Compounds for treating eye diseases associated with excessive angiogenesis

Abstract

The present invention relates to compounds for treating diseases or disorders associated with excessive ocular neovascularization, such as intracorneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, exudative age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy.

Description

[Technical Field]

[0001] The present invention relates to compounds and compositions for treating diseases or disorders associated with excessive ocular neovascularization, such as corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, exudative age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy. [Background technology]

[0002] Laquinimod and taquinimod Laquinimod and tasquinimod are second-generation quinoline-3-carboxamide compounds intended as oral immunomodulators for the treatment of relapsing multiple sclerosis (MS) and chemotherapy-naive metastatic prostate cancer (mCRPC), respectively.

[0003] The efficacy and safety of laquinimod have been evaluated in Phase 1-3 clinical trials, with a known clinical safety profile based on multi-year treatment of 14,000 patients with relapsing MS at doses up to 0.6 mg daily. Data from this clinical development program in MS demonstrated consistent clinical benefit in annualized relapse rates, an endpoint commonly used in relapsing MS. Treatment with laquinimod also demonstrated efficacy in specific disability progression measures.

[0004] The efficacy and safety of tasquinimod have been evaluated in international, randomized, placebo-controlled phase 2 and 3 trials, which showed that treatment with tasquinimod significantly delayed disease progression (the primary endpoint).

[0005] eye disorders Many eye diseases and disorders have no early symptoms. They may be painless, and patients may not notice any changes in their vision until the disease is well advanced. Therefore, prevention, treatment, and / or slowing the progression of such diseases or disorders is of great importance.

[0006] Age-related macular degeneration (AMD) is a serious disease affecting individuals over the age of 60. It is the leading cause of severe, irreversible vision loss in the developed world. The disease impairs sharp central vision, which is necessary to see objects clearly and is essential for normal daily activities such as reading and driving. AMD affects the macula, the central part of the retina that the eye needs to see fine details clearly. There are two types of AMD: wet (exudative) and dry (atrophic) AMD.

[0007] Dry AMD causes gradual blurring of central vision as the macula weakens over time as part of the aging process. This dry form is more common, accounting for 70-90% of AMD cases, but progresses more slowly than wet AMD. As macular function deteriorates over time, the affected eye gradually loses central vision. Dry AMD typically affects both eyes. One of the most common early signs of dry AMD is drusen.

[0008] The exudative ("wet") or neovascular form of AMD, called exudative AMD, is caused by abnormal blood vessel growth in the choriocapillaris (choroidal neovascularization) extending into Bruch's membrane, ultimately leading to leakage of blood and proteins under the macula, resulting in blindness. Bleeding, leakage, and damage from these blood vessels can lead to detachment of the retinal pigment epithelium and irreversible damage to photoreceptors, which, if left untreated, can rapidly lead to blindness. Summary of the Invention

[0009] As mentioned above, it is highly desirable to treat eye diseases or eye disorders associated with excessive angiogenesis, such as wet age-related macular degeneration. Such treatment can potentially prevent or reduce damage to eye tissues such as the macula, and will greatly improve the prognosis of subjects suffering from such eye diseases or eye disorders.

[0010] The present disclosure relates to a composition comprising a compound of formula (I), which is used to treat an ocular disease or disorder associated with excessive ocular neovascularization. The inventors of the present disclosure unexpectedly found that treating induced neovascularization in ocular tissues reduces either corneal or choroidal neovascularization. More specifically, the inventors unexpectedly found that a composition comprising a compound of the present invention inhibits choroidal neovascularization in a laser-induced choroidal neovascularization rat model. The inventors also unexpectedly found an effect in treating growth factor-stimulated angiogenesis in a mouse model; that is, a composition comprising a compound of the present invention was able to reduce the area of ​​neovascularization. These findings may enable entirely novel methods for treating diseases and disorders associated with excessive ocular vascularization, potentially resulting in better outcomes for patients suffering from diseases such as corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, wet age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy.

[0011] That is, the present disclosure provides a composition containing a compound represented by any one of chemical formulas (I) to (IX), which is used to treat an eye disease or eye disorder.

[0012] In one aspect of the present disclosure, there is provided a composition comprising a compound represented by the following formula (IX), or a pharmaceutically acceptable salt thereof, for use in treating an ocular disease or disorder: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R 5 is hydrogen or hydroxy, and R 6 is methyl or hydrogen.

[0013] In one aspect, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is Chloro, R 2 is ethyl, and R 3 is hydrogen or R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl, or R 1 is Chloro, R 2 is hydrogen, and R 3 is hydrogen or or R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl.

[0014] In one particular aspect of the present disclosure, there is provided a composition comprising a compound of Formula (II), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof, for use in treating an ocular disease or disorder: [ka] [ka] [ka] [ka]

[0015] In one particular aspect of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound selected from the group consisting of: Laquinimod, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione, Taskinimod, 4-hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0016] In one aspect of the disclosure, there is provided a method of treating an ocular disease or disorder, comprising administering a composition comprising a compound of formula (IX) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen.

[0017] In one aspect of the present disclosure, there is provided the use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an ocular disease or disorder: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen. [Brief explanation of the drawings]

[0018] [Figure 1] Photograph of a mouse eye showing clearly visible neovascularization. Overlaid on it is a drawing showing how to measure mean vessel length (VL) and continuous circumferential distance (time span within the clock face = CH) from the limbal vessels toward the pellet. [Figure 2] Inhibition of VEGF-induced intracorneal neovascularization. Laquinimod. 5 mg / kg Avastin inhibits 100% (reference). 0.5 mg / kg laquinimod (twice daily) does not inhibit. 2.5 mg / kg laquinimod (twice daily) inhibits 46%. 0.5 mg / kg laquinimod (four times daily) inhibits 8%. 2.5 mg / kg laquinimod (four times daily) inhibits 50%. [Figure 3] Inhibition of bFGF-induced intracorneal neovascularization. Laquinimod. 40 mg / kg Sutent inhibits 80%. 0.5 mg / kg laquinimod (twice daily) inhibits 11%. 2.5 mg / kg laquinimod (twice daily) inhibits 35%. 0.5 mg / kg laquinimod (four times daily) inhibits 37%. 2.5 mg / kg laquinimod (four times daily) inhibits 56%. [Figure 4] Normalized effect sizes relative to mean vessel length. Data were normalized assuming a mean effect size of 0% for vehicle and 100% for the positive control, sulforaphane. Eylea tended to increase effect size (effect size 18%). Test compound ABR215174 significantly increased effect size compared to vehicle (effect size 88.2%). Test compound ABR215062 tended to increase effect size (effect size 53%). DETAILED DESCRIPTION OF THE INVENTION

[0019] definition The term "C1-C4 alkyl" means a moiety containing or consisting of 1, 2, 3, or 4 carbon atoms and multiple hydrogen atoms. Examples of C1-C4 alkyl groups include methyl, ethyl, vinyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl, or sec-butyl.

