JP2016074650A - Itch preventive or improving agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an itch preventive or improving agent which can prevent or improve skin itch early by inhibiting MrgprX1 activity.SOLUTION: The invention provides an itch preventive or improving agent by inhibiting MrgprX1 activity to inhibit the flow of calcium ion through MrgprX1 into cells, the agent containing at least one compound selected from (1) galaxolide, (2) diacetyl, (3) suzararu, and (4) trance-2-decanal as an active ingredient.SELECTED DRAWING: None

Description

  The present invention relates to an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, and an agent for preventing or improving itching.

  Skin diseases such as atopic dermatitis, dry skin and urticaria are accompanied by “itching” which is one of the skin sensations. Such itching is temporarily eliminated by scratching the skin. However, scratching the skin may form secondary skin lesions. Therefore, it is clinically important to prevent or ameliorate itch and control (relieve) itch.

Histamine is known as an inducing substance in the living body. When histamine is released in vivo and binds to the histamine receptor, the histamine receptor is activated. Histamine receptors are expressed in sensory nerves such as C fibers that recognize itch. When the histamine receptor is activated by histamine, itching of the skin is induced through sensory nerves.
Antihistamines are widely used to treat such itch caused by histamine. This antihistamine is effective for the treatment of acute skin diseases such as urticaria.

However, there is also a non-histamine-dependent itch that shows resistance to antihistamines. Non-histamine-dependent itch is known to be chronic itch such as atopic dermatitis, dry skin, and itch caused by sweating.
There are many receptors other than histamine receptors in sensory nerves that recognize itch, and one of them is known as MrgprX1. This MrgprX1 is activated by chloroquine or bovine adrenal medullary peptide (8-22) (hereinafter also referred to as “BAM (8-22)”). Non-patent document 1 describes that when MrgprX1 is activated, itching is induced via sensory nerves such as C fibers, and that antihistamines have little effect on this itching. Furthermore, it is described in Non-Patent Document 2 that mice lacking mouse MrgprA3 corresponding to human MrgprX1 do not cause chronic itching due to atopic dermatitis or dry skin.

  Therefore, inhibiting MrgprX1 activity is very important in preventing or improving chronic itch. To date, in order to mitigate pruritus by inhibiting the activity of MrgprX1, 3-substituted-2- (diphenylmethyl) -1-azabicyclo [2.2.2] octane (3-substituted-2- (diphenylmethyl) -1- The administration of compounds such as azabicyclo [2.2.2] octane) is described in US Pat.

International Publication No. 2010/065085

J. Neurosci., 2011, 31 (20), p. 7563-7567 Nat. Neurosci., 2013, 16 (2), p. 174-182

An object of the present invention is to provide an MrgprX1 activity inhibitor that inhibits MrgprX1 activity.
Another object of the present invention is to provide an inhibitor of calcium ion influx into cells via MrgprX1, which suppresses the inflow of calcium ions into cells via MrgprX1.
Furthermore, this invention makes it a subject to provide the itch prevention or improvement agent which prevents or improves the itch of skin early.

The present inventors have intensively studied in view of the above problems. As a result, it has been found that the compounds represented by the following formulas (1) to (4) have an action of inhibiting the activity of MrgprX1 and suppressing the inflow of calcium ions into the cell via MrgprX1. Furthermore, it discovered that these compounds have the effect | action which prevents or improves the itching of skin.
The present invention has been completed based on these findings.

The present invention comprises a compound represented by the following formula (1), a compound represented by the following formula (2), a compound represented by the following formula (3), and a compound represented by the following formula (4). The present invention relates to an MrgprX1 activity inhibitor comprising at least one compound selected from the group as an active ingredient.
The present invention also includes a compound represented by the following formula (1), a compound represented by the following formula (2), a compound represented by the following formula (3), and a compound represented by the following formula (4). The present invention relates to an inhibitor of calcium ion inflow into cells via MrgprX1, comprising at least one compound selected from the group consisting of
The present invention further includes a compound represented by the following formula (1), a compound represented by the following formula (2), a compound represented by the following formula (3), and a compound represented by the following formula (4). The present invention relates to an agent for preventing or improving itchiness comprising at least one compound selected from the group consisting of as active ingredients.

The MrgprX1 activity inhibitor of the present invention can inhibit MrgprX1 activity.
Moreover, the inhibitor of the inflow of calcium ions into cells via MrgprX1 of the present invention can suppress the inflow of calcium ions into cells via MrgprX1.
Furthermore, the itching preventive or ameliorating agent of the present invention can prevent or ameliorate itching at an early stage.

10 is a graph showing the results of Test Example 3. FIG. 1 (a) is a graph showing changes in relative fluorescence intensity ratios when chloroquine is added to cells expressing MrgprX1. FIG. 1 (b) is a graph showing changes in the relative fluorescence intensity ratio when BAM (8-22) is added to cells expressing MrgprX1. FIG.1 (c) is a graph which shows the change of relative fluorescence intensity ratio when histamine is added to the cell which H1R is expressing. FIG. 1 (d) is a graph showing changes in the relative fluorescence intensity ratio when ATP is added to cells expressing P2Y2. 10 is a graph showing the results of Test Example 5. FIG. 2A is a graph showing the MrgprX1 activity inhibitory action of the compounds represented by formulas (1) to (4). FIG.2 (b) is a graph which shows the H1R activity inhibitory effect of the compound represented by Formula (1)-(4). FIG.2 (c) is a graph which shows the P2Y2 activity inhibitory effect of the compound represented by Formula (1)-(4). 10 is a graph showing the results of Test Example 6. FIG. 3A is a graph showing changes in the total score of itch when the compound represented by formula (1) is applied to the skin in which itch is induced. FIG. 3 (b) is a graph showing changes in the total score of itchiness when Musk ketone is applied to the skin in which itchiness is induced.

In this specification, “MrgprX1” means Mas-related G-protein coupled receptor member X1. This MrgprX1 is a protein encoded by the MRGPRX1 gene in humans.
MrgprX1 is a receptor specific to sensory neurons involved in itching and pain, and is known to control nociceptive stimuli. Specifically, when an agonist such as chloroquine or BAM (8-22) binds to MrgprX1, MrgprX1 is activated. Activation of MrgprX1 stimulates ion channel activation and endoplasmic reticulum, which are involved in the regulation of intracellular calcium concentration. A series of these processes induces an increase in intracellular calcium ion concentration in cells expressing MrgprX1, causing depolarization, and firing sensory nerves involved in nociceptive stimulation, causing pain and itching.
In this specification, “calcium ions flow into cells via MrgprX1” means that activation of MrgprX1 stimulates the activation of ion channels and the endoplasmic reticulum, increasing the intracellular calcium ion concentration. Refers to being triggered.

