or different, and may be selected from hydrogen, (C1~C4)alkoxy, hydroxy, halo, nitro or (C1~C4)alkylcarboxy, but is not limited thereto.

[0033] Preferably, the compound may be a compound represented by the following chemical formula 2.

[0034] [Chemical Formula 2]

[0035]

[0036] In the above chemical formula 2,

[0037] n is an integer from 0 to 1,

[0038] R 1 ′ and R 2 ′ may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

[0039] The compound represented by the above chemical formula 1 or chemical formula 2 can be named a PRG-A compound.

[0040] 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.;

[0041] More preferably, the pharmaceutical composition can inhibit the aggregation of tau protein and the aggregation of presenilin 1.

[0042]

[0043] The pharmaceutical composition of the present invention can be prepared using pharmaceutically suitable and physiologically acceptable adjuvants in addition to the active ingredient, and the adjuvants may include solubilizers such as excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, glidants, or flavoring agents. The pharmaceutical composition of the present invention can be preferably formulated as a pharmaceutical composition by additionally including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration. In the composition formulated as a liquid solution, acceptable pharmaceutical carriers are sterile and biocompatible, and may include saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these components. If necessary, other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added. In addition, diluents, dispersants, surfactants, binders and lubricants can be additionally added to formulate the composition into injectable formulations such as aqueous solutions, suspensions and emulsions, pills, capsules, granules or tablets.

[0044] The pharmaceutical formulation 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 formulations of the active compound, etc. The pharmaceutical composition of the present invention may be administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. 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 a disease. Therefore, it can be adjusted according to various factors including the type of disease, the severity of the disease, the types and contents of the active ingredient and other ingredients contained in the composition, the type of formulation, and the patient's age, body weight, general health condition, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs. Although not limited thereto, for example, in the case of adults, the composition of the present invention may be administered once to several times a day at a dosage of 0.01 ng / kg to 10 g / kg.

[0045]

[0046] 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 chemical formula 1, a hydrate thereof, or a salt thereof.

[0047] [Chemical Formula 1]

[0048]

[0049] In the above chemical formula 1,

[0050] This is a single bond or double bond,

[0051] n is an integer from 0 to 1,

[0052] X is CH or N,

[0053] R 1 and R 2may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

[0054] Preferably, the compound is When this is a single bond, n is 1, X is CH, and R 1 and R 2 may be the same or different, and may be selected from (C1~C4)alkoxy, hydroxy, or (C1~C4)alkylcarboxy, but is not limited thereto.

[0055] Preferably, the compound is When this double bond is n, an integer from 0 to 1, X is CH or N, and R 1 and R 2 may be the same or different, and may be selected from hydrogen, (C1~C4)alkoxy, hydroxy, halo, nitro or (C1~C4)alkylcarboxy, but is not limited thereto.

[0056] Preferably, the compound may be a compound represented by the following chemical formula 2.

[0057] [Chemical Formula 2]

[0058]

[0059] In the above chemical formula 2,

[0060] n is an integer from 0 to 1,

[0061] R 1 ′ and R 2 ′ may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

[0062] The compound represented by the above chemical formula 1 or chemical formula 2 can be named a PRG-A compound.

[0063] 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.;

[0064]

[0065] 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 acids may be, but are not limited to, citric acid, fumaric acid, adipic acid, lactic acid, or malic acid, the phosphates may be, but are not limited to, sodium phosphate, potassium phosphate, acid pyrophosphate, or polyphosphate (polyphosphate), and the antioxidants may be, but are not limited to, natural antioxidants such as polyphenols, catechins, alpha-tocopherol, rosemary extract, licorice extract, chitosan, tannic acid, or phytic acid.

[0066] In another specific embodiment of the present invention, the health functional food may contain, in addition to the effective ingredient, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the food composition according to one embodiment of the present invention may contain fruit pulp for producing natural fruit juice, fruit juice drinks, and vegetable drinks.

[0067] According to one embodiment of the present invention, the formulation of the health functional food may be in the form of a solid, powder, granule, tablet, capsule, liquid or beverage, but is not limited thereto.

[0068] In addition, the above health functional food can be used in the manufacture of foods such as, but not limited to, confectionery, sugar, ice cream products, dairy products, meat products, fish products, tofu or jelly, edible oils, noodles, tea, beverages, special nutritional foods, health supplements, seasoned foods, ice, ginseng products, kimchi pickled foods, dried foods, fruits, vegetables, dried fruits or vegetables, cut products, fruit juice, vegetable juice, mixed juices thereof, chips, noodles, processed livestock foods, processed fishery foods, processed dairy foods, fermented dairy foods, legume foods, grain foods, microbial fermented foods, confectionery and bakery products, seasonings, processed meat products, acidic beverages, licorice, herbs, etc.

[0069] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

[0070]

[0071] <Experimental Example>

[0072] The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present invention.

[0073]

[0074] 1. Prepare the compound

[0075] The chemical structures and NMR data of the compounds used in the present invention are as follows.