[0020] "Laquinimod" or "ABR-215062" means a compound of formula (II): [ka]

[0021] "Tasquinimod" means a compound of formula (III): [ka]

[0022] "ABR-215174" means 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid phenylamide, i.e., a compound of formula (IV): [ka]

[0023] "ABR-215691" means 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, a compound of formula (V): [ka]

[0024] "Angiogenesis" and "neovascularization" refer to the process of new blood vessel formation. "Angiogenesis" and "neovascularization" are used synonymously herein.

[0025] As used herein, "vascularisation of the eye" is synonymous with ocular neovascularisation.

[0026] "Excessive angiogenesis" means angiogenesis occurring to a degree that is detrimental to the normal function of the affected tissue, such as during the development of or as a consequence of an ocular disease or disorder, such as corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, proliferative diabetic retinopathy, retinopathy of prematurity, ischemic optic neuropathy, retinal neovascularization, and wet age-related macular degeneration.

[0027] In the context of the present disclosure, the terms "ocular disease or disorder associated with excessive ocular vascularization" and "ocular disease or disorder associated with ocular neovascularization" refer to any ocular disease or disorder that is considered by those skilled in the art to result from and / or cause vascularization of one or more tissues of the eye, including tissues where the vascularization is deleterious to the normal function of the affected tissue. Such diseases or disorders may result in blindness.

[0028] "Treating" is generally meant to include inhibiting, arresting, suppressing, and slowing, halting, or reversing the progression or severity of an eye disease or eye disorder.

[0029] With respect to angiogenesis, the term "degree" refers to the severity of angiogenesis. The degree of angiogenesis can be assessed using several different measurable parameters, such as the area of ​​neovascularization, the amount of blood vessels in the angiogenic region, the length of blood vessels in the angiogenic region, or the thickness of blood vessels in the angiogenic region.

[0030] "Laquinimod carrier" means a carrier for use with laquinimod, which does not contain laquinimod.

[0031] "VEGF" means vascular endothelial growth factor. In mammals, the VEGF family includes five members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PGF). VEGF stimulates cellular responses by binding to VEGF receptors (VEGFRs).

[0032] "bFGF" means basic fibroblast growth factor.

[0033] Compounds and compositions used In one embodiment of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is Chloro, R 2 is ethyl, and R 3 is hydrogen or R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl, or R 1 is Chloro, R 2 is hydrogen, and R 3 is hydrogen or or R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl.

[0034] In a further embodiment of the present disclosure, there is provided a composition comprising a compound of formula (I) for use in treating an ocular disease or disorder, wherein R 1 is chloro, R 2 is ethyl, and R 3 is hydrogen. R 1 is Cl, R 2 is ethyl, and R 3 The generic name of the compound where is H is laquinimod.

[0035] In yet a further embodiment of the present disclosure, there is provided a composition comprising a compound of formula (I) for use in treating an ocular disease or disorder, wherein R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl. R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl. The generic name for the compound is tasquinimod.

[0036] In one embodiment, there is provided a method of treating an ocular disease or disorder, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is Chloro, R 2 is ethyl, and R 3 is hydrogen or R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl, or R 1 is Chloro, R 2 is hydrogen, and R 3 is hydrogen or or R 1 is methoxy, R2 is hydrogen, and R 3 is trifluoromethyl.

[0037] In one embodiment, the present disclosure relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an ocular disease or disorder: [ka] where R 1 is Chloro, R 2 is ethyl, and R 3 is hydrogen or R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl, or R 1 is Chloro, R 2 is hydrogen, and R 3 is hydrogen or or R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl.

[0038] Metabolites of laquinimod and tasquinimod are also disclosed herein. Laquinimod and tasquinimod are metabolized upon administration to a subject. Certain metabolites as disclosed herein have therapeutic activity. In one embodiment of the present disclosure, a composition comprising laquinimod, tasquinimod, or an active metabolite thereof is provided for use in treating an ocular disease or disorder. In one embodiment of the present disclosure, laquinimod or an active metabolite thereof is administered to a subject in need thereof. In another embodiment, tasquinimod or an active metabolite thereof is administered to a subject in need thereof.

[0039] Metabolites of laquinimod include those produced by quinoline hydroxylation (at various sites), quinoline demethylation, aniline deethylation, and aniline hydroxylation in the para position. Specific examples of metabolites of laquinimod include: 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, and 5'-Chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione.

[0040] In one preferred embodiment of the present disclosure, there is provided the laquinimod metabolite 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide (5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid phenylamide, ABR-215174).

[0041] Metabolites of tasquinimod include those produced by aniline demethylation, quinoline-N demethylation, and quinoline-O demethylation. Specific examples of metabolites of tasquinimod include: 4-hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0042] In one preferred embodiment of the present disclosure, there is provided 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, a metabolite of tasquinimod.

[0043] In a preferred embodiment of the present disclosure, the compound is selected from the group consisting of laquinimod, tasquinimod, 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid phenylamide (compound of formula (IV)), and 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide (compound of formula (V)).

[0044] In one embodiment of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound selected from the group consisting of: Laquinimod, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione, Taskinimod, 4-hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0045] In one embodiment of the present disclosure, there is provided a method of treating an ocular disease or disorder, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound selected from the group consisting of: Laquinimod, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione, Taskinimod, 4-hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0046] In one embodiment of the present disclosure, there is provided the use of a compound selected from the group consisting of: Laquinimod, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione, Taskinimod, 4-hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0047] In one embodiment of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound of formula (VI) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is chloro; R 2 is ethyl or hydrogen; R 3 is hydrogen or hydroxy; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen.

