JP2003252760A - Retinal disease therapeutic and / or prophylactic agent - Google Patents

Abstract

(57) [Problem] A novel preventive and / or therapeutic agent for retinal light damage, a preventive and / or therapeutic agent for retinal disease and / or eye disease caused by retinal light damage, and a photoreceptor protective agent As a useful medicine. SOLUTION: The following formula: (Each symbol in the formula has the same meaning as described in the specification.) The hydrate or the pharmacologically acceptable salt thereof is contained as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preventive and / or therapeutic agent for retinal photodamage, a preventive and / or therapeutic agent for retinal diseases and / or eye diseases caused by retinal photodamage, and a photoreceptor protecting agent. The present invention relates to a useful medicine.

[0002]

2. Description of the Related Art When the retina receives external light, its energy is absorbed by a visual substance called rhodopsin, which is located in the outer cell of the photoreceptor cell, and is converted into an electrical signal. Visual conduction pathways in cells are photoreceptor cells, bipolar cells,
It is in the order of ganglion cells, and then is transmitted to the visual cortex of the occipital lobe via the visual pathway and perceived as an image.

The outer segment of photoreceptor cells containing this visual substance contains a large amount of higher unsaturated fatty acids such as docosahexaenoic acid and arachidonic acid, and docosahexaenoic acid is present in the largest amount as compared with other tissues in the body. ing. Due to the high content of such higher unsaturated fatty acids, photoreceptor cells are likely to degenerate, and once degeneration occurs, it is almost irreversible, causing serious visual impairment. This degeneration of photoreceptor cells occurs genetically, but it is known to occur due to various oxidative stresses such as light (ultraviolet rays), iron, oxygen and radiation. The main oxidative stress in the eye is light that is received throughout life, and photodamage in the retina is a typical oxidative stress.

On the other hand, the following formula (I)

(In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms, and R ² represents hydrogen atom, aryloxy, arylmercapto, carbon 1 to 5 alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ is hydrogen atom, 1 to 5 carbon atoms Alkyl,
Cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons, benzyl, naphthyl or phenyl, or alkoxy having 1 to 5 carbons, hydroxyalkyl having 1 to 3 carbons, alkoxy having 2 to 5 carbons in total. Carbonyl, C1-C3 alkyl mercapto, C1-C4
Same or different 1 to 3 selected from the group consisting of alkylamino, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide.
Represents phenyl substituted with 4 substituents. ), A pyrazolone derivative represented by the formula (1) has a function of normalizing brain function (Japanese Patent Publication No. 5-31523), a lipid peroxide production inhibitory action (Japanese Patent Publication No. 5-35128, Example 1).
Compound), an inhibitory effect on blood sugar elevation (Japanese Patent Application Laid-Open No. 3-21542)
No. 6), an inhibitory effect of lipid peroxide in the eye (Japanese Patent Laid-Open No. 7-
25765), retinal degeneration suppressing action (WO02 / 0)
No. 0260) is known.

However, in the examples described in Japanese Patent Application Laid-Open No. 7-25765, only the effect of the above-mentioned pyrazolone derivative is observed by causing damage to the entire eyeball by metachloroperoxybenzene. Therefore, it is not known whether the above-mentioned pyrazolone derivative is effective against retinal photodamage, and it is unclear whether it is acting on photoreceptor cells or other places. On the other hand, WO02 / 00
In the example described in Japanese Patent Publication No. 260, the intraocular perfusate is transcorneally administered into the anterior chamber to treat the intraocular pressure. As a result, a large load is applied to the vicinity of the inner layer of the retina (ganglion cell layer, inner plexiform layer), and it is shown that the above-mentioned pyrazolone derivative is effective for optic nerve disease. However, since the photoreceptor cells are located outside the retina (outer granular layer to outer segment), it is unclear whether the treatment of ocular hypertension also affects the photoreceptor cells located outside the retina. It is also unclear whether the pyrazolone derivative of is effective against retinal photodamage.

The compound of the above formula (I) is
It has been put on the market as a brain protectant (generic name "edaravone", trade name "Radicut": manufactured and sold by Mitsubishi Wel Pharma Co., Ltd.) since June 2012. This compound is a retina caused by retinal light damage and retinal light damage. -There have been no reports that it is useful for eye diseases and protection of photoreceptor cells.

[0008]

The object of the present invention is to prevent and / or treat retinal photodamage, prevent and / or treat retinal diseases and / or eye diseases caused by retinal photodamage, and protect photoreceptor cells. The purpose of the present invention is to provide a useful medicine.

[0009]

As a result of diligent efforts to solve the above problems, the present inventor has obtained a pyrazolone derivative, a hydrate thereof, which has hitherto been known to have a brain protecting action.
Or a pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient, for preventing and / or treating retinal photodamage, preventing and / or treating retinal disease and / or eye disease caused by retinal photodamage, Moreover, they have found that they are useful for protecting photoreceptor cells, and have completed the present invention.

That is, the gist of the present invention is as follows.

1. The following formula (I) (In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1
3 represents a hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, and R ³
Is a hydrogen atom, alkyl having 1 to 5 carbons, cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons,
Benzyl, naphthyl or phenyl, or carbon number 1
5 alkoxy, hydroxyalkyl having 1 to 3 carbon atoms,
Alkoxycarbonyl having 2 to 5 carbon atoms, 1 to 3 carbon atoms
Of the same or selected from the group consisting of alkylmercapto, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 different substituents. ) A preventive and / or therapeutic agent for retinal photodamage containing a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof as an active ingredient.

A preventive and / or therapeutic agent for retinal photodamage, which comprises 2.3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient.

3. The following formula (I) (In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1
3 represents a hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, and R ³
Is a hydrogen atom, alkyl having 1 to 5 carbons, cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons,
Benzyl, naphthyl or phenyl, or carbon number 1
5 alkoxy, hydroxyalkyl having 1 to 3 carbon atoms,
Alkoxycarbonyl having 2 to 5 carbon atoms, 1 to 3 carbon atoms
Of the same or selected from the group consisting of alkylmercapto, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 different substituents. ) A preventive and / or therapeutic agent for a retinal disease and / or an eye disease caused by retinal photodamage, which comprises a pyrazolone derivative represented by the formula 4) or a physiologically acceptable salt thereof as an active ingredient.

Prevention of retinal disease and / or eye disease caused by retinal photodamage containing 4.3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient Agents and / or therapeutic agents.

5. The following formula (I) (In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1
3 represents a hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, and R ³
Is a hydrogen atom, alkyl having 1 to 5 carbons, cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons,
Benzyl, naphthyl or phenyl, or carbon number 1
5 alkoxy, hydroxyalkyl having 1 to 3 carbon atoms,
Alkoxycarbonyl having 2 to 5 carbon atoms, 1 to 3 carbon atoms
Of the same or selected from the group consisting of alkylmercapto, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 different substituents. ) A photoreceptor protective agent containing a pyrazolone derivative represented by the formula (4) or a physiologically acceptable salt thereof as an active ingredient.

A photoreceptor protecting agent containing 6.3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient.

The pyrazolone derivative of the above formula (I) contained in a preventive and / or therapeutic agent for retinal photodamage and retinal disease and / or eye disease caused by retinal photodamage and a photoreceptor protecting agent is purposeful. It can be synthesized by any method, and an example of a preferable synthesis method is Japanese Patent Laid-Open No.
The method described in JP-A-2-108814 is mentioned.

The preventive agent for retinal light damage and / or retinal disease and / or eye disease caused by the retinal light damage of the present invention, and / or
Alternatively, the active ingredient of the therapeutic agent and the photoreceptor protecting agent may be a free form of the pyrazolone derivative of the formula (I), but any solvate thereof, or the pyrazolone derivative of the formula (I) or Physiologically acceptable salts of any solvates thereof can also be used.

The pyrazolone derivative is disclosed in Japanese Patent Publication No.
Although there are tautomers (the following formula (I ′) or (I ″)) as shown in the chemical structural formula in the upper column of column No. 31523, the active ingredient of the medicament of the present invention contains these tautomers. It goes without saying that all isomers of are included.

In the formula (I), the aryl group in the definition of R ¹ is a phenyl group or a methyl group,
Examples thereof include a butyl group, a methoxy group, a butoxy group, a phenyl group substituted with a substituent such as a chlorine atom and a hydroxyl group.

Carbon number 1 in the definition of R ¹ , R ² and R ³
As the alkyl group of ~ 5, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, se
Examples thereof include c-butyl group, tert-butyl group, pentyl group and the like.

Examples of the alkoxycarbonylalkyl group having 3 to 6 carbon atoms in the definition of R ¹ include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylpropyl group and the like. .

Examples of the aryloxy group in the definition of R ² include a phenoxy group, a p-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxy group and a p-hydroxyphenoxy group. Examples of the mercapto group include a phenylmercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorophenylmercapto group and a p-hydroxyphenylmercapto group.

The hydroxyalkyl group having 1 to 3 carbon atoms in the definition of R ² and R ³ is a hydroxymethyl group,
Examples thereof include 2-hydroxyethyl group and 3-hydroxypropyl group. Examples of the cycloalkyl group having 5 to 7 carbon atoms in the definition of R ³ include a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

In the definition of R ³ , examples of the alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and a pentyloxy group. Total carbon number 2
Examples of the alkoxycarbonyl group of ~ 5 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like, having 1 to 3 carbon atoms.
Examples of the alkylmercapto group include a methylmercapto group, an ethylmercapto group, a propylmercapto group, and the like, and an alkylamino group having 1 to 4 carbon atoms includes a methylamino group, an ethylamino group, a propylamino group, and a butylamino group. Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group, a diethylamino group, a dipropylamino group and a dibutylamino group.

Specific examples of the compound of the formula (I) used in the present invention include the compounds shown below.

3-Methyl-1-phenyl-2-pyrazolin-5-one, 3-methyl-1- (2-methylphenyl) -2-pyrazolin-5-one, 3-methyl-1-
(3-methylphenyl) -2-pyrazolin-5-one,
3-Methyl-1- (4-methylphenyl) -2-pyrazolin-5-one, 3-methyl-1- (3,4-dimethylphenyl) -2-pyrazolin-5-one, 1- (4-ethyl Phenyl) -3-methyl-2-pyrazolin-5-one, 3-methyl-1- (4-propylphenyl) -2-
Pyrazolin-5-one, 1- (4-butylphenyl)-
3-Methyl-2-pyrazolin-5-one, 1- (3-trifluoromethylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-trifluoromethylphenyl) -3-methyl- 2-pyrazolin-5-one, 1-
(2-Methoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (3-methoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-methoxyphenyl) -3 -Methyl-2-pyrazolin-5-one,
1- (3,4-dimethoxyphenyl) -3-methyl-2
-Pyrazolin-5-one, 1- (4-ethoxyphenyl) -3-methyl-2-pyrazolin-5-one, 3-methyl-1- (4-propoxyphenyl) -2-pyrazolin-5-one, 1 -(4-butoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (2-chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1
-(3-Chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1- (3,4-dichlorophenyl) -3 -Methyl-2-pyrazolin-5-one, 1- (4-bromophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-fluorophenyl)-
3-Methyl-2-pyrazolin-5-one, 1- (3-chloro-4-methylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (3-methylmercaptophenyl) -3-methyl -2-Pyrazolin-5-one, 1-
(4-methylmercaptophenyl) -3-methyl-2-
Pyrazolin-5-one, 4- (3-methyl-5-oxo-2-pyrazolin-1-yl) benzoic acid, 1- (4-ethoxycarbonylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-nitrophenyl) -3-methyl-2-pyrazolin-5-one, 3-ethyl-1-phenyl-2-pyrazolin-5-one, 1-phenyl-3
-Propyl-2-pyrazolin-5-one, 1,3-diphenyl-2-pyrazolin-5-one, 3-phenyl-1
-(P-tolyl) -2-pyrazolin-5-one, 1-
(4-Methoxyphenyl) -3-phenyl-2-pyrazolin-5-one, 1- (4-chlorophenyl) -3-phenyl-2-pyrazolin-5-one, 3,4-dimethyl-1-phenyl-2 -Pyrazolin-5-one, 4-isobutyl-3-methyl-1-phenyl-2-pyrazolin-
5-one, 4- (2-hydroxyethyl) -3-methyl-1-phenyl-2-pyrazolin-5-one, 3-methyl-4-phenoxy-1-phenyl-2-pyrazolin-
5-one, 3-methyl-4-phenylmercapto-1-
Phenyl-2-pyrazolin-5-one, 2,3a, 4
5,6,7-Hexahydro-2-phenylindazol-3-one, 3- (ethoxycarbonylmethyl) -1-
Phenyl-2-pyrazolin-5-one, 1-phenyl-
2-pyrazolin-5-one, 3-methyl-2-pyrazolin-5-one, 1,3-dimethyl-2-pyrazolin-5
-One, 1-ethyl-3-methyl-2-pyrazolin-5
-One, 1-butyl-3-methyl-2-pyrazolin-5
-One, 1- (2-hydroxyethyl) -3-methyl-2
-Pyrazolin-5-one, 1-cyclohexyl-3-methyl-2-pyrazolin-5-one, 1-benzyl-3-
Methyl-2-pyrazolin-5-one, 1- (α-naphthyl) -3-methyl-2-pyrazolin-5-one, 1-methyl-3-phenyl-2-pyrazolin-5-one, 3-
Methyl-1- (4-methylphenyl) -2-pyrazolin-5-one, 1- (4-butylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-methoxyphenyl) -3 -Methyl-2-pyrazolin-5-one, 1-
(4-Butoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-hydroxyphenyl) -3- Methyl-2-pyrazolin-5-one,
1- (3,4-dihydroxyphenyl) -3-methyl-
2-pyrazolin-5-one, 1- (2-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one, 1-
(3-Hydroxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-hydroxyphenyl) -3
-Methyl-2-pyrazolin-5-one, 1- (3,4-
Hydroxyphenyl) -3-methyl-2-pyrazoline-
5-one, 1- (4-hydroxyphenyl) -3-phenyl-2-pyrazolin-5-one, 1- (4-hydroxymethylphenyl) -3-methyl-2-pyrazolin-5
-One, 1- (4-aminophenyl) -3-methyl-2
-Pyrazolin-5-one, 1- (4-methylaminophenyl) -3-methyl-2-pyrazolin-5-one, 1-
(4-Ethylaminophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-butylaminophenyl)
-3-Methyl-2-pyrazolin-5-one, 1- (4-
Dimethylaminophenyl) -3-methyl-2-pyrazolin-5-one, 1- (acetamidophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-cyanophenyl) -3-methyl-2 -Pyrazolin-5-one

As the salt of the pyrazolone derivative of the formula (I), an acid addition salt or a base addition salt can be used. For example, mineral salts such as hydrochloride, sulfate, hydrobromide, or phosphate; methanesulfonate, paratoluenesulfonate, acetate, oxalate, citrate,
Organic acid salts such as malate or fumarate; metal salts such as sodium salt, potassium salt or magnesium salt; ammonium salt; or organic such as ethanolamine or 2-amino-2-methyl-1-propanol An amine salt or the like can be used, but the type of salt is not particularly limited as long as it is physiologically acceptable.

The preventive and / or therapeutic agent for retinal light damage, the preventive and / or therapeutic agent for retinal disease and / or eye disease caused by retinal light damage and the active ingredient of photoreceptor protective agent of the present invention One or more of the compound of formula (I) or a salt thereof may be directly administered to a patient, but preferably, the active ingredient and pharmacologically and pharmaceutically acceptable additives are added to It should be provided as a formulation in a form well known to those skilled in the art.

The pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents,
Bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives and the like can be used. Examples of formulations suitable for oral administration include, for example:
Tablets, capsules, powders, fine granules, granules, liquids, syrups and the like can be mentioned. Examples of suitable formulations for parenteral administration include injections, drops, eye drops or suppositories. Can be mentioned.

For the preparation suitable for oral administration, as an additive, for example, an excipient such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; a disintegrating agent such as carboxymethyl cellulose, starch, or carboxymethyl cellulose calcium, or Disintegration aids; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; hydroxypropylmethylcellulose, sucrose,
A coating agent such as polyethylene glycol or titanium oxide; a base such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used.

Formulations suitable for injection or drip include solubilizers or solubilizers that can constitute aqueous or injectable solutions such as distilled water for injection, physiological saline, and propylene glycol; glucose, sodium chloride, Tonicity agents such as D-mannitol and glycerin; pharmaceutical additives such as pH adjusting agents such as inorganic acids, organic acids, inorganic bases or organic bases can be used.

As a formulation suitable for eye drops, an aqueous solvent such as sterilized purified water or physiological saline or a non-aqueous solvent such as cotton oil, soybean oil, sesame oil, peanut oil or the like is used. It can be obtained by dissolving or suspending the compound of 1) or a salt thereof. At this time, an isotonicity agent, a pH adjusting agent, a viscosity adjusting agent, a suspending agent, an emulsifying agent, a preservative and the like may be appropriately added as necessary. As the isotonicity agent, sodium chloride, boric acid, sodium nitrate, potassium nitrate, D-mannitol, glucose or the like can be used, and as the pH adjusting agent, boric acid, anhydrous sodium sulfite, hydrochloric acid, citric acid, sodium citrate, Acetic acid, potassium acetate, sodium carbonate, borax, or the like can be used, and as the viscous agent, methyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, polyvinyl pyrrolidone, or the like can be used. Polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxy castor oil or the like can be used as a suspending agent, and egg yolk lecithin as an emulsifier,
Polysorbate 80 or the like can be used, and as a preservative, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, paraoxybenzoic acid esters, or the like can be used.

A brain protector (drip solution) containing the compound of the above formula (I) as an active ingredient has already been used clinically (generic name "edaravone", trade name "Radicut": Mitsubishi Wel Pharma Manufacturing and sales)
As the preventive / therapeutic agent for radiation damage of the present invention, the above-mentioned commercially available preparation can be used as it is.

The medicament of the present invention acts as a preventive agent for preventing retinal photodamage, as a therapeutic agent for restoring retinal photodamage to a normal state, and for retinal diseases and / or eye diseases caused by retinal photodamage. Action as a preventive agent for preventing, action as a therapeutic agent for restoring a retinal disease and / or eye disease caused by retinal photodamage to a normal state, and a substance capable of damaging photoreceptor cells (for example, iron, light ( It has the effect of protecting photoreceptor cells from (ultraviolet rays) oxygen and radiation.
In the present specification, various diseases caused by retinal photodamage refer to various diseases caused by light-induced retinal damage. This term should be interpreted in its broadest sense as long as it is consistent with the above definition, and should not be construed in the context of different disease names. Examples of the disease caused by retinal photodamage include age-related macular degeneration. Whether or not the disease corresponds to various diseases caused by retinal light damage can be easily diagnosed by a skilled doctor.

The route of administration of the medicament of the present invention is not particularly limited, and it can be administered orally or parenterally. The dose of the drug of the present invention can be appropriately selected according to conditions such as prevention and / or treatment of various diseases caused by disorders of retinal pigment epithelial cells, protection of retinal pigment epithelial cells, and patient's age and condition. However, in general, about 0.1 to 100 mg / kg is administered to an adult by injection or drip, about 0.1 to 100 mg / kg is orally administered, or 1 to 20 mg / kg. 1-2 drops of ml, 1
It is preferable to instill it once to several times a day. When administered by injection, it is preferable to use, for example, the injections described in JP-A-63-132833. The above-mentioned compound, which is an active ingredient of the medicament of the present invention, is highly safe (intraperitoneally administered mouse LD ₅₀ 2012 mg / k
g; Rat oral administration LD ₅₀ 3,500 mg / kg:
Registry of Toxic Effects
of Chemical Substances, 1
981-1982), which has also been proved non-carcinogenic (National Cancer Institute).
te Report, 89, 1978).

[0037]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Synthesis example: 1-phenyl-3-methyl-2-
Synthesis of pyrazolin-5-one 13.0 g of ethyl acetoacetate and 10.8 g of phenylhydrazine were added to 50 ml of ethanol, and the mixture was stirred under reflux for 3 hours. After allowing the reaction solution to cool, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 11.3 g of the title compound as colorless crystals. Yield 67% Melting point 127.5-128.5 ° C