[0076]

[0077] (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)

[0078]

[0079] 1 H NMR (acetone-d6, 400MHz)

[0080] 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) +

[0081]

[0082] (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)

[0083]

[0084] 1 H NMR: EW15731-164-P1D4 (400 MHz, CDCl3)

[0085] 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).

[0086]

[0087] (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)

[0088]

[0089] 1 H NMR (CD2Cl2, 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).

[0090]

[0091] (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)

[0092]

[0093] 1 H NMR (CDCl3, 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).

[0094]

[0095] (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)

[0096]

[0097] 1H NMR (CDCl3, 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).

[0098]

[0099] (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)

[0100]

[0101] 1 H NMR (CD2Cl2, 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).

[0102]

[0103] (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)

[0104]

[0105] 1 H NMR (CDCl3, 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).

[0106]

[0107] (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)

[0108]

[0109] 1H NMR (400 MHz, CDCl3): δH 7.64 (1H, s, H-6'), 7.58 (1H, d, J = 9.6Hz, H-4), 7.56 (1H, d, J = 16.0Hz, 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).

[0110]

[0111] 2. Cell culture and reagents

[0112] HEK293 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) and maintained in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. SK-N-SH cells were purchased from the Korean Cell Line Bank (KCLB, Seoul, South Korea) and maintained in MEM medium containing 10% fetal bovine serum, 1% antibiotics, 25 mM 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, 2 mM glutamine, and 26 mM HEPES without antibiotics.

[0113]

[0114] 3. Western blot analysis

[0115] Proteins were extracted 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. Samples were separated by SDS-PAGE and transferred to PVDF membranes. The blotted membranes were blocked with 3% skim milk containing TBST buffer for 1 h and incubated with specific antibodies. The reacted antibodies were detected by electrophoresis (ECL) and exposure to X-ray film. HA (sc-7392) and GFP (green fluorescent protein; sc-8036) were purchased from Santa Cruz biotechnology (Santa Cruz, CA, USA). Actin antibodies (66009-1-lg) and α-tubulin antibodies (66240-1-lg) were obtained from Proteintech (Rosemont, IL, USA). Anti-TH antibodies (NB300-109) were purchased from Novus Biologicals (CO, USA). HRP-conjugated goat anti-mouse, goat anti-rabbit, and mouse anti-goat antibodies (Pierce, Thermo Fisher Scientific, Inc., Rockford, IL, USA) were used as secondary antibodies. After incubation, cells were harvested with TNN buffer (50 mM Tris-Cl, pH 7.5, 150 mM NaCl, 0.3% NP-40) and centrifuged at 14,000 rpm for 30 min. The pellet (insoluble) and supernatant (soluble) were separated. The input represents the whole cell lysate (WCL) harvested with RIPA buffer. Actin was used as a loading control.

[0116]

[0117] 4. Immunofluorescence staining

[0118] Cells on coverslips were washed with PBS, fixed with 4% paraformaldehyde (PFA) for 30 min at room temperature, and then permeabilized with 0.1% Triton X-100 / PBS for 10 min. After treating the cells with blocking solution (3% anti-human antibody diluted 1:500 in PBS) for 1 h, the cells were incubated with HA (diluted 1:500 in blocking solution) overnight at 4°C. Finally, the cells were incubated with FITC- and rhodamine-conjugated secondary antibodies for 6 h at 4°C. Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI), and the endoplasmic reticulum (ER) was stained with ER-Tracker Red dye for 10 min. 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).

[0119]

[0120] 5. Transfection of vectors

[0121] 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 150 mM NaCl buffer, and the mixture was incubated for 15 minutes. The mixture was added to cells in serum-free medium for 4 hours. After incubation, the cells were replaced with culture medium supplemented with 10% FBS.

[0122]

[0123] 6. Measurement of cell viability

[0124] To investigate cell viability, cells were treated with a chemical (PRG-A compound) for 48 h. Then, the 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. The excess solution was removed, washed with PBS, and the precipitated material was dissolved in 200 μL of DMSO and quantified by measuring the absorbance at 540 nm.

[0125]

[0126] <Example 1>

[0127] To determine the effect of PRG-A compounds on tau aggregation (tau tangles), we transfected HEK293 cells with the indicated vectors (Tau-WT, Tau-P301L) and treated them with the selected compounds (5 μM) for 24 hours. Cells were harvested with TNN buffer, centrifuged at 14,000 rpm for 30 minutes, and the pellet (insoluble) and supernatant (soluble) were separated (Fig. 1A and B). Transfected mutant tau (P301L) also recovered an insoluble fraction due to aggregation (Fig. 1A). However, treatment with PRG-A-01 and PRG-A-02 clearly reduced the insoluble mutant tau fraction (Fig. 1A). A similar effect was also observed with treatment with PRG-A-04 (Fig. 1B). Cells were also transfected with the 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 immunofluorescence was performed using an α-tubulin antibody (white arrow, high Tau intensity) (Fig. 1C). As a result, abnormal tubulin arrangement (yellow arrow) and mutant Tau aggregation (white arrow) were normalized or dissolved by PRG-A compound (Fig. 1C). Chem-001 (decursinol) showed minimal effect in inhibiting Tau aggregation.