[0048] In one embodiment of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound of formula (VII) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is methoxy or hydroxy; R 2 is methyl or hydrogen; R 3 is trifluoromethyl; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen.

[0049] In one embodiment of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound of formula (VIII) or a pharmaceutically acceptable salt thereof: [ka] where R 1is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; and R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro.

[0050] 1. A composition for use in treating an ocular disease or disorder, comprising a compound of formula (IX) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen.

[0051] In one embodiment of the present disclosure, there is provided a method of treating an ocular disease, the method comprising administering a composition comprising a therapeutically effective amount of a compound of Formula (VI), Formula (VII), Formula (VIII), or Formula (IX), or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0052] In one embodiment of the present disclosure, there is provided the use of a compound of Formula (VI), Formula (VII), Formula (VIII), or Formula (IX) or a pharmaceutically acceptable salt thereof as disclosed herein for the manufacture of a medicament for treating an ocular disease or disorder.

[0053] Excessive vascularization of ocular tissues The present disclosure relates to the treatment of ocular diseases or disorders associated with excessive ocular vascularization. Such angiogenesis can occur in response to external stimuli to the eye, such as excessive stress. Angiogenesis can also occur as a natural consequence of aging. Angiogenesis of certain ocular tissues can be detrimental to vision. The eye is composed of several different tissues, such as the cornea, iris, ciliary body, choroid, retina, or macula. Each of these tissues can be subject to angiogenesis.

[0054] In one embodiment of the present disclosure, a compound is provided for treating a subject, wherein the subject is suffering from neovascularization of the cornea, iris, ciliary body, choroid, retina, or macula.

[0055] In one embodiment of the present disclosure, a compound is provided for treating a subject, wherein the subject suffers from neovascularization of anterior ocular tissues such as the cornea, iris, or ciliary body.Corneal transparency is important for visual function.Therefore, corneal neovascularization is harmful to human vision.That is, in a preferred embodiment, the present disclosure provides a composition comprising the compound of the present disclosure for treating intracorneal neovascularization.

[0056] In one embodiment of the present disclosure, the ocular disease or disorder is selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, wet age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy.

[0057] In one embodiment of the present disclosure, the ocular disease or ocular disorder is associated with excessive ocular neovascularization. In one embodiment of the present disclosure, the ocular disease or ocular disorder is corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, exudative age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, or ischemic optic neuropathy associated with excessive ocular neovascularization.

[0058] Retinopathy is damage to the retina that can cause visual impairment. Retinopathy can also refer to damage to the retina caused by retinal vascular disease or abnormal blood flow. Thus, in one embodiment of the present disclosure, a compound is provided for treating a subject, wherein the subject suffers from proliferative diabetic retinopathy, retinopathy of prematurity, or ischemic optic neuropathy. Diabetes is the leading cause of retinopathy, and diabetic retinopathy is one of the leading causes of blindness in working-age people. Thus, in one embodiment of the present disclosure, a composition comprising a compound of the present disclosure is provided for treating a subject, wherein the subject suffers from proliferative diabetic retinopathy.

[0059] In one embodiment of the present disclosure, a compound for treating a subject is provided, wherein the subject suffers from neovascularization of the tissues behind the eye, such as the choroid, retina, or macula. The function of the retina is to receive light collected by the lens, convert it into neural signals, and transmit the signals to the brain for visual recognition. Therefore, any destruction of the retina, such as neovascularization, can adversely affect a person's vision. That is, in a preferred embodiment of the present disclosure, a composition comprising a compound of the present disclosure is provided for treating a subject suffering from retinal neovascularization.

[0060] The macula is the central region of the retina. It plays a key role in central, high-resolution color vision, which can occur under good lighting conditions. Damage to the macula can result in loss of central vision, which can have a significant adverse effect on a person's ability to read and recognize other people's faces. Therefore, in the most preferred embodiment of the present disclosure, a composition comprising a compound of the present disclosure is provided for treating a subject suffering from macular neovascularization. Macular neovascularization is also known as wet age-related macular degeneration. Therefore, in the most preferred embodiment of the present disclosure, a composition comprising a compound of the present disclosure is provided for treating a subject suffering from wet age-related macular degeneration. In one embodiment of the present disclosure, wet age-related macular degeneration is associated with excessive ocular neovascularization.

[0061] In a preferred embodiment of the present disclosure, the term "ocular disease or disorder associated with ocular hypervascularization" does not include uveitis or conjunctivitis.

[0062] Combination Administration of the Compositions of the Disclosure with VEGF Inhibitors Vascular endothelial growth factor (VEGF) stimulates angiogenesis. VEGF inhibitors have the effect of reducing tissue angiogenesis by binding to VEGF. Alternatively, VEGF inhibitors can affect the activity of VEGF by binding to VEGF receptors.

[0063] The composition of the present disclosure may be administered in combination with a VEGF inhibitor to treat eye diseases or eye disorders, such as eye diseases or eye disorders associated with excessive ocular angiogenesis. Such combined therapy is potentially more effective in treating eye diseases or eye disorders than the composition of the present disclosure and / or a VEGF inhibitor alone. Therefore, in one embodiment of the present disclosure, the compound of the present disclosure is administered in combination with a VEGF inhibitor to treat eye diseases or eye disorders.

[0064] VEGF inhibitors include antibodies, antibody-derived fragments, recombinant proteins, and recombinant fusion proteins (such as aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, and faricimab). Accordingly, in one embodiment of the present disclosure, a compound of the present disclosure is administered in combination with aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, or faricimab to treat an ocular disease or disorder. In a preferred embodiment, a compound of the present disclosure is administered in combination with aflibercept, ranibizumab, bevacizumab, or brolucizumab to treat an ocular disease or disorder.

[0065] Aflibercept (Eylea), a recombinant protein, has affinity for VEGF-A, VEGF-B, and PGF. This VEGF inhibitor has been shown to be effective in treating wet AMD. In a preferred embodiment of the present disclosure, the compound of the present disclosure is administered in combination with aflibercept to treat ocular diseases or disorders.

