JP2015189693A - Sirt1 activator and use of the sirt1 activator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the use of a novel compound which can be used for a Sirt1 activator.SOLUTION: This invention provides a Sirt1 activator comprising at least one of compounds represented by chemical formulae 1-4 as an active ingredient, and a humectant, an aging prevention/inhibition agent, and cosmetics and food and drink, all of which comprise the Sirt1 activator.

Description

  The present invention relates to a Sirt1 activator and use of the Sirt1 activator.

  Skin keratinization (a keratinocyte layer or stratum corneum, which is a thin barrier film derived from the epidermis) prevents invasion of toxins, microorganisms / viruses, allergens, etc. from the outside world. Functions as a barrier to protect The skin keratin also functions to control moisture evaporation from the body surface (having a moisturizing function) so that moisture is not lost transiently from the living body surface.

  However, with age, the epidermal metabolism decreases, the keratinocyte layer becomes difficult to peel off, and it tends to dry and become a dry skin. In such a state, the hand cracks and induces pain, and soft skin such as the back becomes bulky and induces itching. For this reason, when moisturizing cream is applied to the skin and the water is replenished and smoothed, it becomes difficult to feel itching, so skin care with a moisturizing agent is performed.

  On the other hand, moisturizers that contain natural ingredients as active ingredients have attracted attention in recent years for safety and security. For example, Patent Document 1 discloses a humectant containing a fermented soybean product or an extract thereof aged for 2 years or more as a humectant derived from a natural material.

JP 2013-126966 A

  An object of the present invention is to provide a novel humectant that can be substituted for a conventionally known humectant derived from a natural material.

  In view of the current state of the prior art as described above, the present inventors have intensively studied. As a result, the present inventors have found that the linoleic acid derivative that has been focused on conventionally has a Sirt1 activation action. And based on this knowledge, it came to complete this invention.

  That is, according to one embodiment of the present invention, the following chemical formulas 1 to 4:

In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.

In the formula, R ² is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.

In the formula, R ³ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.

In the formula, R ⁴ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
The Sirt1 activator which contains at least 1 sort (s) of the compound represented by as an active ingredient is provided.

  ADVANTAGE OF THE INVENTION According to this invention, the novel moisturizing agent which can substitute for a conventionally well-known moisturizing agent derived from a natural material, and its use (a moisturizing agent, an anti-aging / prevention agent) are provided.

In an Example, it is the chromatogram obtained when the compound was isolated by HPLC conditions 1. In an Example, it is the chromatogram obtained when the compound was isolated by HPLC conditions 2. In an Example, it is a photograph which shows the result of having evaluated Sirt1 protein expression.

  One embodiment of the present invention has the following chemical formula 1:

In the formula, ^{R 1} is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
Compound 1, represented by the following chemical formula 2:

In the formula, R ² is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
Compound 2, represented by the following chemical formula 3:

In the formula, R ³ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
And the following chemical formula 4:

In the formula, R ⁴ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
It is a Sirt1 activator which contains at least 1 sort (s) selected from the group which consists of the compound 4 represented by these as an active ingredient.

  The inventors of the present application have conducted intensive studies on a new moisturizing agent that can be substituted for a conventionally known natural material-derived moisturizing agent. On the other hand, J Invest Dermatol, 2009, 129, 41-49 reports that the Sirt1 protein promotes the differentiation of normal human keratinocytes (keratinocytes). For this reason, when the expression promoting effect of the Sirt1 protein was examined for certain linoleic acid derivatives (compounds 1 to 4 of the above chemical formulas 1 to 4) using the expression of the Sirt1 protein as an index of the moisturizing effect, an increase in the expression of the Sirt1 protein It has been found to show an effect. For this reason, it is speculated that the linoleic acid derivative can be used to effectively promote epidermal metabolism (skin keratinization).

Sirtuin belongs to class III of HDAC (histone deacetylase) and is an enzyme (NAD-dependent deacetylase group) that deacetylates lysine residues of proteins in an NAD ⁺ dependent manner. It is. Sirtuin proteins act to regulate biological functions and are thought to be associated with increased lifespan. In particular, it has been suggested that the activity of Sirt1 and Sirt2 mainly contributes to aging. For this reason, it is speculated that the linoleic acid derivative (compounds 1 to 4 of the above chemical formulas 1 to 4) having an effect of increasing the expression of Sirt1 protein can be used to effectively prevent aging.

