Compounds for treating ocular diseases associated with excessive angiogenesis

Abstract

The present invention relates to compounds useful for treating diseases or conditions associated with excessive vascularization of the eye, 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 retinopathy.

Description

Technical Field

[0001] The present invention relates to compounds and compositions for treating diseases or conditions associated with excessive vascularization of the eye, 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 retinopathy. Background Art

[0002] Laquinimod and taquinimod

[0003] Laquinimod and tasquinimod are second-generation quinoline-3-carboxamide compounds that have been developed as oral immunomodulators for the treatment of relapsing forms of multiple sclerosis (MS) and metastatic prostate cancer that has not been treated with chemotherapy, respectively. prostate cancer, mCRPC).

[0004] The efficacy and safety of laquinimod have been evaluated in Phase 1-3 clinical studies, and it has a confirmed clinical safety profile based on exposure to daily doses of up to 0.6 mg in relapsing MS patients for more than 14,000 patient years. Data from the MS clinical development program have demonstrated consistent clinical benefits on annual relapse rate, a widely used endpoint in relapsing MS. Laquinimod treatment also resulted in certain measures of disability progression.

[0005] The efficacy and safety of taquimod have been evaluated in global, randomized, placebo-controlled Phase 2 and Phase 3 studies. In the Phase 2 and Phase 3 studies, taquimod treatment significantly delayed disease progression (primary endpoint).

[0006] Eye Conditions

[0007] Many eye diseases and conditions have no early symptoms. They may be painless, and patients may not see changes in their vision until the disease becomes quite severe. Therefore, preventing, treating and / or slowing the progression of these diseases or conditions is of paramount importance.

[0008] Age-related macular degeneration (AMD) is a devastating disease that affects individuals over the age of 60. It is the leading cause of irreversible, severe vision loss in developed countries. The disease causes impairment of sharp and central vision. Central vision is necessary to see objects clearly and for everyday tasks such as reading and driving. AMD affects the macula, the central part of the retina that allows the eye to see fine details. There are two forms of AMD - wet and dry.

[0009] Dry AMD occurs when the macula thins over time as part of the aging process, gradually blurring central vision. The dry form is more common, accounting for 70-90% of AMD cases, and progresses more slowly than the wet form. Over time, the affected eye gradually loses central vision as the macula loses function. Dry AMD usually affects both eyes. One of the most common early signs of dry AMD is drusen.

[0010] The exudative ("wet") or neovascular form of AMD, wet AMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris through Bruch's membrane, ultimately leading to leakage of blood and protein beneath the macula. If left untreated, bleeding, leakage, and scarring of these vessels can lead to detachment of the retinal pigment epithelium and irreversible damage to photoreceptors and rapid vision loss. Summary of the invention

[0011] As described above, there is a great need for treatments for ocular diseases or conditions associated with excessive vascularization, such as wet age-related macular degeneration. Such treatments could potentially prevent or reduce damage to ocular tissues such as the macula, which would significantly improve the prognosis for subjects suffering from such ocular diseases or conditions.

[0012] The present disclosure relates to compositions comprising a compound of formula (I) for use in treating ocular diseases or ocular conditions associated with excessive vascularization of the eye. The inventors of the present disclosure surprisingly found that treating induced vascularization of ocular tissue resulted in reduced vascularization of the cornea or choroid. More specifically, the inventors surprisingly found that a composition comprising a compound of the present invention inhibited choroidal neovascularization in a rat model of laser-induced choroidal neovascularization. The inventors also found surprising effects in treating growth factor-stimulated neovascularization in a mouse model, wherein a composition comprising a compound of the present invention was able to reduce the area of ​​vascularization. These findings provide a completely new approach to treating diseases and conditions associated with excessive vascularization of the eye, which may result in better prognosis for patients with 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 retinopathy.

[0013] Accordingly, the present disclosure provides a composition comprising a compound according to any one of formulae (I) to (IX) for use in treating an ocular disease or ocular disorder.

[0014] One aspect of the present disclosure provides a composition comprising a compound according to formula (IX) or a pharmaceutically acceptable salt thereof:

[0015]

[0016] in

[0017] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0018] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0019] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0020] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0021] R 5 is hydrogen or hydroxyl, and

[0022] R 6 is methyl or hydrogen,

[0023] It is used to treat eye diseases or eye conditions.

[0024] In one aspect, a composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0025]

[0026] in:

[0027] R 1 is chlorine, R 2 is ethyl, and R 3 It is hydrogen,

[0028] R 1 is methoxy, R 2 is a methyl group, and R 3 is trifluoromethyl,

[0029] R 1 is chlorine, R 2 is hydrogen, and R 3 It is hydrogen,

[0030] or

[0031] R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl;

[0032] It is used to treat eye diseases or eye conditions.

[0033] A specific aspect of the present disclosure provides a composition comprising a compound of formula (II), formula (III), formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof:

[0034]

[0035] It is used to treat eye diseases or eye conditions.

[0036] A specific aspect of the present disclosure provides a composition comprising a compound selected from the following or a pharmaceutically acceptable salt thereof:

[0037] Laquinimod,

[0038] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0039] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0040] 5-Chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0041] 5-Chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0042] 5-Chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0043] 5-Chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0044] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide,

[0045] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0046] N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0047] 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione,

[0048] Taquimod,

[0049] 4-Hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0050] 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0051] 4-Hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0052] 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0053] 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0054] 4,8-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0055] It is used to treat eye diseases or eye conditions.

[0056] One aspect of the present disclosure provides a method of treating an ocular disease or condition, wherein the method comprises administering a composition comprising a compound according to formula (IX) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] in

[0059] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0060] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0061] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0062] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0063] R 5 is hydrogen or hydroxyl, and

[0064] R 6 is methyl or hydrogen.

[0065] One aspect of the present disclosure provides the use of a compound according to formula (IX) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating an ocular disease or ocular condition:

[0066]

[0067] in

[0068] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0069] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0070] R3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0071] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0072] R 5 is hydrogen or hydroxyl, and

[0073] R 6 is methyl or hydrogen. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 : Photograph of a mouse eye with clearly visible vascularization. The overlay illustrates how the mean vessel length (VL) (expressed in clock hours = CH) was measured from marginal vessels to granular and continuous circumferential regions.

[0075] Figure 2 : Inhibition of VEGF-induced corneal angiogenesis. Laquin. = Laquinimod. Avastin 5 mg / kg provided 100% inhibition (reference). A dose of 0.5 mg / kg laquinimod twice daily provided no inhibition. A dose of 2.5 mg / kg laquinimod twice daily provided 46% inhibition. A dose of 0.5 mg / kg laquinimod four times daily provided 8% inhibition. A dose of 2.5 mg / kg laquinimod four times daily provided 50% inhibition.

[0076] Figure 3 : Inhibition of bFGF-induced corneal angiogenesis. Laquin. = Laquinimod. Sutent 40 mg / kg provided 80% inhibition. A dose of 0.5 mg / kg laquinimod twice daily provided 11% inhibition. A dose of 2.5 mg / kg laquinimod twice daily provided 35% inhibition. A dose of 0.5 mg / kg laquinimod four times daily provided 37% inhibition. A dose of 2.5 mg / kg laquinimod four times daily provided 56% inhibition.