As used herein, “prevention” refers to preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of developing an individual's disease or symptom.
In the present specification, “improvement” refers to improvement of disease, symptom or condition, prevention or delay of deterioration of disease, symptom or condition, or reversal, prevention or delay of progression of disease, symptom or condition.
Further, in the present specification, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by therapy.

  The MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itch prevention or amelioration agent are represented by the compound represented by formula (1) and formula (2). An active ingredient is at least one compound selected from the group consisting of a compound, a compound represented by formula (3), and a compound represented by formula (4). Further, at least one selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4). By applying a seed compound, it is possible to inhibit MrgprX1 activity, suppress calcium ion influx into cells via MrgprX1, and prevent or improve itching.

The said compound used by this invention may be a commercial item, and can also be manufactured based on a conventional method. Moreover, in this invention, you may use individually by 1 type among the said compounds, and may be used in combination of 2 or more type. The compound includes isomers such as geometric isomers, optical isomers, and stereoisomers. Here, the compound used by this invention is not limited to the compound represented by Formula (1)-(4), The isomer of these compounds is also included. Furthermore, the compound used in the present invention may be any isomer or a mixture of isomers.
Each of the compounds is a highly safe compound that has been conventionally used as a fragrance. Here, common names and IUPAC names of the above compounds are shown below.

Compound represented by formula (1) : Galaxolide: International flavor and fragrance
1,3,4,6,7,8-Hexahydro-4,6,6,7,8,8-hexamethylcyclopenta (γ) -2-benzopyran (1,3,4,6,7,8- Hexahydro-4,6,6,7,8,8-hexamethylcyclopenta (γ) -2-benzopyran)

Compound represented by formula (2) Diacetyl
2,3-butanedione

Compound represented by formula (3) : Suzaral: Takasago International Corporation Silvia: Dibutton
2-methyl-3- [4- (2-methylpropyl) phenyl] propanal (2-methyl-3- [4- (2-methylpropyl) phenyl] propanal)

Compound represented by formula (4) : Trans-2-decenal
Dec-2-enal

As demonstrated in the below-mentioned Example, the compound represented by each of Formula (1)-(4) inhibits MrgprX1 activity, and suppresses the inflow of the calcium ion into a cell through MrgprX1. Furthermore, the compounds represented by formulas (1) to (4) each having an action of inhibiting MrgprX1 activity suppress and relieve the itching of the skin caused by activating MrgprX1 in a short time. Therefore, the compounds represented by formulas (1) to (4) are useful for inhibiting MrgprX1 activity, inhibiting calcium ion influx into cells via MrgprX1, and preventing or improving itching.
In addition, as demonstrated in the below-mentioned Example, the compound represented by each of Formula (1)-(4) acts on MrgprX1 and inhibits MrgprX1 activity. However, the compounds represented by formulas (1) to (4) do not act on the histamine receptor H1R or ATP receptor, which are the same G protein as MrgprX1. Here, the histamine receptor H1R and ATP receptor are receptors that induce itch caused by inflammation, cell injury or the like that induces the production of histamine or ATP. In contrast, MrgprX1 is a receptor that induces itching due to dry skin and atopic dermatitis. Therefore, the compounds represented by formulas (1) to (4), which do not act on histamine receptor H1R or ATP receptor but act on MrgprX1 to inhibit MrgprX1 activity, are particularly nonhistamines to which antihistamines are not effective. Especially useful for prevention or improvement of addictive chronic itching (atopic dermatitis, senile pruritus, contact dermatitis, prurigo, psoriasis, dry skin, itching due to perspiration, itching in delicate areas) It is.

  The form of the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itch prevention or amelioration agent can be appropriately selected. For example, the active ingredient alone may be used as an inhibitor of MrgprX1 activity of the present invention, an inhibitor of calcium ion influx into cells via MrgprX1, and an agent for preventing or improving itching. Alternatively, a pharmaceutical composition comprising the MrgprX1 activity inhibitor of the present invention comprising the active ingredient and a pharmaceutically acceptable carrier, an inhibitor of calcium ion influx into cells via MrgprX1, and an agent for preventing or improving itchiness It may be used as a product. Alternatively, the MrgprX1 activity inhibitor of the present invention, an inhibitor of calcium ion influx into cells via MrgprX1, and an agent for preventing or improving itch may be used as a cosmetic composition, or may be contained in these. .

  When preparing a pharmaceutical composition, it is usually prepared as a preparation containing the active ingredient and preferably a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier generally refers to an inert, non-toxic, solid or liquid, bulking agent, diluent or encapsulating material that does not react with the active ingredient, eg, water. , Ethanol, polyols (for example, propylene glycol, butylene glycol, glycerin, and polyethylene glycol), suitable mixtures thereof, solvents or dispersion media such as vegetable oils, and the like.

  The pharmaceutical composition is orally, parenterally, e.g., in the oral cavity, in the skin, subcutaneously, in the mucosa, intravenously, in the artery, in the muscle, in the abdominal cavity, in the vagina, in the lungs. Administered intracerebrally, ocularly or intranasally. Examples of the preparation for oral administration include tablets, granules, fine granules, powders, capsules, chewables, pellets, syrups, solutions, suspensions and inhalants. Parenteral preparations include suppositories, retention enemas, drops, eye drops, nasal drops, pessaries, injections, mouth washes, and ointments, creams, lotions, gels, controlled release patches And skin external preparations such as patches. The pharmaceutical compositions may be administered parenterally in the form of sustained release subcutaneous implants or in the form of targeted delivery systems (eg, monoclonal antibodies, vector delivery, ion implantation, polymer matrices, liposomes and microspheres). .

  The pharmaceutical composition may further contain additives conventionally used in the pharmaceutical field. Such additives include, for example, excipients, binders, disintegrants, lubricants, antioxidants, coloring agents, corrigents and the like, and can be used as necessary. In order to achieve sustained release so that it can act for a long time, it can also be coated with a known retarder or the like. Excipients include, for example, sodium carboxymethylcellulose, agar, light anhydrous silicic acid, gelatin, crystalline cellulose, sorbitol, talc, dextrin, starch, lactose, sucrose, glucose, magnesium metasilicate magnesium phosphate, calcium hydrogen phosphate, etc. Can be used. Examples of the binder include gum arabic, sodium alginate, ethyl cellulose, sodium caseinate, sodium carboxymethyl cellulose, agar, purified water, gelatin, starch, tragacanth, and lactose. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, crystalline cellulose, starch, hydroxypropyl starch and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, hydrogenated oil, sucrose fatty acid ester, waxes and the like. Examples of the antioxidant include tocopherol, gallic acid ester, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid and the like. Other additives and drugs as required, such as antacids (sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, synthetic hydrotalcite, etc.), gastric mucosa protective agents (synthetic aluminum silicate, sucralfate, copper chlorophyllin sodium, etc.) ) May be added.