[0066] The monoclonal antibody fragment ranibizumab has affinity for VEGF-A. This antibody fragment is known to be effective in treating wet AMD. In one embodiment of the present disclosure, the compound of the present disclosure is administered in combination with ranibizumab to treat eye diseases or eye disorders.

[0067] Bevacizumab (Avastin) is an IgG1-based antibody that binds to VEGF-A. Bevacizumab has been shown to be effective in treating wet AMD. Therefore, in one embodiment of the present disclosure, a compound of the present disclosure is administered in combination with bevacizumab to treat an eye disease or eye disorder.

[0068] Brolucizumab is an sc antibody fragment with affinity for VEGF-A. In one embodiment of the present disclosure, a compound of the present disclosure is administered in combination with the administration of bevacizumab to treat an ocular disease.

[0069] The peptide abicipar pegol is a known VEGF-A inhibitor. In one embodiment of the present disclosure, a compound of the present disclosure is administered in combination with the administration of abicipar pegol to treat an ocular disease or disorder.

[0070] Conbercept is a recombinant fusion protein that has affinity for VEGF-A. Thus, in one embodiment of the present disclosure, a compound of the present disclosure is administered in combination with the administration of conbercept to treat an ocular disease or disorder.

[0071] Faricimab, a bispecific monoclonal antibody, modulates the activity of both Angiopoietin-2 and VEGF-A. Thus, in one embodiment of the present disclosure, a compound of the present disclosure is administered in combination with faricimab to treat an ocular disease or disorder.

[0072] In one embodiment of the present disclosure, the composition of the present disclosure comprises or is administered in combination with an angiogenesis inhibitor. In one particular embodiment of the present disclosure, the angiogenesis inhibitor is aflibercept.

[0073] In one embodiment of the present disclosure, a composition comprising a compound of the present disclosure may be administered topically, orally, intravitreally, subconjunctivally, retrobulbarly, intracamerally, or systemically to a subject in need thereof.

[0074] In the treatment of diseases or disorders that are limited to only one part of the body, such as ocular diseases and / or disorders, it may be beneficial to administer the drug targeting the disease or disorder via a route that allows the drug to be primarily localized at the site of the disease or disorder. Thus, in a preferred embodiment of the present disclosure, a composition comprising a compound of the present disclosure may be administered to a subject in need thereof via topical, intravitreal, subconjunctival, retrobulbar, or intracameral routes.

[0075] In one embodiment of the present disclosure, the composition of the present disclosure is administered in a manner that achieves systemic administration of the composition of the present disclosure. In a further embodiment of the present disclosure, the administration of the composition of the present disclosure is oral administration.

[0076] In the treatment of diseases or disorders that require frequent administration of a drug to a subject, it may be beneficial to formulate the drug in a manner that allows for self-administration. Those skilled in the art will understand the types of formulations that are suitable for self-administration.

[0077] As outlined herein, the compositions of the present invention may be administered in combination with a VEGF inhibitor, i.e., in one embodiment, the composition of the present disclosure and the VEGF inhibitor are administered simultaneously by being included in the same formulation.

[0078] The combination therapy described herein is not limited to compositions containing both a compound of the present disclosure and a VEGF inhibitor. Alternatively, the compound of the present disclosure and the VEGF inhibitor may be administered in different formulations. The choice of administering the compound of the present disclosure and the VEGF inhibitor as separate formulations may be due to different preferred dosing schedules for the compound of the present disclosure and the VEGF inhibitor, respectively. For example, it may be more preferable to administer the VEGF inhibitor less frequently, such as every few months, while it may be beneficial to administer the compound of the present disclosure more frequently, such as daily or weekly. The choice of administering the compound of the present disclosure and the VEGF inhibitor as separate formulations may also be due to the compound of the present disclosure and the VEGF inhibitor not being suitable for the same type of administration route. For example, the compound of the present disclosure may be suitable for one type of administration route, particularly topical administration, while the VEGF inhibitor may be suitable for a second type of administration route, such as intravitreal injection. Thus, in one embodiment, the compound of the present disclosure and the VEGF inhibitor are each contained in different formulations, and each formulation is administered at a different frequency. In another embodiment, the compound of the present disclosure and the VEGF inhibitor are each in different formulations, and each formulation is administered using a different route of administration.

[0079] VEGF inhibitors are typically administered via intravitreal injection to treat ocular diseases or disorders, such as those associated with ocular neovascularization. Intravitreal injections are often administered in hospitals or general practitioner clinics. Intravitreal injections used to treat ocular neovascularization-related diseases are typically administered every few months, for example, monthly, every three months, or every six months. Intravitreal injections are administered under local anesthesia. Adverse effects of intravitreal injections include increased intraocular pressure, floaters, inflammation, bleeding, corneal damage, retinal damage or peripheral nerve damage, and infection. Furthermore, the need to visit a general practitioner clinic or hospital every few months for injection procedures can be inconvenient. In addition, some individuals may find intravitreal injections uncomfortable or unpleasant. Local treatment with a compound of the present disclosure before, at the time of, or between intravitreal injections of a VEGF inhibitor can extend the time until further VEGF injections are required. Thus, in one embodiment of the present disclosure, topical treatment of an ocular disease or disorder (such as an ocular disease or disorder associated with excessive ocular vascularization) with a composition comprising a compound of the present disclosure results in the need for less frequent intravitreal injections of a VEGF inhibitor than would be the case with intravitreal injections of a VEGF inhibitor alone. Furthermore, in one embodiment, the compound of the present disclosure and the VEGF inhibitor are contained in different compositions, where administration of the composition comprising a compound of the present disclosure results in treatment of the ocular disease or disorder and reduces the need for intravitreal VEGF inhibitor injections.

[0080] treatment In one embodiment of the present disclosure, there is provided a composition comprising a compound of the present disclosure. In a further embodiment, there is provided a composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0081] There are different routes for administering a drug to the eye. For example, a drug may be administered topically to the eye. That is, in one embodiment, a composition comprising a compound of the present disclosure is administered topically to the eye. Those skilled in the art will understand the types of administration routes suitable for administration to the eye.

[0082] In one embodiment of the present disclosure, a composition comprising a compound of the present disclosure is administered orally.

