JP2694320B2 - Cataract prevention and treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive and therapeutic drug for cataract.

[0002]

DISCLOSURE OF THE INVENTION The preventive and therapeutic agents for cataract of the present invention have the general formula (1):

[0003]

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[In the formula, R ¹ represents a lower alkanoyl group-substituted lower alkoxy group. 3 and 4 of the carbostyril skeleton
The carbon-carbon bond at the position represents a single bond or a double bond. ] A carbostyril derivative represented by or its salt, 5-dimethylamino-1- [4- (2-methylbenzoylamino)]
Benzoyl] -2,3,4,5-tetrahydro-1H-
Benzazepine and 5-hydroxy-7-chloro-1-
At least one selected from [2-methyl-4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine is used as an active ingredient.

The carbostyril derivative represented by the above general formula (1) or a salt thereof is described in JP-A-3-173870 and 5-dimethylamino-1- [4].
-(2-methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine and 5-hydroxy-7-chloro-1- [2-methyl-4-
(2-Methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine is disclosed in JP-A-4-154765 and JP-A-4-32166.
It is also known that these compounds are useful as vasopressin antagonists.

The inventors of the present invention have conducted various studies to develop new preventive and therapeutic agents for cataract which are useful for the prevention and treatment of cataract, and as a result, have developed the carbostyril derivative represented by the general formula (1) or a salt thereof. , 5-dimethylamino-1
-[4- (2-methylbenzoylamino) benzoyl]
-2,3,4,5-Tetrahydro-1H-benzazepine and 5-hydroxy-7-chloro-1- [2-methyl-4- (2-methylbenzoylamino) benzoyl]-
At least one selected from 2,3,4,5-tetrahydro-1H-benzazepine, especially 1- {1- [4-
(3-Acetylaminopropoxy) benzoyl] -4-
It was found that piperidinyl} -3,4-dihydrocarbostyril or a salt thereof is useful as a preventive and therapeutic drug for cataract, and the present invention has been completed here.

Cataract refers to a state in which the transparency of the lens is lost due to the accumulation of water in and between lens fibers and the presence of lumps formed by protein aggregation. Cataracts include congenital cataract, senile cataract, anterior subcapsular cataract, posterior subcapsular cataract, diabetic cataract, cataract associated with myotonic atrophy, radiation cataract, cataract due to iron rust, Down's syndrome cataract, Christmas tree decoration There are acquired cataracts such as cataract. Regarding the cause of cataracts, what is required in the lens, what is required for changes in the permeability of the lens capsule and epithelium,
Changes in the ciliary epithelium, and therefore changes in aqueous humor, etc.
There are many theories, but no established theory is currently available.

The carbostyril derivative represented by the above general formula (1) or a salt thereof, 5-dimethylamino-1- [4]
-(2-methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine and 5-hydroxy-7-chloro-1- [2-methyl-4-
(2-Methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine is
In a cataract model induced by streptozotocin (STZ), it has an action of suppressing the occurrence of cataract without depending on blood glucose concentration. Therefore, the compound of the present invention can be preferably used for the treatment and prevention of cataract.

Each group represented by the above general formula (1) is more specifically as follows.

Examples of the lower alkanoyl group include straight-chain or branched-chain alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups.

Examples of the lower alkanoyl group-substituted lower alkoxy group include acetylaminomethoxy, 2- (formylamino) ethoxy, 1- (propionylamino) ethoxy, 3- (butyrylamino) propoxy, 3- (acetylamino) propoxy, 4 -(Isobutyrylamino) butoxy, 5- (pentanoylamino) pentyloxy, 6- (hexanoylamino) hexyloxy, etc., having a straight or branched chain alkoxy group having 1 to 6 carbon atoms Examples thereof include linear or branched alkoxy groups of 1 to 6.

Among the compounds (1) used as the active ingredient in the present invention, the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Such basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate and sodium hydrogen carbonate, sodium methylate And alkali metal alcoholates such as potassium ethylate. In addition, in the compound (1) as an active ingredient in the present invention, the compound having a basic group can easily form a salt with a usual pharmacologically acceptable acid. Examples of such an acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid and hydrobromic acid, organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, citric acid, succinic acid and benzoic acid. An acid can be illustrated.

The preventive and therapeutic agents for cataract of the present invention are used in the form of general pharmaceutical preparations. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories,
Examples include injections (solutions, suspensions, etc.), ointments, eye drops and the like. In molding into tablets, various carriers well-known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate excipient, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, etc., sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, gly Phosphorus, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablet can be made into a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet. When molding into pill form,
As the carrier, those conventionally known in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin, talc, binders such as gum arabic, tragacanth, gelatin, ethanol, disintegrants such as laminaran, agar, etc. Can be used. In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Capsules are prepared according to a conventional method, usually by mixing an active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like. When prepared as an injection, liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used as diluents in the art when molded into these forms. And water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. Incidentally, a sufficient amount of sodium chloride to prepare the case isotonic solution may be contained a dextrose or glycerol in the pharmaceutical formulation, and usually the solubilizer, buffering agent, adding a soothing agent, etc. You may. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation. When forming into a paste, cream or gel form, a wide range of diluents known in the art can be used as a diluent.
For example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite and the like can be exemplified. In addition, the eye drops are manufactured by a conventional method. Specifically, it is produced by mixing the active ingredient compound of the present invention with an appropriate base and sterilizing the mixture.
As the base, for example, sterile purified water is preferably used.
Furthermore, eye drops may include solubilizing agents, buffers, and
Antioxidants, preservatives, tonicity agents, pH adjusters and the like can be added. Examples of the dissolution aid include sodium carboxymethylcellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, and polyethylene glycol higher fatty acid esters such as polyethylene glycol monolaurate and polyethylene glycol monooleate. , Polyoxyethylene sorbitan monolaurate, polyoxyethylene fatty acid ester and the like. Examples of the buffer include sodium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, epsilon aminocaproic acid, sodium glutamate and the like. Can be mentioned. Examples of the antioxidant include sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, ascorbic acid and the like. Examples of the preservative include chlorobutanol, benzalkonium chloride, benzethonium chloride, phenylmercury salt, thimerosal, phenethyl alcohol, methylparaben, propylparaben and the like. Examples of the tonicity agent include salt, glucose, D-mannitol, glycerin and the like. Examples of the pH adjuster include sodium hydroxide and hydrochloric acid.

The amount of the active ingredient compound to be contained in the agent for preventing and treating cataract of the present invention is not particularly limited and may be appropriately selected from a wide range, but it is usually about 1 in the pharmaceutical composition.
The content is preferably about 70% by weight, preferably about 5% to 50% by weight.

There are no particular restrictions on the method of administration of the prophylactic and therapeutic agents for cataract of the present invention, and they may be administered according to various dosage forms, patient age, sex and other conditions, and degree of disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally. In the case of an ointment, it is applied. In the case of eye drops, it can be administered in the same manner as conventional eye drops, for example, by instilling it in the eye from a suitable drip container,
Alternatively, it may be sprayed on the eye with a spraying device.

The dose of the prophylactic and / or therapeutic agent for cataract of the present invention is appropriately selected depending on the usage, the age of the patient, the sex and other conditions, the degree of disease and the like. Usually, the amount of the active ingredient compound is the body weight per day. It is preferable that the amount is about 0.6 to 50 mg per kg. It is desirable that the active ingredient compound is contained in the dosage unit form in a range of about 10 to 1000 mg.

[0017]

EXAMPLES In order to explain the present invention in more detail, formulation examples of the cataract and therapeutic agents of the present invention are given below, and test examples of active ingredient compounds are given.

Formulation Example 1 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 40 g After mixing and polishing the active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate, sugar coating R10 mm
Tablet with kine. The obtained tablets were treated with hydroxypropyl methylcellulose, polyethylene glycol-600.
0, coating with a film coating agent consisting of castor oil and ethanol to produce film-coated tablets.

Formulation Example 2 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 150 g citric acid 1.0 g lactose 33.5 g phosphoric acid diphosphate Calcium 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate amount The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture is sieved through a N0.60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. If necessary, alcohol is added to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture is passed through a N0.10 screen, placed in a tray and placed in an oven at 100 ° C for 1
Dry for 2-14 hours. The dry particles are screened through a N.16 screen, dry sodium lauryl sulphate and dry magnesium stearate are added and mixed and compressed to the desired shape on a tablet machine.

The core is treated with varnish and sprinkled with talc to prevent moisture absorption. An undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. A further subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Color coating is carried out until the desired hue is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Pharmacological test method 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -as the test compound
3,4-dihydrocarbostyril was used.

Wistar male rats (280-330
The left kidney (g, 9 weeks) was removed under ether anesthesia. One week later, streptozotocin (STZ) was dissolved in 50 mM citrate buffer (pH 4.5) and administered at a dose of 1 ml / kg through the tail vein of 60 mg / kg. After STZ administration, it was divided into 2 groups, and 1 group was orally ingested by mixing the test compound (0.2%) in the feed. The other group was given a normal diet (MF) as a control group. S
Blood glucose levels were measured 4 weeks and 16 weeks after TZ administration. Table 1 shows the results. In addition, sustained-release insulin (Ultralente) 4U / body, s. c. Was administered every other day. At 16 weeks after the STZ administration, the incidence of cataracts was measured by setting the case in which an apparent opacity of the crystalline lens was observed by macroscopic observation as an onset case. Table 2 shows the results.

[0024]

[Table 1]

[0025]

[Table 2]

Continuation of the front page (72) Inventor Toshiyuki Ono, 4 61, Kawamuji, Osamachi market, Naruto City, Tokushima Prefecture (72) Inventor Norihisa Yamada 7 (72) invention, 4 Uchida, Kizu, Otsu Town, Naruto City, Tokushima Prefecture Kenji Tsujimae 10 (72) at 463 Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture (72) Inventor Hidenori Ogawa 18 (72) Nakase Nishinogetsu, 25, Nakaki, Itamo-gun, Itano-gun, Tokushima Naruto Tokushima Prefecture 48, Kitanohama, Okuwajima, Fuyo-cho, Ichi, Japan (72) Inventor Michiaki Tominaga 6 of 310 Takaiso, Ueita-cho, Itano-gun, Tokushima Prefecture

Claims (5)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a lower alkanoyl group-substituted lower alkoxy group. The carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton represent a single bond or a double bond. ] The carbostyril derivative represented by or its salt, 5-dimethylamino-1
-[4- (2-methylbenzoylamino) benzoyl]
-2,3,4,5-Tetrahydro-1H-benzazopine and 5-hydroxy-7-chloro-1- [2-methyl-4- (2-methylbenzoylamino) benzoyl]-
A preventive and / or therapeutic agent for cataract comprising at least one selected from 2,3,4,5-tetrahydro-1H-benzazepine as an active ingredient. 2. The active ingredient is represented by the general formula: [In the formula, R ¹ and the carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton are the same as above. ] The preventive and therapeutic agent for cataract according to claim 1, which is a carbostyril derivative represented by the following formula or a salt thereof. 3. R ¹ Is an acetylaminomethoxy group, 2-
(Formylamino) ethoxy group, 1- (propionylua
Mino) ethoxy group, 3- (butyrylamino) propoxy
Group, 3- (acetylamino) propoxy group, 4- (iso
Butyrylamino) butoxy group, 5- (pentanoylami)
No) Pentyloxy group or 6- (hexanoylamino)
Carboxyryl derivative having hexyloxy group or the
The prevention and cure of cataract according to claim 2, wherein salt is an active ingredient.
Remedy. 4. The active ingredient is 5-dimethylamino-1-.
[4- (2-methylbenzoylamino) benzoyl]-
2,3,4,5-Tetrahydro-1H-benzazepine or 5-hydroxy-7-chloro-1- [2-methyl-
4- (2-methylbenzoylamino) benzoyl]-
The preventive and therapeutic agent for cataract according to claim 1, which is 2,3,4,5-tetrahydro-1H-benzazepine. 5. The cataract of claim 2, wherein the active ingredient is 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril or a salt thereof. Preventive and therapeutic drugs.