JP2010024164A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition which is suitably used as a therapeutic agent or a preventing agent in cognitive disorders such as a drop of attentiveness and a disorder of learning memory or anxiety exasperation. <P>SOLUTION: The pharmaceutical composition comprises a vasopressin antagonist of a benzoazepin compound, its salt or the like. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition.

Vasopressin antagonists include hypertension, edema, ascites, heart failure, renal dysfunction, vasopressin secretion syndrome (SIADH), cirrhosis, hyponatremia, hypokalemia, polycystic kidney disease, diabetes, circulatory failure, myocardial infarction, It is known to be useful for the prevention and / or treatment of diseases such as cerebral infarction (Patent Document 1).
Japanese Patent Laid-Open No. 4-154765

  An object of the present invention is to provide a pharmaceutical composition capable of exhibiting a therapeutic or prophylactic effect in cognitive impairment such as reduced attention, learning and memory impairment, or increased anxiety.

  In order to solve the above problems, the present inventors have conducted various studies, and as a result, vasopressin antagonists have the effect of suppressing cognitive impairment such as reduced attention, learning and memory impairment, or increased anxiety. I found out. The present invention has been completed based on such findings.

The present invention provides pharmaceutical compositions shown in the following items 1 to 4.
Item 1. A pharmaceutical composition comprising a vasopressin antagonist as an active ingredient and used for suppressing cognitive impairment or increased anxiety.
Item 2. Vasopressin antagonists have the general formula (1)

[Wherein, R ¹ represents a hydrogen atom or a halogen atom. R ² represents a hydroxyl group or a group —NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each 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 represents a halogen atom, a lower alkyl group or a lower alkoxy group. ]
Item 2. A pharmaceutical composition according to Item 1, which is a benzazepine compound represented by the formula:
Item 3. Item 3. The pharmaceutical composition according to Item 2, wherein the benzoazepine compound represented by the general formula (1) is tolvaptan.
Item 4. Item 2. The pharmaceutical composition according to Item 1, wherein the cognitive disorder is reduced attention or impaired learning memory.

  As a vasopressin antagonist used by this invention, a well-known vasopressin antagonist can be used widely, Preferably the benzoazepine compound or its salt represented by General formula (1) is mentioned.

[Wherein, R ¹ represents a hydrogen atom or a halogen atom. R ² represents a hydroxyl group or a group —NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each 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 represents a halogen atom, a lower alkyl group or a lower alkoxy group. ]
The benzazepine compound represented by the general formula (1) and a salt thereof are competitive or non-competitive for binding of vasopressin to arginine vasopressin (AVP) type 1A (V1A) receptor and type 2 (V2) receptor. Has an action of selectively inhibiting competitive or non-competitive binding of vasopressin to the V2 receptor (ie, V1 / V2).

  More specifically, each group shown in the general formula (1) is as follows.

  As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are shown.

  The lower alkyl group includes a linear or branched alkyl group having 1 to 6 carbon atoms. Preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl. , N-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl group and the like.

  The lower alkoxy group includes a linear or branched alkoxy group having 1 to 6 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec -Butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy group and the like can be mentioned.

  Among the benzoazepine compounds represented by the general formula (1) and salts thereof, tolvaptan, mozabaptan and mozabaptan hydrochloride are preferable, and tolvaptan is more preferable.

  The benzazepine compound represented by the general formula (1) and a salt thereof are disclosed in, for example, WO 91/05549, USP 5258510, USP5753677, JP-A-4-154765, JP-A-6-80641, and the like. It is easily manufactured by the described method.

  The benzazepine compound represented by the general formula (1) of the present invention includes stereoisomers and optical isomers.

  Among the benzoazepine compounds represented by the general formula (1) of the present invention, a compound having a basic group can easily form a salt with a normal pharmacologically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid and maleic acid. , Organic acids such as fumaric acid, malic acid, succinic acid and lactic acid.

  Among the benzoazepine compounds represented by the general formula (1) of the present invention, a compound having an acidic group can easily form a salt by acting a pharmaceutically acceptable basic compound. Examples of such basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. And alkali metal alcoholates such as sodium methylate and potassium methylate.

  Furthermore, compounds in the form of solvates (for example, hydrates, ethanol solvates, etc.) are also included in the benzazepine compound of the general formula (1).

  The pharmaceutical composition of the present invention is prepared by formulating a vasopressin antagonist in the form of a normal medical preparation, and is generally used as a filler, a bulking agent, a binder, a moistening agent, a disintegrant, a surfactant, It is prepared using a diluent such as a lubricant and / or an excipient.

  Such a medical preparation can be selected from various forms depending on the purpose of treatment, and representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories. Agents, injections (solutions, suspensions, etc.) and the like.

  As the carrier used for molding into a tablet form, known ones can be widely used, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients, Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, hydrogen carbonate Sodium, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors, quaternary ammonium Group, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Lubricants and the like.

  Furthermore, the tablets can be coated with a normal coating material as necessary, and can be, for example, sugar coatings, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  As the carrier used for forming into a pill form, known ones can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.

  As the carrier used for forming into a suppository form, known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

  When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. As the diluent used for forming these liquids, emulsions and suspensions, known ones that are widely used can be used, for example, water, ethanol, propylene glycol, ethoxy Isooxyallyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbetane fatty acid esters and the like. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizing agent, buffer, soothing agent, etc. If necessary, colorants, preservatives, fragrances, flavors, sweeteners, and / or other pharmaceuticals may be included.

  The amount of the active ingredient (vasopressin antagonist) contained in the medical preparation is not particularly limited and can be appropriately selected from a wide range. Usually, the active ingredient is added in an amount of 0.1 to 95 in the medical preparation pharmaceutical composition. It is preferable to contain about 1% by weight, preferably about 1 to 70% by weight.

  There is no restriction | limiting in particular as the administration method of the medical formulation which concerns on this invention, It administers by the method according to various formulation forms, a patient's age, sex, a disease state, and other conditions. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of injections, they are administered alone or mixed with normal fluids such as glucose and amino acids and administered intravenously, or further alone, intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. Can be administered. In the case of a suppository, it is administered intrarectally.

  As used herein, “effective amount” refers to the amount of a vasopressin antagonist that is routinely used in clinical therapy. A general effective amount is about 0.05 to 5000 mg, preferably about 0.05 to 2500 mg, of a vasopressin antagonist per day per adult.

  The dosage of the above-mentioned medical preparation may be appropriately selected according to the usage, patient age, sex, degree of disease, and other conditions, and is generally 0.1 per person per body (body per day). About 1000 mg, preferably about 0.5 to 500 mg, more preferably 1 mg to 100 mg is administered in 1 to several divided doses.

  Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage exceeding the above range may be necessary.

  The pharmaceutical composition of the present invention is suitably used as a therapeutic or prophylactic agent in cognitive impairment such as reduced attention, learning and memory impairment, or increased anxiety.

  The present invention will be further clarified by the following examples.

Pharmacological test 1 (behavioral pharmacological test)
1. Chronic hyponatremia model test method moderate and severe, a peptidic vasopressin V ₂ receptor agonist using osmotic minipumps awake male SD rats [deamino-Cys1, D-Arg8 ] - vasopressin (hereinafter, "DDAVP") was administered by continuous subcutaneous administration (0.3 ng / h and 1 ng / h), and combined with a liquid feed for water loading. About 0.3 mL of blood was collected from the tail vein on days 0, 5, 9, and 13 from the first administration of DDAVP, and the plasma sodium concentration was measured. Various behavioral pharmacological tests were carried out from the fifth day of the test when the symptoms were stabilized.

  First, the general symptoms of rats in hyponatremia were observed over 38 items using the Irwin observation test method.

  In the open field test, a 100 cm × 100 cm open field surrounded by a 40 cm high wall is divided into 25 areas of 20 cm square, and a device that illuminates from above is used. The number of crossings, the total walking distance and the number of standing up were measured with an automatic analyzer.

  In the elevated plus maze test, two open arms with a width of 10 cm and a length of 50 cm located at a height of 50 cm from the floor and two closed arms intersecting at right angles to it (a wall made of black acrylic with a height of 25 cm) Measure the number of times of entry into each arm, the staying time and the distance traveled in each arm with an automatic analyzer immediately after placing the rat in the center of the maze. did.

  In the rotor rod test, a rat was first trained to walk on a rotor rod treadmill rotating at 6 rpm for more than 1 minute, and then the rotor was set to accelerate to 6 to 60 rotations in 3 minutes. The time from when the rat was placed on the rod treadmill until it dropped was measured.

  In the passive avoidance learning test, as a training, first place the rat in the light room of the chamber divided by the electric drop door in the light room and the dark room, and close the door as soon as the rat moves to the dark room. Second, an electric shock of 2 mA was applied. After 24 hours, the rats were similarly placed in the light room and the time until moving to the dark room was measured, and the difference between the movement time during training and the movement time during measurement was calculated (upper limit 180 seconds).

2. Test Results and Discussion Moderate (plasma sodium concentration: about 125 mEq / L) and severe (plasma sodium concentration: about 117 mEq / L) hyponatremia developed by continuous administration of DDAVP and liquid feed intake (FIG. 1) In all cases, no abnormality was observed in general symptoms (observation in Irwin observation test).

  There was no difference in spontaneous movement (index: total distance traveled in the open field test and elevated plus maze, FIGS. 2 and 3) and motor function (index: time spent on the device in the rotor rod test).

  However, even in such a seemingly asymptomatic state, hyponatremia rats showed a reduction in central residence time and a decrease in standing behavior in the open field test (FIG. 2), and an elevated plus maze. The open arm residence time was shortened in the test (FIG. 3), suggesting increased anxiety.

  Furthermore, in the passive avoidance learning test, in hyponatremia rats, the time to move to the dark room (staying time in the light room) was clearly shortened (FIG. 4), suggesting that learning memory impairment was inherent. It was done.

Pharmacology test 2 (Improvement test for anxiety and learning memory impairment)
In the above pharmacological test 1, vasopressin V ₂ receptor antagonist (tolvaptan) was orally administered (starting from 0.25 mg / kg for the first time, 0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg every two days) It is possible to confirm that the increase in anxiety and impaired learning memory due to gradual oral administration of tolvaptan are improved.

FIG. 1 is a graph showing the relationship between the number of days since administration of DDAVP and plasma sodium concentration. FIG. 2 is a graph showing the results of an open field test in Pharmacological Test 1. FIG. 3 is a graph showing the results of an elevated plus maze test in Pharmacological Test 1. FIG. 4 is a graph showing the results of the passive avoidance learning test in Pharmacological Test 1.

Claims (4)

  A pharmaceutical composition comprising a vasopressin antagonist as an active ingredient and used for suppressing cognitive impairment or increased anxiety. Vasopressin antagonists have the general formula (1)

[Wherein, R ¹ represents a hydrogen atom or a halogen atom. R ² represents a hydroxyl group or a group —NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each 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 represents a halogen atom, a lower alkyl group or a lower alkoxy group. ]
The pharmaceutical composition according to claim 1, which is a benzazepine compound represented by the formula:   The pharmaceutical composition according to claim 2, wherein the benzoazepine compound represented by the general formula (1) is tolvaptan.   The pharmaceutical composition according to claim 1, wherein the cognitive disorder is reduced attention or learning memory disorder.

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