Example 1 Effect on Retinal Light Damage 10-week-old Wistar rats were bred for 12 hours while being irradiated with light under a fluorescent lamp of 3200 lux. For the compound administered with the compound of the present invention, 36 hours before the start of light irradiation, 12 hours, and 3 times immediately after the light irradiation, commercially available radicut (trade name, 1-phenyl-3-methyl-2-pyrazolin-5-one The contained formulation) was intravenously administered at a dose of 0.6 mg. The control group was bred under the same conditions as those of the compound-administered group of the present invention, without any administration. The evaluation was performed by removing the eyeballs and measuring the thickness of the photoreceptor layer 24 hours and 48 hours after the end of light irradiation. The results are shown in Fig. 1. At 24 hours after the end of light irradiation, no significant difference was observed in the thickness of the photoreceptor layer, even when the radical cut administration group was compared with the control group (Fig. 1, left graph). But,
After 48 hours, the photoreceptor layer of the control group was clearly thinner than that of the compound administered with the compound of the present invention (Fig. 1, right graph). Also, after the light irradiation is completed, 48
Looking at the tissue sample (Fig. 2) after the lapse of time, in the Radicut administration group (Fig. 2, right picture), it is seen as the outer granular layer which is the third layer from the top and the fourth layer from the top. The photoreceptor cell layer is cleanly separated (outer granular layer: a layer located approximately 1.0 to 1.8 cm from the upper end. Photoreceptor layer:
A layer that is located approximately 1.8 to 2.1 cm from the top, with almost no image in the layer. ). On the other hand, in the control group, the boundary between the photoreceptor layer and the outer granular layer was partly unclear, and it was found that the photoreceptor layer was damaged.

From these results, it was revealed that the compound of the present invention reduces light-induced retinal disorders, particularly photoreceptor cell disorders.

[0041]

The compound of the present invention, 1-phenyl-3-
Since methyl-2-pyrazolin-5-one was shown to be effective in a model experiment of light-induced retinal damage, the drug of the present invention is effective in preventing retinal light damage and retinal diseases and / or eye diseases caused by retinal light damage. It is useful as an agent and / or a therapeutic agent. And when looking at the specimen of the damaged retina, 1-phenyl-3-methyl-2-pyrazolin-5-one exerts its effect particularly on photoreceptor cells in the retina, and thus is useful as a photoreceptor protecting agent. is there.

[Brief description of drawings]

FIG. 1 is a diagram showing the thickness of a photoreceptor layer when light causes a retinal disorder.

FIG. 2 is a diagram (micrograph) showing a tissue sample of the retina 48 hours after the end of light irradiation.

Claims (6)

[Claims] 1. The following formula (I) (In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1
3 represents a hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, and R ³
Is a hydrogen atom, alkyl having 1 to 5 carbons, cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons,
Benzyl, naphthyl or phenyl, or carbon number 1
5 alkoxy, hydroxyalkyl having 1 to 3 carbon atoms,
Alkoxycarbonyl having 2 to 5 carbon atoms, 1 to 3 carbon atoms
Of the same or selected from the group consisting of alkylmercapto, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 different substituents. ) A preventive and / or therapeutic agent for retinal photodamage containing a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof as an active ingredient. 2. A preventive and / or therapeutic agent for retinal photodamage comprising 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient. 3. The following formula (I) (In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1
3 represents a hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, and R ³
Is a hydrogen atom, alkyl having 1 to 5 carbons, cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons,
Benzyl, naphthyl or phenyl, or carbon number 1
5 alkoxy, hydroxyalkyl having 1 to 3 carbon atoms,
Alkoxycarbonyl having 2 to 5 carbon atoms, 1 to 3 carbon atoms
Of the same or selected from the group consisting of alkylmercapto, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 different substituents. ) A preventive and / or therapeutic agent for a retinal disease and / or an eye disease caused by retinal photodamage, which comprises a pyrazolone derivative represented by the formula 4) or a physiologically acceptable salt thereof as an active ingredient. 4. Prevention of retinal disease and / or eye disease caused by retinal photodamage containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient. Agents and / or therapeutic agents. 5. The following formula (I) (In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1
3 represents a hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, and R ³
Is a hydrogen atom, alkyl having 1 to 5 carbons, cycloalkyl having 5 to 7 carbons, hydroxyalkyl having 1 to 3 carbons,
Benzyl, naphthyl or phenyl, or carbon number 1
5 alkoxy, hydroxyalkyl having 1 to 3 carbon atoms,
Alkoxycarbonyl having 2 to 5 carbon atoms, 1 to 3 carbon atoms
Of the same or selected from the group consisting of alkylmercapto, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 different substituents. ) A photoreceptor protective agent containing a pyrazolone derivative represented by the formula (4) or a physiologically acceptable salt thereof as an active ingredient. 6. A photoreceptor protecting agent containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient.