JPH10120592A - Therapeutic agent for meniere's disease or meniere's syndrome - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine capable of effectively and surely treating Meniere's disease or Meniere's syndrome by including a compound having a vasopressin antagonism as an active ingredient. SOLUTION: This medicine comprises a compound having vasopressin antagonism, especially preferably a carbostyril compound (salt) of formula I [R<1> is a group of O-A-NR<2> R<3> (A is a lower alkyl; R<2> and R<3> are each H or a lower alkanoyl; bond between carbon atoms at 3- and 4-position of carbostyril skeleton is single bond or double bond)] and a benzohetero compound (salt) of formula II [R<4> is H or a halogen; R<5> is NR<8> R<9> (R<8> and R<9> are each H or lower alkyl); R<6> is H, a halogen, etc.; R<7> is a halogen, a lower alkyl, etc.]. An amount of an active ingredient compound to be contained in the medicine is about 1-70wt.%, preferably about 5-50wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for Meniere's disease or Meniere's syndrome.

[0002]

2. Description of the Related Art Meniere's disease or Meniere's syndrome
Among the cases showing paroxysmal severe rotational vertigo and cochlear symptoms such as tinnitus and hearing loss appearing in connection therewith, it is a disease whose causative disease is not clear. When dizzy attacks are repeated over a long period of time and the hearing loss is high, social life is greatly impaired, so Meniere's disease or Meniere's syndrome is designated as an intractable disease.

[0003] Vertigo occurs as a subjective symptom of disease states such as Meniere's disease and Meniere's syndrome. Vertigo is a type of dizziness that appears to rotate around.
o), there are dizziness, etc., which cause a wobbling feeling.

[0004] For treatment of Meniere's disease or Meniere's syndrome, a method of resting during seizures and parenterally administering an antihistamine such as a 7% aqueous sodium bicarbonate solution or a phenothiazine derivative is generally used. However, this method is only a symptomatic treatment and is not a fundamental treatment.

[0005] Once a patient with Meniere's disease or Meniere's syndrome experiences a vertigo attack, the patient may fall into anxiety. Therefore, there is an urgent need to develop an effective and reliable therapeutic agent.

[0006]

An object of the present invention is to provide a novel therapeutic agent capable of effectively and surely treating Meniere's disease or Meniere's syndrome.

[0007]

Means for Solving the Problems The present inventors have conducted various studies in order to develop a novel therapeutic agent capable of effectively and surely treating Meniere's disease or Meniere's syndrome, and found that a compound having a vasopressin antagonism was discovered. It has been found that it can be suitably used as a therapeutic drug for Meniere's disease or Meniere's syndrome. Such a finding is that even a person skilled in the art cannot easily imagine from pharmacological actions such as vasodilatory action, blood pressure lowering action and hepatic glucose release inhibitory action which are exerted based on vasopressin antagonistic action. The present invention has been completed based on such findings.

[0008] That is, the present invention relates to a therapeutic agent for Meniere's disease or Meniere's syndrome, comprising a compound having vasopressin antagonistic activity as an active ingredient.

The therapeutic agent for Meniere's disease or Meniere's syndrome of the present invention is an agent capable of effectively and surely treating Meniere's disease or Meniere's syndrome, which has been regarded as an intractable disease.

According to the present invention, there is provided a therapeutic agent for Meniere's disease or Meniere's syndrome, comprising a compound having vasopressin antagonistic activity as an active ingredient.

According to the present invention, there is provided a therapeutic agent for Meniere's disease or Meniere's syndrome, wherein the compound having vasopressin antagonistic activity is a compound having vasopressin V ₁ receptor antagonistic activity.

According to the present invention, there is provided a therapeutic agent for Meniere's disease or Meniere's syndrome, wherein the compound having vasopressin antagonistic activity is a compound having vasopressin V ₂ receptor antagonistic activity.

According to the present invention, the compound having vasopressin antagonistic activity is represented by the general formula:

[0014]

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[In the formula, R ¹ represents a group -OA-NR ² R ³ . A represents a lower alkylene group. R ² and R ³ are the same or different and each represent a hydrogen atom or a lower alkanoyl group. The carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton represent a single bond or a double bond. And a therapeutic agent for Meniere's disease or Meniere's syndrome, which is at least one member selected from the group consisting of a carbostyril derivative represented by the formula:

According to the present invention, the compound having vasopressin antagonistic activity is represented by the general formula:

[0017]

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Wherein R ⁴ represents a hydrogen atom or a halogen atom. R ⁵ represents a group —NR ⁸ R ⁹ . R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom or a lower alkyl group.
R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. R ⁷ represents a halogen atom, a lower alkyl group or a lower alkoxy group. And a therapeutic agent for Meniere's disease or Meniere's syndrome, which is at least one member selected from the group consisting of a benzohetero compound and a salt thereof.

