WO2005037277A1 - A novel use of riluzole for treating retinopathy - Google Patents

Abstract

The present invention relates to riluzole and its similar benzthiazole family compounds for treating retinopathy. Riluzole can not only effectively inhibits the endothelial growth stimulated by vascular endothelial growth factor (VEGF) in the culture of endothelial cells, but also inhibit abnormal vascular formation in the mouse model of retinopathy of prematurity (ROP), thus being able to apply to ischemic or proliferative retinopathies such as diabetic retinopathy, arteriosclerosis of the retina, and ROP. As such, the present invention aims to provide riluzole in treating neovascular proliferative retinopathy.

Description

DESCRIPTION A NOVEL USE OF RILUZOLE FOR TREATING RETINOPATHY

Technical Field The present invention relates to riluzole and its similar benzthiazole-family compounds for treating retinopathy.

Background Art: Ischemic or proliferative retinopathies, such as diabetic retinopathy, arteriosclerosis of the retina and ROP, are a prime cause of blindness in terms of its frequency and seriousness. Likewise, it is known that the main mechanism in this regard is abnormal neovascularization which is secondarily created due to retinal vascular occlusion, and that such neovascularization is induced by an increase in

VEGF; thus an effective treatment of this process is crucial. Abnormal neovascularization induces vitreous hemorrhage, retinal detachment and blindness. These diseases can be treated mainly by laser treatment aimed at inhibiting abnormal neovascularization or by excising the corpus vitream. However, despite laser treatment and surgical treatment, retinopathy may continue to advance and give rise to blindness. Thus, it is required to develop new effective drugs aimed at resolving the high incidence of diabetic retinopathy. VEGF, which is the prime cause of stimulating the growth of new vessels in ischemic retinopathy, is produced in numerous retinal cells at low oxygen, and works on Flk-1 and KDR, receptors of tyrosine kinase, in vascular endothelial cells. To date, the mechanism has not yet been disclosed distinctly, but it is already known that VEGF dominantly controls in diabetic retinopathy and ROP as well. It is likewise presumed that a similar mechanism is manifested in hyperglycemia such as relative hypoxia (ROP) and hyperinsulinemia (diabetic retinopathy) as well. With VEGF increasing, retinal vascular endothelial cells grow and give rise to neovascularization. However, since new blood vessels are very weak, effusion and bleeding may be created in blood vessels. In the signaling sub-pathway of VEGF receptors such as Flk-1 and KDR, PKC serves as a crucial mediator for proliferating vascular endothelial cells. Thus, the inhibition of PKC can be used as an appropriate method to inhibit the growth of vascular endothelial cells in retinopathy. However, since PKC is essential for normal signaling in cells, total inhibition of PKC may adversely affect cells. Recent research has revealed that PKC-βll is the prime mediator for generating the effect of VEGF in endothelial cells. Thus, since mainly PKC-βll is manifested in retinal cells, if PKC-βll is selectively inhibited, the growth of endothelial cells can be inhibited effectively without adversely affecting other kinds of PKC. According to cell culture experiments and animal experiments, it was disclosed that LY333531, a selective PKC-βll inhibitor, can inhibit the growth of vascular endothelial cells, and corresponding clinical experiments are being conducted. It has been known that riluzole, a benzthiazole-family compound, is effective in inhibiting the transportation of glutamatergic, and this suggests that the riluzole' s effect of inhibiting extracellular toxicity can provide protective working to the death of nervous cells in their various pathologic states. Thus, in the 1990s, riluzole was widely used clinically as a drug for treating amyotrophic lateral sclerosis (ALS) after it was approved by FDA. Various previous patented technologies related to riluzole have been known. For instance, they include EP1299102 aimed at providing riluzole in treating adrenoleukodystrophy, GR3035957T aimed at providing riluzole in treating AIDS-related nervous abnormality, US2002004516 aimed at providing riluzole in treating acoustic traumas, and WO0195907 aimed at providing riluzole in treating multiple sclerosis. However, technologies aimed at providing riluzole in treating retinopathy have not yet been announced. These inventors have revealed through experiments that riluzole, a drug for treating ALS, is effective in inhibiting PKC, and this can inhibit the cell growth stimulated by VEGF in cultured endothelial cells, as well as abnormal neovascularization in the mouse model of ROP.

DISCLOSURE OF THE INVENTION The purpose of this invention is to provide riluzole and its similar benzthiazole-family compounds as drugs for treating ischemic or proliferative retinopathies .