[0077] Figure 4 : Normalized effect size for mean vessel length. Data were normalized so that the mean effect size for vehicle was 0% and the mean effect size for the positive control sulforaphane was 100%. Eylea tended to increase the effect size (18% effect size). Test compound ABR215174 had a significant increase in effect size compared to vehicle (88.2% effect size). Test compound ABR215062 tended to increase the effect size (53% effect size). DETAILED DESCRIPTION OF THE INVENTION

[0079] definition

[0080] The term "C1-C4 alkyl" refers to a moiety comprising or consisting of one, two, three or four carbon atoms and a plurality of hydrogen atoms. Examples of C1-C4 alkyl are methyl, ethyl, vinyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl or sec-butyl.

[0081] "Laquinimod" or "ABR-215062" refers to a compound of formula (II):

[0082]

[0083] "Taquinimod" refers to a compound of formula (III):

[0084]

[0085] "ABR-215174" refers to 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid phenylamide, a compound of formula (IV):

[0086]

[0087] "ABR-215691" refers to 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, a compound of formula (V):

[0088]

[0089] "Vascularisation" and "neovascularisation" refer to the process of new blood vessel formation. "Vascularisation" and "neovascularisation" are used interchangeably herein.

[0090] As used herein, "vascularisation of the eye" is synonymous with ocular neovascularization.

[0091] "Excessive vascularisation" refers to an event in which vascularisation occurs to an extent that is detrimental to the normal function of the affected tissue. Such excessive vascularisation occurs during or as an effect of an ocular disease or ocular condition, such as corneal neovascularisation, iris neovascularisation, ciliary body neovascularisation, corneal pannus, choroidal neovascularisation, proliferative diabetic retinopathy, retinopathy of prematurity, ischemic retinopathy, retinal neovascularisation and wet age-related macular degeneration.

[0092] In the context of the present disclosure, the terms "ocular disease or ocular condition associated with excessive vascularization of the eye" and "ocular disease or ocular condition associated with vascularization of the eye" mean any ocular disease or ocular condition recognized by one skilled in the art to be caused by and / or affecting vascularization of one or more tissues of the eye, e.g., wherein the vascularization is detrimental to the normal function of the affected tissues. Such diseases or conditions can lead to loss of vision.

[0093] "Treatment" is generally meant to encompass arresting, preventing, inhibiting, and slowing, stopping or reversing the progression or severity of an ocular disease or ocular condition.

[0094] The term "extent" in relation to vascularization refers to the severity of the vascularization. The extent of such vascularization can be assessed using several different measurable parameters, such as the area of ​​vascularization, the amount of blood vessels in a vascularized area, the length of blood vessels in a vascularized area, or the thickness of blood vessels in a vascularized area.

[0095] "Laquinimod vehicle" refers to a vehicle for laquinimod. The vehicle does not contain laquinimod.

[0096] "VEGF" refers to vascular endothelial growth factor. In mammals, the VEGF family includes five members, namely VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PGF). VEGF stimulates cellular responses by binding to VEGF receptors (VEGFR).

[0097] "bFGF" refers to basic fibroblast growth factor.

[0098] Uses of compounds and compositions

[0099] In one embodiment of the present disclosure, a composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0100]

[0101] in:

[0102] R 1 is chlorine, R 2 is ethyl, and R 3 It is hydrogen,

[0103] R 1 is methoxy, R 2 is a methyl group, and R 3 is trifluoromethyl,

[0104] R 1 is chlorine, R 2 is hydrogen, and R 3 It is hydrogen,

[0105] or

[0106] R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl;

[0107] It is used to treat eye diseases or eye conditions.

[0108] In another embodiment of the present disclosure, a composition comprising a compound of formula (I) is provided, wherein R 1 is chlorine, R 2 is ethyl, and R 3 is hydrogen, which is used to treat eye diseases or eye disorders. 1 It is Cl, R 2 is ethyl, and R 3 The common name of the compound H is laquinimod.

[0109] In yet another embodiment of the present disclosure, a composition comprising a compound of formula (I) is provided, wherein R 1 is methoxy, R 2 is a methyl group, and R 3 is a trifluoromethyl group, which is used to treat eye diseases or eye disorders. 1 is methoxy, R 2 is a methyl group, and R 3 The common name of the trifluoromethyl compound is taquinimod.

[0110] In one embodiment, a method of treating an ocular disease or condition is provided, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof:

[0111]

[0112] in:

[0113] R 1 is chlorine, R 2 is ethyl, and R 3 It is hydrogen,

[0114] R 1 is methoxy, R 2 is a methyl group, and R 3 is trifluoromethyl,

[0115] R 1 is chlorine, R 2 is hydrogen, and R 3 It is hydrogen,

[0116] or

[0117] R 1 is methoxy, R 2 is hydrogen, and R 3 It is trifluoromethyl.

[0118] In one embodiment, the disclosure relates to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an ocular disease or ocular condition,

[0119]

[0120] in:

[0121] R 1 is chlorine, R 2 is ethyl, and R 3 It is hydrogen,

[0122] R 1 is methoxy, R 2 is a methyl group, and R 3 is trifluoromethyl,

[0123] R 1 is chlorine, R 2 is hydrogen, and R 3 It is hydrogen,

[0124] or

[0125] R 1 is methoxy, R 2 is hydrogen, and R 3 It is trifluoromethyl.

[0126] Also disclosed herein are metabolites of laquinimod and tasquinimod. Laquinimod and tasquinimod are metabolized after administration to a subject. Certain metabolites, such as those disclosed herein, have therapeutic activity. One embodiment of the present disclosure provides a composition comprising laquinimod, tasquinimod, or an active metabolite thereof, for use in treating an ocular disease or an ocular condition. In one embodiment of the present disclosure, laquinimod or its active metabolite is administered to a subject in need thereof. In another embodiment, tasquinimod or its active metabolite is administered to a subject in need thereof.

[0127] Metabolites of laquinimod include those formed by quinoline hydroxylation at different positions, quinoline demethylation, aniline deethylation, and aniline hydroxylation at the para position. Specific examples of laquinimod metabolites include:

[0128] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0129] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0130] 5-Chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0131] 5-Chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0132] 5-Chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0133] 5-Chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0134] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide,

[0135] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0136] N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, and

[0137] 5'-Chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione.

[0138] A preferred embodiment of the present disclosure provides 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).

[0139] Metabolites of tasquinimod include those formed by aniline demethylation, quinoline-N demethylation, and quinoline-O demethylation. Specific examples of tasquinimod metabolites include:

[0140] 4-Hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0141] 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0142] 4-Hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0143] 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0144] 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0145] 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0146] A preferred embodiment of the present disclosure provides the tasquinimod metabolite 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0147] In a preferred embodiment of the present disclosure, the compound is selected from 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))).

[0148] One embodiment of the present disclosure provides a composition comprising a compound selected from the following or a pharmaceutically acceptable salt thereof:

[0149] Laquinimod,

[0150] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0151] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0152] 5-Chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0153] 5-Chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0154] 5-Chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0155] 5-Chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0156] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide,

[0157] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0158] N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0159] 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione,

[0160] Taquimod,

[0161] 4-Hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0162] 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0163] 4-Hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0164] 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0165] 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0166] 4,8-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0167] It is useful for treating ocular diseases or conditions where the ocular diseases or conditions are associated with excessive vascularization of the eye.

