JP3066561B2 - Myopia prevention / treatment agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for preventing or treating myopia.

[0002]

2. Description of the Related Art Myopia is a phenomenon in which parallel rays coming from a distant place form an image in front of a retina at the fundus.

However, generally speaking, myopia is
There are two types: First, there is what is called axial myopia. This is caused by the fact that the lens has a normal refractive power but the depth to the fundus (ocular axis) is too long. This axial myopia usually starts from the time of an infant, gradually extends the axis of the eye, and causes abnormalities in the fundus. That is, the retina and choroid may atrophy, the pigments may abnormally increase and decrease, the vitreous body may become turbid, and the retina may bleed, eventually detach and even become blind.

[0004] Next, there is what is called refractive myopia.
This is because despite the normal eye axis, the curvature of the cornea is abnormal, or the thickness of the crystalline lens is increased by acquired work (close work) such as reading, VDT (buddy tea) work, It occurs because the cornea or lens has too strong a refractive power. In addition, there is what is called pseudomyopia (pseudomyopia), which refers to a state in which the tension of the ciliary muscles is increased and not yet fixed. Although the lens is thickened, the refractive value (refractive index) changes by 1 D (diopter) or more toward the hyperopic side after instillation of the paralytic agent.

However, these two types of myopia, axial myopia and refractive myopia, cannot be clearly distinguished,
It is generally said that these two types of myopia are mixed. At present, the cause of myopia is still unknown, but it is a well-known fact that continuing myopia is one of the causes of myopia. That is, since it is necessary to adjust the lens thickly in the near work, the ciliary muscles are tense (contracted). If this condition persists for a long time, the ciliary muscles will not return to their original state, and there will be substrate changes in the ciliary muscles, causing refractive myopia, and further weakening of the posterior ocular membrane, extending the axis of the eye. It is said that axial myopia may occur.

Accordingly, it is said that myopia can be cured by improving the tension of the ciliary muscle. Therefore, as a method of improving the tension of the ciliary muscle,
Attempts have been made to locally administer a drug such as tropicamide (for example, Midrin M (registered trademark)) (instillation), but the effect varies depending on the human and cannot be said to be sufficient. In addition, low-frequency, ultrasound treatment, telephoto training, and the like are performed as physical therapy, but none of them has a satisfactory effect.

The compound which is an active ingredient of the agent for preventing or treating myopia of the present invention is described in, for example, JP-A-61-10587.
It describes that it is a drug that has both SRS-A production inhibitory action and SRS-A antagonistic action and also suppresses histamine release due to IgE-related allergy, and has a strong antiallergic action and anti-inflammatory action. However, it has not been described at all that these compounds have an excellent ciliary muscle relaxing action, and the present inventors have found for the first time.

[0008]

As described above, at present, there are no satisfactory methods for preventing or treating myopia and agents for preventing or treating myopia. Therefore, development of an excellent myopia prevention / treatment method and myopia prevention / treatment agent is strongly desired by both patients and physicians.

[0009]

In view of such circumstances, the present inventors have searched for various compounds in search of a drug having an excellent preventive / therapeutic effect for myopia. As a result, the present inventors have found that the compound of the present invention is unexpectedly different from a conventionally used drug containing tropicamide as an active ingredient.
Shows the action of relaxing the ciliary muscle that controls the lens,
It has been found for the first time that an excellent preventive / therapeutic effect for myopia is exhibited by returning the refractive power of myopia to the emmetropia by this action, and the present invention has been completed.

That is, the present invention relates to (1)

Embedded image Wherein ring A may be substituted, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton; or a salt thereof. (2) Ring A forms a benzene ring with a halogen atom, a nitro group, an alkyl group, an alkoxy group, or two adjacent carbon atoms at positions 6, 7, 8, and 9 Butadienylene group (-CH = CH-CH =
(3) The agent for preventing or treating myopia according to item 1, which may be substituted with CH-), (3) the agent for preventing or treating myopia according to item 1, wherein the group capable of releasing a proton is a carboxyl group or a tetrazolyl group, 4) The compound has the general formula

Embedded image Wherein R is an alkyl group, R ₁ is hydrogen or an amino group which may be protected, and R ₂ is a group capable of releasing a proton. Agent,
(5) The agent for preventing or treating myopia according to item 4, wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms, (6) the agent for preventing or treating myopia according to item 4, wherein the alkyl group is isopropyl.
(7) The agent for preventing or treating myopia according to the above (1) or (4), wherein R ₁ is an amino group, and (8) the first agent wherein R ₂ is a carboxyl group.
Or the agent for preventing or treating myopia according to item 4, wherein the compound (9) has the formula

Embedded image 2. The prophylactic / therapeutic agent for myopia according to item 1, wherein the agent is for local ocular administration,
1) The agent for preventing or treating myopia according to item 10, which is an eye drop,
(12) The prophylactic / therapeutic agent for myopia according to (11), which is an aqueous ophthalmic solution;
(14) The agent for preventing or treating myopia according to (13), wherein the solubilizing agent is polyvinylpyrrolidone.

In the general formula [I], the substituent on the ring A is, for example, a halogen atom, a nitro group, an alkyl group, an alkoxy group, or two adjacent carbon atoms at positions 6, 7, 8, 9 and benzene. Butadienylene group forming a ring (-
CH = CH-CH = CH-). Here, examples of the halogen atom include chlorine, bromine, fluorine and the like. The alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like. The alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. The alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms. Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. One or more substituents on the ring A may be the same or different and may be substituted on any position of the ring A.

In the general formulas [I] and [II], examples of the protecting group in the optionally protected amino group represented by R ₁ include (1) (a) a halogen atom (eg, chlorine, bromine, Fluorine, etc.), (b) an alkanoyl group having 1 to 7 carbon atoms (eg,
Formyl, acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, pivaloyl, n-hexanoyl, etc.) and (c)
An alkanoyl group having 2 to 7 carbon atoms which may have 1 to 3 substituents selected from nitro group and the like (eg, acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, Pivaloyl, n-hexanoyl, etc.), (2) above (a), (b) and
(c) an arylcarbonyl group having 7 to 11 carbon atoms optionally having 1 to 3 substituents selected from (c) and the like (eg, benzoyl, p-toluoyl, 1-naphthoyl,
2-naphthoyl, etc.), (3) an alkoxycarbonyl group having 2 to 7 carbon atoms which may have 1 to 3 substituents selected from the above (a), (b) and (c) (eg, Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.), (4) 1 selected from the above (a), (b) and (c)
Or an aryloxycarbonyl group having 7 to 11 carbon atoms which may have 3 to 3 substituents (eg, phenoxycarbonyl and the like), (5) selected from the above (a), (b) and (c) An aralkylcarbonyl group having 8 to 13 carbon atoms which may have 1 to 3 substituents (eg, benzylcarbonyl, phenethylcarbonyl, etc.), (6) the above (a), (b) and (c), etc. Aralkyloxycarbonyl groups having 8 to 13 carbon atoms which may have 1 to 3 substituents selected from (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), (7) the above (a), (b) ) And (c) a phthaloyl group optionally having 1 to 3 substituents selected from (8) one to three phthaloyl groups selected from (a), (b) and (c) and the like 6 to 10 carbon atoms which may have a substituent
(E.g., phenylsulfonyl, tosyl, etc.), (9) having 1 to 3 carbon atoms which may have 1 to 3 substituents selected from the above (a), (b) and (c) Or 6
Alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, etc.), (10)
1 to 3 selected from (a), (b), (c) and amino group
Alkyl groups having 1 to 6 carbon atoms which may have one or more substituents (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), (11) above
an aralkyl group having 7 to 19 carbon atoms which may have 1 to 3 substituents selected from (a), (b) and (c) (eg, benzyl, phenethyl, benzhydryl, trityl, etc.); Is mentioned.

The protecting group in the amino group is preferably 1 to 3 selected from the group consisting of (a) a halogen atom, (b) an alkanoyl group having 1 to 7 carbon atoms and (c) a nitro group.
Alkanoyl group having 2 to 7 carbon atoms, arylcarbonyl group having 7 to 11 carbon atoms, alkoxycarbonyl group having 2 to 7 carbon atoms, aryloxy having 7 to 11 carbon atoms, each of which may have A carbonyl group, an aralkylcarbonyl group having 8 to 13 carbon atoms, an aralkyloxycarbonyl group having 8 to 13 carbon atoms, and the like.

In the general formulas [I] and [II], the group capable of releasing a proton represented by R ₂ is, for example, a carboxyl group, a tetrazolyl group, a trifluoromethanesulfonylamino group (—NHSO ₂ CF ₃₎ ), A phosphono group, a sulfo group, etc., which can easily anionize by releasing H ⁺ , and these groups are an alkyl group optionally substituted by a suitable substituent (eg, methyl, n-butyl) Etc. carbon number 1
Or an optionally substituted acyl group (eg, an alkanoyl group having 2 to 4 carbon atoms such as acetyl, propionyl, etc., optionally substituted with a halogen atom, etc.), a halogen atom, amino, etc. May be protected under biological or physiological conditions (eg, in vivo reactions such as oxidation / reduction or hydrolysis by in vivo enzymes).
Or a group capable of chemically releasing a proton or a group capable of changing the proton. The group capable of releasing a proton is preferably a carboxyl group, a tetrazolyl group, or the like.

In the general formula [II], the alkyl group represented by R is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n
-Hexyl and the like. R is more preferably a straight-chain or branched alkyl group having 1 to 3 carbon atoms. R is particularly preferably an isopropyl group.

The compound represented by the formula [I] is preferably a compound represented by the formula [II], particularly preferably a compound represented by the formula [III].

The compound represented by the general formula [I] is, for example,

Embedded image It is produced by reacting a compound represented by the formula [wherein the symbols have the same significance as described above] with an active methylene compound or an acetylene carboxylic acid derivative, followed by hydrolysis. Examples of the active methylene compound include methyl acetoacetate, ethyl acetoacetate, methyl cyanate, ethyl cyanate, cyanoacetamide, malononitrile,
Oxaloacetic acid ethyl ester, malonic acid diethyl ester, malonic acid dimethyl ester, ethyl benzoyl acetate, methyl 3-oxo-n-caproate, and the like. The amount of these active methylene compounds to be used is generally 1 to 1 mol per mol of the starting compound [IV] or a salt thereof.
It is about 10 times mol. Examples of the acetylenecarboxylic acid derivative include acetylenedicarboxylic acid dimethyl ester, acetylenedicarboxylic acid diethyl ester, methyl propiolate, and ethyl propiolate. When a propiolic acid ester is used, the intermediate amino acrylate derivative can be isolated, but the ring closure reaction can be carried out without isolation. The amount of these acetylene carboxylic acid derivatives to be used is generally 1 to 10 in practice based on 1 mol of the starting compound [IV] or a salt thereof.
It is about twice the mole.

