JP2020007262A - Skin external composition - Google Patents

Abstract

To provide a new skin external composition capable of reducing itches in skin disease accompanied by itching.SOLUTION: A skin external composition capable of reducing itches in skin disease accompanied by itching comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate of them as an active ingredient.SELECTED DRAWING: None

Description

  The present disclosure relates to a composition for external use on the skin for suppressing itch in skin diseases accompanied by pruritus, and a method for suppressing itch in skin diseases accompanied by pruritus using the composition.

Itching is one of the symptoms that significantly impairs quality of life (QOL). Itching is also known to be caused not only by skin diseases but also by visceral lesions. Treatment for itch often involves administration of antihistamines. Antihistamines are remarkably effective in diseases in which mast cells are greatly involved in the disease state, such as urticaria, but are often insufficiently effective in skin diseases accompanied by itch.
On the other hand, due to changes in the living environment and dietary habits, the number of patients suffering from inflammatory skin diseases such as allergic dermatitis has increased rapidly in recent years. Treatment of inflammatory skin diseases such as allergic dermatitis is performed by administering a steroid agent having an anti-inflammatory effect or an antihistamine agent. However, a definitive treatment method has not yet been established.

  Patent Document 1 discloses a pharmaceutical composition for internal use for treating inflammatory skin disease or inflammatory bowel disease, which contains a pyrazolo [1,5-a] pyrimidine compound having a PAR2 inhibitory activity as an active ingredient. .

WO2018 / 043461

  Skin diseases such as allergic dermatitis usually accompany itching. Itching causes stress, insomnia, etc. in the patient and significantly impairs the patient's QOL. In addition, it is considered that the scratching damages the skin, exacerbates the skin symptoms, and stimulates the secretion of a causative substance causing itching. Therefore, a new therapeutic agent capable of suppressing or reducing itch as soon as possible is required.

  The present disclosure provides, in one aspect, a novel external skin composition capable of suppressing itch in skin diseases accompanied by pruritus, and a method for suppressing itch in skin diseases accompanied by pruritus using the same.

The present disclosure, in one or a plurality of embodiments, comprises a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, and itching of a skin disease accompanied by pruritus. The present invention relates to a composition for external use on the skin for suppressing skin irritation.
In the formula (I),
R ¹ is a methyl group, an isopropyl group or an isobutyl group,
R ² is a methyl group, a methoxy group, a phenyl group, a propyl group, a dimethylpropyl group or a phenylethyl group substituted with one or two selected from the group consisting of fluorine and chlorine;
R ³ is a chlorodifluorophenyl group, a trifluorophenyl group, a chlorofluorophenyl group or a dimethylcyclohexyl group,
R ⁴ is a methyl group and R ⁵ is a carboxyisopropyl group, or R ⁴ and R ⁵ together with the nitrogen atom marked with a
To form

  The present disclosure provides, in one or more embodiments, administration of an effective amount of a skin external composition containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. The present invention relates to a method for suppressing itching in skin diseases accompanied by pruritus.

  The present disclosure provides a novel external skin composition capable of suppressing itch in skin diseases accompanied by pruritus, and a method for suppressing itch in skin diseases accompanied by pruritus using the same.

FIG. 1 is an example of a graph showing the evaluation results of the itch suppression effect of skin diseases in Examples.

In one embodiment of the present disclosure, a compound represented by the formula (I) including the following compound 1 can provide a sufficient inhibitory effect on pruritus in a pruritus skin disease such as atopic dermatitis by oral administration. Despite the absence, it is based on the finding that transdermal administration as an external preparation for the skin, such as a cream, can exert an unexpectedly superior effect of suppressing or reducing itch.

  In one or more embodiments, the `` skin disease accompanied by pruritus '' in the present disclosure includes eczema / dermatitis, hives, pruritus, prurigo, atopic dermatitis, lichen amyloid, drug eruption, psoriasis, Ringworm, cutaneous candidiasis, scabies, mites, lice, insect bites, cutaneous T-cell lymphoma, skin pruritus associated with kidney disease, skin pruritus associated with liver disease, and the like.