  Therefore, it is expected that the above compounds 1 to 4 can be suitably used as a humectant or an anti-aging / preventing agent. In addition, the said mechanism is estimation and this invention is not limited at all by the said estimation.

  Embodiments of the present invention will be described below. In addition, this invention is not limited only to the following embodiment.

  In the present specification, “X to Y” indicating a range means “X or more and Y or less”, and “weight” and “mass”, “wt%” and “mass%”, “part by weight” and “ “Part by weight” is treated as a synonym. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.

  The Sirt1 activator of the present invention has the following chemical formulas 1-4:

In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
Compound 1, represented by the following chemical formula 2:

In the formula, R ² is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
Compound 2, represented by the following chemical formula 3:

In the formula, R ³ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
And the following chemical formula 4:

In the formula, R ⁴ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
As an active ingredient, at least one compound selected from the group consisting of compound 4 represented by the formula: The “Sirt1 activator” means an agent having an action of promoting the expression of Sirt1 protein and / or promoting the differentiation of epidermal keratinocytes as compared to the absence of a compound. In addition, the Sirt1 protein expression improvement effect by the Sirt1 activator is, for example, after culturing epidermal keratinocytes in the presence of a predetermined concentration of compounds (compounds 1 to 4), and then from epidermal keratinocytes (culture). The protein can be collected and evaluated by Western blot analysis by comparing the expression level of the collected protein with a comparison target (DMSO added instead of the compound).

  The Sirt1 activator having such a function can be used for applications such as promoting moisturizing action, preventing aging, or promoting wound healing, for example. Therefore, the Sirt1 activator can be used as a moisturizer, an anti-aging agent (in this specification, also simply referred to as “anti-aging agent”), a wound healing agent, an anti-cancer agent or the like.

  In this specification, the compound represented by Chemical Formula 1 is represented by “Compound 1”, the compound represented by Chemical Formula 2 is represented by “Compound 2”, the compound represented by Chemical Formula 3 is represented by “Compound 3”, and Chemical Formula 4 The compounds represented by are respectively referred to as “compound 4”.

  The Sirt1 activator of the present invention contains at least one of the aforementioned compounds 1 to 4 as an active ingredient. Here, the Sirt1 activator may contain the above compounds 1 to 4 alone or in the form of a mixture of two or more. Here, “containing as an active ingredient” means that the Sirt1 activator according to the present invention is an amount (that is, an effective amount) of a compound 1 to 1 sufficient to exert a desired Sirt1 protein expression promoting (improving) effect. 4 means that at least one of 4 is contained.

In the above chemical formulas 1 to 4, R ^{1 to} R ⁴ are each independently a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. Here, as a C1-C10 alkyl group, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group , A cyclohexyl group, an n-octyl group, a 2-ethylhexyl group, a nonyl group, a decyl group and the like. Among them, examples of the alkyl group having 1 to 10 carbon atoms include a methyl group, an n-propyl group, and an n-butyl group. Group, isobutyl group, tert-butyl group, n-hexyl group, cyclohexyl group or 2-ethylhexyl group is preferable, methyl group, ethyl group, n-butyl group, isobutyl group or 2-ethylhexyl group is more preferable, methyl group or More preferred is an ethyl group. However, it is most preferable that each of R ^{1 to} R ⁴ is a hydrogen atom. Compound 1 in which R ^{1 in} formula 1 is a hydrogen atom is 13-oxo-9Z, 11E-octadecadienoic acid. In addition, Compound 2 in which R ^{2 in} formula 2 is a hydrogen atom is 13-oxo-9E, 11E-octadecadienoic acid. Compound 3 in which R ^{3 in} formula 3 is a hydrogen atom is 9-oxo-10E, 12Z-octadecadienoic acid. Compound 4 in which R ^{4 in} formula 4 is a hydrogen atom is 9-oxo-10E, 12E-octadecadienoic acid.

About the compounds 1-4 which are the active ingredients of the Sirt1 activator which concerns on this form, when a commercial item exists, what obtained the said commercial item may be used, or what was synthesize | combined itself may be used. Good. Moreover, you may use what was extracted and refine | purified from the natural product depending on the case. As described in Examples below, the present inventors have determined that R ^{1 to} R ^{4 in} each of the above chemical formulas 1 to 4 are derived from an edible portion of Cynara scolymus, which is a perennial plant belonging to the genus Chrysanthemum. You may extract the compound (compounds 1-4) which is a hydrogen atom. At this time, for example, the method described in Japanese Patent Application No. 2013-72616 filed on March 29, 2013 by the applicant of the present application can be preferably used. In more detail, it is also possible to obtain the compounds 1 to 4 according to the present invention by using a method described in Examples described later or a method obtained by partially modifying the method.

  The compounds represented by the chemical formulas 1 to 4 described above may be the compounds themselves, and include pharmaceutically acceptable salts, prodrugs and solvates of the compounds as long as they are applicable. For example, a salt can be formed between a cation and a negatively charged group on the compound. Suitable cations include sodium cations, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. The compounds also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which can provide active compounds upon administration to a subject. Solvate means a complex formed between an active compound and a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid and ethanolamine.

  As described above, the compounds represented by Chemical Formulas 1 to 4 according to the present invention promote Sirt1 protein expression. Here, the Sirt1 protein is known to function to promote the differentiation of normal human keratinocytes (keratinocytes) (J Invest Dermatol, 2009, 129, 41-49). For this reason, the Sirt1 activator containing the compound represented by the above chemical formulas 1 to 4 as an active ingredient according to the present invention promotes the metabolism (skin keratinization) of the epidermis, thereby promoting moisturizing action and / or aging. Thus, the Sirt1 activator of the present invention having a preventive / preventive action is useful as a humectant and / or an aging preventive / preventive agent. That is, the present invention also provides a humectant and an aging preventive / preventive agent containing the Sirt1 activator of the present invention.

  In the present invention, one or more of compounds 1 to 4 may be used as they are as a Sirt1 activator. However, compounds 1 to 4 are contained in an effective amount as an active ingredient, and Sirt1 activation (Sirt1 protein expression) As long as the (promoting) effect is not impaired, the Sirt1 activator according to the present invention comprises a composition (drug / drug composition) together with a pharmaceutically acceptable carrier and other additives according to the desired product form. It may be configured. Further, the Sirt1 activator according to the present invention is mixed with additives such as excipients and is suitable for parenteral administration, oral administration or external administration, as well as pharmaceutical compositions such as pharmaceuticals and quasi drugs, It can be used in the form of food, cosmetics, etc. For example, according to a preferred embodiment of the present invention, a skin external preparation composition comprising a Sirt1 activator comprising at least one of the above-described compounds 1 to 4 as an active ingredient and a pharmaceutically acceptable carrier. Is provided. When the skin external preparation composition is a pharmaceutical product, it can be used, for example, for moisturizing the skin and promoting wound healing. Moreover, when the said skin external preparation composition is cosmetics, it can be used for uses, such as suppression / prevention of aging.

  The dosage when the Sirt1 activator of the present invention is used as a pharmaceutical varies greatly depending on the age, weight, symptoms, etc. of the patient, but generally, in the case of oral administration, the dry weight ranges from 1 to 2000 mg / day. It is desirable that When mix | blending with a foodstuff, it is preferable to set it as the density | concentration range of 0.01-50 mass% in view of the effect, the scent at the time of addition, and the point of a color tone.

  For use in medicine, a therapeutically effective amount of the above compound (at least one of compounds 1-4) is formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the medicament (pharmaceutical composition) according to the present invention can be specifically formulated for administration in solid or liquid form. Examples of oral administration include liquid medicine (aqueous solution or non-aqueous solution or suspension), tablet, bolus, powder medicine, granule, paste for application to the tongue. For parenteral administration, for example, as a sterile solution or suspension, for example, a formulation for subcutaneous, intramuscular or intravenous injection, or a dosage form for topical use or administration into the vagina or rectum And can be formulated. In particular, when it is used as an external preparation for skin, its form is not particularly limited. Examples of pharmaceuticals include forms such as sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. For cosmetics, lotion, cosmetic emulsion, cosmetic cream, cosmetic gel, cosmetic liquid, pack, foundation, lipstick, lip balm, lip gloss, facial cleanser, body soap, hand cream, shampoo, rinse Examples of the form of skin care products such as hair styling products or makeup products are illustrated. Of these, lotions, cosmetic gels, cosmetic emulsions, cosmetic creams, and cosmetics are preferred, and lotions, cosmetic emulsions, and cosmetic creams are more preferred because they can be applied to a wide range of sites.

  As used herein, “therapeutically effective amount” refers to an agent (at least one of compounds 1-4) that is effective to produce any desired therapeutic effect at a reasonable benefit / risk ratio applicable to any medical treatment. 1) or the amount of the composition (the total amount if the active substance is a mixture of two or more). For example, the dose of the Sirt1 activator according to the present invention varies depending on the target disease, administration subject, administration route, etc., but the dose can easily vary depending on the subject's body weight and other conditions. It can be appropriately selected by a trader. Ultimately, a therapeutically effective dose will be determined by the attending physician, with due consideration of the above aspects.

  “Pharmaceutically acceptable” means that within the scope of good medical judgment, commensurate with a reasonable benefit / risk ratio, and without problems and complications such as excessive toxicity, irritation, and allergic reactions, in humans and animals. Used to refer to compounds, materials, compositions, and / or dosage forms suitable for use in contact with tissue.

  “Pharmaceutically acceptable carrier” refers to a liquid or solid filler involved in carrying or transporting the Sirt1 activator of the present invention from one organ or part of the body to another organ or part of the body. Means a pharmaceutically acceptable material, composition or excipient, such as a diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the dosage form and not injurious to the patient. Some of the materials that can function as pharmaceutically acceptable carriers are exemplified below: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate. Cellulose and its derivatives; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; fats and oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; propylene Glycols such as glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; Buffering agents such as magnesium and aluminum hydroxide; including and compatible substances other non-toxic to be used in the drug formulation; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution. In some embodiments, the drug formulation is non-pyrogenic. That is, those that do not increase the patient's body temperature are preferred.

  In addition, wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, and colorants, release agents, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants are also pharmaceuticals (pharmaceutical compositions). May be present in the product).

  Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, etc .; ascorbyl palmitate, butylhydroxy Oil-soluble antioxidants such as anisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like Such a metal chelating agent can also be contained as needed.

  Suitable dosage forms of the invention for oral administration are also in the form of capsules, sachets, pills, tablets, lozenges (with seasoned active ingredients, usually sucrose and gum arabic or tragacanth), powders, granules Well, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or pastry tablets (such as gelatin and glycerin, or sucrose and gum arabic) An inert base is used) and / or a gargle and the like, each containing a predetermined amount of the compound of the present invention as an active ingredient. The agent of the present invention may be administered as a bolus, electuary or paste.

  In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is one or more pharmaceuticals such as sodium citrate or dicalcium phosphate. A top acceptable carrier and / or mixed with any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; eg carboxymethylcellulose, alginate, gelatin , Polyvinylpyrrolidone, binders such as sucrose and / or gum arabic; humectants such as glycerol; disintegration such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate Agents; dissolution retardants such as paraffin; 4 Absorption enhancers such as ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and Lubricants such as mixtures thereof; and colorants. In the case of capsules, tablets and pills, the drug composition may comprise a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules with excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be binders (eg, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium glycolate starch or crosslinked sodium carboxymethylcellulose), surfactants Alternatively, it can be prepared using a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Solid dosage forms such as tablets of the drug (pharmaceutical composition) according to the present invention, such as sugar-coated tablets, capsules, pills and granules, are optionally scored or enteric coatings well known in the field of drug dispensing, etc. And may be prepared using coatings and shells. They use, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile, and slow or controlled release of the internal active ingredient. May be formulated to provide. They may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved in a sterile injectable medium such as sterile water immediately before use. . The medicament (pharmaceutical composition) may optionally comprise an opacifier and releases one or more active ingredients only in certain parts of the gastrointestinal tract or preferentially in an optionally delayed manner. It may be a composition. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient may be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, inert diluents commonly used in the art, such as water and other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Like fatty acid esters of benzyl, propylene glycol, 1,3-butadiene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan Solubilizers and emulsifiers, and mixtures thereof.

  In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents. Suspensions may be suspended in addition to the active compound, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. A turbidity agent may be included.