In general, the reaction is preferably carried out in the presence of a base. As the base used, organic amines such as primary amines such as n-butylamine, benzylamine and aniline, diethylamine, dipropylamine, dibutylamine, piperidine and pyrrolidine can be used. , A secondary amine such as morpholine, 1,8-diazabicyclo [5,4,0] -7-
Examples include tertiary amines such as undecene and triethylamine, and heterocyclic bases such as imidazole and 2-methylimidazole. The amount of these organic bases to be used is usually from a catalytic amount to 1 mole of the starting compound [IV] or a salt thereof.
It is about 5 times mol. In general, the reaction is preferably carried out in an organic solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons such as benzene and toluene, and dimethylformamide. The other reaction conditions such as the reaction temperature and the reaction time are not particularly limited, but the reaction is generally carried out at a temperature from room temperature to around the boiling point of the solvent used for about 1 to 24 hours. In the present production process, a protection reaction of the amino group of cyanoacetamide, which is an active methylene compound, may be performed, if desired. The protection reaction can be performed according to a conventional method in this technical field. As a condition for the hydrolysis, a usual acidic hydrolysis method is used. For example, sulfuric acid, hydrochloric acid, phosphoric acid or the like is used in excess, and the acid alone or together with an organic solvent such as organic acids such as formic acid and acetic acid or alcohols such as methanol, ethanol, propanol and butanol is usually used in an amount of 50 to 1
It is performed by heating at around 50 ° C. The reaction time varies depending on the compound, but is usually about 1 hour to several days.

Compound [I] can also be used as a pharmacologically acceptable salt. Examples of such salts include salts with bases such as inorganic bases and organic bases, and acid addition salts such as inorganic acids, organic acids, basic or acidic amino acids. Examples of the inorganic base include alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; and aluminum and ammonium. Examples of the organic base include primary amines such as ethanolamine, diethylamine, diethanolamine, dicyclohexylamine, N, N'-
Secondary amines such as dibenzylethylenediamine; and tertiary amines such as trimethylamine, triethylamine, pyridine, picoline and triethanolamine. As the inorganic acid, for example, hydrochloric acid, hydrobromic acid,
Nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of the organic acid include 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, and the like. Can be Examples of the basic amino acid include arginine, lysine, and ornithine. Examples of acidic amino acids include aspartic acid and glutamic acid. Salts of compound [I] are described, for example, in JP-A-61-10587, JP-A-61-10588 and JP-A-54-48.
798, JP-A-54-88298, and the like, or a method analogous thereto.

The compound [I] or a salt thereof has an excellent ciliary muscle relaxing action as apparent from the test examples described later, and thus can be used as an agent for preventing or treating myopia.

The prophylactic / therapeutic agent for myopia of the present invention has low toxicity and can be used in mammals (eg, humans, rabbits, dogs, cats, cows,
To horses, monkeys, etc.) orally or parenterally.

The agent for preventing or treating myopia of the present invention can be produced, for example, by mixing the compound [I] or a salt thereof with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials. In solid preparations, excipients, lubricants, binders, disintegrants, etc. are used. A solubilizing agent, a suspending agent, a thickening agent, a tonicity agent, a buffering agent, a soothing agent and the like are appropriately compounded. If necessary, preparation additives such as preservatives, chelating agents, antioxidants, coloring agents, sweeteners, flavoring agents, and fragrances may be used in accordance with a conventional method. Suitable examples of excipients include, for example, lactose,
Examples include sucrose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, sucrose, mannitol,
Maltitol, starch, gelatin, gum arabic, gum tragacanth, crystalline cellulose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate, chitin, chitosan and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, chitin, chitosan and the like.

Preferred examples of the solvent include water for injection, alcohols (eg, ethanol, propylene glycol, macrogol, glycerin, etc.), oils and fats (eg, olive oil, sesame oil, peanut oil, cottonseed oil, castor oil,
Corn oil). Preferred examples of the dissolution aid include, for example, polyvinylpyrrolidone, cyclodextrin, caffeine, polyethylene glycol, propylene glycol, mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate And the like. Preferable examples of the suspending agent include, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glyceryl monostearate, and polysorbate 80.
Surfactants such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose,
Hydrophilic polymers such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, gelatin, and albumin are exemplified. Preferable examples of the thickener include egg yolk lecithin, gelatin, gum arabic, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium polyacrylate, sodium alginate, pectin and the like. . Preferable examples of the tonicity agent include sorbitol, glycerin, polyethylene glycol, propylene glycol, glucose, sodium chloride and the like. Preferred examples of the buffer include, for example, a phosphate buffer,
Examples include borate buffer, citrate buffer, tartrate buffer, acetate buffer and the like. Preferred examples of the soothing agent include benzyl alcohol and the like.

Preferred examples of the preservative include, for example, paraoxybenzoic acid esters, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid or a salt thereof, and parachloromethaxinol Chlorcresol, thimerosal and the like. Preferable examples of the chelating agent include sodium edetate, sodium citrate, condensed sodium phosphate and the like. Preferred examples of the antioxidant include, for example, sulfite, ascorbic acid, α-tocopherol, cysteine and the like. Preferable examples of the coloring agent include, for example, tar dye, licorice extract, riboflavin, zinc oxide and the like. Suitable examples of the sweetener include, for example, glucose, sucrose, fructose, honey, saccharin, licorice and the like. Suitable examples of the flavoring agent include, for example, vanillin, menthol, rose oil and the like. Preferable examples of the fragrance include fennel oil, borneol, menthol and the like. In addition to the above, pharmaceutically acceptable carriers include, for example, agar, casein, collagen and the like.

Further, other myopic prophylactic / therapeutic agents (eg, neostigmine methyl sulfate, tropicamide or the like containing these as an active ingredient), components having other medicinal effects, and the like may be appropriately added to the preparation. .

When the agent for preventing or treating myopia of the present invention is used in the form of an aqueous solution, the pH is preferably 4 to 9 in consideration of the stability of compound [I] or a salt thereof.

Preparations for oral administration include, for example, powders,
Examples include solid preparations such as granules, tablets and capsules, and liquid preparations such as emulsions, syrups and suspensions. For example, a tablet is produced by appropriately adding the above-mentioned excipient, disintegrant, binder or lubricant to compound [I] or a salt thereof, and compression-molding. At this time, if desired, following the compression molding, the above-mentioned sweetener, flavoring agent, fragrance and the like may be further added, or coating may be performed by a method known per se for enteric or sustained purposes. Is also good. As a coating agent used for coating, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate,
Hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, ethylcellulose and the like are used. A suspending agent can be produced, for example, by suspending compound [I] or a salt thereof in the above-mentioned solvent. At this time, if necessary, the above-mentioned suspending agent or the like may be appropriately used.

Examples of preparations for parenteral administration include injections and preparations for topical ocular administration. Injections
It includes subcutaneous injections, intravenous injections, intramuscular injections, and the like. The injection may be an aqueous or non-aqueous injection, and may be a solution or a suspension. Examples of the preparation for topical administration to the eye include eye drops, eye ointments, gels, and the like, and particularly preferable are eye drops. The eye drop may be an aqueous or non-aqueous eye drop, and may be a solution or a suspension. The agent for preventing or treating myopia of the present invention is preferably used as a preparation for topical administration to the eye, and is more preferably used as an eye drop, particularly an aqueous eye drop.

The injection may be prepared as an aqueous injection by dissolving the compound [I] or a salt thereof together with the above-mentioned preservative, isotonic agent and the like in water for injection, or propylene glycol, olive oil, sesame oil, cottonseed oil and the like. Can be produced as an oily injection by dissolving or suspending in water.

Aqueous eye drops can be produced, for example, by heating purified water, dissolving a preservative, adding a solubilizing agent, and then adding compound [I] or a salt thereof to completely dissolve. . At this time, if necessary, a buffer,
Tonicity agents, chelating agents, thickeners and the like may be used. The solubilizer is preferably polyvinylpyrrolidone, cyclodextrin, caffeine, or the like, and particularly preferably polyvinylpyrrolidone. When polyvinylpyrrolidone is used, the solubility of the compound [I] or a salt thereof is remarkably improved, and the stability of the compound [I] or a salt thereof is particularly increased. (See JP-A-62-123116 (Japanese Patent Publication No. 4-78614)) For example, polyvinylpyrrolidone has an average molecular weight of about 25,000 to about 1
20,000, preferably about 40,000 are used. The amount of polyvinylpyrrolidone added is usually 0.1.
2 to 20 (W / V)%, preferably 0.5 to 1
5 (W / V)%, particularly preferably 1 to 10 (W / V)
V)%.

The buffer is particularly preferably a borate buffer. When a borate buffer is used as a buffer, a liquid with lower irritation can be obtained as compared with the case where another buffer, for example, a phosphate buffer is used. At this time, the added amount of boric acid is 0.2 to 4 (W / V)%, preferably 0.5 to 4 (W / V).
To 2 (W / V)%.

The aqueous suspension ophthalmic solution can be produced by appropriately selecting and using the above-mentioned suspending agents in addition to the additives used in the above aqueous ophthalmic solution. The pH of the above-mentioned aqueous eye drops and aqueous suspension eye drops is preferably from 4 to 9, particularly preferably from 5 to 8.

The non-aqueous eye drops are prepared by converting compound [I] or a salt thereof into a water-soluble solvent such as alcohols (eg, ethanol, propylene glycol, macrogol, propylene glycol, glycerin, etc.) or fats and oils (eg, olive oil, sesame oil). , Peanut oil, cottonseed oil, castor oil, corn oil, etc.).

The ophthalmic ointment can be produced, for example, by appropriately selecting and using vaseline, plastibase, liquid paraffin and the like as a base.

The ophthalmic gel can be produced, for example, by appropriately selecting and using a carboxyvinyl polymer, an ethylene maleic anhydride polymer, a polyoxyethylene-polyoxypropylene block copolymer, a gellan gum or the like as a base.

The dose of the agent for preventing or treating myopia of the present invention varies depending on the route of administration, symptoms, age and weight of the patient, etc., but usually the dose of compound [I] or a salt thereof is as follows.
About 0.01 to 500 mg / day is used per adult. The prophylactic / therapeutic agent for myopia of the present invention comprises, for example, in one adult myopic patient, 0.05 to 2 (W / V) of compound [I] or a salt thereof as an active ingredient per eye.
%, Preferably about 0.1 to 1 (W / V)%, depending on symptoms, administration of 1 to several drops per dose one to several times a day, preferably about 2 to 5 times. It is desirable to do.

Hereinafter, the present invention will be described in more detail with reference to Examples, and the effects of the present invention will be clarified by Test Examples. However, these are merely examples, and the scope of the present invention is limited by these. Not something.

[0038]

【Example】

 Example 1 Aqueous Eye Drops (Formulation Formulation) Compound [III] 5 g Boric acid 16 g Borax 10 g Polyvinylpyrrolidone (average molecular weight 40,000) 20 g Caffeine 2 g Polyethylene glycol (average molecular weight 4000) 5 g Methyl paraoxybenzoate 0.26 g Paraoxybenzoic acid Propyl 0.14g Add sterile purified water and add 1000ml (pH 6.0)

(Preparation method) After heating 800 ml of sterilized purified water to dissolve methyl paraoxybenzoate and propyl paraoxybenzoate, boric acid, borax, polyvinylpyrrolidone (average molecular weight 40,000), caffeine,
Polyethylene glycol and compound [III] were sequentially added and dissolved. After cooling, add sterile purified water to this and add a total of 1
000 ml, sterilized by filtration through a 0.22 μm membrane filter, and filled in a predetermined container to produce an aqueous eye drop.

Example 2 Aqueous Eye Drops (Formulation Formulation) Compound [III] 2.5 g Boric acid 16 g Borax 7 g Polyvinylpyrrolidone (average molecular weight 4000) 20 g Methyl parahydroxybenzoate 0.26 g Propyl paraoxybenzoate 0.14 g Sterilization and purification Add water to 1000ml in total (pH 7.5)

(Preparation method) 800 ml of sterilized purified water was heated to dissolve methyl paraoxybenzoate and propyl paraoxybenzoate by heating, and cooled to room temperature. To this solution, boric acid, borax and polyvinylpyrrolidone were added to dissolve, and then the compound [III] was sequentially added to this solution to dissolve. Add sterile purified water to this and add 1000m
After the solution was sterilized and filtered through a 0.22 μm membrane filter, the solution was filled in a predetermined container to produce an aqueous eye drop.

Example 3 Aqueous Suspension Eye Drops (Formulation Formulation) Compound [III] 10 g Sodium dihydrogen phosphate 50 g Sodium chloride 9 g Polysorbate 80 20 g Chlorobutanol 3 g Sodium hydroxide Appropriate amount .0)

(Preparation method) 800 ml of sterile purified water was heated to dissolve chlorobutanol, and then sodium dihydrogen phosphate, sodium chloride and polysorbate 80 were sequentially added and dissolved, followed by cooling to room temperature. The obtained solution was adjusted to pH 5.0 with sodium hydroxide, and sterilized purified water was added thereto to make the total volume 1000 ml. The solution was sterilized by filtration through a 0.22 μm membrane filter. An aqueous suspension of eye drops was prepared by uniformly dispersing the previously sterilized compound [III].

Example 4 Oily Eye Drops (Formulation Formulation) Compound [III] 20 g Cotton seed oil was added, and the total amount was 1000 ml.

(Preparation Method) Compound [III] was added to previously sterilized cottonseed oil to produce an oily eye drop.

Example 5 Ophthalmic ointment (formulation formulation) Compound [III] 10 g Liquid paraffin 100 g White petrolatum was added and the total amount was 1000 g

(Preparation method) Liquid paraffin and white petrolatum were heat-sterilized in advance. Next, the compound [III] was sufficiently slurried with liquid paraffin, and then sufficiently kneaded with white petrolatum to produce an eye ointment.

Example 6 Gel (combination formulation) Compound [III] 5 g Carboxyvinyl polymer 10 g Phenethyl alcohol 5 g Sodium hydroxide Appropriate amount Sterilized purified water was added, and the total amount was 1000 g (pH 7.0).

(Preparation method) After phenethyl alcohol was dissolved in 800 ml of sterilized purified water, the solution was sterilized by filtration through a 0.22 μm membrane filter. After pre-sterilized compound [III] was suspended in this liquid, sterilized carboxyvinyl polymer was added and dissolved with vigorous stirring. After adjusting the pH of the obtained solution to 7.0 with sodium hydroxide, sterilized purified water was added to make the total amount 1000 g, and a gel was produced.

Example 7 Tablets (Formulation) Compound [III] 10 mg Lactose 35 mg Corn starch 150 mg Microcrystalline cellulose 30 mg Magnesium stearate 5 mg One tablet 230 mg

(Preparation method) Compound [III], lactose,
Corn starch, 2/3 amount of microcrystalline cellulose and 1
The mixture was granulated after admixing with 1/2 amount of magnesium stearate. The remaining microcrystalline cellulose and magnesium stearate were added to the obtained granules, followed by press molding to produce tablets.

Example 8 Capsule (Formulation Formulation) Compound [III] 10 mg Lactose 90 mg Microcrystalline cellulose 70 mg Magnesium stearate 10 mg 1 capsule 180 mg

(Preparation method) Compound [III], lactose,
After mixing microcrystalline cellulose and a half amount of magnesium stearate, the mixture was granulated. The remaining magnesium stearate was added to the obtained granules, and the whole was encapsulated in a gelatin capsule to produce a capsule.

Example 9 Injection (combination formulation) Compound [III] 10 mg Inositol 100 mg Benzyl alcohol 20 mg 1 ampule 130 mg

(Preparation method) Compound [III], inositol and benzyl alcohol were added to a total volume of 2 ml.
It was dissolved in distilled water for injection and sealed in an ampoule. All steps were performed under aseptic conditions.

Test Example 1 Antagonism of Compound [III] for Carbachol Contraction Using Colored Rabbit Ciliary Muscle The antagonistic action of compound [III] for carbachol contraction using colored rabbit ciliary muscle was examined. (Experimental materials) Male colored rabbits (Dutch species) weighing about 2 kg were used as experimental animals. Carbachol (3 × 10 ⁻⁷ M to 3 × 1) having a ciliary muscle contraction action was used as a reagent.
0 ^-3 M), compound [III] (10 ^-6 M to 10 ^-3 M) and tropicamide (1
0 ^-7 M to 3 × 10 ^-5 M) [Active ingredient of Midrin M (registered trademark: mydriatic and regulating paralytic agent manufactured by Santen Pharmaceutical Co., Ltd.)]
Was used. () Indicates the final drug concentration (the same applies hereinafter). In this test example, carbachol and tropicamide were obtained from Krebs-Ringer.
Compound [III] was used as a phosphate buffer (pH 7.6) solution as a liquid solution (pH 7.6).

(Experimental method) Specimen preparation: After the eyeball of a colored rabbit was excised, the rear part of the eyeball was cut off, and the front part of the eyeball was divided into half. The vitreous and lens were removed from one of them and the iris was cut off. Next, the ciliary muscle was carefully peeled off from the sclera, and the width was 1 mm and the length was 1
A 0 mm muscle specimen was prepared. Measurement method: 95% O ₂ −
It was suspended in a 10 ml bath filled with Krebs-Ringer solution kept at 37 ° C. with 5% CO ₂ . The response to the drug was recorded isometric under a resting tension of about 30 mg. Compound [III] (3 × 10 ⁻⁵ M or 10 ⁻⁴ M) and tropicamide (10 ⁻⁶ M) were pretreated for 5 minutes, and the inhibitory effect of each of the reagents on the rapid contraction of carbachol and carbachol (3 × 10 ^-5 compounds for sustained contraction occurs following rapid contraction of M) (III) (10 ^-6
M- ^10-3 M) and tropicamide ( ^10-7 M- ³ x 1).
FIG. 1 shows the measurement results for the relaxation effect of 0 ⁻⁵ M).
And FIG.

(Results) (1) Rabbit ciliary muscle showed a concentration-dependent contractile response to carbochol of 10 ⁻⁶ M to 10 ⁻⁴ M (see FIG. 1). (2) Tropicamide (10 ⁻⁶ M) translated the carbachol dose-response curve to the higher concentration side. That is, tropicamide is a competitive antagonist (see FIG. 1). Compound [III] exhibited a maximum contraction due to carbachol of 3 × 10
^At a concentration of ^-5 M, the inhibition was about 25% and at a concentration of 10 ^-4 M, about 70%. That is, compound [III] is considered to be a non-competitive antagonist because it strongly suppressed the maximum contraction caused by carbachol (see FIG. 1). (3) At a concentration of 3 × 10 ⁻⁷ M or more, tropicamide relaxed the sustained contraction by carbachol (3 × 10 ⁻⁵ M) in a concentration-dependent manner, but did not relax it below the resting tension ( 100% relaxation from sustained maximum contraction to resting tension
(See FIG. 2). Compound [III] is 3 × 10 ⁻⁶
At concentrations above M, the sustained contraction by carbachol (3 × 10 ⁻⁵ M) was relaxed in a concentration-dependent manner. Further, the compound [III] was relaxed to a static tension or less (116%) (see FIG. 2).

From the above results, it was clarified that the compound [III] exhibited a relaxing action on rabbit ciliary muscle. Tropicamide, an active ingredient of Midrin M, inhibited premature contraction and exhibited a relaxing effect on the subsequent sustained contraction. Compound [III] also exhibited a similar effect. Tropicamide competitively antagonizes carbachol and nervous terminal receptors, which have the same action as acetylcholine, which is a ciliary muscle neuronal constrictor. It is possible that they did not competitively antagonize the cholinergic receptor, but acted directly on ciliary muscle by other mechanisms to exert a relaxing effect. Therefore, compound (III)
Is thought to relax ciliary muscle contraction not only by acetylcholine but also by other neurotransmitters that cause ciliary muscle contraction. Assuming that myopia is caused by contractions other than acetylcholine, compound [III] is expected to be developed as a new drug for preventing and treating myopia.

Test Example 2 Effect of the Myopia Prevention / Treatment Agent of the Present Invention on Myopia Patients whose Visual Acuity did not Recover Even After Administration of Midrin M and Myopin Midrin M and Myopin (registered trademark: neostigmine methyl sulfate) as active ingredients The aqueous eye drops obtained in Example 2 (hereinafter sometimes abbreviated as this drug) to 5 myopic patients whose visual acuity did not recover even after administration of Santen Pharmaceutical Co., Ltd.) Was administered to examine the effect of the agent for preventing or treating myopia of the present invention.

First, naked eye acuity (right, left) and automatically measured refraction values for five patients (A to E) 9 to 28 years old as shown in Table 1 who visited the hospital complaining that their visual acuity had decreased. (Right, left) [Use auto refractometer,
Unit: D (diopters)] was measured. Table 1 shows the results. The axial length and the corneal curvature radius were all within normal ranges for all five subjects.

Both eyes of patients A to E received one drop of myopin at a time, three to four times a day, and one drop of midrin M before bedtime for three months. Table 1 shows the results of measurements of naked eye visual acuity (right, left) and automatically measured refraction values (right, left) at the visit three months after the first visit for patients A to E. As is evident from Table 1, the visual acuity and the automatically measured refraction value of each of the five subjects were almost the same as those of the initial measurement values, and no effects for preventing or treating myopia were observed.

Then, in place of myopine, this drug was instilled in both eyes of patients A to E one drop at a time, three to four times a day, and one drop of midrin M before bedtime for three months. did. For patients A to E, at the visit 3 months later (at the visit 6 months after the first visit), the naked eye acuity (right,
Table 1 shows the measurement results of the refraction values (right, left) measured automatically.
Shown in As is clear from Table 1, the visual acuity of all five subjects recovered to 1.0 or more, and the automatically measured refraction value was also clearly improved.

[0064]

[Table 1]

From the above test results, it was confirmed that this drug was treated with Midrin M
When used in combination with myopin and myoline M, which are conventional myopia prophylactic / therapeutic agents, are not effective for myopic patients.
The effect of preventing and treating myopia was demonstrated. Therefore, the usefulness of this drug as a preventive / therapeutic agent for myopia was shown.

Test Example 3 Effect of the Myopia Prevention / Therapeutic Agent of the Present Invention on Myopia Patients The aqueous ophthalmic solution (this drug) obtained in Example 2 was administered to 5 myopic patients to prevent / treat the myopia of the present invention. The effect of the agent was examined. First, he visited our hospital complaining that his eyesight had deteriorated.
Patients aged 9 to 28 years as shown in (F to J)
Visual acuity (right, left), automatically measured refraction (right, left) for 5 subjects [use auto refractometer, unit:
D (diopters)] are shown in Table 2. The axial length and the corneal curvature radius were all within normal ranges for all five subjects.

This drug was applied to both eyes of patients F to J once at a time.
Drops were administered 3 to 4 times daily for 3 months. Patient F
Table 2 shows the results obtained by measuring naked eye acuity (right, left) and automatically measured refraction values (right, left) at the time of visit three months later. As is clear from Table 2, the visual acuity of all five subjects recovered to 1.0 or more, and the automatically measured refraction value was also clearly improved.

[0068]

[Table 2]

The patients used in the test examples of the present invention showed that the eye axis length was within the normal range as described above and that the corneal curvature radius did not change. The patient was considered to be a refractive myopic patient. Therefore, the myopia prevention / treatment effect of this drug in this test example is
It was considered that it acted on the ciliary muscle and relaxed the contraction of the ciliary muscle. From the above, it was found that this agent exhibited excellent myopia prevention / treatment effects and was useful as a myopia prevention / treatment agent.

Test Example 4 The effect of the compound [III] on monkey acute refractive myopia due to carbachol eye drops was examined. (Experimental Materials) Two male cynomolgus monkeys weighing about 3 kg were used as experimental animals. Examples of the reagents include carbachol, which contracts ciliary muscles and changes the refractive index of the lens to cause myopia, phenylephrine having an α-receptor stimulating effect on dilated pupil muscles and mydriasis [neocinedin Kowa 5%
Active ingredient of ophthalmic solution (registered trademark: Mydriatic agent manufactured by Kowa Co., Ltd.)] and compound [III] which is a test drug were used. In this test example, carbachol was used as a Krebs-Ringer solution (pH 7.6), and compound [III] was used as a phosphate buffer (pH 7.6) solution. (Experimental method) 0.75% carbachol was instilled into both eyes at 30 minute intervals, and the refractive index was measured over time. The measurement was performed at intervals of 15 minutes before instillation of carbachol and 30 minutes after the first instillation of carbachol, and continued until the pupil diameter became about 1 mm or less. The test drug compound [III] was instilled in one eye and physiological saline solution was instilled four times in one eye at intervals of 5 minutes 90 minutes before instillation of carbachol. In addition, 5% phenylephrine was instilled into both eyes six times at intervals of 5 minutes 120 minutes before instillation of carbachol for the purpose of maintaining mydriasis for refractive index measurement. The eye drops of all drugs were all 20 μl. The protocol is shown below.

Embedded image (Results) In the physiological saline instillation, 15D myopia was observed 15 minutes after the second instillation of carbachol, whereas 1%
Compound [III] did not show any change in the refractive index with eye drops. In the case of the physiological saline instillation, myopia was further observed in the instillation of carbachol three times, but in the case of the compound [III] instillation, myopia was almost completely suppressed. (See Fig. 3)

Test Example 5 Formula

Embedded image 7-isopropyl-3- (1H-tetrazol-5-yl) -1-azaxanthone (JP-A-54-4)
No. 8798), the relaxation effect of the compound on the contraction of carbachol was examined in the same manner as in Test Example 1. The compound was found to be carbachol (3 × 10 ⁻⁵ M) at a concentration of 3 × 10 ⁻⁶ M or more. Caused the continuous contraction to be relaxed in a concentration-dependent manner. Therefore, the usefulness of the present compound as a preventive / therapeutic agent for myopia was shown. In this test example, carbachol was used as a physiological saline solution.

[0072]

EFFECTS OF THE INVENTION The agent for preventing or treating myopia of the present invention not only has a relaxing effect on rabbit ciliary muscle but also human ciliary muscle, and is almost ineffective with conventional agents for preventing or treating myopia. It shows an excellent myopia prevention / treatment effect even for patients with no myopia and has no mydriatic action (side effect), so that it can be advantageously used as a safe myopia prevention / treatment agent. The prophylactic / therapeutic agent for myopia of the present invention can also be applied to accommodation tension convulsions, etc., which are precursors of myopia.

[0073]

[Brief description of the drawings]

FIG. 1 is a graph showing a dose-response curve of carbachol after pretreatment with compound [III] or tropicamide (the ratio of the maximum contraction of carbachol alone as 100%). The horizontal axis is the common logarithm (log) of carbachol concentration (M).
M), and the vertical axis indicates the shrinkage rate (%). In the figure, ○ indicates a dose-response curve of carbachol alone (n = 8), and ▲ indicates a dose-response curve of carbachol after pretreatment with compound [III] (3 × 10 ⁻⁵ M) for 5 minutes (n = 7). ) And △ are compounds [II
I] (10 ⁻⁴ M) for 5 minutes after pretreatment with carbachol (n = 7), □ indicates tropicamide (10 ⁻⁶ M)
M) represents the dose-response curve of carbachol (n = 6) after pretreatment for 5 minutes, respectively.

FIG. 2 is a graph showing the relaxing effect of compound [III] and tropicamide on sustained contraction of carbachol (3 × 10 ⁻⁵ M) (the relaxation from sustained maximum contraction to resting tension is defined as 100%). The horizontal axis indicates the common logarithm (logM) of the drug concentration (M), and the vertical axis indicates the relaxation rate (%). In the figure, △ indicates compound [III] (n = 7), and □ indicates tropicamide (n = 7).

FIG. 3 is a graph showing a change in refractive index after instillation of carbachol. The horizontal axis indicates time (minutes), and carbachol 1
The time immediately before the instillation was set to 0 minutes. The vertical axis indicates the change (D) from the initial value of the refractive index (the value immediately before instillation of carbachol).
In the figure, △ and ▲ indicate changes in the refractive index of physiological saline or compound [III], respectively, and the arrows indicate carbachol instillation. Each value indicates the average and standard error of the change in refractive index of the two animals.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Noriko Watanabe 1-9-24 Kishibe Minami, Suita-shi, Osaka Sentporia 501 No. 58 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/436 A61P 27/10 C07D 491/052 CA (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] 1. A compound of the general formula [Wherein ring A is a halogen atom, a nitro group, an alkyl group,
R ₁ may be substituted with an alkoxy group or a butadienylene group (—CH ＝ CH—CH ＝ CH—) forming a benzene ring with two adjacent carbon atoms at positions 6,7,8,9. Hydrogen or an amino group which may be protected, R ₂ represents a carboxyl group, a tetrazolyl group, a trifluoromethanesulfonylamino group, a phosphono group or a sulfo group (these groups are an alkyl group having 1 to 4 carbon atoms;
A alkanoyl group having 2 to 4 carbon atoms which may be substituted by a halogen atom or a benzoyl group which may be substituted by a halogen atom or amino)) or a salt thereof. An agent for preventing or treating myopia. 2. The agent for preventing or treating myopia according to claim 1, wherein R ₂ is a carboxyl group or a tetrazolyl group. (3) a compound represented by the general formula: Wherein R is an alkyl group, R ₁ is hydrogen or an amino group which may be protected, R ₂ is a carboxyl group, a tetrazolyl group, a trifluoromethanesulfonylamino group,
A phosphono group or a sulfo group (these groups are an alkyl group having 1 to 4 carbon atoms, an alkanoyl group having 2 to 4 carbon atoms which may be substituted with a halogen atom, or a benzoyl group which may be substituted with a halogen atom or amino) Which may be protected by the above)]. 4. The agent for preventing or treating myopia according to claim 3, wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms. 5. The agent for preventing or treating myopia according to claim 3, wherein the alkyl group is an isopropyl group. 6. The agent for preventing or treating myopia according to claim 1, wherein R ₁ is an amino group. 7. The method for preventing or treating myopia according to claim 1, wherein R ₂ is a carboxyl group. (8) a compound represented by the formula: The myopic prophylactic / therapeutic agent according to claim 1, which is represented by the following formula: 9. The agent for preventing or treating myopia according to claim 1, which is for topical administration to the eye. 10. The method for preventing myopia according to claim 9, which is an eye drop.
Therapeutic agent. 11. The agent for preventing or treating myopia according to claim 10, which is an aqueous eye drop. 12. The agent for preventing or treating myopia according to claim 11, further comprising a solubilizing agent. 13. The agent for preventing or treating myopia according to claim 12, wherein the solubilizing agent is polyvinylpyrrolidone.