  The “skin external composition” in the present disclosure refers to a dosage form that can be directly applied (administered) to a local surface of the skin, and is not particularly limited as long as it is such a dosage form. Examples of the form of the composition for external use on the skin include creams (emulsion ointments), water-soluble ointments, oil-soluble ointments, gels, lotions, tapes, patches, sprays, gels, reservoir patches and the like. In one or more embodiments, the external composition for skin in the present disclosure may be in the form of an external pharmaceutical composition, an external quasi-drug, or a cosmetic.

[Skin composition for external use]
In one embodiment of the present disclosure, a skin for suppressing itching of a skin disease accompanied by pruritus, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient: The present invention relates to an external composition (a skin external composition of the present disclosure).

  According to the composition for external use of the skin of the present disclosure, in one or more embodiments, itching of a skin disease accompanied by pruritus can be effectively suppressed or reduced. Since the composition for external use of the skin of the present disclosure is an external preparation, in one or a plurality of embodiments, there is little concern about side effects caused by swallowing such as an internal medicine, and a therapeutic effect can be improved safely.

In the formula (I), R ¹ is a methyl group, an isopropyl group or an isobutyl group, preferably a methyl group.

R ² is a phenyl group, a propyl group, a dimethylpropyl group or a phenylethyl group substituted by one or two selected from the group consisting of a methyl group, a methoxy group, fluorine and chlorine. In one or a plurality of embodiments, R ² is a 2-fluoro-6-methylphenyl group, a 2-chloro-6-methylphenyl group, a 2-chloro-6-fluorophenyl group, a 2-chlorophenyl group, a 2-chlorophenyl group, A fluoro-6-methoxyphenyl group, a 2,6-dimethylphenyl group, a 2-methoxy-6-methylphenyl group, an ethylphenyl group, a propyl group, a dimethylpropyl group or a phenylethyl group; -6-methylphenyl group.

R ³ is a chlorodifluorophenyl group, a trifluorophenyl group, a chlorofluorophenyl group or a dimethylcyclohexyl group, preferably a chlorodifluorophenyl group, and more preferably a 4-chloro-3,5-difluorophenyl group. .

R ⁴ is a methyl group and R ⁵ is a carboxyisopropyl group, or R ⁴ and R ⁵ together with the nitrogen atom marked with a
To form In the above formula, a bond with a wavy line is a bond to the compound represented by the formula (I). Further, in the present disclosure, “*” in the configuration indicates a relative configuration, and indicates any one enantiomer unless otherwise specified.

R ⁴ and R ⁵ together with the nitrogen atom marked with a
Is preferably formed, and more preferably
To form

In one or more embodiments, the compound represented by the formula (I) includes a compound represented by the following formula (II) or (III).
In the formula (II), R ⁶ is a methyl group, a fluorine atom, a chlorine atom or a methoxy group, and is preferably a fluorine atom. R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, a fluorine atom or a chlorine atom, preferably R ⁷ and R ⁹ are a fluorine atom, and R ⁸ is a chlorine atom.
In the formula (III), R ⁶ is a methyl group, a chlorine atom or a methoxy group. R ¹⁰ is a hydrogen atom, a methyl group, or a methoxy group. R ¹¹ , R ¹² and R ¹³ are each independently a fluorine atom or a chlorine atom.

In one or more embodiments, the compound represented by the formula (I) is at least one selected from the group consisting of the following compounds 1 to 18. The notation of "(3R ^* , 4S ^* )" in the following compounds 2 to 12 indicates the relation of each asymmetric center with respect to the relative configuration. That is, "(3R ^* , 4S ^* )" indicates a particular enantiomer of any one of (3R, 4S) or (3S, 4R).