[0083] In one embodiment of the present disclosure, there is provided a composition for use in treating an ocular disease or disorder, comprising a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein the ocular disease or disorder is wet age-related macular degeneration: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen.

[0084] In one embodiment of the present disclosure, there is provided a method of treating wet age-related macular degeneration in a subject, the method comprising administering to the subject a composition comprising a compound of formula (I): [ka] where R 1 is Chloro, R 2 is ethyl, and R 3 is hydrogen; R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl; R 1 is Chloro, R 2 is hydrogen, and R 3 is hydrogen; or R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl.

[0085] In a further embodiment, the present disclosure provides a method for treating wet age-related macular degeneration in a subject, the method comprising administering laquinimod to the subject.In another embodiment, the present disclosure provides a method for treating wet age-related macular degeneration, the method comprising administering a therapeutically effective amount of tasquinimod to the subject.In yet another embodiment, the present disclosure provides a method for treating wet age-related macular degeneration, the method comprising administering a therapeutically effective amount of ABR-215691 to the subject.In yet another embodiment, the present disclosure provides a method for treating wet age-related macular degeneration, the method comprising administering a therapeutically effective amount of ABR-215174 to the subject.

[0086] The compounds disclosed herein may be used in the manufacture of a medicament. Thus, in one embodiment of the present invention, a compound of formula (I) is used in the manufacture of a medicament for treating wet age-related macular degeneration: [ka] where R 1 is Chloro, R 2 is ethyl, and R 3 is hydrogen; R 1 is methoxy, R 2 is methyl, and R 3 is trifluoromethyl; R 1 is Chloro, R 2 is hydrogen, and R 3 is hydrogen; or R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl.

[0087] In another embodiment, laquinimod is used in the manufacture of a medicament for treating wet age-related macular degeneration. In yet another embodiment, tasquinimod is used in the manufacture of a medicament for treating wet age-related macular degeneration. In yet another embodiment, ABR-215174 is used in the manufacture of a medicament for treating wet age-related macular degeneration. In yet another embodiment, ABR-215691 is used in the manufacture of a medicament for treating wet age-related macular degeneration.

[0088] item Item 1: A composition comprising a compound of the following chemical formula (IX) or a pharmaceutically acceptable salt thereof, for use in treating an eye disease or eye disorder: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen. Item 2: A composition for use according to item 1, wherein the compound is a compound of the following chemical formula (VIII) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; and R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro. Item 3: A composition for use according to any one of the preceding items, wherein the compound is a compound of the following chemical formula (VII) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is methoxy or hydroxy; R 2 is methyl or hydrogen; R 3 is trifluoromethyl; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen. Item 4: A composition for use according to any one of the preceding items, wherein the compound is a compound of the following chemical formula (VI) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is chloro; R 2 is ethyl or hydrogen; R 3 is hydrogen or hydroxy; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen. Item 5: A composition comprising 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione or a pharmaceutically acceptable salt thereof, for use in treating an eye disease or eye disorder. Item 6: A composition for use according to any one of the preceding items, wherein the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof: Laquinimod, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide, 5-chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, Taskinimod, 4-hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide. Item 7: A composition for use according to any one of the preceding items, wherein the compound is a compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is chloro; R 2 is ethyl or hydrogen; and R 3 is hydrogen; or R 1 is methoxy; R 2 is methyl or hydrogen; and R 3 is trifluoromethyl. Item 8: A composition for use according to any one of the preceding items, wherein the compound is laquinimod or a pharmaceutically acceptable salt thereof. Item 9: A composition for use according to any one of the preceding items, wherein the compound is tasquinimod or a pharmaceutically acceptable salt thereof. Item 10: A composition for use according to any one of the preceding items, wherein the compound is a compound of the following chemical formula (IV) or a pharmaceutically acceptable salt thereof: [ka] Item 11: A composition for use according to any one of the preceding items, wherein the compound is a compound of the following chemical formula (V) or a pharmaceutically acceptable salt thereof: [ka] Item 12: A composition for use according to any one of the preceding items, wherein the ocular disease or disorder is selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, exudative age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy. Item 13: A composition for use according to any one of the preceding items, wherein the ocular disease or disorder is selected from the group consisting of intracorneal neovascularization, iris neovascularization, ciliary body neovascularization, and corneal pannus. Item 14: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is intracorneal neovascularization. Item 15: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is selected from the group consisting of proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy. Item 16: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is proliferative diabetic retinopathy. Item 17: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is retinopathy of prematurity. Item 18: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is ischemic optic neuropathy. Item 19: A composition for use according to any one of the preceding items, wherein the ocular disease or disorder is selected from the group consisting of choroidal neovascularization, retinal neovascularization, and wet age-related macular degeneration. Item 20: A composition for use according to any one of the preceding items, wherein the ocular disease or disorder is choroidal neovascularization. Item 21: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is retinal neovascularization. A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is wet age-related macular degeneration. Item 22: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is not uveitis or conjunctivitis. Item 23: A composition for use according to any one of the preceding items, wherein the eye disease or eye disorder is associated with excessive ocular vascularization. Item 24: A composition for use according to any one of the preceding items, wherein the composition comprises an angiogenesis inhibitor such as aflibercept or the composition is administered in combination with an angiogenesis inhibitor such as aflibercept. Item 25: A composition for use according to any one of the preceding items, wherein the composition is administered in combination with one or more VEGF inhibitors. Item 26: A composition for use according to any one of the preceding items, wherein the composition is administered in combination with one VEGF inhibitor. Item 27: A composition for use according to any one of the preceding items, wherein the composition further comprises one VEGF inhibitor. Item 28: A composition for use according to any one of the preceding items, wherein the composition further comprises one VEGF inhibitor. Item 29: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is selected from the group consisting of aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, and faricimab. Item 30: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is selected from the group consisting of aflibercept, ranibizumab, bevacizumab, and brolucizumab. Item 31: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is aflibercept. Item 32: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is ranibizumab. Item 33: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is bevacizumab. Item 34: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is brolucizumab. Item 35: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is abicipar pegol. Item 36: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is conbercept. Item 37: A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is faricimab. Item 38: A composition for use according to any one of the preceding items, wherein the composition comprises at least one pharmaceutically acceptable excipient or is administered in combination with at least one pharmaceutically acceptable excipient. Item 39: A composition for use according to any one of the preceding items, wherein the route of administration is topical, oral, intravitreal, subconjunctival, retrobulbar, intracameral, or systemic. Item 40: A composition for use according to any one of the preceding items, wherein the route of administration is topical. Item 41: A composition for use according to any one of the preceding items, wherein the route of administration is oral. Item 42: A composition for use according to any one of the preceding items, wherein the route of administration is intravitreal. Item 43: A composition for use according to any one of the preceding items, wherein the route of administration is subconjunctival. Item 44: A composition for use according to any one of the preceding items, wherein the route of administration is retrobulbar. Item 45: A composition for use according to any one of the preceding items, wherein the route of administration is intracameral. Item 46: A composition for use according to any one of the preceding items, wherein the route of administration is systemic. Item 47: A method for treating wet age-related macular degeneration, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of the following chemical formula (IX) or a pharmaceutically acceptable salt thereof: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen. Item 48: Use of a compound of the following chemical formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an eye disease or eye disorder: [ka] where R 1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl (such as methyl, ethyl, or vinyl); R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; R 4 is selected from the group consisting of hydrogen, fluoro and chloro, with the proviso that R 3 When R is selected from fluoro and chloro, 4 is selected only from fluoro and chloro; R 5 is hydrogen or hydroxy; and R 6 is methyl or hydrogen.

[0089] Example 1: Inhibition of choroidal neovascularization in a laser-induced choroidal neovascularization rat model Study Design Forty-eight Brown Norway pigmented rats were divided into six groups of eight animals each. On day 0, choroidal neovascularization was induced in the right eye using a 532 nm argon laser photocoagulator (six 75 μm spots; 150 mW for 0.1 seconds). From immediately after choroidal neovascularization induction on day 0 (D0) until day 21 (the final day of the study), test substances were administered by eye drop administration three times daily or orally twice daily. Vehicle control was administered by eye drop administration three times daily from immediately after neovascularization induction on day 0 until day 21, and dexamethasone (in olive oil) was administered orally daily as a reference. Neovascularization in the fundus of the right eye was evaluated on days 14 and 21 using a Heidelberg retinal angiography (HRA). At the end of the in vivo period, lesion size was measured on flattened, mounted samples of the choroid labeled with isolectin-B4.

[0090] Induction of angiogenesis On day 0, animals were anesthetized intramuscularly with a mixture of xylazine (5 mg / kg) and ketamine (25 mg / kg). The pupil of the right eye was dilated with a single drop of 0.5% tropicamide. Then, choroidal ablation (75 μm spot size) was performed at six sites between the major vascular branches around the optic disc using an argon laser photocoagulator (532 nm; 150 mW for 0.1 seconds) at a slit lamp with a contact lens. Bruch's membrane rupture was confirmed by the appearance of bubbles during the laser treatment.

[0091] Route and method of administration From day 0 (immediately after induction) through day 21 (the final day of the study), test, control, or reference substances were administered topically via eye drops (10 μL each) or orally (1 mL / kg). Test and control substances were administered three times daily via eye drops and twice daily via oral administration. The reference substance was administered orally once daily.

[0092] body weight The body weight of all animals was recorded before the start of the study and then weekly.

[0093] Fluorescein angiography Fluorescein angiography was performed using a Heidelberg Retinal Angiograph (HRA) on days 14 and 21. After anesthesia (using the same mixture as used for ChNV induction) and pupil dilation, 250 μL / 100 g (body weight) of 10% fluorescein sodium salt was injected subcutaneously using a 26-gauge insulin syringe, and photographic images of the fluorescein were recorded 10 min after dye injection.

[0094] Fluorescein angiographic evaluation Fluorescein leakage on the angiogram was examined in a blinded manner by two examiners and scored as follows: score 0, no leakage; score 1, slight staining; score 2, moderate staining; score 3, strong staining; In cases where there was a discrepancy between the two scores given to a particular lesion, the higher score was used for analysis.

[0095] Data Processing For each animal, the lesions visualized by HRA and the flattened mounted specimens were scored and statistically analyzed using the Mann-Whitney U test or an appropriate statistical model.

[0096] Animal behavior and mortality The general behavior and appearance of all animals were observed and recorded as raw data. No specific signs were observed, and the general behavior and appearance of the animals were normal. All animals survived until scheduled euthanasia.

[0097] Animal weight Animal weights were recorded before induction and treatment (baseline) and weekly thereafter. Animal weights were within the normal range, ranging from 166 to 202 g (min-max, n = 48) at baseline. At day 21, no significant differences were observed between test and control items. Animals treated with the reference item (dexamethasone) showed a 21% weight loss over the study period. This loss is an expected adverse effect of orally administered corticosteroids.

[0098] Angiographic evaluation Fluorescein angiography (FA) was scored based on the fluorescence intensity of each lesion. For each treatment group, results were expressed as the mean score within the group for each time point. Table 1 summarizes the FA scores recorded at 10 minutes on days 14 and 21 (n = 8 animals per group, right eyes). Statistical analysis was performed on the median individual intensity scores using the Kruskal-Wallis test followed by the Mann-Whitney multiple comparison U test (used to compare the test, control, or reference groups, respectively).

[0099] [Table 1]

[0100] conclusion Vehicle-treated animals showed leakage in 63% and 66% of the assessed spots on days 14 and 21, respectively, indicating the occurrence and persistence of choroidal neovascularization (ChNV). However, daily topical administration of laquinimod effectively reduced vascular leakage, suggesting that laquinimod effectively reduced ChNV.

[0101] Example 2: Inhibition of VEGF-induced angiogenesis and bFGF-induced angiogenesis Evaluation method for the area of ​​neovascularization The vascularized area can be measured using the following formula: Area=0.2·VL·CH·π Here, the vessel length (VL) and continuous circumferential distance (time width within the clock face = CH) are measured as defined in Figure 1.

[0102] Laquinimod treatment of VEGF-induced intracorneal neovascularization To induce angiogenesis, a Hydron pellet was prepared using a stimulator (VEGF) and a binder (sucralfate).