[0168] One embodiment of the present disclosure provides a method for treating an ocular disease or an ocular condition, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound selected from the following or a pharmaceutically acceptable salt thereof:

[0169] Laquinimod,

[0170] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0171] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0172] 5-Chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0173] 5-Chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0174] 5-Chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0175] 5-Chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0176] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide,

[0177] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0178] N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0179] 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione,

[0180] Taquimod,

[0181] 4-Hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0182] 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0183] 4-Hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0184] 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0185] 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0186] 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0187] One embodiment of the present disclosure provides a use of a compound selected from the following or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an ocular disease or ocular condition:

[0188] Laquinimod,

[0189] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0190] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0191] 5-Chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0192] 5-Chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0193] 5-Chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0194] 5-Chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0195] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide,

[0196] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0197] N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0198] 5'-chloro-1-ethyl-1'-methyl-2'H-spiro[indoline-3,3'-quinoline]-2,2',4'(1'H)-trione,

[0199] Taquimod,

[0200] 4-Hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0201] 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0202] 4-Hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0203] 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0204] 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0205] 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0206] One embodiment of the present disclosure provides a composition comprising a compound according to formula (VI) or a pharmaceutically acceptable salt thereof:

[0207]

[0208] in

[0209] R 1 It's chlorine.

[0210] R 2 is ethyl or hydrogen,

[0211] R 3 is hydrogen or hydroxyl,

[0212] R 5 is hydrogen or hydroxyl, and

[0213] R 6 is methyl or hydrogen,

[0214] It is used to treat eye diseases or eye conditions.

[0215] One embodiment of the present disclosure provides a composition comprising a compound according to formula (VII) or a pharmaceutically acceptable salt thereof:

[0216]

[0217] in:

[0218] R 1 is a methoxy group or a hydroxy group,

[0219] R 2 is methyl or hydrogen,

[0220] R 3 is trifluoromethyl,

[0221] R 5 is hydrogen or hydroxyl, and

[0222] R 6 is methyl or hydrogen,

[0223] It is used to treat eye diseases or eye conditions.

[0224] One embodiment of the present disclosure provides a composition comprising a compound according to formula (VIII) or a pharmaceutically acceptable salt thereof:

[0225]

[0226] in

[0227] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0228] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0229] R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy, and

[0230] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0231] It is used to treat eye diseases or eye conditions.

[0232] A composition comprising a compound according to formula (IX) or a pharmaceutically acceptable salt thereof:

[0233]

[0234] in

[0235] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0236] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0237] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0238] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0239] R 5 is hydrogen or hydroxyl, and

[0240] R 6is methyl or hydrogen,

[0241] It is used to treat eye diseases or eye conditions.

[0242] One embodiment of the present disclosure provides a method for treating an eye disease, the method comprising administering a composition comprising a therapeutically effective amount of a compound according to Formula (VI), Formula (VII), Formula (VIII) or Formula (IX) as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0243] One embodiment of the present disclosure provides the use of a compound according to Formula (VI), Formula (VII), Formula (VIII) or Formula (IX) as disclosed herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating an ocular disease or ocular condition.

[0244] Excessive vascularization of ocular tissue

[0245] The present disclosure relates to the treatment of ocular diseases or ocular conditions associated with excessive vascularization of the eye. Such vascularization may occur in response to external stimuli to the eye, such as excessive stress. Vascularization may also occur as a natural result of age. Vascularization of certain ocular tissues may be harmful to vision. The eye is composed of many different tissues, such as the cornea, iris, ciliary body, choroid, retina, or macula. Each of these tissues may undergo vascularization.

[0246] In one embodiment of the present disclosure, a compound is provided for use in treating a subject, wherein the subject suffers from vascularization of the cornea, iris, ciliary body, choroid, retina, or macula.

[0247] In one embodiment of the present disclosure, a compound for treating a subject is provided, wherein the subject suffers from angiogenesis of anterior ocular tissue (e.g., cornea, iris, or ciliary body). Importantly, the cornea is transparent for functioning vision. Therefore, angiogenesis of the cornea is harmful to human vision. Therefore, in a preferred embodiment, the present disclosure provides a composition comprising a compound of the present disclosure for treating corneal neovascularization.

[0248] In one embodiment of the present disclosure, the ocular disease or ocular disorder is selected from 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 retinopathy.

[0249] In one embodiment of the present disclosure, the ocular disease or ocular condition is associated with excessive vascularization of the eye. In one embodiment of the present disclosure, the ocular disease or ocular condition is corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, wet age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, or ischemic retinopathy associated with excessive vascularization of the eye.

[0250] Retinopathy is damage to the retina, which may lead to visual impairment. Retinopathy may refer to retinal vascular disease or damage to the retina caused by abnormal blood flow. Therefore, in one embodiment of the present disclosure, a compound for treating a subject is provided, wherein the subject suffers from proliferative diabetic retinopathy, retinopathy of prematurity, or ischemic retinopathy. Diabetes is a common cause of retinopathy, and diabetic retinopathy is one of the main causes of blindness in working age people. Therefore, in one embodiment of the present disclosure, a composition for treating a subject is provided, the composition comprising a compound of the present disclosure, wherein the subject suffers from proliferative diabetic retinopathy.

[0251] In one embodiment of the present disclosure, a compound for treating a subject is provided, wherein the subject suffers from angiogenesis of the posterior tissue of the eye (e.g., choroid, retina, or macula). The purpose of the retina is to receive light focused by the lens, convert the light into neural signals, and send these signals to the brain for visual recognition. Therefore, any damage to the retina, such as angiogenesis, can affect a person's vision. Therefore, 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.

[0252] The macula is the central area of ​​the retina. The macula is responsible for the central high-resolution color vision that is possible in good light. Damage to the macula will result in loss of central vision, which can seriously affect a person's ability to read and recognize faces. Therefore, in a 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 vascularization. Macular vascularization is also known as wet age-related macular degeneration. Therefore, in a 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 vascularization of the eye.

[0253] In a preferred embodiment of the present disclosure, the term "ocular disease or ocular disorder associated with excessive vascularization of the eye" does not include uveitis or conjunctivitis.

[0254] Administering the disclosed compositions with VEGF inhibitors

[0255] Vascular endothelial growth factor (VEGF) stimulates the formation of blood vessels. VEGF inhibitors have the potential to reduce tissue vascularization by binding to VEGF. Alternatively, VEGF inhibitors can affect the activity of VEGF by binding to VEGF receptors.

[0256] The compositions of the present disclosure may be administered in combination with a VEGF inhibitor to treat an ocular disease or condition, such as those associated with excessive vascularization of the eye. Such a combined treatment may be more effective than the compositions of the present disclosure and / or VEGF inhibitor alone in treating an ocular disease or condition. Thus, in one embodiment of the present disclosure, an ocular disease or condition is treated by administering a composition of the present disclosure in combination with administering a VEGF inhibitor.

