Prophylactic or therapeutic agent for periostin-mediated diseases and pruritus associated with said diseases

Abstract

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

Description

Technical Field

[0001] The present invention relates to a preventive or therapeutic agent for periostin-mediated diseases and pruritus associated with the diseases. Background Art

[0002] Atopic dermatitis is a chronic skin disease characterized by recurrent eczema and severe itching. The prevalence of atopic dermatitis among young people in developed countries reaches more than 10% of the total population. Itching is one of the most unpleasant sensations. It not only reduces the concentration, judgment and work efficiency required for daily life, but also causes insomnia and significantly reduces QOL. As a treatment for atopic dermatitis, topical immunosuppressants and steroids are generally used.

[0003] In addition to conventional antihistamines and antiallergic drugs, molecular targeted drugs targeting the receptors of interleukin (IL)-4 and IL-13 and their downstream signal transduction molecules Janus kinase (JAK) have been developed for the itchy skin symptoms of diseases such as atopic dermatitis, and have shown a certain degree of good therapeutic effect. As with atopic dermatitis, the causes of itchy skin symptoms are often complex, and some patients have difficulty improving their itchy skin symptoms even with the above-mentioned molecular targeted drugs.

[0004] Periostin is an extracellular matrix protein that binds to cell surface receptors belonging to the integrin family and transmits signals into cells. It has been shown to play an important role in the exacerbation and chronicity of allergic dermatitis (Non-patent Document 1). It is reported that in the lesions of atopic dermatitis, the local production of periostin is significantly hyperactive, and the severity of atopic dermatitis is related to the lesion site and serum periostin level. It is also reported that when periostin is administered intradermally or subcutaneously to mice, dogs and monkeys, scratching behavior is induced (Non-patent Document 2). In addition, a method for treating or alleviating pruritus or chronic pruritus by blocking the intracellular signal transduction caused by the binding of periostin and integrin is disclosed (Patent Document 1).

[0005] It is reported that periostin mediates the pathology of various diseases. As diseases mediated by periostin, in addition to atopic dermatitis and the pruritus associated with atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scar, allergic rhinitis, chronic liver disease and chronic kidney disease, etc., and the pruritus associated with these diseases have also been reported (Non-Patent Documents 3 to 5).

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent document 1: WO2021 / 055713

[0009] Non-patent literature

[0010] Non-patent literature 1: Masuoka M, et al. J Clin Invest. 122: 2590-2600, 2012

[0011] Non-patent literature 2: Mishra et al, Cell reports, 31: 107472, 2020

[0012] Non-patent literature 3: Izuhara K, et al. Cell. Mol. Life Sci. 74: 4293-4303, 2017

[0013] Non-patent literature 4: Hashimoto T, et al. J Invest Dermatol. 141: 2338-2343, 2021

[0014] Non-patent document 5: Yang L, Cells. 12, 50, 2023 Summary of the invention

[0015] Problem that the invention aims to solve

[0016] Under such circumstances, it is desired to develop a new technique for preventing or treating periostin-mediated diseases and pruritus associated with the diseases, which can improve the diseases and pruritus.

[0017] Solutions for solving problems

[0018] The present invention has been made in view of the above-mentioned circumstances, and provides the following prophylactic or therapeutic agents for periostin-mediated diseases or pruritus associated with the diseases.

[0019] (1) A preventive or therapeutic agent for a periostin-mediated disease or pruritus associated with the above-mentioned disease, comprising a periostin receptor antagonist as an active ingredient, wherein the above-mentioned antagonist is at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid (hereinafter sometimes referred to as "SC-68448") and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid (hereinafter sometimes referred to as "CP derivative 6"), or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0020]

[0021] [Wherein,

[0022] R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0023] R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0024] R 3 is an alkyl group, an aryl group or an aralkyl group.]

[0025] (2) The preventive or therapeutic agent according to the above (1), wherein the compound of the above formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamide)propanoic acid (hereinafter sometimes referred to as "CP4715").

[0026] (3) The preventive or therapeutic agent according to the above (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.

[0027] (4) The preventive or therapeutic agent according to (1) above, wherein the periostin-mediated disease is atopic dermatitis.

[0028] (5) A pharmaceutical composition for preventing or treating a periostin-mediated disease or pruritus associated with the above-mentioned disease, comprising a periostin receptor antagonist as an active ingredient, wherein the above-mentioned antagonist is at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid (SC-68448) and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid (CP derivative 6), or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0029]

[0030] [Wherein,

[0031] R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0032] R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0033] R 3is an alkyl group, an aryl group or an aralkyl group.]

[0034] (6) The pharmaceutical composition according to (5) 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)benzamide)-2-(phenylsulfonamide)propanoic acid (CP4715).

[0035] (7) The pharmaceutical composition according to (5) 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.

[0036] (8) The pharmaceutical composition according to (5) above, wherein the periostin-mediated disease is atopic dermatitis.

[0037] (9) Use of at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid (SC-68448) and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid (CP derivative 6), or their prodrugs, or their pharmacologically acceptable salts, or their hydrates or solvates for the manufacture of a medicament for the prevention or treatment of periostin-mediated diseases or pruritus associated with the above-mentioned diseases.

[0038]

[0039] [Wherein,

[0040] R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0041] R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0042] R 3 is an alkyl group, an aryl group or an aralkyl group.]

[0043] (10) The use according to (9) 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)benzamide)-2-(phenylsulfonamide)propanoic acid (CP4715).

[0044] (11) The use according to (9) 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.

[0045] (12) The use according to (9) above, wherein the periostin-mediated disease is atopic dermatitis.

[0046] (13) A method for preventing or treating a periostin-mediated disease or pruritus associated with the above-mentioned disease, comprising the step of administering an effective amount of a periostin receptor antagonist to a subject in need of treatment, wherein the above-mentioned antagonist is at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid (SC-68448) and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid (CP derivative 6), or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0047]

[0048] [Wherein,

[0049] R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0050] R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0051] R 3 is an alkyl group, an aryl group or an aralkyl group.]

[0052] (14) The method according to the above (13), wherein the compound of the above formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamide)propanoic acid (CP4715).

[0053] (15) The method according to (13) 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.

[0054] (16) The method according to (13) above, wherein the periostin-mediated disease is atopic dermatitis.

[0055] It should be noted that in the inventions described in (1), (5), (9) and (13) above, R in formula (I) is 1 , R 2 and R 3 The alkyl group in is preferably a lower alkyl group (e.g., an alkyl group having 1 to 4 carbon atoms), and specifically, preferably, methyl, ethyl, propyl, etc. are mentioned. As the aryl group, preferably, phenyl, tolyl, xylyl, isopropyl, mesyl, naphthyl, biphenyl, etc. are mentioned. As the aralkyl group, preferably, benzyl, phenethyl, etc. are mentioned. It should be noted that the alkyl group, aryl group, and aralkyl group are not limited and may be substituted by a known appropriate substituent.

[0056] In addition, as a preferred specific example of the compound of the above formula (I), there is no limitation, and preferably the compound of the following formula (II) ((S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamide)propionic acid (CP4715)) is listed.

[0057]

[0058] Effects of the Invention

[0059] According to the present invention, in addition to providing a preventive or therapeutic agent for periostin-mediated diseases and the pruritus associated with the diseases, a pharmaceutical composition for preventing or treating the diseases and the pruritus, and a preventive or therapeutic method for the diseases and the pruritus can also be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 This is a graph showing the inhibitory effect of repeated systemic administration of CP4715 on the scratching behavior of Facial Atopic Dermatitis with Scratching (FADS) mice (see Example 1 described below).

[0061] Figure 2 is a graph showing the inhibitory effect of a single systemic administration of CP4715 on the scratching behavior of FADS mice.

[0062] Figure 3 The graph shows the inhibitory effect of CP4715 on spontaneous firing recorded from superficial cells of the dorsal horn of the spinal cord of FADS mice.

[0063] Figure 4This is a graph showing the inhibitory effect of a single systemic administration of various compounds on the scratching behavior of FADS mice.

[0064] Figure 5 This is a graph showing the inhibitory effect of a single systemic administration of GLPG-0187 on the scratching behavior of FADS mice.

[0065] Figure 6 The graph shows the periostin-dependent cell adhesion blocking effect of various compounds.

[0066] Figure 7 This is a graph showing the inhibitory effect of repeated transdermal administration of CP4715 on the scratching behavior of FADS mice. DETAILED DESCRIPTION

[0067] The present invention is described in detail below. The scope of the present invention is not limited by these descriptions, and for those other than the following examples, it can also be implemented by appropriately changing within the scope that does not damage the main purpose of the present invention. It should be noted that this specification includes the entire contents of Japanese Patent Application No. 2022-120377 (filed on July 28, 2022), which is the basis for the priority claim of this application. In addition, all publications cited in this specification, such as prior art documents and patent documents such as public gazettes and patent gazettes, are integrated into this specification by reference.

[0068] As described above, the preventive or therapeutic agent for periostin-mediated diseases and pruritus (e.g., pruritus of the skin) associated with the disease (hereinafter sometimes referred to as "the preventive or therapeutic agent of the present invention") and the pharmaceutical composition for the prevention or treatment of periostin-mediated diseases and pruritus (e.g., pruritus of the skin) associated with the disease (hereinafter sometimes referred to as "the pharmaceutical composition of the present invention") are characterized by comprising a compound selected from the group consisting of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid (SC-6 8448) and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid (CP derivative 6) (hereinafter sometimes referred to as "the compound of the present invention"), or their prodrugs, or their pharmacologically acceptable salts, or their hydrates or solvates (hereinafter, "the compounds of the present invention and the above-mentioned prodrugs, salts, hydrates and solvates are collectively referred to as the compounds of the present invention, etc.") as an active ingredient.

[0069]

[0070] [Wherein,

[0071] R1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0072] R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group,

[0073] R 3 is an alkyl group, an aryl group or an aralkyl group.]

[0074] Here, as R in the above formula (I), 1 , R 2 and R 3 The alkyl group in is preferably a lower alkyl group (e.g., an alkyl group having 1 to 4 carbon atoms), and specifically, methyl, ethyl, propyl, etc. are preferably mentioned. As the aryl group, phenyl, tolyl, xylyl, isopropyl, methanesulfonyl, naphthyl, biphenyl, etc. are preferably mentioned. As the aralkyl group, benzyl, phenethyl, etc. are preferably mentioned. It should be noted that the alkyl group, aryl group, and aralkyl group are not limited and may be substituted by a known appropriate substituent.

[0075] In the present invention, preferred specific examples of the compound of the above formula (I) are not limited, but preferably the compound of the following formula (II) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid.

[0076]

[0077] The compound of the above formula (II) is known as "CP4715" (Nanri Y, et al. Am J Respir Cell Mol Biol. 62: 204-216, 2020) and its CAS registration number is 247034-73-7 (free form).

[0078] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propanoic acid is known as "SC-68448" (Carron CP, et al. Cancer Res. 58: 1930-1935, 1998), and is a compound having the chemical structure of the following formula (III). The CAS registration number of SC-68448 is 188804-07-1 (free form).

[0079]

[0080] (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propanoic acid ((S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propanoic acid) (CP derivative 6) is a well-known compound (Nanri Y, et al. Am J Respir Cell Mol Biol. 62: 204-216, 2020) and has the chemical structure of the following formula (IV). "CP derivative 6" has the same basic structure as CP4715. The CAS registration number of CP derivative 6 is 334618-85-8 (free form).

[0081]

[0082] "CP4715", "SC-68448" and "CP derivative 6" may also use commercial products, and are not limited thereto, and may also use those synthesized, extracted and purified by themselves. "CP4715" is a compound that has an antagonistic effect on both the glycoprotein (GP) IIb / IIIa receptor that plays a major role in thrombosis and the αvβ3 integrin (cell adhesion molecule) that participates in leukocyte adhesion, etc., and is known to be an active ingredient of a circulatory system disease therapeutic drug (antithrombotic agent). Here, αvβ3 integrin is a receptor for periostin, fibronectin and vitronectin, etc., and periostin is known to activate sensory nerves with the help of αvβ3 integrin (see the above-mentioned non-patent document 2). It is reported that SC-68448 blocks the binding of integrin αvβ3 and vitronectin as an integrin αvβ3 antagonist (Carron CP, et al. Cancer Res. 58: 1930-1935, 1998). It is reported that CP derivative 6 blocks the binding of integrin αvβ3 to periostin or vitronectin (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020).

[0083] It should be noted that, in addition to the above-mentioned preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention, the present invention also includes:

[0084] (i) a method for preventing or treating a periostin-mediated disease or pruritus associated with the disease, comprising the step of using the compound of the present invention, etc., specifically, for example, administering an effective amount of the compound of the present invention, etc. to a subject in need of treatment (a patient who has developed a periostin-mediated disease or pruritus associated with the disease (e.g., itchy symptoms of the skin) or a patient who is likely to have such a disease, or such a non-human mammal);

[0085] (ii) Use of the compound of the present invention for the manufacture of a medicament for preventing or treating a periostin-mediated disease or pruritus associated with the disease (e.g., itchy symptoms of the skin);

[0086] (iii) use of the compounds of the present invention for preventing or treating periostin-mediated diseases or pruritus associated with the diseases (e.g., itchy symptoms of the skin); and

[0087] (iv) The compounds of the present invention for use in preventing or treating periostin-mediated diseases or pruritus associated with the diseases (e.g., itchy symptoms of the skin).

[0088] In the present invention, periostin-mediated diseases refer to diseases in which periostin is involved in the onset or progression of the disease. Periostin mediation refers to the following state: due to the direct effect of periostin on somatic cells or tissues, such as the binding of periostin to its receptor, the intracellular signal transduction system is activated and participates in the onset or progression of the disease. Further, periostin mediation also refers to the following state: due to the effect of periostin on somatic tissues or cells, biological molecules are re-produced, expressed, freed or activated, and the disease is caused or progressed due to the biological molecules.

[0089] Examples of periostin-mediated diseases include, but are not limited to, atopic dermatitis, prurigo nodularis, bullous pemphigoid, stasis dermatitis, cutaneous T-cell lymphoma, systemic sclerosis, keloid / hypertrophic scars, allergic rhinitis, chronic liver disease, chronic kidney disease, and the pruritus associated with these diseases.

[0090] Atopic dermatitis is a chronic skin disease with eczema that repeatedly worsens / remits and is itchy as the main lesion. It is reported that the serum periostin level of patients with atopic dermatitis is higher than that of healthy people, the local production of periostin in the lesion site is significantly hyperactive, and the severity of atopic dermatitis is correlated with the lesion site and serum periostin level (the above-mentioned non-patent documents 1 and 2).

[0091] It is known that scratching associated with itch can lead to a vicious cycle of worsening skin symptoms and then aggravated itching (itch-scratch cycle), and is involved in the pathogenesis of atopic dermatitis (Tominaga M, Takamori K. Allergol Int. (2022) 71: 265-277). It is known that IL-31, a cytokine mainly produced by Th2 cells, is one of the main itch-inducing substances in atopic dermatitis (Datsi A, et al. Allergy. 76: 2982-2997, 2021). It is reported that it binds to the IL-31 receptor and transmits the itch signal 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 showed an effect of improving skin inflammation while improving itching (Kabashima K, et al. N Engl J Med. 383: 141-150, 2020). That is, it is shown that drugs that reduce the itching associated with atopic dermatitis can also be used as a preventive or therapeutic agent for atopic dermatitis.

[0092] Prurigo nodularis is a papular skin disease accompanied by intense itching. It has been reported that the immunostaining intensity of periostin in the dermis is correlated with the itching intensity of prurigo nodularis (Hashimoto T, et al. Acta Derm Venereol. 101: adv00375, 2021).

[0093] Bullous pemphigoid is an autoimmune bullous disease caused by Th2 immunity and is a skin disease accompanied by moderate to severe itching. The intensity of itching in bullous pemphigoid is directly correlated with dermal periostin deposition (Hashimoto T, et al. J Am Acad Dermatol. 83: 53-62, 2020), indicating that periostin may be directly related to the itching associated with bullous pemphigoid.

[0094] Stasis dermatitis is a disease that typically causes inflammation of the skin of the lower legs of the elderly, caused by chronic venous insufficiency and lymphedema. It has been reported that periostin may promote the itching associated with stasis dermatitis by promoting the production of IL-31 by macrophages (Hashimoto T, et al. J Invest Dermatol. 140: 850-859, 2020).

[0095] Cutaneous T-cell lymphoma is a group of malignant lymphomas that occur in the skin. It is a disease in which the tumor-derived cells are T cells. Cutaneous T-cell lymphoma has a high rate of itching, and the expression of periostin is elevated in the lesion skin samples of cutaneous T-cell lymphoma. (Furudate S, et al. Exp Dermatol. 25:107-112, 2016), suggesting that periostin may be partially involved in the itching of cutaneous T-cell lymphoma.

[0096] Systemic sclerosis and keloid / hypertrophic scars are common abnormal dermal fibrosis diseases, both of which are accompanied by a high proportion of itching. In skin samples from the lesions of patients with systemic sclerosis and keloid, hyperexpression of dermal periostin was observed (Maeda D, et al. J Plast Surg Hand Surg. 53: 288-294, 2019). In addition, it has been reported that in patients with systemic sclerosis, serum periostin concentrations are increased and correlated with disease severity (Yamaguchi Y, et al. Br J Dermatol. 168: 717-725, 2013). These results suggest that periostin may be involved in the itching associated with systemic sclerosis and keloid / hypertrophic scars.

[0097] Allergic rhinitis is often accompanied by itching, and periostin has been confirmed to be 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 promote the itching of allergic rhinitis (Ohta N, et al. Allergol Int. 63: 171-180, 2014).

[0098] It is reported that periostin induces liver fibrosis by blocking the expression of peroxisome proliferator-activated receptor-α (J Gastroenterol Hepatol. 35: 2140-2150, 2020). In addition, in chronic liver diseases such as cirrhosis, intractable itching that is difficult to be cured even with the administration of antihistamines sometimes occurs, so periostin is believed to be involved.

[0099] There are also reports of periostin involvement in chronic kidney disease. The expression level of periostin in kidney and urine has been shown to be highly correlated with pathological stage and decreased renal function (Prakoura N, et al. Cell Mol Life Sci. 74: 4315-4320, 2017, Jia YY, et al. Ren Fail. 42: 1166-1172, 2020). Decreased renal function requires artificial dialysis. In patients with artificial dialysis, dry skin is produced, which is the cause of concurrent itching (Morton CA, et al. Nephrol Dial Transplant. 10: 2031-2036, 1996). As the skin becomes drier, nerve fibers (C fibers) extend to the epidermis as the skin barrier function decreases (Andoh T, et al. Neurosci Lett. 672: 84-89, 2018). If the periostin receptors present in the nerve fibers are activated by periostin, it may cause itching (non-patent document 2 above).

[0100] As described above, various human diseases mediated by periostin are known. However, there are no reports on actually administering periostin receptor antagonists to obtain therapeutic or preventive effects on these human diseases.

[0101] In the present invention, examples of pruritus include pruritus symptoms of the skin. Examples of pruritus symptoms of the skin include, but are not limited to, pruritus symptoms of the skin caused by skin diseases or inflammation. Examples of skin diseases or inflammation include, but are not limited to, atopic dermatitis, contact dermatitis, prurigo, etc.

[0102] "Prevention" and "treatment" in the present invention also include the meaning of inhibiting and / or blocking or alleviating periostin-mediated diseases and the itch (e.g., itchy skin symptoms) associated with the disease. Therefore, the present invention may also include: inhibitors, blockers or alleviators of periostin-mediated diseases and itch (e.g., itchy skin symptoms) associated with the disease, including the compounds of the present invention, etc.; pharmaceutical compositions for inhibiting, blocking or alleviating the symptoms, including the compounds of the present invention, etc.; methods for inhibiting, blocking or alleviating the symptoms, including the step of administering the compounds of the present invention, etc. to the subject; and the use of the compounds of the present invention, etc. in the manufacture of medicaments for inhibiting, blocking or alleviating the symptoms. In addition, as a treatment for periostin-mediated diseases and itch (e.g., itchy skin symptoms), for example, it also includes treatments for inhibiting the progression of symptoms, improving prognosis and achieving relief, and further, it is not limited to the general meaning of treatment, but also includes the prevention of symptoms and prevention of recurrence, etc.

[0103] As the active ingredient of the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention, the derivative of the compound of the present invention may also be used together with or in place of the compound of the present invention. As the derivative, any derivative having a chemical structure derived from the compound of the present invention, etc., which is generally considered to be the derivative based on the technical common sense of those skilled in the art, is not limited, and preferably has the same degree of preventive or therapeutic effect on periostin-mediated diseases and pruritus (e.g., itching symptoms of the skin) associated with the disease as the compound of the present invention.

[0104] As the compound or its derivative of the present invention, in addition to metabolizers such as those that undergo oxidation, reduction, hydrolysis or conjugation in vivo, it also includes compounds (so-called prodrugs) that undergo metabolism such as oxidation, reduction or hydrolysis in vivo to generate the compound or its derivative of the present invention. In the present invention, a prodrug refers to a pharmacologically acceptable compound formed by modifying a parent compound using a group commonly used for a prodrug, for example, a compound that is endowed with characteristics such as chemical stability, sustained effect or improved in vivo absorbability and is converted into a parent compound in the intestine or skin tissue and is expected to show an effect. For example, the prodrug of the compound of the present invention can be manufactured as follows: using a prodrug reagent such as a corresponding halide, by conventional methods, one or more of the groups selected from the prodrug-capable groups (such as hydroxyl, amino, carboxyl and other groups) in the compound is appropriately introduced into the group constituting the prodrug according to conventional methods, and then isolated and purified as needed. Here, the group constituting the above-mentioned prodrug is not limited, and 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-.

[0105] As the active ingredient of the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention, pharmacologically acceptable salts thereof may be used together with or instead of the compound of the present invention, its derivative or its prodrug.

[0106] The pharmacologically acceptable salts of the compounds of the present invention and their derivatives are not limited, and preferably include, for example, hydrohalide salts (e.g., hydrochloride, hydrobromide and hydroiodide), inorganic acid salts (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate), organic carboxylate salts (e.g., acetate, trifluoroacetate, maleate, tartrate, fumarate and citrate), organic sulfonate salts (e.g., methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphorsulfonate), amino acid salts (e.g., aspartate and glutamate), quaternary ammonium salts, alkali metal salts (e.g., sodium salt and potassium salt), alkaline earth metal salts (e.g., magnesium salt and calcium salt), and the like.

[0107] The compounds of the present invention used as active ingredients include all isomers (e.g., geometric isomers, optical isomers based on asymmetric carbon, rotational isomers, stereoisomers, and tautomers, etc.) that can be produced in the compound structure and mixtures of two or more of these isomers, and are not limited to the description of the structural formula for convenience. In addition, the compounds of the present invention can be any of the S-body, R-body, or RS-body, without limitation. Furthermore, the compounds of the present invention sometimes exist in the form of hydrates or solvates depending on their types. In the present invention, the hydrates and solvates are also included in the compounds of the present invention, and can be used as the inhibitors or blockers of the present invention and the active ingredients of the pharmaceutical composition of the present invention. As the solvate, there is no limitation, and examples thereof include solvates with ethanol, etc.

[0108] In the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention, the content ratio of the compound of the present invention as an active ingredient is not limited and can be appropriately set, for example, relative to the whole of the preventive or therapeutic agent or the pharmaceutical composition, it can be set in the range of 0.01 to 99 weight %, preferably 0.01 to 30 weight %, more preferably 0.05 to 20 weight %, and further preferably 0.1 to 10 weight %. By making the content ratio of the active ingredient within the above range, the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention can give full play to the preventive or therapeutic effect of periostin-mediated diseases and pruritus (e.g., itchy symptoms of the skin) associated with the disease.

[0109] The preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention may contain other ingredients in addition to the compound of the present invention, etc., within the range that does not significantly damage the effect of the present invention. As other ingredients, known or developing medicaments, such as moisturizers, steroids, immunosuppressants, antihistamines, JAK blockers, and IL-4 / IL-13 blockers, etc., may be used in combination. One or more of them. Furthermore, the inhibitor or blocker of the present invention and the pharmaceutical composition of the present invention, for example, may also contain ingredients commonly used in the manufacture of medicaments described later, etc.

[0110] The preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention can be administered to humans or non-human mammals (e.g., rats, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, etc.) as subjects by various routes of administration, specifically oral or parenteral (e.g., intravenous injection (intravenous injection), intramuscular injection, intraperitoneal injection, subcutaneous injection, rectal administration, transdermal administration, and coating). Therefore, the compound of the present invention, etc. can be used alone, but can also be formulated into an appropriate dosage form using a pharmaceutically acceptable carrier according to the route of administration by a common method.

[0111] As dosage forms, in the case of oral agents, for example, tablets, powders, fine granules, granules, coated tablets, capsules, oral aqueous solutions, suspensions, emulsions, syrups and lozenges can be listed, and in the case of parenteral agents, for example, injections (including drips), inhalants, ointments, creams, nasal drops and liposomes can be listed. It should be noted that when the above-mentioned various oral agents are prepared, the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention can be used as a supplement (for example, corresponding to functional foods) according to the circumstances. It should be noted that when manufacturing each dosage form, it can be manufactured by the manufacturing method recorded in the Japanese Pharmacopoeia.

[0112] As carriers that can be used in the formulation of these preparations, for example, in addition to commonly used excipients, binders, disintegrants, lubricants, colorants and flavoring agents, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, extenders, wetting agents, surfactants, dispersants, buffers, preservatives, solubilizers, oily bases, emulsifying bases, water-soluble bases, suspending bases and pain-relieving agents, etc., can be used, and known components that can be used as raw materials for pharmaceutical preparations can be added and formulated by conventional methods.

[0113] Examples of nontoxic substances that can be used as the component include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, vaseline, a composite ointment base (Plastibase) of liquid paraffin and polyethylene, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetearyl alcohol and behenyl alcohol; silicone resins; silicone oils; polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene Surfactants such as hydrogenated castor oil and polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyols such as glycerol, propylene glycol, dipropylene glycol, sorbitol and polyethylene glycol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate; inorganic salts such as sodium chloride and sodium phosphate; purified water, etc., can all be salts or hydrates thereof.

[0114] Preferred examples of the excipient include lactose, fructose, corn starch, saccharide, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide. Preferred examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol / polyoxyethylene block polymer, and meglumine. Preferred examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose (Carmellose), and carboxymethyl cellulose calcium (Carmellose). As lubricants, preferably, for example, magnesium stearate, talc, polyethylene glycol, silicon dioxide and hydrogenated vegetable oil can be mentioned; as colorants, preferably, colorants allowed to be added to medicines can be mentioned; as flavor correctives, for example, cocoa powder, menthol, aromatic powder, peppermint oil, borneol and cinnamon powder can be mentioned, all of which can be salts or hydrates thereof.

[0115] In addition, pH adjusters are used in the case of formulation into injections, etc. There are no particular restrictions on pH adjusters as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, they include: alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, and potassium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal or alkaline earth metal carbonates; alkali metal alcoholates, etc. The pH adjusters used may be used alone or in any combination of two or more. When the formulation is formulated into injections, etc., the pH adjuster may be used to appropriately adjust it to an appropriate pH. In the present invention, the pH is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and particularly preferably 3.5 to 4.5.

[0116] It should be noted that when the formulation is made into an injection, cyclodextrins may be contained. There is no particular limitation on cyclodextrins, as long as they are medically, pharmacologically (pharmaceutically) or physiologically acceptable. As such cyclodextrins, for example, unmodified cyclodextrins, modified cyclodextrins, etc. may be cited. As unmodified cyclodextrins, for example, α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, etc. may be cited. In addition, examples of modified cyclodextrins include alkylated cyclodextrins (e.g., dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, etc.), hydroxyalkylated cyclodextrins (e.g., hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, etc.), sulfoalkyl ether cyclodextrins (e.g., sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin), branched cyclodextrins (e.g., maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, etc.), and the like.

[0117] The cyclodextrins may be used alone or in any combination of two or more. The cyclodextrin to be blended is preferably hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin, and more preferably sulfobutyl ether-β-cyclodextrin.

[0118] The content of cyclodextrins is not particularly limited and can be appropriately set according to the type, purpose of the injection, method of use, etc. The content of cyclodextrins is preferably 5 to 50% by weight, more preferably 10 to 40% by weight, and further preferably 10 to 30% by weight, based on the total amount of the injection.

[0119] The dosage of the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention can generally be appropriately set within a wide range based on the age, weight and type and progression of the disease of the subject (patient), as well as the route of administration, the number of administrations ( / day) and the administration period, taking into account the formulation ratio of the active ingredients (compounds of the present invention, etc.) in the preparation.

[0120] The case where the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention are used as a parenteral agent or an oral agent will be specifically described below.

[0121] When used as a parenteral agent, its form is usually not limited. In the case of various injections, for example, it can be provided in the state of a unit dose ampoule or a multi-dose container or in the state of a freeze-dried powder that is redissolved in a dissolving liquid during use. In the parenteral agent, in addition to the compound of the present invention as an active ingredient, etc., various known excipients and additives can be contained in various forms in a range that does not damage the effect of the above-mentioned active ingredient. For example, in the case of various injections, aliphatic polyols such as water, glycerol, propylene glycol or polyethylene glycol can be listed.

[0122] The dosage (per day) of the parenteral preparation is not limited. For example, in the case of various injections, the compound of the present invention as an active ingredient can usually be administered in an amount of 0.01 to 1000 mg, 0.05 to 500 mg, or 0.1 to 50 mg per kg body weight of the application object (subject, patient, etc.). Alternatively, it can be set to an amount of 0.5 to 20 mg or an amount of 1 to 10 mg.

[0123] When used in the form of an oral dosage form, the form is usually not limited, and it can be any of the above-mentioned dosage forms, or it can be made into a dry product that is redissolved when used. In the oral dosage form, in addition to the compound of the present invention as an active ingredient, etc., various known excipients or additives can be contained in various forms in a range that does not damage the effect of the above-mentioned active ingredient. For example, adhesives (syrup, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinyl pyrrolidone, etc.), fillers (lactose, sugar, corn starch, potato starch, calcium phosphate, sorbitol, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silicon dioxide, etc.), disintegrants (various starches, etc.) and wetting agents (sodium lauryl sulfate, etc.) can be listed.

[0124] Regarding the dosage of oral agents (per day), the compound of the present invention as an active ingredient can usually be set to an amount of 0.05 to 5000 mg, 0.1 to 1000 mg, or 0.1 to 100 mg per 1 kg body weight of the application object (subject, patient, etc.), or it can be set to an amount of 0.5 to 50 mg or an amount of 1 to 10 mg. In addition, the proportion of the active ingredient in the oral agent is not limited, and it can be appropriately set considering the number of administrations per day.

