阅读说明：本技术 用于保护角膜的组合物 (Composition for protecting cornea ) 是由 池田华子 垣塚彰 木下茂 中村隆宏 永田真帆 小泉范子 奥村直毅 于 2018-12-26 设计创作，主要内容包括：发明人发现VCP抑制剂保护角膜内皮细胞和角膜上皮细胞。据此,本发明提供了用于保护角膜的组合物,其包含式(I)的化合物或其酯,氧化物,药学上可接受的盐或溶剂合物。在另一个方面,本发明提供了用于治疗和/或预防角膜疾病的组合物,其包含式(I)的化合物。另一方面,本发明提供了用于眼部灌流的组合物,其包含式(I)的化合物。在又一的方面,本发明提供了用于保存角膜移植物的组合物,其包含式(I)的化合物。(The inventors have found that VCP inhibitors protect corneal endothelial cells and corneal epithelial cells. Accordingly, the present invention provides a composition for protecting the cornea, comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof. In another aspect, the present invention provides a composition for treating and/or preventing corneal diseases, comprising a compound of formula (I). In another aspect, the present invention provides a composition for ocular perfusion comprising a compound of formula (I). In yet another aspect, the present invention provides a composition for preserving a corneal graft comprising a compound of formula (I).)

1. A composition for protecting the cornea comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein the content of the first and second substances,

ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

2. The composition according to claim 1, wherein each Ra group is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, and alkoxy.

3. The composition according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:

4-amino-3- (6-phenylpyridin-3-ylazo) naphthalene-1-sulfonic acid;

4-amino-3- (6-p-tolylpyridin-3-ylazo) naphthalene-1-sulfonic acid;

4-amino-3- (6-m-tolylpyridin-3-ylazo) naphthalene-1-sulfonic acid;

4-amino-3- (6-o-tolylpyridin-3-ylazo) naphthalene-1-sulfonic acid;

4-amino-3- (6-biphenyl-2-ylpyridin-3-ylazo) naphthalene-1-sulfonic acid;

3- [6- (2-acetylphenyl) pyridin-3-ylazo ] -4-aminonaphthalene-1-sulfonic acid;

3- [6- (3-acetylphenyl) pyridin-3-ylazo ] -4-aminonaphthalene-1-sulfonic acid;

3- [6- (4-acetylphenyl) pyridin-3-ylazo ] -4-aminonaphthalenesulfonic acid;

4-amino-3- [6- (2, 4-dichlorophenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-trifluoromethylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-trifluoromethylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-chlorophenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3-chlorophenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-chlorophenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-methoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-methoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-isopropoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-isopropoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-phenoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3-methoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2, 3-xylyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2, 5-xylyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3, 5-xylyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3-trifluoromethylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4- {4- [5- (1-amino-4-sulfonaphthalen-2-ylazo) pyridin-2-yl ] phenyl } -4-oxobutanoic acid;

4-amino-3- (6-biphenyl-3-ylpyridin-3-ylazo) naphthalene-1-sulfonic acid;

4-amino-3- [6- (3-cyanophenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-cyanophenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3, 5-bistrifluoromethylphenyl) pyridin-3-ylazo ] naphthalenesulfonic acid;

4-amino-3- [6- (4-benzoylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-propoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (5-fluoro-2-propoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-fluoro-6-propoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-fluoro-2-propoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (5-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-fluoro-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-butoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-hexyloxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-butylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-hydroxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- {6- [2- (6-hydroxyhexyloxy) phenyl ] pyridin-3-ylazo } naphthalene-1-sulfonic acid;

4- {2- [5- (1-amino-4-sulfonaphthalen-2-ylazo) pyridin-2-yl ] phenoxy } butanoic acid;

4-amino-3- {6- [2- (3-hydroxypropoxy) phenyl ] pyridin-3-ylazo } naphthalene-1-sulfonic acid;

4-amino-3- [6- (2-isobutoxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (5-chloro-2-hydroxyphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4-methyldiphenyl-2-yl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4' -chloro-4-methyldiphenyl-2-yl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (4, 3 ', 5' -trimethylbiphenyl-2-yl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3' -chloro-4-methyldiphenyl-2-yl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (2, 6-xylyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid;

4-amino-3- [6- (3-formyl-2-isopropoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid; and

4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

4. The composition according to claim 1, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid or 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

5. The composition according to any one of claims 1 to 4, wherein the composition is for use in the treatment or prevention of corneal diseases.

6. The composition according to claim 5, wherein the corneal disease is a corneal endothelial disease.

7. The composition according to claim 5, wherein the corneal disease is a corneal epithelial disease.

8. The composition according to claim 5, wherein the corneal disease is corneal punctate degeneration, Fuchs endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, Iris corneal endothelial syndrome, congenital hereditary corneal endothelial dystrophy, cytomegalovirus endophthalmitis, herpetic endophthalmitis, exfoliation syndrome, corneal endothelial transplant rejection, uveitis, interstitial keratitis, corneal endophthalmitis, corneal endothelial cell loss after corneal transplantation, corneal injury after intraocular surgery, corneal injury due to glaucoma attack, corneal injury due to long-term use of contact lens, corneal trauma at childbirth, large-bleb keratopathy, superficial punctate keratitis, corneal erosion, corneal ulcer, dry eye, keratoconjunctivitis sicca, or corneal limbic ulcer.

9. The composition according to claim 5, wherein the corneal disease is Fuchs endothelial corneal dystrophy, bullous keratopathy, corneal erosion, dry eye, or corneal trauma.

10. The composition according to any one of claims 1 to 9, wherein the composition is an eye drop.

11. The composition according to any one of claims 1 to 9, wherein the composition is an ocular perfusion fluid or a composition to be added to an ocular perfusion fluid.