[0257] VEGF inhibitors include antibodies, antibody-derived fragments, recombinant proteins, and recombinant fusion proteins, such as aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, and faricimab. Therefore, in one embodiment of the present disclosure, an eye disease or eye condition is treated by co-administering a composition of the present disclosure with aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, or faricimab. In a preferred embodiment, an eye disease or eye condition is treated by co-administering a composition of the present disclosure with aflibercept, ranibizumab, bevacizumab, brolucizumab, abicipar pegol, conbercept, or faricimab.

[0258] The recombinant protein aflibercept (Eylea) 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, an eye disease or eye condition is treated by administering a combination of the composition of the present disclosure and aflibercept.

[0259] 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, an eye disease or eye condition is treated by administering a composition of the present disclosure in combination with administering Ranibizumab.

[0260] 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, an eye disease or eye condition is treated by administering a composition of the present disclosure in combination with administering bevacizumab.

[0261] Bricezumab is a sc antibody fragment with affinity for VEGF-A. In one embodiment of the present disclosure, an ocular disease or an eye is treated by administering a composition of the present disclosure in combination with administration of bevacizumab.

[0262] The peptide abicipar pegol is a known VEGF-A inhibitor. In one embodiment of the present disclosure, an ocular disease or ocular condition is treated by administering a composition of the present disclosure in combination with administering abicipar pegol.

[0263] Conbercept is a recombinant fusion protein with affinity for VEGF-A. Therefore, in one embodiment of the present disclosure, an ocular disease or ocular condition is treated by administering the composition of the present disclosure in combination with administering Conbercept.

[0264] The bispecific monoclonal antibody faricitumab modulates angiopoietin-2 and VEGF-A activity. Thus, in one embodiment of the present disclosure, an ocular disease or ocular disorder is treated by administering a compound of the present disclosure in combination with faricitumab.

[0265] In one embodiment of the present disclosure, the composition of the present disclosure comprises an angiogenesis inhibitor or is administered in combination with an angiogenesis inhibitor. In a specific embodiment of the present disclosure, the angiogenesis inhibitor is aflibercept.

[0266] In one embodiment of the present disclosure, a composition comprising a compound of the present disclosure may be administered to a subject in need thereof by topical, oral, intravitreal, subconjunctival, retrobulbar, intracameral or systemic routes.

[0267] In the treatment of a disease or condition that is highly localized to one part of the body (e.g., an ocular disease or an ocular condition), it may be advantageous to administer the drug for the disease or condition by a route that ensures that the drug is primarily localized to the site of the disease or condition. 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 by topical, intravitreal, subconjunctival, retrobulbar, or intracameral routes.

[0268] 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. In another embodiment of the present disclosure, the administration of the composition of the present disclosure is oral administration.

[0269] In the treatment of a disease or condition where the disease or condition requires frequent administration of a dose of a drug to a subject, it may be advantageous if the drug is formulated in a manner that allows self-administration. Those skilled in the art will know which types of formulations are suitable for self-administration.

[0270] As described herein, the compositions of the present invention can be administered in combination with a VEGF inhibitor. Thus, in one embodiment, the compositions of the present disclosure and the VEGF inhibitor are contained in the same formulation and are thus administered simultaneously.

[0271] The combination therapy described herein is not limited to compositions comprising both the compounds of the present disclosure and the VEGF inhibitor. Instead, the compounds of the present disclosure and the VEGF inhibitor may be administered as different formulations. The choice to administer the compounds of the present disclosure and the VEGF inhibitor as separate formulations may be driven by the fact that the compounds of the present disclosure and the VEGF inhibitor have different preferred dosage regimens. For example, it may be advantageous to administer the compounds of the present disclosure frequently (e.g., daily or weekly), while it is better to administer the VEGF inhibitor infrequently (e.g., every few months). The choice to administer the compounds of the present disclosure and the VEGF inhibitor as separate formulations may also be driven by the fact that the compounds of the present disclosure and the VEGF inhibitor are not suitable for the same type of administration route. For example, the compounds of the present disclosure may be particularly suitable for one type of administration route, such as topical administration, while the VEGF inhibitor may be suitable for a second type of administration route, such as intravitreal injection. Therefore, in one embodiment, the compounds of the present disclosure and the VEGF inhibitor are contained in different formulations, wherein the formulations are administered at different frequencies. In another embodiment, the compounds of the present disclosure and the VEGF inhibitor are contained in different formulations, wherein the formulations are administered using different administration routes.

[0272] VEGF inhibitors are usually administered as intravitreal injections to treat eye diseases or eye conditions, such as those associated with vascularization of the eye. Intravitreal injections are often performed in hospitals or general practitioners' offices. Intravitreal injections for treating diseases associated with vascularization of the eye are usually given at a frequency of several months, such as every month, every 3 months, or every 6 months. Intravitreal injections are given under local anesthesia. Adverse reactions to intravitreal injections include increased intraocular pressure, floaters, inflammation, bleeding, corneal scratches, retinal or peripheral nerve damage, and infection. In addition, it may be inconvenient to go to a general practitioner or hospital for an injection every few months, and people who receive intravitreal injections may find the experience unpleasant and uncomfortable. Topical treatment with a compound of the present invention before, during, or between two injections of a VEGF inhibitor can extend the time period before an additional injection of VEGF is required. Therefore, in one embodiment of the present disclosure, a composition comprising a compound of the present disclosure is used to treat an eye disease or eye condition (such as those associated with excessive vascularization of the eye), and the effect is to reduce the frequency of intravitreal injections of VEGF inhibitors compared to intravitreal injections of VEGF inhibitors alone. Furthermore, in one embodiment, the compound of the present disclosure and the VEGF inhibitor are contained in different compositions, wherein administration of the composition comprising the compound of the present disclosure achieves treatment of the ocular disease or ocular disorder and reduces the required frequency of intravitreal VEGF inhibitor injections.

[0273] treat

[0274] In one embodiment of the present disclosure, a composition is provided, which comprises a compound of the present disclosure. In a further embodiment, a composition is provided, which comprises a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0275] There are different routes for administering a drug to the eye. For example, a drug can be administered topically to the eye. Thus, in one embodiment, a composition comprising a compound of the present disclosure is administered topically to the eye. One skilled in the art will know what type of route of administration is suitable for administration to the eye.

[0276] In one embodiment of the present disclosure, the compositions comprising the compounds of the present disclosure are administered orally.

[0277] One embodiment of the present disclosure provides a composition comprising a compound according to formula (IX) or a pharmaceutically acceptable salt thereof:

[0278]

[0279] in

[0280] R1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0281] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0282] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0283] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0284] R 5 is hydrogen or hydroxyl, and

[0285] R 6 is methyl or hydrogen,

[0286] It is used to treat an ocular disease or ocular condition, wherein the ocular disease or ocular condition is wet age-related macular degeneration.

[0287] One embodiment of the present disclosure provides 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):

[0288]

[0289] in:

[0290] R 1 is chlorine, R 2 is ethyl, and R 3 It is hydrogen,

[0291] R 1 is methoxy, R 2 is a methyl group, and R 3 is trifluoromethyl,

[0292] R 1 is chlorine, R 2 is hydrogen, and R 3 It is hydrogen,

[0293] or

[0294] R 1 is methoxy, R 2 is hydrogen, and R 3 It is trifluoromethyl.

[0295] In a further embodiment, the present disclosure provides a method of 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 of 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 of 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 of treating wet age-related macular degeneration, the method comprising administering a therapeutically effective amount of ABR-215174 to the subject.

[0296] The compounds disclosed herein can be used to manufacture drugs. Therefore, in one embodiment of the present invention, the compound of formula (I):

[0297]

[0298] in:

[0299] R 1 is chlorine, R 2 is ethyl, and R 3 It is hydrogen,

[0300] R 1 is methoxy, R 2 is a methyl group, and R 3 is trifluoromethyl,

[0301] R 1 is chlorine, R 2 is hydrogen, and R 3 It is hydrogen,

[0302] or

[0303] R 1 is methoxy, R 2 is hydrogen, and R 3 is trifluoromethyl,

[0304] For the manufacture of a medicament for the treatment of wet age-related macular degeneration. In another embodiment, laquinimod is used in the manufacture of a medicament for the treatment of wet age-related macular degeneration. In yet another embodiment, tasquinimod is used in the manufacture of a medicament for the treatment of wet age-related macular degeneration. In yet another embodiment, ABR-215174 is used in the manufacture of a medicament for the treatment of wet age-related macular degeneration. In yet another embodiment, ABR-215691 is used in the manufacture of a medicament for the treatment of wet age-related macular degeneration.

[0305] project

[0306] 1. A composition comprising:

[0307] A compound according to formula (IX) or a pharmaceutically acceptable salt thereof:

[0308]

[0309] in

[0310] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0311] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0312] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0313] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0314] R 5 is hydrogen or hydroxyl, and

[0315] R 6 is methyl or hydrogen,

[0316] It is used to treat eye diseases or eye conditions.

[0317] 2. The composition for use according to item 1, wherein the compound is a compound according to formula (VIII) or a pharmaceutically acceptable salt thereof:

[0318]

[0319] in

[0320] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0321] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0322] R 3 is selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy, and

[0323] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R3 When R is selected from fluorine and chlorine, 4 Selected from fluorine and chlorine.

[0324] 3. A composition for use according to any one of the preceding items, wherein the compound is a compound according to formula (VII) or a pharmaceutically acceptable salt thereof:

[0325]

[0326] in:

[0327] R 1 is a methoxy group or a hydroxy group,

[0328] R 2 is methyl or hydrogen,

[0329] R 3 is trifluoromethyl,

[0330] R 5 is hydrogen or hydroxyl, and

[0331] R 6 is methyl or hydrogen,

[0332] 4. A composition for use according to any one of the preceding items, wherein the compound is a compound according to formula (VI) or a pharmaceutically acceptable salt thereof:

[0333]

[0334] in

[0335] R 1 It's chlorine.

[0336] R 2 is ethyl or hydrogen,

[0337] R 3 is hydrogen or hydroxyl,

[0338] R 5 is hydrogen or hydroxyl, and

[0339] R 6 is methyl or hydrogen.

[0340] 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 an eye disorder.

[0341] 6. The composition for use according to any one of the preceding items, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0342] Laquinimod,

[0343] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0344] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0345] 5-Chloro-N-ethyl-4-hydroxy-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0346] 5-Chloro-N-ethyl-4,8-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0347] 5-Chloro-N-ethyl-4,7-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0348] 5-Chloro-N-ethyl-4,6-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0349] 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-N-vinyl-1,2-dihydroquinoline-3-carboxamide,

[0350] 5-Chloro-N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide,

[0351] N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide,

[0352] Taquimod,

[0353] 4-Hydroxy-5-methoxy-N-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0354] 4,5-dihydroxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0355] 4-Hydroxy-5-methoxy-1-methyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0356] 4,6-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide,

[0357] 4,7-dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide, and

[0358] 4,8-Dihydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide.

[0359] 7. A composition for use according to any one of the preceding items, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0360]

[0361] in:

[0362] R 1 is chlorine, R 2 is ethyl or hydrogen, and R 3 It is hydrogen,

[0363] or

[0364] R 1 is methoxy, R 2 is methyl or hydrogen, and R 3 It is trifluoromethyl.

[0365] 8. The composition for use according to any one of the preceding items, wherein the compound is laquinimod or a pharmaceutically acceptable salt thereof.

[0366] 9. The composition for use according to any one of the preceding items, wherein the compound is taquimod or a pharmaceutically acceptable salt thereof.

[0367] 10. The composition for use according to any one of the preceding items, wherein the compound is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0368]

[0369] 11. A composition for use according to any one of the preceding items, wherein the compound is a compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0370]

[0371] 12. A composition for use according to any of the preceding items, wherein the ocular disease or ocular disorder is selected from 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 retinopathy.

[0372] 13. A composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is selected from corneal neovascularization, iris neovascularization, ciliary body neovascularization and corneal pannus.

[0373] 14. A composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is corneal neovascularization.

[0374] 15. The composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is selected from proliferative diabetic retinopathy, retinopathy of prematurity and ischemic retinopathy.

[0375] 16. The composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is proliferative diabetic retinopathy.

[0376] 17. The composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is retinopathy of prematurity.

[0377] 18. The composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is ischemic retinopathy.

[0378] 19. A composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is selected from choroidal neovascularization, retinal neovascularization and wet age-related macular degeneration.

[0379] 20. The composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is choroidal neovascularization.

[0380] 21. A composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is retinal neovascularization.

[0381] The composition for use according to any of the preceding items, wherein the ocular disease or ocular disorder is wet age-related macular degeneration.

[0382] 22. A composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is not uveitis or conjunctivitis.

[0383] 23. A composition for use according to any one of the preceding items, wherein the ocular disease or ocular disorder is associated with excessive vascularization of the eye.

[0384] 24. A composition for use according to any one of the preceding items, wherein the composition comprises or is administered in combination with an angiogenesis inhibitor, such as aflibercept.

[0385] 25. The composition for use according to any one of the preceding items, wherein the composition is administered in combination with one or more VEGF inhibitors.

[0386] 26. The composition for use according to any of the preceding items, wherein the composition is administered in combination with a VEGF inhibitor.

[0387] 27. A composition for use according to any one of the preceding items, wherein the composition further comprises one or more VEGF inhibitors.

[0388] 28. A composition for use according to any one of the preceding items, wherein the composition further comprises a VEGF inhibitor.

[0389] 29. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is selected from aflibercept, ranibizumab, bevacizumab, bruceizumab, abicipar pegol, conbercept and faricizumab.

[0390] 30. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is selected from aflibercept, ranibizumab, bevacizumab and bruceizumab.

[0391] 31. A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is aflibercept.

[0392] 32. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is ranibizumab.

[0393] 33. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is bevacizumab.

[0394] 34. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is bucexizumab.

[0395] 35. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is abiciparpegol.

[0396] 36. A composition for use according to any one of the preceding items, wherein the VEGF inhibitor is Conbercept.

[0397] 37. The composition for use according to any one of the preceding items, wherein the VEGF inhibitor is faricizumab.

[0398] 38. A composition for use according to any one of the preceding items, wherein the composition comprises or is administered in combination with at least one pharmaceutically acceptable excipient.

[0399] 39. The 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.

[0400] 40. The composition for use according to any one of the preceding items, wherein the administration route is a topical administration route.

[0401] 41. The composition for use according to any one of the preceding items, wherein the administration route is an oral administration route.

[0402] 42. The composition for use according to any one of the preceding items, wherein the administration route is the intravitreal administration route.

[0403] 43. The composition for use according to any one of the preceding items, wherein the administration route is the subconjunctival administration route.

[0404] 44. The composition for use according to any one of the preceding items, wherein the administration route is the retrobulbar administration route.

[0405] 45. The composition for use according to any of the preceding items, wherein the administration route is the intracameral administration route.

[0406] 46. ​​The composition for use according to any of the preceding items, wherein the route of administration is a systemic route of administration.

[0407] 47. A method of 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 according to formula (IX) or a pharmaceutically acceptable salt thereof:

[0408]

[0409] in

[0410] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0411] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0412] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0413] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0414] R 5 is hydrogen or hydroxyl, and

[0415] R 6 is methyl or hydrogen.

[0416] 48. Use of a compound according to formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an ocular disease or ocular condition:

[0417]

[0418] in

[0419] R 1 is selected from hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0420] R 2 is selected from hydrogen and C1-C4 alkyl, such as methyl, ethyl or vinyl,

[0421] R 3 is selected from hydrogen, hydroxy, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy,

[0422] R 4 is selected from hydrogen, fluorine and chlorine, provided that only when R 3 When R is selected from fluorine and chlorine, 4 is selected from fluorine and chlorine,

[0423] R 5 is hydrogen or hydroxyl, and

[0424] R 6 is methyl or hydrogen.

[0425] Example 1: Inhibition of Choroidal Neovascularization in a Laser-Induced Choroidal Neovascularization Rat Model

[0426] Study Design

[0427] Forty-eight (48) Brown Norway pigmented rats were divided into six (6) groups of eight (8) animals each. On day 0, choroidal neovascularization was induced in the right eye using a 532 nm argon laser photocoagulation device (six (6) 75 μm sized spots, 150 mW, duration 0.1 seconds). From day 0 (D0) just after induction with ChNV to day 21 (the last day of the study), the test item was administered 3 times a day by instillation or twice a day by oral administration. From day 0 to day 21 just after induction of neovascularization, the control item (vehicle) was instilled 3 times a day, and the reference item (dexamethasone in olive oil) was administered daily by oral administration. On days 14 and 21, fundus neovascularization was evaluated in the right eye using Heidelberg retinal angiography (HRA). At the end of the in vivo period, lesion size was determined on choroidal flatmounts labeled with Isolectin-B4.

[0428] Induce new blood vessel formation

[0429] On day 0, animals were anesthetized by intramuscular injection of a mixture of xylazine (5 mg / kg) and ketamine (25 mg / kg). The pupil of the right eye was dilated by instillation of one drop of 0.5% tropicamide. Then, six (6) choroidal burns (75 μm spot size) were made around the optic disc between the main vascular branches using an argon laser photocoagulator (532 nm; 150 mW; 0.1 sec duration) via a slit lamp with a contact lens. Bubbles generated during laser treatment confirmed rupture of Bruch's membrane.

[0430] Routes and methods of administration

[0431] From day 0 (just after induction) to day 21 (end of study), test, control or reference items were administered topically by instillation (10 μL each) or by oral route (1 mL / kg). Test and control items were administered 3 times a day (for instillation) and 2 times a day (for oral administration). Reference items were administered once a day by oral route.

[0432] weight

[0433] Body weights of all animals were recorded before the start of the study and then weekly.

[0434] Fluorescein angiography

[0435] Fluorescein angiography was performed using HRA (Heidelberg retinal angiography) on days 14 and 21. After anesthesia (same mixture as used for ChNV induction) and pupil dilation, 250 μL / 100 g (body weight) of 10% sodium fluorescein was injected subcutaneously using a 26-G insulin syringe, and fluorescein pictures were recorded 10 minutes after dye injection.

[0436] Evaluation by fluorescein angiography

[0437] Fluorescein leakage on angiograms was evaluated in a masked fashion by two examiners and graded as follows:

[0438] 0 points, no leakage;

[0439] 1 point, slight staining;

[0440] 2 points, moderate staining;

[0441] 3 points, strong staining.

[0442] When the two scores assigned to a specific lesion disagreed, the higher score was used for analysis.

[0443] Data processing

[0444] Scoring of lesions visualized by HRA and scores of flat mount preparations were statistically analyzed for each animal using the Mann-Whitney U test or appropriate statistical models.

[0445] Animal behavior and mortality

[0446] The general behavior and appearance of all animals were observed and recorded in the raw data. No special signs were observed, and the general behavior and appearance of the animals were normal. All animals survived until the scheduled euthanasia.

[0447] Animal weight

[0448] Animal body weights were recorded before induction and treatment (baseline) and then weekly. Animal body weights were within the normal range at baseline: 166-202 g (min-max, n=48). No significant differences were observed between the test and control items on day 21. Animals treated with the reference item (dexamethasone) showed a 21% weight loss during the study. This reduction is an expected side effect of oral corticosteroids.

[0449] Angiographic evaluation

[0450] The grading of fluorescein angiography (FA) was based on the fluorescence intensity of each lesion. For each treatment group, the results were expressed as the group mean score at each time point. Table 1 summarizes the evaluation of FA recorded at 10 minutes on days 14 and 21 (n=8 animals per group, right eyes). The median of the individual intensity scores was statistically analyzed using the Kruskall-Wallis test followed by the Mann & Whitney U multiple comparison test for comparison of each test, control or reference group.

[0451] Table 1: FA evaluation per treatment group (per os = oral)

[0452]

[0453] in conclusion

[0454] On days 14 and 21, 63% and 66% of the evaluated puncta leaked in vehicle-treated animals, respectively, indicating the formation and persistence of ChNV. However, daily topical application of laquinimod effectively reduced vascular leakage, indicating that laquinimod is effective against ChNV.

[0455] Example 2: Inhibition of VEGF- and bFGF-induced neovascularization

[0456] Methods for assessing the area of ​​neovascularization

[0457] The area of ​​neovascularization can be measured using the following formula:

[0458] Area = 0.2·VL·CH·π

[0459] Among them Figure 1 The vessel length (VL) and the continuous circumferential area (expressed in clock hours = CH) were measured as defined in .

[0460] Treatment of VEGF-induced corneal angiogenesis with laquinimod

[0461] Hydron pellets for inducing angiogenesis were prepared from a stimulator (VEGF) and a binding agent (sucralfate).

[0462] Fifty-three 6- to 8-week-old CR female C57BL / 6 mice were prepared for surgery under anesthesia by intraperitoneal injection of 90 mg / kg pentobarbital. Corneal angiogenesis was induced by placing a pellet in a corneal pocket cut in one eye. Eyes were carefully monitored for signs of irritation or infection.

[0463] Doses of laquinimod, vehicle (DDW = double distilled water) and Avastin (positive control) in DI (deionized) water were applied directly to the eye containing the pellets. Vascularization was measured on day 8. The treatment regimen is shown in Table 2. The results are shown in Tables 3 and Figure 2 middle.

[0464] Table 2: Treatment regimen for induction of corneal angiogenesis with VEGF followed by administration of laquinimod.

[0465]

[0466]

[0467] *mg / kg

[0468] laqui.=Laquinimod

[0469] veh. = solvent

[0470] avas.=Avastin

[0471] Table 3: Treatment outcomes of VEGF-induced corneal angiogenesis

[0472]

[0473] vasc.=angiogenesis

[0474] Treatment of VEGF-induced angiogenesis after laquinimod administration showed a dose-dependent effect: low doses (0.5 mg / kg, bid, Group 4) did not provide any inhibition. Increasing the frequency of administration provided only a small inhibition (0.5 mg / kg, qid, Group 6, 8% inhibition). Increasing doses provided good inhibition of angiogenesis, both at low (2.5 mg / kg, bid, Group 5, 46% inhibition) and multiple (2.5 mg / kg, qid, Group 7, 50% inhibition) daily doses.

[0475] Treatment of corneal angiogenesis induced by bFGF with laquinimod

[0476] Hydron pellets for inducing angiogenesis were prepared from a stimulator (bFGF) and a binding agent (sucralfate).

[0477] Forty-seven 6- to 8-week-old CR female C57BL / 6 mice were prepared for surgery by anesthesia with an intraperitoneal injection of 90 mg / kg pentobarbital. Corneal angiogenesis was induced by placing a pellet in a corneal pocket cut in one eye. Eyes were carefully monitored for signs of irritation or infection.

[0478] Doses of laquinimod, vehicle (DDW = double distilled water) and Avastin (positive control) in DI (deionized) water were applied directly to the eye containing the pellets. Vascularization was measured on day 6. The treatment regimen is shown in Table 4. The results are shown in Tables 5 and Figure 3 middle.

[0479] Table 4: Treatment regimen of inducing corneal angiogenesis with bFGF followed by laquinimod administration.

[0480]

[0481]

[0482] *mg / kg

[0483] laqui.=Laquinimod

[0484] veh. = solvent

[0485] Table 5: Treatment results of corneal angiogenesis induced by bFGF

[0486]

[0487] vasc. =angiogenesis.

[0488] in conclusion

[0489] Treatment of bFGF-induced angiogenesis after administration of laquinimod showed a dose-dependent effect: low dose (0.5 mg / kg, bid, Group 4) inhibited angiogenesis by 11%, while higher dose (2.5 mg / kg, bid, Group 5) inhibited angiogenesis by 35%. Increasing the dose frequency further improved the inhibition, with multiple low doses (0.5 mg / kg, qid, Group 6) providing similar inhibition (37%) to fewer high doses (Group 5). Multiple daily high doses (2.5 mg / kg, qid, Group 7) even further inhibited (56%) angiogenesis.

[0490] Example 3: Laquinimod and ABR-215174 have effects on LPS-activated microglia-induced human retinal microvascular endothelial cell tube formation

[0491] method

[0492] The following experimental groups were included in this study:

[0493] Group 1: Control (vehicle, 0.1% DMSO)

[0494] Group 2: Sulforaphane (10 μM, positive control, anti-angiogenic effect)

[0495] Group 3: Aflibercept ("Ailiya" 40μg / ml, positive control, partial anti-angiogenic effect)

[0496] Group 4: ABR-215174 (0.1 μM)

[0497] Group 5: ABR-215062 (10 μM)

[0498] Human retinal microvascular endothelial cells (HRMEC) were purchased from Neuromics (Cat. No. HEC09, Lot. No. 2872) and cultured in Endo-Growth medium (Cat. No. EKG001, Lot. No. EKG0011902269) supplemented with endothelial growth factor (Cat. No. EKG001, Lot. No. EGK00125) on AlphaBiocoat-coated T25 flasks at 37°C, 5% CO2 according to the manufacturer's instructions.

[0499] Primary human microglia from the brain were purchased from Celprogen (Cat. No. 37089-01, Batch No. 1614454-01) and cultured on poly-L-lysine (PLL, 50 mg / ml)-coated T25 flasks at 37°C, 5% CO2, in microglial complete growth medium with antibiotics (Cat. No. M37089-01, Batch No. 2010089205-03) supplemented with 10% standard fetal bovine serum (Neuromics, Batch No. 042P20).

[0500] 103 000 cells / cm 2 Human microglia were seeded onto PLL-coated cell culture inserts (Sarstedt, Cat. No. 83.3932.040). Microglia were treated with study compounds, aflibercept, and vehicle for 24 h prior to lipopolysaccharide (LPS) activation in complete microglial growth medium using the following concentrations:

[0501] Vehicle (0.1% DMSO)

[0502] Aflibercept 40g / ml), 0.1% DMSO

[0503] ABR-215174 (0.1μM), 0.1% DMSO

[0504] ABR-215062 (10μM), 0.1% DMSO

[0505] According to 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-culturedRMECs. 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, LeeJ, Park JG, Cho YL, Hun Kim J,Jang H,Park YJ,Lee SH,Min JK.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) was used to modify the co-culture method of microglia and HRMEC. Microglia were activated with LPS (100 ng / ml) in complete microglia growth medium without FBS and treated with freshly prepared study compounds, Erythra, and vehicle for 24 hours. HRMEC were incubated in basal Endo-Growth medium for 24 hours before co-culture.

[0506] HRMEC were seeded into Coated 24-well plates (42 000 cells / cm 2 ) and treated simultaneously with freshly prepared study compound, aflibercept, and sulforaphane in basal Endo-Growth medium:

[0507] Vehicle (0.1% DMSO)

[0508] Sulforaphane (10M), 0.1% DMSO

[0509] Aflibercept 40 μg / ml), 0.1% DMSO

[0510] ABR-215174 (0.1μM), 0.1% DMSO

[0511] ABR-215062 (10μM), 0.1% DMSO

[0512] The medium in the microglial chamber containing LPS was replaced with the corresponding freshly prepared study compound, aflibercept and sulforaphane in basal Endo-Growth medium. The chamber containing activated microglia was transferred to the 24-well containing HRMEC. The co-culture was incubated at +37°C 5% CO2, stained with calcein-AM (5 μM) for 30 minutes, and imaged using a fluorescence microscope (Leica Thunder 3D Tissue Imager, Leica Microsystems).

[0513] Images were analyzed using AngioTool software (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) for ImageJ (NIH public domain). Total tube area, tube length, density, gap degree, and branching index (number of junctions and endpoints) were quantified.

[0514] Images were analyzed using AngioTool software (NIH, Bethesda, MD; available in the public domain) for the following readouts: mean vessel length, total vessel length, vessel area, vessel percentage area, total number of junctions, junction density, total number of endpoints, and mean gap size. Raw data for length and area measurements were given in mm or μm (and mm 2 or μm 2 ) were used as the unit for plotting. Raw data for each readout were plotted and analyzed by ordinary one-way ANOVA with Dunnett's multiple comparison post hoc test.

[0515] Effect sizes were calculated by subtracting the mean of the vehicle group from each value and then normalizing the data to the sulforaphane (positive control) condition so that the mean of the sulforaphane group equaled the maximum effect size (100%) and the mean of vehicle equaled the no effect size (0%). Effect size data were analyzed by the nonparametric Kruskal-Wallis test using Dunn's multiple comparison post hoc test.

[0516] Results and Conclusions

[0517] The difference in the normalized effect size for mean vessel length between the sulforaphane and vehicle groups reached statistical significance ( Figure 4 ). Test compound ABR215174 (88.2% effect size) had a significant increase in effect size for mean vessel length compared to vehicle. The effect sizes of Eiliya (18% effect size) and test compound ABR215062 (53% effect size) were not statistically significant but trended toward an increase in effect size for mean vessel length.

[0518] Since sulforaphane is a known and well-accepted positive control for the prevention of angiogenesis, these results suggest that the test compounds ABR215174 and ABR215062 may also be useful for the prevention of angiogenesis.

[0519] Example 4: When laquinimod or ABR-215174 is combined with angiogenesis inhibitors such as aflibercept compared to monotherapy The additive effect of combined therapy on LPS-activated microglia-induced tube formation in human retinal microvascular endothelial cells

[0520] Microglia, especially activated microglia, play an important role in angiogenesis and hemostasis in the retinal microvasculature to maintain vascular function (Ding et al., 2018). It is expected that co-cultures of human retinal microvasculature endothelial cells (HRMEC) and human microglia from the brain can be used to evaluate the effects of compounds of the present disclosure such as laquinimod, tasquinimod, ABR-215174 or ABR-215691 on new blood vessel formation. For example, the following method can be used.

[0521] method

[0522] This study can be performed essentially as described in Example 3.

[0523] Tube formation assay

[0524] Tube formation assays were performed in 96-well plates or 24-well plates coated with Matrigel as described by Ding et al., 2018 (Ding et al. BMC Ophthalmology (2018) 18:249): 96-well plates were coated with 50 μL / well Matrigel for 30 min at 37°C. After 24 h of co-culture with microglia, HRMECs were incubated at 1.5 × 10 4Cells / well were seeded on Matrigel. After a period of time (e.g., 4 hours), tube formation was observed with a microscope (Leica Microsystems) and photographed. Images were analyzed using the Angiotool plug-in (Zudaire et al., 2011, PLoS one, 6, 11, e27385) for ImageJ (NIH public domain). Total tube area, tube length, density, gap degree, and branch index (number of junctions and endpoints) were quantified.

[0525] Results and Conclusions

[0526] It is expected that when a compound of the present disclosure (eg, laquinimod 1 and 10 μM or ABR-215174 0.01 and 0.1 μM) is combined with aflibercept (30 nM), a significant additive effect will be seen compared to each compound used as a monotherapy.

Claims

1. Use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an eye disease or an eye condition: in: R 1 is chlorine, R 2 is ethyl or hydrogen, and R 3 It is hydrogen, wherein the ocular disease or ocular disorder is selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization and ischemic retinopathy.

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

3. The use according to claim 1, wherein the compound is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

4. The use according to any one of claims 1 to 3, wherein the ocular disease or ocular disorder is selected from corneal neovascularization, iris neovascularization, ciliary body neovascularization and corneal pannus.

5. The use according to claim 4, wherein the ocular disease or ocular disorder is corneal neovascularization.

6. The use according to any one of claims 1 to 3, wherein the ocular disease or ocular disorder is ischemic retinopathy.

7. Use according to claim 6, wherein the ocular disease or ocular disorder is selected from proliferative diabetic retinopathy and retinopathy of prematurity.

8. The use according to claim 7, wherein the ocular disease or ocular disorder is proliferative diabetic retinopathy.

9. The use according to claim 7, wherein the ocular disease or ocular disorder is retinopathy of prematurity.

10. The use according to any one of claims 1 to 3, wherein the ocular disease or ocular disorder is selected from choroidal neovascularization and retinal neovascularization.

11. The use according to claim 10, wherein the ocular disease or ocular disorder is choroidal neovascularization.

12. The use according to claim 10, wherein the ocular disease or ocular disorder is retinal neovascularization.

13. The use according to claim 12, wherein the ocular disease or ocular disorder is wet age-related macular degeneration.

14. Use according to any one of claims 1 to 3, wherein the composition comprises an angiogenesis inhibitor.

15. The use according to claim 14, wherein the angiogenesis inhibitor is aflibercept.

16. The use according to any one of claims 1 to 3, wherein the composition comprises a VEGF inhibitor.

17. The use according to claim 16, wherein the VEGF inhibitor is selected from aflibercept, ranibizumab, bevacizumab, bruceizumab, abicipar pegol, conbercept and faricizumab.

18. Use according to any one of claims 1 to 3, wherein the composition comprises at least one pharmaceutically acceptable excipient.

19. The use according to any one of claims 1 to 3, wherein the administration route is a topical or systemic administration route.

20. The use according to any one of claims 1 to 3, wherein the administration route is oral, intravitreal, subconjunctival, retrobulbar or intracameral administration route.

21. Use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an angiogenesis inhibitor in the preparation of a medicament for treating an eye disease or an eye condition: in: R 1 is chlorine, R 2 is ethyl or hydrogen, and R 3 It is hydrogen, wherein the ocular disease or ocular disorder is selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization and ischemic retinopathy.

22. The use according to claim 21, wherein the compound is laquinimod or a pharmaceutically acceptable salt thereof.

23. The use according to claim 21, wherein the compound is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

24. The use according to any one of claims 21 to 23, wherein the angiogenesis inhibitor is aflibercept.

25. Use according to any one of claims 21 to 23, wherein the ocular disease or ocular disorder is selected from proliferative diabetic retinopathy and retinopathy of prematurity.

26. The use according to claim 24, wherein the ocular disease or ocular disorder is selected from proliferative diabetic retinopathy and retinopathy of prematurity.

27. The use according to any one of claims 21 to 23, wherein the ocular disease or ocular disorder is wet age-related macular degeneration.

28. The use according to claim 24, wherein the ocular disease or ocular disorder is wet age-related macular degeneration.

29. Use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a VEGF inhibitor in the preparation of a medicament for treating an eye disease or an eye condition: in: R 1 is chlorine, R 2 is ethyl or hydrogen, and R 3 It is hydrogen, wherein the ocular disease or ocular disorder is selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization and ischemic retinopathy.

30. The use according to claim 29, wherein the compound is laquinimod or a pharmaceutically acceptable salt thereof.

31. The use according to claim 29, wherein the compound is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

32. The use according to any one of claims 29 to 31, wherein the VEGF inhibitor is selected from aflibercept, ranibizumab, bevacizumab, bruceizumab, abicipar pegol, conbercept and faricizumab.

33. Use according to any one of claims 29 to 31, wherein the ocular disease or ocular disorder is selected from proliferative diabetic retinopathy and retinopathy of prematurity.

34. Use according to claim 32, wherein the ocular disease or ocular disorder is selected from proliferative diabetic retinopathy and retinopathy of prematurity.

35. The use according to any one of claims 29 to 31, wherein the eye disease or eye condition is wet age-related macular degeneration.

36. The use according to claim 32, wherein the ocular disease or ocular disorder is wet age-related macular degeneration.

Images