According to the present invention, the compound having vasopressin antagonistic activity is 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,
An agent for treating Meniere's disease or Meniere's syndrome, which is at least one member selected from the group consisting of 4-dihydrocarbostyril and a salt thereof, is provided.

According to the present invention, the compound having vasopressin antagonistic activity is 5-dimethylamino-1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
A therapeutic agent for Meniere's disease or Meniere's syndrome, which is at least one selected from the group consisting of 5-tetrahydro-1H-benzazepine and a salt thereof, is provided.

According to the present invention, there is provided a therapeutic agent for vertigo comprising a compound having vasopressin antagonistic activity as an active ingredient.

According to the present invention, there is provided a therapeutic agent for vertigo wherein the compound having vasopressin antagonism is a compound having vasopressin V ₁ receptor antagonism.

According to the present invention, there is provided a therapeutic agent for vertigo wherein the compound having vasopressin antagonism is a compound having vasopressin V ₂ receptor antagonism.

According to the present invention, there is provided a therapeutic agent for vertigo wherein the compound having vasopressin antagonistic activity is at least one selected from the group consisting of the carbostyril derivative represented by the general formula (1) and a salt thereof. You.

According to the present invention, there is provided a therapeutic agent for vertigo wherein the compound having a vasopressin antagonistic activity is at least one selected from the group consisting of the benzohetero compounds represented by the above general formula (2) and salts thereof. .

According to the present invention, the compound having vasopressin antagonistic activity is 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,
There is provided a therapeutic agent for vertigo which is at least one selected from the group consisting of 4-dihydrocarbostyril and a salt thereof.

According to the present invention, the compound having vasopressin antagonistic activity is 5-dimethylamino-1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
There is provided a therapeutic agent for vertigo which is at least one selected from the group consisting of 5-tetrahydro-1H-benzazepine and a salt thereof.

[0028]

BEST MODE FOR CARRYING OUT THE INVENTION As a compound having vasopressin antagonistic activity which is used as an active ingredient of the therapeutic agent for Meniere's disease or Meniere's syndrome of the present invention, widely known compounds can be used as long as they can be an active ingredient of a vasopressin antagonist. Can be used.

Examples of the compound having the vasopressin antagonistic activity include a peptide vasopressin antagonist, a non-peptide vasopressin antagonist and the like. Specific examples of the peptidic vasopressin antagonist include [1-β-mercapto-β, β-cyclopentamethylenepropionic acid, 2
-(O-methyl) tyrosine-8-arginine] vasopressin, [1-deaminopenicillamine, 2- (O-methyltyrosine) -8-arginine] vasopressin, and various types described in JP-A-2-32098. Of vasopressin. Further, specific examples of the non-peptide vasopressin antagonist include the general formula

[0030]

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[In the formula, R ¹ represents a group -OA-NR ² R ³ . A represents a lower alkylene group. R ² and R ³ are the same or different and each represent a hydrogen atom or a lower alkanoyl group. The carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton represent a single bond or a double bond. A carbostyril derivative or a salt thereof represented by the general formula

[0032]

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Wherein R ⁴ represents a hydrogen atom or a halogen atom. R ⁵ represents a group —NR ⁸ R ⁹ . R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom or a lower alkyl group.
R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. R ⁷ represents a halogen atom, a lower alkyl group or a lower alkoxy group. Or a salt thereof. Specific examples of non-peptide vasopressin antagonists are further described in EP-A-469984 and JP-A-5-32013.
No. 5, JP-A-6-16643, JP-A-6-161
Various compounds described in JP-A-57480 can be exemplified. More specifically, [2R- [2α (S), 3β]
-1-[[5-chloro-3- (2-chlorophenyl)-
1-[(3,4-dimethoxyphenyl) sulfonyl]-
2,3-dihydro-3-hydroxy-1H-indol-2-yl] carbonyl] -2-pyrrolidinecarboxamide, 4 ′-[(2-methyl-1,4,5,6-tetrahydroimidazole [4,5- d] [1] Benzoazepin-6-yl) carbonyl] -2-phenylbenzanilide monohydrochloride, (Z) -N- [4- [5- [4- (dimethylamino) piperidin-1-yl- Carbonylmethylene] -4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl] phenyl] biphenyl-2-carboxamide hydrochloride.