  When preparing a cosmetic composition, the form thereof can be selected as appropriate, such as solution, emulsion, powder, water-oil two-layer system, water-oil-powder three-layer system, gel, tablet and other solids, aerosol, It can be in any form such as mist, capsule, and sheet. In addition, the product form of the cosmetic composition is also arbitrary. For example, skin care cosmetics such as face wash, makeup remover, lotion, cosmetic liquid, pack, milky lotion, cream and sunscreen, foundation, makeup base, lipstick, eye Makeup cosmetics such as shadow, eyeliner, mascara, eyebrow, blusher and nail enamel, hair cosmetics such as hair shampoo, hair rinse, hair styling, hair dye and hair restorer, soap, body soap, deodorant cosmetic and bath preparation And other body cleansing agents, oral cosmetics such as dentifrices and mouthwashes, and aromatic cosmetics such as perfumes. In addition, this cosmetic may belong to either a cosmetic or a quasi-drug according to the Japanese Pharmaceutical Affairs Law.

The cosmetic composition includes other components commonly used in cosmetics, quasi drugs and pharmaceuticals, such as powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, anions. Surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickener, film agent, UV absorber, sequestering agent, lower alcohol, polyhydric alcohol , Sugar, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant auxiliaries, fragrances, water, etc. may be blended as necessary and manufactured by conventional methods. it can.
Examples of other components that can be incorporated into the cosmetic composition include preservatives (ethyl paraben, butyl paraben, etc.), anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc. ), Whitening agents (for example, ascorbic acid and its derivatives, placenta extract, saxifrage extract, arbutin, etc.), various extracts (for example, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe , Mallow, iris, grape, yokuinin, loofah, lily, saffron, senkyu, ginger, hypericum, onionis, garlic, capsicum, chimpi, red snapper, seaweed, etc.), activator (eg royal jelly, photosensitizer, cholesterol derivative, etc.) , Blood circulation promoter For example, nonyl acid valenylamide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ictamol, tannic acid, α-borneol, nicotinic acid tocopherol, inositol hexanicotinate, cyclandrate, cinnarizine , Trazoline, acetylcholine, verapamil, cephalanthin, γ-oryzanol, etc.), antiseborrheic agents (eg, sulfur, thianthol, etc.), anti-inflammatory agents (eg, tranexamic acid, thiotaurine, hypotaurine, etc.) and fungicides (eg, triclosan, Cetylpyridinium chloride, thymols, benzalkonium chloride, etc.).

The pharmaceutical composition and the cosmetic composition can be applied in the form of an oral composition, an external composition, an internal use composition, etc., and is preferably applied in the form of a skin external composition.
When used in the form of a composition for external use on the skin, in addition to the above-mentioned active ingredients, the ingredients used for the normal composition for external use of the skin, such as surfactants, oily substances, polymer compounds, preservatives, various medicinal ingredients, powders UV absorbers, dyes, fragrances, emulsion stabilizers, pH adjusters, and the like can be appropriately blended.

  The MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent should be added to foods, beverages, feeds, pet foods and used in combination. Can do. Alternatively, the indication was made based on the concept of treatment, prevention or improvement of diseases or conditions that can be treated, prevented or ameliorated by inhibiting MrgprX1 activity and / or suppressing calcium ion influx into cells via MrgprX1. It can be used by being added to or blended with foods and beverages, that is, health foods, functional foods, foods for the sick, foods for specified health use and the like. The above-mentioned health food, functional food, food for the sick, and food for specified health use are specifically fine granules, tablets, granules, powders, capsules, syrups, liquids, liquid foods, etc. It can be used as a pharmaceutical form. A food in the form of a preparation can be produced in the same manner as a pharmaceutical preparation. The active ingredient and a carrier acceptable as a food, for example, an appropriate excipient (for example, starch, processed starch, lactose, glucose, water, etc.), etc. Can be prepared using conventional means. Furthermore, liquid food compositions such as soups, juices, milk drinks, tea drinks, coffee drinks, cocoa drinks, jelly drinks, sports drinks and diet drinks, semi-solid food compositions such as pudding and yogurt, breads, Udon, noodles, cookies, chocolate, candy, gum, rice crackers and other sweets, sprinkles, butters, jams and other spreads, etc. A food composition can be produced by adding or blending an inflow suppressor or a stagnation preventive or improving agent.

The content of the active ingredient in the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itch prevention or amelioration agent can be determined as appropriate.
For example, in the total amount of the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itch prevention or amelioration agent, the content of the active ingredient is 0.001% by mass or more. Preferably, 0.05 mass% or more is more preferable, 0.1 mass% or more is more preferable, 10 mass% or less is preferable, 1 mass% or less is more preferable, 0.5 mass% or less is more preferable, 0.001 10 mass% is preferable, 0.05-1 mass% is more preferable, 0.1-0.5 mass% is further more preferable.

  The subject of administration or ingestion of the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1 and the itch prevention or amelioration agent is preferably a warm-blooded vertebrate, more preferably a mammal. Is an animal. As used herein, mammals include, for example, humans and non-human mammals such as monkeys, mice, rats, rabbits, dogs, cats, cows, horses, and pigs. The MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the agent for preventing or improving itchiness are suitable for administration to humans.

  The above-mentioned compound used in the present invention, and the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent are skin itching, preferably skin nonhistamine The present invention can be preferably applied to a subject who desires suppression of dependent chronic itching. In addition, the compound used in the present invention, the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent are skin itching, preferably skin. It can be preferably applied under conditions where non-histamine-dependent chronic itching is induced, preferably under dry or sweat conditions. Further, the compound used in the present invention, and the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent are preferably applied to the skin, It is more preferable to apply to the skin where the itch caused by drying or the itch caused by sweating occurs, or the itch caused by the itch caused by the drying or sweating.

In the method for inhibiting the activity of MrgprX1 of the present invention, the method for suppressing the influx of calcium ions into cells via MrgprX1, and the method for preventing or improving itchiness, the effective amount of the active ingredient applied by administration or ingestion is the It can be appropriately determined depending on the condition, body weight, sex, age, activity of the material, administration or intake route, administration or intake schedule, formulation form or other factors. For example, the effective amount of the active ingredient is preferably 0.0015 mg or more, more preferably 0.075 mg or more, preferably 22.5 mg or less, more preferably 2.4 mg or less, or preferably, per kg of body weight per day. Is 0.0015 to 22.5 mg, more preferably 0.075 to 2.4 mg. The active ingredient can be taken or administered once a day to several times a day, or at an arbitrary period and interval.
In the present invention, the dosage of the active ingredient is J.P. Neurosci., 2011, 31 (20), p. It can be determined appropriately according to a conventional method such as the method described in 7563-7567. Moreover, administration or ingestion of the active ingredient may be systemic administration or ingestion, or local administration or ingestion.

  In relation to the above-described embodiments, the present invention further discloses the following MrgprX1 activity inhibitor, inhibitors of the inflow of calcium ions into cells via MrgprX1, agents for preventing or improving itch, use and methods.

<1> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4) An inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx through MrgprX1, or an agent for preventing or improving itchiness, comprising one compound as an active ingredient.

<2> The MrgprX1 activity inhibitor according to <1>, wherein the MrgprX1 is human-derived MrgprX1, or an inhibitor of calcium ion influx into cells via MrgprX1.
<3> The itch prevention or amelioration agent according to <1>, wherein the itch is prevented or ameliorated by inhibiting MrgprX1 activity.
<4> The itching is a non-histamine-dependent chronic itching, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, psoriasis, itching with dryness (dry skin), itching with sweating Or the itch in the delicate area, more preferably the itch due to drying or the itch due to sweating, or the itch prevention or improvement agent according to <1> or <3>.
<5> In the total amount of the above-mentioned MrgprX1 activity inhibitor, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness, the content of the active ingredient is 0.001% by mass or more, Preferably, it is 0.05% by mass or more, more preferably 0.1% by mass or more, 10% by mass or less, preferably 1% by mass or less, more preferably 0.5% by mass or less, <1 An inhibitor of MrgprX1 activity according to any one of> to <4>, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness.

<6> a compound represented by formula (1), represented by formula (2) as an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness Use of at least one compound selected from the group consisting of a compound represented by formula (3), and a compound represented by formula (4):
<7> a compound represented by formula (1) for producing an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itch, Formula (2) Use of at least one compound selected from the group consisting of a compound represented by formula (3), a compound represented by formula (3), and a compound represented by formula (4).
<8> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4) A method of using one kind of compound as an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness.
<9> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4) A method for inhibiting MrgprX1 activity, a method for suppressing the inflow of calcium ions into cells via MrgprX1, or a method for preventing or improving itchiness, wherein one compound is applied.
<10> The use or method according to any one of <6> to <9>, wherein the MrgprX1 is human-derived MrgprX1.
<11> The use or method according to any one of <6> to <10>, wherein the itching is prevented or improved by inhibiting the activity of MrgprX1.
<12> The itching is a non-histamine-dependent chronic itching, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, psoriasis, itching due to dryness (dry skin), itching due to sweating Or the use or method according to any one of the above <6> to <11>, which is itchiness in a delicate area, more preferably itchiness due to drying or itchiness due to sweating.
<13> The compound according to any one of <8> to <12>, wherein the compound is applied to a human who desires suppression of skin itching, preferably non-histamine-dependent chronic itching of the skin. Method.
<14> Any one of the above <8> to <13>, which is applied under a condition in which itching of skin, preferably non-histamine-dependent itching of skin, is preferably caused under dry or sweating conditions. The method described in 1.
<15> The above compound <8> to <<, wherein the compound is applied to the skin, preferably the skin that is itchy due to drying or itching, or the skin that is likely to be itchy due to drying or itching. 14. The method according to any one of 14>.
<16> In the total amount of the above-mentioned inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness, the content of the compound is preferably 0.001% by mass or more. Is 0.05% by mass or more, more preferably 0.1% by mass or more, and is 10% by mass or less, preferably 1% by mass or less, more preferably 0.5% by mass or less, <6> Use or method of any one of-<15>.

<17> A compound represented by the formula (1), which is used for the method of inhibiting MrgprX1 activity, the method of suppressing the influx of calcium ions via cells via MrgprX1, or the method of preventing or improving itch, At least one compound selected from the group consisting of a compound represented by formula (3) and a compound represented by formula (4):
<18> a compound represented by formula (1) for producing an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itch, Formula (2) Use of at least one compound selected from the group consisting of a compound represented by formula (3), a compound represented by formula (3), and a compound represented by formula (4).
<19> a compound represented by the formula (1), which is used for inhibition of MrgprX1 activity, inhibition of calcium ion influx into cells via MrgprX1, or non-therapeutic treatment methods for prevention or improvement of itch. Use of at least one compound selected from the group consisting of a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4).
<20> The compound or use according to any one of <17> to <19>, wherein the MrgprX1 is human-derived MrgprX1.
<21> The compound or use according to any one of <17> to <20>, wherein the itching is prevented or improved by inhibiting MrgprX1 activity.
<22> The itch is a nonhistamine-dependent itch, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, psoriasis, dry itch, dry itch, or delicate itch The compound or use according to any one of the above <17> to <21>, which is itch in an area, more preferably itch caused by drying or itch caused by sweating.
<23> The compound according to any one of <17> to <22>, wherein the compound is applied to a human who desires suppression of skin itching, preferably non-histamine-dependent chronic itching of the skin. Compound or use.
<24> The above <17> to <23, wherein the compound is applied under a condition that causes skin itching, preferably non-histamine-dependent chronic itching of the skin, preferably under dry or sweating conditions. > The compound or use of any one of>.
<25> The above-mentioned <17> to <<, wherein the compound is applied to skin, preferably skin with itchiness due to drying or itchiness due to sweating, or skin apt to cause itchiness due to drying or itchiness due to sweating. 24> The compound or the use according to any one of 24>.
<26> The compound or use according to any one of <17> to <25>, wherein the compound is applied in the form of a pharmaceutical composition or a cosmetic composition.
<27> The compound or use according to <26>, wherein the compound is applied in the form of an external composition for skin.
<28> The compound or use according to any one of <17> to <25>, wherein the compound is applied in the form of food, beverage or feed.
<29> The content of the compound is 0.001% by mass or more, preferably 0.05% by mass or more, more preferably 0.1% by mass or more, and 10% by mass or less, preferably 1% by mass or less. The use according to any one of <17> to <28>, which is more preferably 0.5% by mass or less.

<30> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4). A method of inhibiting non-therapeutic MrgprX1 activity, a method of non-therapeutic suppression of the influx of calcium ions via MrgprX1, or a method of preventing or ameliorating non-therapeutic itch by applying an effective amount of one compound.
<31> The method according to <30>, wherein the MrgprX1 is human-derived MrgprX1.
<32> The method according to <30> or <31>, wherein the itching is prevented or improved by inhibiting the activity of MrgprX1.
<33> The itching is a non-histamine-dependent chronic itching, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, psoriasis, itching due to dryness (dry skin), itching due to sweating Or the itch in the delicate area, more preferably the itch due to drying or the itch due to perspiration, and the method according to any one of <30> to <32>.
<34> The compound according to any one of <30> to <33>, wherein the compound is applied to a human who desires suppression of skin itching, preferably non-histamine-dependent chronic itching of the skin. Method.
<35> Any one of the above <30> to <34>, which is applied under conditions in which itching of skin, preferably non-histamine-dependent itching of skin, is caused, preferably under dry or sweating conditions. The method described in 1.
<36> The above compound <30> to <<, wherein the compound is applied to the skin, preferably the skin that is itchy due to drying or itching, or the skin that is likely to be itchy due to drying or itching. 35> The method of any one of 35>.
<37> An effective amount of the compound per day per kg of body weight is 0.0015 mg or more, preferably 0.075 mg or more, 22.5 mg or less, preferably 2.4 mg or less, 30. The method according to any one of <30> to <36>.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.

(Test Example 1) Cloning of receptor gene Using cDNA obtained by reverse transcription of total RNA of human neuroblastoma SK-N-MC cells as a template, using PrimeSTAR GXL DNA Polymerase (trade name, manufactured by TaKaRa) The MRGPRX1 gene, the H1R gene, and the P2Y2 gene were amplified by polymerase chain reaction (PCR).
PCR conditions were 98 ° C. for 2 minutes → [98 ° C. for 15 seconds, 68 ° C. for 1.5 minutes] × 30 cycles → 68 ° C. for 2 minutes. The base sequences of various primers used in PCR are shown in Table 1 below.

The obtained PCR product was purified using High Pure PCR Product Purification Kit (trade name, manufactured by Roche). Then, using pcDNA3.1 Directional TOPO Expression Kit (trade name, manufactured by Life technologies), the purified PCR product was inserted into an expression vector (trade name: pcDNA3.1D / V5His-TOPO, manufactured by Life technologies). Thus, a plasmid for receptor gene expression was constructed. The sequence analysis of the receptor gene insert was entrusted to Takara Bio Inc., and it was confirmed that the human MRGPRX1 gene, the H1R gene, and the P2Y2 gene were each correctly inserted into the expression vector.

(Test Example 2) Introduction of receptor gene into HEK293 cells and strong expression of receptor gene Each of the receptor gene expression plasmids constructed in Test Example 1 was used to transform Escherichia coli JM109 strain. Then, a large number of plasmids for receptor gene expression were extracted and purified using NucleBond Xtra Midi EF (trade name, manufactured by TaKaRa).

Human fetal kidney cells HEK293 were cultured in T-75 cell culture flasks. Then, 8 μg of a plasmid into which each receptor gene was inserted was introduced into 70-80% confluent HEK293 using a transfection reagent (trade name: TransIT-293, manufactured by Mirus) and cultured for 24 hours.
Cells adhered to the culture flask were detached using an adherent cell dispersion reagent (trade name: Detachin, manufactured by Genlantis). The peeled cells were seeded on a 96 well Optical Bottom Plate (trade name, manufactured by Nunc) at 1.5 × 10 ⁴ cells / well and further cultured for 24 hours.
As a control, a plasmid into which lacZ was inserted (trade name: pcDNA3.1D / V5-His / lacZ, Life technologies) was introduced into human fetal kidney cell HEK293, and cells were prepared by the same method as described above. did.

(Test Example 3) Measurement of receptor activity As an indicator of receptor activation, calcium ion influx into cells in which each receptor was strongly expressed was calculated using Calcium Kit II-fluo-4 (trade name, DOJINDO). The measurement was performed using The measurement operation was performed according to the protocol of the kit.
Loading buffer containing a calcium fluorescent indicator (trade name: fluo-4-AM) was added to the cells prepared in Test Example 2 and incubated at 37 ° C. for 1 hour. Thereafter, the fluorescence intensity was measured by FDSS (manufactured by Hamamatsu Photonics) at 37 ° C.
30 seconds after the start of the measurement, agonists of the receptors shown in Table 2 were added to cells expressing any of the receptors of MrgprX1, H1R and P2Y2. Thereafter, the fluorescence intensity was measured every 2 seconds for 300 seconds. The relative fluorescence intensity ratio with respect to the fluorescence intensity before adding the agonist was calculated with the fluorescence intensity before adding the agonist being 1.
The result is shown in FIG. FIG. 1 (a) is a graph showing the change in relative fluorescence intensity ratio when chloroquine is added as a receptor agonist to cells expressing MrgprX1. FIG. 1 (b) is a graph showing changes in the relative fluorescence intensity ratio when BAM (8-22) is added as a receptor agonist to cells expressing MrgprX1. FIG. 1 (c) is a graph showing changes in the relative fluorescence intensity ratio when histamine is added as a receptor agonist to cells expressing H1R. FIG. 1 (d) is a graph showing changes in the relative fluorescence intensity ratio when ATP is added as a receptor agonist to cells expressing P2Y2.

The activities of human-derived MrgprX1, H1R, and P2Y2 were measured based on changes in the amount of calcium flowing into the cells. As a result, as shown in FIGS. 1 (a) to 1 (d), it was confirmed that by adding an agonist of each receptor, the fluorescence intensity increased depending on the concentration of the agonist to be added. That is, it was confirmed that each receptor is activated by adding an agonist.
As a control, when a plasmid in which lacZ was inserted (trade name: pcDNA3.1D / V5-His / lacZ) was introduced, no change in fluorescence intensity was detected.

(Test Example 4) Search for MrgprX1 activity inhibitors In Test Example 3, when BAM (8-22) was added as an agonist of MrgprX1, the final concentration of BAM (8-22) at which MrgprX1 activity was around EC ₅₀ was 0.5 μM.
Therefore, a loading buffer containing a calcium fluorescent indicator (trade name: fluo-4-AM) and BAM (8-22) were added so that the final concentration was 0.5 μM to the cells expressing MrgprX1. . Various materials were further added thereto, and the relative fluorescence intensity ratio was measured in the same manner as in Test Example 3. Then, based on the measured relative fluorescence intensity ratio, the search for MrgprX1 activity inhibitor was performed.

As a result, the compound represented by Formula (1)-(4) was discovered as a raw material which inhibits MrgprX1 activity 80% or more.
In addition, the compound represented by Formula (1)-(4) is conventionally used as a fragrance | flavor. On the other hand, Musk ketone (1- (4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl), which has been conventionally used as a fragrance, like the compounds represented by formulas (1) to (4) ethanone) 's MrgprX1 activity inhibition rate was 11.8%.

(Test Example 5) Receptor activity inhibition test
A loading buffer containing a calcium fluorescent indicator (trade name: fluo-4-AM) was added to cells expressing MrgprX1, cells expressing H1R, and cells expressing P2Y2. To this, a mixed solution of each compound represented by the formulas (1) to (4) with BAM (8-22), histamine, or ATP as an agonist of each receptor was added. The addition amount of an agonist of the receptor activity of each receptor from the results of Test Example 4 was appropriately set so that the vicinity of the EC _50. Moreover, the addition amount of the compound represented by Formula (1)-(4) was set so that a final concentration might be 0-0.01%.
Then, after the mixed solution was added, the fluorescence intensity was measured for 300 seconds, and the maximum value of the relative fluorescence intensity ratio was measured. Furthermore, the value of the maximum relative fluorescence intensity ratio when the compound concentration was 0% was set to 1.0, and each receptor activity was calculated. The result is shown in FIG.

As shown in FIG. 2, MrgprX1 activity was inhibited depending on the concentration of these compounds by adding the compounds represented by formulas (1) to (4). On the other hand, the compounds represented by the formulas (1) to (4) hardly act on H1R and P2Y2, and no action of inhibiting H1R activity and P2Y2 activity was observed.
From the above results, it was confirmed that the compounds represented by the formulas (1) to (4) specifically act on MrgprX1 among G protein-coupled receptors and inhibit MrgprX1 activity.

(Test Example 6) Itching induction test by application of BAM (8-22) and prevention or improvement test of itching
J. Neurosci., 2011, 31 (20), p. With reference to the method described in 7563-7567 (Non-patent Document 1), a stagnation induction test by application of BAM (8-22) and a stagnation prevention or improvement test were performed.

  Apply 10 µL of ethanol to the human skin (extended arm), let stand for 1 minute, and then stab at the same site at 1 mm intervals with a prick lancet, and after 30 seconds, 5 mM BAM (8-22) in HEPES solution 5 μL was applied. Every 30 seconds from the application of BAM (8-22), the itch score of 0 to 10 (0: regarded as itch, 10: worst itch so far) was evaluated for 5 minutes. And the sum total of the itch score evaluated every 30 seconds was calculated as a itch score.

On the other hand, before applying the above-mentioned BAM (8-22), 10 μL of an ethanol solution (concentration: 0.1%) of the compound represented by the formula (1) was applied and allowed to stand for 1 minute. BAM (8-22) was applied on the street. And operation similar to the above was performed, the itch score of 0-10 was each evaluated, and the itch total score was computed.
These results are shown in FIG.

  The total itch score was calculated in the same manner as described above except that Musk ketone was used instead of the compound represented by formula (1). The result is shown in FIG.

As shown in FIG. 3, itching was induced by applying BAM (8-22) to the skin. On the other hand, as shown in FIG. 3A, by applying the compound represented by the formula (1), the total itch score was significantly reduced in a short time. This indicates that the stagnation induced by the application of BAM (8-22) is alleviated in a short time by applying the compound represented by the formula (1).
On the other hand, as shown in FIG. 3 (b), when the Musk ketone which does not have the action of inhibiting the MrgprX1 activity is applied instead of the compound represented by the formula (1), it is prominent in the total itch score. No reduction was observed, and the itch induced by application of BAM (8-22) was not relieved.

(Test Example 7) Prevention or improvement test of itch caused by drying A body lotion (Galaxolide (G) and Placebo (P)) having the composition shown in Table 3 below was prepared,
It was provided in a mist spray bottle (discharge amount per push: 0.1 mL).

  The prevention or improvement test of itchiness was conducted in the winter according to the schedule shown below for 4 healthy men / women who feel itchiness due to dryness in the lower limbs at least once a day in winter.

From the weekend just before using the body lotion of the test article, the usual care for the lower limbs is stopped, and the body lotion (Galaxolide (G) or Placebo (P)) of the test article is applied to the left and right lower limbs for 5 days (monthly). ~ Friday, Week 1) Used.
Then, in the next week (Monday to Friday, Week 2), a test using the body lotion of the test article was performed in the same manner by changing the left and right legs of the test article.
Body lotion was used as appropriate when it was worried about dryness or itching during the day, as well as twice a day after getting up in the morning and after bathing in the evening (before going to bed if not bathing). The maximum amount of body lotion used per day was 3.0 mL each. The itch prevention or amelioration test was a double-blind test, the test article was encoded at the bottled stage, and the subject and data analyst were not notified of the contents of the test article.

<Evaluation of itchiness>
The degree of itching (subjective evaluation) was recorded every night during the period when the body lotion of the test article was used. About the average of the degree of itchiness felt in one day, itchiness (10cmVAS, left edge (0): feel no itchiness, right edge (10): feel very strong itchiness) and itch score (0: itchiness) None, 1: slight itch, 2: weak itch, 3: moderate itch, 4: strong itch, 5: very strong itch. The results are shown in Table 5.

  As shown in Table 5, as a result of analyzing the average value of dry itch 10 cmVAS for 5 days, the average of the degree of itch felt on one day was lowered in all four people by using Galaxolide. In addition, the index based on the itch score was confirmed to decrease due to the use of Galaxolide in 2 out of 4 people. In addition, there was a reply that "Galaxolide feels that itching is suppressed", and the effect of mitigating itching by Galaxoldie was felt.

<Degree of dryness>
During the period when using the body lotion of the test article, a score (subjective evaluation) of the degree of skin dryness was recorded every night (0: no dryness, 1: slight dryness, 2: slightly dryness) Felt 3: moderately dry, 4: felt strongly dry, 5: felt very dry).
As a result, the average score of the degree of dryness felt during the test period was 2.80 on the Placebo side and 2.85 on the Galaxolide side, and the degree of dryness of the skin was unchanged on the left and right.

(Test Example 8) Prevention or improvement test of itch caused by sweating In the winter, a itch prevention or improvement test is conducted in the following schedule for one woman who feels itch caused by sweating in the trunk at least once a day in summer Implemented.

From the weekend immediately before using the body lotion of the test article prepared in Test Example 7, the usual care for the trunk is stopped, and Placebo (P) body lotion is placed on the trunk (neck, chest, waist) For 5 days (Monday to Friday).
And next week (Monday to Friday), Galaxolide (G) body lotion was used as well.
Body lotion was used three times a day before going to work in the morning, working during the day, and leaving the evening. The maximum amount of body lotion used per day was 2.0 mL each. The itching prevention or improvement test was a double blind test as in Test Example 7.

<Evaluation of itchiness>
Based on the same evaluation criteria as in Test Example 7, during the period in which the body lotion of the test product was used, the “average of the degree of itchiness felt per day” was evaluated with the itch strength and the itch score. The results are shown in Table 7.

  As shown in Table 7, as a result of analyzing the average values of dry itch 10 cmVAS and itch score for 5 days, both 10 cmVAS and itch score values were reduced when using Galaxolide compared to using Placebo. . Furthermore, when using Placebo, “the neck has a sense of incongruity and itching was accompanied”, whereas when using Galaxolid, “the itching felt on the front side of the neck is relieved in the evening, and itching does not bother me Was the answer. In other words, the effect of easing itchiness by Galaxoldie was felt.