The present invention has accomplished its technological assignments by confirming that riluzole has the effects of inhibiting the HUVEC and REC growth stimulated by VEGF, the REC growth stimulated by PMA (PKC activation factor) , the phosphorylation of PKC in the culture of HUVEC, and abnormal neovascularization in the mouse model of ROP, thus providing riluzole and its similar compounds as drugs for treating retinopathies.

The present invention relates to riluzole and its similar benzthiazole-family compounds for treating ischemic or proliferative retinopathies. The chemical formula of riluzole and its similar benzthiazole-family compounds is shown in Chemical Formula 1 as follows.

In the above Chemical Formula 1, Ri is hydrogen, Cl- CIO alkyl, C1-C10 acyl, C3-C8 cycloalkyl or C1-C4 alkylphenyl. R₂ is hydrogen, C1-C10 alkyl, C1-C10 acyl, C3- C8 cycloalkyl, or C1-C4 alkylphenyl. R₃ and R are identical or different from each other, and they are hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, trifluoromethyl, or nitro, or both together form methylenenedioxybenzene.

To maximize the effects of riluzole and others, various pharmaceutical formulations can be conducted to include various compounds of salt and acid in addition to free-type riluzole. Pharmaceutically allowable salts include inorganic acid added salts such as hydrochloride, phosphate, nitrate, and sulfate, as well as organic acid added salts such as acetate, oxalate, succinate, fumarate, alate, benzoate, propionate, salicylate, methanesulfonate, theophyllineacetate, phenolphthalinate, isethionate, and β- hydroxynaphtoate, and also their substituted derivatives. Under this invention, oral administration-type compounds can be formulated using riluzole, not only in the form of tablets, pills, and granules, but also in the form of powder and capsules involving these. Likewise, parenteral administration-type compounds can be formulated in the form of liquid agents, ucinoid agents, spray-type collyrium, nasal aerosol, foams, suppositories, and various injections (intramuscular, subcutaneous, and intravascular) . Also, for abovementioned administration methods, various pharmaceutically allowable additives can be included in those compounds. To maximize the effects of these drugs, doctors and related personnel may determine dosages and administration methods appropriately in consideration of target patients' age, weight, physical qualities, and history of diseases. The present invention consists of the step wherein riluzole is confirmed as effective in inhibiting the HUVEC and REC growth stimulated by VEGF; the step wherein riluzole is confirmed as effective in inhibiting the REC growth stimulated by PMA; the step wherein riluzole is confirmed as effective in inhibiting the phosphorylation of PKC in the culture of HUVEC; and the step wherein riluzole is confirmed as effective in inhibiting abnormal neovascularization in the mouse model of ROP. Brief Description of Drawings Figure 1 is a photograph of the control group to which no treatment was given in the culture of human umbilical vein endothelial cells (HUVEC) . Figure 2 is a photograph where 100 ng/ l VEGF treatment was given in HUVEC. Figure 3 is a photograph where 100 ng/ml VEGF and 10 μM riluzole treatment was given in HUVEC. Figure 4 shows a numeric increase in nuclei in each sample in graph. Figure 5 is a photograph of the control group to which no treatment was given in the culture of cow's retinal endothelial cells (REC) . Figure 6 is a photograph where 100 ng/mL VEGF treatment was given in REC. Figure 7 is a photograph where 100 ng/mL VEGF and 10 μM riluzole treatment was given in REC. Figure 8 shows a numeric increase in nuclei in each sample in graph. Figure 9 is a photograph of the control group to which no treatment was given in REC. Figure 10 is a photograph where 20 nM PMA was treated in REC. Figure 11 is a photograph where 20 nM PMA and lOμM riluzole treatment was given in REC. Figure 12 shows a numeric increase in nuclei in each sample in graph. Figure 13 shows the result of Western blotting-based experiment on riluzole inhibiting the protein kinase C (PKC) phosphorylation stimulated by VEGF. Figure 14 shows the result of immunoprecipitation- based experiment on riluzone inhibiting the PKC phosphorylation stimulated by VEGF. Figure 15 is a photograph where young mice, after raised in normal oxygen, were given an injection of physiological salt solution, and their retinal vessels were observed with a fluorescence microscope. Figure 16 is a photograph where young mice, after raised in normal oxygen, were given an injection of riluzole, and their retinal vessels were observed with a fluorescence microscope. Figure 17 is a photograph where young mice, after raised in high-density oxygen, were given an injection of physiological salt solution, and their retinal vessels were observed with a fluorescence microscope. Figure 18 is a photograph where young mice, after raised in high-density oxygen, were given an injection of physiological salt solution, and their retinal vessels were observed at 40 times magnification with a fluorescence microscope. Figure 19 is a photograph where young mice, after raised in high-density oxygen, was given an injection of physiological salt solution, and their retinal vessels were observed at 200 times magnification with a fluorescence microscope. Figure 20 is a photograph where young mice, after raised in high-density oxygen, were given an injection of riluzole, and their retinal vessels were observed with a fluorescence microscope. Figure 21 is. a photograph where young mice, after raised in high-density oxygen, were given an injection of riluzole, and their retinal vessels were observed at 40 times magnification with a fluorescence microscope. Figure 22 is a photograph where young mice, after being raised in high-density oxygen were given injection of riluzole, and their retinal vessels were observed at 200 times magnification with a fluorescence microscope. Figure 23 shows a scaling graph according to the retinopathy scoring system. Figure 24 is a photograph where young mice, after raised in normal-density oxygen, were given a physiological salt solution treatment, and their retinas were dyed with hematoxylin and eosin. Figure 25 is a photograph where young mice, after raised in normal-density oxygen, were given a riluzole treatment, and their retinas were dyed with hematoxylin and eosin. Figure 26 is a low-magnification photograph where young mice, after raised in high-density oxygen, were given a physiological salt solution treatment, and their retinas were dyed with hematoxylin and eosin. Figure 27 is a high-magnification photograph where young mice, after raised in high-density oxygen, were given a physiological salt solution treatment, and their retinas were dyed with hematoxylin and eosin. Figure 28 is a low-magnification photograph where young mice, after raised in high-density oxygen, were given a riluzole treatment, and their retinas were dyed with hematoxylin and eosin. Figure 29 is a high-magnification photograph where young mice, after raised in high-density oxygen, were given a riluzole treatment, and their retinas were dyed with hematoxylin and eosin. Figure 30 shows the number of nuclei of vascular cells in each sample in graph.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.