Among the compounds having the vasopressin antagonistic activity, particularly preferred compounds are the carbostyril derivative represented by the general formula (1) or a salt thereof, and the benzohetero compound represented by the general formula (2) or a benzohetero compound represented by the general formula (2). Salt.

The carbostyril derivative represented by the general formula (1) and a salt thereof include 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydro Carbostyril and its salts are included.

The benzohetero compound represented by the general formula (2) and a salt thereof include 5-dimethylamino-1- [4
-(2-methylbenzoylamino) benzoyl] -2,
3,4,5-tetrahydro-1H-benzazepine and salts thereof are included.

Each of the groups represented by the general formulas (1) and (2) is more specifically as follows.

The lower alkylene group includes, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene C1 of group etc.
To 6 linear or branched alkylene groups.

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

As the halogen atom, for example, a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms, such as ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

Examples of the lower alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

The compound of the general formula (1) used as an active ingredient of the present invention can be prepared by a known method, for example, as described in JP-A-3-17.
It can be easily produced according to the method described in Japanese Patent No. 3870.

The compound of the general formula (2) used as an active ingredient of the present invention can be easily produced according to a known method, for example, a method described in European Patent No. 45,097.

Among the compounds of the general formula (1) and the compounds of the general formula (2) used as the active ingredient in the present invention, the compound having an acidic group forms a salt with a pharmacologically acceptable basic compound. obtain. Examples of such a basic compound include sodium hydroxide, potassium hydroxide, lithium hydroxide,
Metal hydroxides such as calcium hydroxide, sodium carbonate,
Examples thereof include alkali metal carbonates or bicarbonates such as sodium hydrogen carbonate, and alkali metal alcoholates such as sodium methylate and potassium ethylate. Further, among the compounds of the general formula (1) and the compounds of the general formula (2) as active ingredients in the present invention, the compound having basicity can easily form a salt with a usual pharmacologically acceptable acid. . Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, citric acid, succinic acid, benzoic acid, and the like. Organic acids can be exemplified.
These salts can also be used as an active ingredient compound in the present invention, similarly to the compound of the general formula (1) and the compound of the general formula (2) in a free form. Incidentally, the compound of the general formula (1) and the compound of the general formula (2) include stereoisomers and optical isomers, and these can be similarly used as the active ingredient compound.

The compound having vasopressin antagonistic activity is effective as a therapeutic agent for Meniere's disease or Meniere's syndrome, and the therapeutic agent is used in the form of a general pharmaceutical preparation. 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 according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.)
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, excipients such as starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Disintegrating agents such as sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; quaternary ammonium bases; and absorption promoters such as sodium lauryl sulfate;
Humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid;
Lubricants such as purified talc, stearates, boric acid powder, and 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. In molding into the form of pills, a wide variety of carriers conventionally known in this field can be 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, the liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood. When formed into these forms, those commonly used as diluents in this field are used. Can be used, for example, water, ethyl alcohol, macrogol, propylene glycol,
Ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. 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.

The amount of the active ingredient compound to be contained in the therapeutic agent for Meniere's disease or Meniere's syndrome of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight in the pharmaceutical composition. %, Preferably about 5-5
The content is preferably 0% by weight.

The method of administration of the therapeutic agent for Meniere's disease or Meniere's syndrome of the present invention is not particularly limited, and is administered by a method according to various preparation forms, patient's age, gender and other conditions, degree of disease, and the like. 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.

The dose of the therapeutic agent for Meniere's disease or Meniere's syndrome of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like. 0.6 kg / kg
It is preferable to use about 50 mg. It is desirable that the active ingredient compound is contained in the dosage unit form in a range of about 10 to 1000 mg.

[0050]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the therapeutic agent for Meniere's disease or Meniere's syndrome of the present invention will be described, and then test examples of active ingredient compounds will be described.

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 stearin Magnesium acid salt 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 R10m
Tablet with m-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 1 1- {1- [4- (3-Acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 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 dried sodium stearate 3 0.0 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 No. 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 was passed through a No. 10 screen, placed in a tray, and placed in an oven at 100 ° C. for 1 hour.
Dry for 2-14 hours. The dry particles are sieved through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added, mixed and compressed into the desired shape on a tablet press.

The above core is treated with varnish and talc is sprayed 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.

