WO2008044339A1

WO2008044339A1 - Therapeutic/preventive agent for intraocular disease containing statin compound

Info

Publication number: WO2008044339A1
Application number: PCT/JP2007/001112
Authority: WO
Inventors: Yasuaki Hata; Tadahisa Kagimoto; Hirotaka Iwaki; Tatsuro Ishibashi
Original assignee: Aqumen Biopharmaceuticals K.K.; Kyushu University
Priority date: 2006-10-13
Filing date: 2007-10-15
Publication date: 2008-04-17
Also published as: TW200824682A

Abstract

It is intended to provide a DNA synthesis inhibitor in retinal vascular endothelial cells, and a therapeutic agent and a preventive agent for an intraocular disease associated with an intraocular disease. The invention is based on Examples in which a lipophilic statin compound inhibits the DNA synthesis in retinal vascular endothelial cells thereby to prevent the cell growth, and relates to a therapeutic agent or a preventive agent for an intraocular disease containing a lipophilic statin compound as an active ingredient. That is, the above object can be achieved by the DNA synthesis inhibitor of retinal vascular endothelial cells, and the therapeutic agent or preventive agent for an intraocular disease, each containing a lipophilic statin compound as an active ingredient.

Description

Specification

Treatment of intraocular diseases containing statin compounds

Technical field

The present invention relates to a therapeutic / prophylactic agent for intraocular diseases containing a statin compound as an active ingredient. More specifically, the present invention relates to treatment of intraocular diseases having growth inhibition, contraction suppression, anti-inflammation, antioxidant action, or neuroprotective action for intraocular cells containing a statin compound as an active ingredient. Background art

[0002] This application claims priority based on Japanese Patent Application Nos. 2006-279338 and 2007-6 5927, and the contents disclosed in these applications are incorporated herein by reference. It is incorporated into the specification.

[0003] Age-related macular degeneration (exudative, atrophic), diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, uveitis, allergic conjunctivitis, spring cataract, and glaucoma Intraocular diseases such as these are lacking in effective therapeutic and preventive agents. Therefore, the development of effective drugs for the prevention and treatment of these diseases is desired.

[0004] Statins are acid forms in vivo, including the prodrug lactone type. All acid-type statin compounds have 3,5-dihydroxyvaleric acid (DHVA) and other hydrophobic moieties. A structure similar to DHVA is found in the substrate of HMG_CoA reductase and its reaction intermediate. Thus, all statin compounds function as HMG_CoA reductase inhibitors. Statin compounds are widely known as therapeutic or prophylactic agents for hyperlipidemia.

[0005] Special Table 2003-5 1 1 347 (Patent Document 1 below) states that the name of the invention is "upregulation of type III endothelial cell nitric oxide synthase by HMG-CoA reductase inhibitor. An invention is disclosed. Specifically, the document contains an effective amount of HMG—to increase endothelial cell nitric oxide synthase activity. It is disclosed that a CoA reductase inhibitor is administered (claim 1, paragraph [

00 1 0]). In addition, simvastatin and lovastatin are listed as HMG-CοΑ reductase inhibitors (claim 97, paragraph [00 1 6] and examples). In another example, simpastatin and oral pastatin were administered to measure e c NOS activity (paragraph [0089]).

[0006] That is, JP-T 2003-5 1 1 347 discloses that statin compounds increase endothelial cell nitric oxide synthase activity.

[0007] Japanese Patent Laid-Open No. 2004-1 49480 (Patent Document 2 below) discloses an invention that is the title of the invention <<, "a therapeutic agent for ophthalmic diseases for oral or transdermal administration". Specifically, claim 4 of the same document contains an agent for improving lipid metabolism abnormality selected from mevalotin, oral pastatin, lipitol, and evadale, and is an ophthalmic disease for oral or transdermal administration. A therapeutic agent is disclosed. In the example of this document, an example in which the visual field is expanded by oral administration of mevalotin to an open-angle glaucoma patient with high intraocular pressure is disclosed (paragraph [0008]). Mevalotin is a hyperlipidemia treatment sold by Sankyo Pharmaceutical, and its active ingredient is pravastatin, a kind of statin compound. Further, claim 7 of the same document states that “the ophthalmological disease is glaucoma, retinitis pigmentosa, diabetic retinopathy, central retinal vein occlusion or macular degeneration” as the target disease.

[0008] Japanese Patent Application Laid-Open No. 2004-1 49480 discloses an example in which mevalotin is orally administered in order to widen the visual field in open-angle glaucoma with high intraocular pressure. However, in this document, the compound that is considered effective for the treatment of retinitis pigmentosa is carnitine (paragraph [0009], paragraph [00 1 0]) and is not a statin compound. In addition, the compound that is considered effective in the treatment of diabetic retinopathy, central retinal vein occlusion, or macular degeneration is a combination of carnitine and taurine (paragraph [00 13)].

[0009] The most common complication of retinal detachment is proliferative vitreoretinopathy (PVR)

1 ferat ι vev ι teoret ι nopathy), and it is said that it will merge with 5-10% of Akizuki 旲 J. PVR is a benign cell growth in the eyeball It is a disease caused by Traction retinal detachment by PVR generates traction force that acts directly on the inner and outer surfaces of the retina, and eventually the retina is detached from the retinal pigment epithelium (RP E) layer. There is no effective prophylactic treatment for PVR, and PVR is currently treated mainly by surgical techniques.

[0010] Proliferative vitreoretinopathy (PVR) is characterized by the formation of contractile cell membranes on both sides of the retina (eg, Fastenberg, eta, Am. J. Ohthal mo, V ol 93, p p. 565-572 (1 98 2)). Retinal pigment epithelium (RP E) cells are thought to be involved in the proliferation of plasma membranes associated with PVR. When RPE cells that have been in a quiescent state migrate to the vitreous cavity and are exposed to the appropriate combination of site forces, RPE cells are thought to divide and differentiate. This differentiation results in cells with myofibroblastic properties including adhesion and contractility. When these cell membranes attach to the surface of the retina, traction is generated and the retina is considered to be detached.

[0011] Proliferative vitreoretinopathy (PVR) is a proliferation of intraocular cells such as retinal pigment epithelium (RPE) cells (especially replicating ocular cells (ROC)), and the proliferation membrane Since it is caused by contraction and pulling of the retina, a drug or composition that can inhibit the proliferation or contraction of these intraocular cells is considered to be effective in the treatment of PVR. Such drugs or compounds are considered to be effective in the treatment and prevention of diseases associated with PVR such as diabetic retinal detachment.

[0012] International Publication WO 97/37542 (Patent Document 3) discloses a gene therapy method for proliferative vitreous retinoplasty (PVR) in which a replicated eye cell is transduced using a retroviral vector. ing.

In addition, International Publication W099 / 00 129 (Patent Document 4 below) discloses a method for treating proliferative vitreoretinopathy (PVR) using a calcium blocker.

Patent Document 1: Special Table 2003— 5 1 1 347

Patent Document 2: Japanese Patent Laid-Open No. 2004_1 49480 Patent Document 3: International Publication WO 97/37542 Pamphlet

Patent Document 4: International Publication W099 / 00 1 No. 29 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0014] An object of the present invention is to provide a DNA synthesis inhibitor of retinal vascular endothelial cells, and a therapeutic and prophylactic agent for intraocular diseases related to intraocular diseases.

[0015] The present invention relates to an intraocular neovascular inhibitor, an intraocular cell growth inhibitor or cell contraction inhibitor, a replication eye cell growth inhibitor or a replica eye cell contraction inhibitor, exudation-type aging yellow, Treatment or prevention agent for macular degeneration, treatment or prevention agent for atrophic age-related macular degeneration, diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, A therapeutic or prophylactic agent for uveitis, allergic conjunctivitis, or spring catarrh, a therapeutic agent or prophylactic agent for glaucoma, a PVR therapeutic agent or prophylactic agent effective for prophylactic treatment of proliferative vitreoretinopathy (PVR), and The purpose is to provide a preventive agent for retinal detachment, a therapeutic agent or preventive agent for retinal vein occlusion, and the like.

Means for solving the problem

[0016] In the present invention, basically, a fat-soluble statin compound inhibits DNA synthesis of retinal vascular endothelial cells, inhibits cell proliferation, and has cell contraction suppression, anti-inflammatory, antioxidant and neuroprotective actions. The present invention relates to a therapeutic or prophylactic agent for intraocular diseases containing a statin compound as an active ingredient.

[0017] In addition, the present invention basically uses a liposoluble statin compound such as cin / statin, which is known as an HMG-CoA reductase inhibitor and the like, so that This is based on the knowledge in the examples that synthesis can be inhibited and proliferation / contraction of intraocular cells can be effectively inhibited. Furthermore, the present invention is based on the finding that inhibition of intraocular cell proliferation or contraction leads to prophylactic treatment of proliferative vitreoretinopathy (PVR) and can prevent traction retinal detachment.

Specifically, the present invention relates to the following inventions.

[1] Fat-soluble statin, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable Recombinant DNA synthesis inhibitor of retinal vascular endothelial cells, containing solvate as an active ingredient.

[2] The agent described in [1] above, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

[3] The agent according to the above [1], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[4] The agent described in [2] or [3] above, which is administered intraocularly.

[5] The agent described in [2] or [3] above, which has a sustained release carrier administered or placed in the eye.

[6] The agent according to [2] or [3] above, which has a sustained release carrier administered or placed in the vitreous.

[7] A therapeutic agent for ophthalmic diseases comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[8] The agent described in [7] above, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

[9] The agent according to [7] above, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[10] The agent described in [8] or [9] above, which is administered intraocularly.

[1 1] The agent according to [8] or [9] above, which has a sustained release carrier administered or placed in the eye.

[12] The agent described in [8] or [9] above, which has a sustained release carrier administered or placed in the vitreous.

[13] An intraocular neovascular inhibitor comprising as an active ingredient a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[14] The above fat-soluble statin is one or more of simvastatin, flupastatin, oral vastatin and cerivastatin [1 3] The agent described in 1.

[15] The agent described in [13] above, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[16] The agent according to [14] or [15], which is administered intraocularly.

[17] The agent described in [14] or [15] above, which has a sustained release carrier administered or placed in the eye.

[18] The agent described in [14] or [15] above, which has a sustained release carrier administered or placed in the vitreous.

[19] The agent described in [14] or [15], which is used for inhibiting the generation of new blood vessels from the retina.

[20] An intraocular cell growth inhibitor or cell contraction inhibitor containing a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[21] The agent according to [20] above, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral bustin, or cerivastatin.

[22] The agent according to the above [20], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[23] The agent described in [21] or [22] above, which is administered intraocularly.

[24] The agent described in [21] or [22] above, which has a sustained release carrier administered or placed in the eye.

[25] The agent described in [21] or [22] above, which has a sustained release carrier administered or placed in the vitreous.

[0022] [26] Cell growth inhibitor for replication eye or suppression of cell contraction of replication eye containing fat-soluble statin, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof as an active ingredient Agent.

[27] The above fat-soluble statin is one or more of simvastatin, flupastatin, oral vastatin and cerivastatin [26] The agent described in 1.

[28] The agent according to [27], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[29] The agent described in [27] or [28] above, which is administered intraocularly.

[30] The agent according to [27] or [28] above, which has a sustained release carrier administered or placed in the eye.

[31] The agent described in [27] or [28] above, which has a sustained release carrier administered or placed in the vitreous.

[0023] [32] A therapeutic or prophylactic agent for wet age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[33] The agent according to [32] above, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral bustin, or cerivastatin.

[34] The agent according to [32], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[35] The agent described in [33] or [34] above, which is administered intraocularly.

[36] The agent described in [33] or [34] above, which has a sustained release carrier administered or placed in the eye.

[37] The agent described in [33] or [34] above, which has a sustained release carrier administered or placed in the vitreous body.

[0024] [38] A therapeutic or preventive agent for atrophic age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[39] The agent according to the above [38], wherein the fat-soluble statin is one or more of simvastatin, flupastatin, oral vastatin and cerivastatin.

[40] The fat-soluble statin is simpastatin or flupastatin. The agent according to [38] above, which is either or both.

[41] The agent described in [39] or [40] above, which is administered intraocularly.

[42] The agent described in [39] or [40] above, which has a sustained release carrier administered or placed in the eye.