EXAMPLE 1: Riluzole' s effects of inhibiting the HUVEC and REC growth stimulated by VEGF HUVEC and cow' s REC were cultured as endothelial growth medium (EGM, a product of Clonetics) using fibronectin-coated cell culture containers (a product of NUNC) . Experiments were carried out on 5 to 9 days after seeding. During the first seeding, REC were cultured in the EGM with 10% cow' s fetal serums added, and one day after seeding, the medium was replaced by EGM. When cells grew by 30% in EGM, after the medium was replaced by the endothelial basic medium (EBM) , cells were classified into a sample with 100 ng/mL VEGF added, a sample with O.lμM riluzole added after VEGF treatment, a sample with lμM riluzole added after VEGF treatment, a sample with lOμM riluzole added after VEGF treatment, a sample with 5μM GF109203X (known as a total PKC inhibitor) added after VEGF treatment, and a sample (control group) with nothing added, and these were cultured for four days in C0₂ incubators at 37 ^°C Afterwards, after cells were washed three times with phosphoric buffer solution (PBS) , they were fixed with 4% paraformaldehyde. Then, they had a five-minute reaction with Hoechst 33258, were washed with PBS, and were observed with a fluorescence microscope. Nuclei were observed (at 200 magnification of a microscope) randomly across over four places per well in 24-well cell culture trays, and the number of cultured cells was measured by counting the number of nuclei dyed with Hoechst 33258. In the HUVEC culture, vascular endothelial cells that were exposed to A00 ng/mL VEGF for four days multiplied three times as much as the control group. Figure 1 is a photograph of the control group, and Figure 2 is a photograph where 100 ng/mL VEGF treatment was given. The HUVEC growth stimulated by VEGF was significantly inhibited gradually, by adding 0.1, 1, and 10 μM riluzole, and 5μM GF109203X. Figure 3 is a photograph that 10 μMri riluzole treatment was given. Figure 4 shows a numeric increase in nuclei in each sample in graph, and the significance was verified by Student's t-Test. In Figure 4, ** denotes below 0.01 significance for the control group, # denotes below 0.05 significance for VEGF-treated cells, and ## denotes below 0.01 significance for VEGF-treated cells. Likewise, in the cow's REC culture, REC that were exposed to 100 ng/mL VEGF for four days multiplied 2.5 times as much as the control group. Figure 5 is a photograph of the control, and Figure 6 is a photograph where 100 ng/mL VEGF treatment was given. Also, the REC growth stimulated by VEGF was significantly inhibited gradually, . by adding 0.1, 1, and lOμM riluzole, and 5μM GF109203X. Figure 7 is a photograph where lOμM riluzole treatment was given. Figure 8 shows a numerical increase in nuclei in each sample in graph, and the significance was verified by Student's t-Test. In Figure 8, ** denotes below 0.01 significance for the control group, # denotes below 0.05 significance for VEGF-treated cells, and ## denotes below 0.01 significance for VEGF- treated cells. EXAMPLE 2: Riluzole' s effects of inhibiting the REC growth stimulated by PMA PKC is multi-functional protein kinase. PKC s typical isomers are PKC-α, β, and γ, and these are activated by calcium and phospholipid. VEGF activates PKC, via its receptors, Flk-1 and KDR. PKC-βll is known to serve as a mediator for VEGF to stimulate the growth of endothelial cells. Since activated PKC can crucially signal for VEGF to stimulate the growth of REC, experiments were conducted using PMA, a PKC activation factor, with the same method as that of Embodiment 1 above. Likewise, raised for four days in EBM at 37^°Cin C0₂ incubators were a sample with 20 nM PMA added to REC, a sample with O.lμM riluzole added after PMA treatment, a sample with lμM riluzone added after PMA treatment, a sample with lOμM riluzole after PMA treatment, and a sample (control group) with nothing added. Afterwards, cells were washed three times with PBS, and were fixed with 4% parafor aldehyde. Then, they had a five-minute reaction with Hoechst 33258, were washed again with PBS, and were observed with a fluorescence microscope. Nuclei were observed (at 200 magnification of a microscope) randomly across over four places per well in 24-well cell culture trays, and the number of cultured cells were measured by counting the number of nuclei dyed with Hoechst 33258. As a result, the sample with 20 nM PMA treatment given to REC proliferated cells remarkably as much as the sample treated with 100 ng/mL, compared to the control group. Figure 9 is a photograph of the control group, and Figure 10 is a photograph where 20 nM PMA treatment was given. In cases where riluzole was added, the endothelial cell growth stimulated by PMA was significantly inhibited. Figure 11 is a photograph where lOμM riluzole treatment was given. Figure 12 shows a numeric increase in nuclei in each sample in graph, and the significance was verified by Student' s-t Test. In Figure 12, * denotes below 0.05 significance for the control group, # denotes below 0.05 significance for PMA- treated cells, and ## denotes below 0.01 significance for PMA-treated cells.

