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WO2025146725A1 - External preparation - Google Patents

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Publication number
WO2025146725A1
WO2025146725A1 PCT/JP2024/000085 JP2024000085W WO2025146725A1 WO 2025146725 A1 WO2025146725 A1 WO 2025146725A1 JP 2024000085 W JP2024000085 W JP 2024000085W WO 2025146725 A1 WO2025146725 A1 WO 2025146725A1
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WO
WIPO (PCT)
Prior art keywords
propionic acid
amino
periostin
phenylsulfonamido
tetrahydropyrimidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2024/000085
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French (fr)
Japanese (ja)
Inventor
賢治 出原
聡 布村
康弘 南里
勲 北島
大介 歌
ともみ 滋野
健司 當別當
明裕 石畠
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Maruho Co Ltd
Saga University NUC
University of Toyama NUC
Original Assignee
Maruho Co Ltd
Saga University NUC
University of Toyama NUC
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Publication date
Application filed by Maruho Co Ltd, Saga University NUC, University of Toyama NUC filed Critical Maruho Co Ltd
Priority to PCT/JP2024/000085 priority Critical patent/WO2025146725A1/en
Publication of WO2025146725A1 publication Critical patent/WO2025146725A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/025—Halogenated hydrocarbons carbocyclic
    • A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to topical preparations and the like for preventing or treating periostin-mediated diseases and pruritus associated with such diseases.
  • Periostin is an extracellular matrix protein that binds to cell surface receptors belonging to the integrin family and transmits signals intracellularly, and it has been suggested that it plays an important role in the aggravation and chronicity of allergic skin inflammation (Non-Patent Document 1).
  • Local production of periostin is significantly increased in lesions of atopic dermatitis, and it has been reported that the severity of atopic dermatitis correlates with the lesion and serum periostin levels. It has also been reported that periostin induces scratching behavior when administered intradermally or subcutaneously to mice, dogs, and monkeys (Non-Patent Document 2).
  • a method for treating or alleviating pruritus or chronic pruritus using an integrin ⁇ v ⁇ 3 antagonist that blocks intracellular signaling generated by the binding of periostin to integrin has been disclosed (Patent Document 1).
  • Periostin has been reported to mediate the pathology of various diseases. Diseases in which periostin is mediated include atopic dermatitis and pruritus associated with atopic dermatitis, 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, and pruritus associated with these diseases (Non-Patent Documents 3 to 5).
  • the present invention has been made in consideration of the above circumstances, and provides the following topical preparations and the like for preventing or treating periostin-mediated diseases or pruritus associated with such diseases.
  • 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):
  • R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group
  • R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group
  • R3 is an alkyl group, an aryl group, or an aralkyl group.
  • 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.
  • periostin-mediated disease is atopic dermatitis.
  • 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):
  • R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group
  • R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group
  • R3 is an alkyl group, an aryl group, or an aralkyl group.
  • 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 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)amin
  • 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.
  • periostin-mediated disease is atopic dermatitis.
  • 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.
  • the periostin-mediated disease is atopic dermatitis.
  • 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.
  • 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.
  • the periostin-mediated disease is atopic dermatitis.
  • the alkyl group in R 1 , R 2 , and R 3 in formula (I) is preferably a lower alkyl group (e.g., 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 suitable substituent, but are not limited thereto.
  • 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).
  • the present invention can provide an external preparation and an external pharmaceutical composition useful for improving a periostin-mediated disease and the pruritus associated with the disease, for preventing or treating the disease and the pruritus, and a method for preventing or treating the disease and the pruritus by applying the external preparation and the external pharmaceutical composition to a subject.
  • 1 is a graph showing the inhibitory effect of single systemic administration of various compounds on scratching behavior in FADS mice.
  • 1 is a graph showing the periostin-dependent cell adhesion inhibitory effect of various compounds.
  • 1 is a graph showing the inhibitory effect of repeated transdermal administration of various compounds on the scratching behavior of FADS mice. Same as Figure 3-1.
  • the topical preparation for prevention or treatment of a periostin-mediated disease and itching associated with such disease e.g., itchy skin symptoms
  • the topical pharmaceutical composition for prevention or treatment of a periostin-mediated disease and itching associated with such disease e.g., itchy skin symptoms
  • a periostin-mediated disease comprising a compound represented by the following formula (I):
  • R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group
  • R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group
  • R3 is an alkyl group, an aryl group, or an aralkyl group.
  • the alkyl group in R 1 , R 2 and R 3 in the above formula (I) is preferably a lower alkyl group (e.g., an alkyl group having 1 to 4 carbon atoms), and specific examples thereof include methyl, ethyl, propyl, etc.
  • Preferred examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, mesyl, naphthyl, biphenyl, etc.
  • Preferred examples of the aralkyl group include benzyl, phenethyl, etc.
  • the alkyl group, aryl group and aralkyl group may be substituted with a known suitable substituent, but are not limited thereto.
  • 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 called "CP4715".
  • 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, etc.
  • CP4715 is a compound that has an antagonistic effect against both the glycoprotein (GP) IIb/IIIa receptor, which plays a major role in thrombus formation, and ⁇ v ⁇ 3 integrin (a cell adhesion molecule) involved in leukocyte adhesion, etc., and is known as an active ingredient of a therapeutic drug for cardiovascular disease (antithrombotic agent).
  • ⁇ v ⁇ 3 integrin is a receptor for periostin, fibronectin, vitronectin, etc.
  • periostin is known to activate sensory nerves via ⁇ v ⁇ 3 integrin (see Non-Patent Document 2 cited above).
  • SC-68448 an integrin ⁇ v ⁇ 3 antagonist, has been reported to inhibit the binding of integrin ⁇ v ⁇ 3 to vitronectin (Carron CP, et al. Cancer Res. 58:1930-1935, 1998).
  • CP derivative 6 has been reported to inhibit the binding of integrin ⁇ v ⁇ 3 to periostin or vitronectin (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020).
  • the present invention also includes the following: (i) a method for preventing or treating a periostin-mediated disease or pruritus associated with such a disease, comprising using the compound of the present invention, specifically, for example, applying (administering) an effective amount of the compound of the present invention (i.e., the topical preparation or pharmaceutical composition for topical application of the present invention) to a subject in need of treatment (a patient exhibiting or at risk of exhibiting a periostin-mediated disease or pruritus associated with such a disease (e.g., an itchy skin symptom), or a non-human mammal such as such); (ii) use of the compound of the present invention or the like for producing a medicament as an external preparation for the prevention or treatment of a periostin-mediated disease or pruritus (e.g., skin itching symptoms) associated with such a disease; (iii) topical use of the compounds
  • Periostin-mediated diseases include, but are not limited to, atopic dermatitis, 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.
  • Atopic dermatitis is a chronic skin disease whose main lesion is a pruritic eczema that repeatedly worsens and remits. It has been reported that serum periostin levels are higher in atopic dermatitis patients than in healthy individuals, that local production of periostin is significantly increased in lesions, and that the severity of atopic dermatitis correlates with lesions and serum periostin levels (Non-Patent Documents 1 and 2 cited above).
  • itch-scratch cycle Scratching associated with pruritus worsens skin symptoms and further increases pruritus, creating a vicious cycle (itch-scratch cycle) that 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 produced mainly 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) and has been reported to bind to the IL-31 receptor and transmit itch signals to the central nervous system (Mollanazar NK, et al.
  • nemolizumab an antibody against the IL-31 receptor
  • nemolizumab was shown to improve pruritus while also improving skin inflammation
  • drugs used as topical agents to reduce pruritus associated with atopic dermatitis are also useful for preventing or treating atopic dermatitis.
  • 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).
  • Bullous pemphigoid is a Th2-mediated autoimmune blistering skin disease associated with moderate to severe pruritus.
  • the intensity of pruritus in bullous pemphigoid is directly correlated with dermal deposition of periostin (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.
  • Stasis dermatitis is a disease that typically causes inflammation in the skin of the lower legs of 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).
  • topical agent and 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.
  • non-human mammals e.g., rats, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.
  • Emulsifiers emulsify topical agents into oil-in-water (o/w) or water-in-oil (w/o) emulsions.
  • Stabilizers prevent or inhibit chemical decomposition or physical changes in active ingredients.
  • the stabilizer is not particularly limited, but examples thereof include sodium hydrogen sulfite.
  • the dosage form of the topical agent and topical pharmaceutical composition of the present invention may generally be any dosage form that can be applied to the skin (affected area) as a topical drug, and is not particularly limited, but examples include ointments, creams, gels, and lotions. These are described in detail below.
  • the application (administration) amount of the topical agent of the present invention and the topical pharmaceutical composition of the present invention can generally be set appropriately within a wide range, taking into consideration the mixing ratio of the active ingredient (the compound of the present invention, etc.) in the formulation, as well as the age, weight, and type and progress of the disease of the subject (patient), as well as the number of administrations (per day) and administration period, etc.
  • Facial Atopic Dermatitis with Scratching MiceBy crossing Nestin-cre transgenic mice with Ikk2 f/f mice, we generated Nestin-cre/Ikk2 f/f mice, which specifically lack IKK2 in facial skin fibroblasts (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 skin rash and severe itching symptoms limited to the face.
  • FADS Facial Atopic Dermatitis with Scratching
  • FADS mice have significantly increased periostin levels in serum compared with control mice, and periostin is highly expressed in the dermis of the facial skin; periostin gene disruption in FADS mice significantly suppresses scratching behavior compared with control mice; and scratching behavior in FADS mice is suppressed by intraperitoneal administration of an anti-periostin monoclonal antibody that neutralizes periostin, indicating that the scratching behavior of FADS mice is periostin-mediated (Nunomura S, et al. Cell Rep. 42:111933, 2023).
  • FADS mice of 3 to 4 weeks of age or older that exhibit spontaneous scratching behavior were used.
  • the percentage change from baseline in the number of scratching bouts for each compound is shown in Table 1.
  • the dose of each compound was standardized at 53.7 ⁇ mol/kg.
  • integrin ⁇ 3 was stably expressed in SW480 cells, a human colon cancer cell line that does not express integrin ⁇ 3 (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020).
  • the adhesion inhibitory activity of integrin ⁇ v ⁇ 3 and periostin for the compounds shown in Table 1 was examined as follows. First, a 96-well plate was treated with 10 ⁇ g/mL recombinant human periostin (Bio-Techne) at 4°C for 16 hours to immobilize periostin.
  • Integrin ⁇ v ⁇ 3-expressing SW480 cells (5 ⁇ 104 cells) were reacted with the above compounds at 0.001, 0.01, 0.1, and 1 ⁇ M in serum-free DMEM (Dulbecco's Modified Eagle Medium) containing 0.5% bovine serum albumin and 0.25 mM MnCl2 at room temperature for 15 minutes. The compound-free group was used as a control.
  • the cell suspension after the reaction was added to each well of the above human periostin-immobilized plate, and the plate was centrifuged at 10 ⁇ g for 5 minutes and then cultured 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.
  • the absorbance of crystal violet derived from cells adhered to a bovine albumin-immobilized plate was 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.
  • the results are shown in Figure 2.
  • the 50% inhibitory concentration (IC50 value) of cell adhesion inhibitory activity was 0.001 ⁇ M or less for CP4715, CP derivative 2, CP derivative 6, and CP derivative 7, and these compounds showed high cell adhesion inhibitory effects.
  • the IC50 values of SC-68448 and SB-267268 were 0.02 ⁇ M or less, and they showed moderate cell adhesion inhibitory effects.
  • the IC50 value of SM-256 was 0.1 ⁇ M or less, and the inhibitory effect was low, 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 called periostin receptor antagonists.
  • the IC50 values of the SB-267268 enantiomers were 1 ⁇ M or more.
  • SC-68448 is a compound represented by the following formula (III) (3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propanoic acid).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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 enantiomer can be produced by the method described in WO98/14192.

