JPH07101862A - Urease inhibitor - Google Patents

Abstract

PURPOSE:To obtain a urease inhibitor containing a carbostyryl derivative as an active ingredient. CONSTITUTION:The inhibitor contains, as an active ingredient, a compound of the formula (R is halogen), for example, 2-(4-chlorobenzoyl-amino)-3-(2- quinolon-4-yl)propionic acid or its salt in an amount of 1 to 70wt.%, based on the total composition. The dose is 0.6 to 50mg/kg/day. Urease is an enzyme to catalyze the hydrolysis of urea and useful in prophylaxis and treatment for the diseases caused by production of ammonia, when the urease activity is increased by proliferation of a variety of bacteria. For example, it is useful in prophylaxis and treatment for gastric mucosa disorders which has been thought to be caused by ammonia formation due to proliferation of Helicobacter pyrrolii. Further, the inhibition of enteric dimonia formation is useful in prophylaxis and treatment for hyperammonemia and symptoms accompanied by the hyperammonemia, concretely, hepatic encephalopathy, psychoneurotic disorders, brain wave anomaly, finger tremor.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a urease inhibitor, more specifically, a compound represented by the general formula (I)

[Chemical 2] [Wherein R represents a halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom), the substituent on the carbostyryl skeleton has a substitution position of 3 or 4 position, and The bond between the 3-position and the 4-position represents a single bond or a double bond] or a salt thereof, preferably 2- (4-chlorobenzoylamino) -3- (2-quinolone-4). -Yl) to a urease inhibitor containing propionic acid or a salt thereof as an active ingredient.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION The carbostyril derivative represented by the above general formula (I) and its manufacturing method are described in JP-B-63-35623, and they are useful as an anti-gastric ulcer agent. It is also known. Further, JP-A-3-74329 describes that these compounds are also useful as urease inhibitors.

Urease is an enzyme that catalyzes the hydrolysis of urea. This enzyme has a wide distribution from microorganisms such as legumes, including bacteria and filamentous fungi, to animals, and is present in gastric mucosa and erythrocytes in mammals (Nanzandou Medical Dictionary). By the way, it is said that this enzyme causes various diseases in the living body, and the urease activity is increased by the growth of bacteria and the like, urea is analyzed and ammonia is produced, which causes various diseases. There is. For example, it is known that Helicobacter pylori present in the stomach exhibits a strong urease activity, and its growth produces ammonia, which causes gastric mucosal damage.

[0004]

Means for Solving the Problems The present inventors have conducted various studies to find a new drug useful for the prevention and treatment of diseases associated with the activity of urease, and as a result, the above-mentioned general formula (I ), A carbostyril derivative represented by the formula: 2- (4-chlorobenzoylamino)-
The inventors have found that 3-quinolon-4-yl) propionic acid or a salt thereof has an excellent urease inhibitory action, and completed the present invention.

The urease inhibitor of the present invention is prepared by preparing the carbostyril derivative represented by the general formula (I) or a salt thereof in the form of a general pharmaceutical preparation. Such a preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( (Liquids, suspensions, etc.) and the like.

In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder , Laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agent such as lactose, sucrose, stearin,
Cocoa butter, disintegration inhibitor such as hydrogenated oil, quaternary ammonium base, absorption enhancer such as sodium lauryl sulfate, glycerin, moisturizer such as starch, starch,
Examples thereof include adsorbents such as lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearates, boric acid powders, lubricants such as polyethylene glycol.
Further, the tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet or a double-layered tablet or a multi-layered tablet.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc, Gum arabic powder,
Examples include tragacanth powder, gelatin, binders such as ethanol, disintegrators such as laminaran and agar.

In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

When prepared as an injection, a liquid preparation,
It is preferably prepared as an emulsion or suspension, which is usually sterile and isotonic with blood. When molding into the form of these solutions, emulsions and suspensions,
Any diluent customary in the art can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol,
Examples thereof include polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the therapeutic agent, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. Further, if necessary, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the therapeutic agent.

The urease inhibitor of the present invention is useful for the prevention and treatment of diseases that are considered to be caused by the production of ammonia by increasing urease activity due to the growth of various bacteria and, for example, the growth of Helicobacter pylori. Can be used for the prevention and treatment of gastric mucosal disorders, which are thought to occur due to the production of ammonia. In addition, by suppressing the production of ammonia in the intestinal tract, improvement and treatment of hyperammonemia and symptoms associated with hyperammonemia, specifically, hepatic encephalopathy and neuropsychiatric disorders caused by liver diseases such as hepatitis and cirrhosis. It can be used for prevention and treatment of EEG abnormalities and finger tremor. The amount of the carbostyril derivative (I) or its salt to be contained in the urease inhibitor of the present invention is not particularly limited and can be selected within a wide range, but usually 1 in the total composition.
˜70 wt%, preferably 5 to 50 wt%.

The method for administering the urease inhibitor of the present invention is not particularly limited, and it may be administered according to various formulation forms, patient age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. In the case of suppositories, it will be administered rectally.

The dose of the urease inhibitor of the present invention is appropriately selected depending on the usage, age of the patient, sex and other conditions, degree of disease and the like, but usually the amount of the carbostyril derivative (I) or its salt is 1 0.6 per 1kg body weight per day
The dosage is preferably about 50 to 50 mg, and 10 to 1000 mg of the active ingredient is contained in the dosage unit form.

[0013]

EXAMPLES Next, the urease inhibitor of the present invention will be described more specifically with reference to formulation examples and pharmacological experiments.

Formulation Example 1 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic acid 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl Methyl cellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40 g The compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and polished, and then tableted with a sugar coated R10 mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropylmethylcellulose, polyethylene glycol-6000, castor oil and methanol to produce film-coated tablets.

Formulation Example 2 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic acid 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulphate 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 lauryl sulphate 3.0 g Dry magnesium stearate 3 0.0g ethanol suitable amount

The compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed. The above mixture was added to No. 60
Screen and wet granulate with an alcoholic solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. Alcohol is added as needed to make the powder a pasty mass. Add cornstarch,
Continue mixing until uniform particles are formed. Pass through a No. 10 screen, place in a tray and dry in an oven at 100 ° C for 12-14 hours. The dry particles are screened through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added and mixed and compressed into the desired shape on a tablet machine. The core is treated with a varnish and sprinkled with talc to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish enough times for internal use. Further subbing layers and smooth coatings are applied to make the tablets perfectly round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic acid 5 g Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan mono Oleate 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 parabens, sodium metabisulfite and sodium chloride are dissolved in about half the above distilled water at 80 ° C. with stirring. The resulting solution is cooled to 40 ° C. and the compound of the invention, then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilizing filtration using an appropriate filter paper to prepare an injection.

Pharmacological test 1. As the drug used, urease (EC3.5.1.5), a commercially available enzyme preparation made from nata beans (Sigma) was used. Phosphate buffer (Wako Pure Chemical), sodium salicylate (Wako Pure Chemical), sodium nitrosylpentacyanoferrate (III) (Wako Pure Chemical), sodium hypochlorite (Wako Pure Chemical), sodium hydroxide (Wako Pure Chemical) medicine). 2- (4-chlorobenzoylamino) -3- (2-quinolon-4-yl) propionic acid (test drug).

2. Urease activity assay method Urease activity was determined by measuring the amount of ammonia produced by urease in the presence of urea by the indophenol method. That is, 10 μl of the test drug solution prepared so that the final concentration was 3 mM was mixed with 10 μl of a urea solution ((1.07 mg / ml), and preincubated at 37 ° C. for 10 minutes. 1U / ml), sodium salicylate (0.25m
M), phosphate buffer (90 mM, pH containing sodium nitrosyl pentacyanoferrate (III) (6.7 mM)
7.0) 1 ml was added and incubated for another 30 minutes. To this, 1 ml of a mixed solution of sodium hypochlorite and sodium hydroxide was added as a coloring reagent to stop the reaction. After leaving it at room temperature for 10 minutes, the absorbance at 570 nm was measured by a spectrophotometer (JASCO, UNIDEC-340) using a reagent blind test in which distilled water was used instead of urea.
It was measured at. The inhibitory activity was expressed with the absorbance of the control group (without the test drug) as 100%. The inhibition rate was calculated by the following formula. 3. Experimental Results The above experimental results are shown in Table 1.

[0021]

[Table 1] Drug concentration (mM) Absorbance * Average inhibition rate of absorbance (%) Control group 0 0.301 0.293 0.297 Rebamipide 3 0.177 0.172 0.1745 41.2 * Absorbance at 570 nm As is clear from the above results, the test drug was 41.2% at a concentration of 3 mM. The urease inhibition rate was shown.

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[Procedure amendment]

[Submission date] November 2, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0002

[Correction method] Change

[Correction content]

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION The carbostyril derivative represented by the above general formula (I) and its manufacturing method are described in JP-B-63-35623, and they are useful as an anti-gastric ulcer agent. It is also known. Further, JP-A-3-74329 describes that these compounds are also useful as therapeutic agents for gastritis.

Claims (2)

[Claims] 1. A general formula: [In the formula, R represents a halogen atom, the substitution position of the substituent on the carbostyryl skeleton is the 3-position or 4-position, and the bond between the 3-position and the 4-position of the carbostyryl skeleton is a single bond or Showing a double bond], which is a urease inhibitor containing a carbostyril derivative or a salt thereof as an active ingredient. 2. The urease inhibitor according to claim 1, wherein the active ingredient is 2- (4-chlorobenzoylamino) -3- (2-quinolon-4-yl) propionic acid or a salt thereof.