[43] The agent described in [39] or [40] above, which has a sustained release carrier administered or placed in the vitreous.

[0025] [44] Diabetic retinopathy containing a fat-soluble statin, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate as an active ingredient, traction retinal detachment, vitreous hemorrhage, A therapeutic or prophylactic agent for macular edema or retinopathy of prematurity (especially a therapeutic or prophylactic agent for traction retinal detachment).

[45] The agent according to the above [44], wherein the fat-soluble statin is one or more of simvastatin, flupastatin, oral bustin, or cerivastatin.

[46] The agent according to [44], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[47] The agent described in [45] or [46] above, which is administered intraocularly.

[48] The agent described in [45] or [46] above, which has a sustained release carrier administered or placed in the eye.

[49] The agent described in [45] or [46] above, which has a sustained release carrier administered or placed in the vitreous.

[0026] [50] Uveitis, allergic conjunctivitis, or spring catarrhine containing fat-soluble statin, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof as an active ingredient Therapeutic agent.

[51] The agent according to [50], wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral bustin, or cerivastatin.

[52] The agent according to [50], wherein the fat-soluble statin is one or both of sympastatin and flupastatin. [53] The agent described in [51] or [52] above, which is administered intraocularly.

[54] The agent described in [51] or [52] above, which has a sustained release carrier administered or placed in the eye.

[55] The agent described in [51] or [52] above, which has a sustained-release carrier administered or placed in the vitreous body.

[56] A therapeutic or prophylactic agent for glaucoma comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[57] The agent according to [56], wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral bustin, or cerivastatin.

[58] The agent according to [56], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[59] The agent described in [57] or [58] above, which is administered intraocularly.

[60] The agent described in [57] or [58] above, which has a sustained release carrier administered or placed in the eye.

[61] The agent described in [57] or [58] above, which has a sustained release carrier administered or placed in the vitreous.

[0028] [62] A therapeutic or prophylactic agent for proliferative vitreoretinopathy comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[63] The agent according to [62], wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral bustin, or cerivastatin.

[64] The agent according to [62], wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[65] The agent described in [63] or [64] above, which is administered intraocularly.

[66] The agent described in [63] or [64] above, which has a sustained release carrier administered or placed in the eye. [67] The agent described in [63] or [64] above, which has a sustained release carrier administered or placed in the vitreous.

The invention's effect

[0029] According to the present invention, it is possible to provide a DNA synthesis inhibitor of retinal vascular endothelial cells, and a therapeutic and prophylactic agent for intraocular diseases related to intraocular diseases.

[0030] According to the present invention, an intraocular neovascular inhibitor, an intraocular cell growth inhibitor or cell contraction inhibitor, a replication eye cell growth inhibitor or a replica eye cell contraction inhibitor, exudation-type aging Treatment or prevention agent for macular degeneration, Treatment or prevention agent for atrophic age-related macular degeneration, Diabetic retinopathy, Traction retinal detachment, Vitreous hemorrhage, Macular edema, Retinopathy of prematurity, Grape Therapeutic or preventive agent for meningitis, allergic conjunctivitis, or spring catarrh, therapeutic agent or prophylactic agent for glaucoma, PVR therapeutic agent or preventive agent effective for the treatment of proliferative vitreoretinopathy (PVR), retinal vein occlusion A therapeutic or prophylactic agent can be provided.

Brief Description of Drawings

[0031] [Fig. 1] Fig. 1 is a graph showing the effect of sympastatin on DNA synthesis induced by TNF-s, PDGF-BB, and HGF in vitreous cells.

FIG. 2 is a graph showing the effect of sympastatin on DNA synthesis induced by VEG F, HG F, or TNF in retinal vascular endothelial cells.

FIG. 3 is a graph showing the effect of simpastatin acid on proliferation of retinal vascular endothelial cells induced by VEGF.

[Fig. 4] Fig. 4 (A) A photograph replacing a drawing showing the results of I, tu b e for mat mat ion (blood vessel formation ability). The upper three pictures in Fig. 4 (A) show the case where VEG F is not added, and the lower three pictures in Fig. 4 (A) show the case where VEGF is added. Figure 4 (B) is a graph showing the lumen area at each well when the lumen area without addition of VEGF is 100%. In the bar graph in Fig. 4 (B), the three from the left indicate that VEGF is not added, and the right three indicate that VEGF is not added.

[FIG. 5] FIG. 5 is a diagram for verifying the contractile inhibitory effect of sympastatin. Figure Fig. 5 (A) shows a photograph replacing the collagen gel drawing, and Fig. 5 (B) shows the collagen gel in each well when the diameter of the collagen gel without adding sympastatin is 100%. It is a graph which shows a diameter. Figures 5 (C) and 5 (D) show the results of using pravastatin instead of sympastatin. The photographs and graphs in Fig. 5 show from the left simvastatin (or pravastatin) 0 (control), 0.1 M, 0.3 μΜ,

1 U M.

[FIG. 6] FIG. 6 is a diagram for verifying the contractile inhibitory effect of sympastatin. Figure

Figure 6 (A) shows a photograph replacing the drawing of collagen gel when sympastatin sodium salt is administered. Figure 6 (B) shows a photograph replacing the drawing of the collagen gel when pravastatin is administered. Figure 6 (C) shows a photograph replacing the drawing of the collagen gel when full-pastin is administered.

[FIG. 7] FIG. 7 is a diagram for verifying the inhibition of contraction of collagen gel containing vitreous cells stimulated by TGF_S2 by sympastatin and flupastatin. Fig. 7 (A) shows a photograph replacing the drawing of the collagen gel when sympastatin (SS), flupastatin (FS), and pravastatin (PS) are administered. Figure 7 (B) is a graph showing the diameter of the collagen gel in each tool when the diameter of the collagen gel to which TGF_S2 and statin compounds are not added is 100%.

[FIG. 8] FIG. 8 is a diagram for examining the inhibition of contraction of collagen gel containing vitreous cells stimulated by growth factors by inactive sympastatin and active sympastatin. Fig. 8 (A) shows a photograph replacing the collagen gel drawing when inactive sympastatin is administered, and Fig. 8 (B) shows a drawing replacing the collagen gel drawing when inactive sympastatin is administered. A photograph is shown.

[Fig. 9] Fig. 9 is a diagram for verifying the inhibition of contraction of collagen gel containing MIO-M1 cells, which are cell lines of Mu II er cells stimulated by TG F_S2, by sympastatin. . Figure 9 (A) shows a simple pasta The photograph replaced with drawing of the collagen gel at the time of administering a tin is shown. Figure 9 (B) shows a photograph replacing the drawing of the collagen gel when pravastatin is administered.

FIG. 10 (A) is a photograph of the results of Western blotting instead of a drawing showing the inhibitory effect of sympastatin on TG F_; S 2 -dependent myosin light chain phosphorylation in vitreous cells. The upper part of the photo shows the amount of phosphorylated myosin light chain (MLC), and the lower part shows the total amount of myosin light chain. Figure 10 (B) shows the ratio of the pMLC / MLC value of the cells to each stimulus when the pMLC / M 1_ ○ value of the cells to which TG F_S 2 and the statin compound are not added is 100%. It is a graph to show. In the figure, S S is sympastatin, FS is flupastatin, PS is pravastatin, and C is control.

[Fig. 11] Fig. 11 shows the inhibitory effect of mevalonate or geranylgeranyl pyophosphate on the inhibition of myosin light chain phosphorylation of vitreous cells stimulated by TG F_; S 2 by simpastatin acid. It is a photograph of the result of alternative Western blotting.

[Figure 12] Figure 12 shows the outline of the mevalonate pathway.

[Fig. 13] Fig. 13 is a photograph of Western plotting instead of a drawing to verify the effect of sympastatin on p65 nuclear translocation in vitreous cells.

[FIG. 14] FIG. 14 shows the inhibitory effect of simpastatin acid (SSS) on phosphorylation of KDR induced by VEGF in retinal endothelial cells. Figure 14 (A) is a photograph of western blotting instead of a drawing showing the amount of phosphorylated KDR on the top and the total amount of KDR on the bottom. Figure 14 (B) shows the p KDR / KD of the cells for each stimulus when the p KDR / 0? ¾ value of the cells stimulated with sympastatin acid 0 M and VEGF 25 ng / mL was 100%. It is a graph which shows the ratio of R value.

[FIG. 15] FIG. 15 is a graph showing the phosphorylation inhibitory effect of p44 / 42MA P kinase (MAPK) induced by VEGF of sympastatin acid (SSS). is there. Figure 15 (A) is a photograph of western blotting instead of a drawing showing the amount of phosphorylated p44 / 42MA PK in the upper row and the total amount of P44 / 42 MA PK in the lower row. Fig. 15 (B) shows that [pp 44/42 MAPK amount] / [p 44 / 42MA PK amount] values of cells stimulated with simpastatin acid 0 M and V EG F 25 ng / mL were 100%. The graph shows the ratio of the [pp 44/42 MAPK amount] / [p 44/42 MAPK amount] value of cells to each stimulus.

[Fig. 16] Fig. 16 is a photograph replacing a drawing, showing the effect of simpastatin on the suppression of traction retinal detachment in the rabbit PVR model. Figure 16 (A) is a photograph of an eye of a Usagi PVR model that did not receive sympastatin. Figure 16 (B) is a photograph of an eye of a Usagi PVR model administered with shin / kustatin.

[Fig. 17] Fig. 17 is a graph that evaluates the inhibitory effect of simpastatin on PVR progression in the Rabbit PVR model based on the PVR progression classification shown in Fig. 18.

[Fig. 18] Fig. 18 shows the PVR progression classification.

[Figure 19] Figure 19 shows the inhibition of contraction of collagen gel containing vitreous cells stimulated by TG F_; S 2 by simpastatin (SS), lovastatin (LS), and cerivastatin (CS) It is a figure for doing. Fig. 19 (A) shows a photograph replacing a drawing of a collagen gel when sympastatin (SS), lovastatin (LS), flupastatin (FS), and pravastatin (PS) are administered. Figure 19 (B) shows a photograph replacing the drawing of the collagen gel when celipastatin (CS) was administered instead of oral pastatin (LS).

BEST MODE FOR CARRYING OUT THE INVENTION

[0032] The first aspect of the present invention is a DNA for retinal vascular endothelial cells containing a fat-soluble statin compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. It relates to a synthesis inhibitor.

[0033] The statin compound is an active ingredient in the agent of the present invention. Also called things. That is, the agent of the present invention contains an effective amount of a fat-soluble statin compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient.

[0034] Examples of the statin compounds include compounds represented by any one of the following general formulas (I) to (XII), pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. . The general formulas (I) to (V I) indicate the lactone type, and the general formulas (V I I) to (X I I) indicate the corresponding acid types.

[0035] [Chemical 1]

[0036] In the above general formula (I), R ^{11 to} R ¹⁶ may be the same or different, and are a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ _C ₆ alkyl group, a d-CsT alkoxy group, d _C _6. A haloalkyl group, a C ₂ _C ₆ alkenyl group, or a C ₂ _C 6 alkynyl group;

—Preferable as R ^{11 in the} general formula (I) is a C ₁ —C ₆ alkyl group, more preferable is a C — C ₃ alkyl group, and particularly preferable is a methyl group.

[0038] R ^{12 in the} general formula (I) is preferably a hydrogen atom, a halogen atom, a hydroxyl group, or a C ₁ _C ₃ alkyl group, more preferably a hydrogen atom or a hydroxyl group, and particularly preferably. Things are hydrogen atoms.

[0039] —Preferable R ^{13 in the} general formula (I) is a hydrogen atom or a C ₁ _C ₆ alkyl group, more preferable is a hydrogen atom or a C-C ₃ alkyl group, and particularly preferable are A hydrogen atom or a methyl group. [0040] —In the general formula (I), R ¹⁴ and R ¹⁵ may be the same or different. R ¹⁴ and R ¹⁵ are preferably C ₁ _C ₆ alkyl groups, more preferably c − A C ₃ alkyl group, particularly preferred is a methyl group. However, it is more preferable that at least one or both of R ¹⁴ and R ¹⁵ are methyl groups.

[0041] R ^{16 in the} general formula (I) is preferably a hydrogen atom, a halogen atom, a hydroxyl group, or a C ₁ _C ₃ alkyl group, more preferably a hydrogen atom or a hydroxyl group, especially Preferred is a hydrogen atom.