[0125] It should be noted that in the present invention, when preventing or treating periostin-mediated diseases and the itching associated with the disease (e.g., itching symptoms of the skin), a kit containing the compound of the present invention, etc. (as a specific example, a kit containing the above-mentioned preventive or therapeutic agent of the present invention or the pharmaceutical composition of the present invention) can also be used.

[0126] The form of the compound of the present invention etc. in the kit is not limited, and the compound may be provided in a dissolved state, for example, in consideration of stability (storability) and ease of use. The kit may contain other components as appropriate in addition to the compound of the present invention etc.

[0127] The kit only needs to have at least the compound of the present invention as a constituent element. Therefore, the kit may have all the constituent elements necessary for preventing or treating periostin-mediated diseases and pruritus (e.g., pruritus of the skin) associated with the disease together with the compound of the present invention, or may have them separately, without limitation.

[0128] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

[0129] [Example 1]

[0130] Facial Atopic Dermatitis with Scratching (FADS) mice Production

[0131] By making Nestin-cre transgenic mice and IKK2 f / f Nestin-cre / Ikk2, which specifically lacks IKK2 in facial skin fibroblasts, was generated by mating mice f / fMice (Nunomura S, et al. J Invest Dermatol. 139: 1274-1283, 2019). The mice will inevitably develop atopic dermatitis-like rashes and severe itching symptoms limited to the face, so they are named facial atopic dermatitis with pruritus (FADS) mice. Compared with control mice, FADS mice have significantly increased periostin in serum. In addition, periostin is highly expressed in the dermis of facial skin; when the periostin gene of FADS mice is destroyed, the scratching behavior is significantly inhibited compared with control mice; and, the scratching behavior of FADS mice can be inhibited by intraperitoneal administration of anti-periostin monoclonal antibodies that can neutralize periostin, indicating that the scratching behavior of FADS mice is periostin-mediated (Nunomura S, et al. Cell Rep. 42: 111933, 2023). In the evaluation of the preventive or therapeutic agent of the present invention, FADS mice aged 3 to 4 weeks and later that show spontaneous scratching behavior are used. It should be noted that, in this example, the compound of the above formula (I) (specifically, "CP4715") was used as the preventive or therapeutic agent of the present invention.

[0132] Blockade of scratching behavior in FADS mice by repeated systemic administration of CP4715

[0133] After acclimating the FADS mice in the cage for 20 minutes, the mice were filmed with a video camera. The filmed video was played back, and the action of scratching the face with the hind paw followed by licking the toes or putting the toes back on the ground was counted as one scratching behavior.

[0134] From the solution (containing 50% dimethyl sulfoxide (DMSO), 89.5mM hydrochloric acid in physiological saline), CP4715 (100mg / mL) was taken out in an amount equivalent to 107.4μmol / kg per mouse, diluted in 0.2mL PBS, and administered subcutaneously to the back twice a day. Mice administered with 0.2mL PBS containing an equal amount of the solution based on body weight were used as a control group.

[0135] One week and two weeks after drug administration, 60 minutes of filming and analysis were performed, and the number of scratches per minute was calculated and evaluated. The Mann-Whitney U test was used for statistical analysis. When the P value was less than 0.05, it was judged to be significantly different. The results are shown in Figure 1 .like Figure 1 As shown, scratching behavior was significantly inhibited 1 week and 2 weeks after administration of CP4715 (P<0.05).

[0136] Blockade of scratching behavior in FADS mice by a single systemic administration of CP4715

[0137] Before administration of CP4715, FADS mice were photographed for 60 minutes, and then the mice were allowed to rest for 30 minutes. After that, CP4715 (89.5 mM) in the solution (physiological saline containing 50% DMSO and 89.5 mM HCL) was taken out in an amount equivalent to 53.7 μmol / kg per mouse, diluted in 0.3 mL of PBS and administered intraperitoneally. Mice administered with 0.3 mL of PBS containing an equal amount of the solution based on body weight were used as the control group.

[0138] The images were taken for 80 minutes from the time of drug administration. The number of scratches per minute was calculated from the number of scratches per 20 minutes before and after drug administration for evaluation. The Mann-Whitney U test was used for statistical analysis. When the P value was less than 0.05, it was judged to be significantly different. The results are shown in Figure 2 .like Figure 2 As shown, the scratching behavior was significantly inhibited 20 minutes and thereafter after administration of CP4715 (P<0.05), and the effect lasted until 60 minutes after administration.

[0139] In vivo extracellular recordings from the superficial layers of the spinal cord dorsal horn in FADS mice

[0140] FADS mice were anesthetized by intraperitoneal administration of urethane 1.5 g / kg, and then thoracic and lumbar vertebrae were collaterally removed. The 1st to 6th lumbar vertebrae were exposed, and the mice were placed on a positioning fixture. The dura mater, arachnoid mater, and pia mater were removed under a microscope, the surface of the spinal cord was heated at 36±1°C, and artificial cerebrospinal fluid saturated with 95% O2-5% CO2 (composition: NaCl (117 mM), KCl (3.6 mM), CaCl2 (2.5 mM), MgCl2 (1.2 mM), NaH2PO4 (1.2 mM), glucose (11 mM), NaHCO3 (25 mM)) was perfused at 15-20 mL / min. A tungsten electrode (tip diameter 25 mm, tip resistance 9-12 MΩ) (latero-medial) was inserted into the exposed spinal cord, and recording was obtained from neurons in the surface layer of the dorsal horn of the spinal cord.

[0141] From the CP4715 (89.5 mM) in the dissolving solution (physiological saline containing 50% DMSO and 89.5 mM hydrochloric acid), an amount equivalent to 53.7 μmol / kg per mouse was taken out, diluted in 0.3 mL of physiological saline, and then administered intraperitoneally (ip). 0.3 mL of physiological saline containing an amount of the dissolving solution equivalent to the body weight was administered as a control. When recording from the dorsal horn of the spinal cord of FADS mice, neurons with spontaneous firing were able to be recorded. First, when the above-mentioned control solution was administered intraperitoneally, almost no change in the spontaneous firing frequency was observed within 30 minutes of administration. Next, when CP4715 was administered intraperitoneally, the firing frequency began to decrease 20 minutes after administration, and the firing frequency was suppressed to the maximum intensity at 40 minutes after administration, and returned to the original firing frequency 60 minutes after administration ( Figure 3 ).

[0142] These results suggest that periostin acts directly on sensory neurons to induce neuronal firing, and that CP4715 blocks the binding of periostin to sensory neurons to inhibit neuronal firing, resulting in inhibition of scratching behavior. It is known that periostin induces scratching behavior in FADS mice, and that scratching behavior can be inhibited by administering anti-periostin monoclonal antibodies.

[0143] [Example 2]

[0144] Blockade of scratching behavior in FADS mice by a single systemic administration of an αvβ3 integrin blocker

[0145] The following compounds reported as αvβ3 integrin blockers were used to compare the scratching behavior blocking effect of FADS mice. That is, CP derivatives 2, CP derivatives 6, CP derivatives 7 and CP derivatives 9, which share the basic skeleton of CP4715, as well as SC-68448, BS-1417, SB-273005, GLPG-0187, Cilengitide, SM-256 and SB-267268 were used. In addition, the SB-267268 mirror image isomer was used as a negative control. These compounds are all known compounds. CP4715, CP derivative 2, CP derivative 6, CP derivative 7 and CP derivative 9 are disclosed in Nanri Y, et al. Am J Respir Cell Mol Biol. 62: 204-216, 2020. In addition, SC-68448 is disclosed in Carron CP, et al. Cancer Res. 58: 1930-1935, 1998, BS-1417 is disclosed in Sakai M, Yoshimura R. Biol Pharm Bull. 44: 416-421, 2021, SB-273005 is disclosed in Badger AM, et al. Arthritis Rheum. 44: 128-137, 2001, GLPG-0187 is disclosed in Helen M, et al. J Med. Chem. 57: 6301-6315, 2014, Cilengitide is disclosed in Eskens FA, et al. Eur J Cancer. 39: 917-926, 2003, SM-256 is disclosed in Mousa SA, et al. J Cardiovasc Pharmacol. 33: 641-646, 1999, and SB-267268 is disclosed in Wilkinson-Berka JL, et al. Invest Ophthalmol Vis Sci. 47: 1600-1605, 2006.

[0146] The chemical name (free form), chemical structure and CAS registration number (free form) of each compound are as follows: CP4715, CP derivative 6 and SC-68448 are as described above.

[0147] CP derivative 2: (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid (CAS registration number: 247034-18-0)

[0148]

[0149] CP derivative 7: (S)-3-(2-fluoro-4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid (CAS registration number: 334619-09-9)

[0150]

[0151] CP derivative 9: (S)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(thiophene-2-sulfonamido)propanoic acid ((S)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benza mido)-2-(thiophene-2-sulfonamido)propanoic acid) (CAS registration number: 334619-69-1)

[0152]

[0153] BS-1417: (2S)-5-(4-(3-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-2-((isobutoxycarbonyl)amino)-5-oxopentanoic acid (CAS registration number: 461719-50-6)

[0154]

[0155] SB-273005: (S)-2-(8-(2-(6-(methylamino)pyridin-2-yl)ethoxy)-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)acetic acid (CAS registration number: 205678-31-5)

[0156]

[0157] GLPG-0187: (S)-3-((2,5-dimethyl-6-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-((4-methoxyphenyl)sulfonamido)propanoic acid (CAS registration number: 1320346-97-1)

[0158]

[0159] Cilengitide: 2-((2S,5R,8S,11S)-5-benzyl-11-(3-guanidinopropyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid (CAS registration number: 188968-51-6)

[0160]

[0161] SM-256: (S)-3-(1-(3-((1H-imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxamido)-2-((2,4,6-trimethylphenyl)sulfonamido)propanoic acid (CAS registration number: 192944-48-2)

[0162]

[0163] SB-267268: (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 (CAS No. 205678-26-8)

[0164]

[0165] SB-267268 mirror image isomer: (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 (CAS registration number: 205678-27-9)

[0166]

[0167] CP4715 is provided by Meiji Seika Pharma Co., Ltd. Cilengitide and SB-273005 are purchased from Selleck. GLPG-0187 is purchased from MedChemExpress. CP4715 and CP derivative 2 can be manufactured by the method described in WO1999 / 052872. CP derivative 6, CP derivative 7 and CP derivative 9 can be manufactured by the method described in WO2001 / 027082. Cilengitide can be manufactured by the method described in DE19534177. GLPG-0187 can be manufactured by the method described in WO2011 / 119282. SC-68448 can be manufactured by the method described in WO97 / 08145. BS-1417 can be manufactured by the method described in WO2002 / 074743. SB-273005 can be manufactured by the method described in WO98 / 14192. SM-256 can be produced by the method described in WO09 / 723480. SB-267268 and SB-267268 mirror image isomer can be produced by the method described in WO98 / 14192.

[0168] Before administering the above-mentioned αvβ3 integrin blocker to FADS mice, the mice were filmed with a camera for 60 minutes, and then the mice were allowed to rest for 15 minutes. For compounds other than GLPG-0187, an amount of each compound (89.5 mM) in the dissolving solution (physiological saline containing 50% DMSO and 89.5 mM HCL) was taken out in an amount equivalent to 53.7 μmol / kg per mouse, diluted in 0.3 mL of PBS, and then administered intraperitoneally. Since GLPG-0187 has low solubility, an 8.95 mM dissolving solution was prepared, and an amount equivalent to 5.37 μmol / kg per mouse was taken out, diluted in 0.3 mL of PBS, and then administered intraperitoneally. Mice administered with 0.3 mL of PBS containing an equal amount of the dissolving solution based on body weight were used as a control group.

[0169] Immediately after administration of the above-mentioned αvβ3 integrin blocker, camera recording was performed for 60 minutes. The number of scratches before administration was used as the baseline, and the rate of change after administration from the baseline was calculated. Paired t-test was used for statistical analysis. When the P value was less than 0.05, it was judged to be significantly different. The blocker effect with an average rate of change from the baseline of -65% or more and a P value of less than 0.01 was expressed as "++", the blocker effect with an average rate of change of less than -60% and a P value of less than 0.05 was expressed as "+", and the blocker effect with an average rate of change of less than -60% and a P value of more than 0.05 was expressed as "-".

[0170] The change rate (%) of the scratching frequency from the baseline for each compound is shown in Table 1. The dosage of each compound was standardized to 53.7 μmol / kg except for GLPG-0187.

[0171]

Table 1

[0172]

[0173] The results for compounds other than GLPG-0187 are shown in Figure 4 In addition, the results of GLPG-0187 are shown in Figure 5 . Figure 4 and 5 The internal values ​​represent P values. According to Table 1 and Figure 4 The change rate of the number of scratching times from the baseline was "++" for CP4715, SC-68448 and CP derivative 6, "+" for BS-1417 and SB-273005, and "-" for the other compounds.

[0174] Blockade of periostin-dependent cell adhesion by αvβ3 integrin blockers

[0175] In the cell adhesion experiment, cells that stably express the human integrin β3 gene by introducing the human integrin β3 gene into the human colon cancer cell line SW480 cells that do not express integrin β3 were used (Nanri Y, et al. Am J Respir Cell Mol Biol. 62: 204-216, 2020). For the compounds shown in Table 1, the adhesion blocking activity of integrin αvβ3 and periostin was investigated by the following steps. First, a 96-well plate was treated with 10 μg / mL recombinant human periostin (Bio-Techne) at 4°C for 16 hours to solidify periostin. SW480 cells (5×10 4 ) were reacted with 0.001, 0.01, 0.1 and 1 μM of the above compounds in serum-free DMEM (Dulbecco's Modified Eagle Medium) containing 0.5% bovine serum albumin and 0.25mM MnCl2 at room temperature for 15 minutes. The group without added compounds was used as a control. The cell suspension after the reaction was added to each well of the above-mentioned human periostin immobilized plate, and the plate was centrifuged at 10×g for 5 minutes and incubated at 37°C for 60 minutes. Thereafter, the adherent cells were washed to remove the unbound cells, and then the adherent cells were fixed with 1% formaldehyde and stained with 0.5% crystal violet. The fixed and stained cells were dissolved with 0.2% Triton X-100, and the absorbance at 595nm was measured. The absorbance of the control (group without added compounds) was set to a blocking rate of 0%. In addition, the absorbance of crystal violet derived from cells adhered to the plate immobilized with bovine albumin without adding the compound was measured by the same procedure, and the blocking rate was taken as 100%. Cell adhesion in this test system depends on periostin, and compounds that block this cell adhesion can be called periostin receptor antagonists.

[0176] The obtained results are shown in Figure 6 The 50% blocking concentration (IC 50 The IC values ​​of SC-68448, SB-273005, and SB-267268 were less than 0.001 μM, indicating that these compounds have high cell adhesion blocking effects. 50 The value is below 0.02 μM, indicating that the cell adhesion blocking effect is moderate. IC 50 The IC values ​​of SB-267268 mirror image isomer and BS-1417 are below 0.1 μM, indicating low blocking effect. 50 The value was above 1 μM.

[0177] It can be seen that the relationship between the cell adhesion blocking effect of the compound and the scratching behavior blocking effect of FADS mice is not necessarily related. CP4715, CP derivative 2, CP derivative 6, CP derivative 7 and CP derivative 9 all showed IC 50 The strong cell adhesion blocking activity was below 0.001 μM. On the other hand, in terms of scratching behavior blocking effect in FADS mice, CP4715 and CP derivative 6 exerted strong blocking effects indicated by "++", while CP derivative 2, CP derivative 7, and CP derivative 9 only showed weak effects indicated by "-". SC-68448 showed a strong scratching behavior blocking effect indicated by "++" in FADS mice, while SB-273005 and SB-267268, which had the same degree of cell adhesion blocking activity as SC-68448, had weak scratching behavior blocking effects, indicated by "+" and "-", respectively.

[0178] [Example 3]

[0179] Blockade of scratching behavior in FADS mice by repeated transdermal administration of CP4715

[0180] CP4715 was dissolved in a dissolving solution (5% DMSO / 15% N-methyl-2-pyrrolidone / 80% ethanol) to prepare a 26.85 mM solution. 30 μL of CP4715 solution was applied to the facial rash of FADS mice once a day for 28 days. Mice that were percutaneously administered with an equal amount of the dissolving solution were used as a control group. The number of scratching times for 60 minutes was measured before the start of administration and 3, 7, 14, 21 and 28 days after administration for evaluation. The results are shown in Figure 7 .like Figure 7 As shown, the temporal enhancement of scratching behavior of FADS mice was suppressed by application of CP4715.

[0181] Industrial Applicability

[0182] According to the present invention, a preventive or therapeutic agent for periostin-mediated diseases and pruritus associated with the diseases can be provided, and a preventive or therapeutic pharmaceutical composition for the disease and pruritus, and a preventive or therapeutic method for the disease and pruritus can be provided.

Claims

1. A preventive or therapeutic agent for a periostin-mediated disease or pruritus associated with the disease, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, In the formula, R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 3 is an alkyl group, an aryl group or an aralkyl group.

2. The preventive or therapeutic agent according to claim 1, wherein The compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamide)propanoic acid.

3. The preventive or therapeutic agent 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.

4. The preventive or therapeutic agent according to claim 1, wherein The periostin-mediated disease is atopic dermatitis.

5. A pharmaceutical composition 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 at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, In the formula, R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 3 is an alkyl group, an aryl group or an aralkyl group.

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

7. The pharmaceutical composition according to claim 5, 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.

8. The pharmaceutical composition according to claim 5, wherein The periostin-mediated disease is atopic dermatitis.

9. Use of at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof for the manufacture of a medicament for the prevention or treatment of a periostin-mediated disease or pruritus associated with the disease, In the formula, R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 3 is an alkyl group, an aryl group or an aralkyl group.

10. The use according to claim 9, wherein The compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamide)propanoic acid.

11. The use according to claim 9, 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.

12. The use according to claim 9, wherein The periostin-mediated disease is atopic dermatitis.

13. A method for preventing or treating a periostin-mediated disease or pruritus associated with the disease, comprising the step of administering an effective amount of a periostin receptor antagonist to a subject in need of treatment, wherein the antagonist is at least one compound selected from the group consisting of a compound of the following formula (I), 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamide)acetamide)propionic acid and (S)-2-(phenylsulfonamide)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, In the formula, R 1 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 2 are independently a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, R 3 is an alkyl group, an aryl group or an aralkyl group.

14. The method according to claim 13, wherein: The compound of formula (I) is (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamide)propanoic acid.

15. The method according to claim 13, 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.

16. The method according to claim 13, wherein: The periostin-mediated disease is atopic dermatitis.

Images