Preventive or therapeutic agent for allergic conjunctival disease

Abstract

Provided is a technology for preventing or treating allergic conjunctival disease. The present invention relates to a preventive or therapeutic agent for allergic conjunctival disease, and a pharmaceutical composition for prevention or treatment of allergic conjunctival disease.

Description

Preventive or therapeutic agent for allergic conjunctival diseases

[0001] The present invention relates to an agent for preventing or treating allergic conjunctival diseases such as atopic keratoconjunctivitis.

[0002] Atopic keratoconjunctivitis is a chronic allergic conjunctival disease that develops against the background of type 2 inflammation. Existing treatments include tacrolimus eye drops and steroid eye drops. However, the etiology of atopic keratoconjunctivitis is complex, and these treatments are ineffective in some patients. Furthermore, steroid eye drops can induce side effects, such as increased intraocular pressure. In addition to elucidating the pathogenesis of atopic keratoconjunctivitis, there is a need for the development of therapeutic or preventive drugs with new mechanisms of action for allergic conjunctival diseases, including atopic keratoconjunctivitis.

[0003] Meanwhile, periostin (osteoblast-specific factor 2), an IL-4 and IL-13-inducible matricellular protein, is an extracellular matrix protein that binds to a cell surface receptor belonging to the integrin family (αVβ3 / β5 integrin) to transmit signals intracellularly, and has been suggested to play an important role in the exacerbation and chronicity of inflammation in allergic diseases (Non-Patent Document 1).

[0004] Masuoka M, et al. J Clin Invest. 122:2590-2600, 2012

[0005] Under these circumstances, there has been a demand for the development of a technology for preventing or treating the symptoms of allergic conjunctival diseases.

[0006] The present invention has been made in consideration of the above circumstances, and provides the following preventive or therapeutic agents for allergic conjunctival diseases.

[0007] (1) A preventive or therapeutic agent for allergic conjunctival diseases, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３ is an alkyl group, an aryl group, or an aralkyl group.] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (SC-68443), (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid ((S)-SC-68443), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 2), and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0008] (2) The preventive or therapeutic agent 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 (CP4715). (3) The preventive or therapeutic agent according to (1) above, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal keratoconjunctivitis, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

[0009] (4) A pharmaceutical composition for preventing or treating an allergic conjunctival disease, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group.], 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (SC-68443), (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid ((S)-SC-68443), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido the pharmaceutical composition is 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 (CP derivative 2), and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0010] (5) The pharmaceutical composition according to (4) 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). (6) The pharmaceutical composition according to (4) above, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal keratoconjunctivitis, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

[0011] (7) Use of a periostin receptor antagonist for producing a medicament for preventing or treating an allergic conjunctival disease, wherein the antagonist is represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group.] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid ((S)-SC-68443), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2 1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 2), and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0012] (8) The use according to (7) 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). (9) The use according to (7) above, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal keratoconjunctivitis, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

[0013] (10) A method for preventing or treating an allergic conjunctival disease, comprising administering an effective amount of a periostin receptor antagonist to a subject in need of treatment, wherein the antagonist is represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group.] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (SC-68443), (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid ((S)-SC-68443), (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide) the compound used in the method for preventing or treating rheumatoid arthritis is 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 (CP derivative 2), and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

[0014] (11) The method according to (10) 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). (12) The method according to (10) above, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal keratoconjunctivitis, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

[0015] In the inventions described in (1), (4), (7) and (10) above, in formula (I), R １ , R ２ and R ３The alkyl group in is preferably a lower alkyl group (for example, an alkyl group having 1 to 4 carbon atoms), and specific examples thereof include methyl, ethyl, and propyl. Preferred examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, mesyl, naphthyl, and biphenyl. Preferred examples of the aralkyl group include benzyl and phenethyl. The alkyl group, aryl group, and aralkyl group may be substituted with a known appropriate substituent, but are not limited thereto.

[0016] Furthermore, preferred specific examples of the compound of formula (I) include, but are not limited to, compounds of the following formula (II): 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).

[0017] According to the present invention, it is possible to provide not only a preventive or therapeutic agent for allergic conjunctival diseases, but also a pharmaceutical composition for preventing or treating said diseases, a preventive or therapeutic method for said diseases, and the like.

[0018] 1 shows periostin expression in corneal proliferative lesions (left panel of FIG. 1 ) and the level of periostin expression in tears (right panel of FIG. 1 ) in Facial Atopic Dermatitis with Scratching (FADS) mice (see Example 1 below). In the left panel of FIG. 1 , the brown-stained areas are periostin expression sites. Periostin expression in FADS mice is significantly elevated at lesion sites and in tears compared with control mice. FIG. 3 shows the incidence of corneal proliferative lesions in periostin-deficient FADS mice. Compared with FADS mice, the incidence of corneal proliferative lesions is significantly delayed in periostin-deficient FADS mice. FIG. 4 shows the corneal epithelial thickness (left panel of FIG. 3 ), corneal stromal thickness (middle panel of FIG. 3 ), and stromal eosinophil count (right panel of FIG. 3 ) in periostin-deficient FADS mice. Compared with FADS mice, periostin-deficient FADS mice have significantly reduced corneal epithelial thickness, corneal stromal thickness, and stromal eosinophil count. This figure shows the number of CD31+ blood vessels / corneal stroma in periostin-deficient FADS mice. Compared with FADS mice, periostin-deficient FADS mice have significantly reduced numbers of CD31+ blood vessels / corneal stroma. This figure shows results confirming that 2-week instillation of CP4715, (S)-SC-68448, or CP derivative 2 into FADS mice with atopic keratoconjunctivitis improved ocular lesions. The notation "SC68448(S)" in FIG. 5 means "(S)-SC-68448." 6 shows the results of suppressing corneal epithelial and stromal thickening and eosinophil and mast cell infiltration in FADS mice with atopic keratoconjunctivitis by 2-week instillation of CP4715, (S)-SC-68448, or CP derivative 2. The notation "SC68448(S)" in FIG. 6 means "(S)-SC-68448." The notation "SC68448(S)" in FIG. 7 shows the results of suppressing angiogenesis in FADS mice with atopic keratoconjunctivitis by 2-week instillation of CP4715, (S)-SC-68448, or CP derivative 2. The notation "SC68448(S)" in FIG. 7 means "(S)-SC-68448."9 shows the results of suppressing the infiltration of eosinophils, neutrophils, and mast cells in the palpebral conjunctiva by 2-week eye drop administration of CP4715 to FADS mice that develop atopic keratoconjunctivitis.

[0034] FIG. 9 shows the effects and actions of CP4715 on blepharitis that developed in FADS mice (eyelid skin epidermal thickness (leftmost diagram in FIG. 9), eyelid dermal eosinophils (second diagram from the left in FIG. 9), eyelid dermal neutrophils (second diagram from the right in FIG. 9), eyelid dermal mast cells (rightmost diagram in FIG. 9)).

[0035] FIG. 9 shows the results of suppressing the thickening of the eyelid skin epidermis and the infiltration of eosinophils, neutrophils, and mast cells by 2-week eye drop administration of CP4715 to FADS mice that developed atopic keratoconjunctivitis.

[0019] The present invention will be described in detail below. The scope of the present invention is not limited to these descriptions, and other than the following examples, appropriate modifications can be made without departing from the spirit of the present invention. This specification encompasses the entirety of Japanese Patent Application No. 2024-000656 (filed January 5, 2024), from which priority is claimed. All publications cited in this specification, such as prior art documents, published patent applications, patent publications, and other patent documents, are incorporated herein by reference.

[0020] The preventive or therapeutic agent for allergic conjunctival diseases according to the present invention (hereinafter may be referred to as the "preventive or therapeutic agent of the present invention") and the pharmaceutical composition for preventing or treating allergic conjunctival diseases (hereinafter may be referred to as the "pharmaceutical composition of the present invention") comprise, as described above, a compound represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are each independently a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３is an alkyl group, an aryl group, or an aralkyl group.] 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid (SC-68448), (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid ((S)-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), and (S)-2-(phenylsulfonamido) and (S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)propionic acid (CP derivative 6), 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 salt, hydrate, and solvate thereof may be collectively referred to as the "compound of the present invention, etc.").

[0021] Here, R in the above formula (I) １ , R ２ and R ３ The alkyl group in is preferably a lower alkyl group (for example, an alkyl group having 1 to 4 carbon atoms), and specific examples thereof include methyl, ethyl, and propyl. Preferred examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, mesyl, naphthyl, and biphenyl. Preferred examples of the aralkyl group include benzyl and phenethyl. The alkyl group, aryl group, and aralkyl group may be substituted with a known appropriate substituent, but are not limited thereto.

[0022] In the present invention, preferred examples of the compound of formula (I) that can be used as a periostin receptor antagonist include, but are not limited to, the compound of formula (II) below.

[0023] The compound of formula (II), (S)-3-(3-methoxy-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamido)-2-(phenylsulfonamido)propanoic acid, is known as "CP4715" (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020). The CAS registration number for CP4715 is 247034-73-7 (free form).

[0024] In the present invention, SC-68448, (S)-SC-68448, CP derivative 2, and CP derivative 6, which can be used as periostin receptor antagonists similarly to the compounds of formula (I) and formula (II), are specifically compounds represented by the following formulae (III), (III-2), (IV), and (V).

[0025] The compound of formula (III), 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). The CAS registration number for SC-68448 is 188804-07-1 (free form).

[0026]

[0027] The compound of formula (III-2), (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propanoic acid, is referred to as "(S)-SC-68448" and is the S-isomer of SC-68448, a compound of formula (III).

[0028]

[0029] The compound of 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 2), is a known compound. "CP derivative 2" shares a basic structure with CP4715. The CAS registration number of CP derivative 2 is 247034-18-0 (free form).

[0030]

[0031] The compound of 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 6), is a known compound (Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020). "CP derivative 6" has the same basic structure as CP 4715. The CAS registration number of CP derivative 6 is 334618-85-8 (free form).

[0032]

[0033] "CP4715," "SC-68448," "(S)-SC-68448," "CP derivative 2," and "CP derivative 6" may all be commercially available products, and are not limited thereto. They may also be synthesized, extracted, purified, and the like. CP4715 and CP derivative 2 can be produced by the method described in WO 1999 / 052872, CP derivative 6 can be produced by the method described in WO 2001 / 027082, and SC-68448 and (S)-SC-68448 can be produced by the method described in WO 97 / 08145. "CP4715" is a compound that has antagonistic effects on both the glycoprotein (GP) IIb / IIIa receptor, which plays a major role in thrombus formation, and αvβ3 integrin (a cell adhesion molecule), which is involved in leukocyte adhesion, etc., and is known as an active ingredient in therapeutic agents for cardiovascular diseases (antithrombotic agents). Here, αvβ3 integrin is a receptor for periostin, fibronectin, vitronectin, etc., and it is known that periostin activates sensory neurons via αvβ3 integrin (see Mishra et al., Cell reports, 31:107472, 2020). SC-68448, as an integrin αvβ3 antagonist, has been reported to inhibit the binding of integrin αvβ3 to vitronectin (see 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 (see Nanri Y, et al. Am J Respir Cell Mol Biol. 62:204-216, 2020).

[0034] In addition to the above-mentioned prophylactic or therapeutic agents of the present invention and pharmaceutical compositions of the present invention, the present invention may also include: (i) a method for preventing or treating allergic conjunctival diseases, which uses the compound etc. of the present invention, specifically, for example, administering an effective amount of the compound etc. of the present invention to a subject in need of prevention or treatment (a patient suffering from an allergic conjunctival disease or a patient at risk or possibility of suffering from an allergic conjunctival disease, or such a non-human mammal); (ii) use of the compound etc. of the present invention for producing a medicament for preventing or treating allergic conjunctival diseases; (iii) use of the compound etc. of the present invention for preventing or treating allergic conjunctival diseases; and (iv) the compound etc. of the present invention for preventing or treating allergic conjunctival diseases.

[0035] In the present invention, allergic conjunctival diseases include allergic conjunctivitis and / or keratitis, regardless of the presence or absence of proliferative lesions or atopic diseases. Examples of such allergic conjunctival diseases include, but are not limited to, atopic keratoconjunctivitis, vernal conjunctivitis, seasonal or perennial allergic conjunctivitis, and giant papillary conjunctivitis. Furthermore, in the present invention, the allergic conjunctival disease is preferably a periostin-mediated disease. Here, a periostin-mediated disease is a disease in which periostin is involved in the onset or progression of the disease. "Periostin-mediated" refers to a state in which the intracellular signal transduction 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 disease is involved in the onset or progression of the disease. Furthermore, "periostin-mediated" also refers to a state in which the action of periostin on somatic tissues or somatic cells results in the production, expression, release, or activation of a biomolecule, causing the onset or progression of the disease. There have been no reports that administration of a periostin receptor antagonist actually results in a therapeutic or preventive effect on allergic conjunctival diseases.

[0036] Atopic keratoconjunctivitis, an example of an allergic conjunctival disease, often occurs in conjunction with atopic dermatitis of the facial eyelids. It may be accompanied by eosinophilic infiltration of the cornea and conjunctiva, and may cause corneal damage and visual impairment. It is an intractable disease with the risk of repeated exacerbations and remissions. Similar to other allergic conjunctival diseases, atopic keratoconjunctivitis presents with symptoms such as severe itching, conjunctival thickening, hyperemia, and cloudiness. Furthermore, eyelid thickening and bacterial infection can reduce the protective effect of the cornea through blinking and tears, leading to corneal epithelial disorders such as superficial punctate keratopathy and corneal erosions.

[0037] In the present invention, "prevention" and "treatment" also include the meaning of suppressing and / or inhibiting or alleviating the symptoms of allergic conjunctival disease. Accordingly, the present invention also encompasses suppressors, inhibitors, or alleviators of symptoms of allergic conjunctival disease, which contain the compounds of the present invention, pharmaceutical compositions for suppressing, inhibiting, or alleviating the symptoms, which contain the compounds of the present invention, methods for suppressing, inhibiting, or alleviating the symptoms, which comprise administering the compounds of the present invention to a subject, and use of the compounds of the present invention in the manufacture of medicaments for suppressing, inhibiting, or alleviating the symptoms. Furthermore, treatment of allergic conjunctival disease includes, for example, suppression of progression of symptoms, improvement of prognosis, and treatment until remission is achieved. Furthermore, the terms "treatment" are not limited to the general meaning of treatment, but also include prevention of symptoms and prevention of recurrence.

[0038] As an active ingredient of the prophylactic or therapeutic agent of the present invention and the pharmaceutical composition of the present invention, a derivative of the compound of the present invention can be used together with or instead of the compound of the present invention. The derivative is not limited as long as it has a chemical structure derived from the compound of the present invention and is considered to be a derivative based on the common technical knowledge of a person skilled in the art, but it is preferable that the prophylactic or therapeutic effect on allergic conjunctival diseases is comparable to that of the compound of the present invention.

[0039] The compounds of the present invention or derivatives thereof include those that undergo metabolism in vivo, such as oxidation, reduction, hydrolysis, or conjugation, as well as compounds that undergo metabolism in vivo, such as oxidation, reduction, or hydrolysis, to produce the compounds of the present invention or derivatives thereof (so-called prodrugs). In the present invention, a prodrug refers to a compound obtained by modifying a parent compound with a pharmacologically acceptable group typically used in prodrugs, such as a compound that is conferred properties such as chemical stability, duration of effect, or improved systemic absorption, and that is expected to be converted to the parent compound in the intestinal tract, skin tissue, or the like to exhibit its effect. For example, a prodrug of a compound of the present invention can be produced by conventionally introducing a suitable prodrug-constituting group into one or more groups in the compound that can be converted into a prodrug (e.g., a hydroxyl group, an amino group, a carboxyl group, and other groups) using a prodrug-converting reagent such as a corresponding halide, followed by isolation and purification, as necessary. Here, preferred examples of groups constituting the prodrug include, but are not limited to, lower alkyl-CO—, lower alkyl-O-lower alkylene-CO—, lower alkyl-OCO-lower alkylene-CO—, lower alkyl-OCO—, and lower alkyl-O-lower alkylene-OCO—.

[0040] As the active ingredient of the prophylactic or therapeutic agent of the present invention and the pharmaceutical composition of the present invention, a pharmacologically acceptable salt thereof can be used together with the compound of the present invention, a derivative thereof, or a prodrug thereof, or instead of the compound of the present invention, a derivative thereof, or a prodrug thereof.

[0041] Preferred examples of the pharmaceutically acceptable salts of the compounds of the present invention and derivatives thereof include, but are not limited to, hydrohalides (e.g., hydrochlorides, hydrobromides, hydroiodides, etc.), inorganic acid salts (e.g., sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, etc.), organic carboxylates (e.g., acetates, trifluoroacetates, maleates, tartrates, fumarates, citrates, etc.), organic sulfonates (e.g., methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, camphorsulfonates, etc.), amino acid salts (e.g., aspartates, glutamates, etc.), quaternary amine salts, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., magnesium salts, calcium salts, etc.), and the like.

[0042] The compounds of the present invention used as the active ingredient include all isomers (e.g., geometric isomers, optical isomers based on asymmetric carbons, rotational isomers, stereoisomers, tautomers, etc.) that may arise from the structure of the compound, as well as mixtures of two or more of these isomers, and are not limited to the structural formulae described for convenience. Furthermore, the compounds of the present invention may be in the S-, R-, or RS-form, and are not limited thereto. Furthermore, the compounds of the present invention may exist in the form of hydrates or solvates depending on their type. In the present invention, these hydrates and solvates are also included in the compounds of the present invention and can be used as the active ingredient of the inhibitors or inhibitors of the present invention and the pharmaceutical compositions of the present invention. Examples of such solvates include, but are not limited to, solvates with ethanol.

[0043] In the prophylactic 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 or the like as an active ingredient is not limited and can be set appropriately, but may be, for example, within the range of 0.01 to 99% by weight, preferably 0.01 to 30% by weight, more preferably 0.05 to 20% by weight, and even more preferably 0.1 to 10% by weight, based on the total weight of the prophylactic or therapeutic agent or pharmaceutical composition. When the content ratio of the active ingredient is within the above range, the prophylactic or therapeutic agent of the present invention and the pharmaceutical composition of the present invention can fully exert the effect of preventing or treating allergic conjunctival diseases.

[0044] The prophylactic 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, to the extent that the effects of the present invention are not significantly impaired. Examples of other ingredients include known or under-developed drugs, and for example, one or more of moisturizers, steroids, immunosuppressants, antihistamines, JAK inhibitors, and IL-4 / IL-13 inhibitors may be used in combination. Furthermore, the suppressing or inhibitory agent of the present invention and the pharmaceutical composition of the present invention may also contain, for example, ingredients generally used in drug production, as described below.

[0045] Subjects for the prophylactic or therapeutic agents of the present invention and the pharmaceutical compositions of the present invention include, but are not limited to, humans or non-human mammals (e.g., rats, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, etc.), preferably humans. The route of administration to the subject is not limited, and various routes of administration (various parenteral administrations (e.g., intravenous injection (intravenous injection), subcutaneous injection, intramuscular injection, transdermal administration, and topical application) or oral administration) can be adopted, but eye drops or topical application to the eyelid are preferable because they can be administered directly and simply to the diseased site. In the prophylactic or therapeutic agents of the present invention and the pharmaceutical compositions of the present invention, the compounds of the present invention can be used alone, or can be formulated into an appropriate dosage form using a pharmaceutically acceptable carrier by a method commonly used depending on the administration route.

[0046] Dosage forms include, for example, parenteral preparations such as eye drops, injections (including drip infusions), inhalants, ointments, creams, and liposomes, and oral preparations such as tablets, powders, fine granules, granules, coated tablets, capsules, oral solutions, suspensions, emulsions, syrups, and lozenges. When used as the various oral preparations described above, the preventive or therapeutic agent and pharmaceutical composition of the present invention can also be used as supplements (e.g., functional foods) in some cases. Each dosage form can be produced according to the manufacturing method described in the Japanese Pharmacopoeia.

[0047] Carriers that can be used to formulate these preparations include, for example, commonly used excipients, binders, disintegrants, lubricants, colorants, and flavoring agents, as well as stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, bulking agents, wetting agents, surface activators, dispersants, buffers, preservatives, solubilizers, oleaginous bases, emulsifying bases, water-soluble bases, suspending bases, and soothing agents, as needed. These preparations can be formulated by conventional methods by blending known ingredients that can be used as raw materials for pharmaceutical preparations.

[0048] Examples of non-toxic 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, petrolatum, plastibase, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene-polyoxypropylene block copolymers. water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols (polyols) such as glycerin, propylene glycol, dipropylene glycol, sorbitol, and polyethylene glycol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate, and aluminum silicate; inorganic salts such as sodium chloride and sodium phosphate; purified water, and the like, all of which may be salts or hydrates thereof.

[0049] Examples of excipients include lactose, fructose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide. Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and meglumine. Examples of disintegrants include starch, agar, gelatin powder, crystalline cellulose, and the like. Preferred examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oils. Preferred examples of coloring agents include those permitted for addition to pharmaceuticals. Preferred examples of flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, and cinnamon powder, and each of these may be a salt or a hydrate thereof.

[0050] In addition, pH adjusters are used when formulating the composition as an injection. The pH adjuster is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable. Specific examples 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; carbonates of alkali metals or alkaline earth metals; and alkali metal alkoxides. The pH adjusters may be used alone or in any combination of two or more. When formulating the composition as an injection, the pH can be appropriately adjusted using a pH adjuster. In the present invention, the pH is preferably 3 to 6, more preferably 3 to 5, even more preferably 3 to 4.5, and particularly preferably 3.5 to 4.5.

[0051] When formulated as an injection, the composition may contain cyclodextrins. The cyclodextrins are not particularly limited as long as they are medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable. Examples of such cyclodextrins include unmodified cyclodextrins and modified cyclodextrins. Examples of unmodified cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Modified cyclodextrins include, for example, 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), and branched cyclodextrins (e.g., maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, etc.).

[0052] The cyclodextrins may be used alone or in any combination of two or more. The cyclodextrins to be added are preferably hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and more preferably sulfobutylether-β-cyclodextrin. The content of the cyclodextrins is not particularly limited and is appropriately determined depending on the type, the purpose of the injection, the method of use, etc. The content of the cyclodextrins is, for example, preferably 5 to 50 wt %, more preferably 10 to 40 wt %, and even more preferably 10 to 30 wt %, based on the total amount of the injection.

[0053] The dosage of the prophylactic or therapeutic agent of the present invention and the pharmaceutical composition of the present invention can generally be set appropriately within a wide range, taking into consideration the blending ratio of the active ingredient (the compound of the present invention, etc.) in the formulation, as well as the age, body weight, and type and progress of the disease of the subject (patient), as well as the administration route, number of administrations (per day), administration period, etc.

[0054] The use of the preventive or therapeutic agent of the present invention and the pharmaceutical composition of the present invention as a parenteral or oral preparation will be specifically described below.

[0055] When used as a parenteral preparation, the form is generally not limited, but for example, in the case of various injections, it can be provided in the form of a unit-dose ampule or multi-dose container, or in the form of a lyophilized powder that is redissolved in a dissolving solution at the time of use. In addition to the compound of the present invention as the active ingredient, the parenteral preparation can contain various known excipients and additives depending on the form, to the extent that the effects of the above-mentioned active ingredient are not impaired. For example, in the case of various injections, examples include water, glycerol, propylene glycol, aliphatic polyalcohols such as polyethylene glycol, etc.

[0056] The dosage (per day) of a parenteral preparation is not limited, but for example, in the case of various injections, the amount of the compound of the present invention, which is the active ingredient, administered per kg of body weight of the subject (subject, patient, etc.) can generally be 0.01 to 1000 mg, 0.05 to 500 mg, or 0.1 to 50 mg, or alternatively, 0.5 to 20 mg, or 1 to 10 mg.

[0057] When used as an oral preparation, its form is generally not limited, and it may be any of the dosage forms described above, or may be a dried product that is redissolved when used. In addition to the compound of the present invention as an active ingredient, the oral preparation may contain various known excipients or additives depending on the form, to the extent that the effects of the active ingredient are not impaired. For example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), fillers (lactose, sugar, corn starch, potato starch, calcium phosphate, sorbitol, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (various starches, etc.), and wetting agents (sodium lauryl sulfate, etc.).

[0058] The dosage (per day) of an oral preparation can generally be an amount that allows the compound of the present invention, etc., as an active ingredient, to be taken in an amount of 0.05 to 5000 mg, 0.1 to 1000 mg, or 0.1 to 100 mg per kg of body weight of the target (subject, patient, etc.). The blending ratio of the active ingredient in the oral preparation is not limited and can be appropriately set taking into consideration the number of doses per day, etc.

[0059] In the present invention, when preventing or treating allergic conjunctival diseases, a kit containing the compound of the present invention (specifically, a kit containing the above-mentioned preventive or therapeutic agent of the present invention or pharmaceutical composition of the present invention) can also be used.

[0060] The form of the compound of the present invention etc. in the kit is not limited, but may be provided in a dissolved state, for example, in consideration of stability (storage stability), ease of use, etc. The kit may contain other components as appropriate in addition to the compound of the present invention etc.

[0061] The kit may include at least the compound of the present invention as a component, and is not limited thereto, and may include all of the components essential for the prevention or treatment of allergic conjunctival diseases together with the compound of the present invention, or may include them separately.

[0062] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0063] The present inventors have demonstrated that periostin is highly expressed in tears of patients with atopic keratoconjunctivitis and is a biomarker that can accurately predict therapeutic response to tacrolimus eye drops in combination with Ccl17, IL-8, age, and the like (Fujishima et al., J Allergy Clin Immunol, 148:1596-1602, 2016; Okada et al., Allergy, 78:319-321, 2023). Furthermore, in a mouse model of atopic conjunctivitis induced by ragweed eye drops, periostin deficiency reduced the expression of IL-4, IL-5, and IL-13 and attenuated basophil infiltration in the conjunctival tissue (Asada et al., Allergol Int, 68:233-239, 2019).

[0064] The present inventors have generated mice lacking IKK2, a positive regulator of the NF-kB canonical pathway, in facial skin fibroblasts (see below). These mice developed atopic dermatitis-like skin rash and severe itching limited to the face, and were named Facial Atopic Dermatitis with Scratching (FADS) mice (Nunomura et al., J Invest Dermatol, 139:1274-1283, 2019). Furthermore, it has been reported that FADS mice inevitably develop atopic keratoconjunctivitis, which is primarily caused by type 2 inflammation, and are an excellent model mouse that sensitively reflects the therapeutic effects of topical tacrolimus and topical steroids (Nunomura et al., J Allergy Clin Immunol, 148:1596-1602, 2021).

[0065] Periostin expression is also significantly elevated in the stromal region of corneal proliferative lesions and in tears of FADS mice (Figure 1). Because periostin is involved in the aggravation of atopic dermatitis in FADS mice (Nunomura et al., Cell Rep, 2023, 42:111933), the present inventors suspected that periostin might also play an important role in the pathogenesis of atopic keratoconjunctivitis, and generated periostin-deficient FADS mice (see below) and analyzed them.

[0066] Generation of Facial Atopic Dermatitis with Scratching (FADS) Mice Nestin-cre Transgenic Mice and IKK2 ｆ／ｆ By crossing with mice, we generated the Nestin-cre / Ikk2 strain, which specifically lacks IKK2 in facial skin fibroblasts. ｆ／ｆ Mice were generated and named Facial Atopic Dermatitis with Scratching (FADS) mice.

[0067] Generation of periostin-deficient (FADS) mice. By crossing with periostin-deficient mice, periostin-deficient Nestin-cre transgenic mice and periostin-deficient IKK2 mice were generated. ｆ／ｆ We established periostin-deficient Nestin-cre transgenic mice and periostin-deficient IKK2 mice. ｆ／ｆ The periostin-deficient FADS mice were generated by crossbreeding with FADS mice.

[0068] As a result, periostin-deficient FADS mice showed a reduced incidence of corneal proliferative lesions, and markedly reduced corneal epithelial and stromal thickening, eosinophil infiltration, and angiogenesis in the formed proliferative lesions ( Figures 2 , 3 , and 4 ). Because periostin is involved in the pathogenesis of atopic keratoconjunctivitis in FADS mice, it was suggested that periostin receptor inhibitors (periostin receptor antagonists) might be effective in ameliorating the symptoms of atopic keratoconjunctivitis. Therefore, in this example, the compounds of formulae (II), (III-2), and (IV) (i.e., "CP4715," "(S)-SC-68448," and "CP derivative 2") were dissolved in a solvent (10% DMSO / 90% saline) to prepare 8.9 mM solutions. When 10 μL of CP4715 solution, (S)-SC-68448 solution, or CP derivative 2 solution was administered by eye dropwise twice daily for 14 consecutive days to FADS mice with atopic keratoconjunctivitis, improvement of ocular lesions was confirmed ( FIG. 5 ), and thickening of the corneal epithelium and stroma, infiltration of eosinophils and mast cells, and angiogenesis were suppressed ( FIGS. 6 and 7 ). Furthermore, CP4715 suppressed infiltration of eosinophils, neutrophils, and mast cells in the palpebral conjunctiva, thickening of the eyelid skin epidermis, and infiltration of eosinophils, neutrophils, and mast cells ( FIGS. 8 and 9 ). These results demonstrate that inhibition of αVβ3 integrin-mediated periostin signaling is effective in improving atopic keratoconjunctivitis and blepharitis.

[0069] Based on the above results, the present inventors have demonstrated that the periostin-αVβ3 integrin pathway plays an important role in the symptoms of atopic keratoconjunctivitis, and that the compounds of formula (I) of the present invention (e.g., CP4715, etc.), SC-68448 (e.g., (S)-SC-68448), and CP derivative 2 are useful as agents for the prevention or treatment of atopic keratoconjunctivitis, and therefore allergic conjunctivitis.

[0070] According to the present invention, it is possible to provide not only a preventive or therapeutic agent for allergic conjunctival diseases, but also a pharmaceutical composition for preventing or treating said diseases, a preventive or therapeutic method for said diseases, and the like.

Claims

1. A prophylactic or therapeutic agent for allergic conjunctival diseases, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ２ are, independently of each other, a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound of 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or at least one compound selected from the group consisting of their pharmacologically acceptable salts, or their hydrates or solvates, said prophylactic or therapeutic agent.

2. The prophylactic 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-(phenylsulfonamido)propionic acid.

3. The prophylactic or therapeutic agent according to claim 1, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal catarrh, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

4. A pharmaceutical composition for preventing or treating allergic conjunctival diseases, comprising a periostin receptor antagonist as an active ingredient, wherein the antagonist is represented by the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ２ are, independently of each other, a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound of the formula, 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-(((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-2-(phenylsulfonamido)-3-(4-(((S)-3-(((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or at least one compound selected from the group consisting of pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, said pharmaceutical composition.

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

6. The pharmaceutical composition according to claim 4, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal catarrh, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

7. Use of a periostin receptor antagonist for the manufacture of a medicament for the prevention or treatment of allergic conjunctival diseases, wherein the antagonist is a compound of the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ２ are, independently of one another, a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound selected from the group consisting of 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, said use.

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

9. The use according to claim 7, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal catarrh, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

10. A method for preventing or treating allergic conjunctival diseases, comprising administering an effective amount of a periostin receptor antagonist to a subject in need of treatment, wherein the antagonist is a compound of the following formula (I): [In the formula, R １ is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ２ are, independently of each other, a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, R ３ is an alkyl group, an aryl group, or an aralkyl group.], a compound of 3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3,5-dichlorophenyl)-3-(2-(3-guanidinobenzamido)acetamido)propionic acid, (S)-3-(3-fluoro-4-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid, and (S)-2-(phenylsulfonamido)-3-(4-((S)-3-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)propionic acid, or at least one compound selected from the group consisting of their pharmacologically acceptable salts, or their hydrates or solvates, said preventive or therapeutic method.

11. The method according to claim 10, wherein the compound of formula (I) is (S)-3-(3-methoxy-4-(4-(((1,4,5,6-tetrahydropyrimidin-2-yl)amino)piperidin-1-yl)benzamide)-2-(phenylsulfonamido)propionic acid.

12. The method according to claim 10, wherein the allergic conjunctival disease is atopic keratoconjunctivitis, vernal catarrh, seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, or blepharitis.

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