EXAMPLE 3: Riluzole' s effects of inhibiting the phosphorylation of PKC in the culture of HUVEC To confirm that riluzole was effective in inhibiting the phosphorylation of PKC in the culture of HUVEC, Western blotting and immunoprecipitation were conducted. An identical amount of protein was separated using 6%~8% SDS-PAGE, and was transferred to PVDF membranes. Membranes were made to react to anti-phospho-PKC_pan-antibody and phospho-Flk-1 antibody at 4°C and were confirmed using ECL. The result is shown in Figure 13. According to this, riluzole can inhibit the PKC phosphorylation stimulated by VEGF. Figure 4a shows the PKC phosphorylation degree in graph as measured by an optical densimetry, and the measurement was conducted after VEGF was exposed for 21 hours. The significance was verified by Student's t-Test. * denotes below 0.05 significance for the control group, # denotes below 0.05 significance for VEGF-treated cells, and ## denotes below 0.01 significance for VEGF-treated cells. Meanwhile, immunoprecipitation was conducted 21 hours after VEGF and riluzole treatment. After an identical amount of protein was secured, identical amounts of antibodies (PKC- , βl, βll, and γ) each were inserted and these were made to undergo reaction at 4 °Covernight, and added to these the next day were agarose G (PKC-βl-reacted sample) and agarose A (PKC-α, βll, and γ-reacted sample) before they were shaken for over three hours. Afterwards, the samples were washed three times, and were boiled for five minutes after adding twice as much sample buffer as the resulted solution. These were separated using 8% SDS-PAGE, and were transferred to PVDF membranes. Membranes were inserted into anti- phospho-PKCpan antibody and underwent reaction overnight at 4^°Covernight, and they were confirmed using ECL. The result is shown in Figure 14, and according to this result, it is confirmed that the addition of riluzole can remarkably reduce the PKC phosphorylation stimulated by PKC-βll. From results above, it is learned that riluzole can inhibit the PKC phosphorylation stimulated by PKC-βl and PKC-βll, and likewise, there is no change in phosphorylation of Flk-1, VEGF's receptor.

EXAMPLE 4: ROP mouse model experiment Young mice were raised in the room with oxygen density of 75+5% together with their mother for 5-12 days after they were born. They then were raised in the room with normal-density oxygen during the period of 12-17 days after born to create a ROP model. Mice in the control group were raised for 5-17 days in the room with normal-density oxygen. To ensure accuracy in the measurement, the oxygen density was observed twice a day using a Hudson Oxygen Analyzer (a product of Hudson Ventronic) . Sprague-Dawley mice were secured from the Charles Lieber' s Laboratory. To experiment on the riluzole' s effects with the ROP mouse model, ROP was induced as above, and the degree of abnormal retinal vascular formation was measured. Likewise, during the period of 12-17 days after born, mice were given an intraperitoneal injection of daily lOmg/kg riluzole dissolved in physiological salt solution containing 5% DMSO. The control group was given an injection of an identical amount of physiological salt solution containing 5% DMSO using the same method. All mice were given an intraperitoneal injection of

80mg/kg ketamine and 15mg/kg xylazin to anesthetize them deeply. Afterwards, their thoracic cavities were opened, and were given an injection into their left ventricles 0.5mL of 20mg/mL dextran (product with molecular weight of 2,000,000. sigma) marked as fluorescein isothhiocyanate. 15 minutes later, their eyes were separated, and were fixed in 4% paraformaldehyde fixative. Retinas were separated from fixed eyes while they were being watched under a microscope. They were observed under a fluorescence microscope after they were spread on a slide glass. Observation was made of retinal blood vessels under a fluorescence microscope. Likewise, in the case of young mice that were given an injection of physiological salt solution after raised in normal-density oxygen (refer to Figure 15) , or in the case of young mice that were given an injection of riluzole after raised in normal-density oxygen (refer to Figure 16) , no abnormal retinal vascular formation was created, and also there were almost no vascular distortion and tuft-shaped vascular formation, thus showing normal blood vessels. Meanwhile, In the case of young mice that were given an injection of physiological salt solution after raised in high-density oxygen, observed was much abnormal neovascularization, namely, formation of many tuft-shaped blood vessels, a weakening of central blood vessels, and increased distortion of blood vessels (refer to Figures 17, 18, and 19) . Figure 18 shows an observation made at 40 times magnification, and Figure 19 at 200 times magnification. Meanwhile, in the case of young mice that were given an injection of riluzole after raised in high-density oxygen, they, compared to the control group with no riluzole treatment given, remarkably reduced abnormal neovascularization, and the weakening of their central blood vessels was reduced (refer to Figures 20, 21, and 22) . Figure 21 shows an observation made at 40 times magnification, and Figure 22 at 200 times magnification. Above results were expressed using Retinopathy Scoring System. The system is the International Classification of ROP (ICROP) . The scoring system is shown in Table 1 below. The degree of maturity was measured in three levels, as with ICROP. The degree of disease progress was measured in terms of retina's circumference and clock hours, as with ICROP.

[Table l]

Table 2 shows the seriousness degree of retinopathy in each sample expressed in terms of Retinopathy Scoring System (refer to Table 1) .

[Table 2]

The average score of the control group raised in normal-density oxygen was 1.19 (in the case of an injection of physiological salt solution given) and 1.46 (in the case of an injection of riluzole given), while the average score of the group with physiological salt solution given after raised in high-density oxygen was 8.75. Meanwhile, the score of the group with riluzole treatment given after raised in high-density oxygen was 4.84. According to these results, the retinopathy seriousness degree of the riluzole-treated group can be reduced by about 50%, compared to that of the physiological salt solution-treated group, though they are raised under the same conditions (refer to Figure 23) . Also, to quantify retinopathy, mice were given an injection of lethal dose and killed, and their eyes were separated. These were frozen in liquid nitrogen, and were cut in thickness of 8 μm to be parallel to the optical nerve and perpendicular to the corena, using a freezing microtome. Cut pieces were fixed in 4% paraformaldehyde and were dyed with hematoxylin and eosin (H&E) before the number of nuclei formed in the limiting membranes in the retina was measured using a microscope. At least eight cut pieces per eye at an internal of over 50 jm were made. To quantify retinopathy, the number of nuclei of vascular cells formed up to the corpus vitream of the internal limiting membrane was measured under a microscope. Abnormal vascularization was quantified by dyeing 8 μm- thick cut pieces with H&E and measuring the number of nuclei of blood vessels that existed on the surface of the corpus vitream of the internal limiting membrane. For this reason, if nuclei of vascular cells exist on the surface of the corpus vitream of the internal limiting membrane, this can be considered as a result of new blood vessel formation. As a result, the control groups (physiological salt solution- treated group and riluzole-treated group) increased their vascular cell nuclei only by less than five. However, the ROP group (physiological salt solution-treated group) that was raised in high-density oxygen increased their vascular cell nuclei by over 80. The group that was given an injection of riluzole after exposed to high-density oxygen reduced their vascular cell nuclei remarkably at about 20. Figure 30 shows the above result in graph. 28 animals were used for experiments, the significance was verified by ANOVA, and ** and ## denote below 0.01 significance. Figures 24 - 29 show photographs of above results. In the photograph where young mice, after raised in normal- density oxygen, were given physiological salt solution treatment, and their retinas were dyed with H&E (refer to Figure 24), or in the photograph where young mice, after raised in normal-density oxygen, were given riluzole treatment, and their retinas were dyed with H&E (refer to Figure 25) , almost no vascular cell nuclei are found on the surface of the corpus vitream of the internal limiting membrane. Meanwhile, in the photograph where young mice, after raised in high-density oxygen, were given a physiological salt solution treatment, and their retinas were dyed with H&E, vascular endothelial cell nuclei remarkably increase on the surface of the corpus vitream of the internal limiting membrane (refer to Figures 26 and 27) . Figure 26 is a photograph at low magnificence, and Figure 27 at high magnificence. Meanwhile, in the photograph where young mice, after raised in high-density oxygen, were given riluzole treatment, and their retinas were dyed with H&E, the nuclei decrease considerably (refer to Figures 28 and 29) . Figure 28 is a photograph at low magnificence, and Figure 29 at high magnificence. Embodiments above have confirmed that riluzole can effectively inhibit the endothelial cell growth stimulated by VEGF in the endothelial cell culture, as well as inhibit abnormal vascular formation in the mouse model of ROP. This suggests that since riluzole works as a PKC inhibitor, it is effective in treating human ischemic or proliferative retinopathies such as diabetic retinopathy, arteriosclerosis of the retina, and ROP. Meanwhile, since PKC plays a crucial role in enabling various tissues to have normal functions, side effects of PKC inhibitors pose a crucial problem. However, riluzole was approved by FDA and has already been applied to human beings, proving its safety; thus it can be used as a powerful drug in treating neovascular proliferative retinopathy.

Advantageous Effects This invention relates to riluzole and its similar benzhiazole-family compounds for treating retinopathy. As such, riluzole can effectively inhibit the endothelial cell growth stimulated by VEGF in the culture of endothelial cells, as well as inhibit abnormal vascular formation in the mouse model of ROP, thus being able to apply to ischemic or proliferative retinopathies such as diabetic retinopathy, arteriosclerosis of the retina. Riluzole has already been applied to humans for other treatment purposes, and was approved by U.S. Food and Drug Administration (FDA) thus proving its safety. Accordingly, the present invention is very useful in medicine industrially.

Claims

CLAIMS 1. A composition for treating retinopathies including compounds that are expressed in terms of the following Chemical Formula 1;

wherein, Ri is hydrogen, C1-C10 alkyl, C1-C10 acyl, C3-C8 cycloalkyl or C1-C4 alkylphenyl. R₂ is hydrogen, C1-C10 alkyl, C1-C10 acyl, C3-C8 cycloalkyl, or C1-C4 alkylphenyl. R₃ and R₄ are identical or different from each other, and they are hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, trifluoromethyl, or nitro, or both together form ethylenenedioxybenzene.

2. The composition for treating retinopathies according to claim 1, wherein the compounds are riluzole that is expressed in terms of the following Chemical Formula 2;

3. The composition for treating retinopathies according to claim 1 or 2, the composition include additionally pharmaceutically allowable salts such as inorganic acid added salts comprising hydrochloride, phosphate, nitrate, and sulfate; organic acid added salts comprising acetate, oxalate, succinate, fumarate, malate, benzoate, propionate, salicylate, methanesulfonate, theophyllineacetate, phenolphthalinate, isethionate, and β- hydroxynaphtoate; and their substituted derivatives.