  Dosage forms of the drug composition of the present invention for rectal or vaginal administration may be presented as a suppository. This suppository is a mixture of one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and one or more agents of the present invention. Which is solid at room temperature but liquid at body temperature, it will melt in the rectum or vaginal cavity and release the active compound.

  The dosage forms of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray dosage forms containing carriers as known to be suitable in the art.

  Dosage forms for topical or transdermal administration of one or more Sirt1 activators of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active agent may be mixed under sterile conditions with a pharmaceutically acceptable base material and, if necessary, preservatives, buffers, or propellants.

  Ointments, pastes, creams and gels, in addition to the active compounds according to the invention, contain animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and oxidation An excipient may be included such as zinc, or a mixture thereof.

  Powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The spray may further comprise customary high pressure gases such as chlorofluorinated hydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

  Transdermal patches have the further advantage of controlled delivery of the Sirt1 activator of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the Sirt1 activator of the present invention in a suitable medium. Absorption enhancers can also be used to increase the flux of substances containing the Sirt1 activator of the present invention across the skin. The speed of such flux can be controlled by either providing a speed control membrane or by dispersing the compound in a polymer matrix or gel.

  A drug (pharmaceutical composition) having a Sirt1 activator of the present invention suitable for parenteral administration, together with one or more active compounds of the present invention (at least one of compounds 1-4), one or more Pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted in sterile injectable solutions or dispersions just before use, which are antioxidants , Buffers, bacteriostats, solutes that make the preparation isotonic with the blood of the intended recipient, or suspensions or concentrates.

  Examples of suitable aqueous and non-aqueous carriers that can be used in a medicament having a Sirt1 activator of the present invention (pharmaceutical composition) include water, ethanol, polyol (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and There are suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. The inherent fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersants and by the use of surfactants.

  The drug (drug composition) may contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbate and the like. It is preferable to include isotonic agents such as sugar and sodium chloride in the composition. In addition, prolonged absorption of the injectable drug form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

  According to this invention, the food / beverage products containing the Sirt1 activator mentioned above are also provided. Here, it is preferable that the said food / beverage products contain the said Sirt1 activator in a suitable quantity so that the effective component of the active ingredient of a Sirt1 activator may be included. Here, “including an effective amount of an active ingredient” means that the active ingredient is contained in such an amount that an effect as an active ingredient can be exhibited as a result of ingesting an amount of each food or drink normally consumed. You may mix | blend the active ingredient which concerns on this invention with the food / beverage products which concern on this invention as it is or in the form of the Sirt1 activator as mentioned above. In addition, the food and drink according to the present invention are prepared as food and drink by adding conventional additives such as stabilizers to the active ingredient according to the present invention, various proteins, sugars, fats, trace elements, vitamins, etc. It may be prepared by further blending them, liquid, semi-liquid or solid, paste, or a general food or drink with active ingredients added.

  In the present invention, the “food or drink” is not a drug and is not particularly limited as long as it is in a form that can be taken orally by mammals, and the form is also a liquid (solution, suspension, emulsion). Liquid, etc.), semi-liquid, powder, or solid molded product. Therefore, the food and drink may be in the form of a beverage, for example, or may be in the form of a dietary supplement tablet such as a supplement.

  Specific examples of food and drink include instant noodles, retort foods, canned foods, microwave foods, instant soups and miso soups, freeze-dried foods, etc .; soft drinks, fruit juice drinks, vegetable drinks, soy milk drinks, coffee Beverages such as beverages, tea beverages, powdered beverages, concentrated beverages, nutritional beverages, alcoholic beverages; flour products such as bread, pasta, noodles, cake mixes, fried flour, bread crumbs; rice cakes, caramels, chewing gums, chocolates, cookies, Confectionery such as biscuits, cakes, pies, snacks, crackers, Japanese confectionery, dessert confectionery; sauces, processed tomato seasonings, flavor seasonings, cooking mixes, sauces, dressings, soups, curry and stew Seasonings; processed fats and oils, butter, margarine, mayonnaise, etc .; milk drinks, yogurts, lactic acid bacteria drinks Dairy products such as ice cream and cream; processed fishery products such as fish ham and sausages and fish paste products; processed livestock products such as livestock ham and sausages; canned agricultural products, jams and marmalades, pickles, boiled beans, cereals, etc. Processed agricultural products; frozen foods; nutritional foods.