[0042] —In the general formula (I), when R ¹¹ and R ¹⁴ are methyl groups and R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are hydrogen atoms, JP-A-50_155690, and It can be produced according to the method disclosed in Japanese Patent Publication No. 59_45360. In general formula (I), R ¹¹ and R ¹⁴ are methyl groups, R ¹² is a hydroxyl group, and R ¹³ , R ¹⁵ and R ¹⁶ are hydrogen atoms, disclosed in JP-B-1_41 1 30 Manufactured according to the described method. In general formula (I), those in which ¹¹ and ¹⁴ are methyl groups, R ¹² , R ¹³ and R ¹⁵ are hydrogen atoms and R ¹⁶ is a hydroxyl group are disclosed in JP-B-3_66297. Can be manufactured according to the method. In general formula (I), those in which R ¹¹ , R ¹³ and R ¹⁴ are methyl groups and R ¹² , R ¹⁵ and R ¹⁶ are hydrogen atoms are disclosed in JP-A-55_11 1 790 Can be manufactured according to In the general formula (I), when R ¹¹ , R ¹³ , ¹⁴ and ₁₅ are methyl groups and R ¹² and R ¹⁶ are hydrogen atoms, the method disclosed in Japanese Examined Patent Publication No. 64-14476 is used. Can be manufactured. In general formula (I), R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ are methyl groups, R ¹² is a hydroxyl group, and R ¹⁶ is a hydrogen atom, which is disclosed in Japanese Patent Publication No. 03-33698. Can be manufactured according to different methods. Each compound contained in the general formula (I) can be produced according to the above-mentioned publication and known organic synthesis methods.

[0043] [Chemical 2]

[0044] In the general formula (II), R ^{21 to} R ²⁵ may be the same or different from each other, and are hydrogen atom, halogen atom, hydroxyl group, C ₁ _C ₆ alkyl group, C ₁ _C ₆ alkoxy group, d _C ₆ /, showing the mouth alkyl group, C ₂ _C ₆ alkenyl group, or a C ₂ _ C ₆ alkynyl group.

[0045] —Preferable as R ^{21 in the} general formula (II) is a hydrogen atom, a C ₁ _C ₆ alkyl group or a C _C ₆ alkoxy group, and more preferable is a d—Cg alkyl group. Particularly preferred is a 1-methylethyl group.

In the general formula (II), R ²² and R ²³ may be a substituent at any position of the benzene ring or a hydrogen atom. Preferred as R ²² and R ²³ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ -C ₆ alkyl group is more preferable, and a hydrogen atom or a C ₃ -C ₃ alkyl group is more preferable, and a hydrogen atom is particularly preferable.

[0047] R ²⁴ and R ^{25 in} the general formula (II) may be a substituent at any position of the benzene ring or a hydrogen atom, and preferred as R ²⁴ and R ²⁵ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ _C ₆ alkyl group is more preferable, and a hydrogen atom, a halogen atom or a C ₁ _C ₃ alkyl group is more preferable, and a fluorine atom is particularly preferable. The position of the substituent is arbitrary, but the ortho or para position is preferred, and the para position is more preferred.

[0048] — In general formula (II), R ²¹ is a 1_methylethyl group, R ^{22 to} R ²⁴ are hydrogen atoms, and R ²⁵ is a para fluorine atom. It can be produced according to the method disclosed in Japanese Patent No. -46031. Each compound contained in the general formula (II) can be produced according to the above-mentioned publication and known organic synthesis methods.

[0049] [Chemical 3]

[0050] In the general formula ^{^{(III), R 31 ~R 3}} 7 may each different dates any of hydrogen atom, halogen atom, hydroxyl group, C ₁ _C ₆ alkyl group, d_c 6 alkoxy group, d- Cs / represents a mouth alkyl group, a C ₂ _C ₆ alkenyl group, or a C ₂ _C ₆ alkynyl group.

[0051] —Preferable R ^{31 in the} general formula (III) is a hydrogen atom, a C ₁ _C ₆ alkyl group or a C ₁ _C ₆ alkoxy group, and more preferable is a C ₁ _C ₃ 7 alkyl group. Particularly preferred is a 1-methylethyl group.

[0052] R ³² and R ^{33 in} the general formula (III) may be a substituent or a hydrogen atom at any position of the benzene ring. Preferred as R ³² and R ³³ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ _C ₆ alkyl group, more preferably a hydrogen atom or a C ₁ _C ₃ alkyl group, and particularly preferably a hydrogen atom.

[0053] R ³⁴ and R ^{35 in} the general formula (III) may be a substituent or a hydrogen atom at any position of the benzene ring. Preferred as R ³⁴ and R ³⁵ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ _C ₆ alkyl group, more preferably , A hydrogen atom or a c ₁ _c ₃ alkyl group, particularly preferred is a hydrogen atom

In the general formula (III), R ³⁶ and R ³⁷ may be a substituent at any position of the benzene ring or a hydrogen atom, and preferred as R ³⁶ and R ³⁷ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ —C ₆ alkyl group is more preferred, and a hydrogen atom, a halogen atom or a C ₁ —C ₃ alkyl group is more preferred, and a fluorine atom is particularly preferred. The position of the substituent is arbitrary, but the ortho or para position is preferred, and the para position is more preferred.

[0055] — In the general formula (III), R ³¹ is a 1_methylethyl group, and R ³² to

A compound in which R ³⁴ is a hydrogen atom and R ³⁷ is a fluorine atom in the para position can be produced according to the method disclosed in Japanese Patent Publication No. 7_57751. Each compound contained in the general formula (III) can be produced according to the above-mentioned publication and known organic synthesis methods.

[0056] [Chemical 4]

In the above general formula (IV), R ⁴¹ , R ⁴² , R ^{44 to} R ⁴⁵ may be the same or different from each other, hydrogen atom, halogen atom, hydroxyl group, d-Ce alkyl group, C—Cs alkoxy group, C — Cs haloalkyl group, C ₂ _C ₆ alkenyl group, or C ₂ _C ₆ alkynyl group, R ⁴³ is hydrogen atom, halogen atom, hydroxyl group, C ₁ _C ₆ alkyl group, C ₁ _C ₆ alkoxy group, d— Cs / roalkyl group, C ₂ _C ₆ alkenyl group, C ₂ _C ₆ alkynyl group or a group represented by the formula _R ^{4 6} _R 47, R ⁴⁶ represents a C — Cs alkylene group or C ₂ _C ₆ alkenyle R ⁴⁷ represents a hydroxyl group or a C ₁ _C ₆ alkoxy group.

[0058] —R ^{41 in the} general formula (IV) is preferably a hydrogen atom, a C ₁ _C ₆ alkyl group or a C _C ₆ alkoxy group, more preferably a d—Cg alkyl group, Particularly preferred is a 1-methylethyl group.

[0059] —R ^{42 in the} general formula (IV) is preferably a hydrogen atom, a C ₁ _C ₆ alkyl group or a C _C ₆ alkoxy group, more preferably a d—Cg alkyl group, Particularly preferred is a 1-methylethyl group.

[0060] —Preferable R ^{43 in the} general formula (IV) is a hydrogen atom, a C ₁ _C ₆ alkyl group, a C ₁ _C ₆ alkoxy group, or a group represented by the formula _R ^{4 6} _R 47. preferred are C _C ₃ alkoxy d-Cg alkyl group, particularly preferably castings are main Tokishimechiru group.

[0061] R ⁴⁴ and R ^{45 in} the general formula (IV) may be a substituent at any position of the benzene ring or a hydrogen atom. Preferred as R ⁴⁴ and R ⁴⁵ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ _C ₆ alkyl group is more preferable, and a hydrogen atom, a halogen atom or a C ₁ _C ₃ alkyl group is more preferable, and a fluorine atom is particularly preferable. The position of the substituent is arbitrary, but the ortho or para position is preferred, and the para position is more preferred.

[0062] —In general formula (IV), R ⁴¹ and R ⁴² are 1_methylethyl groups,

A compound in which R ⁴³ is a methoxymethyl group, R ⁴⁴ is a hydrogen atom, and R ⁴⁵ is a fluorine atom in the para position can be produced according to the method disclosed in Japanese Patent No. 2786363. Each compound contained in the general formula (IV) can be produced according to the above-mentioned publication and known organic synthesis methods.

[0063] [Chemical 5]

[0064] In the general formula (V), R 5 i~R 5 3 may be the same or different and each represent a hydrogen atom, a halogen atom, a hydroxyl group, C ₁ _C ₆ alkyl, d-CsT alkoxy group, d _C ₆ haloalkyl group, C ₂ _C ₆ alkenyl group, or C ₂ _C 6 alkynyl group, R 54 is hydroxyl group, d—Cs alkyl group, d—Cs alkyl group, d _C ₆ haloalkyl group, C ₂ _C ₆ alkenyl group, C ₂ _C ₆ 7 alkynyl group, _S0 ₂ H, _S0 ₃ CH ₃ , _S0 ₂ NH ₂ , _S0 ₂ NH (CH 3), -S0 ₂ N (CH ₃ ) ₂ , or the formula _N (-R ⁵⁵ ) _R ^{56 represents} a group represented by R ⁵⁵ and R ^{56, which} may be the same or different, hydroxyl group, C ₁ _C ₆ alkyl group, C — Cs alkoxy group, C — Cs haloalkyl group, C ₂ _C ₆ 7 Lucenyl group, C ₂ _C ₆ alkynyl group, _S0 ₂ H, _S0 ₂ CH ₃ , -S0 ₂ NH ₂ , -S0 ₂ NH (CH ₃ ), or _S0 ₂ N (CH ₃ ) ₂ are shown.

[0065] —Preferable R ^{51 in the} general formula (V) is a hydrogen atom, a C ₁ _C ₆ alkyl group or a d _C ₆ alkoxy group, and more preferable is a d—Cg alkyl group. Preferred is a 1-methylethyl group.

[0066] R ⁵² and R ^{53 in} the general formula (V) may be a substituent or a hydrogen atom at any position of the benzene ring, and preferred examples of R ⁵² and R ⁵³ include a hydrogen atom and a halogen atom. , A hydroxyl group or a C ₁ _C ₆ alkyl group, more preferably a hydrogen atom, a halogen atom or a C ₁ _C ₃ alkyl group, and particularly preferably a fluorine atom. The position of the substituent is arbitrary, but the ortho or para position Preferred is the para position.

[0067] —Preferable as R ⁵¹ in the general formula (V) is a group represented by the formula N (—R ⁵⁵ ) _R ⁵⁶ . Preferred as R ⁵⁵ and R ⁵⁶ are a hydroxyl group, a C ₁ _C ₃ 7 alkyl group, _S0 ₂ H, or _S 0 ₂ CH ₃ , and more preferred one is a d _C ₃ alkyl group and the rest is _S. 0 ₂ H, or _S 0 ₂ CH ₃

[0068] In the general formula (V), R ⁵¹ is a 1_methylethyl group, R ⁵² is a hydrogen atom, R ⁵³ is a fluorine atom in the para position, and R ⁵⁴ is a formula _N (_CH ₃ )- A compound which is a group represented by S 0 ₂ CH ₃ can be produced according to the method disclosed in Japanese Patent No. 2648897. Each compound contained in the general formula (V) can be produced according to the above-mentioned publication and known organic synthesis methods.

[0069] [Chemical 6]

[0070] In the above general formula (VI), R ^{61 to} R ⁶⁵ may be the same or different from each other, and are hydrogen atom, halogen atom, hydroxyl group, C ₁ _C ₆ alkyl group, C ₁ _C ₆ alkoxy group, C _C ₆ haloalkyl group, C ₂ _C ₆ alkenyl group, C ₂ _C ₆ alkynyl group or C ₃ _C 0 cycloalkyl group.

[0071] — Preferable as R ⁶¹ of the general formula (VI) is a hydrogen atom, a C ₁ _C ₆ alkyl group, a C ₁ _C ₆ alkoxy group, or Cg-d. The cycloalkyl group is more preferably a C ₃ _C ₁₀ cycloalkyl group, and particularly preferably a cyclopropyl group. [0072] R ⁶² and R ^{63 in} the general formula (VI) may be a substituent at any position of the benzene ring or a hydrogen atom. Preferred as R ⁶² and R ⁶³ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ -C ₆ alkyl group is more preferable, and a hydrogen atom or a C ₃ -C ₃ alkyl group is more preferable, and a hydrogen atom is particularly preferable.

