External preparation

Abstract

Provided is a technique for preventing or treating a periostin-mediated disease and pruritus associated with the disease. The present invention relates to, for example, an external preparation for preventing or treating a periostin-mediated disease or pruritus associated with the disease, said preparation containing a specific periostin receptor antagonist as an active ingredient.

Description

Topical medications

[0001] The present invention relates to topical preparations and the like for preventing or treating periostin-mediated diseases and pruritus associated with such diseases.

[0002] Periostin is an extracellular matrix protein that binds to cell surface receptors belonging to the integrin family and transmits intracellular signals, and has been suggested to play an important role in the exacerbation and chronicity of allergic skin inflammation (Non-Patent Document 1). Local production of periostin is significantly increased in atopic dermatitis lesions, and it has been reported that the severity of atopic dermatitis correlates with the lesion area and serum periostin levels. It has also been reported that intradermal or subcutaneous administration of periostin induces scratching behavior in mice, dogs, and monkeys (Non-Patent Document 2). Furthermore, a method for treating or alleviating pruritus or chronic pruritus using an integrin αvβ3 antagonist that blocks intracellular signaling induced by the binding of periostin to integrin has been disclosed (Patent Document 1).

[0003] Periostin has been reported to mediate the pathology of various diseases. Diseases mediated by periostin include atopic dermatitis and its associated pruritus, as well as prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloids / hypertrophic scars, allergic rhinitis, chronic liver disease, and chronic kidney disease, as well as pruritus associated with these diseases (Non-Patent Documents 3 to 5).

[0004] WO2021 / 055713

[0005] Masuoka M, et al. J Clin Invest. 122:2590-2600, 2012Mishra et al, Cell reports, 31:107472, 2020Izuhara K, et al. Cell. Mol. Life Sci. 74:4293-4303, 2017Hashimoto T, et al. J Invest Dermatol. 141:2338-2343, 2021Yang L, Cells. 12, 50, 2023

[0006] Under these circumstances, there has been a need for the development of a new technology for preventing or treating periostin-mediated diseases and the pruritus associated with the diseases, which can improve the diseases and the pruritus associated with the diseases. In particular, because many periostin-mediated diseases are skin diseases as described above, topical preparations that can be administered directly to the lesion site are useful.

[0007] The present invention has been made in consideration of the above circumstances and provides the following external preparations and the like for preventing or treating periostin-mediated diseases or pruritus associated with such diseases.

[0008] (1) An external preparation for preventing or treating a periostin-mediated disease or pruritus associated with the disease, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is a compound represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group. ], 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (hereinafter, may be referred to as "SC-68448"), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (hereinafter, may be referred to as "CP derivative 2"), (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (hereinafter, may be referred to as "CP derivative 6"), The topical preparation is at least one compound selected from the group consisting of (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (hereinafter sometimes referred to as "CP derivative 7") and (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (hereinafter sometimes referred to as "SM-256"), or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0009] (2) The topical preparation according to (1) above, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (hereinafter, sometimes referred to as "CP4715"). (3) The topical preparation according to (1) above, wherein the antagonist is (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 2), (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 7), or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (SM-256). (4) The topical preparation according to (1), wherein the periostin-mediated disease is atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease, or chronic kidney disease. (5) The topical preparation according to (1), wherein the periostin-mediated disease is atopic dermatitis.

[0010] (6) A pharmaceutical composition for external application for preventing or treating a periostin-mediated disease or pruritus associated with the disease, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is a compound represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group.] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (SC-68448), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 2), (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), The pharmaceutical composition for external application is at least one compound selected from the group consisting of (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 7) and (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (SM-256), or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0011] (7) The topical pharmaceutical composition according to (6) above, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP4715). (8) The pharmaceutical composition for external application according to (6) above, wherein the antagonist is (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 2), (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 7), or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (SM-256). (9) The topical pharmaceutical composition according to (6), wherein the periostin-mediated disease is atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease, or chronic kidney disease. (10) The topical pharmaceutical composition according to (6), wherein the periostin-mediated disease is atopic dermatitis.

[0012] (11) A compound represented by the following formula (I): for producing an external preparation for preventing or treating a periostin-mediated disease or pruritus associated with the disease: [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group.] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (SC-68448), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 2), (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), Use of at least one compound selected from the group consisting of (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 7) and (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (SM-256), or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0013] (12) The use according to (11) above, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP4715). (13) The use according to (11) above, wherein the antagonist is (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 2), (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP derivative 7), or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (SM-256). (14) The use according to (11), wherein the periostin-mediated disease is atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease, or chronic kidney disease. (15) The use according to (11), wherein the periostin-mediated disease is atopic dermatitis.

[0014] (16) A method for preventing or treating a periostin-mediated disease or pruritus associated with the disease, comprising applying the topical preparation according to any one of (1) to (5) and / or the topical pharmaceutical composition according to any one of (6) to (10) to a subject in need of treatment.

[0015] (17) The method according to (16), wherein the periostin-mediated disease is atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease, or chronic kidney disease. (18) The method according to (16), wherein the periostin-mediated disease is atopic dermatitis.

[0016] In the inventions described in (1), (6), and (11) above, in formula (I), R １ , R ２ and R ３ The alkyl group in is preferably a lower alkyl group (for example, an alkyl group having 1 to 4 carbon atoms), and specific examples thereof include methyl, ethyl, and propyl. Preferred examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, mesyl, naphthyl, and biphenyl. Preferred examples of the aralkyl group include benzyl and phenethyl. The alkyl group, aryl group, and aralkyl group may be substituted with a known appropriate substituent, but are not limited thereto.

[0017] Furthermore, preferred specific examples of the compound of formula (I) include, but are not limited to, the compound of formula (II) below: A preferred example is the compound represented by the formula ((S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid (CP4715).

[0018] The present invention can provide an external preparation and an external pharmaceutical composition useful for ameliorating periostin-mediated diseases and the itching associated with the diseases, for preventing or treating the diseases and the itching, and a method for preventing or treating the diseases and the itching by applying the external preparation and the external pharmaceutical composition to a subject.

[0019] 3-1 shows graphs indicating the inhibitory effect of single systemic administration of various compounds on scratching behavior in FADS mice. 3-2 shows graphs indicating the inhibitory effect of various compounds on periostin-dependent cell adhesion. 3-3 shows graphs indicating the inhibitory effect of repeated transdermal administration of various compounds on scratching behavior in FADS mice. 3-4 shows the same as Figure 3-1.

[0020] The present invention will be described in detail below. The scope of the present invention is not limited to these descriptions, and other than the following examples, the present invention can be appropriately modified and implemented without departing from the spirit of the present invention. All publications cited in this specification, such as prior art documents, published patent applications, patent publications, and other patent documents, are incorporated herein by reference.

[0021] The topical preparation for prevention or treatment of periostin-mediated diseases and itching associated with such diseases (e.g., itchy skin symptoms) according to the present invention (hereinafter sometimes referred to as the "topical preparation of the present invention") and the topical pharmaceutical composition for prevention or treatment of periostin-mediated diseases and itching associated with such diseases (e.g., itchy skin symptoms) (hereinafter sometimes referred to as the "topical pharmaceutical composition of the present invention") comprise, as described above, a periostin-mediated disease comprising a compound represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group. ] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid, (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid, and The present invention is characterized by comprising, as an active ingredient, at least one compound selected from the group consisting of (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid (hereinafter, sometimes referred to as "the compound of the present invention"), or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof (hereinafter, the compound of the present invention and the prodrug, salt, hydrate, and solvate may be collectively referred to as "the compound of the present invention, etc.").

[0022] Here, R in the above formula (I) １ , R ２ and R ３ The alkyl group in is preferably a lower alkyl group (for example, an alkyl group having 1 to 4 carbon atoms), and specific examples thereof include methyl, ethyl, and propyl. Preferred examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, mesyl, naphthyl, and biphenyl. Preferred examples of the aralkyl group include benzyl and phenethyl. The alkyl group, aryl group, and aralkyl group may be substituted with a known appropriate substituent, but are not limited thereto.

[0023] In the present invention, preferred specific examples of the compound of formula (I) include, but are not limited to, the compound of formula (II) below: A preferred example is the compound (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid. The compound of formula (II) is also known as "CP4715."

[0024] The periostin receptor antagonist of the present invention may be a commercially available product, but is not limited thereto, and may be one that has been independently synthesized, extracted, purified, or the like. For example, CP4715 is a compound that antagonizes both the glycoprotein (GP) IIb / IIIa receptor, which plays a major role in thrombus formation, and αvβ3 integrin (a cell adhesion molecule) involved in leukocyte adhesion, and is known as an active ingredient in therapeutic drugs for cardiovascular diseases (antithrombotic agents). αvβ3 integrin is a receptor for periostin, fibronectin, vitronectin, and the like, and periostin is known to activate sensory neurons via αvβ3 integrin (see Non-Patent Document 2 cited above). SC-68448, an integrin αvβ3 antagonist, has been reported to inhibit the binding of integrin αvβ3 to vitronectin (Carron CP, et al. Cancer Res. 58:1930-1935, 1998). CP derivative 6 has been reported to inhibit the binding of integrin αvβ3 to periostin or vitronectin (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020).