Compound 1: 2-((3R, 4S) -1- (5- (4-chloro-3,5-difluorophenyl) -7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [ 1,5-a] pyrimidine-2-carbonyl) -3-methoxypiperidin-4-yl) acetic acid

Compound 2: 2-((3R ^* , 4S ^* )-1- (7-((2,6-dimethylphenyl) (methyl) amino) -5- (3,4,5-trifluorophenyl) pyrazolo [1 , 5-a] Pyrimidin-2-carbonyl) -3-methoxypiperidin-4-yl) acetic acid

Compound 3: 2-((3R ^* , 4S ^* )-1- (5- (3-chloro-4-fluorophenyl) -7-((2,6-dimethylphenyl) (methyl) amino) pyrazolo [1, 5-a] Pyrimidine-2-carbonyl) -3-methoxypiperidin-4-yl) acetic acid

Compound 4: 2-((3R ^* , 4S ^* )-3-methoxy-1- (7-((2-methoxy-6-methylphenyl) (methyl) amino) -5- (3,4,5-tri Fluorophenyl) pyrazolo [1,5-a] pyrimidine-2-carbonyl) piperidin-4-yl) acetic acid

Compound 5: 2-((3R ^* , 4S ^* )-1- (5- (4-chloro-3-fluorophenyl) -7-((2-chloro-6-methylphenyl) (methyl) amino) pyrazolo [ 1,5-a] pyrimidine-2-carbonyl) -3-methoxypiperidin-4-yl) acetic acid

Compound 6: 2-((3R ^* , 4S ^* )-1- (5- (4-chloro-3,5-difluorophenyl) -7-((2-chloro-6-methylphenyl) (methyl) amino) Pyrazolo [1,5-a] pyrimidine-2-carbonyl) -3-methoxypiperidin-4-yl) acetic acid

Compound 7: 2-((3R ^* , 4S ^* )-1- (7-((2,6-dimethylphenyl) (methyl) amino) -5- (3,4,5-trifluorophenyl) pyrazolo [1 , 5-a] Pyrimidine-2-carbonyl) -3-fluoropiperidin-4-yl) acetic acid

Compound 8: 2-((3R ^* , 4S ^* )-1- (5- (4,4-dimethylcyclohexyl) -7-((2,6-dimethylphenyl) (methyl) amino) pyrazolo [1,5- a] Pyrimidine-2-carbonyl) -3-fluoropiperidin-4-yl) acetic acid

Compound 9: 2-((3R ^* , 4S ^* )-3-fluoro-1- (7-((2-methoxy-6-methylphenyl) (methyl) amino) -5- (3,4,5-tri Fluorophenyl) pyrazolo [1,5-a] pyrimidine-2-carbonyl) piperidin-4-yl) acetic acid

Compound 10: 2-((3R ^* , 4S ^* )-1- (7-((2-chloro-6-fluorophenyl) (methyl) amino) -5- (3,4,5-trifluorophenyl) pyrazolo [1,5-a] pyrimidine-2-carbonyl) -3-fluoropiperidin-4-yl) acetic acid

Compound 11: 2-((3R ^* , 4S ^* )-1- (5- (4-chloro-3,5-difluorophenyl) -7-((2-chlorophenyl) (methyl) amino) pyrazolo [1,5 -A] pyrimidine-2-carbonyl) -3-fluoropiperidin-4-yl) acetic acid

Compound 12: 2-((3R ^* , 4S ^* )-1- (5- (4-chloro-3,5-difluorophenyl) -7- (isopropyl (propyl) amino) pyrazolo [1,5-a] pyrimidine -2-carbonyl) -3-methylpiperidin-4-yl) acetic acid

Compound 13: (R) -3- (7-((2-fluoro-6-methoxyphenyl) (methyl) amino) -N-methyl-5- (3,4,5-trifluorophenyl) pyrazolo [1, 5-a] pyrimidine-2-carboxamide) butanoic acid

Compound 14: (R) -3- (7- (isobutyl ((R) -3-methylbutan-2-yl) amino) -N-methyl-5- (3,4,5-trifluorophenyl) pyrazolo [1 , 5-a] Pyrimidine-2-carboxamide) butanoic acid

Compound 15: 2-((1α, 5α, 6α) -3- (5- (4-chloro-3,5-difluorophenyl) -7- (isobutyl ((R) -3-methylbutan-2-yl) amino ) Pyrazolo [1,5-a] pyrimidine-2-carbonyl) -3-azabicyclo [3.1.0] hexane-6-yl) acetic acid

Compound 16: 2-((1α, 5α, 6α) -3- (5- (4-chloro-3,5-difluorophenyl) -7- (isopropyl (propyl) amino) pyrazolo [1,5-a] pyrimidine -2-carbonyl) -3-azabicyclo [3.1.0] hexane-6-yl) acetic acid

