CCL5 / CXCL10 inhibitor containing heterocyclideneacetamide derivatives

Abstract

This invention provides a means of treating a disease characterized by elevated levels of CCL5 and / or CXCL10. [Solution] An ophthalmic composition for inhibiting or suppressing CCL5 production and / or CXCL10 production, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.

Description

[Technical Field]

[0001] The present disclosure relates to fields including medicine, healthcare, biology and biotechnology. The present disclosure relates particularly to inhibition or suppression of CCL5 production, and inhibition or suppression of CXCL10 production. The present disclosure further relates to treatment and / or prevention of diseases characterized by elevated levels of CCL5 and / or CXCL10. [Background Art]

[0002] C-C motif chemokine ligand 5 (also known as CCL5, RANTES) and C-X-C motif chemokine ligand 10 (also known as CXCL10, IP-10) are known as chemokines. CCL5 is produced by most inflammatory cells such as T cells, and exhibits affinity for chemokine receptors including CCR5 (C-C motif chemokine receptor 5). Downstream pathways of CCL5 / CCR5 include pathways such as PI3K / AKT and Nf-κB, which are reported to be associated with angiogenesis, apoptosis, inflammation and the like (Non-Patent Document 1). CXCL10 is produced by various cells including T cells, endothelial cells and keratinocytes, and exhibits affinity for CXCR3 (C-X-C motif chemokine receptor 3). CXCL10 is reported to be associated with chemotaxis, apoptosis and the like (Non-Patent Document 2)(Non-Patent Document 3). Diseases in which the expression of CCL5 or CXCL10 is enhanced include ocular diseases including dry eye. [Prior Art Literature] [Non-Patent Literature]

[0003] [Non-Patent Document 1] Genes Dis. 2022 Jan;9(1):12-27 [Non-Patent Document 2] Autoimmun Rev. 2014 Mar;13(3):272-280 [Non-Patent Document 3] Cytokine Growth Factor Rev. 2011 Jun;22(3):121-130 [Overview of the project] [Means for solving the problem]

[0004] This disclosure provides novel therapeutic agents for inhibiting or suppressing the production of CCL5 and / or CXCL10, which may be used for the treatment and / or prevention of diseases characterized by elevated levels of CCL5 and / or CXCL10, particularly ocular diseases accompanied by increased CCL5 and / or CXCL10 expression. Specifically, this disclosure relates to the inhibition or suppression of CCL5 production and / or CXCL10 production using (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, one of the heterocyclideneacetamide derivatives. Furthermore, this disclosure relates to the treatment and / or prevention of diseases characterized by elevated levels of CCL5 and / or CXCL10, particularly ocular diseases accompanied by increased CCL5 and / or CXCL10 expression, using the compound.

[0005] Examples of embodiments of this disclosure include at least the following: (Item 1-1) A composition for inhibiting or suppressing the production of CCL5, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. (Item 1-2) An ophthalmic composition for inhibiting or suppressing the production of CCL5, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. (Items 1-3) A composition according to any of the above items for inhibiting or suppressing the production of CCL5 in corneal epithelial cells. (Items 1-4) A composition according to any of the above items for treating and / or preventing a disease characterized by an elevated CCL5 level. (Items 1-5) A composition according to any of the above items for treating and / or preventing dry eye. (Items 1-6) The composition according to any one of the above items, wherein the dry eye is dry eye accompanied by increased CCL5 expression. (Items 1-7) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Items 1-8) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Items 1-9) The composition according to any of the above items, wherein the dry eye is dry eye associated with Sjögren's syndrome. (Items 1-10) A composition according to any of the above items for improving conjunctival goblet cell density in dry eye. (Items 1-11) A composition according to any of the above items for improving the reduction of tear film breakup time in dry eye. (Items 1-12) A composition according to any of the above items, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. (Items 1-13) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Items 1-14) A composition according to any of the above items, in the form of eye drops. (Items 1-15) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Items 1-16) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0006] (Item 2-1) A composition for treating and / or preventing an eye disease, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to be administered to subjects whose tear fluid CCL5 volume is increased compared to healthy individuals without eye disease. (Item 2-2) The composition according to the above item, wherein the subject whose CCL5 amount in the tear fluid is increased compared to a healthy person without the above eye disease is a patient with dry eye. (Item 2-3) The composition according to any of the above items, wherein the subject in whom the amount of CCL5 in the tear fluid is increased compared to a healthy person without the aforementioned eye disease is a patient with dry eye associated with Sjögren's syndrome. (Items 2-4) A composition according to any of the above items for treating and / or preventing dry eye. (Items 2-5) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Items 2-6) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Items 2-7) The composition according to any of the above items, wherein the dry eye is dry eye associated with Sjögren's syndrome. (Items 2-8) A composition according to any of the above items for inhibiting or suppressing the production of CCL5. (Items 2-9) A composition according to any of the above items for improving conjunctival goblet cell density. (Item 2-10) A composition according to any of the above items for improving the reduction of tear film breakdown time. (Item 2-11) A composition according to any of the above items for inhibiting or suppressing the production of CCL5 in corneal epithelial cells. (Item 2-12) A composition according to any of the above items, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. (Item 2-13) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Item 2-14) A composition described in any of the above items, in the form of eye drops. (Item 2-15) The composition according to any of the above items, wherein the subject is a human. (Item 2-16) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Item 2-17) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0007] (Item 3-1) A composition for treating and / or preventing eye diseases accompanied by increased CCL5 expression, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. (Item 3-2) The composition according to the item, wherein the eye disease accompanied by increased CCL5 expression is dry eye accompanied by increased CCL5 expression. (Item 3-3) The composition according to any of the above items, wherein the eye disease accompanied by increased CCL5 expression is dry eye associated with Sjögren's syndrome accompanied by increased CCL5 expression. (Items 3-4) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Items 3-5) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Items 3-6) A composition according to any of the above items for inhibiting or suppressing the production of CCL5. (Items 3-7) A composition according to any of the above items for improving conjunctival goblet cell density. (Items 3-8) A composition according to any of the above items for improving the reduction of tear film breakdown time. (Items 3-9) A composition according to any of the above items for inhibiting or suppressing the production of CCL5 in corneal epithelial cells. (Item 3-10) A composition according to any of the above items, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. (Item 3-11) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Item 3-12) A composition described in any of the above items, in the form of eye drops. (Item 3-13) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. [Item 3-14] The composition according to any one of the preceding items, wherein said (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.

[0008] [Item 4-1] A composition for inhibiting or suppressing the production of CXCL10, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. [Item 4-2] An ophthalmic composition for inhibiting or suppressing the production of CXCL10, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. [Item 4-3] The composition according to any one of the preceding items, for inhibiting or suppressing the production of CXCL10 in corneal epithelial cells. [Item 4-4] The composition according to any one of the preceding items, for treating and / or preventing a disease characterized by an increased level of CXCL10. [Item 4-5] The composition according to any one of the preceding items, for treating and / or preventing dry eye. [Item 4-6] The composition according to any one of the preceding items, wherein said dry eye is dry eye accompanied by increased CXCL10 expression. [Item 4-7] The composition according to any one of the preceding items, wherein said dry eye is dry eye with decreased tear secretion. [Item 4-8] The composition according to any one of the preceding items, wherein said dry eye is evaporative dry eye with increased evaporation. [Item 4-9] The composition according to any one of the preceding items, wherein said dry eye is dry eye associated with meibomian gland dysfunction. (Items 4-10) A composition according to any of the above items for improving meibomian gland function in dry eye. (Item 4-11) A composition according to any of the above items for improving the reduction of tear film breakup time in dry eye. (Item 4-12) A composition according to any of the above items, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. (Item 4-13) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Item 4-14) A composition described in any of the above items, in the form of eye drops. (Item 4-15) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Item 4-16) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0009] (Item 5-1) A composition for treating and / or preventing an eye disease, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to be administered to subjects whose tear fluid CXCL10 volume is increased compared to healthy individuals without eye disease. (Item 5-2) The composition according to the above item, wherein the subject whose tear fluid CXCL10 volume is increased compared to a healthy person without the aforementioned eye disease is a patient with dry eye. (Item 5-3) The composition according to any of the above items, wherein the subject whose tear fluid CXCL10 volume is increased compared to a healthy person without the above eye disease is a patient with dry eye due to meibomian gland dysfunction. (Item 5-4) A composition according to any of the above items for treating and / or preventing dry eye. (Item 5-5) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Items 5-6) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Items 5-7) The composition according to any of the above items, wherein the dry eye is dry eye due to meibomian gland dysfunction. (Items 5-8) A composition according to any of the above items for inhibiting or suppressing the production of CXCL10. (Items 5-9) A composition according to any of the above items for improving meibomian gland function. (Items 5-10) A composition according to any of the above items for improving the reduction of tear film breakdown time. (Items 5-11) A composition according to any of the above items for inhibiting or suppressing the production of CXCL10 in corneal epithelial cells. (Items 5-12) A composition according to any of the above items, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. (Item 5-13) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Item 5-14) A composition described in any of the above items, in the form of eye drops. (Item 5-15) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Item 5-16) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0010] (Item 6-1) A composition for treating and / or preventing ocular diseases accompanied by increased CXCL10 expression, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. (Item 6-2) The composition according to the item, wherein the eye disease accompanied by increased CXCL10 expression is dry eye accompanied by increased CXCL10 expression. (Item 6-3) The composition according to any of the above items, wherein the ocular disease accompanied by increased CXCL10 expression is dry eye due to meibomian gland dysfunction accompanied by increased CXCL10 expression. (Item 6-4) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Item 6-5) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Item 6-6) A composition according to any of the above items for inhibiting or suppressing the production of CXCL10. (Items 6-7) A composition according to any of the above items for improving meibomian gland function. (Items 6-8) A composition according to any of the above items for improving the reduction of tear film breakdown time. (Items 6-9) A composition according to any of the above items for inhibiting or suppressing the production of CXCL10 in corneal epithelial cells. (Items 6-10) A composition according to any of the above items, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. (Items 6-11) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Items 6-12) A composition according to any of the above items, in the form of eye drops. (Item 6-13) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Item 6-14) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0011] (Item 7-1) A method for treating and / or preventing an eye disease accompanied by increased CCL5 expression, comprising administering a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment and / or prevention. (Item 7-2) A method for treating and / or preventing an eye disease accompanied by increased CCL5 expression, comprising administering a therapeutically effective amount of a CCL5 production inhibitor or CCL5 production suppressant to a subject in need of treatment and / or prevention, wherein the CCL5 production inhibitor or CCL5 production suppressant comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. (Item 7-3) The method according to any of the above items, wherein the subject has an increased amount of CCL5 in the tear fluid compared to a healthy person without eye disease.

[0012] (Item 8-1) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for the treatment and / or prevention of eye diseases associated with increased CCL5 expression. (Item 8-2) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment and / or prevention of eye disease in subjects with increased CCL5 levels in tears compared to healthy individuals without eye disease. (Item 8-3) Use of a CCL5 production inhibitor or CCL5 production suppressant in the manufacture of a medicament for the treatment and / or prevention of an eye disease accompanied by increased CCL5 expression, wherein the CCL5 production inhibitor or CCL5 production suppressant comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0013] (Item 9-1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of ocular diseases associated with increased CCL5 expression. (Item 9-2) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of eye disease in subjects with increased CCL5 levels in tears compared to healthy individuals without eye disease. (Item 9-3) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, CCL5 production inhibitor or CCL5 production suppressant for use in the treatment and / or prevention of ocular diseases accompanied by increased CCL5 expression.

[0014] (Item 10-1) A method for treating and / or preventing an ocular disease associated with increased CXCL10 expression, comprising administering a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment and / or prevention. (Item 10-2) A method for treating and / or preventing an ocular disease accompanied by increased CXCL10 expression, comprising administering a therapeutically effective amount of a CXCL10 production inhibitor or CXCL10 production suppressant to a subject in need of treatment and / or prevention, wherein the CXCL10 production inhibitor or CXCL10 production suppressant comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. (Item 10-3) The method according to any of the above items, wherein the subject has an increased amount of CXCL10 in the tear fluid compared to a healthy person without an eye disease.

[0015] (Item 11-1) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for the treatment and / or prevention of ocular diseases associated with increased CXCL10 expression. (Item 11-2) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for the treatment and / or prevention of eye disease in subjects with increased CXCL10 levels in their tears compared to healthy individuals without eye disease. (Item 11-3) Use of a CXCL10 production inhibitor or CXCL10 production suppressant in the manufacture of a medicament for the treatment and / or prevention of an eye disease accompanied by increased CXCL10 expression, wherein the CXCL10 production inhibitor or CXCL10 production suppressant comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0016] (Item 12-1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of ocular diseases associated with increased CXCL10 expression. (Item 12-2) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of ocular diseases in subjects with increased CXCL10 levels in tears compared to healthy individuals without ocular diseases. (Item 12-3) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising a CXCL10 production inhibitor or CXCL10 production suppressor for use in the treatment and / or prevention of ocular diseases accompanied by increased CXCL10 expression.

[0017] (Item 13-1) A composition for treating and / or preventing dry eye associated with Sjögren's syndrome, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. (Item 13-2) The composition according to any of the above items, wherein the dry eye is dry eye accompanied by increased CCL5 expression. (Item 13-3) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Item 13-4) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Item 13-5) The composition according to any of the above items, wherein the treatment and / or prevention of dry eye associated with Sjögren's syndrome is improvement of conjunctival goblet cell density. (Item 13-6) The composition according to any of the above items, wherein the treatment and / or prevention of dry eye associated with Sjögren's syndrome is an improvement in shortening of tear film breakup time. (Item 13-7) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Item 13-8) A composition according to any of the above items, in the form of eye drops. (Item 13-9) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Item 13-10) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0018] (Item 14-1) A method for treating and / or preventing dry eye associated with Sjögren's syndrome, comprising administering a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment and / or prevention.

[0019] (Item 15-1) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for the treatment and / or prevention of dry eye associated with Sjögren's syndrome.

[0020] (Item 16-1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of dry eye associated with Sjögren's syndrome.

[0021] (Item 17-1) A composition for treating and / or preventing dry eye associated with meibomian gland dysfunction, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient. (Item 17-2) The composition according to any of the above items, wherein the dry eye is dry eye accompanied by increased CXCL10 expression. (Item 17-3) The composition according to any of the above items, wherein the dry eye is of the type of dry eye characterized by reduced tear secretion. (Item 17-4) The composition according to any of the above items, wherein the dry eye is of the evaporative dry eye type. (Item 17-5) The composition according to any of the above items, wherein the treatment and / or prevention of dry eye associated with meibomian gland dysfunction is improvement of meibomian gland function. (Item 17-6) The composition according to any of the above items, wherein the treatment and / or prevention of dry eye associated with meibomian gland dysfunction is an improvement in shortening of tear film breakup time. (Item 17-7) The composition according to any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%. (Item 17-8) A composition described in any of the above items, in the form of eye drops. (Item 17-9) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. (Item 17-10) The composition according to any of the above items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0022] (Item 18-1) A method for treating and / or preventing dry eye associated with meibomian gland dysfunction, comprising administering a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment and / or prevention.

[0023] (Item 19-1) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical product for the treatment and / or prevention of dry eye associated with meibomian gland dysfunction.

[0024] (Item 20-1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of dry eye associated with meibomian gland dysfunction. [Effects of the Invention]

[0025] The present disclosure provides means for treating and / or preventing diseases characterized by elevated CCL5 and / or CXCL10 levels, particularly ocular diseases accompanied by increased CCL5 and / or CXCL10 expression, preferably means for treating and / or preventing dry eye. More preferably, inhibition or suppression of CCL5 and / or CXCL10 production can lead to improved tear film breakup time, improved conjunctival goblet cell density, and improved meibomian gland function in dry eye. [Brief explanation of the drawing]

[0026] [Figure 1] This figure shows the inhibitory effect of compound (1) on CCL5 expression. Hyperosmotic stimulation with sucrose significantly increased CCL5 levels (Figure 1 left: mRNA expression level, Figure 1 right: protein concentration) in human corneal epithelial cells. On the other hand, 0.1 μM, 1 μM, or 10 μM of compound (1) inhibited CCL5 mRNA expression (Figure 1 left) in a concentration-dependent manner compared to the control (DMSO). Furthermore, 1 μM or 10 μM of compound (1) inhibited CCL5 protein production (Figure 1 right) in a concentration-dependent manner compared to the control (DMSO). [Figure 2]This figure shows the inhibitory effect of compound (1) on CXCL10 expression. Hyperosmotic stimulation with sucrose significantly increased CXCL10 mRNA expression in human corneal epithelial cells. On the other hand, 1 μM or 10 μM of compound (1) suppressed CXCL10 mRNA expression in a concentration-dependent manner compared to the control (DMSO). [Figure 3-1] Figure 3-1 shows the changes in tear film breakup time (BUT) in the largest analysis group (FAS). At all evaluation time points (Day 1, Day 8, Day 15, Day 29, and Day 57), the group administered 0.3 w / v% compound (1) eye drops showed a tendency to show a greater improvement in reducing tear film breakup time in dry eye patients compared to the placebo group. [Figure 3-2] Figure 3-2 shows the changes in tear film breakup time (BUT) in a subgroup with meibomian gland dysfunction. At all evaluation time points (Day 1, Day 8, Day 15, Day 29, and Day 57), the group administered 0.3 w / v% compound (1) eye drops showed a tendency to show a greater improvement in reducing tear film breakup time compared to the placebo group in patients with dry eye and meibomian gland dysfunction. [Modes for carrying out the invention]

[0027] Embodiments of this disclosure will be described in detail. However, this disclosure should not be understood to be limited to the following embodiments.

[0028] The following describes this disclosure. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Thus, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Thus, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail. In this specification, "about" means ±10% of the following value. In this specification, times are expressed in 24-hour format unless otherwise specified.

[0029] In this specification, “Subject” means the subject to which the compositions, compounds, inhibitors, suppressants, pharmaceuticals or methods of this disclosure are applied, and includes mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs, cattle, horses, sheep, monkeys, etc.), but primates are preferred, and humans are particularly preferred. “Subject” includes “patients.”

[0030] In this specification, "or" is used when "at least one" of the items listed in the text can be adopted. The same applies to "or else" and "alternatively." In this specification, when it is specified that "within the range" of "two values," that range includes the two values ​​themselves.

[0031] In this specification, “treatment” means the cure, improvement, suppression, or alleviation of a disease or symptom.

[0032] In this specification, "prevention" means preventing the onset of a disease or symptom, and this concept also includes minimizing the onset of a disease or symptom by delaying its onset or by taking action before it develops.

[0033] A "therapeutic dose" is a sufficient amount that is effective in producing a beneficial or desirable therapeutic (including preventative) outcome.

[0034] In this specification, “pharmaceutically acceptable salt” means an inorganic or organic acid addition salt of the compound of this disclosure that is relatively nontoxic. These salts can be prepared temporarily during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid, and then isolating the salt thus formed.

[0035] In this specification, "solvate" refers to a solvate of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and includes, for example, solvates with organic solvents (e.g., solvates with alcohols (ethanol, etc.)), hydrates, etc. When forming a hydrate, it may be coordinated with any number of water molecules. Examples of hydrates include monohydrates, dihydrates, etc.

[0036] In this specification, “ophthalmic composition” means a composition intended for application to the eye, or to related or surrounding tissues such as the eyelid or cornea. The term also includes compositions intended for the therapeutic treatment of conditions of the eye itself or the tissues surrounding the eye.

[0037] In this specification, "diseases characterized by elevated CCL5 and / or CXCL10 levels" refers to diseases resulting from increased gene expression levels of CCL5 and / or CXCL10, or diseases resulting from increased protein concentrations of CCL5 and / or CXCL10. Such diseases include ocular diseases accompanied by increased CCL5 and / or CXCL10 expression, where, for example, the gene expression levels or protein concentrations of CCL5 and / or CXCL10 are higher in the ocular tissue of a patient with the disease than in the ocular tissue of a non-disease subject (e.g., a healthy individual). Examples of ocular diseases resulting from increased gene expression levels of CCL5 and / or CXCL10, or from increased protein concentrations of CCL5 and / or CXCL10, include dry eye. More specifically, examples of diseases characterized by elevated CCL5 levels include dry eye associated with Sjögren's syndrome, and examples of diseases characterized by elevated CXCL10 levels include dry eye associated with meibomian gland dysfunction.

[0038] In this specification, "Break-Up Time (BUT)" refers to the time from when the eye is opened without blinking until the tear film covering the cornea is destroyed. The tear film (also simply called "tears") consists of three layers from the surface: a lipid layer, a water layer, and a mucin layer. The lipid layer is mostly composed of secretions from the meibomian glands called meibum lipids (Ocul Surf. 2017 Jul;15(3):366-403). Tear film destruction includes thinning.

[0039] In this specification, "dry eye" refers to a disease diagnosed as "dry eye" according to clinical diagnostic criteria, and is defined as "a multifactorial disease of the tear film and ocular surface caused by various factors, accompanied by ocular discomfort, visual dysfunction, tear film instability, or ocular surface damage." The diagnosis of dry eye is typically made by observing a tear film breakup time (BUT) of 5 seconds or less using fluorescein staining, and the presence of subjective symptoms (ocular discomfort or visual dysfunction). In this specification, "reduced tear film breakup time" refers to one of the symptoms of dry eye, for example, a condition in which the tear film breakup time (BUT) measured by fluorescein staining is 5 seconds or less.

[0040] In this specification, "tear-reducing dry eye" refers to dry eye that develops due to tissue destruction of the lacrimal gland or impaired tear drainage from the lacrimal gland to the ocular surface, such as Sjögren's syndrome, aging, or graft-versus-host disease (GVHD), resulting in a decrease in tear volume.

[0041] In this specification, "evaporative dry eye" refers to dry eye caused by a decrease in the function of the lipid layer of the tear film, resulting from endogenous causes such as meibomian gland dysfunction (MGD) and eyelid abnormalities such as lagophthalmos, or extrinsic causes such as vitamin A deficiency, preservatives (contained in eye drops), contact lens wear, and allergic conjunctivitis.

[0042] In this specification, "improving the reduction of tear film breakup time" means "not reducing (maintaining) the tear film breakup time," "suppressing the reduction of tear film breakup time," and "extending or increasing the tear film breakup time." "Improving the reduction of tear film breakup time" means that the effect is improved after application compared to before application of the composition, compound, inhibitor, suppressant, pharmaceutical, or method of this disclosure to a particular subject.

[0043] In this specification, "improving conjunctival goblet cell density" means "not decreasing (maintaining) conjunctival goblet cell density," "suppressing the decrease in conjunctival goblet cell density," and "increasing conjunctival goblet cell density."

[0044] "Improving meibomian gland function" means "preventing deterioration (maintaining)," "suppressing deterioration," or "partially or completely normalizing or restoring" meibomian gland function. For example, meibomian gland function can be evaluated based on the MGE score regarding meibomian gland pressure function, the MQ score regarding meibomian gland quality, the lid margin score regarding blepharitis symptoms, and the Meibograde regarding the percentage of meibomian gland defects (Dis Markers. 2022 Nov 23;2022:4259067).

[0045] In this specification, "amount of CCL5 in tears" and "amount of CXCL10 in tears" refer to "the amount of CCL5 gene expression and / or the concentration of CCL5 protein in tears" and "the amount of CXCL10 gene expression and / or the concentration of CXCL10 protein in tears," respectively.

[0046] In this specification, "inhibition" or "suppression" of a phenomenon means reducing or eliminating that phenomenon occurring in a living organism. "Inhibition" or "suppression" may be achieved in a manner in which the inhibitory effect is realized by a specific substance competing with molecules (ligands, substrates, etc.) with which it is to interact (i.e., "antagonism").

[0047] In this specification, "inhibiting or suppressing CCL5 production" means reducing the amount of CCL5 by inhibiting or suppressing CCL5 production. More specifically, it means reducing the gene expression level of CCL5 and the protein concentration of CCL5 by inhibiting or suppressing CCL5 production. "Reducing the amount of CCL5" by inhibiting or suppressing CCL5 production includes "reducing the increase in the amount of CCL5," "preventing an increase in the amount of CCL5 (maintaining it)," and "decreasing the amount of CCL5."

[0048] In this specification, "inhibiting or suppressing CXCL10 production" means reducing the amount of CXCL10 by inhibiting or suppressing the production of CXCL10. More specifically, it means reducing the gene expression level of CXCL10 and the protein concentration of CXCL10 by inhibiting or suppressing the production of CXCL10. "Reducing the amount of CXCL10" by inhibiting or suppressing the production of CXCL10 includes "reducing the increase in the amount of CXCL10," "preventing an increase in the amount of CXCL10 (maintaining it)," and "decreasing the amount of CXCL10."

[0049] In this specification, "CCL5 production inhibitor" and "CXCL10 production inhibitor" refer to agents used to inhibit "CCL5 production" and "CXCL10 production," respectively.

[0050] In this specification, "CCL5 production inhibitor" and "CXCL10 production inhibitor" refer to agents used to suppress "CCL5 production" and "CXCL10 production," respectively.

[0051] In this specification, “kit” refers to a unit in which the parts to be provided (e.g., therapeutic drugs, preventive drugs, their respective components, instructions, etc.) are provided, usually divided into two or more compartments.

[0052] In this specification, “Instructions” means instructions given to a physician or other user on how to use the Disclosure.

[0053] (compound) In this disclosure, compositions comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or pharmaceutically acceptable salts or solvates thereof, or methods of using them may be provided. (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide includes the R-isomer (CAS. No. 920332-28-1), the S-isomer (CAS. No. 920332-29-2), or the racemic mixture (CAS. No. 920332-27-0), but more preferably is the R-isomer ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide (also referred to as compound (1) in this disclosure)).

[0054] The pharmaceutically acceptable salts of the compounds disclosed herein are not particularly limited as long as they are pharmaceutically acceptable, but specifically include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, and mandelic acid; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid; and aliphatic tricarboxylic acids such as citric acid. Examples include organic carboxylic acids; aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid; aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; acid addition salts with acidic amino acids such as aspartic acid and glutamic acid; salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium; salts with organic bases such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, and ornithine; and ammonium salts.

[0055] These salts can be obtained by conventional methods, for example, by mixing an equivalent amount of the compounds of this disclosure with a solution containing a desired acid or base, and then filtering out the desired salt or by distilling off the solvent. Furthermore, the compounds of this disclosure or their salts can form solvates with solvents such as water, ethanol, and glycerol.

[0056] The R-isomer (compound (1)), S-isomer, or racemic mixture of ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is described in International Publication 2007 / 010383, Japanese Patent No. 4754566, Japanese Patent No. 6230743, and International Publication 2018 / 221543, Japanese Patent No. 6830569, International Publication 2021 / 038889, and International Publication 2021 / 039023. The R-isomer (compound (1)), S-isomer, or racemic mixture can be produced by the manufacturing methods described in said publications. The contents of said publications are incorporated herein by reference in their entirety.

[0057] Examples of the present disclosure show that (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof can be newly used as a "CCL5 production inhibitor or CCL5 production suppressor" or a "CXCL10 production inhibitor or CXCL10 production suppressor." The present disclosure provides "CCL5 production inhibitors or CCL5 production suppressors" and "CXCL10 production inhibitors or CXCL10 production suppressors" comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof. (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide has CCL5 production inhibitory activity or suppressive activity, and CXCL10 production inhibitory activity or suppressive activity, and therefore, as detailed elsewhere herein, it may be expected to have therapeutic and / or preventive effects on diseases characterized by elevated CCL5 and / or CXCL10 levels, particularly on ocular diseases accompanied by increased CCL5 and / or CXCL10 expression.

[0058] (Target diseases) Diseases characterized by elevated CCL5 and / or CXCL10 levels include ocular diseases, including dry eye.

[0059] (Dry eyes) This disclosure may provide compositions, compounds, inhibitors, suppressants, pharmaceuticals, or methods for treating and / or preventing dry eye. This disclosure shows that (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide (which may be a pharmaceutically acceptable salt or solvate thereof) may be used for the treatment of dry eye. In another embodiment, this disclosure shows that "CCL5 production inhibitors or suppressants" and "CXCL10 production inhibitors or suppressants" may be used for the treatment and / or prevention of dry eye. Treatment and / or prevention of dry eye with the compositions of this disclosure may include, but are not limited to, improvement of tear film breakup time, improvement of conjunctival goblet cell density, or improvement of meibomian gland function.

[0060] (Types of dry eye) Dry eye can be classified in several ways, but it is mainly divided into "tear secretion-reduced type" and "evaporative type." "Tear secretion-reduced type" is also called "tear reduction type" or "decreased tear secretion type." "Tear secretion-reduced type dry eye" is dry eye that develops due to tissue destruction of the lacrimal gland or impaired tear drainage from the lacrimal gland to the ocular surface due to Sjögren's syndrome, aging, or graft-versus-host disease (GVHD), resulting in a decrease in tear volume. "Evaporative type dry eye" is dry eye that develops due to a decrease in the function of the lipid layer of the tear film, caused by intrinsic factors such as meibomian gland dysfunction (MGD) and eyelid abnormalities such as lagophthalmos, or extrinsic factors such as vitamin A deficiency, preservatives (contained in eye drops), contact lens wear, and allergic conjunctivitis (Japanese Journal of Ophthalmology, Vol. 123, No. 5, 2019 Dry Eye Treatment Guidelines). The compositions, compounds, inhibitors, suppressants, pharmaceuticals, or methods of this disclosure are not particularly limited, but can be used to treat and / or prevent either "tear-reducing" or "evaporative" dry eye.

[0061] (BUT (Block Breakdown Time), Conjunctival Goblet Cell Density) The break-up time (BUT) is a well-known indicator of tear film stability. In particular, fluorescein BUT, measured using fluorescein staining solution, is widely used clinically. In dry eye, the break-up time (BUT) is reduced (shortened), and as mentioned earlier, the diagnosis of dry eye is typically made by observing that the break-up time (BUT) measured by fluorescein staining is 5 seconds or less, and that the patient has subjective symptoms (eye discomfort or visual dysfunction). One example of a method for measuring fluorescein BUT is to stain the lower eyelid margin of the subject by touching a fluorescein test strip with a certain amount of water to it. The subject is then allowed to blink naturally and keep their eyelids closed for a certain period of time, after which they are asked to keep their eyelids open. The point at which the eyelids open is taken as the start of the BUT measurement, and the time until the appearance of a dark spot (an area with reduced fluorescence intensity), which is an indicator of thinning of the tear film, is measured using a stopwatch or similar device while observing with a slit-lamp microscope ("Ophthalmic Examination Guide," 2nd edition, September 28, 2016, Bunko-do Co., Ltd.). Conjunctival goblet cells produce mucin, a viscous substance, and contribute to the stabilization of the tear film. It is believed that a decrease in conjunctival goblet cell density leads to a decrease in mucin secretion, which in turn reduces the stability of the tear film and worsens the symptoms of dry eye.

[0062] CCL5 is known to correlate with tear film and ocular surface parameters. It has been reported that CCL5 levels are increased in the tear film and ocular surface of dry eye patients compared to healthy individuals, and that this increase is particularly pronounced in dry eye patients with Sjögren's syndrome compared to those without Sjögren's syndrome. Furthermore, increased CCL5 levels are statistically significantly correlated with reduced tear film breakup time and decreased conjunctival goblet cell density (Curr Eye Res. 2012 Jan;37(1):12-7).

[0063] The compositions, compounds, inhibitors, suppressants, pharmaceuticals, or methods of this disclosure may provide therapeutic effects by inhibiting or suppressing the production of CCL5, thereby improving the reduction of tear film breakup time and the reduction of conjunctival goblet cell density.

[0064] (Meibomian gland dysfunction) In meibomian gland dysfunction (MGD), the function of the meibomian glands becomes abnormal due to various causes, leading to a decrease in the function of the lipid layer of the tear film and causing dry eye accompanied by chronic eye discomfort. In this disclosure, meibomian gland function can be evaluated based, for example, on the MGE score for meibomian gland pressure function, the MQ score for meibomian gland quality, the lid margin score for blepharitis symptoms, and the Meibograde for the percentage of meibomian gland defects (Dis Markers. 2022 Nov 23;2022:4259067).

[0065] The compositions, compounds, inhibitors, suppressants, pharmaceuticals, or methods of this disclosure may provide a therapeutic effect of improving meibomian gland function, and consequently, may improve the reduction of tear film breakup time in dry eye associated with meibomian gland dysfunction.

[0066] CXCL10 levels were shown to be increased in meibomian gland dysfunction patients with higher MQ scores (lower quality meibomian glands) than in patients with lower MQ scores (higher quality meibomian glands), and a significant correlation between CXCL10 in meibomian glands and meibomian gland function has been reported (Dis Markers. 2022 Nov 23;2022:4259067). Furthermore, CXCL10 in meibum strongly affects tear film stability, and it has been reported that the higher the concentration of CXCL10 in meibum, the shorter the fluorescein BUT (Dis Markers. 2022 Nov 23;2022:4259067).

[0067] The compositions, compounds, inhibitors, suppressants, pharmaceuticals, or methods of this disclosure may provide therapeutic effects such as improving the shortening of tear film breakup time and improving meibomian gland function by inhibiting or suppressing the production of CXCL10.

[0068] (Improvement in reducing tear film breakup time) In one embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving the reduction of tear film breakup time in dry eye. In another embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving the reduction of tear film breakup time in dry eye associated with Sjögren's syndrome. In yet another embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving the reduction of tear film breakup time in dry eye associated with meibomian gland dysfunction.

[0069] (Improvement of conjunctival goblet cell density) In one embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving conjunctival goblet cell density in dry eye. In another embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving conjunctival goblet cell density in dry eye associated with Sjögren's syndrome.

[0070] (Improvement of meibomian gland function) In one embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving meibomian gland function in dry eye. In another embodiment, the compositions, compounds, inhibitors, inhibitors, pharmaceuticals, or methods of the present disclosure may be for improving meibomian gland function in dry eye associated with meibomian gland dysfunction.

[0071] (CCL5 production inhibitors or CCL5 production suppressants) A CCL5 production inhibitor or CCL5 production suppressant provided as one embodiment of the present disclosure can inhibit or suppress CCL5 production to reduce the amount of CCL5. More specifically, it can inhibit or suppress CCL5 production to reduce the gene expression level of CCL5 and the protein concentration of CCL5. The target tissue is not particularly limited, but preferably ocular tissue, more preferably corneal epithelial cells.

[0072] (CXCL10 production inhibitors or CXCL10 production suppressants) A CXCL10 production inhibitor or CXCL10 production suppressant provided as one embodiment of this disclosure can inhibit or suppress the production of CXCL10 and reduce the amount of CXCL10. More specifically, it can inhibit or suppress the production of CXCL10 and reduce the gene expression level of CXCL10 and the protein concentration of CXCL10. The target tissue is not particularly limited, but preferably ocular tissue, more preferably corneal epithelial cells.

[0073] The compositions, compounds, inhibitors, suppressants, or pharmaceuticals of this disclosure are not limited to administration to specific subjects, but can be administered to subjects in whom the amount of CCL5 and / or CXCL10 in the tear fluid is increased compared to healthy individuals without eye diseases, and can preferably be administered to patients with dry eye. Examples of dry eye include dry eye with increased CCL5 and / or CXCL10 expression, dry eye with reduced tear secretion, dry eye with increased evaporation, dry eye associated with Sjögren's syndrome, and dry eye associated with meibomian gland dysfunction.

[0074] The compositions, compounds, inhibitors, suppressants, or pharmaceuticals of this disclosure are not particularly limited, but can be administered for several days without safety concerns, for example, from 1 to 56 days. The compositions, compounds, inhibitors, suppressants, or pharmaceuticals of this disclosure do not show any decrease in effectiveness even when used continuously for a certain period of time, and can sustainably improve the shortening of the tear film breakup time (BUT) in dry eye.

[0075] By administering the compositions, compounds, inhibitors, suppressants, or pharmaceuticals of this disclosure, the tear film breakup time (BUT) in dry eye can be extended compared to before administration, preferably by 1 second, more preferably by 2 seconds.

[0076] (Dosage form) The compositions of this disclosure can be formulated into appropriate dosage forms. For example, if the compositions of this disclosure are ophthalmic compositions, they may be provided as ophthalmic injections, ophthalmic ointments, eye drops, or ophthalmic irrigation solutions. The compositions can be formulated into any dosage form, such as aerosols, liquids, extracts, elixirs, capsules, granules, pills, ointments, powders, tablets, solutions, suspensions, emulsions, etc.

[0077] For example, an ophthalmic composition may be provided in the form of a suspension in which the active ingredient is suspended in an aqueous solvent (e.g., phosphate-buffered saline), or in the form of a dissolved solution. The ophthalmic composition of this disclosure may be an eye drop. The composition of this disclosure may be a suspension.

[0078] The compositions of this disclosure can be administered by any suitable route determined by those skilled in the art, and may be formulated to be suitable for administration by routes of administration selected from, but not limited to, ocular injection, topical application (including application to the eyes), eye drops, intravenous injection, intravenous drip infusion, oral administration, parenteral administration, transdermal administration, etc.

[0079] (Additives and / or excipients) The composition may contain a pharmaceutically acceptable carrier. Such a “pharmaceutically acceptable carrier” may be any pharmaceutically acceptable additive and / or excipient known in the art. Examples of additives include, but are not limited to, stabilizers, pH adjusters, buffers, preservatives, and surfactants.

[0080] Examples of stabilizers include sodium bisulfite, and their content is preferably 0 to about 1 w / v% relative to the total amount of the composition.

[0081] Examples of pH adjusting agents include acids such as carbonic acid, acetic acid, and citric acid, as well as bases such as alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, alkali metal acetates such as sodium acetate, and alkali metal citrates such as sodium citrate. The content of these agents is, for example, 0 to about 20 w / v% of the total amount of the composition.

[0082] Examples of preservatives include sorbic acid, potassium sorbate, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate, quaternary ammonium salts such as chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkyl polyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine. The amount of each preservative can be appropriately varied depending on the type, but for example, 0 to about 0.2 w / v% of the total amount of the composition is typical.

[0083] The surfactant is not particularly limited, but examples include nonionic surfactants, anionic surfactants, or cationic surfactants. Nonionic surfactants are preferred from the viewpoint of lower toxicity. Nonionic surfactants are not particularly limited, but examples include polyoxyethylene (40) monostearate (polyoxyl 40 stearate), sorbitan sesquioleate (sorbitan sesquioleate), or polyoxyethylene (20) sorbitan monooleate (polysorbate 80).

[0084] Anionic surfactants are not particularly limited, but examples include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, and α-olefin sulfonic acids.

[0085] Cationic surfactants are not particularly limited, but examples include benzalkonium chloride and benzethonium chloride. The surfactant content is not particularly limited, but is, for example, 0 to about 1.0 w / v% of the total amount of the composition.

[0086] When preparing eye drops, for example, the desired components can be dissolved or suspended in an aqueous solvent such as sterile purified water, physiological saline, or buffer solution (e.g., phosphate buffer, citrate buffer, or acetate buffer), or in a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, adjusted to a predetermined osmotic pressure, and then sterilized by methods such as filtration sterilization. When a suspension is used, a surfactant may be included. Furthermore, when preparing an eye ointment, an ointment base may be included in addition to the various components mentioned above. The ointment base is not particularly limited, but examples include oily bases such as petrolatum, liquid paraffin, and polyethylene; and water-soluble bases such as emulsion bases obtained by emulsifying an oil phase and an aqueous phase with a surfactant.

[0087] The compositions or pharmaceuticals of this disclosure may be provided as therapeutic or prophylactic kits. In certain embodiments, the disclosure provides a drug pack or kit comprising one or more containers filled with one or more components of the compositions or pharmaceuticals of this disclosure. Optionally, such containers may also include information indicating authorization by a government agency for manufacture, use, or sale for human administration, in a form prescribed by the government agency regulating the manufacture, use, or sale of pharmaceutical or biological products.

[0088] (kit) In this specification, "kit" is used to provide a composition that, for stability or other reasons, should not be provided mixed, but is preferably mixed immediately before use. Such a kit is preferably provided with instructions or a manual describing how to use the provided parts (e.g., therapeutic drugs, prophylactic drugs) or how to handle the reagents. When a kit is used as a reagent kit in this specification, the kit usually includes instructions describing how to use the therapeutic drug, prophylactic drug, etc.

[0089] (Instructions) In this specification, “Instructions” include, but are not limited to, wording that instructs the administration of, for example, the detection method, the use of the diagnostic agent, or a drug, etc., disclosed herein. The instructions may also include wording that instructs the administration site to be the eye (e.g., by eye drops, eye ointment, or injection). The instructions shall be prepared in accordance with the format prescribed by the supervisory authority of the country in which this disclosure is implemented (e.g., the Ministry of Health, Labour and Welfare in Japan, the Food and Drug Administration (FDA) in the United States, etc.) and shall clearly state that they have been approved by that supervisory authority. The instructions are a so-called package insert or label and are usually provided in paper format, but are not limited to that and may also be provided in electronic format (e.g., a homepage provided on the Internet, email, etc.).

[0090] (Description in the attached document) In light of the information based on the trials provided in this disclosure, the instructions, such as the package insert (or label in the U.S., etc.), may include information on efficacy and effects (which may include the characteristics of the target patients or target diseases, disorders, or symptoms), method of administration, dosage, and precautions for use.

[0091] (Route of administration) In one embodiment, an example of use of the present disclosure is eye drops, but is not limited thereto. Other forms of administration (methods of administration and dosage forms) include eye ointments, intra-anterior chamber injections, impregnation into sustained-release formulations, subconjunctival injections, and systemic administration (oral administration, intravenous injection).

[0092] (dose) The concentration of the compounds disclosed herein is not particularly limited, but is typically about 0.1 to about 100,000 μM (μmol / L). From the viewpoint of lower toxicity and greater efficacy, it is preferably about 0.5 to about 80,000 μM, more preferably about 5 to about 80,000 μM, even more preferably about 50 to about 75,000 μM, particularly preferably about 500 to about 70,000 μM, even more preferably about 2,000 to about 50,000 μM, and most preferably about 5,000 to about 30,000 μM. Other concentration ranges include, for example, typically approximately 0.1 to 1 μM, 1 to 10 μM, 10 to 100 μM, 100 to 1000 μM, 1000 to 2000 μM, 2000 to 4000 μM, 4000 to 7000 μM, 7000 to 10000 μM, 10000 to 12000 μM, 12000 to 15000 μM, and 15000 to 2 Examples of acceptable upper and lower limits include 0000 μM, approximately 20000 to 22000 μM, approximately 22000 to 25000 μM, approximately 25000 to 30000 μM, approximately 30000 to 40000 μM, approximately 40000 to 50000 μM, approximately 50000 to 70000 μM, approximately 70000 to 85000 μM, or approximately 85000 to 100000 μM, but are not limited to these. These upper and lower limits can be set in appropriate combinations.

[0093] The concentration of the compounds disclosed herein is not particularly limited, but ranges from about 0.00001 to about 5.0 w / v%. From the viewpoint of lower toxicity and greater efficacy, a concentration of about 0.00003 to about 3.0 w / v% is preferred, and from the viewpoint of obtaining a more significant effect, the concentration of the compounds in the composition is about 0.0003 to about 3.0 w / v%, more preferably about 0.03 to about 3.0 w / v%, particularly preferably about 0.1 to about 1.0 w / v%, even more preferably about 0.3 to about 1.0 w / v%, and most preferably about 0.3 w / v%. The compounds disclosed herein may be effective at a wide range of concentrations. Other examples of concentrations of the compounds disclosed herein include approximately 0.00001 to approximately 0.0001 w / v%, approximately 0.0001 to approximately 0.001 w / v%, approximately 0.001 to approximately 0.01 w / v%, approximately 0.01 to approximately 0.02 w / v%, approximately 0.02 to approximately 0.05 w / v%, approximately 0.05 to approximately 0.1 w / v%, approximately 0.1 to approximately 0.2 w / v%, approximately 0.2 to approximately 0.3 w / v%, and approximately 0.3 to approximately 0.4 w / v%. Possible ranges include w / v%, approximately 0.4-0.5 w / v%, approximately 0.5-0.6 w / v%, approximately 0.6-0.7 w / v%, approximately 0.7-0.8 w / v%, approximately 0.8-0.9 w / v%, approximately 0.9-1 w / v%, approximately 1-1.1 w / v%, approximately 1.1-1.2 w / v%, approximately 1.2-1.3 w / v%, approximately 1.3-1.4 w / v%, approximately 1.4-1.5 w / v%, etc. These upper and lower limits can be set in appropriate combinations.

[0094] The concentration of the compound in the eye drops of this disclosure is not particularly limited, but can range from about 0.00001 to about 5.0 w / v%. From the viewpoint of lower toxicity and greater efficacy, the concentration of the compound in the eye drops can range from about 0.0003 to about 3.0 w / v%, more preferably about 0.03 to about 3.0 w / v%, particularly preferably about 0.1 to about 1.0 w / v%, even more preferably about 0.3 to about 1.0 w / v%, and most preferably about 0.3 w / v%. The compound in this disclosure may be effective at a wide range of concentrations. Other examples of concentrations of the compounds disclosed herein include approximately 0.00001 to approximately 0.0001 w / v%, approximately 0.0001 to approximately 0.001 w / v%, approximately 0.001 to approximately 0.01 w / v%, approximately 0.01 to approximately 0.02 w / v%, approximately 0.02 to approximately 0.05 w / v%, approximately 0.05 to approximately 0.1 w / v%, approximately 0.1 to approximately 0.2 w / v%, approximately 0.2 to approximately 0.3 w / v%, and approximately 0.3 to approximately 0.4 w / v%. Possible ranges include w / v%, approximately 0.4-0.5 w / v%, approximately 0.5-0.6 w / v%, approximately 0.6-0.7 w / v%, approximately 0.7-0.8 w / v%, approximately 0.8-0.9 w / v%, approximately 0.9-1 w / v%, approximately 1-1.1 w / v%, approximately 1.1-1.2 w / v%, approximately 1.2-1.3 w / v%, approximately 1.3-1.4 w / v%, approximately 1.4-1.5 w / v%, etc. These upper and lower limits can be set in appropriate combinations.

[0095] The effective dose of the medicament disclosed herein for the treatment of a specific disease, disorder, or condition may vary depending on the nature of the disorder or condition, but can be determined by standard clinical techniques based on the description herein for those skilled in the art. Furthermore, if necessary, in vitro assays may be used to assist in identifying the optimal dosage range. The exact dose to be used in the formulation may also vary depending on the route of administration and the severity of the disease or disorder, and should be determined according to the judgment of the attending physician and the circumstances of each patient. However, the dose is not particularly limited, and may be, for example, 0.001, 1, 5, 10, 15, 100, or 1000 mg / kg body weight per dose, or within the range of any two of these values.

[0096] (Dosage interval) The administration interval is not particularly limited, but it can be administered at general intervals, for example, 1 to 6 times per day. Preferably, it is 2 to 5 times per day, more preferably 2 to 4 times per day, and most preferably 4 times per day, from the viewpoint of obtaining a better effect and improving patient compliance. The dosage, number of administrations, administration interval, duration of administration, and method of administration may be appropriately selected depending on the patient's age, weight, symptoms, form of administration, target organ, etc. For example, the composition disclosed herein can be used as eye drops. Furthermore, it is preferable that the therapeutic agent contains a therapeutically effective amount or an effective amount of the active ingredient that exerts the desired effect.

[0097] (General technology) The molecular biological, biochemical, and microbiological methods used herein are well-known and commonly used in their respective fields, and refer to, for example, Sambrook J. et al. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor and its 3rd Ed. (2001); Ausubel, FM (1987). Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Ausubel, FM (1989). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Innis, MA (1990). PCR Protocols: A Guide to Methods and Applications, Academic Press; Ausubel, FM (1992). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, FM (1995). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Innis, MA et al. (1995). PCR Strategies, Academic Press; Ausubel, FM (1999).Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, JJet al.(1999).PCR Applications: Protocols for Functional Genomics, Academic Press, Gait, MJ(1985).Oligonucleotide Synthesis: A Practical Approach, IRL Press; Gait, MJ(1990).Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein, F. (1991).Oligonucleotides and Analogues: A Practical Approach, IRL Press; Adams, RL et al.(1992).The Biochemistry of the Nucleic Acids, Chapman & Hall; Shabarova, Z. et al.(1994).Advanced Organic Chemistry of Nucleic Acids, Weinheim; Blackburn, GM et al.(1996).Nucleic Acids in Chemistry and Biology, Oxford University This is described in publications such as Hermanson, GT(1996). Bioconjugate Techniques, Academic Press, and the special issue of Experimental Medicine, "Experimental Methods for Gene Transfer & Expression Analysis," Yodosha, 1997. Relevant parts (or all) of these are incorporated herein by reference.

[0098] References and accession numbers, such as scientific literature, patents, and patent applications, cited herein are incorporated herein by reference to the same extent as if they were specifically described herein. [Examples]

[0099] The present disclosure will be described in more detail below based on examples, but these examples are provided for illustrative purposes only and not to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to these examples.

[0100] (Test Example 1) Inhibitory effect of compound (1) on hyperosmotic stimulation-induced CCL5 and CXCL10 expression in human corneal epithelial cells (the purpose) High osmotic pressure in tears is known to be one of the causative mechanisms of dry eye, and human corneal epithelial cells cultured in hyperosmotic medium are used as an in vitro model of dry eye (Ocul Surf. 2022 Oct;26:234-243). Test Example 1 aims to confirm the effects of compound (1) on (i) the enhancement of CCL5 and CXCL10 expression induced by hyperosmotic stimulation, and (ii) the effect of compound (1) on hyperosmotic stimulation-induced CCL5 and CXCL10 expression, using this in vitro model of dry eye. (cell) Immortalized human corneal epithelial cells (HCE-T) (catalog number: RCB2280, Lot No. 006) obtained from the BioResource Center of the RIKEN (National Research and Development Agency) were used. (Test substance) Compound (1) was used as the test substance. Dimethyl sulfoxide (DMSO) (Nacalai Tesque Co., Ltd., Catalog No. 13408-64) was used as the negative control.

[0101] (Test method) (Specimen preparation) Compound (1) was dissolved in DMSO to achieve final concentrations of 0.1 mM, 1 mM, and 10 mM. (Preparation of culture medium) Complete culture media were prepared by adding Fetal Bovine Serum, certified, heat-inactivated, United States (Thermo Fisher Scientific, catalog number: 10082-147), Penicillin-Streptomycin Solution (100x) (Fujifilm Wako Pure Chemical Industries, catalog number: 168-23191), Insulin human recombinant (Fujifilm Wako Pure Chemical Industries, catalog number: 093-06471), and Human EGF (Thermo Fisher Scientific, catalog number: PHG0311) to DMEM / F-12 (Thermo Fisher Scientific, catalog number: 11330-032) to achieve final concentrations of 5%, 1x, 5 μg / mL, and 10 ng / mL, respectively. (Preparation of hyperosmolar medium) Sucrose (Fujifilm Wako Pure Chemical Industries, catalog number: 196-00015) was dissolved in complete medium to a final concentration of 230 mM to prepare a hyperosmolar medium. (Cell seeding and hyperosmolarity stimulation) HCE-T (7.5 x 10 4 Cells / mL, 2 mL / well of complete medium were seeded into a 6-well plate and incubated for 24 hours. After 24 hours, the medium was changed to complete medium containing DMSO (final concentration 0.1%) or compound (1) (final concentrations 0.1 μM, 1 μM, or 10 μM), and incubated for 2 hours. Subsequently, the medium was changed to hyperosmolar medium containing DMSO (final concentration 0.1%) or compound (1) (final concentrations 0.1 μM, 1 μM, or 10 μM), and incubated for 48 hours. Three replicas were prepared for each condition. (qPCR) Total RNA from cells cultured in hyperosmolar medium for 48 hours was purified using the RNeasy Mini Kit (QIAGEN, catalog number: 74104) and RNase-Free DNase (QIAGEN, catalog number: 79254). cDNA was synthesized using PrimeScript RT Master Mix (Takara, catalog number: RR036A). Quantitative real-time PCR was performed using the Applied Biosystems 7500 Real-Time PCR System (Thermo Fisher Scientific). The qPCR reaction mixture volume was 20 μL and included TB Green Premix Ex Taq II (Takara, catalog number: RR820A), ROX Reference Dye II (Takara, catalog number: RR820A), 100 ng cDNA, and primers (final concentration 0.2 μM) (Eurofins Genomics, catalog number: 12PP-001PPT). The relative gene expression levels of CCL5 and CXCL10 were calculated using the ΔΔCt method, with GAPDH used as an endogenous control. Each primer was constructed based on the nucleotide sequences of the following GenBank accession numbers: NM_002985.3 for CCL5, NM_001565.4 for CXCL10, and NM_002046.7 for GAPDH. The sequences of the primers used are listed in Table 1.

[0102] [Table 1] (ELISA) CCL5 levels in the culture supernatant after 48 hours of incubation in hyperosmolar medium were quantified using the Human CCL5 ELISA Kit (Proteintech, catalog number: KE00093).

[0103] (result) The results are shown in Figures 1 and 2. Hyperosmotic stimulation with sucrose significantly increased CCL5 expression levels (Figure 1 left: mRNA expression level, Figure 1 right: protein concentration) in human corneal epithelial cells (HCE-T). On the other hand, 0.1 μM, 1 μM, or 10 μM of compound (1) suppressed CCL5 mRNA expression (Figure 1 left) in a concentration-dependent manner compared to the control (DMSO). Furthermore, 1 μM or 10 μM of compound (1) suppressed CCL5 protein production (Figure 1 right) in a concentration-dependent manner compared to the control (DMSO). Hyperosmotic stimulation with sucrose significantly increased CXCL10 mRNA expression in human corneal epithelial cells (Figure 2). On the other hand, 1 μM or 10 μM of compound (1) suppressed CXCL10 mRNA expression in a concentration-dependent manner compared to the control (DMSO) (Figure 2). Therefore, compound (1) was shown to suppress the production of CCL5 and CXCL10 in a concentration-dependent manner in human corneal epithelial cells in response to hyperosmotic stimulation.

[0104] (Test Example 2) Study Example 2 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparative study involving patients with dry eye. This study aimed to verify the efficacy and safety of administering 0.3% of the proposed eye drop solution four times a day for 8 weeks (56 days) in patients with dry eye. Note that "the proposed eye drop solution" is a suspension eye drop solution containing compound (1) (the active ingredient of the proposed study), and "0.3% of the proposed eye drop solution" indicates that it contains the active ingredient (compound (1)) at a concentration of 0.3 w / v%. (1) The clinical trial method for this study is as follows: (1-1) Clinical trial schedule After obtaining informed consent, subjects underwent screening and were enrolled in the observation period. The screening and enrollment of subjects in the observation period were carried out according to the selection and exclusion criteria shown below. Enrolled subjects were administered one drop of the base of the eye drop solution of the present invention (hereinafter referred to as "placebo eye drop solution") to both eyes four times a day for two weeks as the investigational drug for the observation period (hereinafter referred to as the "observation period"). After the observation period, subjects were randomly assigned in a 1:1 ratio to either the placebo group (placebo eye drop solution administration group) or the eye drop solution group (eye drop solution administration group), and were administered one drop of the investigational drug for the treatment period (placebo eye drop solution or eye drop solution of the present invention) to each eye four times a day for eight weeks (56 days) (hereinafter referred to as the "treatment period"). (1-2) Investigational drug The composition of the "placebo eye drops," which is the control drug for the observational and therapeutic phases of the investigational drug, and the "present eye drops," which is the investigational drug for the therapeutic phase, are as follows. (i) Ophthalmic solution of the present invention Active ingredient: 3 mg (0.3 w / v%) of the active ingredient in this application per 1 mL Additives: Tyloxapol, methylcellulose, boric acid, zinc chloride, and borax Properties: Aqueous suspension eye drops pH: 7.2~7.7 Osmotic pressure ratio: Ratio to physiological saline: 0.9~1.1 (ii) Placebo eye drops Active ingredients: Not included Additives: Tyloxapol, methylcellulose, boric acid, zinc chloride, and borax Properties: Aqueous eye drops pH: 7.2~7.7 Osmotic pressure ratio: Ratio to physiological saline: 0.9~1.1

[0105] (1-3) Measurement items Prior to enrollment in the observation period, background factors of the subjects were investigated, including their sex, age, race, primary or related dry eye disease, presence or absence of prior dry eye medications, and prior dry eye medications (if present). Furthermore, tear film breakup time (BUT) was measured as one of the indicators for evaluating efficacy. Tear film breakup time (BUT) was measured on the screening test day, before administration of the investigational drug on the treatment initiation day (Day 1), before administration of the investigational drug on days 8 (Day 8), 15 (Day 15), and 29 (Day 29) of the treatment period, and on day 57 (Day 57) of the treatment period. Days 8 (Day 8), 15 (Day 15), 29 (Day 29), and 57 (Day 57) of the treatment period are referred to as evaluation days, with the treatment initiation day being Day 1 (Day 1), and the number of days for each evaluation day is indicated. The measurement taken before administration of the investigational drug on the treatment initiation day (Day 1) is referred to as the baseline.

[0106] (2) The main selection criteria for this clinical trial are as follows: (2-1) Items to be confirmed when obtaining consent: 1) After receiving a thorough explanation of the details of this clinical trial, written consent will be obtained from the subject of their own free will. 2) Outpatients who are 18 years of age or older on the date of obtaining consent (regardless of gender) 3) Residing in Japan 4) Having continuously experienced subjective symptoms related to dry eye in both eyes for more than 180 days prior to the date of obtaining consent. (2-2) Items to be confirmed on the screening test date and the start date of the treatment period: 1) Subjective symptoms of dry eye include a score of 1 or higher on one or more items of the Dry Eye Quality of Life Questionnaire (DEQS), a Visual Analog Scale (VAS) score of 40 or higher for eye dryness, and a total score of 6 or higher on the 5-Item Dry Eye Questionnaire (DEQ-5). 2) The average tear film breakup time (BUT) is 5 seconds or less in both eyes.

[0107] (3) The main exclusion criteria for this clinical trial are as follows: (3-1) Things to confirm on the day of the screening test: 1) Have you previously received eye drops containing the active ingredient of this eye drop solution in either eye? 2) You cannot discontinue wearing contact lenses (regardless of their intended use) from the start of the screening test until the end of the treatment period. 3) Within the past 365 days prior to the screening test date, you have a history of Intense Pulsed Light (IPL) or Thermal Pulsation (e.g., LipiFlow®) treatment in either eye, or you are scheduled to undergo such treatment during the period leading up to the completion of your treatment. (3-2) Items to be confirmed on the screening test date and the start date of the treatment period: 1) The patient has an active eye disease other than dry eye in either eye. 2) Having a disease that cannot be ruled out as influencing the subjective symptoms of dry eye (e.g., cataracts), excluding diseases that cause dry eye (e.g., Sjögren's syndrome or meibomian gland dysfunction, etc.). 3) Administration of dry eye treatment agents and corneal and conjunctival epithelial damage treatment agents cannot be discontinued from 28 days before the start of the treatment period until the end of the treatment period. 4) Except for diagnostic reagents used in ophthalmic examinations, all topical ophthalmic agents, including over-the-counter and prescription-only medications, cannot be discontinued from the start of the observation period. 5) In addition, the principal investigator (or co-investigator) determines that there are other obstacles to participation in the clinical trial.

[0108] (4) In this clinical trial, there were prohibitions or restrictions on concomitant medications and therapies. The main prohibitions and restrictions are as follows: (4-1) Concomitant medications From 28 days prior to the start of treatment until the end of treatment, the concomitant use of all topical ophthalmic agents (e.g., eye drops, eye ointments, intraocular injections, local administration to the skin around the eyelids, etc.), including over-the-counter and prescription-only drugs, was prohibited for both eyes, with the exception of dry eye treatment agents, corneal and conjunctival epithelial damage treatment agents, and diagnostic agents used for ophthalmic examinations. Furthermore, the concomitant use of drugs that affect tear production and secretion (including over-the-counter and prescription-only medications) was prohibited from the start of the observation period until the end of the treatment period. (4-2) Combination therapy From the screening examination date until the end of the treatment period, both eyes were prohibited from undergoing surgery on the eye or ocular adnexa, wearing contact lenses, insertion of punctal plugs, treatment for diseases affecting dry eye symptoms such as meibomian gland dysfunction, eye massage or warm compresses, and any other procedures that could damage the ocular surface or improve ocular symptoms.

[0109] (5) The testing methods for the items tested on the screening test date, the start date of the treatment period, and each evaluation point during the treatment period are as follows: (5-1) Evaluation using the Dry Eye Quality of Life Questionnaire (DEQS) Based on the Dry Eye-related Quality of Life Score (DEQS) questionnaire developed by the Dry Eye Research Society, participants were asked about the frequency and severity of each question on the DEQS. QOL scores were then calculated from the participants' responses (frequency and severity) according to the QOL score calculation method (Sakane Y, Yamaguchi M, Yokoi N, Uchino M, Dogru M, Oishi T, et al. Development and validation of the Dry Eye-Related Quality-of-Life Score questionnaire. JAMA Ophthalmol. 2013;131:1331-8.). (5-2) Evaluation of eye dryness using a Visual Analog Scale (VAS) The Visual Analog Scale (VAS) is used to evaluate a subject's condition at a point on a 100 mm line segment, where the leftmost point represents the best condition (0) and the rightmost point represents the worst condition (100). The distance from the leftmost point (mm) is the VAS value. Subjective symptoms related to dry eye, such as dryness of the eyes (i.e., the feeling of dryness in the eyes), were evaluated by subjects on a scale of 0 (not at all) to 100 (the highest degree they could imagine) (European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical development of medicinal products intended for the treatment of pain. (15 Dec 2016) EMA / CHMP / 970057 / 2011). (5-3) Evaluation using the 5-Item Dry Eye Questionnaire (DEQ-5) Participants were given a questionnaire regarding each question of the DEQ-5 (frequency and severity of eye discomfort, frequency and severity of dryness of the eyes, and frequency of seeing or feeling that their eyes were excessively watery), and the results were scored according to Chalmers RL, Begley CG, Caffery B. Validation of the 5-Item Dry Eye Questionnaire (DEQ-5): Discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses. Cont LensAnterior Eye. 2010;33:55-60. (5-4) Method for measuring tear film breakup time (BUT) A fluorescein test strip moistened with saline solution (limited to preservative-free solutions) was placed in contact with the conjunctival sac, and subjects were instructed to blink several times. The tear film breakup time (BUT) was then measured. The measurement was repeated until three measurements were obtained in which the difference between the maximum and minimum values ​​was less than 3 seconds. The average of the three measurement results was used for the analysis of the tear film breakup time (BUT). (5-5) Measurement of fluorescein staining score across the entire cornea Fluorescein staining was performed, and corneal staining spots were observed using a slit-lamp microscope. The cornea was divided into five regions (central, upper, temporal, nasal, and lower), and staining spots were counted. A score was assigned according to Table 2 below, using a modified version of Baylor's evaluation criteria (De Paiva CS et al. The incidence and risk factors for developing dry eye after myopic LASIK. Am J Ophthalmol. 2006;141:438-45.). The highest score for each region is 5, and the highest total score for all five regions is 25. [Table 2]

[0110] (6) Evaluation Method (6-1) Effectiveness We investigated the improvement effect of the eye drops in this study on the change from baseline at each evaluation point in time to tear film breakup time (BUT), one of the indicators of dry eye. Baseline refers to the measurement taken on the first day of treatment (Day 1) before administration of the investigational drug for the treatment period. The primary analysis population (largest analysis population: FAS) for efficacy analysis was defined as the group excluding subjects who had never received any of the investigational drug for the treatment phase. Eyes with a high fluorescein staining score across the entire cornea on the start of the treatment phase were selected as the efficacy evaluation eyes. In the case of identical scores, the right eye was selected as the evaluation eye. For the analysis population, we checked the presence or absence of the primary underlying disease or related disease causing dry eye among the subjects' background factors, and performed subgroup analysis on subjects with meibomian gland dysfunction (MGD). For the tear film breakup time (BUT) of the eye being evaluated for efficacy, the mean and standard deviation (SD) of the measured values ​​at each evaluation time point were calculated for each treatment group. The mean and SD were calculated separately for the subgroups of subjects with fetal stenosis (FAS) and meibomian gland dysfunction.

[0111] (7) Results (7-1) Regarding effectiveness The FAS study involved 535 subjects (267 in the placebo group and 268 in the eye drop group). Of these, 15 subjects had meibomian gland dysfunction (9 in the placebo group and 6 in the eye drop group), and 7 subjects had Sjögren's syndrome (2 in the placebo group and 5 in the eye drop group). The results regarding the improvement effect of the eye drops of this invention on shortening the tear film breakup time in patients with dry eye are shown in Tables 3 and 4 and Figure 3 below.

[0112] [Table 3]

[0113] [Table 4]

[0114] Figure 3-1 shows the changes in tear film breakup time (BUT) in FAS, and Figure 3-2 shows the changes in tear film breakup time (BUT) in a subgroup of subjects with meibomian gland dysfunction. As shown in Figure 3-1, in the group using the eye drop solution, the change in tear film breakup time (difference from the Day 1 measurement (baseline) at each evaluation time point) showed a greater extension (improvement) than the placebo group on Day 8, Day 29, and Day 57, confirming a tendency for a higher improvement in reducing tear film breakup time in dry eye patients compared to the placebo group. Furthermore, as shown in Figure 3-2, in patients with dry eye accompanied by meibomian gland dysfunction, the change in tear film breakup time in the present eye drop group showed a greater extension (improvement) than the placebo group on Day 8, Day 15, Day 29, and Day 57, confirming a tendency for a higher improvement in shortening tear film breakup time compared to the placebo group. Furthermore, in a subgroup of subjects with meibomian gland dysfunction, the difference between the change in tear film breakup time in the present eye drop group and the placebo group at each evaluation time point (Day 8, Day 15, Day 29, and Day 57) was confirmed to be larger than the difference between the change in tear film breakup time in the present eye drop group and the placebo group at each evaluation time point (Day 8, Day 15, Day 29, and Day 57) in the FAS. In addition, in all subgroups of subjects with FAS and meibomian gland dysfunction, the change in tear film breakup time was greatest in the group administered the eye drops of the present invention on Day 57. This confirms that the compound (1) does not lose its effect even with continued administration and exhibits a sustained effect of improving tear film breakup time. [Industrial applicability]

[0115] This disclosure is applicable in fields such as medicine, pharmaceuticals, healthcare, biology, and biochemistry.

Claims

1. An ophthalmic composition for inhibiting or suppressing the production of CCL5 and / or CXCL10, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.

2. An ophthalmic composition according to claim 1 for inhibiting or suppressing the production of CCL5 and / or CXCL10 in corneal epithelial cells.

3. An ophthalmic composition according to claim 1 for treating and / or preventing a disease characterized by an increase in the amount of CCL5 and / or CXCL10.

4. An ophthalmic composition according to claim 1 for treating and / or preventing dry eye.

5. The ophthalmic composition according to claim 4, wherein the dry eye is characterized by increased CCL5 expression and / or increased CXCL10 expression.

6. The ophthalmic composition according to claim 4, wherein the dry eye is of the type characterized by reduced tear secretion.

7. The ophthalmic composition according to claim 4, wherein the dry eye is of the evaporative dry eye type.

8. The ophthalmic composition according to claim 4 for shortening the tear film breakup time and / or improving conjunctival goblet cell density in dry eye.

9. An ophthalmic composition according to claim 4 for improving meibomian gland function in dry eye.

10. The ophthalmic composition according to any one of claims 1 to 9, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%.

11. The ophthalmic composition according to claim 10, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

12. An ophthalmic composition for treating and / or preventing dry eye associated with Sjögren's syndrome, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.

13. The ophthalmic composition according to claim 12, wherein the treatment and / or prevention of dry eye associated with Sjögren's syndrome is improvement of shortening of tear film breakup time and / or improvement of conjunctival goblet cell density.

14. The ophthalmic composition according to claim 12 or 13, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%.

15. The ophthalmic composition according to claim 14, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

16. An ophthalmic composition for treating and / or preventing dry eye associated with meibomian gland dysfunction, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.

17. The ophthalmic composition according to claim 16, wherein the treatment and / or prevention of dry eye associated with meibomian gland dysfunction is improvement of shortening the tear film breakup time and / or improvement of meibomian gland function.

18. The ophthalmic composition according to claim 16 or 17, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%.

19. The ophthalmic composition according to claim 18, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

20. An ophthalmic composition for inhibiting or suppressing the production of CCL5 and / or CXCL10, comprising a therapeutically effective amount of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

21. The ophthalmic composition according to claim 20, in the form of eye drops.

22. The ophthalmic composition according to claim 20 or 21, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the composition is about 0.1 w / v% to about 1.0 w / v%.

23. The ophthalmic composition according to claim 22, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

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