<Degree of sweating>
A score of degree of sweating (subjective evaluation) was recorded every night while using the body lotion of the test article (0: no sweating, 1: slightly sweating, 2: slightly sweating, 3: moderate sweating 4: sweated strongly, 5: sweated very strongly).
As a result, the average score of the degree of sweating felt during the test period was 1.4 for the week using Placebo and 1.6 for the week using Galaxolide, and the week of using Galaxolide tended to have more sweating. It was. That is, when Galaxolide was used, the itch produced by perspiration was alleviated despite the large amount of perspiration.

As described above, itching of the skin was alleviated in a short time by applying a compound having an action of inhibiting MrgprX1 activity. This indicates that a compound having an action of inhibiting MrgprX1 activity is effective in preventing or improving skin itching. Furthermore, it has shown that the compound which has the effect | action which inhibits MrgprX1 activity has the immediate effect with respect to itching that the itching of skin is reduced in a short time.
Furthermore, the results of the above examples show that the compound defined in the present invention has an action of inhibiting the activity of MrgprX1 against non-histamine-dependent chronic itch such as itch caused by drying and itch caused by sweating. It has the effect of preventing or improving.

As demonstrated in the below-mentioned Example, the compound represented by each of Formula (1)-(4) inhibits MrgprX1 activity, and suppresses the inflow of the calcium ion into a cell through MrgprX1. Furthermore, the compounds represented by formulas (1) to (4) each having an action of inhibiting MrgprX1 activity suppress and relieve the itching of the skin caused by activating MrgprX1 in a short time. Therefore, the compounds represented by formulas (1) to (4) are useful for inhibiting MrgprX1 activity, inhibiting calcium ion influx into cells via MrgprX1, and preventing or improving itching.
In addition, as demonstrated in the below-mentioned Example, the compound represented by each of Formula (1)-(4) acts on MrgprX1 and inhibits MrgprX1 activity. However, the compounds represented by formulas (1) to (4) do not act on the histamine receptor H1R or ATP receptor, which are the same G protein as MrgprX1. Here, the histamine receptor H1R and ATP receptor are receptors that induce itch caused by inflammation, cell injury or the like that induces the production of histamine or ATP. MrgprX1 contrast, a receptor that induces pruritus by atopic dermatitis. Therefore, the compounds represented by formulas (1) to (4), which do not act on histamine receptor H1R or ATP receptor but act on MrgprX1 to inhibit MrgprX1 activity, are particularly nonhistamines to which antihistamines are not effective. dependent chronic itching (atopic dermatitis, senile pruritus, contact dermatitis, prurigo, pruritus accompanying sweating, itching in sensitive areas (genital)) is particularly useful for prevention or amelioration of such.

The above-mentioned compound used in the present invention, and the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent are skin itching, preferably skin nonhistamine The present invention can be preferably applied to a subject who desires suppression of dependent chronic itching. In addition, the compound used in the present invention, the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent are skin itching, preferably skin. conditions chronic itching non histamine independent, is raised, preferably to sweating conditions, in preferred applications. Further, the compound used in the present invention, and the MrgprX1 activity inhibitor of the present invention, the inhibitor of calcium ion influx into cells via MrgprX1, and the itching preventive or ameliorating agent are preferably applied to the skin , skin itching due to sweating is occurring, or is more preferable to apply to the skin that tends to occur is itching associated with sweating.

<2> The MrgprX1 activity inhibitor according to <1>, wherein the MrgprX1 is human-derived MrgprX1, or an inhibitor of calcium ion influx into cells via MrgprX1.
<3> The itch prevention or amelioration agent according to <1>, wherein the itch is prevented or ameliorated by inhibiting MrgprX1 activity.
<4> the itching, chronic itching non histamine-dependent, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, pruritus accompanying sweating or itching in sensitive areas, and more preferably itching associated with sweating, and the <1> or <3> itching preventive or ameliorating agent according to claim.
<5> In the total amount of the above-mentioned MrgprX1 activity inhibitor, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness, the content of the active ingredient is 0.001% by mass or more, Preferably, it is 0.05% by mass or more, more preferably 0.1% by mass or more, 10% by mass or less, preferably 1% by mass or less, more preferably 0.5% by mass or less, <1 An inhibitor of MrgprX1 activity according to any one of> to <4>, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness.

<6> a compound represented by formula (1), represented by formula (2) as an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness Use of at least one compound selected from the group consisting of a compound represented by formula (3), and a compound represented by formula (4):
<7> a compound represented by formula (1) for producing an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itch, Formula (2) Use of at least one compound selected from the group consisting of a compound represented by formula (3), a compound represented by formula (3), and a compound represented by formula (4).
<8> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4) A method of using one kind of compound as an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness.
<9> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4) A method for inhibiting MrgprX1 activity, a method for suppressing the inflow of calcium ions into cells via MrgprX1, or a method for preventing or improving itchiness, wherein one compound is applied.
<10> The use or method according to any one of <6> to <9>, wherein the MrgprX1 is human-derived MrgprX1.
<11> The use or method according to any one of <6> to <10>, wherein the itching is prevented or improved by inhibiting the activity of MrgprX1.
<12> the itching, chronic itching non histamine-dependent, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, pruritus accompanying sweating or itching in sensitive areas, and more preferably itching associated with sweating, and the <6> - use or method according to any one of <11>.
<13> The compound according to any one of <8> to <12>, wherein the compound is applied to a human who desires suppression of skin itching, preferably non-histamine-dependent chronic itching of the skin. Method.
<14> itchy skin, preferably itching non histamine-dependent skin conditions were elicited, preferably sweating conditions, in applying, in any one of the above <8> ~ <13> The method described.
<15> applying the compounds skin, preferably skin itching accompanying sweating occurs, or itching prone skin due to sweating, in the <8> ~ any one of <14> The method described in 1.
<16> In the total amount of the above-mentioned inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itchiness, the content of the compound is preferably 0.001% by mass or more. Is 0.05% by mass or more, more preferably 0.1% by mass or more, and is 10% by mass or less, preferably 1% by mass or less, more preferably 0.5% by mass or less, <6> Use or method of any one of-<15>.

