MXPA00008689A - Pharmaceutical composition for prophylaxis and therapy of diseases associated with ocular fundus tissue cytopathy - Google Patents

Abstract

A pharmaceutical composition for the prophylaxis and therapy of a disease arising from ocular fundus tissue cytopathy such as retinochoroidal disease, glaucoma, and posterior complication arising form photocoagulation, which contains, as an active ingredient, a compound of formula (I) wherein R1 represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which is optionally substituted;R2 and R3 may be the same or different and each represents hydrogen or an alkyl group having 1 to 4 carbon atoms or R2 and R3 may jointly form a ring having 3 to 7 carbon atoms;and R4 represents a lower alkyl group which is optionally substituted by aryl, cycloalkyl, or aromatic heterocyclic residue, or a pharmaceutically acceptable salt thereof.

Description

PHARMACEUTICAL COMPOSITION FOR PROPHYLAXIS AND THERAPY OF DISEASES ASSOCIATED WITH TISSUE CYTOPATHY OF THE FUND OF THE EYE FIELD OF THE INVENTION The present invention relates to a drug for the prophylaxis and therapy of diseases associated with tissue cytopathy of the fundus of the eye.

ANTECEDENTS OF THE TECHNIQUE The tissue of the fundus of the eye comprises the retina, vessels of the retina, retinal pigment epithelium, optic disc, choroid and sclera and constitutes an organ for transmitting light stimuli from the crystalline lens to the brain through optic nerve cells. Therefore, tissue damage in the fundus of the eye induces serious diseases leading to blindness in many cases. The deterioration of the tissue cells of the fundus of the eye is frequently caused by ischemia and changes of several biological substances, such as the elevation of excitatory amino acid levels and decreases in ATP. In addition, the tissue cells of the fundus of the eye are damaged by systemic diseases such as hypertension and diabetes, old age, and trauma. Although laser photocoagulation is used for the inhibition or elimination of neogenetic vessels in diabetic retinopathy and macular degeneration, elimination of occlusion of vessels in the occlusion of vessels of the retina, and the like, tissue cytopathy of the fundus of the eye caused by changes in circulation in the vicinity of the laser irradiation site, inflammatory reaction due to the heat of photocoagulation and the like expose problems. Diseases associated with damage to the fundus tissue develop due to various factors mentioned above or a complicated combination of various factors. Disease arising from damage to the fundus of the eye fund includes retinochoroidal disease (eg, retinal vascular abnormalities such as retinal vessel occlusion, retinal periflebitis, Eales disease, ischemic eye syndrome, retinal arteriolar macroaneurism, etc., associated retinopathy with hypertension or renal diseases, diabetic retinopathy, retinal pigment epithelia, retinal dystrophy, macular dystrophy, retinochoroidal atrophy, retinocoroiditis, macular degeneration, macular edema, retinal pigment epithelial detachment, retinal detachment, degenerative retinoschisis, tumors such as retinoblastoma, retinal pigment epithelium, capillary hemangioma of the optic nerve head, etc., optical neuropathies such as ischemic optic neuropathy etc., optic disc inflammation such as papilledema / papilledema etc.); and glaucoma associated with tissue cytopathy of the fundus of the eye (e.g., open-angle glaucoma, low-tension glaucoma, angle-closure glaucoma, etc.); and further complications that arise from photocoagulation such as macular edema, retinal detachment, optic neuritis, abnormal visual field, abnormal light sensation, and color vision defect. As used herein, subsequent complications arising from photocoagulation refers to tissue cytopathy of the fundus of the eye, caused by changes in circulation in the vicinity of the laser irradiation site, which is attributed to photocoagulation after of laser irradiation, inflammatory reaction due to the heat of photocoagulation, and diseases induced by these disorders. As the current drug therapy of diseases associated with cytopathy of fundus tissue, agents that improve microcirculation such as nicotinate of tocopherol, which is a preparation of vitamin E, pentoxifylline, etc., various steroidal drugs, antiprostaglandins, and Antifologue enzyme preparations are administered orally. However, these therapies are not effective enough or have side effect problems such as hypotension and gastrointestinal disorders. As therapeutic modalities for glaucoma, cholinergic agonists represented by pilocarpine, sympathomimetic drugs such as epinephrine, dipivefrin, etc., and β-adrenergic antagonists such as timolol, pindolol, carteolol, etc., are available for topical administration (e.g. for the eyes), however several side effects associated with their mechanisms of action represent problems.