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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

外用剤Topical agents

　本発明は、ペリオスチン介在性疾患及び該疾患に伴うそう痒の予防又は治療のための外用剤等に関する。 The present invention relates to topical preparations and the like for preventing or treating periostin-mediated diseases and pruritus associated with such diseases.

　ペリオスチンは、インテグリンファミリーに属する細胞表面受容体に結合して、細胞内にシグナル伝達する細胞外マトリックスタンパク質であり、アレルギー性皮膚炎症の増悪と慢性化に重要な役割を果たすことが示唆されている（非特許文献１）。アトピー性皮膚炎の病変部では、ペリオスチンの局所産生が顕著に亢進しており、アトピー性皮膚炎の重症度は、病変部及び血清ペリオスチンレベルと相関することが報告されている。また、ペリオスチンは、マウス、イヌ及びサルに対して皮内又は皮下投与すると掻破行動を誘発することが報告されている（非特許文献２）。さらに、ペリオスチンとインテグリンとの結合により生じる細胞内シグナリングを遮断するインテグリンαvβ3アンタゴニストにより、そう痒症又は慢性そう痒症を治療又は軽減する方法が開示されている（特許文献１）。 Periostin is an extracellular matrix protein that binds to cell surface receptors belonging to the integrin family and transmits signals intracellularly, and it has been suggested that it plays an important role in the aggravation and chronicity of allergic skin inflammation (Non-Patent Document 1). Local production of periostin is significantly increased in lesions of atopic dermatitis, and it has been reported that the severity of atopic dermatitis correlates with the lesion and serum periostin levels. It has also been reported that periostin induces scratching behavior when administered intradermally or subcutaneously to 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 generated by the binding of periostin to integrin has been disclosed (Patent Document 1).

　ペリオスチンは様々な疾患の病態に介在することが報告されている。ペリオスチンが介在する疾患として、アトピー性皮膚炎及びアトピー性皮膚炎に伴うそう痒に加えて、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患及び慢性腎疾患など、並びにこれらの疾患に伴うそう痒が報告されている（非特許文献３～５）。 Periostin has been reported to mediate the pathology of various diseases. Diseases in which periostin is mediated include atopic dermatitis and pruritus associated with atopic dermatitis, 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, and pruritus associated with these diseases (Non-Patent Documents 3 to 5).

WO２０２１／０５５７１３WO2021/055713

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

　このような状況下において、ペリオスチンが介在する疾患及び該疾患に伴うそう痒を改善することができる、新たな該疾患及び該そう痒を予防又は治療する技術の開発が望まれていた。特に、ペリオスチンが介在する疾患は上記のように皮膚疾患が多いため、病変部位に直接投与できる外用剤等は有用である。 Under these circumstances, there has been a demand for the development of new techniques for preventing or treating periostin-mediated diseases and the pruritus associated with these diseases that can improve the diseases and the pruritus associated with these 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.

　本発明は、上記状況を考慮してなされたもので、以下に示す、ペリオスチン介在性疾患又は該疾患に伴うそう痒の予防又は治療のための外用剤等を提供するものである。 The present invention has been made in consideration of the above circumstances, and provides the following topical preparations and the like for preventing or treating periostin-mediated diseases or pruritus associated with such diseases.

（１）ペリオスチン受容体アンタゴニストを有効成分として含む、ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療用の外用剤であって、前記アンタゴニストが、下記式（Ｉ）：

Figure JPOXMLDOC01-appb-C000004
［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸（以下、「SC-68448」と称することがある）、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（以下、「CP誘導体２」と称することがある）、 (S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸（以下、「CP誘導体６」と称することがある）、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（以下、「CP誘導体７」と称することがある）、及び (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（以下、「SM-256」と称することがある）からなる群から選ばれる少なくとも１つの化合物、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物である、前記外用剤。 (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):
Figure JPOXMLDOC01-appb-C000004
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is an alkyl group, an aryl group, or an aralkyl group.
3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (hereinafter sometimes 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 sometimes 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 sometimes 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, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

（２）前記式（Ｉ）の化合物が、(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（以下、「CP4715」と称することがある）である、前記（１）に記載の外用剤。
（３）前記アンタゴニストが、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体２）、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体７）、又は (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（SM-256）である、前記（１）に記載の外用剤。
（４）前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、前記（１）に記載の外用剤。
（５）前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、前記（１）に記載の外用剤。 (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) above, wherein the periostin-mediated disease is atopic dermatitis.

（６）ペリオスチン受容体アンタゴニストを有効成分として含む、ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療用の外用医薬組成物であって、前記アンタゴニストが、下記式（Ｉ）：

Figure JPOXMLDOC01-appb-C000005
［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸（SC-68448）、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体２）、(S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸（CP誘導体６）、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体７）、及び (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（SM-256）からなる群から選ばれる少なくとも１つの化合物、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物である、前記外用医薬組成物。 (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):
Figure JPOXMLDOC01-appb-C000005
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is 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, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

（７）前記式（Ｉ）の化合物が、(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP4715）である、前記（６）に記載の外用医薬組成物。
（８）前記アンタゴニストが、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体２）、(S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体７）、又は (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（SM-256）である、前記（６）に記載の外用医薬組成物。
（９）前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、前記（６）に記載の外用医薬組成物。
（１０）前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、前記（６）に記載の外用医薬組成物。 (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 pharmaceutical composition for external application 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) above, wherein the periostin-mediated disease is atopic dermatitis.

（１１）ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療用の外用剤を製造するための、下記式（Ｉ）：

Figure JPOXMLDOC01-appb-C000006
［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸（SC-68448）、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体２）、(S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸（CP誘導体６）、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体７）、及び (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（SM-256）からなる群から選ばれる少なくとも１つの化合物、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物の使用。 (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:
Figure JPOXMLDOC01-appb-C000006
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is 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.

（１２）前記式（Ｉ）の化合物が、(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP4715）である、前記（１１）に記載の使用。
（１３）前記アンタゴニストが、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体２）、(S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP誘導体７）、又は (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（SM-256）である、前記（１１）に記載の使用。
（１４）前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、前記（１１）に記載の使用。
（１５）前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、前記（１１）に記載の使用。 (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) above, 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) above, wherein the periostin-mediated disease is atopic dermatitis.

（１６）前記（１）～（５）のいずれか一つに記載の外用剤、及び／又は前記（６）～（１０）のいずれか一つに記載の外用医薬組成物を、治療を必要とする被験対象に適用することを含む、ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療方法。 (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.

（１７）前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、前記（１６）に記載の方法。
（１８）前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、前記（１６）に記載の方法。 (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) above, wherein the periostin-mediated disease is atopic dermatitis.

　なお、上記（１）、（６）、及び（１１）に記載の発明において、式（Ｉ）中、Ｒ１、Ｒ２及びＲ３におけるアルキル基としては、低級アルキル基（例えば、炭素数１～４のアルキル基）が好ましく、具体的には、メチル、エチル、プロピル等が好ましく挙げられる。アリール基としては、フェニル、トリル、キシリル、クメニル、メシル、ナフチル、ビフェニル等が好ましく挙げられる。アラルキル基としては、ベンジル、フェネチル等が好ましく挙げられる。なお、当該アルキル基、アリール基、及びアラルキル基は、限定はされないが、公知の適当な置換基で置換されていてもよい。 In the inventions described in (1), (6), and (11) above, the alkyl group in R 1 , R 2 , and R 3 in formula (I) is preferably a lower alkyl group (e.g., 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 suitable substituent, but are not limited thereto.

　また、前記式（Ｉ）の化合物の好ましい具体例としては、限定はされないが、下記式（ＩＩ）：

Figure JPOXMLDOC01-appb-C000007
の化合物（(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（CP4715））が好ましく挙げられる。 In addition, preferred specific examples of the compound of formula (I) include, but are not limited to, the compound of formula (II) below:
Figure JPOXMLDOC01-appb-C000007
 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).

　本発明によれば、ペリオスチン介在性疾患及び該疾患に伴うそう痒の改善に有用な、該疾患及び該そう痒の予防又は治療用の外用剤及び外用医薬組成物、並びにそれら外用剤及び外用医薬組成物を被験対象に適用する、該疾患及び該そう痒の予防又は治療方法等を提供することができる。 The present invention can provide an external preparation and an external pharmaceutical composition useful for improving a periostin-mediated disease and the pruritus associated with the disease, for preventing or treating the disease and the pruritus, and a method for preventing or treating the disease and the pruritus by applying the external preparation and the external pharmaceutical composition to a subject.

FADSマウスの掻破行動に対する、各種化合物の単回全身投与による抑制作用を示すグラフである。1 is a graph showing the inhibitory effect of single systemic administration of various compounds on scratching behavior in FADS mice. 各種化合物のペリオスチン依存的な細胞接着阻害作用を示すグラフである。1 is a graph showing the periostin-dependent cell adhesion inhibitory effect of various compounds. FADSマウスの掻破行動に対する、各種化合物の反復経皮投与による抑制作用を示すグラフである。1 is a graph showing the inhibitory effect of repeated transdermal administration of various compounds on the scratching behavior of FADS mice. 図３－１と同様である。Same as Figure 3-1.

　以下、本発明を詳細に説明する。本発明の範囲はこれらの説明に拘束されることはなく、以下の例示以外についても、本発明の趣旨を損なわない範囲で適宜変更し実施することができる。なお、本明細書において引用された全ての刊行物、例えば先行技術文献、及び公開公報、特許公報その他の特許文献は、参照として本明細書に組み込まれる。 The present invention is 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 modified and implemented as appropriate without impairing the spirit of the present invention. All publications cited in this specification, such as prior art documents, publications, patent publications, and other patent documents, are incorporated herein by reference.

　本発明に係る、ペリオスチン介在性疾患及び該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療用の外用剤（以下、「本発明の外用剤」ということがある。）、及び、ペリオスチン介在性疾患及び該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療用の外用医薬組成物（以下、「本発明の外用医薬組成物」ということがある。）は、前述した通り、下記式（Ｉ）：

Figure JPOXMLDOC01-appb-C000008
［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、及び (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸からなる群から選ばれる少なくとも１つの化合物（以下、「本発明の化合物」ということがある。）、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物（本発明の化合物と、前記プロドラッグ、塩、水和物及び溶媒和物とを含めて、以下、「本発明の化合物等」ということがある。）を有効成分として含むことを特徴とするものである。 The topical preparation for prevention or treatment of a periostin-mediated disease and itching associated with such disease (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 a periostin-mediated disease and itching associated with such disease (e.g., itchy skin symptoms) (hereinafter sometimes referred to as the "topical pharmaceutical composition of the present invention") comprise a periostin-mediated disease comprising a compound represented by the following formula (I):
Figure JPOXMLDOC01-appb-C000008
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is 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 composition 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 are collectively referred to as "the compound of the present invention, etc.").

　ここで、上記式（Ｉ）中のＲ１、Ｒ２及びＲ３におけるアルキル基としては、低級アルキル基（例えば、炭素数１～４のアルキル基）が好ましく、具体的には、メチル、エチル、プロピル等が好ましく挙げられる。アリール基としては、フェニル、トリル、キシリル、クメニル、メシル、ナフチル、ビフェニル等が好ましく挙げられる。アラルキル基としては、ベンジル、フェネチル等が好ましく挙げられる。なお、当該アルキル基、アリール基、及びアラルキル基は、限定はされないが、公知の適当な置換基で置換されていてもよい。 Here, the alkyl group in R 1 , R 2 and R 3 in the above formula (I) is preferably a lower alkyl group (e.g., an alkyl group having 1 to 4 carbon atoms), and specific examples thereof include methyl, ethyl, propyl, etc. Preferred examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, mesyl, naphthyl, biphenyl, etc. Preferred examples of the aralkyl group include benzyl, phenethyl, etc. The alkyl group, aryl group and aralkyl group may be substituted with a known suitable substituent, but are not limited thereto.

　本発明において、前記式（Ｉ）の化合物の好ましい具体例としては、限定はされないが、下記式（ＩＩ）：
 

Figure JPOXMLDOC01-appb-C000009
の化合物(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（(S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid）が好ましく挙げられる。上記式（II）の化合物は、「CP4715」とも称される。 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:

Figure JPOXMLDOC01-appb-C000009
 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 called "CP4715".

　本発明に係るペリオスチン受容体アンタゴニストは、市販のものを使用することができるが、限定はされず、独自に合成、抽出及び精製等したものを使用してもよい。特に限定されないが、例えば、CP4715は、血栓の形成に主要な役割を果たす糖タンパク(GP) IIb/IIIa受容体、及び白血球接着等に関与するαvβ3インテグリン（細胞接着分子）の両方に拮抗する作用を有する化合物であり、循環器系疾患治療薬（抗血栓剤）の有効成分として、知られているものである。ここで、αvβ3インテグリンは、ペリオスチン、ファイブロネクチン及びビトロネクチンなどの受容体であり、ペリオスチンがαvβ3インテグリンを介して知覚神経を活性化することが知られている（前掲の非特許文献２参照）。SC-68448は、インテグリンαvβ3アンタゴニストとして、インテグリンαvβ3とビトロネクチンとの結合を阻害することが報告されている（Carron CP, et al. Cancer Res. 58:1930-1935, 1998）。CP誘導体６は、インテグリンαvβ3とペリオスチン又はビトロネクチンとの結合を阻害することが報告されている（Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020）。 　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, etc. Without being particularly limited thereto, for example, CP4715 is a compound that has an antagonistic effect against 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, etc., and is known as an active ingredient of a therapeutic drug for cardiovascular disease (antithrombotic agent). Here, αvβ3 integrin is a receptor for periostin, fibronectin, vitronectin, etc., and periostin is known to activate sensory nerves 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).

　なお、本発明においては、上記の本発明の外用剤及び本発明の外用医薬組成物のほかにも、
(i) 本発明の化合物等を用いること、具体的には、例えば、本発明の化合物等の有効量（すなわち本発明の外用剤又は外用医薬組成物）を、治療を必要とする被験対象（ペリオスチン介在性疾患又は該疾患に伴うそう痒（例えば皮膚の痒み症状）を呈している患者若しくはその恐れのある患者、又はそのような非ヒト哺乳動物）に適用（投与）することを含む、ペリオスチン介在性疾患又は該疾患に伴うそう痒の予防又は治療方法；
(ii) ペリオスチン介在性疾患又は該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療用の外用剤としての薬剤を製造するための本発明の化合物等の使用；
(iii) ペリオスチン介在性疾患又は該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療用の本発明の化合物等の外用による使用；並びに、
(iv) ペリオスチン介在性疾患又は該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療に用いる外用のための本発明の化合物等
も包含され得る。 In addition to the above-mentioned topical agent and topical pharmaceutical composition of the present invention, the present invention also includes the following:
(i) a method for preventing or treating a periostin-mediated disease or pruritus associated with such a disease, comprising using the compound of the present invention, specifically, for example, applying (administering) an effective amount of the compound of the present invention (i.e., the topical preparation or pharmaceutical composition for topical application of the present invention) to a subject in need of treatment (a patient exhibiting or at risk of exhibiting a periostin-mediated disease or pruritus associated with such a disease (e.g., an itchy skin symptom), or a non-human mammal such as such);
(ii) use of the compound of the present invention or the like for producing a medicament as an external preparation for the prevention or treatment of a periostin-mediated disease or pruritus (e.g., skin itching symptoms) associated with such a disease;
(iii) topical use of the compounds of the invention or the like for the prevention or treatment of periostin-mediated diseases or pruritus (e.g., itchy skin symptoms) associated with such diseases; and
(iv) The present invention also includes the compounds of the present invention for external application for the prevention or treatment of periostin-mediated diseases or pruritus (e.g., skin itching symptoms) associated with such diseases.

　本発明において、ペリオスチン介在性疾患とは、ペリオスチンが発症又は疾患の進展に関与する疾患である。ペリオスチン介在性とは、体細胞又は体組織へのペリオスチンの直接的な作用、例えばペリオスチンがその受容体に結合した結果、細胞内シグナル伝達系が活性化され、疾患の発症又は進展に関与する状態を意味する。さらに、ペリオスチン介在性とは、ペリオスチンが体組織又は体細胞に作用した結果、新たに生体分子が産生、発現若しくは遊離又は活性化され、該生体分子により疾患が発症又は進展する状態をも意味する。 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 disease means a state in which the intracellular signaling system is activated as a result of the direct action of periostin on somatic cells or somatic tissues, for example, binding of periostin to its receptor, and the activation contributes to the onset or progression of the disease. Periostin-mediated disease also means a state in which a biomolecule is newly produced, expressed, released, or activated as a result of the action of periostin on somatic tissues or somatic cells, and the biomolecule causes the onset or progression of the disease.

　ペリオスチン介在性疾患としては、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患及び慢性腎疾患など、並びにこれらの疾患に伴うそう痒が挙げられるが、これらに限定されない。 Periostin-mediated diseases include, but are not limited to, atopic dermatitis, 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.

　アトピー性皮膚炎は、増悪・寛解を繰り返す、そう痒のある湿疹を主病変とする慢性の皮膚疾患である。アトピー性皮膚炎患者においては、血清ペリオスチンのレベルが健常人より高いこと、病変部においてペリオスチンの局所産生が顕著に亢進していること、またアトピー性皮膚炎の重症度は、病変部及び血清ペリオスチンレベルと相関していることが報告されている（前掲の非特許文献１及び２）。 Atopic dermatitis is a chronic skin disease whose main lesion is a pruritic eczema that repeatedly worsens and remits. It has been reported that serum periostin levels are higher in atopic dermatitis patients than in healthy individuals, that local production of periostin is significantly increased in lesions, and that the severity of atopic dermatitis correlates with lesions and serum periostin levels (Non-Patent Documents 1 and 2 cited above).