[0073] R ⁶⁴ and R ^{65 in} the general formula (VI) may be a substituent at any position of the benzene ring or a hydrogen atom. Preferred as R ⁶⁴ and R ⁶⁵ are a hydrogen atom, a halogen atom, A hydroxyl group or a C ₁ _C ₆ alkyl group is more preferable, and a hydrogen atom, a halogen atom or a C ₁ _C ₃ alkyl group is more preferable, and a fluorine atom is particularly preferable. The position of the substituent is arbitrary, but the ortho or para position is preferred, and the para position is more preferred.

[0074] — In general formula (VI), a compound in which R ⁶¹ is a cyclopropyl group, R ^{62 to} R ⁶⁴ are hydrogen atoms, and R ⁶⁵ is a para fluorine atom is disclosed in Japanese Patent No. 2569 746. It can be produced according to the disclosed method. Each compound contained in the general formula (VI) can be produced according to the above-mentioned publication and known organic synthesis methods.

[0075] [Chemical 7]

In the above general formula (VII), R ^{11 to} R ¹⁶ are synonymous with the above general formula (I).

[0077] [Chemical 8]

In the above general formula (VIII), R ^{21 to} R ²⁵ are synonymous with the above general formula (II).

[0079] [Chemical 9]

[0080] In the general formula ^{^{(IX), R 31 ~R 3}} 7 is synonymous with the general formula (III).

[0081] [Chemical 10]

In the above general formula (X), R ^{41 to} R ⁴⁵ are synonymous with the above general formula (IV).

[0083] [Chemical 11]

In the above general formula (XI), R ^{51 to} R ⁵⁴ have the same meaning as in the above general formula (V). [Chemical 12]

[0086] In the general formula ^{(XII), R 6 1 ~R} 6 5 are synonymous above general formula (VI).

[0087] As the compound of the present invention, a statin compound preferably includes "Robustatin, simpastatin, cerivastatin, atorvastatin, rospastatin, fluvastatin, pitapastatin, a pharmaceutically acceptable salt thereof, and a pharmaceutical agent. Or one or more compounds selected from the group consisting of solvates thereof. Among these, any one selected from the group consisting of “lovastatin, simpastatin, seripastatin, flupastatin, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof”. Or two or more compounds are preferred. Furthermore, one or more compounds selected from the group consisting of “sympastatin, flupastatin, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof”. Is more preferable. Statin compounds are generally fat-soluble. On the other hand, among the statin compounds, pravastatin is a highly hydrophilic drug. Statins other than pravastatin are usually fat-soluble. The present invention relates to an agent containing a fat-soluble statin compound which is a statin compound excluding pravastatin as an active ingredient.

In this specification, “C _x _C _y ” means that the subsequent group has _{x to} _y carbon atoms. “Halogen atoms” include fluorine, chlorine, fluorine or iodine. [0089] "C ₁ _C ₆ alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, e.g., methyl group, Echiru group, n _ propyl group, isopropoxy port pill Group, n_butyl group, isobutyl group, s_butyl group, t_butyl group, n-pentyl group, isopentyl group, 1,1-dimethylpropyl group, and n-hexyl group.

[0090] A "C ₁ _C ₆ alkoxy group" is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a 1_propoxy group, Examples include an isopropoxy group, 1_butoxy group, 1_methyl_1_propoxy group, t_butoxy group, and 1_pentyloxy group.

[0091] “〇_C ₆ haloalkyl group” is an alkyl group in which the “C ₁ _C ₆ alkyl group” is substituted with one or more halogen atoms, such as a fluoromethyl group, a difluoromethyl group, a trifluoro group, and the like. Methyl group, 2, 2, 2-trifluoro octyl group, 2, 2, 2_trichloro octyl group, pentafluoro ethyl group, 3, 3, 3 _ trifluoropropyl group, perfluoropropyl group , 4_fluorobutyl group, 4_chlorobutyl group, 4_bromobutyl group, and perfluorinated hexyl group.

[0092] "C ₂ _C ₆ alkenyl group", the "alkyl group" linear or branched carbon atoms 2-6 alkyl having a double bond on one or more at an arbitrary position of the For example, vinyl group, 1_propenyl group, 2_propenyl group, isopropenyl group, 2-butenyl group, 1, 3_butenyl group, 2_pentenyl group, 3_pentenyl group , And 2-hexenyl groups.

[0093] "C ₂ _C ₆ alkynyl group", said has a triple bond on one or more at any position of "alkyl group", straight chain or branched chain having from 2 to 6 carbon atoms An alkynyl group, for example, ethynyl, 1_propynyl, and 2_propynyl.

[0094] “Fd—Cs alkylene group” means a linear or branched alkylene group having 1 to 6 carbon atoms, such as methylene group, ethylene group, 1_methyl ethylene group, 2_methyl. Ethylene group, 1, 1-dimethylethylene group, 1, 2 —Dimethylethylene group, 1,1,2_trimethylethylene group, 1,2,2-trimethylethylene group, 1,1,2,2-tetramethylethylene group, and propylene group.

[0095] “C ₂ _C ₆ alkenylene group” means a linear or branched alkenylene group having 2 to 6 carbon atoms, such as vinylene group, 1_methylethynylene group, 2_methylethynylene group, 1 , 1_dimethylethynylene, 1,2-dimethylethynylene, propenylene, 1_methylpropylene, 2_methylpropylene, 3_methylpropylene, butenylene, and pentenylene It is done.

[0096] r C g—d. A “cycloalkyl group” is a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and an adamantyl group. .

[0097] "The salt" in "pharmaceutically acceptable salt thereof" means a salt of a fat-soluble statin compound. As used herein, “pharmaceutically acceptable” means not harmful to the recipient. Statins can be converted into salts according to conventional methods. Examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt, zinc salt, copper salt and nickel salt. Salts, metal salts such as cobalt salts, inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, Jetylamine salt, Triethylamine salt, Dicyclohexylramine salt, N, N'-Dibenzylethylenediamine salt, Kuroguchi Pro-in salt, Pro-in salt, Diethanolamine salt, N-Benzyl-N-phenethylamine salt Pipette Razine salt, Tetramethylammonium salt, Tris (hydro Amine salts such as organic salts such as xyloxy) aminomethane salt, hydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, perchlorate, sulfuric acid Salt, inorganic acid salt such as phosphate, or salt of lower alkane sulfonic acid such as methanesulfonic acid, trifluoromethane sulfonic acid, ethanesulfonic acid, arylsulfone such as benzenesulfonic acid, p-toluenesulfonic acid, etc. Salts of amino acids such as acid salts, glutamic acid and aspartic acid, organic acids such as salts of carboxylic acids such as fumaric acid, succinic acid, citrate, tartaric acid, citric acid, maleic acid, and ornitinic acid Amino acid salts such as salt, glutamate, and aspartate. Of these, sodium salts are preferred, with alkali metal salts being more preferred.

[0098] “Solvate” means a solvate of a fat-soluble statin compound.

Solvates include hydrates. In addition, statin compounds may absorb moisture, adhere to adsorbed water, or become hydrates by being left in the atmosphere or recrystallized. Such solvates are also included in “the solvate”.

[0099] Statins include various isomers. For example, statin compounds have optical isomers. The compounds of the present invention have stereoisomers that are R-coordinate and S-coordinate. The compounds of the present invention include each of them or a compound containing them in any proportion. Such a stereoisomer can be obtained by synthesizing a statin compound using an optically active raw material compound or by optically resolving the synthesized statin compound using a conventional optical resolution method or separation method as required. be able to. In addition, statin compounds may have geometric isomers such as cis and trans isomers. The compound of the present invention includes each of them or a compound containing them in an arbitrary ratio. In the following, salts, solvates and isomers are also referred to as compounds of the present invention.

[0100] The first aspect of the present invention also provides a method for inhibiting DNA synthesis of retinal vascular endothelial cells, comprising the step of administering the compound of the present invention to a subject. As demonstrated in Example 1 (Fig. 1) and Example 2 (Fig. 2) described below, fat-soluble statin compounds inhibit DNA synthesis in vitreous cells and retinal vascular endothelial cells. Targets include humans or non-human mammals. In addition, the compound of the present invention The preferred method of administration is to administer directly into the eye, such as injection under the Tenon's capsule or in the vitreous or implantation of a sustained-release agent (sustained-release carrier). . The first aspect of the present invention also provides use of the compound of the present invention for producing a DNA synthesis inhibitor of retinal vascular endothelial cells.

[0101] The second aspect of the present invention relates to an intraocular neovascular inhibitor containing the compound of the present invention as an active ingredient. As the compound of the present invention, the above-described compound of the present invention can be used as appropriate. As demonstrated in Example 2 (Fig. 2), which will be described later, a fat-soluble statin compound inhibits DNA synthesis in retinal vascular endothelial cells.

In addition, as demonstrated in Example 3 (Fig. 3) described later, fat-soluble statins inhibit the proliferation of retinal vascular endothelial cells.

Furthermore, as demonstrated in Example 4 (Figs. 4 (A) and (B)), which will be described later, the fat-soluble statin compound inhibits Tuboformation (formation of blood vessels) in umbilical vein endothelial cells. Since the retinal blood vessels in the eye are venous blood vessels, retinal vascular endothelial cells are also considered to inhibit T ub er for mat ion (formation of blood vessels). As a result, the fat-soluble statin compound inhibits the proliferation of retinal vascular endothelial cells and effectively inhibits the development of pathological new blood vessels and the growth of pathological new blood vessels. Therefore, the compound of the present invention is effective in preventing or treating age-related macular degeneration (particularly atrophic age-related macular degeneration or wet age-related macular degeneration).

[0102] HMG—CoA reductase inhibitors are known to inhibit the proliferation of human vascular endothelial cells through the inhibition of geranylgeranylation of Rho A (Journa I of the American society of Nephrology, June 2004, Vol. 1 5, 2429-2439). Since fat-soluble statin compounds are HMG_CoA reductase inhibitors, they have an inhibitory effect on the proliferation of vascular endothelial cells and may function as neovascular inhibitors in the eye.

In addition, Example 1 3 (Figs. 14 (A) and (B)) and Example 14 (Fig. 1 5 (A) and (B)) cause lipophilic statin compounds to inhibit VEGF-induced phosphorylation of KDR (VEGF receptor 2) and p 4 4/4 2 MAP kinase It was shown that. These examples suggest that fat-soluble statin compounds have been shown to inhibit the proliferation of vascular endothelial cells through inhibition of the MAP kinase signaling pathway as well as inhibition of the Rho signaling pathway. It was done.

[0103] The second aspect of the present invention also provides a method for inhibiting neovascularization in the eye, comprising the step of administering the compound of the present invention to a subject. Targets include humans or non-human mammals. The method of administering the compound of the present invention to the subject will be described later, but the preferred method of administration is to administer directly into the eye, such as by injection into the subtenon capsule or into the vitreous, or by installing a sustained release carrier. . The second aspect of the present invention also provides the use of a compound of the present invention for the manufacture of an intraocular neovascular inhibitor. In addition, as a compound of the present invention, all compounds (including pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof) included in the above-described compound of the present invention are included. Alternatively, a combination of two or more types can be used.

[0104] The third aspect of the present invention relates to diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic neuropathy containing the compound of the present invention as an active ingredient. It relates to the therapeutic agent or preventive agent. Among these, it relates to a therapeutic or preventive agent for traction retinal detachment. As the compound of the present invention, the above-described compound of the present invention can be used as appropriate. As demonstrated in Example 2 (Fig. 2), which will be described later, fat-soluble statin compounds inhibit DNA synthesis in retinal vascular endothelial cells. In addition, as demonstrated in Example 3 (Fig. 3), which will be described later, it inhibits the proliferation of retinal vascular endothelial cells.

[0105] Furthermore, as demonstrated in Example 4 (Figs. 4 (A) and (B)) described later, the compound of the present invention inhibits the formation of new blood vessels in umbilical vein endothelial cells. Therefore, it is considered that the compound of the present invention inhibits the formation of new blood vessels in retinal vascular endothelial cells that form venous blood vessels.