[0128]

[0129] <Example 2>

[0130] Furthermore, mutations in presenilin 1 (PS1) are known to be associated with Alzheimer's disease (AD). Therefore, to determine the effect of PRG-A compounds on PS1 expression and localization, cells were transfected with PS1-HA or PS1-GFP vectors for 24 h. After incubation, cells were treated with PRG-A compounds (5 μM) for 24 h. Cells were fixed with 4% PFA and stained with HA antibodies (green) and ER (red) to monitor PS1 inclusions (white arrows, high intensity of PS1) (Figures 2A and B). Ectopically expressed PS1 formed aggregates in the cytoplasm (Figures 2A and B). In contrast, PRG-A-compounds could solubilize PS1 aggregates in IF staining (Figures 2A and B). To confirm the inhibitory effect of PRG-A compounds on PS1 aggregation, SK-N-SH cells were transfected with the indicated vector (PS1-HA) and then treated with the selected compounds (PRG-A-01 and PRG-A-02) for 24 hours. SDS-PAGE was performed using an HA antibody (Fig. 2C). Indeed, oligomeric PS1 was reduced by treatment with PRG-A compounds (Fig. 2C). Considering these results, PRG-A compounds may also be useful for the prevention or treatment of Alzheimer's disease.

[0131]

[0132] <Example 3>

[0133] Finally, to investigate the toxicity of the PRG-A compounds, human normal fibroblasts and neuroblastoma cells (SK-N-SH) were cultured with each compound for 48 hours, and cell viability was measured using the MTT assay. The effects on viability in neuronal cells and normal fibroblasts were confirmed (Fig. 3). Compounds PRG-A-01, 02, and 04 did not exhibit cytotoxic effects in normal human fibroblasts. Compound PRG-A-03 showed a low effect on cell viability at high doses (50 and 100 μM). In summary, since the novel compounds did not show toxicity up to 50 μM in normal cells, it is believed that the side effects of the novel compounds are not serious.

[0134] In conclusion, the novel compound can be used to treat Alzheimer's disease (AD) without serious side effects.

[0135]

[0136] While specific aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing or treating Alzheimer's disease, comprising a compound represented by the following chemical formula 1, a hydrate thereof, or a salt thereof: [Chemical Formula 1] In the above chemical 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 be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

2. In the first paragraph, the compound When this is a single bond, n is 1, X is CH, and R 1 and R 2 A pharmaceutical composition for preventing or treating Alzheimer's disease, characterized in that each of which may be the same or different and is selected from (C1~C4)alkoxy, hydroxy or (C1~C4)alkylcarboxy.

3. In the first paragraph, the compound When this double bond is n, an integer from 0 to 1, X is CH or N, and R 1 and R 2 A pharmaceutical composition for preventing or treating Alzheimer's disease, characterized in that each of which may be the same or different and is selected from hydrogen, (C1~C4)alkoxy, hydroxy, halo, nitro or (C1~C4)alkylcarboxy.

4. In the first paragraph, 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)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], (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)propanoate2-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-(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)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3-acetoxyphenyl)acrylate (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 A pharmaceutical composition for preventing or treating Alzheimer's disease, characterized by being selected from the group consisting of (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[3,2-g]chromen-2-one].

5. In the first paragraph, the compound is a pharmaceutical composition for preventing or treating Alzheimer's disease, characterized by being represented by the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, n is an integer from 0 to 1, R 1 ′ and R 2 ′ may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

6. A pharmaceutical composition for preventing or treating Alzheimer's disease, characterized in that the pharmaceutical composition in claim 1 inhibits aggregation of tau protein and aggregation of presenilin 1.

7. A health functional food composition for preventing or improving Alzheimer's disease, comprising a compound represented by the following chemical formula 1, a hydrate thereof, or a salt thereof: [Chemical Formula 1] In the above chemical 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 be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

8. In the 7th paragraph, the compound When this is a single bond, n is 1, X is CH, and R 1 and R 2 A health functional food composition for preventing or improving Alzheimer's disease, characterized in that each may be the same or different and is selected from (C1~C4)alkoxy, hydroxy or (C1~C4)alkylcarboxy.

9. In paragraph 7, the compound When this double bond is n, an integer from 0 to 1, X is CH or N, and R 1 and R 2 A health functional food composition for preventing or improving Alzheimer's disease, characterized in that each may be the same or different and is selected from hydrogen, (C1~C4)alkoxy, hydroxy, halo, nitro or (C1~C4)alkylcarboxy.

10. In the 7th paragraph, 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)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], (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)propanoate2-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-(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)-8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl (E)-3-(3-acetoxyphenyl)acrylate (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 A health functional food composition for preventing or improving Alzheimer's disease, characterized by being selected from the group consisting of (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[3,2-g]chromen-2-one].

11. In the 7th paragraph, the compound is a health functional food composition for preventing or improving Alzheimer's disease, characterized by being represented by the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, n is an integer from 0 to 1, R 1 ′ and R 2 ′ may be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, hydroxy, halo, nitro, cyano or (C1~C4)alkylcarboxy.

Images