[0025] In addition to the above-described topical preparations and topical pharmaceutical compositions of the present invention, the present invention may also include: (i) a method for preventing or treating a periostin-mediated disease or pruritus associated with such a disease, comprising using the compound etc. of the present invention, specifically, for example, applying (administering) an effective amount of the compound etc. of the present invention (i.e., the topical preparation or topical pharmaceutical composition of the present invention) to a subject in need of treatment (a patient experiencing or at risk of experiencing a periostin-mediated disease or pruritus associated with such a disease (e.g., itchy skin symptoms); (ii) use of the compound etc. of the present invention for producing a medicament as an topical preparation for preventing or treating a periostin-mediated disease or pruritus associated with such a disease (e.g., itchy skin symptoms); (iii) topical use of the compound etc. of the present invention for preventing or treating a periostin-mediated disease or pruritus associated with such a disease (e.g., itchy skin symptoms); and (iv) a compound etc. of the present invention for topical use in preventing or treating a periostin-mediated disease or pruritus associated with such a disease (e.g., itchy skin symptoms).

[0026] In the present invention, a periostin-mediated disease is a disease in which periostin is involved in the onset or progression of the disease. "Periostin-mediated" refers to a state in which the onset or progression of the disease is caused by the direct action of periostin on somatic cells or tissues, for example, by binding of periostin to its receptor, resulting in activation of an intracellular signaling system. "Periostin-mediated" also refers to a state in which the onset or progression of the disease is caused by the newly produced, expressed, released, or activated biomolecules as a result of the action of periostin on somatic tissues or cells.

[0027] Periostin-mediated diseases include, but are not limited to, atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease, and chronic kidney disease, as well as pruritus associated with these diseases.

[0028] Atopic dermatitis is a chronic skin disease characterized by itchy eczema as the main lesion, which repeatedly worsens and remits. It has been reported that serum periostin levels are higher in atopic dermatitis patients than in healthy individuals, that local periostin production is significantly increased in lesions, and that the severity of atopic dermatitis correlates with the lesion and serum periostin levels (Non-Patent Documents 1 and 2 cited above).

[0029] Scratching associated with pruritus worsens skin symptoms, further increasing pruritus, creating a vicious cycle known as the itch-scratch cycle, which is known to be involved in the pathogenesis of atopic dermatitis (Tominaga M, Takamori K. Allergol Int. (2022) 71:265-277). IL-31, a cytokine primarily produced by Th2 cells, is known to be one of the main itch-inducing substances in atopic dermatitis (Datsi A, et al. Allergy. 76:2982-2997, 2021). It has been reported that IL-31 binds to the IL-31 receptor and transmits itch signals to the central nervous system (Mollanazar NK, et al. Clin Rev Allergy Immunol. 51:263-292, 2020). In a clinical trial in which nemolizumab, an antibody against the IL-31 receptor, was administered to patients with atopic dermatitis, nemolizumab was shown to improve pruritus and skin inflammation (Kabashima K, et al. N Engl J Med. 383:141-150, 2020). This indicates that topical drugs that alleviate pruritus associated with atopic dermatitis may also be useful for the prevention or treatment of atopic dermatitis.

[0030] Prurigo nodularis is a papular skin disease accompanied by severe itching, and it has been reported that the intensity of periostin immunostaining in the dermis correlates with the intensity of prurigo nodularis pruritus (Hashimoto T, et al. Acta Derm Venereol. 101:adv00375, 2021).

[0031] Bullous pemphigoid is a Th2-mediated autoimmune blistering skin disease accompanied by moderate to severe pruritus. The intensity of pruritus in bullous pemphigoid is directly correlated with dermal periostin deposition (Hashimoto T, et al. J Am Acad Dermatol. 83:53-62, 2020), suggesting that periostin may be directly involved in the pruritus associated with bullous pemphigoid.

[0032] Stasis dermatitis is a disease that typically causes inflammation in the skin of the lower legs in elderly people due to chronic venous insufficiency and lymphedema. It has been reported that periostin may contribute to the itching associated with stasis dermatitis by promoting IL-31 production by macrophages (Hashimoto T, et al. J Invest Dermatol. 140:850-859, 2020).

[0033] Cutaneous T-cell lymphoma (CTCL) is a group of malignant lymphomas that originate in the skin and are derived from T cells. Itching occurs in a high proportion of CTCL patients, and periostin expression is elevated in lesional skin samples from CTCL (Furudate S, et al. Exp Dermatol. 25:107-112, 2016), suggesting that periostin may be partially involved in the itch caused by CTCL.