[0106] According to these Examples 2 to 4, the fat-soluble statin compound was In addition to inhibiting the proliferation of endothelial cells, it can effectively inhibit the occurrence of pathological new blood vessels and the growth of pathological new blood vessels.

[0107] In diabetes, when the hyperglycemic state continues, the thin blood vessels of the retina, that is, the retina falls into an oxygen deficient state, and as a result, new blood vessels may be generated. Such pathological neovascular walls are brittle and easy to break, and thus easily cause vitreous hemorrhage. When bleeding occurs, cell proliferation occurs, and a membrane covering the bleeding site is formed, which may cause tractional retinal detachment. For eye diseases other than diabetes, pathological neovascularization may occur, causing vitreous hemorrhage and traction retinal detachment. In addition, the occurrence of pathological new blood vessels may increase intraocular pressure and cause angiogenic glaucoma. In addition, when new blood vessels occur around the optic nerve cells, they can compress the optic nerve cells and cause optic nerve damage. Therefore, the compound of the present invention is effective for the prevention or treatment of glycouric retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic neuropathy. In addition, neovascularization may occur in the eye after eye surgery such as corneal surgery, leading to angiogenic glaucoma, vitreous hemorrhage, traction retinal detachment, or optic neuropathy that can be caused by neovascularization. Can happen. Since fat-soluble statin compounds effectively inhibit the development of pathological new blood vessels, the compounds of the present invention are effective in preventing postoperative neovascular diseases. In addition, as a compound of the present invention, one or two of all the compounds (including pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof) included in the above-described compound of the present invention are included. Those appropriately combined can be used.

[0108] The third aspect of the present invention includes a step of administering the compound of the present invention to a subject, and includes retinopathy of diabetes, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenesis A method of treating or preventing glaucoma or optic neuropathy is also provided. Targets include humans or non-human mammals. The method of administering the compound of the present invention to the subject will be described later, but the preferred method of administration is to administer directly into the eye, such as by injection into the subtenon sac or in the vitreous or by placing a sustained release carrier. The third aspect of the present invention includes diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular There is also provided the use of a compound of the present invention for the manufacture of a therapeutic or prophylactic agent for edema, retinopathy of prematurity, angiogenic glaucoma or optic neuropathy.

[0109] The fourth aspect of the present invention relates to a therapeutic agent for uveitis, allergic conjunctivitis, or spring catarrh containing the compound of the present invention as an active ingredient. As the compound of the present invention, the above-described compound of the present invention can be appropriately used. HMG_ Co A reductase inhibitor inhibits protein prenylation, inhibits downstream Rho GT Pase, and as a result also inhibits the I_CAM pathway (the pathway that promotes lymphocyte migration) (T he Journal of Immunology, 2005, 1 74, pp. 2327-2335.). Inhibiting Rho GTPase also inhibits the production of cytokines such as IL-8, MCP-1 and I_P_10 downstream.

[0110] In addition, as demonstrated in Example 12 (see Fig. 13), which will be described later, the lipophilic statin compound shows the amount of p 65 that is a subunit of the transcription factor N F_ / i B in the nucleus. Decrease. Since NF_ / i B is a transcription factor involved in the production of inflammatory cytokines, fat-soluble statins can reduce the amount of NF_ / i B translocated into the nucleus and produce inflammatory site force-in. It is thought to suppress. In other words, fat-soluble statin compounds are thought to be able to suppress inflammatory site force-in, so the compounds of the present invention can suppress uveitis, allergic conjunctivitis, or inflammation caused by spring catarrh. Therefore, it is considered to be effective as a treatment for uveitis, allergic conjunctivitis, or spring catarrh. In addition, the compound of the present invention can suppress inflammation due to proliferative retinal vitreous disease, diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic neuropathy. it can. Therefore, it is considered to be effective as a therapeutic agent for diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma, or inflammation caused by visual neuropathy. It is also considered effective in preventing or treating endophthalmitis that may occur after eye surgery. In addition, as the compound of the present invention, all the compounds (including pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof) included in the above-described compound of the present invention are included. One or a combination of two or more can be used.

[01 1 1] The fourth aspect of the present invention also provides a method for treating uveitis, allergic conjunctivitis, or spring catarrhal comprising the step of administering the compound of the present invention to a subject. Targets include humans or non-human mammals. Although the method of administering the compound of the present invention to the subject will be described later, the preferred method of administration is to administer directly into the eye, such as injection into the Tenon capsule or into the vitreous or placement of a sustained release carrier. is there. The fourth aspect of the present invention also provides the use of a compound of the present invention for the manufacture of a therapeutic agent for uveitis, allergic conjunctivitis, or spring catarrh.

[0112] The fifth aspect of the present invention relates to a therapeutic or prophylactic agent for glaucoma comprising the compound of the present invention as an active ingredient. As the compound of the present invention, the above-described compound of the present invention can be used as appropriate. From Example 10 (see Fig. 10 (A) and (B)) and Example 11 (see Fig. 11) described later, fat-soluble statin compounds inhibit myosin light chain phosphorylation. I understand. By inhibiting phosphorylation of myosin light chain, cytoskeletal structural changes are inhibited, and as a result, cell contraction is suppressed (C irc R es. 2 0 0 2, 9 1, pp. 1 4 3-1 5 0). Therefore, fat-soluble statin compounds inhibit intraocular cell contraction, thus preventing an increase in intraocular pressure and suppressing vascular cell contraction to relax blood vessels, Since intraocular pressure can be lowered, glaucoma can be prevented and glaucoma symptoms can be improved. In addition, as the compound of the present invention, one or two of all the compounds (including pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof) included in the above-described compound of the present invention are included. What combined suitably the seed | species or more can be used.

[0113] The fifth aspect of the present invention also provides a method for treating or preventing glaucoma, comprising the step of administering the compound of the present invention to a subject. Targets include humans or non-human mammals. The method of administering the compound of the present invention to a subject will be described later, but the preferred method of administration is to administer directly into the eye, such as by placing a sustained-release carrier under injection into the Tenon capsule or into the vitreous. The fifth aspect of the present invention also proposes the use of a compound of the present invention for producing a therapeutic or prophylactic agent for glaucoma. Provide.

[0114] The sixth aspect of the present invention relates to a therapeutic or prophylactic agent for proliferative vitreoretinopathy (PVR), a therapeutic agent for proliferative diabetic retinopathy, a protractive retinal detachment preventive agent comprising the compound of the present invention as an active ingredient. , Retinal vein occlusion or proliferation of intraocular cells. “Proliferative vitreoretinopathy therapeutic agent” is, for example, “medicine for the prophylactic treatment of proliferative vitreoretinopathy in patients at risk of developing proliferative vitreoretinopathy”. “Proliferative diabetic retinopathy therapeutic agent” is, for example, “medicine for prophylactic treatment of proliferative diabetic retinopathy in patients at risk of developing diabetic retinopathy”. As demonstrated in Example 16 (see Fig. 17), which will be described later, in the Usagi PVR model, the fat-soluble statin compound significantly suppressed the progression of PVR. Figure 17 is a graph showing the effect of simpastatin on the inhibition of PVR progression in the Rabbit PVR model based on the PVR progression classification shown in Figure 18. Figure 18 shows the PVR progress classification. The progress classification in Figure 18 is as follows.

to s]

0 Healthy eyes

1 Vitreous membrane

2 local traction,

Local vascular changes,

Hyperemia, depression, dilation,

Raised blood vessels

3 Local radiation tissue ablation

4 Extensive retinal detachment,

Complete radiation tissue ablation,

Retinal detachment around the nipple

5 Complete retinal detachment,

Retinal fistula and retinal hole

[0116] Further, Example 10 described later (refer to Figs. 10 (A) and (B)) and As demonstrated by Example 1 1 (see Figure 11), lipophilic statin compounds inhibit phosphorylation of the myosin light chain. By inhibiting phosphorylation of myosin light chain, cytoskeletal structural changes are inhibited, and as a result, cell contraction is suppressed (Circ Res. 2002, 91, pp. 143–150). Furthermore, Examples 5 to 8 and 19 (Figs. 5 to 8 and 19), which will be described later, show that fat-soluble statin compounds suppress the contraction of vitreous cells. Therefore, the compound of the present invention is a therapeutic agent or prophylactic agent for proliferative vitreoretinopathy, a prophylactic agent for proliferative diabetic retinopathy, a prophylactic retinal detachment agent, a therapeutic agent or prophylactic agent for retinal vein occlusion, and a proliferation / contraction of intraocular cells. It is effective as an inhibitor.

The preventive agent for traction retinal detachment of the present invention is a preventive agent for traction retinal detachment containing an effective amount of the compound of the present invention as an active ingredient. Specifically, the preventive agent for retinal detachment is a preventive agent for traction retinal detachment containing the compound of the present invention as an active ingredient. As the compound of the present invention in the preventive agent for traction retinal detachment, a fat-soluble statin compound is preferable. A “preventive agent for tractional retinal detachment” is a medicine for preventing the occurrence of tractional retinal detachment. The “traction retinal detachment” in the “preventive agent for traction retinal detachment” includes retinal detachment caused by proliferative vitreoretinopathy, proliferation of intraocular cells, or retinal detachment caused by contraction of the proliferative membrane. can give. That is, the retinal detachment in the present invention includes “traction retinal detachment” in which the retina detaches when the proliferative tissue formed in the vitreous body contracts due to diabetic retinopathy or retinal vein occlusion. As shown in Examples 1 and 2 below (Figs. 1 and 2), the use of fat-soluble statin compounds can inhibit DNA synthesis in intraocular cells. In addition, as shown in Examples 3 to 9 (Figs. 3 to 9), it is possible to prevent the proliferation or contraction of intraocular cells (particularly replicating ocular cells). The fat-soluble statin compound inhibits phosphorylation of KDR (VEG F receptor) as shown in Example 13 (Figures 14 (A) and (B)). As shown in (Fig. 15 (A) and (B)), it inhibits phosphorylation of MAP kinase p44 / 42 and prevents proliferation of intraocular cells. Also shown in Example 15 (Fig. 16 (A) and (B)). As can be seen, the fat-soluble statin compound significantly suppresses tractional delamination in the Usagi PVR model. Therefore, the agent containing the compound of the present invention is effective as a preventive agent for traction network peeling.

[0118] The reason why a fat-soluble statin compound is desirable as the compound of the present invention is that the fat-soluble statin is superior in intracellular migration and exerts an action on cells. As demonstrated in Examples 5 to 8 and 19 (Figs. 5 to 8 and 19), which are described later, the inhibitory action on the contraction of vitreous cells by the fat-soluble statins sympastatin and fluvastatin was remarkable. . On the other hand, pravastatin, a water-soluble statin compound, did not necessarily show an inhibitory effect on vitreous cell contraction. Therefore, it can be said that a fat-soluble statin compound is preferred as the compound of the present invention.

[0119] The therapeutic or prophylactic agent for retinal vein occlusion of the present invention is a therapeutic or prophylactic agent for retinal vein occlusion containing an effective amount of the compound of the present invention as an active ingredient. Retinal vein occlusion is caused by high blood pressure or vein compression. As demonstrated by Example 10 (FIGS. 10 (A) and (B)) described later, fat-soluble statin compounds inhibit phosphorylation of myosin light chain. Inhibition of myosin light chain phosphorylation suppresses cell contraction, thus suppressing vasoconstriction and suppressing an increase in blood pressure. From Examples 1 to 3 (Figs. 1 to 3), lipophilic statin compounds inhibit DNA synthesis and suppress cell proliferation. Furthermore, from Examples 13 and 15 (Figs. 14 and 15), fat-soluble statin compounds are phosphorylated on the receptor KDR involved in cell proliferation or phosphorylation of MAP kinase p 4 4/4 2. Inhibits oxidation. These examples are considered to prevent the situation where the veins are compressed due to the proliferation of cells in the surrounding or blood vessels. Therefore, the compound of the present invention is effective as a therapeutic or prophylactic agent for retinal vein occlusion.

