JP2694319B2 - Anti-ulcer agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antiulcer agent.

[0002]

DISCLOSURE OF THE INVENTION The antiulcer agent of the present invention has the general formula (1):

[0003]

Embedded image

[In the formula, R ¹ represents a lower alkanoylamino 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 induction body represented by] 1- {1-
[4- (5-Pyrrolidinylpentyloxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril, 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- The active ingredient is at least one selected from 1H-benzazepine and salts thereof .

The carbostyril derivative represented by the general formula (1) or a salt thereof is described in JP-A-3-173870, and it is also known that they are useful as vasopressin antagonists.

The present inventors have conducted various studies to develop an anti-ulcer agent, and as a result, the carbostyril derivative represented by the general formula (1) or a salt thereof, 1- {1- [4- (5
-Pyrrolidinylpentyloxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril, 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-1
At least one selected from H-benzazepines, especially 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril or a salt thereof is an anti-ulcer agent. Therefore, the present invention was completed here.

The carbostyril derivative which is the active ingredient of the present invention has an anti-ulcer action and is useful as a therapeutic agent for digestive ulcers such as gastric ulcer, duodenal ulcer and the like. The carbostyril derivative, which is the active ingredient of the present invention, also has a gastrointestinal mucosal protective action on the stomach, duodenum, etc. and is useful as a preventive and therapeutic agent for ulcers.

More specifically, each group represented by the above general formula (1) is 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.

[0010] The lower alkanoyl amino group-substituted lower alkoxy group, such as acetylamino, methoxy, 2
-(Formylamino) ethoxy, 1- (propionylamino) ethoxy, 3- (butyrylamino) propoxy,
A straight chain or a branched chain having 1 to 6 carbon atoms such as 3- (acetylamino) propoxy, 4- (isobutyrylamino) butoxy, 5- (pentanoylamino) pentyloxy, 6- (hexanoylamino) hexyloxy group. Branched alkoxya
A linear or branched alkoxy group having 1 to 6 carbon atoms having a mino group can be exemplified.

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 antiulcer agent of the present invention 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 depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid,
Suspensions and the like), ointments and the like. In molding into tablets, various carriers well-known in the art can be widely used as carriers. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose, silicic acid, water, ethanol,
Propanol, simple syrup, glucose solution, starch solution,
Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrants such as sodium, monoglyceride stearate, starch, lactose, sucrose,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oil, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Lubricants such as adsorbents, 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. For example,
For example, excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, disintegrating agents such as laminaran and agar 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. In this case, a sufficient amount of salt, grape or the like or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a usual solubilizing agent, buffer, soothing agent, etc. are 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. In the case of molding into a paste, cream or gel form, diluents conventionally known in this field can be widely used, and examples thereof include white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone and bentonite.

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

The administration method of the anti-ulcer agent of the present invention is not particularly limited, and various formulation forms, patient age, sex and other conditions,
The drug is administered according to the degree of the disease. For example, tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, it is orally administered. 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.

The dose of the anti-ulcer agent 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 1 kg of body weight per day, It is preferable to set the amount to about 0.6 to 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.

[0016]

EXAMPLES In order to explain the present invention in more detail, preparation examples of the antiulcer agent of the present invention will be given below, and test examples of active ingredient compounds will be given below.

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 5-Dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine 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 Dry Sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol Adequate amount The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed. I do.

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 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 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 SD male rats were purchased from Charles River Japan,
The animals were kept in the animal breeding room where the room temperature, the humidity and the light and dark were controlled until they were used for the test, by giving water and food freely. Using such a rat having a body weight of 350 to 450 g, fasting for 24 hours and water for 2 hours, and then 1 ml of 75% ethanol solution was used.
An ethanol-induced gastric ulcer was created by oral administration. One hour after the administration of ethanol, the rats were killed by decapitation, the stomachs were excised, fixed with 3% formalin, incised along the bay, and the stomach area and damaged area were measured by an image analyzer (Nikon, LUZEX2D). The ratio of the area of the damaged part to the total area excluding the forestomach was calculated and expressed as a percentage value.

The following compounds were used as test compounds, and the compounds were orally administered at the doses shown below 30 minutes before the administration of ethanol.

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 Test compound 1 and test compound 2 were suspended in 5% gum arabic and orally administered at 100 mg / kg. The administration volume was 1 ml / kg and the control group had the same volume of 5 ml.
% Acacia solution was administered. The gum arabic (acacia) used for ethanol and suspension is Wako Pure Chemical Industries, Ltd.
A special grade reagent manufactured by Mitsui Chemicals, Inc. was used.

The inhibitory rate (%) of gastric ulcer with respect to the control was determined, and 70% or more was evaluated as ++, 10% or more and less than 70% was evaluated as +, and less than 10% was evaluated as-, and the results are shown in Table 1.

[0025]

[Table 1]

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Hidenori Ogawa Nakakirai, Matsushige-cho, Itano-gun, Tokushima 18 Nakasai Nishinoketsu 25 No. 18 (72) Inventor Toyoki Mori Kitahama, Okuwajima, Narato-shi, Tokushima Prefecture Kitanohama 48th (72) Inventor Michiaki Tominaga 6 of 310 Takaiso, Ueita-cho, Itano-gun, Tokushima Prefecture

Claims (3)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a lower alkanoylamino 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 induction body represented by] 1- {1- [4- (5-pyrrolidinyloxy point pen chill oxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril, 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 and an anti-ulcer agent containing at least one selected from salts thereof as an active ingredient. 2. The anti-ulcer according to claim 1, wherein the active ingredient is 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril or a salt thereof. Agent. 3. The active ingredient is 1- {1- [4- (5-pyrro
Lysinylpentyloxy) benzoyl] -4-piperidi
Nyl} -3,4-dihydrocarbostyril, 5-dimethyl
Lumino-1- [4- (2-methylbenzoylamino)
Benzoyl] -2,3,4,5-tetrahydro-1H-
Benzazepine and 5-hydroxy-7-chloro-1-
[2-methyl-4- (2-methylbenzoylamino) be
Nzoyl] -2,3,4,5-tetrahydro-1H-be
At least selected from nzoazepine and salts thereof
The anti-ulcer agent according to claim 1, which is one kind.