12. The composition according to any one of claims 1 to 9, wherein the composition is a solution for preserving a corneal graft or a composition to be added to a solution for preserving a corneal graft.

13. A pharmaceutical composition for treating or preventing a corneal disease comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein the content of the first and second substances,

ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

14. A composition for ocular perfusion comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein the content of the first and second substances,

ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

15. A composition for preserving a corneal graft comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein the content of the first and second substances,

ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

Technical Field

This application claims priority from Japanese patent application No.2017 & 251839, the entire contents of which are incorporated herein by reference.

The present invention relates to a composition for protecting the cornea.

Background

The cornea is one of the tissues that make up the eye. Corneal endothelial cells located in the innermost layer of the cornea act as a pump and are essential for maintaining corneal transparency. The corneal endothelium does not have the ability to divide and cannot regenerate once damaged. When the corneal endothelium is damaged, endothelial cells around the damaged portion expand to cover it. However, if the cells are too reduced, corneal transparency cannot be maintained, and visual acuity is extremely deteriorated.

Corneal endothelium can be damaged by intraocular surgery such as cataract surgery or glaucoma surgery, acute ocular pressure increases, inflammation, trauma, and diseases such as Fuchs endothelial corneal dystrophy. If the damage progresses, it is necessary to compensate for the reduced corneal endothelial cells by corneal transplantation (e.g., penetrating keratoplasty or peeling keratoplasty). There is no effective treatment available for regenerating corneal endothelial cells or inhibiting the decrease of cells.

Corneal epithelial cells are circulated daily by stem cells present at the limbus (the boundary between the cornea and conjunctiva). However, once stem cells are depleted due to, for example, trauma or conjunctival inflammatory disease, the corneal epithelial cells are not sufficiently supplied, and the corneal epithelium is defective. Thus, corneal transparency cannot be maintained, and the corneal epithelium becomes part of the conjunctiva, impairing visual acuity. In addition, corneal epithelial disorders are often accompanied by intense ocular pain. Although anti-inflammatory agents may be used for inhibiting the decrease of corneal epithelial cells and corneal epithelial stem cells, the effect is limited.

In ophthalmic surgery or corneal transplantation, the cornea must be protected. There are several products currently available for ocular perfusion in ophthalmic surgery that contain glutathione to protect corneal endothelial cells and retinal cells. Corneal preservation solutions such as Optisol-GS are commonly used to preserve donated corneas for corneal transplantation, but the preservation effect cannot be longer than about two weeks.

Accordingly, there is a need for corneal protection and treatment or prevention of corneal diseases in a variety of conditions.

It is known that some 4-amino-naphthalene-1-sulfonic acid derivatives having a VCP (valosin-binding protein, a protein containing valosin) atpase inhibitory activity (patent document 1) are effective in treating or preventing ocular diseases affecting retinal tissues and optic nerve at the posterior segment of the eye, such as glaucoma, retinitis pigmentosa, age-related macular degeneration and ischemic ocular diseases (patent documents 2 to 4, non-patent documents 1 and 2). However, any effect of these agents on the cornea is not known.

Reference to the literature

Patent document

Patent document 1: WO2012/014994

Patent document 2: WO2012/043891

Patent document 3: WO2014/129495

Patent document 4: WO2015/129809

Non-patent document

Non-patent document 1: pottama, et al, Sci Rep 4,5970,2014

Non-patent document 2: zhongye era, Heliyon2, e00096, 2016

Summary of The Invention

It is an object of the present invention to provide a composition for protecting the cornea.

The inventors have found that VCP inhibitors protect corneal endothelial cells and corneal epithelial cells.

Accordingly, one aspect of the present invention provides a composition for protecting the cornea comprising a compound of formula (I), or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof:

wherein

Ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

Another aspect of the present invention provides a pharmaceutical composition for treating or preventing corneal diseases, comprising a compound of formula (I), or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof.

Another aspect of the present invention provides a composition for ocular perfusion comprising a compound of formula (I), or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention provides a composition for preserving a corneal graft comprising a compound of formula (I), or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof.

In accordance with the present invention, a composition for protecting the cornea is provided. Specifically, a pharmaceutical composition for treating or preventing corneal diseases is provided. In addition, compositions for ocular perfusion or preservation of corneal grafts are provided that have improved corneal protective effects.

Brief Description of Drawings

FIG. 1 phase difference images of rabbit corneal endothelial cells cultured in the presence of antimycin or oligomycin, indicating KUS121 protected the cells.

Fig. 2 shows phase difference images of rabbit corneal endothelial cells cultured in the absence of glucose, indicating KUS121 protected the cells.

FIG. 3 shows the results of measurement of intracellular ATP concentration in rabbit corneal endothelial cells cultured in the presence of antimycin or oligomycin or in the absence of glucose, indicating that the decrease in intracellular ATP concentration is inhibited in the presence of KUS 121.

Fig. 4 shows a phase difference image showing cell morphology and apoptosis of immortalized human corneal endothelial cells cultured in the presence of thapsigargin, indicating KUS121 inhibited cell damage.

FIG. 5 shows the results of western blot analysis of cleaved caspase 3 and PARP of immortalized human corneal endothelial cells cultured in the presence of thapsigargin, indicating that apoptosis is inhibited in the presence of KUS 121.

FIG. 6 shows HE stained images of tissue sections of rabbit corneas stored in Optisol-GS for 1-4 weeks, indicating that morphological changes in corneal tissue are inhibited in the presence of KUS121 or KUS 187.

FIG. 7 shows the results of measurements of central corneal thickness of rabbit corneas stored in Optisol-GS for 1-4 weeks, indicating that corneal swelling is inhibited in the presence of KUS121 or KUS 187.