[0034] Systemic sclerosis and keloid / hypertrophic scars share abnormal dermal fibrosis and are frequently accompanied by pruritus. Increased dermal periostin expression has been observed in lesional skin samples from patients with systemic sclerosis and keloids (Maeda D, et al. J Plast Surg Hand Surg. 53:288-294, 2019). Furthermore, elevated serum periostin levels have been reported in patients with systemic sclerosis, correlating with disease severity (Yamaguchi Y, et al. Br J Dermatol. 168:717-725, 2013). These findings suggest that periostin may be involved in the pruritus associated with systemic sclerosis and keloid / hypertrophic scars.

[0035] Allergic rhinitis is often accompanied by itching, and it has been confirmed that periostin is highly expressed in the nasal mucosa of patients with allergic rhinitis (Ishida A, et al. Allergol Int, 61:589-595, 2012), suggesting that periostin may partially contribute to the itching caused by allergic rhinitis (Ohta N, et al. Allergol Int. 63:171-180, 2014).

[0036] Periostin has been reported to induce liver fibrosis by inhibiting the expression of peroxisome proliferator-activated receptor-α (J Gastroenterol Hepatol. 35:2140-2150, 2020). Furthermore, chronic liver diseases such as liver cirrhosis can cause intractable itching that is resistant to antihistamines, and periostin is thought to be involved in this.

[0037] Periostin has also been reported to be involved in chronic kidney disease. Periostin expression levels in the kidney and urine have been shown to be highly correlated with the stage of disease and decline in renal function (Prakoura N, et al. Cell Mol Life Sci. 74:4315-4320, 2017, Jia YY, et al. Ren Fail. 42:1166-1172, 2020). Renal function decline leads to the need for dialysis. Dialysis patients experience dry skin, which can lead to pruritus (Morton CA, et al. Nephrol Dial Transplant. 10:2031-2036, 1996). As skin dryness progresses, nerve fibers (C fibers) extend to the epidermis due to a decrease in skin barrier function (Andoh T, et al. Neurosci Lett. 672:84-89, 2018). It is thought that activation of periostin receptors present in these nerve fibers by periostin may result in itching (Non-Patent Document 2 cited above).

[0038] As described above, various human diseases mediated by periostin are known. However, there have been no reports that administration of a periostin receptor antagonist actually has a therapeutic or preventive effect on these human diseases.

[0039] In the present invention, pruritus includes, for example, itchy skin symptoms. Examples of itchy skin symptoms include, but are not limited to, itchy skin symptoms caused by skin diseases or inflammation. Examples of skin diseases or inflammation include, but are not limited to, atopic dermatitis, contact dermatitis, and prurigo.

[0040] The terms "prevention" and "treatment" in the present invention also encompass the suppression and / or inhibition, or alleviation of periostin-mediated diseases and itching (e.g., itchy skin symptoms) associated with such diseases. Accordingly, the present invention may also encompass topical preparations containing the compounds of the present invention or the like as suppressors, inhibitors, or alleviators of periostin-mediated diseases and itching (e.g., itchy skin symptoms) associated with such diseases; topical pharmaceutical compositions containing the compounds of the present invention or the like for suppressing, inhibiting, or alleviating such symptoms; methods for suppressing, inhibiting, or alleviating such symptoms comprising topical application (administration) of the compounds of the present invention or the like to a subject; and use of the compounds of the present invention or the like in the manufacture of medicaments for suppressing, inhibiting, or alleviating such symptoms. Furthermore, treatment of periostin-mediated diseases and itching (e.g., itchy skin symptoms) includes, for example, suppression of progression of symptoms, improvement of prognosis, and treatment until remission is achieved. Furthermore, the terms are not limited to general treatment, but also include prevention of symptoms and prevention of recurrence.

[0041] As an active ingredient of the topical preparation and topical pharmaceutical composition of the present invention, a derivative of the compound of the present invention can be used together with or instead of the compound of the present invention. The derivative is not limited as long as it has a chemical structure derived from the compound of the present invention and is considered to be a derivative based on the common technical knowledge of a person skilled in the art, but preferably has at least the same level of preventive or therapeutic effect as that of the compound of the present invention on periostin-mediated diseases and itching associated with such diseases (e.g., itchy skin symptoms).

[0042] The compounds of the present invention or derivatives thereof include those that undergo metabolism in vivo, such as oxidation, reduction, hydrolysis, or conjugation, as well as compounds that undergo metabolism in vivo, such as oxidation, reduction, or hydrolysis, to produce the compounds of the present invention or derivatives thereof (so-called prodrugs). In the present invention, a prodrug refers to a compound obtained by modifying a parent compound with a pharmacologically acceptable group typically used in prodrugs, such as a compound that is conferred properties such as chemical stability, duration of effect, or improved systemic absorption, and that is expected to be converted to the parent compound in the intestinal tract, skin tissue, or the like to exhibit its effect. For example, a prodrug of a compound of the present invention can be produced by conventionally introducing a suitable prodrug-constituting group into one or more groups in the compound that can be converted into a prodrug (e.g., a hydroxyl group, an amino group, a carboxyl group, and other groups) using a prodrug-converting reagent such as a corresponding halide, followed by isolation and purification, as necessary. Here, preferred examples of groups constituting the prodrug include, but are not limited to, lower alkyl-CO—, lower alkyl-O-lower alkylene-CO—, lower alkyl-OCO-lower alkylene-CO—, lower alkyl-OCO—, and lower alkyl-O-lower alkylene-OCO—.

[0043] As the active ingredient of the topical agent of the present invention and the topical pharmaceutical composition of the present invention, pharmacologically acceptable salts thereof can be used together with the compound of the present invention, its derivatives, or prodrugs thereof, or instead of the compound of the present invention, its derivatives, or prodrugs thereof.

[0044] Preferred examples of the pharmaceutically acceptable salts of the compounds of the present invention and derivatives thereof include, but are not limited to, hydrohalides (e.g., hydrochlorides, hydrobromides, hydroiodides, etc.), inorganic acid salts (e.g., sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, etc.), organic carboxylates (e.g., acetates, trifluoroacetates, maleates, tartrates, fumarates, citrates, etc.), organic sulfonates (e.g., methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, camphorsulfonates, etc.), amino acid salts (e.g., aspartates, glutamates, etc.), quaternary amine salts, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., magnesium salts, calcium salts, etc.), and the like.

[0045] The compounds of the present invention used as the active ingredient include all isomers (e.g., geometric isomers, optical isomers based on asymmetric carbons, rotational isomers, stereoisomers, tautomers, etc.) that may arise from the structure of the compound, as well as mixtures of two or more of these isomers, and are not limited to the structural formulae described for convenience. Furthermore, the compounds of the present invention may be in the S-, R-, or RS-form, and are not limited thereto. Furthermore, depending on the type of compound, the compounds of the present invention may exist in the form of a hydrate or solvate. In the present invention, these hydrates and solvates are also included in the compounds of the present invention and can be used as the active ingredient of the topical agent and topical pharmaceutical composition of the present invention. Examples of such solvates include, but are not limited to, solvates with ethanol.

[0046] In the topical preparation and topical pharmaceutical composition of the present invention, the content of the compound of the present invention or the like as an active ingredient is not limited and can be set appropriately, and may be, for example, within the range of 0.01 to 99 wt %, preferably 0.01 to 30 wt %, more preferably 0.05 to 20 wt %, and even more preferably 0.1 to 10 wt %, based on the total weight of the topical preparation or topical pharmaceutical composition of the present invention. When the content of the active ingredient is within the above ranges, the topical preparation and topical pharmaceutical composition of the present invention can fully exert their preventive or therapeutic effects on periostin-mediated diseases and pruritus (e.g., skin itching symptoms) associated with such diseases.

[0047] The topical preparation and topical pharmaceutical composition of the present invention may contain other ingredients in addition to the compound etc. of the present invention, provided that the effects of the present invention are not significantly impaired, or the compound etc. of the present invention may be used in combination with other ingredients. Examples of other ingredients include known or under-developed drugs, and for example, one or more of steroids, immunosuppressants, antihistamines, JAK inhibitors, and IL-4 / IL-13 inhibitors may be used in combination. The compound etc. of the present invention and other ingredients may be applied (administered) simultaneously or sequentially.

[0048] The topical agent and the topical pharmaceutical composition of the present invention can be administered to humans or various non-human mammals (e.g., rats, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) as test subjects.

[0049] The topical preparation and topical pharmaceutical composition of the present invention may contain additives, including, but not limited to, bases, wetting agents (moisturizers), thickeners, emulsifiers, emulsifier aids, preservatives, stabilizers, and pH adjusters.

[0050] The base may be a hydrophobic base, a hydrophilic base, water, or the like.

[0051] The hydrophobic base is not particularly limited, but examples thereof include squalane, liquid paraffin, light liquid paraffin, and petrolatum.

[0052] The hydrophilic base is not particularly limited, but examples thereof include alcohols such as ethanol.

[0053] Humectants (moisturizers) keep the skin moist when the topical preparation is applied. Examples of humectants include, but are not limited to, petrolatum and glycerin.

[0054] The thickener increases the viscosity of the topical preparation or causes it to gel. Examples of the thickener include, but are not limited to, gelatin and agar.

[0055] The emulsifier emulsifies the topical agent into an oil-in-water (o / w) or water-in-oil (w / o) emulsion.

[0056] The co-emulsifier stabilizes the emulsion when the topical preparation is emulsified into an oil-in-water (o / w) type or a water-in-oil (w / o) type.

[0057] The preservative prevents or inhibits contamination and decomposition of the topical preparation by microorganisms. Examples of the preservative include, but are not limited to, parahydroxybenzoic acid.

[0058] The solubilizing agent is not particularly limited, but examples thereof include ethanol.

[0059] The stabilizer prevents or suppresses chemical decomposition or physical changes of the active ingredient, and examples of the stabilizer include, but are not limited to, sodium bisulfite.

[0060] The pH adjuster maintains the stability of the active ingredient and prevents or reduces irritation of the topical preparation to the living body. There are no particular limitations on the pH adjuster, and it is sufficient if it can adjust the pH to a specific level.

[0061] The dosage form of the topical preparation and topical pharmaceutical composition of the present invention is not particularly limited as long as it can be applied to the skin (affected area) as a topical drug, and examples thereof include ointments, creams, gels, lotions, etc. These will be described in detail below.

[0062] The application (administration) amount of the topical preparation of the present invention and the topical pharmaceutical composition of the present invention can generally be set over a wide range as appropriate, taking into consideration the blending ratio of the active ingredient (the compound of the present invention, etc.) in the formulation, as well as the age, weight, type and progress of the condition of the subject (patient), the number of administrations (per day), the administration period, etc.

[0063] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0064] Generation of Facial Atopic Dermatitis with Scratching (FADS) mice. Nestin-cre transgenic mice and Ikk2. f / f Nestin-cre / Ikk2 mice specifically lack IKK2 in facial skin fibroblasts after crossing with mice f / f We generated mice with this condition (Nunomura S, et al. J Invest Dermatol. 139:1274-1283, 2019). These mice were named Facial Atopic Dermatitis with Scratching (FADS) mice because they inevitably develop atopic dermatitis-like rash limited to the face and severe itching. FADS mice have significantly increased serum periostin levels compared with control mice, and periostin is highly expressed in the dermis of facial skin. Disruption of the periostin gene in FADS mice significantly suppressed scratching behavior compared with control mice. Furthermore, intraperitoneal administration of an anti-periostin monoclonal antibody that neutralizes periostin suppressed scratching behavior in FADS mice, indicating that scratching behavior in FADS mice is periostin-mediated (Nunomura S, et al. Cell Rep. 42:111933, 2023). In this example, FADS mice of 3 to 4 weeks of age or older that exhibit spontaneous scratching behavior were used.

[0065] Inhibition of Scratching Behavior in FADS Mice by Single Systemic Administration. FADS mice were videotaped for 60 minutes before administration of the test drug, followed by a 15-minute rest period. CP4715, CP derivative 2, CP derivative 6, CP derivative 7, SC-68448, SM-256, and SB-267268 were dissolved in a solution (50% DMSO, 89.5 mM HCl saline). An aliquot of each compound (89.5 mM) was diluted in 0.3 mL of PBS and administered intraperitoneally to each mouse at a dose equivalent to 53.7 μmol / kg. Mice received 0.3 mL of PBS containing an equivalent weight-equivalent volume of the solution as a control.

[0066] Video recording was performed for 60 minutes immediately after administration of the test drug. The number of scratchings before administration was used as the baseline, and the rate of change from baseline after administration was calculated. A paired t-test was used for statistical analysis. A P value of less than 0.05 was considered significant. The effect of inhibitors with a mean change rate from baseline of -65% or more and a P value of less than 0.01 was indicated as "++", the effect of inhibitors with a mean change rate of -60% or less and a P value of less than 0.05 was indicated as "+", and the effect of inhibitors with a mean change rate of -60% or less and a P value of 0.05 or more was indicated as "-".

[0067] For each compound, the percentage change from baseline in the number of scratching attempts is shown in Table 1. The dose of each compound was standardized at 53.7 μmol / kg.

[0068]

[0069] The results of the rate of change from baseline are also shown in Figure 1. The numbers in the graph in Figure 1 (e.g., 0.17, 0.0004, etc.) indicate P values.

