JPH0776521A - Respiratory inflammation depressor - Google Patents

Abstract

PURPOSE:To obtain a respiratory inflammation inhibitor excellent in the safety by using a specified carbostyril derivative which is a phosphodiesterase III type inhibitor or its salt as the active component. CONSTITUTION:A respiratory inflammation inhibitor containing a carbostyril derivative of the formula (A is a lower alkylene; R is a cycloalkyl; the 3-4 bond of the carbostyril skeleton is a single or double bond) or its salt as the active component. Among the carbostyril derivativhs of the formula, especially 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril or its salt is preferably used. This medicine is used in the form of tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository, injection, etc. Since this respiratory inflammation inhibitor can inhibit respiratory inflammation, this inhibitor is useful as a preventive and therapeutic agent for acute or chronic bronchitis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for suppressing respiratory tract inflammation, more specifically, a compound represented by the general formula (1)

[Chemical 2] [Wherein A is a lower alkylene group, R is a cycloalkyl group, and the bond between the 3- and 4-positions of the carbostyryl skeleton is a single bond or a double bond], or a carbostyryl derivative thereof, preferably Relates to an airway inflammation inhibitor containing 6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art The carbostyril derivative represented by the general formula (1) and a method for producing the same are described in Japanese Patent Publication No. 63-20235, and these are used as platelet aggregation inhibitors. It is also known to be useful. On the other hand, various studies have been carried out on the development of a drug suitable as an airway inflammation inhibitor, and some compounds such as phosphodiesterase (PD
Although theophylline, which is a non-selective inhibitor of E), is used, it is still desired to develop a new airway inflammation inhibitor.

[0003]

Means for Solving the Problems As a result of various studies, the present inventors have completed a PDE type III inhibitor (cGMP-i).
a carbostyril derivative represented by the above-mentioned general formula (1) which is inhibited, especially 6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy]
-3,4-dihydrocarbostyril or a salt thereof was found to be useful as an excellent airway inflammation suppressant,
The present invention has been completed. Until now, PDE III
There is no example of using a type I inhibitor as an airway inflammation suppressor, and based on the above new findings by the present inventor, PDE III
A more effective and safer respiratory tract inflammation inhibitor containing a carbostyril derivative represented by the above general formula (1) or a salt thereof which is a type inhibitor as an active ingredient is provided. The airway inflammation inhibitor of the present invention is useful as a preventive and therapeutic agent for acute or chronic bronchitis by inhibiting airway inflammation.

Examples of the lower alkylene group in the above general formula (1) include alkylene groups having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and 2-methyl-trimethylene. Tetramethylene is particularly preferable. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being particularly preferred.

The airway inflammation inhibitor of the present invention has the general formula
The carbostyril derivative represented by (1) or a salt thereof is prepared 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, ceramic, 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,
Sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agent such as lactose, sucrose, stearin,
Disintegration inhibitors such as kao butter and hydrogenated oil, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid. , Purified talc, stearates, phonic acid powder, lubricants such as polyethylene glycol, and the like. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film coating agent 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. When molding in the form of suppositories, conventionally known carriers can be widely used, for example, polyethylene glycol,
Examples thereof include cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides.

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.

Injectables are used in the form of solutions, emulsions and suspensions, which are preferably sterilized and isotonic with blood. In forming the solutions, emulsions and suspensions, all diluents commonly used in this field can be used, such as water,
Examples thereof include ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, 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 amount of the carbostyril derivative (I) or its salt to be contained in the respiratory tract inflammation inhibitor of the present invention is not particularly limited and may be selected within a wide range, but usually 1 to
70% by weight, preferably 5 to 50% by weight.

The administration method of the respiratory tract inflammation suppressor of the present invention is not particularly limited, and it may be administered according to various formulation forms, patient age, sex and other conditions, and degree of disease.
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 respiratory tract inflammation inhibitor of the present invention is as follows:
The amount of the carbostyril derivative (I) or its salt is usually 0.6 to 50 mg per 1 kg of body weight per day, though it is appropriately selected depending on the age, sex and other conditions of the patient, and the degree of disease. In addition, the active ingredient in the dosage unit form is 10
It is recommended to contain ~ 1000 mg.

[0013]

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

Formulation Example 1 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 150 g Avicel (trade name, Asahi Kasei Corporation) 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g After mixing and polishing the active compound of the present invention, Avicel, cornstarch and magnesium stearate, sugar coating R10mm
Tablet with the key. The obtained tablets are hydroxypropylmethyl cellulose, polyethylene glycol-600.
A film coating agent consisting of 0, castor oil and methanol is coated to produce a film coated tablet.

Formulation Example 2 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -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 Dry Sodium lauryl sulphate 3.0 g Dry magnesium stearate 3.0 g Ethanol Adequate The active compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulphate are mixed. The above mixture was added to No. Sieve through a 60 screen, 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 corn starch and continue mixing until uniform particles are formed. No. Pass 10 screens, put in a tray and open at 100 ° C for 1
Dry for 2-14 hours. The dried particles were Sift through a 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 completely 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 6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 5 g polyethylene glycol (molecular weight: 4000) 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 Parabens, sodium metabisulfite and chloride Dissolve sodium with stirring at 80 ° C. in about half of the above distilled water. The resulting solution was cooled to 40 ° C. and the active compound of the invention, then polyethylene glycol and polyoxyethylene sorbitan monooleate were 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 Cilostazol [6- [4- (1-cyclohexyl-1,2,3,4-) for pulmonary resistance-increasing action and capillary permeability-increasing action by substance P in guinea pigs
Effect of Tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril [generic name]: Test method Male Hartley guinea pigs (body weight 398 ± 5 g, n = 2
7) was anesthetized by intraperitoneal injection of urethane and fixed in the dorsal position. Insert a tracheal cannula into the cervical trachea and change the ventilation volume to 10 m.
Artificial respiration was performed at l / kg and a respiration rate of 60 times / min. Also,
The left carotid artery and the right jugular vein were cannulated for blood pressure measurement and intravenous drug administration, respectively. Measurement of lung resistance : One end was inserted into the chest cavity, the other end was connected to a side branch of a tracheal cannula, and the airway pressure was measured via a pressure transducer. In addition, airway flow was measured using a pneumotachography, and lung resistance was determined from airway pressure and airway flow by von Neergard and Wirz (Z. Klin. Med. 105: 51:51).
-82, 1927). Measurement of capillary permeability : Evans blue was intravenously administered at 20 mg / kg 1 minute before the administration of substance P. After the experiment was completed, the lumen of the blood vessel was washed with physiological saline to remove the trachea to lungs, and the trachea, main bronchus, proximal lobe bronchus, and distal lobe bronchus 4
It divided and measured the wet weight of each. Evans blue was extracted with formamide, and the amount of Evans blue was measured by measuring the absorbance at 620 nm using a photometer, which was used as an index of capillary permeability. Protocol : Cilostazol was dissolved in 80% ethanol / distilled water, Substance P and Evans Blue were dissolved in physiological saline. Cilostazol 1.5 mg / k 10 minutes after starting artificial respiration
g or 5 mg / kg or 80% ethanol was intravenously administered, and 4 minutes after that, 20 mg / kg of Evans blue was intravenously administered. 1 minute later, 30 nmol / of substance P
kg was intravenously administered, and changes in lung resistance were observed for 5 minutes after the administration. After the observation, the trachea to lungs were removed and the amount of Evans blue was measured.

Test Results Blood pressure : 80% ethanol, cilostazol 1.5 mg / kg or 5 mg / kg changes in mean blood pressure by -15%, respectively
It was -25% and -26%, and there was no significant difference between the three groups. After administration of substance P, the values were −43%, −32%, and −43%, respectively, showing no significant difference between the three groups. Lung resistance : As shown in Table 1 below, cilostazol dose-dependently suppressed the lung resistance increasing effect of substance P at 1.5 mg / kg and 5 mg / kg, and significantly suppressed it at 5 mg / kg. there were. Capillaries : As shown in Table 2 below, cilostazol has an effect of enhancing the capillary permeability of substance P by 5
It showed an inhibitory effect at mg / kg and was significant in the trachea and main bronchus.

[0019]

[Table 1]

[0020]

[Table 2]

Claims (2)

[Claims] 1. A general formula: [Wherein A is a lower alkylene group, R is a cycloalkyl group,
The bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond], which is an airway inflammation inhibitor containing a carbostyril derivative or a salt thereof as an active ingredient. 2. The active ingredient is 6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy].
The drug according to claim 1, which is -3,4-dihydrocarbostyril or a salt thereof.