[0103] Fifty-three CR female C57BL / 6 mice, 6-8 weeks old, were anesthetized with 90 mg / kg pentobarbital intraperitoneally in preparation for surgery. An incision was made in one eye, and a pellet was inserted into the corneal pocket to induce corneal neovascularization. The eye was carefully monitored for signs of inflammation or infection.

[0104] Formulations of laquinimod in DI water (deionized water), carrier (DDW = double distilled water), and Avastin (positive control) were applied directly to the pellet-containing eyeball. Angiogenesis was assessed on day 8. The treatment regimen is shown in Table 2. The results are shown in Table 3 and Figure 2.

[0105] [Table 2]

[0106] [Table 3]

[0107] Laquinimod treatment of VEGF-induced corneal neovascularization showed a dose-dependent effect. No inhibition was observed at the low dose (0.5 mg / kg, twice daily, Group 4). Only slight inhibition was observed with more frequent administration (0.5 mg / kg, four times daily, Group 6, 8% inhibition). Significant inhibition of neovascularization was observed with increasing doses, both at low daily doses (2.5 mg / kg, twice daily, Group 5, 46% inhibition) and at high daily doses (2.5 mg / kg, four times daily, Group 7, 50% inhibition).

[0108] Laquinimod treatment of bFGF-induced intracorneal neovascularization To induce angiogenesis, Hydron pellets were prepared using a stimulator (bFGF) and a binder (sucralfate).

[0109] Forty-seven 6- to 8-week-old CR female C57BL / 6 mice were anesthetized with 90 mg / kg pentobarbital intraperitoneally in preparation for surgery. An incision was made in one eye, and a pellet was inserted into the corneal pocket to induce corneal neovascularization. The eye was carefully monitored for signs of inflammation or infection.

[0110] Formulations of laquinimod in DI water (deionized water), carrier (DDW = double distilled water), and Avastin (positive control) were applied directly to the eyeball containing the pellet. Angiogenesis was assessed on day 6. The treatment regimen is shown in Table 4. The results are shown in Table 5 and Figure 3.

[0111] [Table 4]

[0112] [Table 5]

[0113] conclusion Laquinimod treatment of bFGF-induced corneal neovascularization demonstrated a dose-dependent effect. A low dose (0.5 mg / kg, twice daily, Group 4) inhibited angiogenesis by 11%, while a high dose (2.5 mg / kg, twice daily, Group 5) inhibited angiogenesis by 35%. Increasing the frequency of administration further enhanced the inhibition, with a high-frequency low-dose (0.5 mg / kg, four times daily, Group 6) inhibiting angiogenesis to a similar extent (37%) as a low-frequency high-dose (Group 5). Daily administration of a high-frequency high-dose (2.5 mg / kg, four times daily, Group 7) further inhibited angiogenesis (56%).

[0114] Example 3: Laquinimod and ABR-215174 have effects on LPS-activated microglia-induced human retinal microvascular endothelial cell tube formation method The following experimental groups were included in the study: Group 1: Control (vehicle, 0.1% DMSO) Group 2: sulforaphane (10 μM, positive control, anti-angiogenic effect) Group 3: Aflibercept (Eylea 40 μg / ml, positive control, partial anti-angiogenic effect) Group 4: ABR-215174 (0.1 μM) Group 5: ABR-215062 (10μM)

[0115] Human retinal microvascular endothelial cells (HRMECs) were purchased from Neuromics (catalog number HEC09, lot #2872) and cultured according to the manufacturer's instructions in endothelial growth medium (catalog number EKG001, lot #EKG0011902269) containing endothelial growth factor (catalog number EKG001, lot #EGK00125) at 37°C and 5% CO2 in AlphaBiocoat-coated T25 flasks.

[0116] Brain-derived primary human microglia were purchased from Celprogen (Cat. No. 37089-01, Lot #1614454-01) and cultured in poly-L-lysine (PLL, 50 mg / ml)-coated T25 flasks at 37°C and 5% CO2 using complete microglia growth medium containing antibiotics (Cat. No. M37089-01, Lot #2010089205-03) and standard 10% fetal bovine serum (Neuromics, Lot #042P20).

[0117] Human microglial cells were cultured at 103,000 cells / cm on PLL-coated cell culture inserts (Sarstedt, Cat. No. 83.3932.040). 2 Prior to activation with lipopolysaccharide (LPS), microglia were treated for 24 hours with test compounds, aflibercept, and vehicle in complete microglial growth medium at the following concentrations: Carrier (0.1% DMSO) Aflibercept (Eylea®, 40 g / ml), 0.1% DMSO ABR-215174 (0.1 μM), 0.1% DMSO ABR-215062 (10 μM), 0.1% DMSO

[0118] The method of co-culturing microglia with HRMECs was described in Ding et al., 2018 (Ding X, Gu R, Zhang M, Ren H, Shu Q, Xu G, Wu H. Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs. BMC Ophthalmol. 2018,18(1):249. doi: 10.1186 / s12886-018-0886-z. PMID: 30223824; PMCID: PMC6142340) and Ji Cho et al., 2019 (Ji Cho M, Yoon SJ, Kim W, Park J, Lee J, Park JG, Cho YL, Hun Kim J, Jang H, Park YJ, Lee SH, Min JK. This protocol was modified from that described in Oxidative stress-mediated TXNIP loss causes RPE dysfunction (Exp Mol Med. 2019 Oct 15;51(10):1-13. doi: 10.1038 / s12276-019-0327-y. PMID: 31615975; PMCID: PMC6802648). Microglia were activated with LPS (100 ng / ml) in complete microglia growth medium without FBS and simultaneously treated with freshly prepared test compounds, Eylea, or vehicle for 24 hours. HRMECs were incubated in basal endothelial cell growth medium for 24 hours before co-culture.