　そう痒に伴う掻破は、皮膚症状を悪化させ、さらにそう痒が増強するという悪循環（itch-scratch cycle）を生じさせ、アトピー性皮膚炎の病態形成に関与することが知られている（Tominaga M, Takamori K. Allergol Int. (2022) 71:265-277）。主にTh2細胞から産生されるサイトカインであるIL-31は、アトピー性皮膚炎の主な痒み誘発物質のひとつとして知られており（Datsi A, et al. Allergy. 76:2982-2997, 2021）、IL-31受容体に結合してそう痒のシグナルを中枢に伝達することが報告されている（Mollanazar NK, et al. Clin Rev Allergy Immunol. 51:263-292, 2020）。IL-31受容体に対する抗体（ネモリズマブ、nemolizumab）をアトピー性皮膚炎患者に投与する臨床試験において、ネモリズマブはそう痒を改善すると同時に、皮膚炎症を改善する効果も示した（Kabashima K, et al. N Engl J Med. 383:141-150, 2020）。すなわち、アトピー性皮膚炎に伴うそう痒を軽減する外用剤としての薬物は、アトピー性皮膚炎の予防又は治療にも有用であることが示される。 Scratching associated with pruritus worsens skin symptoms and further increases pruritus, creating a vicious cycle (itch-scratch cycle) that 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 produced mainly 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) and has been reported to bind to the IL-31 receptor and transmit 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 an antibody against the IL-31 receptor (nemolizumab) was administered to patients with atopic dermatitis, nemolizumab was shown to improve pruritus while also improving skin inflammation (Kabashima K, et al. N Engl J Med. 383:141-150, 2020). In other words, it is shown that drugs used as topical agents to reduce pruritus associated with atopic dermatitis are also useful for preventing or treating atopic dermatitis.

　結節性痒疹は、強い痒みを伴う丘疹性皮膚疾患であり、真皮におけるペリオスチンの免疫染色強度が、結節性痒疹のそう痒強度と相関することが報告されている（Hashimoto T, et al. Acta Derm Venereol. 101:adv00375, 2021）。 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).

　水疱性類天疱瘡は、Th2免疫による自己免疫性水疱症であり、中等度から重度の痒みを伴う皮膚疾患である。水疱性類天疱瘡における痒みの強さは、ペリオスチンの真皮沈着と直接相関しており（Hashimoto T, et al. J Am Acad Dermatol. 83:53-62, 2020）、水疱性類天疱瘡に関連した痒みにペリオスチンが直接関与している可能性が示唆される。 Bullous pemphigoid is a Th2-mediated autoimmune blistering skin disease associated with moderate to severe pruritus. The intensity of pruritus in bullous pemphigoid is directly correlated with dermal deposition of periostin (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.

　うっ滞性皮膚炎は、慢性静脈不全及びリンパ浮腫などにより、典型的には高齢者の下腿皮膚に炎症が生じる疾患である。ペリオスチンは、マクロファージのIL-31産生を促進することにより、うっ滞性皮膚炎に伴う痒みに寄与する可能性が報告されている（Hashimoto T, et al. J Invest Dermatol. 140:850-859, 2020）。 Stasis dermatitis is a disease that typically causes inflammation in the skin of the lower legs of 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).

　皮膚Ｔ細胞リンパ腫は、皮膚に生じる悪性リンパ腫の一群で、腫瘍の由来となる細胞がT細胞である疾患である。皮膚Ｔ細胞リンパ腫では、高い割合で痒みが生じるが、皮膚Ｔ細胞リンパ腫の病変皮膚サンプルにおいてペリオスチンの発現が上昇しており（Furudate S, et al. Exp Dermatol. 25:107-112, 2016）、ペリオスチンが皮膚Ｔ細胞リンパ腫の痒みに部分的に関与している可能性が示唆される。 Cutaneous T-cell lymphoma is a group of malignant lymphomas that occur in the skin, and is a disease in which the cells from which the tumor originates are T cells. A high proportion of patients with cutaneous T-cell lymphoma experience pruritus, and periostin expression has been increased in lesional skin samples from cutaneous T-cell lymphoma (Furudate S, et al. Exp Dermatol. 25:107-112, 2016), suggesting that periostin may be partially involved in the pruritus caused by cutaneous T-cell lymphoma.

　全身性強皮症及びケロイド・肥厚性瘢痕は、共通して真皮の異常な線維化を有する疾患であり、いずれも高い割合でそう痒を伴う。全身性強皮症患者及びケロイド患者の病変部の皮膚サンプルでは、真皮ペリオスチンの発現亢進が認められている（Maeda D, et al. J Plast Surg Hand Surg. 53:288-294, 2019）。さらに、全身性強皮症患者では、血清ペリオスチン濃度が上昇し、疾患重症度と相関していることが報告されている（Yamaguchi Y, et al. Br J Dermatol. 168:717-725, 2013）。これらのことより、ペリオスチンが、全身性強皮症及びケロイド・肥厚性瘢痕に伴うそう痒に関与している可能性が示唆される。 Systemic sclerosis and keloid/hypertrophic scars are diseases that commonly involve abnormal fibrosis of the dermis, and both are frequently accompanied by pruritus. Increased expression of periostin in the dermis has been observed in skin samples from lesions of patients with systemic sclerosis and keloids (Maeda D, et al. J Plast Surg Hand Surg. 53:288-294, 2019). Furthermore, it has been reported that serum periostin concentrations are elevated in patients with systemic sclerosis and correlate 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.

　アレルギー性鼻炎では痒みが伴うことが多いが、アレルギー性鼻炎患者の鼻粘膜ではペリオスチンが高発現していることが確認されている（Ishida A, et al. Allergol Int, 61:589-595, 2012）。このため、ペリオスチンはアレルギー性鼻炎の痒みに部分的に寄与する可能性がある（Ohta N, et al. Allergol Int. 63:171-180, 2014）。 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). Therefore, periostin may partially contribute to the itch of allergic rhinitis (Ohta N, et al. Allergol Int. 63:171-180, 2014).

　ペリオスチンは、ペルオキシソーム増殖因子活性化受容体α（peroxisome proliferator-activated receptor-α）の発現を阻害することにより、肝線維化を誘導することが報告されている（J Gastroenterol Hepatol. 35:2140-2150, 2020）。また、肝硬変などの慢性肝疾患では、抗ヒスタミン薬の投与も奏効しにくい難治性の痒みを生じる場合があり、ペリオスチンの関与が考えられる。 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). In addition, 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.

　慢性腎疾患においてもペリオスチンの関与が報告されている。腎臓及び尿中のペリオスチンの発現レベルは、病態のステージ及び腎機能の低下と高い相関があることが示されている（Prakoura N, et al. Cell Mol Life Sci. 74:4315-4320, 2017, Jia Y-Y, et al. Ren Fail. 42:1166-1172, 2020）。腎機能の低下は人工透析の必要性を生じる。人工透析患者では皮膚の乾燥が生じ、そう痒を併発する原因となる（Morton CA, et al. Nephrol Dial Transplant. 10:2031-2036, 1996）。皮膚の乾燥が進むと皮膚バリア機能の低下に伴い神経線維（C線維）が表皮まで伸長するが(Andoh T, et al. Neurosci Lett. 672:84-89, 2018)、その神経線維に存在するペリオスチン受容体がペリオスチンにより活性化されると、痒みを生じる可能性が考えられる（前掲の非特許文献２）。 Periostin has also been reported to be involved in chronic kidney disease. It has been shown that the expression levels of periostin in the kidney and urine are highly correlated with the stage of the disease and the decline in renal function (Prakoura N, et al. Cell Mol Life Sci. 74:4315-4320, 2017, Jia Y-Y, et al. Ren Fail. 42:1166-1172, 2020). The decline in renal function leads to the need for dialysis. Patients undergoing dialysis develop dry skin, which can lead to the complication of pruritus (Morton CA, et al. Nephrol Dial Transplant. 10:2031-2036, 1996). When the skin becomes dry, nerve fibers (C fibers) extend to the epidermis due to a decrease in the skin barrier function (Andoh T, et al. Neurosci Lett. 672:84-89, 2018), and it is thought that itching may occur when the periostin receptor present in the nerve fibers is activated by periostin (Non-Patent Document 2 cited above).

　以上のように、ペリオスチンが介在する各種ヒト疾患が知られている。しかしながら、これらのヒト疾患に対して、実際にペリオスチン受容体アンタゴニストを投与して、治療効果又は予防効果が得られたという報告はない。 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.

　本発明において、そう痒としては、例えば、皮膚の痒み症状が挙げられる。皮膚の痒み症状としては、限定はされないが、皮膚の疾患又は炎症に起因する皮膚の痒み症状が挙げられる。皮膚の疾患又は炎症としては、限定はされないが、例えば、アトピー性皮膚炎、接触性皮膚炎、及び痒疹などが挙げられる。 In the present invention, examples of pruritus include skin itching symptoms. Examples of skin itching symptoms include, but are not limited to, skin itching symptoms caused by skin disease or inflammation. Examples of skin disease or inflammation include, but are not limited to, atopic dermatitis, contact dermatitis, and prurigo.

　本発明における「予防」及び「治療」には、ペリオスチン介在性疾患及び該疾患に伴うそう痒（例えば皮膚の痒み症状）の抑制及び／若しくは阻害又は軽減の意味も含まれるものとする。従って、本発明においては、本発明の化合物等を含むペリオスチン介在性疾患及び該疾患に伴うそう痒（例えば皮膚の痒み症状）の症状の抑制剤、阻害剤、又は軽減剤としての外用剤、本発明の化合物等を含む該症状の抑制、阻害、又は軽減用の外用医薬組成物、本発明の化合物等を外用により被験対象に適用（投与）することを含む該症状の抑制、阻害、又は軽減方法、並びに、該症状を抑制、阻害、又は軽減するための外用剤としての薬剤の製造における本発明の化合物等の使用も、含まれ得る。また、ペリオスチン介在性疾患及びそう痒（例えば皮膚の痒み症状）の治療としては、例えば、症状の進行抑制、予後改善及び寛解に至るまでの治療などが含まれ、さらには、一般的な治療の意味に限らず、症状の予防及び再発防止等も含まれる。 The terms "prevention" and "treatment" in the present invention also include the meaning of suppressing and/or inhibiting, or alleviating a periostin-mediated disease and itching (e.g., skin itching) associated with the disease. Thus, the present invention may also include an external preparation as a suppressor, inhibitor, or alleviator of a periostin-mediated disease and itching (e.g., skin itching) associated with the disease, comprising the compound of the present invention, etc.; an external pharmaceutical composition for suppressing, inhibiting, or alleviating the symptom, comprising the compound of the present invention, etc.; a method for suppressing, inhibiting, or alleviating the symptom, comprising applying (administering) the compound of the present invention, etc., by external application to a subject; and use of the compound of the present invention, etc. in the manufacture of a medicament as an external preparation for suppressing, inhibiting, or alleviating the symptom. In addition, treatment of a periostin-mediated disease and itching (e.g., skin itching) includes, for example, treatment until suppression of progression of the symptom, improvement of prognosis, and remission, and further includes not only a general meaning of treatment but also prevention of the symptom and prevention of recurrence, etc.

　本発明の外用剤、及び本発明の外用医薬組成物の有効成分としては、本発明の化合物と共に、又は本発明の化合物に代えて、本発明の化合物の誘導体を用いることもできる。当該誘導体としては、本発明の化合物由来の化学構造を有するなど、当業者の技術常識に基づいて当該誘導体と考えられるものであればよく、限定はされないが、ペリオスチン介在性疾患及び該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療効果が本発明の化合物と少なくとも同程度ものであることが好ましい。 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 may be any derivative that is considered to be such a derivative based on the technical common sense of a person skilled in the art, such as having a chemical structure derived from the compound of the present invention, and is not limited thereto, but it is preferable that the derivative has at least the same preventive or therapeutic effect on periostin-mediated diseases and pruritus (e.g., skin itching symptoms) associated with such diseases as the compound of the present invention.

　本発明の化合物又はその誘導体としては、例えば、生体内で酸化、還元、加水分解、又は抱合などの代謝を受けるものも包含するほか、生体内で酸化、還元、又は加水分解などの代謝を受けて本発明の化合物又はその誘導体を生成する化合物（いわゆるプロドラッグ）も含まれる。本発明において、プロドラッグとは、薬理学的に許容し得る、通常プロドラッグにおいて使用される基で親化合物を修飾した化合物をいい、例えば、化学的安定性、効果の持続性又は体内吸収性の改善等の特性が付与され、腸管内又は皮膚組織等で親化合物に変換されて効果を発現することが期待できる化合物をいう。例えば、本発明の化合物のプロドラッグは、対応するハロゲン化物等のプロドラッグ化試薬を用いて、常法により、当該化合物中のプロドラッグ化の可能な基（例えば、水酸基、アミノ基、カルボキシル基及びその他の基）から選択される１以上の任意の基に、常法に従い適宜プロドラッグを構成する基を導入した後、必要に応じ、単離精製することにより製造することができる。ここで、上記プロドラッグを構成する基としては、限定はされないが、例えば、低級アルキル－ＣＯ－、低級アルキル－Ｏ－低級アルキレン－ＣＯ－、低級アルキル－ＯＣＯ－低級アルキレン－ＣＯ－、低級アルキル－ＯＣＯ－、及び低級アルキル－Ｏ－低級アルキレン－ＯＣＯ－等が好ましく挙げられる。 The compounds or derivatives of the present invention include those that undergo metabolism such as oxidation, reduction, hydrolysis, or conjugation in the living body, as well as compounds that undergo metabolism such as oxidation, reduction, or hydrolysis in the living body 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 that is usually used in a prodrug, and is expected to be converted to a parent compound in the intestinal tract or skin tissue to exert an effect, for example, to properties such as chemical stability, duration of effect, or improved absorbability in the body. For example, a prodrug of the compound of the present invention can be produced by introducing a group that constitutes a prodrug according to a conventional method to one or more groups selected from groups that can be converted into a prodrug in the compound (e.g., hydroxyl group, amino group, carboxyl group, and other groups) using a prodrug-converting reagent such as a corresponding halide, and then isolating and purifying the resulting compound as necessary. Here, the groups constituting the prodrug are not limited, but preferred examples include 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-.

　本発明の外用剤、及び本発明の外用医薬組成物の有効成分としては、本発明の化合物及びその誘導体若しくはそれらのプロドラッグと共に、又は本発明の化合物及びその誘導体若しくはそれらのプロドラッグに代えて、それらの薬理学的に許容し得る塩を用いることもできる。 As the active ingredient of the topical agent of the present invention and the topical pharmaceutical composition of the present invention, a pharmacologically acceptable salt thereof may be used together with the compound of the present invention and its derivative or prodrug, or instead of the compound of the present invention and its derivative or prodrug.

　本発明の化合物及びその誘導体の薬理学的に許容し得る塩としては、限定はされないが、例えば、ハロゲン化水素酸塩（例えば、塩酸塩、臭化水素酸塩、及びヨウ化水素酸塩など）、無機酸塩（例えば、硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、及び重炭酸塩など）、有機カルボン酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、及びクエン酸塩など）、有機スルホン酸塩（例えば、メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、及びカンファースルホン酸塩など）、アミノ酸塩（例えば、アスパラギン酸塩、及びグルタミン酸塩など）、四級アミン塩、アルカリ金属塩（例えば、ナトリウム塩、及びカリウム塩など）、アルカリ土類金属塩（例えば、マグネシウム塩、及びカルシウム塩など）などが好ましく挙げられる。 Preferred examples of pharmacologically acceptable salts of the compounds of the present invention and their derivatives 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.), etc.

　前記有効成分として用いる本発明の化合物等は、化合物の構造上生じ得るすべての異性体（例えば、幾何異性体、不斉炭素に基づく光学異性体、回転異性体、立体異性体、及び互変異性体等）及びこれら異性体の２種以上の混合物をも包含し、便宜上の構造式の記載等に限定されるものではない。また、本発明の化合物等は、S-体、R-体又はRS-体のいずれであってもよく、限定はされない。さらに、本発明の化合物等は、その種類により水和物又は溶媒和物の形で存在する場合もあり、本発明においては当該水和物及び溶媒和物も本発明の化合物等に含むものとし、本発明の外用剤、及び本発明の外用医薬組成物の有効成分として用いることができる。当該溶媒和物としては、限定はされないが、例えば、エタノールとの溶媒和物等が挙げられる。 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 due to the structure of the compound, as well as mixtures of two or more of these isomers, and are not limited to the description of the structural formula for convenience. The compounds of the present invention may be any of the S-, R-, or RS-forms, and are not limited thereto. Furthermore, the compounds of the present invention may exist in the form of hydrates or solvates depending on the type, and in the present invention, the 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 of the present invention and the topical pharmaceutical composition of the present invention. Examples of the solvates include, but are not limited to, solvates with ethanol.

　本発明の外用剤、及び本発明の外用医薬組成物において、有効成分としての本発明の化合物等の含有割合は、限定はされず、適宜設定することができるが、例えば、本発明の外用剤、又は本発明の外用医薬組成物の全体に対して、0.01～99重量％の範囲内とすることができ、好ましくは、0.01～30重量％、より好ましくは0.05～20重量％、さらに好ましくは0.1～10重量％の範囲内としてもよい。有効成分の含有割合が上記範囲内であることにより、本発明の外用剤、及び本発明の外用医薬組成物は、ペリオスチン介在性疾患及び該疾患に伴うそう痒（例えば皮膚の痒み症状）の予防又は治療効果を十分に発揮することができる。 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 appropriately set; for example, it may be 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 content of the topical preparation or topical pharmaceutical composition of the present invention. When the content of the active ingredient is within the above range, the topical preparation and topical pharmaceutical composition of the present invention can fully exert the effect of preventing or treating periostin-mediated diseases and pruritus (e.g., skin itching symptoms) associated with such diseases.

　本発明の外用剤、及び外用医薬組成物は、本発明の化合物等以外にも、本発明の効果が著しく損なわれない範囲で他の成分を含んでいてもよいし、本発明の化合物等と他の成分とを組み合わせて用いてもよい。他の成分としては、公知の又は開発中の薬剤が挙げられ、例えば、ステロイド剤、免疫抑制剤、抗ヒスタミン薬、JAK阻害剤、及びIL-4/IL-13阻害剤等のうちの１種又は２種以上を、併用することもできる。本発明の化合物等と他の成分とは、同時に適用（投与）されてもよいし、逐次に適用（投与）されてもよい。 The topical agent and topical pharmaceutical composition of the present invention may contain other ingredients in addition to the compound of the present invention, provided that the effect of the present invention is not significantly impaired, or the compound 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 of the present invention and other ingredients may be applied (administered) simultaneously or sequentially.

　本発明の外用剤、及び本発明の外用医薬組成物は、被験対象としてのヒト、又は種々の非ヒト哺乳動物（例えば、ラット、ウサギ、ヒツジ、ブタ、ウシ、ネコ、イヌ、及びサルなど）に対して、投与することができる。 The topical agent and 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.

　本発明の外用剤、及び外用医薬組成物は、添加剤を含んでいてもよい。添加剤としては、特に制限されないが、基剤、湿潤剤（保湿剤）、増粘剤、乳化剤、乳化補助剤、保存剤、安定化剤及びｐＨ調整剤等が挙げられる。 The topical agent and topical pharmaceutical composition of the present invention may contain additives. The additives are not particularly limited, but may include bases, wetting agents (moisturizers), thickeners, emulsifiers, emulsifier assistants, preservatives, stabilizers, and pH adjusters.

　基剤としては、疎水性基剤、親水性基剤、及び水等が挙げられる。 Bases include hydrophobic bases, hydrophilic bases, and water.

　前記疎水性基剤としては、特に制限されないが、スクワラン、流動パラフィン、軽質流動パラフィン、及びワセリン等が挙げられる。 The hydrophobic base may include, but is not limited to, squalane, liquid paraffin, light liquid paraffin, and petrolatum.

　前記親水性基剤としては、特に制限されないが、エタノール等のアルコール類等が挙げられる。 The hydrophilic base is not particularly limited, but examples include alcohols such as ethanol.

　湿潤剤（保湿剤）は、外用剤を塗布した際に皮膚の潤いを保つ。
　湿潤剤としては、特に限定されないが、ワセリン、及びグリセリン等が挙げられる。 Humectants (moisturizers) keep the skin moist when topical agents are applied.
Wetting agents include, but are not limited to, petrolatum, glycerin, and the like.

　増粘剤は、外用剤の粘度を上昇させる、またはゲル化させる。
　増粘剤としては、特に制限されないが、ゼラチン、及びカンテン等が挙げられる。 The thickener increases the viscosity or gels the topical preparation.
The thickening agent is not particularly limited, but examples thereof include gelatin and agar.

　乳化剤は、外用剤を水中油（ｏ／ｗ）型または油中水（ｗ／ｏ）型に乳化させる。 Emulsifiers emulsify topical agents into oil-in-water (o/w) or water-in-oil (w/o) emulsions.

　乳化補助剤は、外用剤を水中油（ｏ／ｗ）型または油中水（ｗ／ｏ）型に乳化させる場合に乳化を安定化させる。 Emulsifiers stabilize emulsions when topical preparations are emulsified into oil-in-water (o/w) or water-in-oil (w/o) emulsions.

　保存剤は、微生物による外用剤の汚染、分解を防止または抑制する。
　保存剤としては、特に制限されないが、パラオキシ安息香酸等が挙げられる。 The preservative prevents or inhibits contamination and decomposition of the topical agent by microorganisms.
The preservative is not particularly limited, but examples thereof include paraoxybenzoic acid.

　溶解補助剤としては、特に制限されないが、エタノール等が挙げられる。 Solubilizing agents include, but are not limited to, ethanol, etc.

　安定化剤は、有効成分の化学的分解や物理的変化を防止または抑制する。
　安定化剤としては、特に制限されないが、亜硫酸水素ナトリウム等が挙げられる。 Stabilizers prevent or inhibit chemical decomposition or physical changes in active ingredients.
The stabilizer is not particularly limited, but examples thereof include sodium hydrogen sulfite.

　ｐＨ調整剤は、有効成分の安定性の保持、外用剤の生体に対する刺激を防止または軽減する。
　ｐＨ調整剤としては、特に制限されず、特定のｐＨに調整できれば良い。 The pH adjuster maintains the stability of the active ingredient and prevents or reduces irritation of the topical agent to the living body.
The pH adjuster is not particularly limited as long as it can adjust the pH to a specific value.

　本発明の外用剤、及び外用医薬組成物の剤形は、一般に、外用の薬剤として、例えば皮膚（患部）に適用できるものであればよく、特に制限されないが、軟膏剤、クリーム剤、ゲル剤、及びローション剤等が挙げられる。これらについて以下に具体的に説明する。 The dosage form of the topical agent and topical pharmaceutical composition of the present invention may generally be any dosage form that can be applied to the skin (affected area) as a topical drug, and is not particularly limited, but examples include ointments, creams, gels, and lotions. These are described in detail below.

　本発明の外用剤、及び本発明の外用医薬組成物の適用（投与）量は、一般には、製剤中の有効成分（本発明の化合物等）の配合割合を考慮した上で、投与対象（患者）の年齢、体重、及び病状の種類・進行状況、並びに、投与回数（／1日）及び投与期間等を勘案し、適宜、広範囲に設定することができる。 The application (administration) amount of the topical agent of the present invention and the topical pharmaceutical composition of the present invention can generally be set appropriately within a wide range, taking into consideration the mixing ratio of the active ingredient (the compound of the present invention, etc.) in the formulation, as well as the age, weight, and type and progress of the disease of the subject (patient), as well as the number of administrations (per day) and administration period, etc.

　以下に、実施例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these.

Facial Atopic Dermatitis with Scratching (FADS)マウスの作製
　Nestin-creトランスジェニックマウスとIkk2f/fマウスとの交配により、顔面皮膚線維芽細胞で特異的にIKK2を欠損するNestin-cre/Ikk2f/fマウスを作製した（Nunomura S, et al. J Invest Dermatol. 139:1274-1283, 2019）。このマウスは、顔面に限局したアトピー性皮膚炎様の皮疹と激しい痒み症状を必発することから、Facial Atopic Dermatitis with Scratching（FADS）マウスと名付けた。FADSマウスは、コントロールマウスと比較して血清中のペリオスチンが有意に増加しており、また顔面皮膚の真皮においてペリオスチンが高発現すること；FADSマウスのペリオスチン遺伝子を破壊すると、コントロールマウスと比較して掻破行動が有意に抑制されること；及び、FADSマウスの掻破行動は、ペリオスチンを中和する抗ペリオスチンモノクローナル抗体の腹腔内投与により抑制されることから、FADSマウスの掻破行動は、ペリオスチン介在性であることが示されている（Nunomura S, et al. Cell Rep. 42:111933, 2023）。
本実施例では、自発的な掻破行動を示す3～4週齢以降のFADSマウスを使用した。 Generation of Facial Atopic Dermatitis with Scratching (FADS) MiceBy crossing Nestin-cre transgenic mice with Ikk2 f/f mice, we generated Nestin-cre/Ikk2 f/f mice, which specifically lack IKK2 in facial skin fibroblasts (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 skin rash and severe itching symptoms limited to the face. FADS mice have significantly increased periostin levels in serum compared with control mice, and periostin is highly expressed in the dermis of the facial skin; periostin gene disruption in FADS mice significantly suppresses scratching behavior compared with control mice; and scratching behavior in FADS mice is suppressed by intraperitoneal administration of an anti-periostin monoclonal antibody that neutralizes periostin, indicating that the scratching behavior of 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.

単回全身投与によるFADSマウスの掻破行動阻害
　FADSマウスに被験薬を投与する前に60分間ビデオカメラ撮影を行った後、15分間休憩させた。CP4715、CP誘導体２、CP誘導体６、CP誘導体７、SC-68448、SM-256及びSB-267268を溶解液(50%DMSO、89.5mM HCLを含有する生理的食塩水)に溶かし、当該溶解液中の各化合物（89.5 mM）から1匹当たり53.7μmol/kgに相当する量を分取し、PBS 0.3mLに希釈後に腹腔内に投与した。体重換算で等量の溶解液を含むPBS 0.3mLを投与したマウスを対照群とした。 Inhibition of scratching behavior in FADS mice by single systemic administration. FADS mice were videotaped for 60 minutes before administration of the test drug, and then rested for 15 minutes. CP4715, CP derivative 2, CP derivative 6, CP derivative 7, SC-68448, SM-256, and SB-267268 were dissolved in a solvent (physiological saline containing 50% DMSO and 89.5 mM HCL), and an amount equivalent to 53.7 μmol/kg per mouse was taken from each compound (89.5 mM) in the solvent, diluted with 0.3 mL of PBS, and administered intraperitoneally. Mice administered with 0.3 mL of PBS containing an equivalent amount of the solvent based on body weight were used as the control group.

　被験薬投与直後から60分間ビデオカメラ撮影を行った。投与前の掻破回数をベースラインとし、ベースラインからの投与後の変化率を算出した。統計学的解析には、対応のあるt-検定を使用した。P値が0.05未満の場合に有意差があると判定した。ベースラインからの変化率平均値が-65%以上でP値0.01未満の阻害剤の効果を「++」、変化率平均値が-60%以下でP値0.05未満の阻害剤の効果を「+」、変化率平均値が-60%以下でP値0.05以上の阻害剤の効果を「－」と表示した。 　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 determined to indicate a significant difference. The effect of inhibitors with a mean rate of change from baseline of -65% or more and a P value of less than 0.01 was displayed as "++", the effect of inhibitors with a mean rate of change of -60% or less and a P value of less than 0.05 was displayed as "+", and the effect of inhibitors with a mean rate of change of -60% or less and a P value of 0.05 or more was displayed as "-".

　各化合物について、掻破回数のベースラインからの変化率（％）を表１に示した。各化合物の投与量は、53.7μmol/kgで統一した。 The percentage change from baseline in the number of scratching bouts for each compound is shown in Table 1. The dose of each compound was standardized at 53.7 μmol/kg.

Figure JPOXMLDOC01-appb-T000010
 　　　　　　　　　　　　　　
Figure JPOXMLDOC01-appb-T000010
  　　　　　　　　　　　　　　

　上記のベースラインからの変化率の結果を、図１にも示す。図１のグラフ内の数値（例えば、0.17や0.0004等）はP値を示す。 The results of the rate of change from the 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.

ペリオスチン依存的な細胞接着阻害作用
　細胞接着実験には、インテグリンβ3を発現していないヒト結腸癌細胞株であるSW480細胞にヒトインテグリンβ3を遺伝子導入し、安定的に発現させた細胞を用いた（Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020）。表１に示した化合物について、インテグリンαvβ3とペリオスチンとの接着阻害活性を、以下の手順で調べた。まず、96-ウェルプレートを、10μg/mLの組換えヒトペリオスチン（Bio-Techne）で4℃、16時間処理し、ペリオスチンを固相化した。インテグリンαvβ3発現SW480細胞（5×10４個）を、0.5％ウシ血清アルブミン及び0.25 mM MnCl2を含む無血清DMEM（Dulbecco's Modified Eagle Medium）中で、0.001、0.01、0.1及び1μMの上記化合物と共に、室温で15分間反応させた。化合物非添加群をコントロールとした。反応後の細胞懸濁液を、上記のヒトペリオスチン固相化プレートの各ウェルに加え、プレートを10×gで5分間遠心した後、37℃で60分間培養した。その後、接着した細胞を洗浄し、結合していない細胞を除去した後、接着細胞を1％ホルムアルデヒドで固定し、0.5%クリスタルバイオレット染色した。固定し染色した細胞を0.2%Triton X-100で可溶化し、595 nmの吸光度を測定した。コントロール（化合物非添加群）の吸光度を阻害率0%とした。また同様の手順で、化合物非添加において、ウシアルブミンを固相化したプレートに接着した細胞に由来するクリスタルバイオレットの吸光度を測定し、これを阻害率100%とした。この試験系における細胞接着はペリオスチン依存的であり、この細胞接着を阻害する化合物はペリオスチン受容体アンタゴニストと呼ぶことができる。 Periostin-dependent inhibitory effect on cell adhesion For cell adhesion experiments, human integrin β3 was stably expressed in SW480 cells, a human colon cancer cell line that does not express integrin β3 (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020). The adhesion inhibitory activity of integrin αvβ3 and periostin for the compounds shown in Table 1 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× 104 cells) were reacted with the above compounds at 0.001, 0.01, 0.1, and 1 μM in serum-free DMEM (Dulbecco's Modified Eagle Medium) containing 0.5% bovine serum albumin and 0.25 mM MnCl2 at room temperature for 15 minutes. The compound-free group was used as a control. The cell suspension after the reaction was added to each well of the above human periostin-immobilized plate, and the plate was centrifuged at 10×g for 5 minutes and then cultured 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 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.

　得られた結果を図２に示す。細胞接着阻害活性の50%阻害濃度 (IC50値)は、CP4715、CP誘導体２、CP誘導体６及びCP誘導体７において0.001μM以下であり、これらの化合物は高い細胞接着阻害効果を示した。SC-68448及びSB-267268のIC50値は0.02μM以下であり、中程度の細胞接着阻害効果を示した。SM-256のIC50値は0.1μM以下であり、阻害効果は低かったものの、CP4715、CP誘導体2、CP誘導体6、CP誘導体7、SC-68448、SB-267268及びSM-256はいずれも細胞接着を阻害したことから、ペリオスチン受容体アンタゴニストと言えることが分かった。一方、SB-267268鏡像異性体のIC50値は1μM以上であった。  The results are shown in Figure 2. The 50% inhibitory concentration ( IC50 value) of cell adhesion inhibitory activity was 0.001 μM or less for CP4715, CP derivative 2, CP derivative 6, and CP derivative 7, and these compounds showed high cell adhesion inhibitory effects. The IC50 values of SC-68448 and SB-267268 were 0.02 μM or less, and they showed moderate cell adhesion inhibitory effects. Although the IC50 value of SM-256 was 0.1 μM or less, and the inhibitory effect was low, 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 called periostin receptor antagonists. On the other hand, the IC50 values of the SB-267268 enantiomers were 1 μM or more.

　化合物の細胞接着阻害作用とFADSマウスにおける掻破行動阻害作用との関係は、必ずしも相関するわけではないことが分かった。CP4715、CP誘導体２、CP誘導体６及びCP誘導体７は、いずれもIC50値が0.00 1μM以下の強い細胞接着阻害活性を示した。一方、FADSマウスの掻破行動阻害作用においては、CP4715及びCP誘導体６が「++」で表示される強い阻害作用を発揮したが、CP誘導体２、CP誘導体７は、「－」で表示される弱い作用を示した。SC-68448は、FADSマウスにおいて「++」で表示される強い掻破行動阻害作用を示したが、SC-68448と同程度の細胞接着阻害活性を持つSB-267268の掻破行動阻害作用は弱く、「－」であった。 It was found that the relationship between the inhibitory activity of the compounds on cell adhesion and their inhibitory activity on scratching behavior in FADS mice was not necessarily correlated. CP4715, CP derivative 2, CP derivative 6, and CP derivative 7 all showed strong inhibitory activity on cell adhesion with IC50 values of 0.00 1μM or less. On the other hand, in terms of the inhibitory activity on scratching behavior in FADS mice, CP4715 and CP derivative 6 exhibited strong inhibitory activity indicated by "++", while CP derivative 2 and CP derivative 7 showed weak inhibitory activity indicated by "-". SC-68448 exhibited strong inhibitory activity on scratching behavior in FADS mice indicated by "++", while SB-267268, which has the same inhibitory activity on cell adhesion as SC-68448, showed weak inhibitory activity on scratching behavior indicated by "-".

反復経皮投与によるFADSマウスの掻破行動阻害
　CP4715、SM-256、SC-68448、CP誘導体7及びSB-267268は、溶解液5%DMSO/15%N-メチル-2-ピロリドン/80%アセトンに添加して溶解し、26.85 mM溶液を調製した。CP誘導体2及びCP誘導体6は、溶解液15%DMSO/20%N-メチル-2-ピロリドン/65%アセトンに溶解して、26.85 mM溶液を調製した。実施例１に記載の方法で作製したFADSマウス顔面皮疹部に、30μLの26.85 mM溶液を１日１回、28日間連続で塗布した。等量の溶解液を経皮投与したマウスを対照群とした。被験薬の投与開始前並びに投与後7日、14日、21日及び28日に60分間の掻破回数を計測し評価した。被験薬の投与日を第0日とした。統計学的解析には、マン・ホイットニーのU検定を使用した。P値が0.05未満の場合に有意差があると判定した。
　得られた結果を、図３－１及び図３－２、並びに表２、表3、表4及び表5に示す。同じペリオスチン阻害薬であってもSB-267268はFADSマウスの掻破行動の抑制効果が認められなかったが、CP4715、SM-256、SC-68448、CP誘導体7、CP誘導体２及びCP誘導体６はFADSマウスの掻破行動を抑制した。図1のin vivo評価では「－」の結果であったSM-256、CP誘導体7及びCP誘導体2は、塗布、すなわち外用（経皮投与とも言う）に変えたところ、FADSマウスの掻破行動を抑制した。
　表３、表4及び表5に示すように、投与後14日以降の掻破回数は、CP4715、SC-68448又はCP誘導体6投与群は、投与後14日、21日及び28日において、溶媒群に対して顕著に掻破行動を抑制した。SM-256、CP誘導体２又はCP誘導体７投与群は、投与後21日及び28日において、溶媒群に対して顕著に掻破行動を抑制した。
　図３－１及び図３－２に示すように、CP4715及びSC-68448は、投与後14日と早期からFADSマウスの掻破行動の抑制効果が認められ、その効果は投与後28日まで継続した。CP誘導体2、CP誘導体7及びSM-256は、全身投与では図１に示す結果であったが、外用に変えたところ、図３－１及び図３－２のようにFADSマウスの掻破行動の高い抑制効果が認められた。
  Inhibition of scratching behavior in FADS mice by repeated transdermal 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 a 26.85 mM solution. CP derivative 2 and CP derivative 6 were dissolved in a solution of 15% DMSO/20% N-methyl-2-pyrrolidone/65% acetone to prepare a 26.85 mM solution. 30 μL of the 26.85 mM solution was applied once a day for 28 consecutive days to the facial rash of FADS mice prepared by the method described in Example 1. Mice administered an equal amount of the solution transdermally were used as the control group. The number of scratchings was measured and evaluated for 60 minutes before the start of administration of the test drug and on the 7th, 14th, 21st and 28th days after administration. The day of administration of the test drug was designated as day 0. The Mann-Whitney U test was used for statistical analysis, and differences were considered significant when P values were less than 0.05.
The results are shown in Figures 3-1 and 3-2, and Tables 2, 3, 4, and 5. Although SB-267268, which is also a periostin inhibitor, had no inhibitory effect on the scratching behavior of FADS mice, CP4715, SM-256, SC-68448, CP derivative 7, CP derivative 2, and CP derivative 6 inhibited the scratching behavior of FADS mice. SM-256, CP derivative 7, and CP derivative 2, which showed "-" results in the in vivo evaluation in Figure 1, inhibited the scratching behavior of FADS mice when applied topically (also called percutaneous administration).
As shown in Tables 3, 4 and 5, the number of scratching behaviors from 14 days after administration onwards was significantly suppressed in the CP4715, SC-68448 or CP derivative 6 administration groups compared to the vehicle group on days 14, 21 and 28 after administration. The SM-256, CP derivative 2 or CP derivative 7 administration groups significantly suppressed scratching behaviors compared to the vehicle group on days 21 and 28 after administration.
As shown in Figures 3-1 and 3-2, CP4715 and SC-68448 were found to have an inhibitory effect on the scratching behavior of FADS mice as early as 14 days after administration, and this effect continued up to 28 days after administration. When CP derivative 2, CP derivative 7, and SM-256 were administered systemically, the results shown in Figure 1 were obtained, but when they were applied topically, a high inhibitory effect on the scratching behavior of FADS mice was observed, as shown in Figures 3-1 and 3-2.

Figure JPOXMLDOC01-appb-T000011
    
Figure JPOXMLDOC01-appb-T000011
     

Figure JPOXMLDOC01-appb-T000012
     　　　　　　　　　　　　　　　
Figure JPOXMLDOC01-appb-T000012
      　　　　　　　　　　　　　　　

Figure JPOXMLDOC01-appb-T000013
     　　　　　　　　　　　　　　　
Figure JPOXMLDOC01-appb-T000013
      　　　　　　　　　　　　　　　

Figure JPOXMLDOC01-appb-T000014
   
Figure JPOXMLDOC01-appb-T000014
    

試験に用いた化合物について
　CP4715は、下記式（II）で示される化合物（(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（(S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid））である。

Figure JPOXMLDOC01-appb-C000015
The compound 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).
Figure JPOXMLDOC01-appb-C000015

　SC-68448は、下記式（III）で示される化合物（3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸（3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propanoic acid）である。

Figure JPOXMLDOC01-appb-C000016
SC-68448 is a compound represented by the following formula (III) (3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propanoic acid).
Figure JPOXMLDOC01-appb-C000016

　CP誘導体２は、下記式（IV）で示される化合物（(S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（(S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid））である。

Figure JPOXMLDOC01-appb-C000017
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).
Figure JPOXMLDOC01-appb-C000017

　CP誘導体６は、下記式（V）で示される化合物（(S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸（(S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propanoic acid））である。

Figure JPOXMLDOC01-appb-C000018
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).
Figure JPOXMLDOC01-appb-C000018

　CP誘導体７は、下記式（VI）で示される化合物（(S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸（(S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid））である。

Figure JPOXMLDOC01-appb-C000019
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).
Figure JPOXMLDOC01-appb-C000019

　SM-256は、下記式（VIII）で示される化合物（(S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸（(S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propanoic acid））である。

Figure JPOXMLDOC01-appb-C000020
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).
Figure JPOXMLDOC01-appb-C000020

　SB-267268は、下記式（IX）で示される化合物（(S)-2-(3-オキソ-8-(3-(ピリジン-2-イルアミノ)プロポキシ)-2-(2,2,2-トリフルオロエチル)-2,3,4,5-テトラヒドロ-1H-ベンゾ[c]アゼピン-4-イル)酢酸（(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））である。

Figure JPOXMLDOC01-appb-C000021
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).
Figure JPOXMLDOC01-appb-C000021

　SB-267268鏡像異性体は、下記式で示される化合物（(R)-2-(3-オキソ-8-(3-(ピリジン-2-イルアミノ)プロポキシ)-2-(2,2,2-トリフルオロエチル)-2,3,4,5-テトラヒドロ-1H-ベンゾ[c]アゼピン-4-イル)酢酸（(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））である。

Figure JPOXMLDOC01-appb-C000022
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).
Figure JPOXMLDOC01-appb-C000022

　上記化合物については、市販のものを使用することができるが、限定はされず、独自に合成、抽出及び精製等したものを使用してもよい。CP4715及びCP誘導体２はWO1999/052872に記載の方法により製造することができる。CP誘導体６、CP誘導体７はWO2001/027082に記載の方法により製造することができる。SC-68448はWO97/08145に記載の方法により製造することができる。SM-256はWO09/723480に記載の方法により製造することができる。SB-267268及びSB-267268鏡像異性体はWO98/14192に記載の方法により製造することができる。 The above compounds may be commercially available, but are not limited thereto, and may be synthesized, extracted, purified, etc. by oneself. 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 enantiomer can be produced by the method described in WO98/14192.

　本発明によれば、ペリオスチン介在性疾患及び該疾患に伴うそう痒の改善に有用な、該疾患及び該そう痒の予防又は治療用の外用剤及び外用医薬組成物、並びにそれら外用剤及び外用医薬組成物を被験対象に適用する、該疾患及び該そう痒の予防又は治療方法等を提供することができる。  The present invention can provide an external preparation and an external pharmaceutical composition useful for improving a periostin-mediated disease and the pruritus associated with the disease, for preventing or treating the disease and the pruritus, and a method for preventing or treating the disease and the pruritus by applying the external preparation and the external pharmaceutical composition to a subject.

Claims (18)

　ペリオスチン受容体アンタゴニストを有効成分として含む、ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療用の外用剤であって、前記アンタゴニストが、下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000001
 ［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸、(S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、及び (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸からなる群から選ばれる少なくとも１つの化合物、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物である、前記外用剤。 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 represented by the following formula (I):
Figure JPOXMLDOC01-appb-C000001
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is 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 topical preparation is 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, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. 　前記式（Ｉ）の化合物が、(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸である、請求項１に記載の外用剤。 The topical 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)benzamido)-2-(phenylsulfonamido)propionic acid. 　前記アンタゴニストが、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、又は (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸である、請求項１に記載の外用剤。 The topical 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)benzamido)-2-(phenylsulfonamido)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, or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、請求項１に記載の外用剤。 The topical preparation according to claim 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. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、請求項１に記載の外用剤。 The topical preparation according to claim 1, wherein the periostin-mediated disease is atopic dermatitis. 　ペリオスチン受容体アンタゴニストを有効成分として含む、ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療用の外用医薬組成物であって、前記アンタゴニストが、下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000002
 ［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸、(S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸、(S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、及び (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸からなる群から選ばれる少なくとも１つの化合物、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物である、前記外用医薬組成物。 A pharmaceutical composition for external application for preventing or treating a periostin-mediated disease or pruritus associated with said disease, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is represented by the following formula (I):
Figure JPOXMLDOC01-appb-C000002
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is 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 pharmaceutical composition for external application is 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, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. 　前記式（Ｉ）の化合物が、(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸である、請求項６に記載の外用医薬組成物。 The pharmaceutical composition for external application 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)benzamido)-2-(phenylsulfonamido)propionic acid. 　前記アンタゴニストが、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、又は (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸である、請求項６に記載の外用医薬組成物。 The pharmaceutical composition for external application 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)benzamido)-2-(phenylsulfonamido)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, or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、請求項６に記載の外用医薬組成物。 The topical pharmaceutical composition according to claim 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. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、請求項６に記載の外用医薬組成物。 The topical pharmaceutical composition according to claim 6, wherein the periostin-mediated disease is atopic dermatitis. 　ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療用の外用剤を製造するための、下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
 ［式中、
　Ｒ１は、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ２は、互いに独立して、水素原子、アルキル基、アリール基、又はアラルキル基であり、
　Ｒ３は、アルキル基、アリール基、又はアラルキル基である。］
の化合物、3-(3,5-ジクロロフェニル)-3-(2-(3-グアニジノベンズアミド)アセトアミド)プロピオン酸、(S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-2-(フェニルスルホンアミド)-3-(4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)プロピオン酸、(S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、及び(S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸からなる群から選ばれる少なくとも１つの化合物、若しくはそれらのプロドラッグ、若しくはそれらの薬理学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物の使用。 For producing an external preparation for preventing or treating a periostin-mediated disease or pruritus associated with said disease,
Figure JPOXMLDOC01-appb-C000003
 [In the formula,
R 1 is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R2 are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group;
R3 is 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, Use of at least one compound selected from the group consisting of (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 (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. 　前記式（Ｉ）の化合物が、(S)-3-(3-メトキシ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸である、請求項１１に記載の使用。 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)benzamido)-2-(phenylsulfonamido)propionic acid. 　前記アンタゴニストが、 (S)-3-(3-フルオロ-4-(4-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、 (S)-3-(2-フルオロ-4-((S)-3-((1,4,5,6-テトラヒドロピリミジン-2-イル)アミノ)ピペリジン-1-イル)ベンズアミド)-2-(フェニルスルホンアミド)プロピオン酸、又は (S)-3-(1-(3-((1H-イミダゾール-2-イル)アミノ)プロピル)-1H-インダゾール-5-カルボキシアミド)-2-((2,4,6-トリメチルフェニル)スルホンアミド)プロピオン酸である、請求項１１に記載の使用。 12. The use of claim 11, 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, (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propionic acid, or (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propionic acid. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、請求項１１に記載の使用。 The use according to claim 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. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、請求項１１に記載の使用。 The use according to claim 11, wherein the periostin-mediated disease is atopic dermatitis. 　請求項１～５のいずれか一項に記載の外用剤、及び／又は請求項６～１０のいずれか一項に記載の外用医薬組成物を、治療を必要とする被験対象に適用することを含む、ペリオスチン介在性疾患又は前記疾患に伴うそう痒の予防又は治療方法。 A method for preventing or treating a periostin-mediated disease or pruritus associated with said disease, comprising applying the topical preparation according to any one of claims 1 to 5 and/or the topical pharmaceutical composition according to any one of claims 6 to 10 to a subject in need of treatment. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎、結節性痒疹、水疱性類天疱瘡、うっ滞性皮膚炎、皮膚Ｔ細胞リンパ腫、全身性強皮症、ケロイド・肥厚性瘢痕、アレルギー性鼻炎、慢性肝疾患又は慢性腎疾患である、請求項１６に記載の方法。 The method according to claim 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. 　前記ペリオスチン介在性疾患が、アトピー性皮膚炎である、請求項１６に記載の方法。  The method of claim 16, wherein the periostin-mediated disease is atopic dermatitis.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000501105A (en) * 1995-12-22 2000-02-02 デュポン ファーマシューティカルズ カンパニー Novel integrin receptor antagonist
JP4064059B2 (en) * 1998-04-09 2008-03-19 明治製菓株式会社 Aminopiperidine derivatives as integrin αVβ3 antagonists
WO2021202643A1 (en) * 2020-03-31 2021-10-07 The Regents Of The University Of California Compositions and methods for treating dysregulated wound healing

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000501105A (en) * 1995-12-22 2000-02-02 デュポン ファーマシューティカルズ カンパニー Novel integrin receptor antagonist
JP4064059B2 (en) * 1998-04-09 2008-03-19 明治製菓株式会社 Aminopiperidine derivatives as integrin αVβ3 antagonists
WO2021202643A1 (en) * 2020-03-31 2021-10-07 The Regents Of The University Of California Compositions and methods for treating dysregulated wound healing

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