[0070] ​Periostin-Dependent Inhibitory Effect on Cell Adhesion In cell adhesion experiments, SW480 cells, a human colon cancer cell line that does not express integrin β3, were transfected with human integrin β3 and stably expressed human integrin β3 (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020). The inhibitory activity of the compounds listed in Table 1 on adhesion between integrin αvβ3 and periostin was examined as follows: First, a 96-well plate was treated with 10 μg / mL recombinant human periostin (Bio-Techne) at 4°C for 16 hours to immobilize periostin. Integrin αvβ3-expressing SW480 cells (5 × 10 ４ The cells (100 cells) were incubated with the above compounds at 0.001, 0.01, 0.1, or 1 μM in serum-free Dulbecco's Modified Eagle Medium (DMEM) containing 0.5% bovine serum albumin and 0.25 mM MnCl2 at room temperature for 15 minutes. A compound-free group served as a control. The cell suspension after the reaction was added to each well of the human periostin-immobilized plate. The plate was centrifuged at 10 × g for 5 minutes and then incubated at 37°C for 60 minutes. The adhered cells were then washed to remove unbound cells, and the adhered cells were fixed with 1% formaldehyde and stained with 0.5% crystal violet. The fixed and stained cells were solubilized with 0.2% Triton X-100, and the absorbance at 595 nm was measured. The absorbance of the control (compound-free group) was defined as 0% inhibition. Using the same procedure, the absorbance of crystal violet derived from cells adhered to a bovine albumin-immobilized plate was also measured without the addition of any compound, and this was defined as 100% inhibition. Cell adhesion in this test system is periostin-dependent, and compounds that inhibit this cell adhesion can be called periostin receptor antagonists.

[0071] The results are shown in Figure 2. The 50% inhibitory concentration (IC 50 The IC values ​​for CP4715, CP derivative 2, CP derivative 6, and CP derivative 7 were 0.001 μM or less, and these compounds exhibited high cell adhesion inhibitory effects.50 The IC value of SM-256 was 0.02 μM or less, indicating a moderate inhibitory effect on cell adhesion. 50 Although the inhibitory effects were low, with IC values ​​of 0.1 μM or less, CP4715, CP derivative 2, CP derivative 6, CP derivative 7, SC-68448, SB-267268, and SM-256 all inhibited cell adhesion, indicating that they can be considered periostin receptor antagonists. 50 The values ​​were above 1 μM.

[0072] It was found that the inhibitory effect of the compounds on cell adhesion and the inhibitory effect on scratching behavior in FADS mice were not necessarily correlated. 50 The compounds showed strong cell adhesion inhibitory activity, with values ​​of 0.00-1 μM or less. On the other hand, in terms of the inhibitory effect on scratching behavior in FADS mice, CP4715 and CP derivative 6 exhibited strong inhibitory effects, indicated by "++," while CP derivatives 2 and 7 exhibited weak inhibitory effects, indicated by "-." SC-68448 exhibited a strong inhibitory effect on scratching behavior in FADS mice, indicated by "++," while SB-267268, which has similar cell adhesion inhibitory activity to SC-68448, showed a weak inhibitory effect, indicated by "-."

[0073] Inhibition of Scratching Behavior in FADS Mice by Repeated Percutaneous Administration. CP4715, SM-256, SC-68448, CP Derivative 7, and SB-267268 were dissolved in a solution of 5% DMSO / 15% N-methyl-2-pyrrolidone / 80% acetone to prepare 26.85 mM solutions. CP Derivative 2 and CP Derivative 6 were dissolved in a solution of 15% DMSO / 20% N-methyl-2-pyrrolidone / 65% acetone to prepare 26.85 mM solutions. 30 μL of the 26.85 mM solution was applied once daily for 28 consecutive days to the facial rash of FADS mice prepared as described in Example 1. Mice receiving an equal amount of the solution percutaneously served as the control group. The number of scratching bouts over a 60-minute period was measured before and on days 7, 14, 21, and 28 after administration. The day of administration of the test drug was designated as day 0. Statistical analysis was performed using the Mann-Whitney U test. A P value of less than 0.05 was considered significant. The results are shown in Figures 3-1 and 3-2 and Tables 2, 3, 4, and 5. Although SB-267268 is also a periostin inhibitor, it did not exhibit any inhibitory effect on scratching behavior in FADS mice. However, CP4715, SM-256, SC-68448, CP derivative 7, CP derivative 2, and CP derivative 6 inhibited scratching behavior in FADS mice. SM-256, CP derivative 7, and CP derivative 2, which showed negative results in the in vivo evaluation in Figure 1, were applied topically (also known as percutaneous administration) and inhibited scratching behavior in FADS mice. As shown in Tables 3, 4, and 5, the number of scratching bouts measured from day 14 onward was significantly greater in the CP4715, SC-68448, or CP derivative 6-treated groups than in the vehicle group on days 14, 21, and 28 after administration. The SM-256, CP derivative 2, or CP derivative 7-treated groups significantly reduced scratching behavior on days 21 and 28 after administration compared to the vehicle group. As shown in Figures 3-1 and 3-2, CP4715 and SC-68448 were effective in suppressing scratching behavior in FADS mice as early as day 14 after administration, and this effect continued up to day 28 after administration. Systemic administration of CP derivative 2, CP derivative 7, and SM-256 produced the results shown in Figure 1. However, topical administration also significantly reduced scratching behavior in FADS mice, as shown in Figures 3-1 and 3-2.

[0074]

[0075]

[0076]

[0077]

[0078] Compounds Used in the Test CP4715 is a compound represented by the following formula (II): (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid.

[0079] SC-68448 is a compound represented by the following formula (III) (3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propanoic acid).

[0080] CP derivative 2 is a compound represented by the following formula (IV) ((S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid). ​​

[0081] CP derivative 6 is a compound represented by the following formula (V) ((S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propanoic acid).

[0082] CP derivative 7 is a compound represented by the following formula (VI) ((S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid).

[0083] SM-256 is a compound represented by the following formula (VIII): ((S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propanoic acid).

[0084] SB-267268 is a compound represented by the following formula (IX) ((S)-2-(3-oxo-8-(3-(pyridin-2-ylamino)propoxy)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)acetic acid).

[0085] The SB-267268 enantiomer is the compound represented by the following formula: (R)-2-(3-oxo-8-(3-(pyridin-2-ylamino)propoxy)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)acetic acid.

[0086] The above compounds can be commercially available, but are not limited thereto; they may also be synthesized, extracted, purified, and the like. CP4715 and CP derivative 2 can be produced by the method described in WO1999 / 052872. CP derivative 6 and CP derivative 7 can be produced by the method described in WO2001 / 027082. SC-68448 can be produced by the method described in WO97 / 08145. SM-256 can be produced by the method described in WO09 / 723480. SB-267268 and SB-267268 enantiomers can be produced by the method described in WO98 / 14192.

[0087] The present invention can provide an external preparation and an external pharmaceutical composition useful for ameliorating periostin-mediated diseases and the itching associated with the diseases, for preventing or treating the diseases and the itching, and a method for preventing or treating the diseases and the itching by applying the external preparation and the external pharmaceutical composition to a subject.

Claims

1. An external preparation for preventing or treating perlecan-mediated diseases or pruritus associated with said diseases, containing a perlecan receptor antagonist as an active ingredient, wherein the antagonist is a compound represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound selected from the group consisting of 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamide)-2-((2,4,6-trimethylphenyl) sulfonamido)propionic acid, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the external preparation.

2. The external preparation according to claim 1, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid.

3. The external preparation according to claim 1, wherein the antagonist is (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamide)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid.

4. The external preparation according to claim 1, wherein the periostin-mediated disease is atopic dermatitis, nodular prurigo, bullous pemphigoid, stasis dermatitis, cutaneous T cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease or chronic kidney disease.

5. The external preparation according to claim 1, wherein the periostin-mediated disease is atopic dermatitis.

6. A topical pharmaceutical composition for preventing or treating a periostin-mediated disease or pruritus associated with said disease, comprising a periostin receptor antagonist as an active ingredient, wherein said antagonist is a compound of the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound selected from the group consisting of 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamide)-2-((2,4,6-trimethylphenyl) sulfonamido)propionic acid, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, said topical pharmaceutical composition.

7. The external pharmaceutical composition according to claim 6, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid.

8. The external pharmaceutical composition according to claim 6, wherein the antagonist is (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamide)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid.

9. The external pharmaceutical composition according to claim 6, wherein the periostin-mediated disease is atopic dermatitis, nodular prurigo, bullous pemphigoid, stasis dermatitis, cutaneous T cell lymphoma, systemic scleroderma, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease or chronic kidney disease.

10. The external pharmaceutical composition according to claim 6, wherein the periostin-mediated disease is atopic dermatitis.

11. For the production of an external preparation for preventing or treating perleostin-mediated diseases or pruritus associated with said diseases, the following formula (I): [wherein, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ２ are, independently of each other, a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound of formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamide)-2-((2,4,6-trimethylphenyl) sulfonamido)propionic acid, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

12. The use according to claim 11, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid.

13. The use according to claim 11, wherein the antagonist is (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamide)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid.

14. The use according to claim 11, wherein the periostin-mediated disease is atopic dermatitis, nodular prurigo, bullous pemphigoid, stasis dermatitis, cutaneous T cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease or chronic kidney disease.

15. The use according to claim 11, wherein the periostin-mediated disease is atopic dermatitis.

16. A method for preventing or treating a periostin-mediated disease or pruritus associated with the disease, comprising applying the external preparation according to any one of claims 1 to 5 and / or the external pharmaceutical composition according to any one of claims 6 to 10 to a subject in need of treatment.

17. The method according to claim 16, wherein the periostin-mediated disease is atopic dermatitis, nodular prurigo, bullous pemphigoid, stasis dermatitis, cutaneous T cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease or chronic kidney disease.

18. The method according to claim 16, wherein the periostin-mediated disease is atopic dermatitis.

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