FIG. 8 shows TUNEL staining images of tissue sections of rabbit corneas stored in Optisol-GS for 1-4 weeks, indicating that apoptosis is inhibited in the presence of KUS121 or KUS 187. Three different views of the image are shown for each slice.

Fig. 9 shows an iodopropidine (PI) stained image of the same field as fig. 8.

FIG. 10 shows the percentage of TUNEL positive cells in rabbit corneal tissue sections preserved for 1-4 weeks in Optisol-GS. The percentage in the presence of KUS121 or KUS187 was lower than the control group during the entire experiment.

FIG. 11 shows Na +/K + ATPase stained images of tissue sections of rabbit corneas preserved for 1-4 weeks in Optisol-GS, indicating that corneal endothelial cells remained better than in the control group in the presence of KUS121 or KUS187, starting at week 1.

Fig. 12 shows PI stained images of the same field as fig. 11.

FIG. 13 shows a transmission electron microscope image of tissue sections of rabbit cornea stored for one week in Optisol-GS. Vacuolization of corneal epithelial cells, disappearance of microvilli, and swollen corneal stroma and corneal endothelial cells were observed in the control, but not in the presence of KUS 121.

Detailed Description

When a value of a numerical value is accompanied by the term "about," the value is intended to represent any value within the range of from-10% of the value to + 10% of the value. For example, "about 20" means a value of "from 18 to 22. ". The range defined by a lower limit for a value and an upper limit for a value covers all values from the lower limit to the upper limit, including both values. When a range is accompanied by the term "about," both limits are understood to be accompanied by the term "about. For example, "about 20 to 30" is understood to mean "18 to 33".

Unless otherwise defined, terms used herein are understood as commonly understood by those of skill in the art, such as organic chemistry, medicine, pharmaceutical science, molecular biology, and microbiology. Several terms used herein are defined as described below. The definitions herein take precedence over general understanding.

"alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, straight and branched chain hydrocarbyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and neopentyl.

The word "substituted" as a qualifier group name means that one or more hydrogen atoms of the group are identically or differently substituted with one or more substituents as defined herein.

"alkylene" means a divalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups.

"alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and n-pentoxy.

"aryl" refers to a monovalent aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthracenyl) of 6 to 14 carbon atoms. Typical aryl groups include phenyl and naphthyl.

"aryloxy" refers to the group-O-aryl, wherein aryl is as defined herein. Examples of the aryloxy group include a phenoxy group and a naphthoxy group.

"cyano" refers to the group-CN.

"Carboxyl (Carboxyl)" or "Carboxyl (Carboxyl)" means a-COOH group or a salt thereof.

"carboxy ester" refers to a-C (O) O-alkyl group, wherein alkyl is as defined herein.

"halogen" means halogen, in particular fluorine, chlorine, bromine or iodine.

"hydroxy" refers to an-OH group.

Unless otherwise indicated, substituents not explicitly defined herein are named by first describing the name of the terminal functional group of the substituent, and in turn describing the adjacent functional group toward the point of attachment to the rest of the compound. For example, the substituent "arylalkoxycarbonyl" refers to (aryl) - (alkyl) -O-C (O) -.

Some compounds of formula (I) have enantiomers or diastereomers, depending on their substituents. They may be racemic mixtures or stereoisomerically pure components which are separated by known methods. Some compounds may be isomeric.

The term "ester" refers to an ester that is hydrolyzed in vivo, which can readily decompose within the human body to leave the parent compound or salt thereof. Suitable esters include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, naphthenic and alkanedioic acids, in which each alkyl or alkenyl moiety has, for example, 6 or fewer carbon atoms. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term "oxide" refers to an oxide in which the nitrogen atom of the heteroaryl group is oxidized to form an N-oxide.

The term "prodrug" refers to prodrugs of compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue adverse effects such as toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs are rapidly converted in vivo, for example by hydrolysis in blood, to yield the parent compound of the above formula. General descriptions are provided in t.higuchi and v.stella, Pro-drugs as novelderlivery Systems, vol.14of the a.c.s.symposium Series, and in Edward b.roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and pergamon Press, 1987, both of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt" may be a salt of a compound of formula (I) with an inorganic or organic acid. Preferred salts include those with inorganic acids such as: salts of hydrochloric, hydrobromic, phosphoric or sulfuric acid, or, with organic carboxylic or sulfonic acids, for example: salts of acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid.

Pharmaceutically acceptable salts also include ammonium salts, in particular sodium salts, derived from conventional bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonia or organic amines (e.g., diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, benzathine (benzathine), ethanolamine, meglumine or tromethamine).

The term "solvate" refers to a compound of formula (I) in the form of a complex with a solvent molecule by coordination in the solid or liquid state. Suitable solvates are hydrates.

The term "compound of formula (I)" referred to in the present invention is meant to include esters, oxides, prodrugs, pharmaceutically acceptable salts, and solvates thereof, unless the context is inappropriate.

In one embodiment, each Ra group in formula (I) is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, and alkoxy.

In one embodiment, each Ra group in formula (I) is independently selected from the group consisting of halogen and alkyl.

In one embodiment, formula (I) has two Ra groups, which are halogen and alkyl.

In one embodiment, each Ra group in formula (I) is independently selected from the group consisting of hydroxy, alkyl, and alkoxy.

In one embodiment, formula (I) has three Ra groups, which are hydroxy, alkyl, and alkoxy.

In one embodiment, the compound of formula (I) is selected from compounds 1-53 listed in Table 1 below:

[ tables 1-1]

Serial number	Name of Compound
		1	4-amino-3- (6-phenylpyridin-3-ylazo) naphthalene-1-sulfonic acid
2	4-amino-3- (6-p-tolylpyridin-3-ylazo) naphthalene-1-sulfonic acid
		3	4-amino-3- (6-m-tolylpyridin-3-ylazo) naphthalene-1-sulfonic acid
4	4-amino-3- (6-o-tolylpyridin-3-ylazo) naphthalene-1-sulfonic acid
		5	4-amino-3- (6-biphenyl-2-ylpyridin-3-ylazo) naphthalene-1-sulfonic acid
6	3- [6- (2-acetylphenyl) pyridin-3-ylazo]-4-aminonaphthalene-1-sulfonic acid
		7	3- [6- (3-acetylphenyl) pyridin-3-ylazo]-4-aminonaphthalene-1-sulfonic acid
8	3- [6- (4-acetylphenyl) pyridin-3-ylazo]-4-aminonaphthalenesulfonic acid
		9	4-amino-3- [6- (2, 4-dichlorophenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
10	4-amino-3- [6- (2-trifluoromethylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		11	4-amino-3- [6- (4-trifluoromethylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
12	4-amino-3- [6- (2-chlorophenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		13	4-amino-3- [6- (3-chlorophenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
14	4-amino-3- [6- (4-chlorophenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		15	4-amino-3- [6- (2-methoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
16	4-amino-3- [6- (4-methoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		17	4-amino-3- [6- (2-isopropoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
18	4-amino-3- [6- (4-isopropoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		19	4-amino-3- [6- (2-phenoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
20	4-amino group-3- [6- (3-methoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid

[ tables 1-2]

21	4-amino-3- [6- (2, 3-xylyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		22	4-amino-3- [6- (2, 5-xylyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
23	4-amino-3- [6- (3, 5-xylyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		24	4-amino-3- [6- (3-trifluoromethylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
25	4- {4- [5- (1-amino-4-sulfonaphthalen-2-ylazo) pyridin-2-yl]Phenyl } -4-oxobutanoic acid
		26	4-amino-3- (6-biphenyl-3-ylpyridin-3-ylazo) naphthalene-1-sulfonic acid
27	4-amino-3- [6- (3-cyanophenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		28	4-amino-3- [6- (4-cyanophenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
29	4-amino-3- [6- (3, 5-bistrifluoromethylphenyl) pyridin-3-ylazo]Naphthalene sulfonic acid
		30	4-amino-3- [6- (4-benzoylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
31	4-amino-3- [6- (2-propoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		32	4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
33	4-amino-3- [6- (5-fluoro-2-propoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		34	4-amino-3- [6- (2-fluoro-6-propoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
35	4-amino-3- [6- (4-fluoro-2-propoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		36	4-amino-3- [6- (5-fluoro-2-methylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
37	4-amino-3- [6- (2-fluoro-5-methylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		38	4-amino-3- [6- (2-butoxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
39	4-amino-3- [6- (2-hexyloxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		40	4-amino-3- [6- (4-butylphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid

[ tables 1 to 3]

41	4-amino-3- [6- (2-hydroxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		42	4-amino-3- {6- [2- (6-hydroxyhexyloxy) phenyl]Pyridin-3-ylazo } naphthalene-1-sulfonic acid
43	4- {2- [5- (1-amino-4-sulfonaphthalen-2-ylazo) pyridin-2-yl]Phenoxy } butanoic acid
		44	4-amino-3- {6- [2- (3-hydroxypropoxy) phenyl]Pyridin-3-ylazo } naphthalene-1-sulfonic acid
45	4-amino-3- [6- (2-isobutoxyphenyl) pyridin-3-yl-azoNitrogen is present in]Naphthalene-1-sulfonic acid
		46	4-amino-3- [6- (5-chloro-2-hydroxyphenyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
47	4-amino-3- [6- (4-methyldiphenyl-2-yl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		48	4-amino-3- [6- (4' -chloro-4-methyldiphenyl-2-yl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
49	4-amino-3- [6- (4, 3 ', 5' -trimethyldiphenyl-2-yl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		50	4-amino-3- [6- (3' -chloro-4-methyldiphenyl-2-yl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
51	4-amino-3- [6- (2, 6-xylyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
		52	4-amino-3- [6- (3-formyl-2-isopropoxy-5-tolyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid
53	4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo]Naphthalene-1-sulfonic acid

In one embodiment, it is preferably 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid, which is represented by the following formula:

or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof, particularly the sodium salt.

In one embodiment, it is preferably 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid, which is represented by the following formula:

or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof, particularly the sodium salt.

Compounds of formula (I), in particular the features of the compounds listed above and methods for synthesizing them, are described in detail in WO2012/014994, WO2012/043891, WO2014/129495, and WO2015/129809 (patent documents 1-4), the contents of which are incorporated herein by reference in their entirety

As demonstrated in the examples below, the compounds of formula (I) protect corneal endothelial and epithelial cells and inhibit cell death, and thus are capable of protecting the cornea. As used herein, the term "protect the cornea" or "corneal protection" refers to inhibiting cell death of corneal endothelial cells and corneal epithelial cells, inhibiting corneal abnormalities (e.g., edema, swelling, or cloudiness), and/or inhibiting the development of a corneal abnormality, wherein the cornea is a cornea present in an eye of a subject or a corneal graft excised for transplantation. The subject may or may not be suffering from corneal disease.

Accordingly, one aspect of the present invention provides a composition for protecting the cornea comprising a compound of formula (I).

One aspect of the present invention provides a method for protecting the cornea comprising administering a compound of formula (I) to a subject in need thereof.

One aspect of the invention provides a method for protecting the cornea comprising allowing the cornea to contact a compound of formula (I).

One aspect of the present invention provides compounds of formula (I) for use in protecting the cornea.

