JPH0692352B2 - γ-Aminobutyric acid derivative, its production method and its pharmaceutical use - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel γ-aminobutyric acid derivative, a process for producing the same, and its pharmaceutical use, in particular, its use as a medicament for preventing and / or treating cerebral dysfunction. .

BACKGROUND ART It is already known that γ-aminobutyric acid plays an important function as an information transmitter in the brain and is involved in metabolic regulation in the brain [GB Makara et al., Neuroendocrino.
logy, 16 , 178 (1975)]. In recent years, focusing on the fact that γ-aminobutyric acid is involved in metabolic regulation in the brain,
Although studies using γ-aminobutyric acid as a medicine have been actively conducted, γ-aminobutyric acid itself hardly passes through the blood-brain barrier and is easily excreted in urine. Is mainly directed to chemically modifying γ-aminobutyric acid into a form that easily crosses the blood-brain barrier, that is, to find a prodrug of γ-aminobutyric acid that can easily cross the blood-brain barrier. ing. As an example, 4- (2,4-dihydroxy-3,3-dimethylbutyramide) butyric acid (generic name: fopanthenic acid) or a pharmacologically acceptable salt thereof is used for head trauma, brain surgery or cerebrovascular disorder. It has been proposed to use it for the treatment of dementia and blurring caused by (see JP-A-55-17329). In addition, it has been reported that intraperitoneal administration of nicotinoyl γ-aminobutyric acid or isonicotinoyl γ-aminobutyric acid shows a prominent sleep time prolonging action and a strong anti-convulsive action [The Japanese Society of Pharmaceutical Sciences 104th year. 6th Meeting Abstracts
Page 66 (1984)].

Problems to be Solved by the Invention Conventionally, many compounds have been taken up to develop a prodrug of γ-aminobutyric acid by focusing on the metabolic regulation effect of γ-aminobutyric acid in the brain, but the above-mentioned hopantenoic acid or its With a few exceptions such as salts, there are problems with their transferability into the brain or toxicity, and they have not been put to practical use.

Therefore, one of the objects of the present invention is to provide a novel and useful γ-aminobutyric acid derivative, particularly a γ-aminobutyric acid derivative which easily migrates into the brain and exhibits a beneficial pharmacological action, for example, a brain function improving action. It is in.

Another object of the present invention is to provide a method for producing such a novel γ-aminobutyric acid derivative.

Another object of the present invention is to provide a brain function improving agent containing the γ-aminobutyric acid derivative as an active ingredient.

Other objects and features of the invention will be apparent from the detailed description below.

Means for Solving the Problems According to the present invention, the following formula The following provides 4- (3,5-dihydroxy-3-methylpentyramide) butyric acid represented by: and pharmacologically acceptable salts and esters thereof.

The above 4- (3,5-dehydroxy-3-methylpentyramide) butyric acid (hereinafter, for simplification, this compound is referred to as MV-GABA
Abbreviated) includes DL-form, D-form, and L-form. MV-GA
Examples of pharmacologically acceptable salts of BA include sodium salt,
Alkali metal salts such as potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts; ammonium salts; organic amine salts such as trimethylamine salts and triethylamine salts. Also, MV-GA
The pharmacologically acceptable ester of BA may be any ester that can be easily cleaved and removed by the action of esterase existing in the human body, and specifically, methyl ester, ethyl ester, propyl ester, Lower alkyl esters such as isopropyl ester, butyl ester, tert-butyl ester and the like can be mentioned.

Further, according to the present invention, a salt or ester of γ-aminobutyric acid is reacted with mevalolactone to form a salt or ester of MV-GABA, and the salt or ester is converted to a free acid, if necessary. Accordingly, there is provided a method for producing MV-GABA or a pharmacologically acceptable salt or ester thereof, which comprises converting the free acid into a pharmacologically acceptable salt or ester.

The reaction of the salt or ester of γ-aminobutyric acid with mevalolactone can usually be carried out in a suitable solvent at a temperature in the range of about -30 ° C to about 100 ° C, preferably room temperature to 80 ° C. Thus, a salt or ester of MV-GABA is obtained. Examples of the solvent used include water; methanol,
Lower alkanols such as ethanol and isopropanol; ethylene glycol, 2-methoxyethanol, 2
-Ethoxyethanol and the like can be mentioned, and particularly water, ethanol, 2-methoxyethanol, 2-ethoxyethanol and the like are advantageously used. The ratio of mevalolactone to the salt or ester of γ-aminobutyric acid is not critical and can be varied over a wide range, but mevalolactone is generally 0.5 to 5 mol, preferably 0.8 mol per mol of the salt or ester of γ-aminobutyric acid. It is suitable to use within the range of ˜2 mol. In particular, it is preferable to use the salt of γ-aminobutyric acid and mevalolactone at a molar ratio of 1: 1 and to carry out the reaction until it is sufficiently completed, in order to facilitate purification of the product after the reaction. Examples of the salt of γ-aminobutyric acid that can be used as a starting material include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; ammonium salt;
Trimethylamine salts, organic amine salts such as triethylamine salts, and the like, and as the ester of γ-aminobutyric acid, for example, methyl ester, ethyl ester,
Examples thereof include lower alkyl esters such as propyl ester, isopropyl ester, butyl ester and tert-butyl ester. However, it is preferred to use, in particular, the calcium salt of γ-aminobutyric acid as the starting material, which is reacted with mevalolactone.

The salt or ester of MV-GABA obtained by the above reaction can be converted into a free acid by a method known per se, for example, treatment with a strongly acidic cation exchange resin or hydrolysis. The free acid may be converted into a pharmacologically acceptable salt or ester.

MV-GABA or a pharmacologically acceptable salt or ester thereof provided by the present invention (hereinafter, these compounds are generically referred to as γ-aminobutyric acid derivatives) can be used in a pharmacological test using animals shown below, It easily crosses the blood-brain barrier and exerts a marked influence on metabolic regulation in the brain, for example, an action of significantly reducing spontaneous locomotor activity, an antagonistic action against increase in locomotor activity by methamphetamine, and pentobarbital (pentobarbital). ) Significantly increases sleep time, atropine (atro
It was confirmed that it exhibits a significant inhibitory effect on the increase in motor activity caused by pine) and a significant memory-improving effect on the cycloheximide-induced amnesia model and the electroconvulsive-induced amnesia model.

Hereinafter, each test example will be described with respect to the pharmacological properties of the compound provided by the present invention.

Pharmacological test The following tests 1 to 4 were carried out using male ddY mice (body weight 20 to 25 g) in a semi-noise-proof room at room temperature of 23 ± 1 ° C and humidity of 55 ± 2%. Ingested freely.

Test 1: Effects on spontaneous locomotion (1) Rotation cage method The effects on the spontaneous locomotion of mice were examined using a rotation cage (manufactured by Kishimoto Medical). Before the test, the mouse was placed in a rotating basket, and a mouse having a rotation speed of 15 to 15 minutes showing a value of 200 to 300 was selected in advance and used for the test. The number of mice was 8 per group, each dose of the test drug was intraperitoneally administered, and then immediately placed in a rotating basket, and the spontaneous locomotor activity (number of rotations) was measured at 15-minute intervals for 90 minutes.
It was compared with the control group. The results are shown in Table 1.

(2) Automex method Automex activity measurement device (Automex activitymet)
er; Columbus) was used to examine the effect on planar locomotion. With the rotating cage
Mice showing a value of 200 to 300 were selected to make 5 mice per group, and each dose of the test drug was intraperitoneally administered,
Immediately, 5 animals were placed in a transparent plastic cage (27 × 17 × 17 cm), placed on an automex, and the amount of exercise for 30 minutes was measured at 5-minute intervals, and compared with the control group. The results are shown in Table 2.

Test 2: Anti-action against methamphetamine (automex method) Using 5 mice each in a group, 3 mg / kg of methamphetamine was subcutaneously administered immediately after intraperitoneal administration of a predetermined amount of the test drug.
The effect of the test drug on methamphetamine-induced hyperlocomotion was examined according to the above-mentioned automation method. The results are shown in Table 3.
Shown in.

As is clear from Table 3, calcium fopanthenate 500m
The g / kg administration showed almost no antagonistic effect on the increase in locomotion by metaamphetamine in mice, but MV-
The administration of 500 mg / kg of GABA-Ca salt markedly suppressed the hyperactivity of methamphetamine in mice.

Test 3: Pentobarbital sleep prolongation effect The effect of the test drug on the sleep induced by pentobarbital was investigated. The sleep index is the disappearance of the righting reflex for more than 5 seconds. The number of mice was 10 per group, and after intraperitoneally administering each dose of the test drug,
Immediately subcutaneously administer Na-pentobarbital 50 mg / kg,
Sleep time was compared with the pentobarbital single administration group (control). The results are shown in Table 4.

Test 4: Antagonism against atropine (automatic method) Using 6 mice per group, each dose of the test drug was immediately administered intraperitoneally to atropine (hereinafter, this may be abbreviated as At) 30 mg / kg was subcutaneously administered, and the effect of the test drug on the hyperactivity caused by atropine was examined according to the above-mentioned automex method. The results are shown in Table 5.

Test 5: Memory-improving effect on amnesia model 1. Tested animal test is ddY male mouse (weight 30-35g)
Was used at room temperature (around 20 ° C.), and the mice were allowed to freely ingest the feed and water.

2. Check of effects on learning behavior (1) Test equipment Floor grid surrounded by a 21 cm square acrylic glass wall and 4 cm x 4 cm x 4c fixed at the center of the floor grid.
The device consisting of m wooden platform was installed and used in a 21 cm × 21 cm × 40 cm wooden semi-insulation box with a 15 W light bulb on the ceiling. Floor grid is 8mm with a 3mm diameter stainless steel rod.
These were placed at intervals and were subjected to intermittent electric shock (1 Hz, 0.5 seconds, 60 VDC) by an electric stimulator and an isolator.

(2) Training test The mouse is orientated in a certain direction and placed on the platform.
Immediately after the mouse descends onto the floor grid (step down: the limb leaves the platform)
Load the electric shock on the floor grid and continue to load the electric shock intermittently until the mouse climbs onto the platform to escape from the electric shock, until the mouse descends from the platform (step down lateney: Time is abbreviated as SDL) and time to escape from electric shock to platform (escape lear
ning latency; hereinafter, this time is abbreviated as ELL).

A mouse in which SDL and ELL fall within a certain range is selected and subjected to the following test.

(3) Retention trial In the same procedure as the above training trial, the mouse is left standing on the platform and the SDL is measured. Cut off time (cut-o
ff time).

After the animal has descended or when the cut-off time is reached, place the mouse head facing away from the platform on the floor grid at the corner of the machine and add an electric shock until it escapes to the platform. Measure ELL.

3. Preparation of amnesia (Amnesia) -loaded animals (1) Cycloheximide (hereinafter, abbreviated as CXM) induction Amnesia-induced amnesia mice were used in groups of 20 or more, and immediately after the training trial, CXM (150 mg / (kg) was subcutaneously administered, and a retention trial was performed 24 hours later.

(2) Electric Convulsive Sh
ock: hereinafter abbreviated as ECS) Induced amnestic mice using 15 or more mice per group, immediately after the training trial, loaded with ECS (300V DC, 0.5 seconds) via both ears, and a retention trial was performed 24 hours later. Ivy.

4. Administration of test drug A 0.9% saline solution of the test drug was intraperitoneally administered immediately after CXM administration or ECS loading. On the other hand, 5% acacia solution of CXM was administered to the animals in the control group.

5. Results (1) Effect on CXM-induced amnesia The results of training trials of mice not pretreated with the test drug were SDL of 6.9 to 7.5 seconds and ELL of 29.0 to 32.0.
It was almost constant for seconds.

Retention trials with trained mice were performed 24 hours after the training trials. The results of the holding trials are shown in Table 6.

In the CXM control group that received CXM (150 mg / kg) immediately after the training trial, its SDL was significantly shortened in the retention trial compared with the control group, and ELL was significantly prolonged, causing amnesia. Admitted.

No memory enhancing effect was observed in the MV-GABA-Ca group and HOPA group to which CXM was not administered, as compared with the control group.

MV-GABA-Ca significantly improved the shortening of SDL by CXM at the doses of 500 mg / kg and 1,000 mg / kg, and significantly prolonged the ELL by CXM at the dose of 1,000 mg / kg.

(2) Effects on ECS-induced amnesia ECS was tested with load voltage of 200 V and 300 V,
No ankylosing convulsions occurred in V, and no ECS-induced amnestic effect was observed in retention trials. The mice developed ankylosing convulsion due to 300 V load and lost the righting reflex, but recovered after 1 to 2 minutes, and after 24 hours, there was no difference in locomotor activity by the automated method from the control group.

Using this 300V ECS load group mouse, MV-GABA-Ca
Was tested for its effect. The results are shown in Table 7.

In the group loaded with 300 V ECS immediately after the training trial, the SDL was significantly shortened and the ELL was significantly prolonged in the retention trial, and the induction of amnesia was observed.

MV-GABA-Ca significantly improved SDL shortening and ELL prolongation at a dose of 750 mg / kg. Also 500
The dose of mg / kg also significantly improved ELL.

Toxicity test Male ddY mice (body weight 20 to 25 g) were set to 8 per group, and 500 mg / kg and 1,000 mg / kg of MV-GABA calcium salt were added to these mice.
It was administered intraperitoneally at a dose of kg, but there were no deaths, and the LD ₅₀ value was determined to be 2,000 mg / kg or more.

Also, using ddY male mice (body weight 20 to 25 g) as a group of 8 mice, behavioral changes according to the 1rwin multidimensional observation method,
From a multifaceted observation and analysis of neurological symptoms, autonomic nervous symptoms, and poisoning symptoms, no significant difference could be found between the control group and the dose of 1,000 mg / kg or less.

As is clear from the results of the experiments described above, the γ of the present invention
-Aminobutyric acid derivative easily crosses the blood-brain barrier and significantly reduces spontaneous locomotor activity, antagonizes the increase in locomotor activity due to methamphetamine, and prolongs sleep time by pentobarbital Action, atropine
It has a significant inhibitory effect on the increase in motor activity caused by cerebral cortex, has a significant memory-improving effect on the CXM-induced amnesia model and the electroconvulsive-induced amnesia model, and has low toxicity. It can be used as a drug for preventing and / or treating cerebral dysfunction, that is, a cerebral function improving agent. For example, dementia caused by head injury, brain surgery, cerebrovascular disorder, blurring; hyperthyroidism or hypothyroidism, parathyroid disease, Wilson's disease, liver disease, hyperlipidemia, hypoglycemia, hypercalcemia Dementia caused by endocrine and metabolic diseases such as hypocalcemia, tattooing syndrome, hypopituitarism, uremia, and defocusing; dementia caused by hypoxia such as cardiopulmonary disease and anemia, and defocusing Dementia and blurring caused by infectious diseases such as brain abscess, bacterial meningitis, tuberculous meningitis, syphilis, and cerebral parasitic disease; central nervous system such as Alzheimer-type senile dementia, Pick's disease, Huntington's disease, and Parkinson's disease It exerts an excellent therapeutic effect for the prevention and / or treatment of dementia, blurring and the like caused by a wide range of parenchymal lesions of the system.

When the γ-aminobutyric acid derivative of the present invention is used for the prevention and / or treatment of cerebral dysfunction as described above, its effective dose is the purpose of administration, the method of administration, the symptoms of the patient to be administered, the body weight, and the year. It can be varied over a wide range depending on the age, sex, judgment of the doctor who is in treatment, etc., but in the case of humans, it is generally 0.01 mg / kg / day to 1,000 mg / kg / day, preferably 0.1 mg / kg / day. ~ 100 mg / kg / day, more preferably 0.
The dose may be in the range of 2 mg / kg / day to 50 mg / kg / day, and this dose may be administered once or several times a day.

The method of administration may be either oral or parenteral, and examples of parenteral administration include intravenous, intraarterial, etc. intravascular administration, intramuscular administration, intraperitoneal administration, intramedullary administration, rectal administration, etc. The method of can be used.

Thus, upon administration of the γ-aminobutyric acid derivative, the compound together with a suitable pharmacologically acceptable diluent or carrier can be used in a dosage form suitable for the above administration method, for example,
Various dosage forms such as tablets, granules, powders, coated tablets, hard capsules, soft capsules and syrups can be formulated into a form suitable for oral administration. further,
For example, a dosage form suitable for injection or drip administration such as suspension, solution, oily or aqueous emulsion (injection, drip)
Can be formulated into

As a pharmacologically acceptable liquid or solid diluent or carrier that can be used to prepare a pharmaceutical composition or drug of such a dosage form, a drug of the above dosage form is conventionally formulated. Auxiliaries usually used in the case of can be used, and specifically, for example, syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, magnesium stearate, talc, polyethylene glycol, silica, lactose, sugar, Examples thereof include corn starch, calcium phosphate, glycine, potato starch, carboxymethyl cellulose calcium, sodium lauryl sulfate, water, ethanol, glycerin, mannitol, and phosphate buffer.

The pharmacological composition or cerebral function-improving agent of the present invention contains, in addition to the pharmacologically acceptable diluents or carriers as exemplified above, other auxiliary agents commonly used in the field of formulation, such as coloring agents, if necessary. , Flavoring agents, flavoring agents, preservatives, solubilizing agents,
Other auxiliaries such as suspending agents, dispersing agents and the like may also be included.

The pharmaceutical composition or cerebral function-improving agent of the present invention is in the form of a fixed dose form such as tablets, capsules, coating tablets and ampoules as exemplified above, and is also contained in a multi-dose container. It can be in the form.

In addition, the pharmacological composition or the brain function-improving agent generally contains a γ-aminobutyric acid derivative in an amount of 0.01 to 50 depending on the form and the like.
It can be contained in a concentration of wt.%, Preferably 0.1 to 20 wt.%.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 0.38 g (5 mmol) of calcium hydroxide and γ-aminobutyric acid
10 ml of water was added to 1.03 g (10 mmol), and the mixture was stirred until the crystals were dissolved. A slightly cloudy white solution was obtained. The supernatant was taken by inclining this, and water was distilled off from this supernatant under reduced pressure. Then, 2-methoxyethanol 8 ml and mevalolactone 1.3 g (10 mmol) were added to the residue,
Form a uniform solution while heating and shaking for 1 hour at room temperature (about 18
C.) and then heated under reduced pressure (up to 0.3 mmHg, 110.degree. C.) to distill off the solvent to obtain 2.41 g of a pale yellow soft solid. This product was subjected to gel permeation chromatography (hereinafter, abbreviated as GPC) two analytical columns [GL-A130 and GL-A120 (each manufactured by Hitachi Chemical Co., Ltd.)
8 mmφ × 50 cm)] connected in series, using tetrahydrofuran as a developing solution and a differential diffractometer as a detector, it was confirmed that 90% of the component corresponding to a molecular weight of about 240 (weight) was calibrated with normal alcohols. ) It was confirmed that the above content was included. Using the same GPC device, a part of the above components was taken, nuclear magnetic resonance (NMR) analysis, infrared (IR)
Analysis and elemental analysis were conducted to confirm that the component was calcium 4- (3,5-dihydroxy-3-methylpentyramide) butyrate.

Elemental analysis: Actual value C: 44.01 H; 6.79 Calculated value C: 44.10 H: 6.66 Example 2 0.28 g (5 mmol) of calcium oxide and 1.03 g (10 mmol) of γ-aminobutyric acid were added to 5 ml of ethanol, and the mixture was boiled and stirred for 5 hours and cooled to precipitate a white powder. Transfer to a shaped flask that makes the supernatant liquid by the gradient method, add 1.3 g (10 mmol) of mevalolactone to this, and stir at room temperature (about 15 ° C) for 12 hours, then distill off ethanol under reduced pressure to give a slightly yellow soft solid. 2.18 g were obtained. NMR analysis of this product in deuterated water (D ₂ O) revealed that it contained a small amount of γ-aminobutyric acid, mevalonic acid and ethanol, but contained 4- (3,5-
It was confirmed to be calcium (dihydroxy-3-methylpentyramide) butyrate. Then, this was dissolved in 5 ml of ethanol, and 50 ml of diethyl ether was gradually added with vigorous stirring to form a slightly yellowish white precipitate. When this precipitate (powder) was separated and analyzed by NMR, it was found to be almost pure. Then
This was dissolved in 50 ml of distilled water and passed through a column packed with a strongly acidic cation exchange resin (Dow Chemicals Co., Ltd., Dowex 50W × 8) at room temperature to treat 4- (3,
5-dihydroxy-3-methylpentyramide) butyric acid. The result of NMR analysis of this product was substantially the same as the result obtained in Example 1, and the result of elemental analysis was as follows.

Elemental analysis: actual value C: 51.09 H: 8.51 calculated value C: 51.47 H; 8.21 Example 3 0.54 g of sodium methoxide (10 mmo in 10 ml of methanol)
l) and γ-aminobutyric acid (1.03 g, 10 mmol) were added, and the mixture was boiled and stirred for 5 hours and then cooled to room temperature. Mevalolactone (1.3 g, 10 mmol) was added thereto, and the mixture was stirred at room temperature (about 15 ° C) for 12 hours. Methanol was distilled off under reduced pressure to obtain a slightly yellow viscous liquid. NMR analysis of this product in D ₂ O revealed that it contained 4- (3,5-dihydroxy-) having a purity of 95% or more, although it contained a small amount of γ-aminobutyric acid, mevalolactone and methanol.
3-Methylpentyramide) sodium butyrate was confirmed. This is the same as in Example 1.
The results of the NMR and IR analyzes after purification by GPC are virtually identical to those obtained in Example 1,
The results of elemental analysis are as follows.

Elemental analysis: Actual value C: 46.91 H: 7.40 Calculated value C: 47.05 H: 7.11 Example 4 2.34 g (20 mmol) of methyl ester of γ-aminobutyric acid and 2.6 g (20 mmol) of mevalocratene were dissolved in 50 ml of ethanol, and the resulting mixture was stirred at room temperature (about 15 ° C) for 15 hours. Ethanol was distilled off from the reaction mixture under reduced pressure to obtain 4.97 g of a brown liquid substance. This liquid material was purified by silica gel column chromatography [ethyl acetate / methanol = 99/1 (volume ratio) was used as a developing solution] to give a colorless transparent liquid.
4.69 g was obtained. This liquid is 4 by NMR analysis and IR analysis.
-(3,5-Dihydroxy-3-methylpentylamide)
It was confirmed to be the methyl ester of butyric acid.

Example 5 (injection) 4- (3,5-dihydroxy-3-methylpentyramide)
30 mg of calcium salt of butyric acid was dissolved in 3 ml of physiological saline, and aseptically packed in a 3 ml ampoule. After the ampoule was sealed and heat-sterilized, a sterile pyrogen-free injection was prepared.

Example 6 (tablets) 4- (3,5-dihydroxy-3-methylpentyramide)
Calcium butyrate 30 mg Lactose 100 mg Hydroxypropyl cellulose 2.5 mg Crystalline cellulose 20 mg Talc 1.7 mg Magnesium stearate 1.8 mg After mixing the above ingredients, tablets were directly compressed into 150 mg tablets with a tableting machine.

Example 7 (tablets) 4- (3,5-dihydroxy-3-methylpentyramide)
Calcium butyrate 100 g Corn starch 145 g Carboxycellulose 40 g Polyvinylpyrrolidone 9 g Calcium stearate 6 g Total amount 300 g One tablet 300 mg was prepared by a conventional method. 4 out of 1 tablet
-Contains 100 mg of (3,5-dihydroxy-3-methylpentyramide) butyrate.

Example 8 (powder, capsule) 4- (3,5-dihydroxy-3-methylpentyramide)
Calcium butyrate 100 g Crystalline cellulose 200 g Total amount 300 g Both powders were mixed to prepare a powder. Further, this powder was filled in a No. 3 hard capsule to prepare a capsule.

EFFECTS OF THE INVENTION The present invention provides a novel γ-aminobutyric acid derivative which exhibits a beneficial pharmacological action, for example, a brain function improving action. The γ
-Aminobutyric acid derivatives show similar and different actions to those of fopanthenic acid, and are useful as agents for preventing and / or treating cerebral dysfunction such as cerebral function improving agents. The pharmacological composition or drug containing the γ-aminobutyric acid derivative provided by the present invention effectively exhibits the beneficial pharmacological action of the γ-aminobutyric acid derivative. Furthermore, as is clear from Examples 1 to 4, the γ-aminobutyric acid derivative is easily produced by the production method provided by the present invention.

Claims (5)

[Claims] 1. 4- (3,5-Dihydroxy-3-methylpentyramide) butyric acid or a pharmacologically acceptable salt or ester thereof. 2. The salt according to claim 1, wherein the pharmacologically acceptable salt is a calcium salt. 3. A salt or ester of γ-aminobutyric acid is reacted with mevalolactone to give 4- (3,5-dihydroxy-3).
-Methylpentyramide) Butyric acid salt or ester is formed, and if necessary, the salt or ester is converted into a free acid, and further if necessary, the free acid is converted into a pharmacologically acceptable salt or ester. 4-
(3,5-dihydroxy-3-methylpentyramide) butyric acid or a method for producing a pharmacologically acceptable salt or ester thereof. 4. A pharmacology of 4- (3,5-dihydroxy-3-methylpentyramide) butyric acid or a pharmacologically acceptable salt or ester thereof, which is effective for the prevention and / or treatment of cerebral dysfunction. Composition for the prevention and / or treatment of cerebral dysfunction containing a pharmaceutically acceptable diluent or carrier. 5. A brain function improving agent containing 4- (3,5-dihydroxy-3-methylpentyramide) butyric acid or a pharmacologically acceptable salt or ester thereof as an active ingredient.