[0119] HRMECs (42,000 cells / cm) were cultured in a 24-well plate coated with Matrigel®. 2 ) were seeded and treated with test compounds, aflibercept and sulforaphane, prepared freshly in parallel in endothelial cell growth basal medium: Carrier (0.1% DMSO) Sulforaphane (10 M), 0.1% DMSO Aflibercept (Eylea®, 40 μg / ml), 0.1% DMSO ABR-215174 (0.1 μM), 0.1% DMSO ABR-215062 (10 μM), 0.1% DMSO

[0120] The medium in the microglial insert containing LPS was replaced with the corresponding basal endothelial cell growth medium containing freshly prepared test compounds, aflibercept, and sulforaphane. The insert containing activated microglial cells was transferred to a 24-well plate containing HRMECs. These co-cultures were incubated at 37°C and 5% CO2, stained with calcein AM (5 μM) for 30 minutes, and imaged using a fluorescence microscope (Leica Thunder 3D Tissue Imager, Leica Microsystems).

[0121] Image analysis was performed using AngioTool software for ImageJ (NIH public domain) (Zudaire E, Gambardella L, Kurcz C, Vermeren S (2011) A Computational Tool for Quantitative Analysis of Vascular Networks. PLOS ONE 6(11): e27385. https: / / doi.org / 10.1371 / journal.pone.0027385). Total vessel area, vessel length, density, porosity, and branching index (number of branch points and end points) were quantified.

[0122] Image analysis was performed using AngioTool software (NIH, Bethesda, MD; released in the public domain) for the following measurements: mean vessel length, total vessel length, vessel area, percent vessel area, total branch points, branch point density, total endpoints, and mean porosity. Raw data for length and area measurements are reported in mm or μm (and mm 2 or μm 2The raw data for each measurement were plotted and analyzed by ordinary one-way analysis of variance and Dunnett's multiple comparison post-hoc test.

[0123] Effect sizes were calculated by subtracting the vehicle group mean from each value and then normalizing the data to the sulforaphane (positive control) condition, where the sulforaphane group mean equals the maximum effect size (100%) and the vehicle mean equals no effect size (0%). Effect size data were analyzed with the nonparametric Kruskal-Wallis test and Dunn's multiple comparison post-hoc test.

[0124] Results and Conclusions The difference in normalized effect size for mean vessel length between the sulforaphane and vehicle groups reached statistical significance (Figure 4). Test compound ABR215174 (88.2% ES) significantly increased the ES for mean vessel length compared to vehicle. Effect sizes for Eylea (18% ES) and test compound ABR215062 (53% ES) showed a trend toward increased ES for mean vessel length, although not statistically significant.

[0125] Since sulforaphane is a known and widely accepted positive control for angiogenesis inhibition, these results indicate that the test compounds ABR215174 and ABR215062 can also be used to inhibit angiogenesis.

[0126] Example 4: Additive effect of laquinimod or ABR-215174 in combination with angiogenesis inhibitors such as aflibercept (Eylea®) on LPS-activated microglia-induced human retinal microvascular endothelial cell tube formation compared to monotherapy Microglia, especially activated microglia, play an important role in retinal microvascular angiogenesis and hemostasis, maintaining vascular function (Ding et al., 2018). Co-culture of human retinal microvascular endothelial cells (HRMECs) and brain-derived human microglia may be used to evaluate the effects of compounds of the present disclosure, such as laquinimod, tasquinimod, ABR-215174, or ABR-215691, on angiogenesis. Methods such as those outlined below may be used.

[0127] method The test may be carried out substantially as outlined in Example 3.

[0128] Tube formation assay Tube formation assays are performed using wells of 24-well plates coated with Matrigel or 96-well plates as described in Ding et al., 2018 (Ding et al., BMC Ophthalmology (2018) 18:249). 50 μL / well of Matrigel is used to coat the 96-well plates for 30 minutes at 37°C. After 24 hours of co-culture with microglia, 1.5 × 10 HRMECs are plated on Matrigel in 100 μL of medium. 4 Seed cells / well. After a set time, e.g., 4 hours, observe and photograph tube formation under a microscope (Leica Microsystems). Analyze images using the Angiotool plugin (Zudaire et al., 2011, PLoS One, 6, 11, e27385) for ImageJ (NIH public domain). Quantify total vessel area, tube length, density, porosity, and branching index (number of branch points and end points).

[0129] Results and Conclusions It is believed that when compounds of the present disclosure, such as laquinimod at 1 μM and 10 μM or ABR-215174 at 0.01 μM and 0.1 μM, are combined with aflibercept (30 nM), a clear additive effect will be seen compared to each compound used as monotherapy.

Claims

1. Chemical formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof: Here, R １ Chloro, R ２ is ethyl or hydrogen, and R ３ is hydrogen; A composition for use in treating an ocular disease or disorder selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, exudative age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy.

2. 10. The composition for use according to claim 1, wherein the compound is laquinimod or a pharmaceutically acceptable salt thereof.

3. 2. A composition for use according to claim 1, wherein the compound has the formula (IV): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

4. A composition for use as described in any one of claims 1 to 3, wherein the ocular disease or ocular disorder is selected from the group consisting of intracorneal neovascularization, iris neovascularization, ciliary body neovascularization, and corneal pannus.

5. 4. A composition for use according to any one of claims 1 to 3, wherein the ocular disease or disorder is selected from the group consisting of proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic optic neuropathy.

6. 4. A composition for use according to any one of claims 1 to 3, wherein the ocular disease or disorder is selected from the group consisting of choroidal neovascularization, retinal neovascularization, and wet age-related macular degeneration.

7. 7. A composition for use according to claim 6, wherein the eye disease or eye disorder is wet age-related macular degeneration.

8. A composition for use as described in any one of claims 1 to 7, wherein the composition comprises an angiogenesis inhibitor comprising aflibercept, or the composition is administered in combination with an angiogenesis inhibitor comprising aflibercept.

9. A composition for use as defined in any one of claims 1 to 8, wherein the composition comprises a VEGF inhibitor or the composition is administered in combination with a VGF inhibitor.

10. 10. The composition for use according to claim 9, wherein the VEGF inhibitor is selected from the group consisting of aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, and faricimab.

11. A composition for use as defined in any one of claims 1 to 10, wherein the composition comprises at least one pharmaceutically acceptable excipient or the composition is administered in combination with at least one pharmaceutically acceptable excipient.

12. A composition for use as defined in any one of claims 1 to 11, wherein the route of administration is topical, oral, intravitreal, subconjunctival, retrobulbar, intracameral, or systemic.

Images