Formulation Example 3 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 5 g polyethylene glycol (molecular weight: 4000) 0.3 g sodium chloride 0 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 10.0 ml The above parabens, sodium metabisulfite and sodium chloride Is dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to prepare a final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Formulation Example 4 5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g corn starch 30 g magnesium stearate 2 g hydroxypropylmethylcellulose 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 m
Tablet with m-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 5 5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine 150 g citric acid 1.0 g lactose 5 g dicalcium phosphate 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. You.

The above mixture is sieved with a No. 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 was passed through a No. 10 screen, placed in a tray, and placed in an oven at 100 ° C. for 1 hour.
Dry for 2-14 hours. The dry particles are sieved through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added, mixed and compressed into the desired shape on a tablet press.

The above core is treated with varnish, and talc is sprayed 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.

Formulation Example 6 5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine 5 g polyethylene glycol (molecular weight: 4000) 0 0.3 g sodium chloride 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 10.0 ml The sodium sulfite and sodium chloride are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to prepare a final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Pharmacological Test The efficacy of a compound having a vasopressin antagonistic effect on patients with Meniere's disease was examined. The following compounds were used as compounds having vasopressin antagonistic activity.

Test compound 1: 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril Test compound 2: 5-dimethylamino-1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
5-tetrahydro-1H-benzazepine.

(1) Test compound 1 was orally administered to 20 patients with Meniere's disease at a dose of 200 mg once a day for 8 weeks. Patient's subjective symptoms after 8 weeks (vertigo of dizziness, dizziness of floating, sway, size of tinnitus,
Ear sensation, head weight, etc.) and hearing impairment (average hearing, 4 minutes or 6 minutes) were examined, and these were comprehensively determined to determine the final overall improvement of the test compound 1. The test compound 1
The efficacy was evaluated in eight stages: marked improvement, improvement, mild improvement, unchanged, mild deterioration, deterioration and marked deterioration. as a result,
12 out of 20 subjects with mild improvement in subjective symptoms of test compound 1
10 out of 20 people with mild improvement in hearing loss
The final overall improvement was 12 or more out of 20 with mild improvement or higher. The effective rate of Test Compound 1 for patients with vertigo (vertigo or vertigo) was 50%.

(2) A single intravenous administration of test compound 2 at a rate of 0.5 mg / kg to 17 patients with Meniere's disease, and the subjective symptoms and hearing impairment of the patient 2 hours after the administration are described in (1) above.
Were examined in the same manner as in the above case, and these were comprehensively determined to determine the final overall improvement of the test compound 2. As a result, 7 out of 17 subjects with mild improvement in subjective symptoms of test compound 2 and 14 out of 17 subjects with mild improvement in hearing loss, and a final overall improvement of 12 out of 17 subjects with mild improvement or more Met. The effective rate of Test Compound 2 for patients with vertigo (vertigo or vertigo) was 50%.

Claims (8)

[Claims] 1. A therapeutic agent for Meniere's disease or Meniere's syndrome comprising a compound having vasopressin antagonistic activity as an active ingredient. 2. A therapeutic agent for vertigo comprising a compound having vasopressin antagonistic activity as an active ingredient. 3. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 1, wherein the compound having vasopressin antagonistic activity is a compound having vasopressin V ₁ receptor antagonistic activity. 4. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 1, wherein the compound having a vasopressin antagonistic activity is a compound having a vasopressin V ₂ receptor antagonistic activity. 5. A compound having a vasopressin antagonistic activity is represented by the general formula: [In the formula, R ¹ represents a group -OA-NR ² R ³ . A represents a lower alkylene group. R ² and R ³ are the same or different and each represent a hydrogen atom or a lower alkanoyl group. The carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton represent a single bond or a double bond. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 1, which is at least one member selected from the group consisting of a carbostyril derivative represented by the formula: and salts thereof. 6. A compound having a vasopressin antagonistic activity is represented by the general formula: [In the formula, R ⁴ represents a hydrogen atom or a halogen atom. R ⁵ represents a group —NR ⁸ R ⁹ . R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom or a lower alkyl group. R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. R ⁷ represents a halogen atom, a lower alkyl group or a lower alkoxy group. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 1, which is at least one member selected from the group consisting of a benzohetero compound represented by the formula: 7. The compound having a vasopressin antagonistic action is selected from the group consisting of 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril and salts thereof. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 5, which is at least one selected from the group consisting of: 8. A compound having a vasopressin antagonistic activity is obtained from 5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine and a salt thereof. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 6, which is at least one member selected from the group consisting of: