JP3002766B2 - Brain edema treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for cerebral edema.

[0002]

2. Description of the Related Art Brain edema is caused by various brain diseases such as cerebral hemorrhage, cerebral infarction, brain tumor and encephalitis, and also when the brain is damaged due to heatstroke or traffic accident. Since cerebral edema shows serious symptoms such as impaired consciousness and convulsions, urgent treatment is required.

At present, hyperosmolar drugs such as mannitol and glyceol are used for the treatment of cerebral edema, but the development of safer and more effective drugs is desired.

On the other hand, the general formula

[0005]

Embedded image

[In the formula, R ¹ represents a hydrogen atom or a halogen atom. R ² represents a group —NR ⁵ R ⁶ . R ⁵ and R
⁶ is the same or different and represents a hydrogen atom or a lower alkyl group. R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. R ⁴ is a halogen atom,
It represents a lower alkyl group or a lower alkoxy group. And salts thereof are known compounds, and it is also known that these compounds have vasopressin antagonism or oxytocin antagonism (European Patent No. 45,097, and Japanese Patent Application Laid-Open No. -92
854).

[0007]

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies in order to develop a safe and effective therapeutic agent for cerebral edema, and found that the benzohetero compound represented by the above general formula (1) and a salt thereof are not suitable for the above pharmacological action. Has an unpredictable brain edema inhibitory action,
It has been found that it can be suitably used as a therapeutic agent for brain edema. The present invention has been completed based on such findings.

[0008] That is, the present invention relates to a therapeutic agent for cerebral edema comprising as an active ingredient at least one selected from the group consisting of the benzohetero compound represented by the general formula (1) and a salt thereof.

The respective groups represented by the general formula (1) are more specifically as follows.

Examples of the halogen atom include 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 active ingredient compound (1) 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 (1) used as an active ingredient in the present invention, the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Examples of such a basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, alkali metal carbonates and bicarbonates such as sodium carbonate and sodium hydrogen carbonate, and sodium methyl carbonate. And alkali metal alcoholates such as potassium ethylate. Further, in the compound (1) as an active ingredient in the present invention, a 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 the active ingredient compound in the present invention, similarly to the compound (1) in the free form. The compound (1)
Include stereoisomers and optical isomers, and these can be similarly used as the active ingredient compound.

The active ingredient compound of the present invention represented by the above general formula (1) is effective as a therapeutic agent for cerebral edema, 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 depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). 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, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrating agents such as sodium, stearic acid monoglyceride, starch, and lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; quaternary ammonium bases; and absorption promoters such as sodium lauryl sulfate; 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 a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-coated 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, hydrogenated vegetable oil, kaolin, talc, etc., binders such as gum arabic, tragacanth, gelatin, ethanol, etc., and 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 the 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. 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, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained in the pharmaceutical preparation as required.

The amount of the active ingredient compound to be contained in the therapeutic agent for cerebral edema 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, preferably about 1 to 70% by weight in the pharmaceutical composition. Is preferably about 5 to 50% by weight.

The method of administering the therapeutic agent for cerebral edema of the present invention is not particularly limited, and is administered in accordance with various preparation forms, age, sex and other conditions of the patient, 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 is administered intravenously, alone or in combination 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 cerebral edema 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. It is preferable to be 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.

[0019]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the therapeutic agent for cerebral edema of the present invention will be given, and then test examples of active ingredient compounds will be given.

Formulation Example 1 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 2 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 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 dried 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 to spray 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.

Formulation Example 3 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 1 (Effect of the Compound of the Present Invention in a Model of Hyperdiuretic Hormone Syndrome) Male SD rats (body weight: 250 to 350) were used as experimental animals.
g) was used.

On the day before the start of the experiment, an osmotic pump was implanted under the skin of the experimental animal. Antidiuretic hormone excess syndrome (SIA)
In the DH group), desmopressin was infused at 30 ng / hr, and in the control group, physiological saline was infused at a rate of 1 μl / hr for 4 days. In addition, desmopressin was prepared so as to contain 30 ng in 1 μl of physiological saline. In addition, only the SIADH group was subjected to a water load of 5% of the body weight twice a day in the morning and evening.

On the fifth day of the test, the SIADH group was divided into two groups, and one group contained the drug (5-dimethylamino-1-).
[4- (2-methylbenzoylamino) benzoyl]-
2,3,4,5-tetrahydro-1H-benzazepine) was orally administered at 30 mg / kg, and the other group was administered with water at 2 ml / kg. Four hours later, decapitated blood was collected, and the plasma osmotic pressure was measured and compared with the plasma osmotic pressure measured before administration of the drug. The cerebrum was taken out, and the water content in the brain was determined according to the following equation.

[0028]

(Equation 1)

The results are shown in FIG. 1 and FIG.

According to FIG. 1, it can be seen that the decrease in the plasma osmotic pressure is suppressed by about 29% by the administration of the drug, and that it has the effect of improving the osmotic pressure. By analogy with the effect of improving the osmotic pressure, it was considered that the cerebral water content was also improved by the same amount as the plasma osmotic pressure, that is, about 29% suppressed by the administration of the drug. However, as is clear from FIG.
It was confirmed that the drug had a remarkable effect (improvement of cerebral edema), which was suppressed by about 81% by the administration of the drug and could not be predicted from the effect of improving the osmotic pressure.

[Brief description of the drawings]

FIG. 1 is a graph showing the plasma osmotic pressure of a control group, a drug non-administration group, and a drug administration group.

FIG. 2 is a graph showing cerebral water content of a control group, a drug-free group, and a drug-treated group.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-4-154765 (JP, A) JP-A-6-92854 (JP, A) Kidney Int. , 46 (1), 237-44 (1994) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/55 CA (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom or a halogen atom. R ²
It is a group -NR ⁵ R ^6. R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom or a lower alkyl group. R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. R ⁴ represents a halogen atom, a lower alkyl group or a lower alkoxy group. ] A therapeutic agent for cerebral edema, comprising, as an active ingredient, at least one selected from the group consisting of a benzohetero compound represented by the formula: (2) 5-dimethylamino-1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
A therapeutic agent for cerebral edema comprising, as an active ingredient, at least one selected from the group consisting of 5-tetrahydro-1H-benzazepine and a salt thereof.