Compound 17: 2-((1α, 5α, 6α) -3- (7- (isobutyl ((S) -1-phenylethyl) amino) -5- (3,4,5-trifluorophenyl) pyrazolo [1 , 5-a] Pyrimidine-2-carbonyl) -3-azabicyclo [3.1.0] hexane-6-yl) acetic acid

Compound 18: 2- (1- (7-((2-chloro-6-fluorophenyl) (methyl) amino) -5- (3,4,5-trifluorophenyl) pyrazolo [1,5-a] pyrimidine -2-carbonyl) piperidin-4-yl) acetic acid

  In the present disclosure, the structural formula of a compound may represent a certain isomer for convenience, but in the present disclosure, all geometric isomers, optical isomers, stereoisomers, tautomers, and the like occurring in the structure of the compound are described. And mixtures of isomers. The compounds of the present disclosure are not limited to the descriptions of formulas for convenience, and may be either one isomer or a mixture. In one or more embodiments, the compound represented by the formula (I) may exist in an optically active form and a racemic form. The compound of formula (I) may include an anhydride and a hydrate in one or more embodiments. So-called metabolites generated by metabolizing (oxidizing, reducing, hydrolyzing, conjugating, etc.) the compound represented by the formula (I) in a living body may also be included in the present disclosure. In addition, a compound that undergoes metabolism (oxidation, reduction, hydrolysis, conjugation, or the like) in a living body to generate the compound of the present disclosure (a so-called prodrug) may be included in the present invention.

  In the present disclosure, a “pharmaceutically acceptable salt” is a pharmacologically and / or pharmaceutically acceptable salt, and is an inorganic acid salt, an organic acid salt, an inorganic base salt, an organic base salt, an acidic amino acid salt or a base. Amino acid salts and the like. In one or more embodiments, the inorganic acid salt includes a hydrochloride, a hydrobromide, a sulfate, a nitrate, a phosphate, and the like. Organic salts include, in one or more embodiments, acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonic acid And salts of p-toluenesulfonate. In one or more embodiments, the inorganic base salt includes an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, an aluminum salt, an ammonium salt, and the like. In one or more embodiments, the organic base salt includes a diethylamine salt, a diethanolamine salt, a meglumine salt, an N, N′-dibenzylethylenediamine salt, and the like. Acidic amino acid salts include, in one or more embodiments, aspartate, glutamate, and the like. In one or more embodiments, the basic amino acid salt includes an arginine salt, a lysine salt, an ornithine salt, and the like.

  The skin external composition of the present disclosure is, in one or a plurality of embodiments, a base, an absorption enhancer, a humectant, a thickener, an emulsifier, a coloring agent, a fragrance, an antioxidant, and a base usually used in the external composition. It may contain a stabilizer, a bactericide or a preservative.

  In one or more embodiments, the external use base may be, in one or more embodiments, white petrolatum, cetanol, stearyl alcohol, stearic acid, glycerol monostearate, beeswax, liquid paraffin, macrogol (polyethylene glycol), lauromacrogol (polyoxyethylene Lauryl ether), squalane, squalene, lanolin, isobutyl myristate, medium chain fatty acid triglyceride, and the like. Even in the case of a base containing water, any of W / O type and O / W type as long as it is an emulsion, can be easily mixed by mixing with oil.

  In one or more embodiments, the absorption enhancer is, in one or more embodiments, urea, crotamiton, diethyl sebacate, diisopropyl adipate, ethanol, isopropyl alcohol, dimethyl sulfoxide, 1-dodecylazacycloheptan-2-one, 1-menthol, salicylic acid. , Pyrrolidones, medium-chain fatty acid esters, phosphatidylcholines, silicone-based accelerators, limonene, and the like.

  Humectants include, in one or more embodiments, polyhydric alcohols such as glycerin, sorbitol, propylene glycol, 1,3-butanediol, sodium pyrrolidone carboxylate, or sodium hyaluronate.

  As the thickener, in one or more embodiments, gum arabic, guar gum, locust bean gum, carrageenan, carboxymethylcellulose, sodium carboxymethylcellulose, polyacrylates, polyacrylates, natural latex, vinyl acetate resin Emulsions, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like can be mentioned.

  In one or more embodiments, the emulsifier may be, in one or more embodiments, glycerin fatty acid ester, sucrose fatty acid ester (sugar ester), sorbitan fatty acid ester, propylene glycol fatty acid ester, lecithin, polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxy Examples include ethylene-hardened castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sodium lauryl sulfate.

  The fragrance in one or more embodiments includes eucalyptus oil, lavender oil, menthol, peppermint oil, rose oil, orange oil, cherry flavor, fruit flavor, vanillin or vanilla flavor.

  Antioxidants include, in one or more embodiments, L-ascorbic acid, ascorbic acid stearate, ascorbic acid palmitate, sodium ascorbate, erythorbic acid, sodium erysorbate, isopropyl citrate, dl-α-tocopherol, dl -Δ-tocopherol, dibutylhydroxytoluene (BHT) or butylhydroxyanisole (BHA).

  Stabilizers include, in one or more embodiments, polysorbate, polyethylene glycol, ethanol, acetone, light anhydrous silicic acid, EDTA, and the like.

  Examples of preservatives include paraoxybenzoates, benzalkonium chloride, sorbic acid, phenol, chlorobutanol, chlorocresol, benzyl alcohol and the like.

  In one or more embodiments, the dosage of the composition for external use on skin of the present disclosure can be appropriately determined according to the type of disease, the degree of symptoms, the area of the onset site, the body weight, the age, the dosage form of the drug, and the like. The method of using the composition for external use of the skin of the present disclosure is not particularly limited, and in one or more embodiments, a dose of 0.1 g to 10 g per day is directly applied to the affected area once or several times a day. And so on.

  The compound represented by the formula (I) can be produced according to the production method described in WO2018 / 044361.

  The skin external composition of the present disclosure can be used as a therapeutic agent for a skin disease accompanied by pruritus in one or more embodiments.

  In another aspect, the present disclosure relates to a method for suppressing pruritus of a skin disease accompanied by pruritus by administering an effective amount of the external composition for skin of the present disclosure.

  Another aspect of the present disclosure relates to an external use for the skin for suppressing itching of skin diseases accompanied by pruritus, using a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof. It relates to a method for producing the composition. In one or more embodiments, the production method of the present disclosure includes, in one or more embodiments, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a base generally used for an external composition, And mixing at least one selected from the group consisting of an absorption promoter, a humectant, a thickener, an emulsifier, a colorant, a fragrance, an antioxidant, a stabilizer, a bactericide and a preservative.

  The present disclosure provides, as another aspect, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a composition for external use on the skin for suppressing itching of a skin disease accompanied by pruritus. For the use of hydrates.

  Hereinafter, the present disclosure will be described in more detail by way of examples. However, these are merely examples, and the present disclosure is not limited to these examples. All documents cited in the present disclosure are incorporated as a part of the present disclosure.

[Preparation example of preparation]
In the following procedure, the compound 1 (2-((3R, 4S) -1- (5- (4-chloro-3,5-difluorophenyl) -7-((2-fluoro-6 -Methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carbonyl) -3-methoxypiperidin-4-yl) acetic acid). Compound 1 was prepared based on WO2018 / 043461.

[procedure]
1) Macrogol 400 (2.1 g) and Macrogol 4000 (0.9 g) were mixed and stirred at 60 ° C. to make them uniform.
2) DMSO (800 mg) was added to compound 1 (200 mg), and the mixture was stirred at 60 ° C. for 10 minutes to make it uniform. Cetanol (800 mg) was added thereto, and the mixture was stirred at 60 ° C. for 5 minutes to be uniform. Further, 1.5 g of the macrogol mixture prepared in 1) was added, and the mixture was stirred at 60 ° C. for 5 minutes to make it uniform. Further, glycerol monostearate (1 g) was added, and the mixture was stirred at 60 ° C. for 5 minutes to homogenize to prepare a compound 1 solution.
3) Milli-Q water (5.5 g) was added to polyethylene (20) cetylether (200 mg) or SDS (200 mg), and the mixture was stirred at 60 ° C. for 5 minutes to be uniform. While stirring it vigorously, all of the compound 1 solution of 2) was added dropwise at 60 ° C. to obtain an emulsion. After stirring at 60 ° C. for 1 minute, the stirrer was taken out and allowed to cool while stirring with a homogenizer at room temperature. Further, the mixture was cooled while stirring with a homogenizer under water cooling to obtain Formulations 1 and 2 (creams) shown in Table 1 below.

[Evaluation of stability]
Formulations 1 and 2 were evaluated for stability after storage at a predetermined temperature. Storage was performed at 4 ° C. for 13 days, at 25 ° C. for 9 days, and at 40 ° C. for 25 days. The stability was evaluated by performing HPLC analysis on the stored formulation under the following conditions, and calculating the purity based on the% area of the HPLC analysis (254 nm).
[HPLC conditions]
Column; Atlantis T3, 4.6x150 mm, 5μm (waters)
Mobile phase A; water / perchloric acid (60%) (1000/1, v / v)
Mobile phase B; acetonitrile / perchloric acid (60%) (1000/1, v / v)
Flow rate; 1 mL / min
Column temperature; 40 ° C
Detection; UV 275 nm
Sample concentration; 0.2 mg / mL
Lysis solution; acetonitrile injection volume; 10 μL

  As a result, each of Formulations 1 and 2 could be stored with a high purity exceeding 97% at any temperature of 4, 25 or 40 ° C.

[Test example: NC / Nga atopic dermatitis spontaneous model]
Using NC / Nga mice, a spontaneous atopic dermatitis model, the following methods were used to evaluate the inhibitory effect of Formulation 1 on skin disease pruritus.
<Method>
Formulation 1 was applied at 50 mg / body once a day for 7 days to NC / Nga mice (male, 12 and 14 weeks old) that developed dermatitis. During the administration period, body weight measurement and dermatitis observation were performed once a day, and the scraping behavior was measured at the end of the administration period.
Using a pruritus measurement system (MicroAct Ver. 2.15A; Neuroscience Co., Ltd.), the scratching behavior was 14 hours from 17:00 to 7:00 the following day under the following conditions (the acclimation time is from 17:00 to 19:00) It was measured. Except for the first 2 hours of habituation, the number of scratching actions (Beat) was 12 hours from 19:00 to 7:00. A maximum of 16 animals were measured at one time, and the measurement was performed on all animals in three times. The result is shown in FIG.
The control group was untreated. In the base group, 50 mg / body of a cream having the same formulation as formulation 1 except that compound 1 was not contained (0% by weight) was applied once a day for 7 days.

FIG. 1 shows the number of scratching actions per hour. As shown in FIG. 1, the value of the preparation 1 group was significantly lower than that of the control group at any time. In addition, Formulation 1 group had significantly lower values compared to the base group in the two time zones of 22-23 and 0-1 hour, and the administration of Formulation 1, which is a cream containing Compound 1, It was shown that the number of times of scratching action was suppressed.
Therefore, it was suggested that the external preparation containing Compound 1 can suppress or reduce itch in skin diseases accompanied by pruritus.

Claims (4)

The following formula (I):
A compound for external use on the skin for suppressing itching of skin diseases accompanied by pruritus, comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient,
In the formula (I),
R ¹ is a methyl group, an isopropyl group or an isobutyl group,
R ² is a methyl group, a methoxy group, a phenyl group, a propyl group, a dimethylpropyl group or a phenylethyl group substituted with one or two selected from the group consisting of fluorine and chlorine;
R ³ is a chlorodifluorophenyl group, a trifluorophenyl group, a chlorofluorophenyl group or a dimethylcyclohexyl group,
R ⁴ is a methyl group and R ⁵ is a carboxyisopropyl group, or R ⁴ and R ⁵ together with the nitrogen atom marked with a
A composition for external use on the skin that forms The compound represented by the formula (I) is
The external composition for skin according to claim 1, which is at least one selected from the group consisting of the compounds.   The composition for external use on the skin according to claim 1 or 2, wherein the skin disease accompanied by pruritus is atopic dermatitis.   A method for suppressing pruritus in a skin disease accompanied by pruritus by administering an effective amount of the composition for external use on the skin according to any one of claims 1 to 3.