<17> A compound represented by the formula (1), which is used for the method of inhibiting MrgprX1 activity, the method of suppressing the influx of calcium ions via cells via MrgprX1, or the method of preventing or improving itch, At least one compound selected from the group consisting of a compound represented by formula (3) and a compound represented by formula (4):
<18> a compound represented by formula (1) for producing an inhibitor of MrgprX1 activity, an inhibitor of calcium ion influx into cells via MrgprX1, or an agent for preventing or improving itch, Formula (2) Use of at least one compound selected from the group consisting of a compound represented by formula (3), a compound represented by formula (3), and a compound represented by formula (4).
<19> a compound represented by the formula (1), which is used for inhibition of MrgprX1 activity, inhibition of calcium ion influx into cells via MrgprX1, or non-therapeutic treatment methods for prevention or improvement of itch. Use of at least one compound selected from the group consisting of a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4).
<20> The compound or use according to any one of <17> to <19>, wherein the MrgprX1 is human-derived MrgprX1.
<21> The compound or use according to any one of <17> to <20>, wherein the itching is prevented or improved by inhibiting MrgprX1 activity.
<22> the itch, non-histamine-dependent itching, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, pruritus accompanying sweating or itching in sensitive areas, and more preferably in perspiration The compound or use according to any one of <17> to <21>, wherein the compound is itch.
<23> The compound according to any one of <17> to <22>, wherein the compound is applied to a human who desires suppression of skin itching, preferably non-histamine-dependent chronic itching of the skin. Compound or use.
<24> itchy skin the compound, preferably under conditions non-histamine-dependent chronic itchy skin, is raised, preferably applied in sweating conditions, the <17> - <23> The compound or use according to any one of the above.
<25> applying the compounds skin, preferably skin itching accompanying sweating occurs, or itching prone skin due to sweating, in the <17> - any one of <24> Or a use according to 1.
<26> The compound or use according to any one of <17> to <25>, wherein the compound is applied in the form of a pharmaceutical composition or a cosmetic composition.
<27> The compound or use according to <26>, wherein the compound is applied in the form of an external composition for skin.
<28> The compound or use according to any one of <17> to <25>, wherein the compound is applied in the form of food, beverage or feed.
<29> The content of the compound is 0.001% by mass or more, preferably 0.05% by mass or more, more preferably 0.1% by mass or more, and 10% by mass or less, preferably 1% by mass or less. The use according to any one of <17> to <28>, which is more preferably 0.5% by mass or less.

<30> At least selected from the group consisting of a compound represented by formula (1), a compound represented by formula (2), a compound represented by formula (3), and a compound represented by formula (4). A method of inhibiting non-therapeutic MrgprX1 activity, a method of non-therapeutic suppression of the influx of calcium ions via MrgprX1, or a method of preventing or ameliorating non-therapeutic itch by applying an effective amount of one compound.
<31> The method according to <30>, wherein the MrgprX1 is human-derived MrgprX1.
<32> The method according to <30> or <31>, wherein the itching is prevented or improved by inhibiting the activity of MrgprX1.
<33> the itching, chronic itching non histamine-dependent, preferably atopic dermatitis, senile pruritus, contact dermatitis, prurigo, pruritus accompanying sweating or itching in sensitive areas, and more preferably itching associated with sweating, and the <30> - the method according to any one of <32>.
<34> The compound according to any one of <30> to <33>, wherein the compound is applied to a human who desires suppression of skin itching, preferably non-histamine-dependent chronic itching of the skin. Method.
<35> itchy skin, preferably a non-histamine-dependent itchy skin, conditions were elicited, preferably sweating conditions, in applying, the <30> - to any one of <34> The method described.
<36> the skin of said compounds, is preferably applied skin itching accompanying sweating occurs, or itching prone skin due to sweating, in the <30> - any one of <35> The method described in 1.
<37> An effective amount of the compound per day per kg of body weight is 0.0015 mg or more, preferably 0.075 mg or more, 22.5 mg or less, preferably 2.4 mg or less, 30. The method according to any one of <30> to <36>.

(Test Example 7) Prevention or improvement test of itch caused by sweating Body lotions (Galaxolide (G) and Placebo (P)) having the compositions shown in Table 3 below were prepared,
It was provided in a mist spray bottle (discharge amount per push: 0.1 mL).

A prevention or amelioration test for itchiness was conducted in the winter according to the schedule shown below for one woman who feels itchiness due to sweating in the trunk at least once a day in summer.

From the weekend immediately prior to use a body lotion of the test product, stop the care of to the trunk, which is doing usually, Placebo (P) Body Lotion the torso (neck, chest, waist) to 5 days (month ~ Friday) Used.
And next week (Monday to Friday), Galaxolide (G) body lotion was used as well.
Body lotion was used three times a day before going to work in the morning, working during the day, and leaving the evening. The maximum amount of body lotion used per day was 2.0 mL each. The itch prevention or amelioration test was a double-blind test , the test article was encoded at the bottled stage, and the subject and data analyst were not notified of the contents of the test article .

<Evaluation of itchiness>
During the period you are using a body lotion of the test product, it was recorded every night of the degree of itching (subjective evaluation). The "average degree of itch felt in one day", itching strength (10cmVAS, left end (0): itching do not feel anything the Mi, right edge (10): very strong feel itching) and, itching score (0: itching None, 1: slight itch, 2: weak itch, 3: moderate itch, 4: strong itch, 5: very strong itch . The results are shown in Table 5 .

As shown in Table 5 , as a result of analyzing the average values of sweating itch 10 cmVAS and itch score for 5 days, both 10 cmVAS and itch score values were reduced when using Galaxlide compared to using Placebo. . Furthermore, when using Placebo, “the neck has a sense of incongruity and itching was accompanied”, whereas when using Galaxolid, “the itching felt on the front side of the neck is relieved in the evening, and itching does not bother me Was the answer. In other words, the effect of easing itchiness by Galaxoldie was felt.

As described above, itching of the skin was alleviated in a short time by applying a compound having an action of inhibiting MrgprX1 activity. This indicates that a compound having an action of inhibiting MrgprX1 activity is effective in preventing or improving skin itching. Furthermore, it has shown that the compound which has the effect | action which inhibits MrgprX1 activity has the immediate effect with respect to itching that the itching of skin is reduced in a short time.
Furthermore, the results of the above embodiment has an effect of inhibiting the MrgprX1 activity, the compounds defined in the present invention, for non-histamine-dependent chronic itching such as pruritus due to sweating, preventing or ameliorating It shows that it has an effect.

Claims (5)

A compound represented by formula (1),
A compound represented by formula (2),
An MrgprX1 activity inhibitor comprising as an active ingredient at least one compound selected from the group consisting of a compound represented by formula (3) and a compound represented by formula (4).
A compound represented by formula (1),
A compound represented by formula (2),
An influx of calcium ions through cells via MrgprX1, comprising as an active ingredient at least one compound selected from the group consisting of a compound represented by formula (3) and a compound represented by formula (4) Inhibitor.
A compound represented by formula (1),
A compound represented by formula (2),
An agent for preventing or improving itchiness comprising as an active ingredient at least one compound selected from the group consisting of a compound represented by formula (3) and a compound represented by formula (4).
  The agent for preventing or improving itchiness according to claim 3, wherein the itchiness is itch caused by drying.   The agent for preventing or improving itchiness according to claim 3, wherein the itchiness is itchiness associated with sweating.