  The food / beverage products which concern on this invention can be used suitably with respect to the person who wants promotion of wound healing as mentioned above and prevention of aging.

  In the present invention, “food and beverage” includes foods classified as health foods, functional foods, foods for specified health use, dietary supplements, foods with a disease risk reduction label, or foods for the sick. Is done. Furthermore, the term “food or drink” can be used to include feed when used for mammals other than humans. The food for specified health here refers to any legal restrictions in each country (for example, Japan) from the viewpoint of health when manufacturing or selling food for the purpose of prevention and / or improvement of hypertension. It means food that may be received. Such a food may be a food that indicates that the food may reduce the risk of disease, that is, a food with a disease risk reduction label. Here, the disease risk reduction label is a label for foods that may reduce the disease risk, and is based on or based on the standard established by the FAO / WHO Joint Food Standards Committee (Codex Committee). The display may be a prescribed display or an approved display with reference to FIG.

  In the food / beverage products of this invention, in addition to the active ingredient mentioned above, you may further add the component which has another function. Further, for example, the active ingredient of the present invention is added to foods, health foods, functional foods and supplements (for example, foods containing one or more vitamins such as minerals such as calcium and magnesium and vitamin K) consumed in daily life. By mix | blending, in addition to the effect by this invention, the food / beverage products which have the function based on another component can be provided.

  According to another aspect of the present invention, it is a food or drink containing the aforementioned Sirt1 activator, and has the desired functions (moisturizing effect, aging prevention / prevention effect, wound healing promoting effect, etc.) A food or drink with the function indication is provided. Here, the function display attached to the food or drink can be attached to, for example, any of the main body of the product, the container, the packaging, the instruction, the attached document, or the promotional material.

  In the production of foods and drinks according to the present invention, sugars, fragrances, fruit juices, food additives, stabilizers and the like that are used in the usual food and beverage product design can be added as appropriate. Manufacture of food-drinks can be implemented with reference to a manufacturing technique well-known in the said technical field. The food / beverage products according to the present invention can take various forms, and the food / beverage products according to the present invention may be manufactured according to known pharmaceutical manufacturing techniques. In that case, it can be produced using a carrier or an additive as described in the item of production of the Sirt1 activator or drug (drug composition) according to the present invention. Moreover, in a manufacturing stage, it is good also as multifunctional food / beverage products by combining with the other component which exhibits functions other than the function in this invention, or another functional food.

  When administering or ingesting the pharmaceutical composition and food or drink according to the present invention, the dose or intake of the active ingredient according to the present invention is the recipient, the age and weight of the recipient, symptoms, administration time, dosage form, administration It can be determined depending on the method, the combination of drugs and the like. In the present invention, the dose or intake of the composition or food / drink per day is taken into consideration so that at least the amount of the active ingredient per day necessary for obtaining the Sirt1 activation effect can be administered or taken. It is preferable to appropriately set the content in the composition or food or drink.

  Therefore, the pharmaceutical composition or food or drink according to the present invention preferably contains at least one of compounds 1 to 4 as active ingredients per day per adult, preferably 30 to 6000 mg, more preferably Includes an amount provided in the range of 50-2000 mg, more preferably 100-1000 mg.

  Hereinafter, preferred embodiments of the present invention will be described in more detail by way of examples. However, the technical scope of the present invention should not be construed as being limited to the following examples. In the following examples, the operation was performed at room temperature (25 ° C.) unless otherwise specified. Unless otherwise specified, “%” and “part” mean “% by weight” and “part by weight”, respectively.

≪Extraction and purification of compounds 1-4 from artichoke≫
To 600 g of the edible portion of dried artichoke, 2300 mL of ethyl acetate was added and extracted at 80 ° C. for 2 hours. After the extract was filtered, the solvent was removed under reduced pressure to obtain 17.5 g of an artichoke ethyl acetate extract. The same extraction was performed again to obtain a total of 32.3 g of extract. After dissolving 32.3 g of the obtained extract in 10 mL of ethyl acetate, 30 g of silica gel was added and dried under reduced pressure with an evaporator to prepare a sample layer. 700 g of silica gel was packed in a chromatographic tube, and the previously prepared sample layer was laminated to produce dry column chromatography. Elution was started with a hexane: ethyl acetate mixed solvent (mixing ratio, 2: 3), and 1400 mL of the eluate was collected per fraction and separated into four fractions. Subsequently, the second fraction was sequentially subjected to dry column chromatography using hexane: ethyl acetate: acetic acid mixed solvent (mixing ratio, 80: 20: 1) and hexane: acetone: methanol (mixing ratio, 40: 8: 1). Fractionation gave 300 mg of crude fraction. Subsequently, about 300 mg of the obtained crude fraction was dissolved in 2.0 mL of dichloromethane, and then 2.0 mL of acetonitrile was added. The solution was filtered through a 0.45 μm membrane filter and subjected to the following separation operation by HPLC.

