Pharmaceutical composition for preventing or treating dementia, containing isoquinoline derivative as active ingredient

Abstract

A pharmaceutical composition for preventing or treating dementia diseases, containing, as an active ingredient, an isoquinoline derivative compound or a pharmaceutically acceptable salt thereof, of the present invention, does not induce cytotoxicity and can alleviate learning and memory abnormalities in an animal model of Alzheimer's dementia, and thus is expected to be effectively used in the development of therapeutic agents for dementia diseases.

Description

Pharmaceutical composition for preventing or treating dementia containing an isoquinoline derivative as an active ingredient

[0001] The present invention relates to the use of novel isoquinoline derivative compounds for the prevention, improvement, and / or treatment of dementia.

[0002] This application claims priority to Korean Patent Application No. 10-2023-0150820, filed on November 3, 2023, the entire disclosure of which is incorporated herein by reference.

[0003]

[0004] Alzheimer's disease (AD) is the most common form of dementia, beginning with a subjective cognitive stage characterized by frequent forgetfulness, progressing to Mild Cognitive Impairment (MCI) and evolving into severe and advanced dementia after approximately 10 years. Depending on the cause, dementia can be categorized into Alzheimer's disease (AD), vascular dementia, and dementia caused by alcoholism, trauma, or the sequelae of Parkinson's disease. Of these, Alzheimer's disease accounts for the most common, at 60%.

[0005] According to the World Health Organization (WHO), it is predicted that 1 in 85 people worldwide will suffer from dementia in 2050, and 43% of dementia patients will require intensive care. The number of dementia patients in Korea is also rapidly increasing. In 2012, the number of elderly people with dementia in Korea was estimated to be 540,000, and it is expected to increase by approximately 1.27 million in 2013 and approximately 2.71 million in 2050, doubling approximately every 20 years.

[0006] The representative drugs currently used for dementia patients are donepezil, tacrine, rivastigmine, galantamine, etc., which are drugs that inhibit the breakdown of acetylcholine precursors or acetylcholine. Since they are mainly cholinergic drugs, they cannot be administered together with other cholinergic drugs, they can neutralize the effects of anticholinergic drugs, and they have cardiovascular side effects. In addition, they must be used with caution in patients with a history of severe asthma or obstructive pulmonary disease.

[0007] Although much research is ongoing to develop treatments for Alzheimer's disease, more than 99% of efforts have not yielded significant results, making the development of new treatments urgently needed. In particular, given the characteristics of Alzheimer's disease, it is of utmost importance to find a drug that can effectively treat and prevent Alzheimer's disease while having low toxicity due to long-term administration.

[0008]

[0009] Accordingly, the inventors of the present invention have made efforts to find a drug that can effectively treat and prevent dementia, and as a result, have confirmed that the isoquinoline derivative compound of the present invention significantly improves memory ability in an animal model of Alzheimer's dementia, thereby completing the present invention.

[0010] Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating dementia, comprising an isoquinoline derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] Another object of the present invention is to provide a food composition for preventing or improving dementia, comprising an isoquinoline derivative compound or a food-related acceptable salt thereof as an active ingredient.

[0012]

[0013] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0014]

[0015] In order to achieve the above object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating dementia disease, which comprises an isoquinoline derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] [Chemical Formula 1]

[0017]

[0018]

[0019] In one embodiment of the present invention, the dementia disease may be, but is not limited to, Alzheimer's dementia.

[0020] In addition, the present invention provides a food composition for preventing or improving dementia disease, which comprises an isoquinoline derivative compound represented by the above chemical formula 1 or a food-related acceptable salt thereof as an active ingredient.

[0021] In one embodiment of the present invention, the food composition may be a health functional food composition, but is not limited thereto.

[0022] In addition, the present invention provides a composition comprising an isoquinoline derivative compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, improving, or treating dementia.

[0023] In addition, the present invention provides a method for preventing or treating dementia, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an isoquinoline derivative compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0024] In addition, the present invention provides a use of an isoquinoline derivative compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for preventing or treating dementia disease.

[0025] In addition, the present invention provides a method for preparing an isoquinoline derivative compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0026]

[0027] A pharmaceutical composition for preventing or treating dementia, comprising the isoquinoline derivative compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, is expected to be useful in the development of a treatment for dementia, as it can improve learning and memory abnormalities in an animal model of Alzheimer's disease without inducing cytotoxicity.

[0028]

[0029] Figure 1 shows the results of analyzing the cytotoxicity of the isoquinoline derivative compound of the present invention using an MTT assay.

[0030] Figures 2a to 2c show the results of analyzing the effects of the isoquinoline derivative compound of the present invention on cell proliferation and cell shape.

[0031] Figure 3a is a schematic diagram of the long-term strengthening analysis method used in the present invention.

[0032] Figure 3b shows the results of analyzing the effect of the isoquinoline derivative compound of the present invention on improving learning and memory ability in an Alzheimer's disease mouse model.

[0033]

[0034] The present invention provides a pharmaceutical composition for preventing or treating dementia disease, comprising an isoquinoline derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0035] [Chemical Formula 1]

[0036]

[0037]

[0038] In the present invention, the compound represented by the chemical formula 1 may have the IUPAC name of 13-allyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium iodide.

[0039] In the present invention, the dementia disease may be Alzheimer's dementia disease, but is not limited thereto.

[0040] In the present invention, the term "Alzheimer's dementia" refers to dementia symptoms caused by Alzheimer's disease. Alzheimer's disease is the most common degenerative brain disease that causes dementia, first reported by Dr. Alzheimer of Germany. It is known that as Alzheimer's disease progresses, overall cognitive function, including memory, gradually deteriorates.

[0041] In one embodiment of the present invention, it was confirmed that the isoquinoline derivative compound did not exhibit cytotoxicity (see Examples 2 and 3).

[0042] In another embodiment of the present invention, it was confirmed through a long-term enhancement assay that the isoquinoline derivative compound improves memory ability in an Alzheimer's disease mouse model (see Example 4).

[0043] In the present invention, "long-term potentiation" refers to a phenomenon in which signal transmission between two neurons is continuously enhanced by simultaneous stimulation of the neurons. Long-term potentiation is considered a key cellular mechanism for learning and memory. Long-term potentiation is formed by strengthening synapses between neurons through new protein synthesis, thereby increasing the ability of presynaptic and postsynaptic neurons to transmit signals through the synapse. Long-term potentiation is applied to various types of learning, from classical conditioning to complex higher cognitive functions.

[0044] In the present invention, the term “pharmaceutically acceptable salt” includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.

[0045] As used herein, the term “pharmaceutically acceptable” means a compound or composition that is suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problems or complications, and with a reasonable benefit / risk ratio, and is within the scope of sound medical judgment.

[0046] Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, they can be prepared by heating equimolar amounts of the compound and the acid or alcohol in water, followed by evaporation of the mixture to dryness, or by suction filtration of the precipitated salt.

[0047] Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as the metal salt, and the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0048] The scope of the compounds of the present invention may include not only pharmaceutically acceptable salts, but also all isomers, hydrates and solvates that can be prepared by conventional methods.

[0049] The pharmaceutical composition according to the present invention may further comprise suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. The excipients may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials, and controlled-release additives.

[0050] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, ellipsoids, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, ointments, lotions, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, according to a conventional method, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.

[0051] Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

[0052] When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0053] The additives of the tablets, powders, granules, capsules, pills, and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC), HPMC 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Disintegrants such as carboxymethylcellulose calcium, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, baking soda, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid;Lubricants such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.

[0054] As additives of the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc. can be used.

[0055] The syrup according to the present invention may include a solution of white sugar, other sugars, or sweeteners, and may also include a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity modifier, and the like, as needed.

[0056] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0057] The suspension according to the present invention may include suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, and HPMC 2910, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

[0058] The injection according to the present invention includes a solvent such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; a solubilizing agent such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nitrile acid amide, hexamine, and dimethylacetamide; a buffer such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; It may include isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; oxidizing agents such as sodium bisulfite 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium cis-methylenediamine, sodium alginate, Tween 80, and aluminum monostearate.

[0059] The suppository according to the present invention comprises cocoa butter, lanolin, withepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecovi (W, R, S, M, Fs), Tezester triglyceride basis (TG-95, MA, 57) can be used.

[0060] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0061] Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0062] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.

[0063] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents. It can be administered sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that achieves maximum efficacy with minimal side effects. This amount can be readily determined by those skilled in the art to which the present invention pertains.

[0064] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All modes of administration are conceivable, including oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, oral or nasal spraying, dermal administration, and transdermal administration.

[0065] The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with various related factors such as the disease to be treated, route of administration, age, sex, weight of the patient, and severity of the disease.

[0066] In addition, the present invention provides a use of a composition comprising an isoquinoline derivative compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, improving, or treating dementia.

[0067] In addition, the present invention provides a method for preventing or treating dementia, comprising a step of administering an isoquinoline derivative compound according to the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0068] In addition, the present invention provides the use of an isoquinoline derivative compound according to the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of dementia disease.

[0069] In addition, the present invention provides a method for preparing an isoquinoline derivative compound according to the present invention or a pharmaceutically acceptable salt thereof.

[0070] In the present invention, the method for preparing the isoquinoline derivative compound or a pharmaceutically acceptable salt thereof may include, but is not limited to, the steps of dissolving berberine in a first solvent, adding acetone, and stirring; filtering, washing, and drying the solid produced by adding water; placing the dried solid in a second solvent, adding allyl iodide, and stirring; and obtaining the compound by adsorbing the mixture to silica and then separating it using silica gel chromatography purification.

[0071] In the present invention, the first solvent may be an aqueous sodium hydroxide solution, and the second solvent may be anhydrous CH2Cl2, but is not limited thereto.

[0072] In the present invention, “subject” means a subject requiring treatment for a disease, and more specifically, may be a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow, but is not limited thereto.

[0073] In the present invention, “administration” means providing a predetermined composition of the present invention to an individual by any appropriate method.

[0074] In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, “treatment” means any action that improves or beneficially changes a target disease and its metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administering a composition according to the present invention.

[0075] In addition, the present invention provides a food composition for preventing or improving dementia disease, which comprises an isoquinoline derivative compound according to the present invention or a food-wise acceptable salt thereof as an active ingredient.

[0076] In the present invention, the term “food-wise acceptable salt” includes a salt derived from a food-wise acceptable organic acid, inorganic acid, or base.

[0077] When the isoquinoline derivative compound of the present invention or its food-related acceptable salt is used as a food additive, it can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the compound of the present invention can be added in an amount of 15 wt% or less, or 10 wt% or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount can be below the above range, and since there is no problem in terms of safety, the active ingredient can also be used in an amount above the above range.

[0078] There are no specific restrictions on the types of the above foods. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and all health functional foods in the conventional sense are included.

[0079] The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages. The natural carbohydrates mentioned above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g, per 100 mL of the composition of the present invention.

[0080] In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, 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 composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients may be used independently or in combination. The proportion of these additives is not particularly critical, but is typically selected within the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0081] In the present invention, the food composition may be a health functional food composition, but is not limited thereto.

[0082] In the present invention, the term "functional health food" is the same as food for special health use (FoSHU), and refers to a food with high medical or healthcare effects that is processed to efficiently exhibit a bioregulatory function in addition to providing nutrition, and may be manufactured in the form of tablets, capsules, pills, granules, powders, liquids, flakes, pastes, syrups, gels, jellies, bars, or films. Here, "functionality" means regulating nutrients for the structure and functions of the human body or obtaining a useful effect for health purposes such as physiological actions.

[0083] The health functional food of the present invention can be manufactured using methods commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly used in the art. Furthermore, unlike conventional drugs, it has the advantage of being food-based, eliminating the side effects that can occur with long-term use of drugs, and can be highly portable.

[0084]

[0085] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[0086]

[0087] Example 1. Synthesis of isoquinoline derivatives

[0088] 1-1. Synthesis of CD1-386

[0089] The isoquinoline derivative according to the present invention refers to a compound represented by the following chemical formula 1.

[0090] [Chemical Formula 1]

[0091]

[0092] 13-allyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium iodide (CD1-386)

[0093]

[0094] Synthetic route:

[0095] Berberine (0.5 g, 1.3 mmol) was dissolved in a 5N sodium hydroxide aqueous solution (20 mL) in a dried round flask, and acetone (5 mL) was added dropwise at 0 °C and stirred for 6 h. After concentration under reduced pressure, cold water (30 mL) was added, and the resulting solid was filtered, washed with distilled water, and dried under vacuum. The dried solid (0.4 g, 1 mmol) was placed in a pressure tube under anhydrous CH2Cl2 (10 mL), and allyl iodide (1.8 g, 10 mmol) was added and stirred at 100 °C for 4 h. After this, the mixture was concentrated under reduced pressure, adsorbed onto silica, and separated using silica gel chromatography purification (CH2Cl2: acetone = 50:1 → 15:1 v / v) to synthesize compound CD1-386 with a yield of 35%.

[0096]

[0097] 1-2. NMR analysis

[0098] NMR results

[0099] CD1-386 1H NMR (CDCl3, 400 MHz) δ(s, 1H), 7.81 (s, 2H), 7.36 (s, 1H), 6.87 (s, 1H), 6.41-6.34 (m, 1H), 6.08 (s, 2H), 5.45 (d, J = 10.8 Hz, 1H), 5.15 (br, 2H), 4.96 (d, J = 17.6 Hz, 1H), 4.40 (s, 3H), 4.06 (s, 3H), 4.00 (br, 2H), 3.27 (t, J = 5.6 Hz, 2H)

[0100]

[0101] Example 2. Cytotoxicity test

[0102] To confirm whether CD1-386 synthesized in Example 1 exhibits cytotoxicity, the MTT assay, which is commonly used in cytotoxicity tests, was performed. BEAS-2B cells, a human normal lung cell line, were treated with CD1-386 at concentrations of 2.5 μM, 5 μM, and 10 μM, and cultured for 24 hours, after which the MTT assay was performed.

[0103] As a result, as shown in Fig. 1, no significant decrease in cell viability was observed even when treated with the highest concentration of 10 μM, and this result indicates that CD1-386 has low cytotoxicity.

[0104]

[0105] Example 3. Experiment to analyze the effects on cell proliferation and shape

[0106] To determine whether CD1-386 synthesized in Example 1 affects cell proliferation and induces cell morphology changes, proliferation assays and microscopic observations were performed. BEAS-2B cells were treated with CD1-386 at a concentration of 5 μM for 24 hours, and then cultured continuously, and cell numbers were measured using tryphan blue staining.

[0107] As a result, as shown in Fig. 2a, cell proliferation at the same rate as the control cell line not treated with the drug was observed.

[0108] Additionally, BEAS-2B cells were treated with CD1-386 at a concentration of 5 μM for 24 hours in 60 mm culture dishes, and then cultured continuously, and the number of colonies formed after 2 weeks was compared. As a result, as shown in Fig. 2b, no significant difference was observed between the CD1-386 treatment group and the untreated control group.

[0109] Accordingly, it was confirmed through the above Figures 2a and 2b that CD1-386 does not inhibit cell proliferation.

[0110] Additionally, BEAS-2B cell line and human lung epithelial cell HEK293 cell line were treated with CD1-386 at a concentration of 5 μM for 24 hours, and then the cell morphology was observed under a microscope.

[0111] As a result, as shown in Fig. 2c, it was confirmed that no significant change in cell size or shape was observed, and the results further support the low cytotoxicity of CD1-386.

[0112]

[0113] Example 4. Therapeutic effect in an animal model of Alzheimer's disease

[0114] To confirm whether CD1-386 synthesized in Example 1 exhibits a therapeutic effect in an animal model of Alzheimer's disease, memory ability was measured using a long-term potentiation (LTP) assay.

[0115] Specifically, the CD1-386 was intranasally administered once daily for 4 weeks at a concentration of 0.25 mg / kg or 0.5 mg / kg to C57-Tg(NSE-hPS2*N1411): Tg(NSE-hAPPsw) / Korl (APP / PS2) mice, an Alzheimer's disease mouse model, and LTP was measured. LTP induction was observed by analyzing the field excitatory postsynaptic potential (fEPSP) by Schaffer-Collateral fiber stimulation after placing each hippocampal slice sample in a recording chamber. The LTP-inducing stimulus was applied twice at 100 Hz, and the fEPSP was recorded for 60 minutes. During the experiment, 30 ℃ aCSF was perfused at a rate of 2-3 ml / min, and the obtained experimental results are shown in Fig. 3b.

[0116] As a result, it was confirmed that LTP was not induced in mice not treated with CD1-386, whereas LTP was normally induced in mice treated with CD1-386 at a concentration of 0.25 mg / kg or 0.5 mg / kg.

[0117] From the above, it was found that CD1-386 of the present invention has the effect of significantly improving the memory ability of Alzheimer's disease animals.

[0118]

[0119] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0120]

[0121] The isoquinoline derivative compound of the present invention or a pharmaceutically acceptable salt thereof does not induce cytotoxicity and has the effect of improving learning and memory abnormalities in an animal model of Alzheimer's disease, and is therefore expected to be useful in the development of a treatment for dementia, and thus has industrial applicability.

Claims

1. A pharmaceutical composition for preventing or treating dementia, comprising an isoquinoline derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] 2. In paragraph 1, A pharmaceutical composition for preventing or treating dementia, characterized in that the above dementia disease is Alzheimer's dementia disease.

3. A food composition for preventing or improving dementia, comprising an isoquinoline derivative compound represented by the following chemical formula 1 or a food-related acceptable salt thereof as an active ingredient: [Chemical Formula 1] 4. In paragraph 3, A food composition for preventing or improving dementia, characterized in that the food composition is a health functional food composition.

5. In paragraph 3, A food composition for preventing or improving dementia, characterized in that the above dementia is Alzheimer's dementia.

6. A method for preventing or treating dementia, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an isoquinoline derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 7. Use of a composition containing an isoquinoline derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of dementia: [Chemical Formula 1] 8. Use of an isoquinoline derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for preventing or treating dementia: [Chemical Formula 1]

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