Recently, it has been reported that compounds having calpain inhibitory activity have an action to inhibit ischemic cell death [Lee K., Frank S., Vanderklish, P., Arai A., Lynch G., Proc. Nati Acad. Sci., 88, 7233-7237 (1991), Rami A., Krieglstein J., Brain Res., 609, 67-70 (1993)]. However, these reports only describe the inhibitory effect on cell death in connection with the death of neurons in the hippocampus and do not indicate the inhibitory effect of drugs on the cytopathy of fundus tissue or its usefulness in the field of ophthalmology. In addition, the inhibitors that have been used so far have some disadvantages in the aspect of tissue transfer and adverse reactions. EPO771565 establishes that a cysteine protease inhibitor is useful for neovascularization in diabetic retinopathy etc., but it does not work for diseases associated with cytopathy of fundus tissue. The object of the present invention is to provide a drug for the prophylaxis and cytopathy therapy of tissue of the fundus of the eye, which counteracts the aforementioned disadvantages. Another object of the present invention is to provide a drug for the prophylaxis and therapy of diseases arising from tissue cytopathy of the fundus of the eye and a method for the prevention and treatment of said diseases. It should be understood that, in the context of the present invention, the term "fundus of the eye fundus" is intended to include the retina, retinane blood vessels, retinal pigment epithelium, optic disc, choroid, sclera, and vitreous base, and that, These tissues, the retina, the retinane blood vessels, the retinal pigment epithelium, the optic disc, and choroids are sometimes referred to collectively as retinochoroid.

BRIEF DESCRIPTION OF THE INVENTION The inventors of the present invention developed a drug for the prophylaxis and therapy of cytopathy of fundus tissue of the eye, which is effective to improve the cytopathy of tissue of the fundus of the eye and which is safe, and found that a compound of the following formula (I) wherein R1 represents an alkyl group having from 1-4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which is optionally substituted; R2 and R3 may be the same and different and each represents hydrogen or an alkyl group having 1 to 4 carbon atoms or R2 and R3 together may form a ring having from 3 to 7 carbon atoms; R 4 represents a lower alkyl group which is optionally substituted by aryl, cycloalkyl or aromatic heterocyclic residue, and a pharmaceutically acceptable salt thereof exhibits remarkable prophylactic or therapeutic efficacy against fundus tissue cytopathy.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagrammatic representation of the effect on damage to rat retinal ganglion cells. The ordinary number represents the number of ganglion cells. In the diagram, a) denotes an important difference (p <0.01) of the normal group by Student's t-test; b) denotes an important difference (p <0.01) of the control group by Student's t-test. Figure 2 is a diagrammatic representation of the effect on cell damage of the rat inner retinal nuclear layer. The ordinary number represents the number of cells in the inner nuclear layer. In the diagram, a) denotes an important difference (p <0.01) of the normal group by Student's t-test; b) denotes an important difference (p <0.01) of the control group by Student's t-test. Figure 3 (a) and Figure 3 (b) are SDS electrophoretic images showing the endocellular spectrin cleavage product obtained after homogenization of retinal tissues detected after incubation of rat retina tissues under hypoxia, in where Figure 3 (a) and Figure 3 (b) show SDS electrophoretic images after incubation for 3 and 6 hours, respectively. In these figures, M is a molecular weight marker, 1 shows retinal tissues incubated in a culture medium containing glucose in the presence of oxygen, 2 shows retinal tissues incubated under hypoxia in a culture medium without glucose, 3 shows retinal tissues incubated under hypoxia in a culture medium without glucose but supplemented with 100 μM of N- (4-fluorophenylsulfonyl) -L-valil-L-leucinal (hereinafter abbreviated as compound 1), and 4 shows retinal tissues incubated under hypoxia in a culture medium without glucose but supplemented with 100 μM Cbz-Val-Phe-H [hereinafter abbreviated as MDL]. The 220 kDa protein band shows intact spectrin molecule, and the 145 and 150 kDa bands show the spectrin cleavage products. The compound of formula (I) for use in the invention and a pharmaceutically acceptable salt thereof are known compounds described in Japanese Unexamined Patent Publication No. 43464/1997 (EP0771565) and can typically be produced by the methods described therein. With reference to formula (I), when the amino acid portions exist as optical isomers, they are L-isomers unless otherwise indicated. Further with reference to formula (I), the C 1 -C 4 alkyl group for R 1 includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Of these, methyl is preferred. The aryl group of C 6 -C 0 for R 1 includes phenyl, naphthyl, indenyl, azulenyl, and so on. Phenyl and naphthyl are preferred. The substituent group which may occur on the aryl group includes, for example, halogen (eg, fluorine, chlorine, etc.), straight or branched C1-C5 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl) , isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl and the like), trifluoromethyl, straight or branched C1-C5 alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, and the like), hydroxy, C2-C5 acyloxy (eg, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy and the like), carboxyl, and acyl of C2-Cs (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaroyl and the like). Halogen and C 1 -C 5 alkyl are preferred. Most preferably fluorine, chlorine and methyl. Preferred examples of the optionally substituted C 1 -C 1 -aryl aryl group for R 1 are 4-fluorophenyl, 4-chlorophenyl, p-tolyl, and 2-naphthyl. The linear or branched C1-C4 alkyl group mentioned for R2 and R3 includes methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl and the like. Propyl, isopropyl and tert-butyl are preferred. Most preferably isopropyl. With reference to R2 and R3, one of them is preferably hydrogen and the other is propyl, isopropyl, isobutyl or tert-butyl. Most preferably, R 2 is propyl, isopropyl, isobutyl or tert-butyl and R 3 is hydrogen. Still most preferably, R 2 is isopropyl and R 3 is hydrogen. The C3-C7 ring that can be formed together by R2 and R3 includes cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, and so on. Cyclopentylidene and cyclohexylidene are particularly preferred.

The lower alkyl group mentioned for R 4 includes linear or branched groups having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Methyl and isobutyl are preferred. The aforementioned lower alkyl group can be substituted by the following aryl group, cycloalkyl group, or aromatic heterocyclic residue. The aryl group includes phenyl, 1-naphthyl, 2-naphthyl, among others. Particularly preferred is phenyl. The cycloalkyl group preferably includes C3-Cβ cycloalkyl; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on. Particularly preferred is cyclohexyl. The aromatic heterocyclic residue includes heteromonocyclic residues that contain at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur as a ring element and corresponding fused heterocyclic residues. The heteromonocyclic residue includes, but is not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, and the like. The fused heterocyclic residue includes, but is not limited to, indolyl, quinolyl, benzothienyl, benzofuryl, indazolyl, quinazolinyl, phthalazinyl, quinoxalinyl, and the like. Particularly preferred is indolyl.

Preferred examples of the lower alkyl group which can be substituted by aryl, cycloalkyl or aromatic heterocyclic residue as expressed for R4 are isobutyl, benzyl, cyclohexylmethyl and indole-3-ylmethyl. Representative compounds of the formula (I) are N- (2-naphthalenesulfonyl) -L-valil-L-leucinal, N- (4-fluorophenylsulfonyl) -L-valil-L-leucinal, N- (4-chlorophenylsulfonyl) -L -valil-L-leucinal, N- (4-methylphenylsulfonyl) -L-valil-L-leucinal, N- (4-fluorophenylsulfonyl) -L-valyl-phenylalaninal, N- (2-naphthalenesulfonyl) -L -valil-L-phenylalaninal, N- (4-chlorophenylsulfonyl) -L-valyl-L-phenylalaninal, N- (4-methylphenylsulfonyl) -L-valyl-L-phenylalaninal, N- (4-chlorophenylsulfonyl) -L-valil -L-tryptophanal, N- (4-fluorophenylsulfonyl) -L-valyl-L-cyclohexylalaninal, N- (2-naphthalenesulfonyl) -L-valyl-L-cyclohexylalaninal, N- (4-chlorophenylsulfonyl) -L-valil-L -cycloexilalaninal, and pharmaceutically acceptable salts thereof. Particularly preferred is N- (4-fluorophenylsulfonyl) -L-valil-L-leucinal, and a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the compound of formula (I) includes salts with inorganic bases; for example, salts with alkali metals such as sodium, potassium, etc., salts such as alkaline earth metals such as calcium, magnesium, etc., aluminum salt, ammonium salt, etc .; salts with organic bases such as triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, etc .; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc .; and salts with amino acids such as arginine, lysine, ornithine, aspartic acid, glutamic acid, among others. The prophylactic and therapeutic drug of the present invention can optionally be provided in dosage form known in the art, which can be manufactured by a known pharmaceutical technology comprising, for example, mixing or dissolving the active compound with a pharmaceutically acceptable carrier or carrier. Of said dosage forms, the oral dosage form for use in humans includes powders, granules, tablets, capsules, syrups and other liquid preparations. Powders, granules, tablets and the like can be prepared using optional pharmaceutically acceptable carriers which are suitable for solid preparations, such as excipients, (eg, starch, fructose glucose, sucrose, lactose, etc.), lubricants (eg, stearate magnesium, calcium stearate, etc.), disintegrants, (for example, starch, crystalline cellulose, etc.), binders (for example, starch, gum arabic, etc.), and so on. Said solid preparation can optionally be coated with a coating agent (for example, gelatin, sucrose, etc.), or an enteric coating (for example, hydroxypropylmethylcellulose phthalate, methacrylic copolymers, shellac, etc.), so that the compound active can be released, specifically in the intestines. For the preparation of syrups and other liquids, various additives such as stabilizers (e.g., sodium edetate, etc.), suspension agents (e.g., gum arabic, carmellose, etc.), corrective agents (e.g., simple syrup, glucose, etc.) perfumes, etc., can be added appropriately. The dosage form for non-oral systemic administration includes injections, suppositories, etc. Injections can be made using solvents (water for injection, etc.), stabilizers (eg, sodium edetate, etc.), isotonizing agents, (eg, sodium chloride, glycerin, mannitol, etc.), pH control (eg, hydrochloric acid, citric acid, sodium hydroxide, etc.), suspending agents (eg, methylcellulose, sodium carboxymethylcellulose, etc.), and other suitable additives. For the preparation of suppositories, a suppository base (e.g., cocoa cream, macrogol, etc.), and the like may suitably be used. The dosage form for topical administration includes, for example, eye drops and ophthalmic ointments. For the preparation of eye drops and ophthalmic ointments, a variety of known substances such as solvents, (eg, physiological saline, sterilized purified water, etc.), stabilizers (e.g., sodium edetate, citric acid) can be appropriately selected. , etc.), emulsifiers (e.g., polyvinyl pyrrolidone), suspending agents (e.g., hydroxypropylmethylcellulose, methylcellulose, hydroxymethylcellulose, etc.), surfactants (e.g., Polysorbate 80, castor oil-hydrogenated polyethoxyethylene, etc.), preservatives (for example, benzalkonium chloride, p-hydroxybenzoic esters, chlorobutanol, etc.), pH regulators (boric acid, borax (sodium borate), sodium acetate, citrate regulator, phosphate buffer, etc.) isotonizing agents (eg, sodium chloride, glycerin, mannitol, etc.), control agents of pH (for example, hydrochloric acid, sodium hydroxide, etc.), and ointment bases (for example, white petrolatum, lanolin, etc.). The prophylactic and therapeutic drug of the present invention is useful for the prevention and treatment of retinochoroidal diseases, glaucoma and hypertension of the eye arising from tissue cytopathy of the fundus of the eye, and subsequent complications arising from photocoagulation. Retinococcal diseases include, but are not limited to, retinal vascular abnormalities such as occlusion of retina vessels, retinal periflebitis, Eales disease, ischemic eye syndrome, retinal arteriolar macroaneurysm, etc.; retinopathy associated with hypertension or kidney disease; diabetic retinopathy, retinal pigment epitheliitis; Retinal dystrophy; macular dystrophy; retinochoroidal atrophy; retinochoroiditis; macular degeneration; macular edema; epithelial detachment of retinal pigment; retinal detachment; degenerative retinoschisis; tumors such as, retinoblastoma, tumors of the retinal pigment epithelium, capillary hemangioma of the optic nerve head, etc .; Optic neuropathies such as ischemic optic neuropathy, etc .; and optic disc inflammation such as papilledema / papilledema, etc. The prophylactic and therapeutic drug of the present invention is particularly useful for the prevention and treatment of occlusion of retina vessels and macular degeneration. Hypertension of the eye and glaucoma arising from tissue cytopathy of the fundus of the eye include open-angle glaucoma, low-tension glaucoma, angle-closure glaucoma, etc., and hypertension of the eye with visual field defects. The prophylactic and therapeutic drug of the present invention is particularly useful for the prevention and treatment of low-tension glaucoma. Subsequent complications arising from photocoagulation include macular edema, retinal detachment, optic neuritis, abnormal visual field, abnormal light sensation, or color vision defect. The dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention depends on the objective disease, clinical condition and other conditions of patients, route of administration and other factors. In general terms, the objective effect can be achieved in a general dose of 1-1000 mg, preferably 10-500 mg, for oral administration, or generally 0.1-300 mg, preferably 1-150 mg, for parenteral administration. For topical administration, a drop for eye having a concentration of 0.001-1.0 w / v%, preferably 0.01-0.5 w / v%, can be instilled into the eye by 20-50 μl per dose, with a frequency of about 5 to 6 doses a day.

Provided that the object of the present invention is not affected, the prophylactic and therapeutic drug of the present invention can be used in combination with other active ingredients. For other active ingredients, there may be mentioned anticoagulants such as potassium warfarin, urokinase, aspirin, etc .; vasoprotectants / hemostats such as sodium sulfonate-carbazochrome, etc .; peripheral vasodilators such as kalidinogenase, pentoxifylline, sarpogrelate hydrochloride, tocopherol nicotinate, etc., adrenocorticoids such as betamethasone, dexamethasone, prednisolone, etc., antifilogistic enzyme preparations such as serrapeptase, streptokinase, streptodornase, etc., antiglaucoma drugs such as β-blockers, mannitol, acetazolamide, etc., and antiprostaglandins.

EXAMPLES The following examples and test examples are intended to illustrate the present invention in greater detail and for no reason should be taken as definitions of the scope of the invention. In the following examples and test examples, compound 1 means N- (4-fluorophenylsulfonyl) -L-valil-L-leucinal.

EXAMPLE 1 Tablets Compound 1 50 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg Crystalline cellulose 10 mg The tablets were prepared by a conventional method, which contained the above ingredients as materials for a tablet.

The tablets can be applied with a conventional enteric coating (for example, hydrixopropylmethylcellulose phthalate), a sugar coating, or a film (for example, ethylcellulose), as necessary.

EXAMPLE 2 Capsules Compound 1 75 mg Mannitol 75 mg Starch 17 mg Calcium stearate 3 mg The above ingredients as materials for a capsule were mixed homogeneously, granulated by a method conventional and filled into hard capsules. The granules may be applied with a conventional enteric coating (e.g., hydroxypropylmethylcellulose phthalate), a sugar coating, or a film (e.g., ethylcellulose), as necessary prior to filling.

EXAMPLE 3 Parenteral suspension Compound 1 750 mg Sodium carboxymethylcellulose 500 mg Water for injection to obtain 100 ml The above ingredients were aseptically mixed by a conventional method to provide a parenteral suspension.

EXAMPLE 4 Eye drops Compound 1 50 mg Boric acid 700 mg Borax q.s Sodium chloride 500 mg Hydroxymethyl cellulose 0.5 g Sodium edetate 0.05 mg Benzalkonium chloride 0.005 mg Sterile purified water to obtain 100 ml EXAMPLE OF TEST 1 Effect of tissue cytopathy of the fundus of the eye in rats Method: Using SD male rats (weight 150 g), the central retinal artery was occluded with an aneurysm clamp under anesthesia with 5 p / v% ketamine HCI / 2 p / v% xylazine HCl (3: 1, 0.5 ml, ip) to arrest the blood flow for 75 minutes. In the normal group, the central retinal artery was exposed but ischemia was not introduced. Tissue specimens were prepared 5 days after reperfusion. To be used as a tissue specimen, the enucleated eyeball was fixed in 4% formaldehyde and embedded in paraffin routinely. Then, thin sections (3 μm thick) were prepared by transverse slicing at right angles to the retinal surface including the optic disc and stained with hematoxylin-eosin. Under the optical microscope, the retinal neurons (ganglion cells) and cells of the inner nuclear layer were counted in 0.25 mm intervals of the retinal section at a predetermined distance (1-2 mm) from the optic disc. As the test drug, a parenteral suspension prepared as in example 3 was administered intraperitoneally in a dose of 100 mg, such as compound 1, per kg of body weight 15 minutes before arterial occlusion, immediately after reperfusion, and once a day (compound 1 administration group). The vehicle used in example 3 was similarly administered to the control and normal groups. In the positive control group, Cbz-Val-Phe-H [S.C. Hong et al., Stroke, 25 (3), 663-669, 1994], 100 mg / kg, was administered similarly (MDL administration group).

Results: The results are shown in Figures 1 and 2. Compared with the normal group, both the ganglion cell count and the nuclear cell layer count decreased significantly by arterial occlusion. An administration of compound 1 significantly inhibited decreases in inner nuclear layer and ganglion cell counts caused by arterial occlusion. In the MDL administration group, the degree of inhibition was slight. The above results indicate that the active compound 1 of the present invention is effective in improving the cytopathy of fundus tissue.

EXAMPLE OF TEST 2 Effect of enucleated retinal cytopathy in rats under hypoxia Method: The fundus of the eye (retina) of male SD rats (weight 150 g) was removed and incubated under hypoxia in RPMI 1640 medium (manufactured by Gibco) without glucose. The tissue of the fundus of the eye was homogenized 3 and 6 hours later, and the endocellular spectrin cleavage product was isolated by SDS electrophoresis and detected using homophily substance prepared by the method of Saido et. to the. [The Journal of Biological Chemistry, 268, 25239-25243 (1993)]. As the test compounds, compound 1 and MDL were dissolved in ethanol at a concentration of 20 mM and added to the culture medium at a concentration of 100 μM (compound administration group 1 and MDL administration group). As a control, the eye fundus tissue of male SD rats (weight 150 g) was incubated in the same manner in the presence of oxygen in RPMI 1640 medium containing glucose.

Results: The results are shown in Figures 3 (a) and 3 (b). When the tissue was incubated in a culture medium containing glucose in the presence of oxygen, spectrin cleavage was not observed. In contrast, when the tissue was incubated for 3 hours and 6 hours in a glucose-free culture medium under hypoxia, the spectrin shown by a 220 kDa band was cut by calpain, which resulted in the detection of the cutting products. of spectrin as shown by the 145 and 150 kDa bands. When the tissue was incubated in a culture medium supplemented with compound 1 and MDL, which are inhibitors of calpain, although a 150 kDa band was detected in some way due to the digestion of spectrin, a band of 145 kDa was not detected. .

The above results indicate elevation of calcium concentrations in the tissue of the fundus of the eye due to the absence of oxygen, which leads to the activation of calpain, ie a calcium-dependent protease, and damage to the cells. The results clearly show the improvement of the lesion by compound 1.

INDUSTRIAL APPLICATION The prophylactic and therapeutic drug of the present invention is useful for the prevention and treatment of diseases arising from tissue cytopathies of the fundus of the eye, for example, retinal vascular abnormalities such as occlusion of retina vessels, retinal periflebitis, Eales disease. , ischemic eye syndrome, retinal arteriolar macroaneurism, etc; retinopathy associated with hypertension or kidney diseases; Diabetic retinopathy; retinal pigment epitheliitis; retina dystrophy; macular dystrophy, retinochoroidal atrophy; retinochoroiditis; macular degeneration; macular edema; detachment of retinal pigment epithelium; retinal detachment; degenerative retinoschisis; tumors such as retinoblastoma, tumors of the retinal pigment epithelium, capillary hemangioma of the optic nerve head, etc .; Optic neuropathies such as ischemic optic neuropathy etc .; Optic disc inflammation such as papilledema / papilledema, etc .; glaucoma such as open-angle glaucoma, low-tension glaucoma, angle-closure glaucoma; and ocular hypertension with visual field defects, subsequent complications arising from photocoagulation such as macular edema, retinal detachment, optic neuritis, abnormal field of vision, abnormal light sensation, and color vision defect. The present invention is based on application No. 53624/1998 issued in Japan, the content of which is incorporated herein by reference.

Claims (37)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for the prophylaxis or therapy of a disease arising from the cytopathy of tissue of the fundus of the eye, comprising, as the active ingredient, a compound of the following formula (I) wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which is optionally substituted; R2 and R3 can be the same or different and each represents hydrogen or an alkyl group having 1 to 4 carbon atoms or R2 and R3 can together form a ring having from 3 to 7 carbon atoms; and R 4 represents a lower alkyl group which is optionally substituted by aryl, cycloalkyl, or aromatic heterocyclic residue, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, further characterized in that R1 in the formula (I) is phenyl or naphthyl, which can be substituted by fluorine, chlorine or methyl.

3. - The pharmaceutical composition according to claim 1, further characterized in that R1 in the formula (I) is a group selected from the group consisting of methyl, 4-fluorophenyl, 4-chlorophenyl, p-tolyl, and 2-naphthyl.

4. The pharmaceutical composition according to claim 1, further characterized in that in the formula (I), R2 is propyl, isopropyl, or tert-butyl and R3 is hydrogen.

5. The pharmaceutical composition according to claim 1, further characterized in that in the formula (I), R2 is isopropyl and R3 is hydrogen.

6. The pharmaceutical composition according to claim 1, further characterized in that in the formula (I), R2 and R3 together form cyclopentylidene or cyclohexylidene.

7. The pharmaceutical composition according to claim 1, further characterized in that in the formula (I), R4 is a group selected from the group consisting of isobutyl, benzyl, cyclohexylmethyl, and indol-3-ylmethyl.

8. The pharmaceutical composition according to claim 1, further characterized in that the active ingredient is N- (4-fluorophenylsulfonyl) -L-valil-L-leucinal or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to any of claims 1 to 8, further characterized in that the disease arising from the cytopathy of fundus tissue is a disease selected from the group consisting of retinochoroidal disease, glaucoma and subsequent complications that arise from photocoagulation.

10. The pharmaceutical composition according to any of claims 1 to 9, further characterized in that the disease arising from tissue cytopathy of the fundus of the eye is retinochoroidal disease.

11. The pharmaceutical composition according to claim 10, further characterized in that the retinochoroidal disease is an element selected from the group consisting of retinal vessel occlusion, retinal periflebitis, Eales disease, ischemic eye syndrome, retinal arteriolar macroaneurysm, retinopathy associated with hypertension or renal diseases, diabetic retinopathy, retinal pigment epitheliitis, retinal dystrophy, macular dystrophy, retinochoroidal atrophy, retinochoroiditis, macular degeneration, macular edema, retinal pigment epithelial detachment, retinal detachment, degenerative retinoschisis, retinoblastoma, epithelial tumors of retinal pigment, capillary hemangioma of the optic nerve head, ischemic optic neuropathy and papilledema / papilledema edema.

12. The pharmaceutical composition according to claim 11, further characterized in that the retinochoroidal disease is retinal vessel occlusion.

13. - The pharmaceutical composition according to claim 11, further characterized in that the retinochoroidal disease is macular degeneration.

14. The pharmaceutical composition according to any of claims 1 to 9, characterized in that the disease arising from tissue cytopathy of the fundus of the eye is a further complication arising from photocoagulation.

15. The pharmaceutical composition according to claim 14, further characterized in that the subsequent complication arising from photocoagulation is an element selected from the group consisting of macular edema, retinal detachment, optic neuritis, abnormal field of view, light sensation abnormal, and color vision defect.

16. The pharmaceutical composition according to any of claims 1 to 9, further characterized in that the disease arising from tissue cytopathy of the fundus of the eye is glaucoma.

17. The pharmaceutical composition according to claim 16, further characterized in that glaucoma is an element selected from the group consisting of open-angle glaucoma, low-tension glaucoma, and angle-closure glaucoma.

18. The pharmaceutical composition according to claim 17, further characterized in that glaucoma is low voltage glaucoma.

19. The use of a compound of the following formula (I) wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which is optionally substituted; R2 and R3 may be identical or different and each represents hydrogen or an alkyl group having 1 to 4 carbon atoms or R2 and R3 together may form a ring having from 3 to 7 carbon atoms; and R 4 represents a lower alkyl group which is optionally substituted by aryl, cycloalkyl or aromatic heterocyclic residue, or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical agent for the prophylaxis or treatment of a disease arising from cytopathy of the background tissue Of the eye.

20. The use as claimed in claim 19, further characterized in that R1 in the formula (I) is phenyl or naphthyl, which can be substituted by fluorine, chlorine or methyl.

21. The use as claimed in claim 19, further characterized in that R1 in the formula (I) is a group selected from the group consisting of methyl, 4-fluorophenyl, 4-chlorophenyl, p-tolyl and 2- naphthyl.

22. The use as claimed in claim 19, further characterized in that in the formula (I), R 2 is propyl, isopropyl or tert-butyl and R 3 is hydrogen.

23. - The use as claimed in claim 19, further characterized in that in the formula (I), R 2 is isopropyl and R 3 is hydrogen.

24. The use as claimed in claim 19, further characterized in that in the formula (I), R2 and R3 together form cyclopentylidene or cyclohexylidene.

25. The use as claimed in claim 19, further characterized in that in the formula (I), R4 is a group selected from the group consisting of isobutyl, benzyl, cyclohexylmethyl and indol-3-ylmethyl.

26. The use as claimed in claim 19, further characterized in that the active ingredient is N- (4-fluorophenylsulfonyl) -L-valil-L-leucinal or a pharmaceutically acceptable salt thereof.

27. The use as claimed in any of claims 19 to 26, further characterized in that the disease arising from tissue cytopathy of the fundus of the eye is a disease selected from the group consisting of retinochoroidal disease, glaucoma and subsequent complications that arise from photocoagulation.

28. The use as claimed in any of claims 19 to 27, further characterized in that the disease arising from tissue cytopathy of the fundus of the eye is retinochoroidal disease.

29. The use as claimed in claim 28, further characterized in that the retinochoroidal disease is an element selected from the group consisting of retinal vessel occlusion, retinal periflebitis, Eales disease, ischemic eye syndrome, retinal arteriolar macroaneurysm. , retinopathy associated with hypertension or renal diseases, diabetic retinopathy, retinal pigment epithelitis, retinal dystrophy, macular dystrophy, retinochoroidal atrophy, retinochoroiditis, macular degeneration, macular edema, retinal pigment epithelial detachment, retinal detachment, degenerative retinoschisis, retinoblastoma, retinal pigment epithelium, capillary hemangioma of the optic nerve head, ischemic optic neuropathy and papilledema / papilledema edema.

30. The use as claimed in claim 29, further characterized in that the retinochoroidal disease is retinal vessel occlusion.

31. The use as claimed in claim 29, further characterized in that the retinochoroidal disease is macular degeneration.

32. The use as claimed in any of claims 19 to 27, further characterized in that the disease arising from tissue cytopathy of the fundus of the eye is a subsequent complication arising from photocoagulation.

33. The use as claimed in claim 32, further characterized in that the subsequent complication arising from photocoagulation is an element selected from the group consisting of macular edema, retinal detachment, optic neuritis, abnormal field of view, sensation of abnormal light, and color vision defect.

34. The use as claimed in any of claims 19 to 27, further characterized in that the disease arising from tissue cytopathy of the fundus of the eye is glaucoma.

35. The use as claimed in claim 34, further characterized in that glaucoma is an element selected from the group consisting of open-angle glaucoma, low-tension glaucoma and angle-closure glaucoma. 36.- The use as claimed in claim 35, further characterized in that glaucoma is low tension glaucoma. 37.- A commercial package comprising the pharmaceutical composition according to any of claims 1 to 8 and a written material associated therewith, the written material stating that the pharmaceutical composition can and should be used to prevent and treat an emerging disease of cytopathy of the fundus of the eye.