One aspect of the present invention provides the use of a compound of formula (I) for protecting the cornea.

One aspect of the present invention provides the use of a compound of formula (I) for the preparation of a composition for the protection of the cornea.

By virtue of the corneal protective effect, the compounds of formula (I) are useful in, for example, compositions for treating or preventing corneal diseases, compositions for ocular perfusion, or compositions for preserving corneal transplants.

(1) Pharmaceutical composition for treating or preventing corneal diseases

The term "corneal disease" refers to a disease that accompanies a corneal lesion, disorder, or injury. The corneal disease may be a corneal endothelial disease or a corneal epithelial disease. Examples of the corneal endothelial diseases include diseases affecting corneal endothelial cells, such as corneal endothelial degeneration (e.g., corneal punctate degeneration, fukes' endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, iridocorneal endothelial syndrome, and congenital hereditary corneal endothelial dystrophy), viral diseases (e.g., cytomegalovirus endophthalmitis and herpetic endophthalmitis), exfoliation syndrome, and corneal endothelial graft rejection; and physical damage associated with inflammation or external factors, such as uveitis, interstitial keratitis, intracorneal dermatitis, corneal endothelial cell loss after corneal transplantation, corneal damage after intraocular surgery (e.g., cataract surgery, vitreous surgery, glaucoma surgery), corneal damage caused by glaucoma attack, corneal damage caused by long-term use of contact lenses, corneal trauma at childbirth, and bullous keratopathy. Examples of corneal epithelial diseases include superficial punctate keratitis, corneal erosion, corneal ulcer, dry eye, keratoconjunctivitis sicca, corneal marginal ulcer (corneal ulcer), and corneal trauma.

As used herein, the term "treatment" or "therapy" refers to a reduction or elimination of the cause of a corneal disease, a delay or cessation of progression of a corneal disease, and/or a reduction, alleviation, amelioration, or elimination of symptoms of a corneal disease in a subject suffering from a corneal disease.

As used herein, the term "prevent" or "prevention" refers to the prevention of the occurrence of a disease or the reduction of the likelihood of the occurrence of a disease in a subject, particularly a subject predisposed to, but not yet affected by, a corneal disease. Examples of subjects who are predisposed to, but not yet affected by, corneal disease include subjects with a genetic predisposition to corneal disease, such as Fuchs endothelial corneal dystrophy and posterior polymorphic corneal dystrophy, and subjects with a predisposition to corneal disease. Examples of causes include intraocular surgery (e.g., cataract surgery, vitreous surgery, glaucoma surgery), corneal transplantation, laser treatment, rapid increase in intraocular pressure, inflammation, trauma, and conjunctivitis.

The subject receiving treatment or prevention of corneal disease may be an animal, typically a mammal (e.g., human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.), particularly a human.

The pharmaceutical composition may be administered by any means commonly known for administration, for example, by oral administration, parenteral administration, injection, infusion, ocular administration, anterior ocular atrial administration, or intravitreal administration. The composition may be in a dosage form suitable for each route of administration.

Dosage forms suitable for oral administration include granules, fine granules, powders, coated tablets, suppositories, powders, capsules, microcapsules, chewable agents, liquids, suspensions, emulsions. The formulation suitable for injection may be one commonly used, for example, for intravenous injection, infusion, intraocular injection, or sustained release formulation of the active ingredient. Dosage forms suitable for ocular administration include liquids, suspensions, and emulsions.

Such dosage forms may be manufactured by formulating the active ingredient using conventional methods. Any of various pharmaceutically acceptable excipients may be added, if necessary for formulation. Any excipient may be used depending on the dosage form used. Examples of the excipient include buffering agents, surfactants, stabilizers, preservatives, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, flavoring agents, sweeteners, solubilizers.

In one embodiment, the pharmaceutical composition is an eye drop. Eye drops can be prepared by using isotonic agents such as sodium chloride or concentrated glycerin; buffering agents such as sodium phosphate, sodium acetate; surfactants such as polyoxyethylene sorbitol monooleate, polyoxyethylene stearate 40, or polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate or sodium edetate; and preservatives such as benzalkonium chloride or paraben, but the ingredients of the eye drop are not limited to these. The eye drops may have a pH in the range acceptable for ophthalmic preparations, for example, in the range of pH 4 to 8.

The pharmaceutical composition may be an ocular perfusion fluid or a composition to be added to an ocular perfusion fluid. The pharmaceutical composition may be a cornea preservation solution or a composition to be added to a cornea preservation solution. The details are as described later.

The dosage and the number of administrations of the pharmaceutical composition can be appropriately set by those skilled in the art depending on the animal species of the subject, the health condition of the subject, the age, the body weight, the administration route and the dosage form, etc., so as to administer an effective amount of the compound of formula (I) to the subject, which can be easily determined by routine experiments for an effective amount in a given case, within the scope of ordinary skill and judgment of a clinician. For example, for systemic administration, the compound of formula (I) may be administered in the range of about 0.001-1,000 mg/kg body weight/day, about 0.01-300 mg/kg body weight/day, about 0.1-100 mg/kg body weight/day, or about 1.0-30 mg/kg body weight/day. For example, by topical administration, the compound of formula (I) may be administered in the range of about 0.01-100 μ g/kg body weight/day, about 0.1-10 μ g/kg body weight/day, or about 0.3-3 μ g/kg body weight/day. The compound of formula (I) is administered once or more daily, for example, twice, three times or four times daily.

The compounds of formula (I) can be used alone or in combination with at least one other active ingredient, in particular an active ingredient for the treatment or prevention of corneal diseases. For example, the pharmaceutical composition may comprise at least one active ingredient other than a compound of formula (I).

When some of the ingredients are used in "combination," a dosage form containing all of the ingredients may be administered, or a combination of dosage forms containing the ingredients separately may be administered. All of the ingredients may be administered simultaneously, or any of the ingredients may be administered at a later point in time, so long as the ingredients are used in the prevention and/or treatment of corneal disease. More than 2 further active ingredients may be used in combination with the compound of formula (I). Examples of active ingredients suitable for use in combination include anti-inflammatory agents, antibacterial agents, antifungal agents, immunosuppressive agents, antiviral agents.

Ophthalmic treatments other than drug treatment may be combined with the treatment or prevention of corneal diseases with compounds of formula (I). Examples of suitable therapies include surgery, photodynamic therapy, gene therapy, regenerative medicine, corneal transplantation, laser therapy.

One aspect of the present invention provides a method for treating or preventing a corneal disease, comprising administering a compound of formula (I) to a subject in need thereof.

One aspect of the present invention provides a compound of formula (I) for use in the treatment or prevention of a corneal disease.

One aspect of the present invention provides the use of a compound of formula (I) for the treatment or prevention of corneal diseases.

One aspect of the present invention provides the use of a compound of formula (I) for the preparation of a composition for the treatment or prevention of corneal diseases.

(2) Composition for ocular perfusion

Ophthalmic surgery, such as cataract surgery, vitreous surgery, or glaucoma surgery, can cause corneal diseases such as corneal edema or corneal clouding. The compound of formula (I) is added to an ocular perfusion solution for ocular perfusion and washing, which is frequently used in ophthalmic surgery, to protect the cornea and prevent corneal diseases.

Compositions for ocular perfusion may be solid, semi-solid, or liquid. The composition may be provided as a ready-to-use ocular perfusion fluid or a composition to be added to an ocular perfusion fluid. When the composition is provided as an ocular perfusion fluid, the composition may contain other ingredients equivalent to those in existing ocular perfusion fluids, preferably similar to those of aqueous body fluids, and may contain further components such as glutathione, e.g. oxyglutathione, and antibiotics. Examples of existing ocular perfusates include, but are not limited to, physiological saline, ringer's lactate, BSS PLUS (trade name), operguard (trade name), and oxyglutathione ocular perfusate (trade name). When the composition is provided as a composition to be added to an ocular perfusion fluid, the composition may comprise any component unless it compromises the function and safety of the ocular perfusion fluid.

The composition for ocular perfusion may comprise any amount of the compound of formula (I) as long as the compound is present in an effective concentration when the composition is used for ocular perfusion. The effective concentration of the compound of formula (I) for use in ocular perfusion may be, for example, in the range of 0.1. mu.M to 10mM, 1. mu.M to 1mM, 2. mu.M to 200. mu.M, 5. mu.M to 100. mu.M, or 10. mu.M to 100. mu.M.

One aspect of the present invention provides a method for ocular perfusion of a subject receiving ophthalmic surgery comprising using an ocular perfusion fluid comprising a compound of formula (I).

One aspect of the present invention provides a method for protecting the cornea comprising ocular perfusion of a subject undergoing ophthalmic surgery with an ocular perfusion fluid comprising a compound of formula (I).

One aspect of the present invention provides compounds of formula (I) for ocular perfusion.

One aspect of the present invention provides compounds of formula (I) for use in protecting the cornea in ocular perfusion.

One aspect of the present invention provides the use of a compound of formula (I) for ocular perfusion.

One aspect of the present invention provides the use of a compound of formula (I) for protecting the cornea in ocular perfusion.

One aspect of the present invention provides the use of a compound of formula (I) for the preparation of a composition for ocular perfusion.

One aspect of the present invention provides the use of a compound of formula (I) for the preparation of a composition for protecting the cornea in ocular perfusion.

(3) Composition for preserving corneal transplants

In corneal transplantation, corneas donated from a corneal donor need to be preserved until the time of transplantation surgery. The addition of the compound of formula (I) to the corneal storage solution can protect and preserve the cornea in a better state.

Compositions for preserving corneal transplants can be in solid, semi-solid, or liquid form. The composition may be provided as a ready-to-use corneal preservation solution or a composition to be added to a corneal preservation solution. When the composition is supplied as a corneal storage solution, the other components contained in the composition may correspond to those in the existing corneal storage solution. Examples of such ingredients include: basic mediators, buffers, chondroitin sulfate, dextran, vitamins, ATP precursors, antibiotics. Examples of the existing cornea preservation solution include, but are not limited to, M199 medium, MEM alpha medium, MK medium, CSM medium, CSMD medium, DMEM/F-12 medium, Optisol-GS (trade name), K-Sol (trade name), and EP2 (trade name). When the composition is provided as a composition added to a corneal preservation solution, the composition may contain any component unless it impairs the function and safety of the corneal preservation solution.

The composition for preserving a corneal graft may comprise any amount of the compound of formula (I) so long as the compound is present in an effective concentration when the composition is used to preserve a corneal graft. An effective concentration of a compound of formula (I) for use in preserving corneal transplants can be, for example, in the range of 0.1. mu.M to 10mM, 1. mu.M to 1mM, 2. mu.M to 200. mu.M, 5. mu.M to 100. mu.M, or 10. mu.M to 100. mu.M.

One aspect of the present invention provides a method for preserving a corneal graft, comprising preserving the corneal graft in a corneal preservation solution comprising a compound of formula (I).

One aspect of the present invention provides a method for protecting a corneal graft, comprising preserving the corneal graft in a corneal preservation solution comprising a compound of formula (I).

One aspect of the invention provides a compound of formula (I) for use in preserving corneal transplants.

One aspect of the invention provides compounds of formula (I) for use in protecting the cornea in the preservation of a corneal transplant.

One aspect of the invention provides the use of a compound of formula (I) for preserving corneal transplants.

One aspect of the present invention provides the use of a compound of formula (I) for protecting the cornea in the preservation of a corneal transplant.

One aspect of the present invention provides the use of a compound of formula (I) for the preparation of a composition for the preservation of corneal transplants.

One aspect of the present invention provides the use of a compound of formula (I) for the preparation of a composition for protecting the cornea in the preservation of a corneal transplant.

For example, the present invention provides the following embodiments.

[1] A composition for protecting the cornea comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein

Ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

[2] The composition according to item 1, wherein each Ra group is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, and alkoxy.

[3] The composition according to item 1 or 2, wherein each Ra group is independently selected from the group consisting of halogen and alkyl.

[4] A composition according to any one of items 1 to 3, wherein formula (I) has two Ra groups which are halogen and alkyl.

[5] The composition according to item 1 or 2, wherein each Ra group is independently selected from the group consisting of hydroxyl, alkyl and alkoxy.

[6] The composition according to item 1, 2 or 5, wherein formula (I) has three Ra groups, which are hydroxyl, alkyl and alkoxy.

[7] A composition according to item 1, wherein the compound of formula (I) is a compound selected from those listed in table 1.

[8] The composition according to item 1, 2 or 7, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid or 4-amino-3- [6- (3-formyl-2-butoxy-5-methylphenyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[9] The composition according to any one of items 1 to 4, 7 and 8, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[10] A composition according to any one of items 1 to 4 and 7 to 9, which comprises 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[11] The composition according to any one of items 1, 2 and 5 to 8, wherein the compound of formula (I) is 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[12] The composition according to any one of items 1, 2, 5 to 8 and 11, which comprises 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[13] The composition according to any one of items 1 to 12, wherein the composition is used for treating or preventing corneal diseases.

[14] The composition according to item 13, wherein the corneal disease is a corneal endothelial disease.

[15] The composition according to item 14, wherein the corneal endothelial disease is corneal punctate degeneration, Fuchs endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, iridocorneal endothelial syndrome, congenital hereditary corneal endothelial dystrophy, cytomegalovirus endophthalmitis, herpetic endophthalmitis, exfoliation syndrome, corneal endothelial transplant rejection, uveitis, interstitial keratitis, corneal endophthalmitis, corneal endothelial cell loss after corneal transplantation, corneal injury after intraocular surgery, corneal injury due to glaucoma attack, corneal injury due to long-term use of a contact lens, corneal trauma at childbirth, or bullous keratopathy.

[16] The composition according to item 14 or 15, wherein the corneal endothelial disease is Fuchs endothelial corneal dystrophy or bullous keratopathy.

[17] The composition according to item 13, wherein the corneal disease is a corneal epithelial disease.

[18] The composition according to item 17, wherein the corneal epithelial disease is superficial punctate keratitis, corneal erosion, corneal ulcer, dry eye, keratoconjunctivitis sicca, corneal limbic ulcer, or corneal trauma.

[19] The composition according to item 13, wherein the corneal disease is corneal punctate degeneration, fukes' endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, iridocorneal endothelial syndrome, and congenital hereditary corneal endothelial dystrophy, cytomegalovirus endophthalmitis, herpetic endophthalmitis, exfoliation syndrome, corneal endothelial graft rejection, uveitis, interstitial keratitis, corneal endophthalmitis, corneal endothelial cell loss after corneal transplantation, corneal injury after intraocular surgery, corneal injury due to glaucoma attack, corneal injury due to long-term use of a contact lens, corneal trauma at childbirth, bullous keratopathy, superficial punctate keratitis, corneal erosion, dry eye, keratoconjunctivitis sicca, or corneal marginal ulcer.

[20] The composition according to item 13 or 19, wherein the corneal disease is Fuchs endothelial corneal dystrophy, bullous keratopathy, corneal erosion, dry eye, or corneal trauma.

[21] The composition according to any one of items 1 to 20, wherein the composition is an eye drop.

[22] The composition according to any one of items 1 to 20, wherein the composition is an ocular perfusion fluid or a composition to be added to an ocular perfusion fluid.

[23] The composition according to any one of items 1 to 20, wherein the composition is a solution for preserving a corneal graft or a composition to be added to a solution for preserving a corneal graft.

[24] A pharmaceutical composition for treating or preventing a corneal disease comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein

Ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

[25] The composition according to item 24, wherein each Ra group is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, and alkoxy.

[26] The composition of clauses 24 or 25, wherein each Ra group is independently selected from the group consisting of halogen and alkyl.

[27] A composition according to any one of items 24 to 26, wherein formula (I) has two Ra groups which are halogen and alkyl.

[28] The composition of item 24 or 25, wherein each Ra group is independently selected from the group consisting of hydroxyl, alkyl, and alkoxy.

[29] A composition according to item 24, 25 or 28 wherein formula (I) has three Ra groups which are hydroxy, alkyl and alkoxy.

[30] A composition according to item 24, wherein the compound of formula (I) is a compound selected from those listed in table 1.

[31] The composition according to item 24, 25 or 30, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid or 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[32] The composition of any one of items 24 to 27, 30, and 31, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[33] A composition according to any one of items 24 to 27 and 30 to 32 comprising 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[34] The composition of any one of items 24, 25, and 28 to 31, wherein the compound of formula (I) is 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[35] A composition according to any one of items 24, 25, 28 to 31 and 34 comprising 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[36] The composition according to any one of items 24 to 35, wherein the corneal disease is a corneal endothelial disease.

[37] The composition according to item 36, wherein the corneal endothelial disease is corneal punctate degeneration, fukes' endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, iridocorneal endothelial syndrome, congenital hereditary corneal endothelial dystrophy, cytomegalovirus endophthalmitis, herpetic endophthalmitis, exfoliation syndrome, corneal endothelial transplant rejection, corneal uveitis, interstitial keratitis, corneal injury after cataract surgery, corneal endothelial cell loss after corneal transplantation, corneal injury after retinal surgery, corneal injury after vitrectomy, corneal injury after glaucoma surgery, corneal injury due to glaucoma attack, corneal injury due to long-term use of a contact lens, corneal trauma at childbirth, or bullous keratopathy.

[38] The composition of item 36 or 37, wherein the corneal endothelial disease is Fuchs endothelial corneal dystrophy or bullous keratopathy.

[39] The composition according to any one of items 24 to 35, wherein the corneal disease is a corneal epithelial disease.

[40] The composition according to item 39, wherein the corneal epithelial disease is corneal erosion, dry eye, or corneal trauma.

[41] The composition according to any one of items 24 to 35, wherein the corneal disease is corneal punctate degeneration, fukes' endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, iridocorneal endothelial syndrome, congenital hereditary corneal endothelial dystrophy, cytomegalovirus endophthalmitis, herpetic endophthalmitis, exfoliation syndrome, corneal endothelial transplant rejection, uveitis, interstitial keratitis, corneal injury after cataract surgery, corneal endothelial cell loss after corneal transplantation, corneal injury after retinal surgery, corneal injury after vitreous surgery, corneal injury after glaucoma surgery, corneal injury due to glaucoma attack, corneal injury due to long-term use of a contact lens, corneal trauma at childbirth, large-vacuolar keratopathy, corneal erosion, or dry eye.

[42] The composition of any one of items 24-35 and 41, wherein the corneal disease is Fuchs endothelial corneal dystrophy, bullous keratopathy, corneal erosion, dry eye, or corneal trauma.

[43] The composition according to any one of items 24 to 42, wherein the composition is an eye drop.

[44] The composition of any one of items 24 to 42, wherein the composition is an ocular perfusion fluid or a composition to be added to an ocular perfusion fluid.

[45] The composition according to any one of items 24 to 42, wherein the composition is a solution for preserving a corneal graft or a composition to be added to a solution for preserving a corneal graft.

[46] A composition for ocular perfusion comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein

Ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

[47] The composition of item 46, wherein each Ra group is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, and alkoxy.

[48] The composition of clauses 46 or 47, wherein each Ra group is independently selected from the group consisting of halogen and alkyl.

[49] A composition according to any one of claims 46 to 48 wherein formula (I) has two Ra groups which are halogen and alkyl.

[50] The composition of clauses 46 or 47, wherein each Ra group is independently selected from the group consisting of hydroxy, alkyl, and alkoxy.

[51] The composition of item 46, 47, or 50, wherein formula (I) has three Ra groups that are hydroxyl, alkyl, and alkoxy.

[52] The composition according to item 46, wherein the compound of formula (I) is a compound selected from those listed in Table 1.

[53] The composition of clauses 46, 47, or 52, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid or 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[54] The composition of any one of items 46 to 49, 52, and 53, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[55] A composition according to any one of items 46 to 49 and 52 to 54 comprising 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[56] The composition of any one of items 46, 47, and 50 to 53, wherein the compound of formula (I) is 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[57] A composition according to any one of items 46, 47, 50 to 53, and 56, comprising 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[58] The composition of any one of items 46 to 57, wherein the composition is an ocular perfusion fluid.

[59] The composition of any one of items 46 to 57, wherein the composition is a composition to be added to ocular perfusion fluid.

[60] A composition for preserving a corneal graft comprising a compound of formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof:

wherein

Ra is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, aryl, halo-or alkyl-substituted aryl, alkoxy, hydroxy-or carboxy-substituted alkoxy, aryloxy, halo-or alkyl-substituted aryloxy, CHO, C (O) -alkyl, C (O) -aryl, C (O) -alkyl-carboxy, C (O) -alkylene-carboxy ester, and cyano, and

m is an integer selected from 0 to 4.

[61] The composition of item 60, wherein each Ra group is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, and alkoxy.

[62] The composition of clauses 60 or 61, wherein each Ra group is independently selected from the group consisting of halogen and alkyl.

[63] A composition according to any one of claims 60 to 62, wherein formula (I) has two Ra groups which are halogen and alkyl.

[64] The composition of clauses 60 or 61, wherein each Ra group is independently selected from the group consisting of hydroxy, alkyl, and alkoxy.

[65] A composition according to item 60, 61 or 64 wherein formula (I) has three Ra groups which are hydroxy, alkyl and alkoxy.

[66] The composition according to item 60, wherein the compound of formula (I) is a compound selected from those listed in table 1.

[67] The composition according to item 60, 61 or 66, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid or 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[68] A composition according to any one of 60 to 63, 66 and 67, wherein the compound of formula (I) is 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[69] A composition according to any one of 60 to 63 and 66 to 68 comprising 4-amino-3- [6- (4-fluoro-2-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[70] A composition according to any one of 60, 61 and 64 to 67, wherein the compound of formula (I) is 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid.

[71] A composition according to any one of 60, 61, 64 to 67 and 70 comprising 4-amino-3- [6- (3-formyl-2-butoxy-5-tolyl) pyridin-3-ylazo ] naphthalene-1-sulfonic acid sodium salt.

[72] The composition according to any one of claims 60 to 71, wherein the composition is a solution for preserving a corneal graft.

[73] The composition according to any one of 60 to 71, wherein the composition is a composition to be added to a solution for preserving a corneal graft.

The entire contents of the documents cited herein are incorporated by reference.

The following examples are not intended to limit or restrict the present invention. The above-described embodiments are non-limiting and can be modified without departing from the scope of the invention as defined in the appended claims.