  The chromatogram obtained under these conditions is shown in FIG. As shown in FIG. 1, three main peaks were observed in the crude fraction. Hereinafter, these will be referred to as peak 1 (Rt: 10.9), peak 2 (Rt: 11.8), and peak 3 (Rt: 12.5), respectively. “Rt” means retention time (minutes).

Subsequently, as a result of performing a fractionation operation on the three main peaks, each peak was purified (peak 1 45 mg; peak 2 22.9 mg; peak 3 22.1 mg).

  Furthermore, the peak 1 obtained above was purified by subjecting it to the following separation operation by HPLC.

  The chromatogram obtained under these conditions is shown in FIG. As is clear from FIG. 2, peak 1 was found to be a mixture, and two main peaks were observed. Hereinafter, these are referred to as peak 1-1 (Rt: 19.8) and peak 1-2 (Rt: 22.1), respectively. “Rt” means retention time (minutes).

  Then, as a result of performing fractionation operation about said peak 1-1 and peak 1-2, it came to the refinement | purification of each peak (peak 1-1 19.5 mg; peak 1-2 17.2 mg).

≪Identification of each compound by instrumental analysis≫
The peaks 1-1, 1-2, 2 and 3 obtained above were identified by instrumental analysis as follows. As a result, the compound corresponding to peak 1-1 is 13-oxo-9Z, 11E-octadecadienoic acid (compound 1); the compound corresponding to peak 1-2 is 13-oxo-9E, 11E- Octadecadienoic acid (compound 2); the compound corresponding to peak 2 is 9-oxo-10E, 12Z-octadecadienoic acid (compound 3); the compound corresponding to peak 3 is 9-oxo- It was found to be 10E, 12E-octadecadienoic acid (Compound 4).

<< Sirt1 protein expression of isolated compound on human keratinocytes >>
Epidermal keratinocytes were cultured at 37 ° C. in the presence of 5% CO ₂ using normal human epidermal keratinocyte growth medium (Kurabo) and seeded in 6-well plates. The cultured cells were further incubated at 37 ° C. for 24 hours in the presence of 5% CO ₂ , and then Compound 1 isolated above was added to 10 μM and 25 μM, respectively. As a control, 1 μl of DMSO alone was added. After adding Compound 1 or DMSO and incubating at 37 ° C. in the presence of 5% CO ₂ for 72 hours, the protein was recovered from epidermal keratinocytes (culture), and protein expression of Sirt1 was confirmed by Western blotting. evaluated. The results are shown in FIG.

FIG. 3 shows that Compound 1 according to the present invention significantly improves the expression of Sirt1 protein. From this result, it is expected that the Sirt1 activator according to the present invention exhibits an excellent moisturizing action / anti-aging action. Therefore, the Sirt1 activator according to the present invention is a very superior one that can be used for humectants and anti-aging / prevention agents.

Claims (7)

The following chemical formulas 1-4:
In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
In the formula, R ² is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
In the formula, R ³ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
In the formula, R ⁴ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
A Sirt1 activator comprising, as an active ingredient, at least one selected from the group consisting of compounds represented by:   A humectant containing the Sirt1 activator according to claim 1.   An anti-aging / preventing agent comprising the Sirt1 activator according to claim 1.   A cosmetic comprising the Sirt1 activator according to claim 1.   Food / beverage products containing the Sirt1 activator of Claim 1. A food or drink containing an effective amount of the Sirt1 activator according to claim 1,
A food and drink having a moisturizing function and / or a function for inhibiting / preventing aging, and a function indication thereof.   The food or drink according to claim 6, which is a health food, a functional food, a food for specified health use, a dietary supplement, a food with a disease risk reduction label, or a food for a sick person.