The intraocular cell proliferation / contraction inhibitor of the present invention is a drug for inhibiting proliferation or contraction of intraocular cells containing an effective amount of the compound of the present invention. Specifically, the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt. It is a growth / shrinkage inhibitor of intraocular cells containing a solvate as an active ingredient. As a compound of the present invention in an intraocular cell proliferation / contraction inhibitor, symbastatin is preferred. Although the present invention may have other uses, it basically prevents proliferative vitreoretinopathy (PVR) by inhibiting the proliferation or contraction of intraocular cells. It is intended to prevent protracted retinal detachment and prevent proliferative diabetic retinopathy. Thus, examples of intraocular cells include retinal pigment epithelium (RPE) cells, glial cells, fibroblasts, fibroblasts, macrophages, and vitreous cells (herein sites). As shown in Examples 5 to 8 and 19 below (Figures 5 to 8 and 19), vitreous cells are candidates for intraocular cells. According to Example 1 (Fig. 1) described later, the compound of the present invention inhibits DNA synthesis of vitreous cells. Since DNA synthesis occurs when cells proliferate, inhibition of DNA synthesis inhibits the growth of vitreous cells. Further, according to Examples 5 to 8 and 19 (FIGS. 5 to 8 and 19) described later, the compounds of the present invention inhibit contraction of contractile cell membranes. Thus, the intraocular cell proliferation / contraction inhibitor of the present invention includes inhibitors that inhibit vitreous cell proliferation or contraction.

[0121] The therapeutic agent for proliferative vitreoretinopathy, the prophylactic agent for proliferative diabetic retinopathy, the prophylactic agent for tractional retinal detachment, and the intraocular cell proliferation / shrinkage inhibitor (the pharmaceutical agent of the present invention) of the present invention It contains the compound of the invention. Here, the effective amount means an amount effective for the treatment of proliferative vitreous retinopathies, the treatment of proliferative diabetic retinopathy, the prevention of traction retinal detachment or the inhibition of intraocular cell proliferation and contraction. That is, it is preferable that the therapeutic agent for proliferative vitreous retinopathies, the preventive agent for retinal detachment, and the growth / contraction inhibitor of intraocular cells of the present invention contain the compound of the present invention as an active ingredient.

[0122] The present invention provides a method for treating proliferative vitreoretinopathy comprising the step of administering an effective amount of the compound of the present invention as an active ingredient to a subject (human or non-human mammal). The present invention also provides a method for treating proliferative diabetic retinopathy, comprising the step of administering an effective amount of the compound of the present invention as an active ingredient to a subject (human or non-human mammal). In addition, the present invention is directed to the compound of the present invention as an active ingredient. A method of preventing traction retinal detachment, comprising the step of administering an effective amount to a non-human mammal). Furthermore, the present invention also provides a method for inhibiting intraocular cell proliferation and a method for inhibiting contraction, comprising the step of administering an effective amount of the compound of the present invention as an active ingredient to a subject (human or non-human mammal). These preferred embodiments are as described above.

[0123] The present invention provides use of the compound of the present invention for producing a proliferative vitreoretinopathy therapeutic agent. The present invention provides use of the compound of the present invention for producing a therapeutic agent for proliferative diabetic retinopathy. The present invention also provides use of the compound of the present invention for producing a preventive agent for traction retinal detachment. Furthermore, the present invention provides use of the compound of the present invention for producing an intraocular cell proliferation / contraction inhibitor. These preferred embodiments are as described above.

[0124] When the compound of the present invention is used as a medicament such as the above-mentioned preventive agent or therapeutic agent (hereinafter also referred to as "the agent of the present invention"), it may be administered as it is or pharmacologically. May be administered in admixture with an acceptable carrier. Moreover, it may be administered in combination with a composition containing a sustained release component, or may be placed in the vitreous in combination with a sustained release carrier. The specific dose of the compound of the present invention may be appropriately adjusted depending on the target disease, administration target, installation route, etc. For example, when the compound of the present invention is administered by injection into the subtenon capsule or by vitreous injection, it is generally l X l 0 ² ng per eye for adults (with a body weight of 60 kg). ˜1 mg, preferably L <Oil X 10 ² ng to 5 xl 0 ² ; U g, more preferably 1 g to 5 X 10 ² g. That is, for example, the compound of the present invention is mixed with a diluent or the like to prepare the agent of the present invention, and the prepared agent of the present invention is placed in a syringe or the like. Administration is sufficient. The number of administrations may be adjusted as appropriate, for example, one administered once a day with an agent containing the compound of the present invention. It may also be administered immediately before the treatment. When the above agents are administered to humans or non-human mammals, the amount converted per 60 kg body weight should be administered as appropriate. The route of administration includes intraocular administration. A fat-soluble statin compound is administered intraocularly By doing so, the disease in the eye can be specifically treated or prevented. The present invention provides a method for treating various diseases, comprising a step of embedding a sustained-release device (sustained-release carrier) in the retrobulbar region or vitreous body and delivering a fat-soluble statin compound to the vitreous body of the eyeball. Also provide. That is, the agent of the present invention may be an agent containing a sustained release carrier (specifically, an agent in which an active ingredient is contained in a sustained release carrier). In the present invention, the sustained-release carrier is preferably administered or placed in the eye. Specifically, the sustained-release carrier is embedded in the choroidal space, under the retina, in the sclera, or in the vitreous. There may be. Furthermore, the present invention also provides the use of a fat-soluble statin compound for the manufacture of a sustained release carrier for the treatment of various diseases. “Sustained release carrier” means a device that can release a drug in a controlled manner over a long period of time.

[0125] The compounds of the present invention can be administered per se or as a pharmaceutical composition. Examples of the pharmaceutical composition containing the compound of the present invention include those containing a pharmacologically acceptable carrier, diluent or excipient.

[0126] For example, when the agent of the present invention is used as an eye drop or injection, an effective amount of the compound of the present invention and a known diluent (the diluent is contained in a pharmacologically acceptable carrier) It may be an eye drop or an injection containing Diluents such as sterilized water, pure water, distilled water, physiological saline, glucose solution, alcohol such as ethanol, polyalcohols such as glycerol, propylene glycol, polyethylene glycol, sterilized organic solvents, or aqueous starch, PBS Any one of these or a mixture of two or more thereof may be mentioned. The agent of the present invention can be easily produced by mixing the compound of the present invention as an active ingredient with a diluent or the like. The produced agent of the present invention may be stored in an ampoule as appropriate.

[0127] Eye drops or injections containing the compound of the present invention include decongestants such as epinephrine, epinephrine hydrochloride, ephedrine, ophthalmic regulators such as neostigmine til sulfate, tropicamide, zinc sulfate, Anti-inflammatory components such as zinc lactate, allantoin, ypsilon monoaminocaproic acid, indomethacin, lysozyme chloride, vasitanolast, amlexanox, ibudilast, tiger 2 last, antihistamine component or antiallergic drug component such as diphenhydramine hydrochloride, amino acid, oxybupro-power-in, cocaine hydrochloride, cornecaine hydrochloride, dibu-power-in local anesthetic component, etc. Also good. Thickeners such as sodium chondroitin sulfate and sodium hyaluronate, surfactants such as benzalkonium chloride, preservatives such as sodium benzoate, ethanol and benzalkonium chloride, bactericides or antibacterial agents, hydrochloric acid, boric acid, sodium hydroxide PH adjusters such as sodium hydrogen carbonate, isotonic agents such as sodium hydrogen sulfite, sodium sulfite, potassium chloride, fragrances or refreshing agents such as menthol, camphor, pepper oil, peppermint oil, citrate buffer, etc. It may contain a suitable buffering agent. Further, as a sustained-release sustained-release component, it may further contain a mucosal mimetic polymer, a gelled polysaccharide, a finely divided carrier single substrate, or a combination of these components.

[0128] The sustained-release carrier containing the compound of the present invention means a device that releases a drug in a controlled state over a long period of time. Examples of sustained release carriers useful in the present invention include, for example, US Pat. No. 5 3 7 8 4 75, US Pat. No. 5 7 7 3 0 19 and US Pat. No. 5 9 0 2 5 98 You can see. These documents are incorporated herein by reference. Sustained-release carriers include those with a structure suitable for implantation in the eye. Specifically, there may be mentioned those provided with a spiral body part for embedding in the eye and a medicine container in the spiral body part. A sustained-release carrier having such a shape contains the compound of the present invention, and the compound of the present invention can be gradually released by rotating the helical trunk and fixing it in the eye. In addition, since the body part is helical, the surface area of the sustained-release carrier is increased, and the compound of the present invention can be released while diffusing into the eye. Thereby, the agent of the present invention can be effectively administered continuously.

[0129] The agent of the present invention may be an orally administered agent such as a tablet, capsule, granule, powder, or syrup. In this case, as a pharmacologically acceptable carrier, Agents, diluents, lubricants, binders, disintegrants, stabilizers, and flavoring agents. However, since fat-soluble statins have various pharmacological effects on the body, it is preferable to administer them directly into the eye, rather than orally.

[0130] The agent of the present invention can be produced according to a known method. An eye drop or injection can be produced, for example, by adding the compound of the present invention to a diluent or the like and placing it in a container such as an ampoule. Tablets can be produced, for example, by compressing a pharmaceutical composition obtained by mixing the compound of the present invention with a known carrier using a tableting machine. Capsules can be produced, for example, by encapsulating the compound of the present invention in a carrier such as a capsule.

[0131] The pharmacological effect of the compound of the present invention can be measured using a pharmacological test method described in the Examples below or a method analogous thereto.

[0132] In the following examples, the following abbreviations have the following meanings. Abbreviations that are not defined have their generally accepted meanings.

° C = degree Celsius

h r = time

m I n = min

s e c = second

M = micromolar concentration

mM = 5 rimole concentration

M = Molar concentration

U L = Microphone mouth

m L = milliliters

U g = microgram

mg = 5 Rikuram

D M E M = Dulbecco's Modified Eagle Medium

F BS = Ushi Fetal Serum

trypsin-ED TA = trypsin-ethylenediamine tetraacetic acid PBS = phosphate buffered saline

T N F—H = Tumor necrosis factor

P D G F- B B = Platelet-derived growth factor

H G F = hepatocyte growth factor

T G F—; S = transforming growth factor

P VR = proliferative vitreoretinopathy

[0133] The sympastatin used in this example was obtained from LKTRLabortiers, Inc., 2203 UnivrsitiAveweStSt.PaulMN 55 1 1 4, Usa).

[0134] The following tests are repeated three times unless otherwise noted, and show data from a representative experiment (mean soil SD). A population with normal distribution was considered statistically significant if p <0.05 using the Student t test. Example 1

[0135] Simpastatin inhibits DNA synthesis in vitreous cells (hearing site) stimulated by TNF—spray, PDGF—BB, HGF

To investigate the effect of sympastatin (SS) on the DNA synthesis ability of vitreous cells stimulated by TNF-spleen, PDGF-BB, and HGF, a [ ³ H] thymidine incorporation assay was performed.

[0136] Ushi vitreous cells were maintained in DM EM medium (Sigma, Japan) supplemented with 10% Usushi fetal serum (FBS). Vitreous cells are cultured on a dish (Iwaki, Japan) coated with type 1 collagen at 37 ° C in 5% CO ₂ and 95% air, and the medium Maintained by changing every 3 days. Cells from passage 4 to 5 were used in the experiment. Vitreous cells were seeded at 1 0 ⁴ / \ ^ e II in 24 multi-well pre-one Bok in DM EM, including a 1 0% FBS, for 24 hours, allowed to stand off the serum concentration than after 24 hours to 3% . Part After 0. 1 M, 0. 3 IJ M , 1. 0 M exists or pretreated for 30 minutes in the absence of sympathizers statins, 5 ng / m L of TNF- shed, of 1 0门_§ / 1_ Treated with 0 GF—BB, 20 ng / mL HGF for 18 hours. Then the cells , 20 UC \ Zm L was exposed to [methyl 1 ³ H] thymidine (Amersham) for 6 hours. Cells were washed with PBS, and trichloroacetic port acetic fixed, harvested and the ^[methyl-3 H] thymidine incorporation; was measured at three counter one. The bar graphs are from the left for simvastatin 0 M, 0.1 UM, 0.3 UM, and 1. OM, respectively.

[0137] By treating the vitreous vitreous cells with TNF-spleen, PDGF-BB, and HGF, the DNA synthesis was about 1.12 times, 1.36 times, respectively, compared to the untreated control. 1.2 Increased 8 times. Simpastatin inhibited all these stimulated DNA synthesis. Figure 1 shows the effect of sympastatin on DNA synthesis in vitreous cells. As shown in Fig. 1, the increased amount of DNA synthesis induced by TNF-, PDGF-BB, and HGF was significantly inhibited by 1 M sympastatin. Example 2

[0138] Inhibition of DNA synthesis of retinal vascular endothelial cells (REC) stimulated by simpastatin VEGF, HGF, TNF—

To examine the effect of sympastatin (SS) on the ability of VEGF, HGF, and TNF-stimulated retinal vascular endothelial cells to synthesize DNA, we performed [ ³ H] thymidine incorporation assay.

[0139] The same procedure as in Example 1 was used, using retinal vascular endothelial cells isolated and cultured from the eyelid eyeball. The site force-in concentrations used were VEGF (25 ng / ml), HGF (25 ng / ml), and TNF_10 (10 ng / ml). Simvastatin was administered at 0 Μ, 0.1 υΜ, 0.3 υΜ, 1.0 Μ.

[0140] As shown in Figure 2, the increased amount of DNA synthesis induced by VEGF, HGF, and TNF_1 was significantly inhibited by 1; UM sympastatin. Example 3

[0141] Inhibition of cell proliferation by sympastatin acid To examine the inhibitory effect of simpastatin acid on the proliferation of vascular retinal vascular endothelial cells induced by VEGF, a cell count test was performed.

[0142] the co one coating has been 6-well plates at a type 1 collagen, 1 0% FBS and in supplemented DM EM medium was added to the, 1. 5 X 1 0 ³ pieces / m L © to a concentration of The retinal vascular endothelial cells were cultured. The next day, each plate was treated with simvastatin acid (SSS) so that the final concentrations were 0.1 M, 1.0 υΜ, and 10 それぞれ, respectively. 24 After 4 hours, stimulation with VEGF (25 ng / mL) was performed and left for 48 hours.

[0143] As shown in the graph of Fig. 3, it was shown that proliferation of urinary retinal vascular endothelial cells induced by VEGF was suppressed in a sympastatin concentration-dependent manner.

Example 4

[0144] Inhibition of tuboformation (angiogenesis) in retinal vascular endothelial cells induced by VEGF by sympastatin

To examine the inhibitory effect of sympastatin on tubeophoration in retinal vascular endothelial cells induced by VEGF, tuboformation s sa y ¾r line 7 Ⅱ.

[0145] Using Kurapo's angiogenesis kit (K Z – 1 0 0 0), the experiment was conducted according to the attached protocol, and the lumen formation ability was evaluated. On the first day, a 24-well plate co-cultured with human umbilical vein endodermal cells (HUVEC) and skin fibrob I ast was cultured in the attached medium (KZ— 1500) and sympastatin (1 UM) After pretreatment with pravastatin for 30 minutes, stimulation with VEGF (25 ng / mL) was performed. The culture medium was replaced with new one on the 4th, 7th and 9th days. Stimulation 1 On the first day, cells were fixed, HUVEC was stained with anti-CD-3 1 antibody, and the area of the formed lumen was measured using the angiogenesis software (K SW—500 0 U) And analyzed statistically.

[0146] As shown in the photograph in Fig. 4 (A) and the graph in Fig. 4 (B), the tubeformation of vascular endothelial cells induced by VEGF was significantly suppressed by 1 M sympastatin. From this result, simpastatin It was shown to suppress neovascularization induced by VEGF stimulation.

Example 5

[0147] Inhibition of contraction of collagen gel containing vitreous cells stimulated by growth factors by sympastatin

To investigate the inhibitory effects of cin / statin and pravastatin on collagen gels containing vitreous cells stimulated by growth factors, we performed collagenase).

[0148] Usi vitreous cells were maintained in DM EM medium supplemented with 10% Usi fetal serum (FBS). The vitreous cells, coated di Mesh type 1 collagen (I waki, J apan) on one DMEM medium supplemented with 0% FBS, in 5% C0 _2, 9 5% in air 3 7 ° C The medium was maintained by changing the medium every 2-3 days. Cells from passage 3-6 were used for the experiments. Vitreous cells were treated with trypsin_EDTA for 3 minutes, washed with DMEM, then resuspended in DMEM and collected. Type 1 collagen, reconstitution buffer, suspended vitreous cells, and distilled water were mixed on ice at a ratio of 7: 1: 1: 1. The mixture 24 well multi-well pre - DOO (N unc, R oskilde, D enmark) placed on and incubated 60 minutes at 5% C0 _2, 9 5% in air 3 7 ° C. After the above gelation work, 0.5 mL DM EM supplemented with 3% FBS was injected into each well of a 24-well multiwell plate. After 24 hours of gelation, the gel was separated from the wall of the plate using a micro spatula and used for the experiment. TG F_; S 2 and sympastatin and pravastatin were administered to the collagen gel thus prepared. The diameter of the collagen gel was measured with a ruler on the fifth day after stimulation.

[0149] TG F_; S 2 (3 ng / ml) and simpastatin or pravastatin become 0 M, 0.1 UM, 0.3 UM, and 1. OM, respectively, on a collagen gel containing vitreous cells. Was administered as follows. From Fig. 5, sympastatin significantly inhibited collagen gel contraction by TGF-β2 at a concentration of 0.3; UM or higher. Example 6

[0150] Inhibition of contraction of collagen gel containing vitreous cells stimulated by growth factor by simvastatin acid and flupastatin

In order to examine the shrinkage-inhibiting effects of sympastatin, pravastatin, and flupastatin on collagen gels containing vitreous cells stimulated by growth factors, a collagen gel contraction assay was performed.

[0151] In the same manner as in Example 5, sympastatin acid (active sympastatin), pravastatin, and flupastatin were pretreated at each concentration for 30 minutes.

Stimulation with GF-; S 2 (3 ng / mL) for 5 days measured the diameter of the gel and evaluated the shrinkage.

[0152] From Figs. 6 (A) and (C), sympastatin and flupastatin inhibited collagen gel contraction by TG F_; S 2 at concentrations of 1; UM or higher.

Example 7

[0153] Inhibition of contraction of collagen gel containing vitreous cells stimulated by growth factors by sympastatin and flupastatin

[0154] Simpastatin (S S) and flupastatin (F

S) and pravastatin (PS) were administered at 1 OM each.

The inhibitory effect on collagen gel contraction by G F-; S 2 stimulation was evaluated.

[0155] From Fig. 7, it was shown that the fat-soluble statin compounds simpastatin and fluvastatin have the effect of inhibiting collagen gel contraction by TGF_; S2. Example 8

[0156] Inhibition of contraction of collagen gel containing vitreous cells stimulated by growth factor by inactive sympastatin (sympastatin) and active sympastatin (sympastatin acid)

In order to examine the contraction-inhibiting effect of inactive sympastatin and active sympastatin on collagen gels containing vitreous cells stimulated by growth factors, a collagen gel contraction assay was performed.

[0157] In the same manner as in Example 5, simpastatin and simpastatin acid Npastatin) was evaluated for its inhibitory effect on collagen gel contraction induced by TG F_; S 2 stimulation.

[0158] From Fig. 8 (B), active sympastatin is 1; UM or higher, and from Fig. 8 (A), inactive sympastatin suppresses collagen gel contraction by TGF-β2 at concentrations of 3 M or higher. did.

Example 9

[0159] Simpastatin inhibits the contraction of collagen gels containing M I 0_M 1 cells, which are c I I I I i ne of M u I l r cells stimulated by TGF_S 2

To investigate the inhibitory effect of cin / statin on the contraction of collagen gel containing MIO-M1 cells stimulated by TGF-β2, a collagen gel contraction assay was performed.

[0160] Collagen gel contraction was examined in the same manner as in Example 5 using MIO-M1, which is the cellylline of MuIller cells.

[0161] TGF-β2, simpastatin, and pravastatin were administered to collagen gel containing MIO-M1 cells at 0 M, 0.1 U M, 0.3 U M, and 1.0 μ μ, respectively. From Fig. 9 (iii), sympastatin inhibited collagen gel contraction by TG F_; S 2 at concentrations above 0.

Example 10

[0162] Inhibition of myosin light chain phosphorylation in vitreous cells stimulated by TG F_S 2 by sympastatin, flupastatin, and pravastatin

The effects of sympastatin, flupastatin, and pravastatin on myosin light chain phosphorylation in vitreous cells stimulated by TGF-; S 2 were examined by Western blotting.

[0163] Phosphorylation of myosin light chain (MLC) was examined by Western plotting. Vitreous cells exposed to starvation were treated with sympastatin (SS), flupastatin (FS), and pravastatin (PS) (30 minutes each before, and stimulated with TG F_S 2 for 24 hours. Phosphate B uf After washing with fered saline (PBS), a protease inhibitor and phosphatase inhibitor were added. 1 XL ae mm I ibuffer

(5 OmM Tris_HCI [pH 6.8], 2% SDS, 10% Glyce Mouth) was extracted. The extracted t ota I ele I l y s a te was electrophoresed by the SDS-PAGE method and transferred to a nitrocellulose membrane. After blocking with 3% skim milk, anti-Phos pho-MLC antibody was added as a primary antibody and allowed to react at 4 ° C for 1 hour. After washing the nitrocellulose membrane, anti-IgG antibody conjugated with horseradish peroxidase (HR P) was added to the secondary antibody (diluted 4000 times) and allowed to react with the primary antibody. Light emission was performed using an ECL detection system manufactured by Amershamm. In order to correct the amount of protein, ML C 2 was detected using an anti-ML C 2 antibody as a primary antibody and an anti-Ig G antibody conjugated with HRP as a secondary antibody. The degree of luminescence was analyzed using N I Himage. The experiment was performed three times, and the difference in the expression was analyzed statistically. In the graph, the control pMLC / MLC was 100%.

[0164] From Fig. 10, simpastatin and flupastatin significantly inhibited myosin light chain phosphorylation in vitreous cells stimulated by TG F_S2. From these results, it was shown that simpastatin and flupastatin inhibit cell skeletal changes due to myosin light chain phosphorylation.

Example 11

[0165] The inhibitory effect of mevalonic acid or geranylgeranyl pyrophosphate on the inhibition of myosin light chain phosphorylation in vitreous cells stimulated by TG F_; S 2 by sympastatin acid (SSS)

The inhibitory effect of simpastatin on myosin light chain phosphorylation of vitreous cells stimulated by TG F_; S 2 is the inhibition of the conversion of HMG _ Co A to mevalonate in the mevalonate pathway, or the inhibition of geranylgeranylation. It was investigated by Western plotting that it was due to suppression.

[0166] Vitreous cells were added to sympastatin acid (SSS) and mevalonic acid (M e V) or geranylgeranyl pyrophosphate (GG PP) was pretreated at each concentration for 24 hours, and then stimulated with TGF_S2 for 24 hours. The phosphorylation of MLC was examined by the Western plot method as in Example 10.

[0167] Figure 11 shows the inhibitory effect of mevalonate or geranylgeranyl pyruphosphate on the inhibition of myosin light chain phosphorylation of vitreous cells stimulated by TG F_; S 2 by simpastatin acid. It is a photograph of the result of alternative Western plotting. As shown in Figure 11, inhibition of myosin light chain phosphorylation of vitreous cells stimulated by TG F-; S 2 by sympastatin is 20; addition of UM mevalonate or 5; addition of UM geranylgeranyl pyrophosphate It turns out that it was suppressed by. From this result, it can be explained that simpastatin suppresses the conversion of HMG-CoA to mevalonate in the mevalonate pathway, or suppresses geranylgeranilation. Figure 12 shows an outline of the mevalonate pathway.

Example 12

[0168] Inhibition of nuclear translocation of p 65 (N F_ i B subunit) by sympastatin

The effect of sympastatin on the nuclear translocation of P65 in vitreous cells was examined by Western blotting.

[0169] After pretreatment of vitreous cells with sympastatin (1; UM) for each hour, T N F_

Stimulation was carried out at (10 ng / ml) for 4 hours. Nucleoprotein was extracted from the cells recovered as per protocol using CelLyTicNuCLEA rxt ract iOnKit (S I GMA). Using the extracted nucleoprotein, Western plotting was performed in the same manner as in Example 7 to examine the expression of p65 (NF_iB subunit). In order to correct the amount of protein, anti-GAPDH antibody was used again for detection.

[0170] Figure 13 is a photograph of Western plotting results instead of a drawing to verify the effect of sympastatin on p65 nuclear translocation in vitreous cells. Fig. 13 shows the control (TNF—symbol and sympathizer) from the left lane. Statins not treated), TNF—treated for 4 hours and sympastatin 0, 1, 4, 10, 24 hours. Figure 13 shows that in vitreous cells treated with sympastatin for 24 hours, the amount of p65 nuclear translocation decreased, indicating that sympastatin is an inflammatory cytokine that is regulated by NF_ / iB. This indicates that there is a possibility of restraining.

Example 13

[0171] Inhibition of K D R phosphorylation induced by V E G F in simian retinal endothelial cells by sympastatin acid (S S S)

We examined the inhibitory effect of simpastatin on phosphorylation of KDR induced by VEGF in rabbit retinal endothelial cells by immunoprecipitation and Western blotting.

[0172] Urushi retinal endothelial cells were cultured in a culture medium supplemented with 3% ushi serum for 24 hours. Twenty-four hours later, sympastatin acid was administered at 0 M, 1 U M, and 10 M, and control or 25 ng / m I VEGF was added for 5 minutes. The collected cell extract is then immunoprecipitated with anti-fI k _1 antibody, and pKDR using Western blotting with anti-phosphorylated f I k _1 antibody or anti-f I k _1 antibody. Alternatively, KDR was detected. K D R and f I k _ 1 combine to form a single receptor for V EG F on the cell membrane. Therefore, anti-f I k _ 1 antibody is used as an antibody for immunoprecipitation of KDR. In Western plot method, anti-phosphorylated f I k _ 1 antibody or anti-f I k-1 antibody is used, and p KDR or KDR Was detected.

[0173] Fig. 14 shows the inhibitory effect of simpastatin acid (SSS) on the phosphorylation of KDR induced by VEGF in retinal endothelial cells. Figure 14 (A) is a photograph of western blotting instead of a drawing showing the amount of phosphorylated KDR on the top and the total amount of KDR on the bottom. Figure 14 (B) shows the p KDR / KDR value of the cells for each stimulus when the p KDR / KDR value of the cells stimulated with 0 M sympastatin acid and VEGF 25 5 ng / mL was 100%. It is a graph which shows the ratio of. Figure 14 shows that it is induced by VEGF. The phosphorylation of KDR was suppressed depending on the concentration of sympastatin acid. These results indicate that sympastatin acid inhibits the phosphorylation of KDR induced by VEGF.

Example 14

[0174] Inhibition of sympastatin acid (SSS) phosphorylation of p44 / 4 2 MAP kinase induced by V EG F

The inhibitory effect of simpastatin acid on phosphorylation of p44 / 42 MAP kinase induced by VEGF was examined by the Western plot method as in Example 13. The concentrations of sympastatin acid and VEGF, and the treatment time are the same as in Example 13.

[0175] In order to investigate the effect of simpastatin acid on cell proliferation, experiments were conducted on phosphorylation of p44 / 42 M A K kinase, which is an indicator of the proliferative response.

The phosphorylation of p44 / 42 MA P kinase induced by VEGF was inhibited in a concentration-dependent manner with sympastatin acid.

[0176] Figure 15 shows the phosphorylation inhibitory effect of p44 / 42 MAP kinase (MAPK) induced by VEGF of sympastatin acid (SSS). Figure 15 (A) is a photograph of western blotting instead of a drawing showing the amount of phosphorylated p44 / 42MAPK on the top and the total amount of p44 / 42MAPK on the bottom. Figure 15 (B) shows that [pp 44/42 MA PK amount] / [p 44/42 MAPK amount] values of cells stimulated with simpastatin acid 0 M and V EG F 25 ng / mL were 100%. This graph shows the ratio of the [pp 44/42 MAPK content] / [p 44/42 MAPK content] value of cells to each stimulus. Figure 15 shows that sympastatin acid inhibits the phosphorylation of p44 / 42 M AP kinase induced by VEG F. Example 15

[0177] Inhibition of traction retinal detachment in the Rabbit PVR model by sympastatin We investigated that sympastatin suppresses traction retinal detachment by using a rabbit PVR model induced by fibroblasts. [0178] The fibroblasts were administered intravitreally to the rabbits that underwent vitrectomy. Each was divided into two groups: those that received simpastatin at the same time and those that did not. In the sympastatin group, the same concentration of sympastatin was administered 1 day, 3 days, 5 days, and 7 days after vitrectomy, and observation was performed using a reverse ophthalmoscope 28 days after surgery.

[0179] Figure 16 (A) is a photograph of an eye of a Usagi PVR model that did not receive sympastatin. A proliferative membrane is observed in the vitreous cavity, which pulls the retina and causes pulling retinal detachment. Figure 16 (B) is a photograph of the eye of a Usagi PVR model administered with simvastatin at a concentration of 15 M. Although the growth membrane is slightly observed, it is shown that traction retinal detachment is suppressed.

[0180] Figure 16 shows that sympastatin suppresses traction retinal detachment in the rabbit PVR model induced by fibroblasts.

Example 16

[0181] Inhibition of PVR progression in the Rabbit PVR model by sympastatin (SS) We investigated that simpastatin inhibits the progression of PVR using a Rabbit PVR model induced by fibroblasts. The experiment was conducted in the same manner as in Example 15.

[0182] Fig. 17 is a graph showing the effect of simpastatin on the inhibition of PVR progression in the Usagi PVR model based on the PVR progression classification shown in Fig. 18. In other words, in this example, the PVR progress was evaluated according to the PVR progress classification shown in Fig. 18. As a result, progression of PVR was suppressed in the rabbits treated with sympastatin 1.

[0183] Figure 17 shows that sympastatin inhibits the progression of PVR in the rabbit PVR model induced by fibroblasts.

Example 17

[0184] Inhibition of contraction of collagen gel containing vitreous cells stimulated by growth factor by sympastatin (SS), lovastatin (LS), and cerivastatin (CS) In order to investigate the shrinkage-inhibiting effects of sympastatin, lovastatin, and cerivastatin on collagen gels containing vitreous cells stimulated by growth factor TG F_; S 2, a collagen gel contraction assay was performed.

[0185] In the same manner as in Example 5, the inhibitory effect of simpastatin, lovastatin, serivastatin, and pravastatin on collagen gel contraction induced by TGF_; S 2 was evaluated. Each statin compound was pretreated with 5; UM for 24 hours, and TG F_S 2 was stimulated with 3 ng / mL for 5 days.

[0186] Figure 19 shows a collagen gel containing vitreous cells stimulated by TG F_; S 2 by sympastatin (SS), flupastatin (FS), robustatin (LS), and cerivastatin (CS). It is a figure for verifying inhibition of contraction. Figure 19 (A) shows a photograph replacing the drawing of the collagen gel when sympastatin, lovastatin, flupastatin (FS), and pravastatin (PS) are administered. Figure 19 (B) shows a photograph replacing the drawing of the collagen gel when seribastine (CS) was administered instead of oral pastatin. Figure 19 shows that TG F_S 2 inhibits collagen gel contraction by the fat-soluble statin compounds simpastatin, flupastatin, lovastatin, and cerivastatin.

Industrial applicability

[0187] The agent of the present invention can be used particularly in the pharmaceutical industry for producing ophthalmic pharmaceuticals.

Claims

The scope of the claims

[I] Inhibitor of DNA synthesis of retinal vascular endothelial cells, containing fat-soluble statin, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof as an active ingredient

[2] The agent according to claim 1, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

[3] The agent according to claim 1, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[4] The agent according to claim 2 or 3, which is administered intraocularly.

[5] The agent according to claim 2 or 3, which has a sustained release carrier administered or placed in the eye.

[6] The agent according to claim 2 or 3, which has a sustained release carrier administered or placed in the vitreous.

8. The agent according to claim 7, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

9. The agent according to claim 7, wherein the fat-soluble statin is either or both of sympastatin and flupastatin.

[10] The agent according to claim 8 or 9, which is administered intraocularly.

[I I] The agent according to claim 8 or 9, which has a sustained release carrier administered or placed in the eye.

[12] The agent according to claim 8 or 9, which has a sustained-release carrier administered or placed in the vitreous.

[13] An intraocular neovascular inhibitor comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

14. The agent according to claim 13, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

15. The agent according to claim 13, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[16] The agent according to claim 14 or claim 15, which is administered intraocularly.

[17] The agent according to claim 14 or 15, which has a sustained release carrier administered or placed in the eye.

[18] The agent according to claim 14 or claim 15, which has a sustained-release carrier administered or placed in the vitreous body.

[19] The agent according to claim 14 or 15, which is used for inhibiting the generation of new blood vessels from the retina.

[20] An intraocular cell growth inhibitor or cell contraction inhibitor containing, as an active ingredient, a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[21] The agent according to claim 20, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

22. The agent according to claim 20, wherein the fat-soluble statin is either or both of sympastatin and flupastatin.

[23] The agent according to claim 21 or claim 22, which is administered intraocularly.

[24] The agent according to claim 21 or claim 22, which has a sustained-release carrier administered or placed in the eye.

[25] The agent according to claim 21 or claim 22, which has a sustained-release carrier administered or placed in the vitreous.

[26] A replication eye cell growth inhibitor or replication eye cell contraction inhibitor containing a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

27. The agent according to claim 26, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

28. The agent according to claim 27, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[29] The agent according to claim 27 or claim 28, which is administered intraocularly.

[30] The agent according to claim 27 or 28, which has a sustained-release carrier administered or placed in the eye.

[31] The agent according to claim 27 or 28, which has a sustained-release carrier administered or placed in the vitreous.

[32] A therapeutic or prophylactic agent for wet age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient

[33] The agent according to claim 32, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

34. The agent according to claim 32, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[35] The agent according to claim 33 or claim 34, which is administered intraocularly.

[36] The agent according to claim 33 or 34, which has a sustained release carrier administered or placed in the eye.

[37] The agent according to claim 33 or 34, which has a sustained-release carrier administered or placed in the vitreous body.

[38] A therapeutic or preventive agent for atrophic age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient

39. The agent according to claim 38, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

40. The agent according to claim 38, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[41] The agent according to claim 39 or 40, which is administered intraocularly.

[42] The agent according to claim 39 or 40, which has a sustained-release carrier administered or placed in the eye.

[43] The method according to claim 39 or claim 4, further comprising a sustained-release carrier administered or placed in the vitreous body. The agent according to 0.

[44] Diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, or immaturity containing fat-soluble statin, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate as an active ingredient A therapeutic or prophylactic agent for retinopathy of infants.

45. The agent according to claim 44, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

46. The agent according to claim 44, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[47] The agent according to claim 45 or claim 46, which is administered intraocularly.

[48] The agent according to claim 45 or claim 46, which has a sustained release carrier administered or placed in the eye.

[49] The agent according to claim 45 or claim 46, which has a sustained-release carrier administered or placed in the vitreous body.

[50] A therapeutic agent for uveitis, allergic conjunctivitis, or spring catarrhage comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[51] The agent according to claim 50, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

52. The agent according to claim 50, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[53] The agent according to claim 51 or 52, which is administered intraocularly.

[54] The agent according to [51] or [52], which has a sustained release carrier administered or placed in the eye.

[55] The agent according to claim 51 or claim 52, which has a sustained-release carrier administered or placed in the vitreous body.

[57] The fat-soluble statin is simpastatin, flupastatin, oral pastatin or The agent according to claim 56, which is one or more of cerivastatin.

[58] The agent according to claim 56, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[59] The agent according to claim 57 or 58, which is administered intraocularly.

[60] The agent according to claim 57 or 58, which has a sustained release carrier administered or placed in the eye.

[61] The agent according to claim 57 or 58, which has a sustained-release carrier administered or placed in the vitreous body.

[62] A therapeutic or prophylactic agent for proliferative vitreoretinopathy comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

63. The agent according to claim 62, wherein the fat-soluble statin is one or more of simpastatin, flupastatin, oral pastatin, and cerivastatin.

64. The agent according to claim 62, wherein the fat-soluble statin is one or both of sympastatin and flupastatin.

[65] The agent according to claim 63 or 64, which is administered intraocularly.

[66] The agent according to claim 63 or 64, which has a sustained release carrier administered or placed in the eye.

[67] The agent according to claim 63 or 64, which has a sustained-release carrier administered or placed in the vitreous body.