JP2001026537A - Antianxiety medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antianxiety medicine which has the more excellent effect than those of honokiol (reduced product) and magnolol without expressing the side effects of benzodiazepine-based medicines, by including a propenylpropylbiphenyldiol compound. SOLUTION: This antianxiety medicine contains 5-(2-propenyl)-5'-propyl-1,1'- biphenyl-2,2'-diol (hereinafter 'magnolol reduced product') as an active ingredient. The magnolol reduced product is a compound obtained by reducing one of the two double bonds of magnolol (5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol), and can be synthesized by deriving from commercially available magnolol or using a compound of the formula as a starting raw material. The antianxiety medicine is usually orally administered at a daily dose of 0.1 to 1,000 mg for an adult as the magnolol reduced product, divided into several portions, or parenterally administered at a daily dose of about 0.1 μg to 100 mg for an adult by an intravenous injection method, a subcutaneous injection method, an intramuscular injection method, or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug such as an anxiolytic using a reduced magnolol.

[0002]

2. Description of the Related Art The general clinical effects of anxiolytics are as follows: anxiety and nervousness as psychogenic disorders causing neurosis and psychosomatic disorders; Can be alleviated and improved. Currently, benzodiazepines are widely used as anxiolytics, but their side effects such as physical dependence and central muscle relaxation are pointed out as serious problems. That is,
In the treatment of patients with anxiety such as neurosis in the foreground, benzodiazepine drugs are only an auxiliary means and it is desirable to use the minimum required amount for the shortest possible time. Reports of dependence, abuse, and long-term careless use have increased. Therefore, there has been a demand for a drug that does not exhibit amnesia, tolerance, dependence, etc., in addition to side effects such as hypnotic action and muscle relaxation action, in place of benzodiazepine drugs.

[0003] The present inventors have previously described honokiol (3 ', 5-di-2-propenyl-1,1') as a substance having an anxiolytic effect from a Chinese herbal preparation, Saiboku-to.
-Biphenyl-2,4'-diol) and magnolol (M
agnolol; 5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) was found, and a patent application was filed (Japanese Patent Application No. Hei 9-146744). Further, compound (a) obtained by reducing honokiol, 3 ′, 5-di-propyl-1,
1′-biphenyl-2,4′-diol, compound (b) 3-propyl-5 ′-(2-propenyl) -1,1′-biphenyl-2 ′,
4-diol and compound (c) 5'-propyl-3- (2-
Propenyl) -1,1′-biphenyl-2 ′, 4-diol is
It has been found that it has an anxiolytic effect superior to magnolol and honokiol, and in particular, compound (c) 5'-
Propyl-3- (2-propenyl) -1,1′-biphenyl-2 ′,
4-diol (hereinafter, this compound is referred to as “honokiol reductant”) is excellent, and a patent application (PCT / J
P98-00114).

Magnolol and honokiol are 2,000- to 5,000-fold the amount of Saiboku-to, and the above-mentioned compounds (a) to (c) obtained by reducing honokiol have higher potency, and the effective amount thereof Among them, it is excellent in that there are no side effects of the benzodiazepine compound such as muscle relaxation, sedation, hypnosis, dependence, amnesia, etc., but the medicinal effect (immediate effect etc.) is not yet sufficient, and There has been a need to provide compounds having excellent anxiety effects. In addition, during research, we found that honokiol reductants act on some benzodiazepine receptors in the same way as benzodiazepine drugs, and side effects occur when high doses are used or when used in combination with benzodiazepine drugs. There was a problem that could be.

[0005]

Accordingly, an object of the present invention is to provide a drug which does not exhibit the side effects of benzodiazepine drugs and has a better anxiolytic effect than honokiol, magnolol and reduced honokiol. With the goal.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a compound in which one of the double bonds of magnolol has been reduced, that is, 5
-(2-propenyl) -5'-propyl-1,1'-biphenyl-
2,2′-diol has anxiolytic effects equivalent to honokiol reductants, is more immediate than these, and exerts its effects without acting on benzodiazepine and GABA receptors. The inventors have found that there are no adverse side effects, and have completed the present invention.

That is, the present invention relates to 5- (2-propenyl)
It is intended to provide an anxiolytic agent comprising, as an active ingredient, -5'-propyl-1,1'-biphenyl-2,2'-diol or a pharmaceutically acceptable salt thereof.

[0008]

DETAILED DESCRIPTION OF THE INVENTION 5- (2-Propenyl) -5 'of the present invention
-Propyl-1,1'-biphenyl-2,2'-diol (hereinafter referred to as "magnolol reduced form") can be obtained by derivatization of a commercially available magnolol or the following synthesis method.

[0009]

Embedded image

(1) 2-bromo-1- (methoxymethoxy)-
Synthesis of 4- (2-propenyl) benzene (4) Dissolve 4- (2-propenyl) anisole (1) in dichloromethane and cool in ice water. Boron tribromide is added dropwise and stirred for 40 minutes under ice cooling. The reaction solution is poured into ice water, neutralized with saturated aqueous sodium hydrogen carbonate, diluted with water, and extracted with dichloromethane.
After drying the organic layer with magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is dried to obtain 4- (2-propenyl) phenol.
(2) can be obtained. Used for the following bromination reaction without further purification. 4- (2-Propenyl) phenol (2) is dissolved in dichloromethane, NBS is added at 0 ° C., and the mixture is stirred for 2 hours. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography (dichloromethane-hexane, 1: 4) to give 2-bromo-4-
(2-Propenyl) phenol (3) can be obtained.
2-Bromo-4- (2-propenyl) phenol (3) and diisopropylethylamine are dissolved in dichloromethane, chloromethyl methyl ether is added dropwise, and the mixture is stirred at room temperature for 16 hours. The reaction is diluted with dichloromethane and treated with hydrochloric acid (pH = 1). The organic layer is washed with saturated aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ether-hexane, 1:10) to give 2-bromo-
1- (methoxymethoxy) -4- (2-propenyl) benzene
(4) can be obtained.

(2) 2-bromo-1- (methoxymethoxy)-
Synthesis of 4-propylbenzene (7) 4-propylphenol (5) is dissolved in dichloromethane, NBS is added at 0 ° C., and the mixture is stirred for 2 hours. The residue obtained by evaporating the solvent is purified by silica gel column chromatography (dichloromethane-hexane, 1: 4) to obtain 2-bromo-4-propylphenol (6). Dissolve 2-bromo-4-propylphenol (6) and diisopropylethylamine in dichloromethane,
After dropping chloromethyl methyl ether, the mixture is stirred at room temperature for 16 hours. The reaction is diluted with dichloromethane and treated with hydrochloric acid (pH = 1). The organic layer is washed with saturated aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ether-hexane, 1:10) to give 2-bromo.
1- (methoxymethoxy) -4-propylbenzene (7) can be obtained.

(3) 5- (2-propenyl) -5'-propyl-
Synthesis of 1,1′-biphenyl-2,2′-diol (reduced magnolol) 2,2′-bis (methoxymethoxy) -5- (2-propenyl) -5′-propyl-1,1′- Biphenyl (8) 2-bromo
1- (Methoxymethoxy) -4-propylbenzene (7) is dissolved in anhydrous THF, n-butyllithium is added at −78 ° C. under an argon stream, and the mixture is stirred for 25 minutes. Next, after adding zinc chloride, the mixture is stirred at room temperature for 30 minutes. To this, 4-allyl-2-bromo-1- (methoxymethoxy) benzene and tetrakistriphenylphosphinepalladium dissolved in anhydrous THF are added, and the mixture is heated under reflux for 15 hours. Water was added to the reaction solution to stop the reaction, extracted with ethyl acetate, and washed with water and saturated saline. After drying the organic layer over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (ether-hexane, 1:10)
2,2'-bis (methoxymethoxy) -5-
(2-propenyl) -5'-propyl-1,1'-biphenyl
(8) can be obtained.

5- (2-propenyl) -5'-propyl-1,1 '
-Biphenyl-2,2'-diol (magnolol reduced form)
(9) Dissolve 2,2'-bis (methoxymethoxy) -5- (2-propenyl) -5'-propyl-1,1'-biphenyl (8) in methanol, add concentrated hydrochloric acid, and heat for 30 minutes Reflux. After cooling, the reaction solution was extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and brine. After drying the organic layer over magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, 1: 5) to give 5- (2-propenyl) -5'-propyl-1,1'-biphenyl-2,2'-diol (9). Obtainable.

[0014] The reduced magnolol or a pharmaceutically acceptable salt thereof obtained in this way has a much better anxiolytic effect than honokiol or a reduced honokiol, and has side effects (dependency, Tolerance) has not been recognized, and thus is extremely promising as a drug such as an anxiolytic.

[0015] The reduced magnolol can be used as a drug or an intermediate thereof after being further purified as required. In some cases, it can be used as a medicament in the form of a pharmaceutically acceptable salt.

In order to prepare the anxiolytic agent of the present invention using a reduced magnolol derivative or a pharmaceutically acceptable salt thereof, it is formulated with a conventional pharmaceutical carrier, and a tablet,
Oral preparations such as capsules, granules, fine granules, powders, and liquid preparations, and parenteral preparations such as injections, drops, and suppositories may be used.
In order to achieve the intended effect as an oral preparation, it is usually necessary to take the magnolol reductant 0.1 mg to 1000 mg per day in several divided doses, depending on the patient's age, weight, and degree of disease. Appropriate.

The pharmaceutical carrier can be selected according to the dosage form and dosage form of the preparation. In the case of an oral preparation, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like can be used. It is manufactured according to a conventional method. In preparing the oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavor, and the like can be further blended. Specific examples thereof include the following.

(Binder) starch, dextrin,
Gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol. (Disintegrant) Starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose. (Surfactant) Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80. (Lubricant) Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol. (Fluidity promoter) Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

It can also be administered as a liquid for oral administration as a suspension, emulsion, syrup or elixir. These various dosage forms may contain flavoring agents and coloring agents. good.

On the other hand, in order to exhibit the desired effect as a parenteral preparation, it depends on the age, weight and degree of the disease of the patient, but usually about 0.1 μg to 100 mg per day as a magnolol reductant in an adult. Is suitably administered by intravenous injection, intravenous injection by drip, subcutaneous injection, intramuscular injection, or the like. This parenteral preparation is manufactured according to a conventional method, and generally contains distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like as diluents. Can be used.
Further, if necessary, a bactericide, a preservative, and a stabilizer may be added.

Further, from the viewpoint of stability, the parenteral preparation can be frozen after filling into a vial or the like, water can be removed by a usual freeze-drying technique, and the liquid preparation can be readjusted from the freeze-dried product immediately before use. . Further, if necessary, a tonicity agent,
Stabilizers, preservatives, soothing agents and the like may be added. Other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, all of which are produced according to a conventional method.

[0022]

The reduced form of magnolol exhibits an excellent anxiolytic effect as shown in the test examples described later. In addition, since it does not act on the benzodiazepine receptor and GABA receptor and exhibits its effects, it is a highly safe drug that does not exhibit the side effects (dependence, tolerance) as seen with benzodiazepine drugs. Therefore, development as an anxiolytic agent is expected.

[0023]

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Anti-anxiety action: The anti-anxiety effect of the reduced magnolol was examined using the following Maruyama-Kurihara type / improved elevated cross maze apparatus. The test method and the results are shown below. In addition, a honokiol reduced product was used as a comparative drug.

(Test method) 1. Experimental animals Seven-week-old male STD-ddY mice (10 mice per group) were used as experimental animals. Polycarbonate cage (30 (W) × 2)
Within 0 (D) x 15 (H) cm), the animals were fed with solid feed (MF: Oriental Yeast, Tokyo) and tap water.
14 hours light period, 10 hours dark period (light period:
(5 am to 7 pm), room temperature was adjusted to 23 ± 1 ° C. and humidity was adjusted to 55 ± 3%. 1 hour before the start of the experiment (3 hours before the start for the honokiol reduced form)
Was orally administered. 2. Experimental equipment The improved elevated plus maze has four arms (6
(W) x 30 (D) cm) are orthogonal, and the intersection consists of a gray opaque floor platform (9 x 9 cm). The two closed arms have black opaque side walls (10
(H) cm) and the floor is gray opaque. The two open arms orthogonal to the closed arm have no side walls and the floor is transparent. The entire maze device was installed at a height of 40 cm. On the other hand, the spontaneous movement of the mouse
It was measured with a large-sized ambulometer (AMB-10; Ohara Medical Industry Co., Ltd., Tokyo) having a measuring cage made of acrylic resin of cm. This device selectively records only the horizontal movement (relocation movement) of the mouse, not the vertical movement. 3. Experimental procedure The mouse was placed on the platform in the center of the maze, facing the closed arm, and the cumulative stay time in the open arm was measured over the next 5 minutes. In addition, when the forelimb and the four hindlimbs completely came out to the open arm from the platform, it was determined that the shift to the open arm was made. Immediately after the 5-minute elevated plus maze experiment was completed, the mice were placed in an ambulometer and the locomotor activity was measured for 5 minutes. These experiments were performed between 9 am and 1 pm.

(Results) The results are shown in Table 1.

[0027]

[Table 1] As is clear from the results, the reduced magnolol showed the same anxiolytic effect as the reduced honokiol.

Example 2 Investigation of the change over time in the anxiolytic effect by oral administration: As a test animal, a 7-week-old male STD-ddY mouse (10 mice per group)
), And each of the reduced form of magnolol and the reduced form of honokiol were orally administered at 1 mg / kg, and administered in the same manner as in Test Example 1 using an improved elevated plus maze apparatus.
The anxiolytic effects at 5, 1, 2, 3, 6, 8, and 12 hours were measured.

Table 2 shows the results.

[0030]

[Table 2] As is clear from the results, it was shown that the honokiol reductant exhibited the maximum effect 3 hours after the administration, whereas the magnolol reductant reached the maximum 1 hour after the administration.

Example 3 Examination of the change over time in the anxiolytic effect by intraperitoneal administration: To confirm the difference in the expression of the effect in Example 2,
The change over time by intraperitoneal administration was examined. STD-ddY male mice 7 weeks old as experimental animals (10 mice per group)
, A magnolol reduced product and a honokiol reduced product were intraperitoneally administered at 1 mg / kg each, and as in Test Example 1, using an improved elevated plus maze device,
The anti-anxiety effects at 30, 60, 120 and 180 minutes were measured.

Table 3 shows the results.

[0033]

[Table 3] As is clear from the results, the magnolol reductant began to exert its effect 15 minutes after intraperitoneal administration, reached its maximum at 30 minutes, and then attenuated and returned to the control level 2 hours later. On the other hand, the honokiol reductant showed an effect similarly after 15 minutes, and was not significant after 30 minutes, but showed a tendency to decrease once.
The maximum value was obtained in minutes, and thereafter, it gradually decreased, and after 3 hours, decreased to 75% of the peak. From this, it was clarified that the reduced form of magnolol exerts an effect more quickly than the reduced form of honokiol when it is transferred to the blood without passing through the digestive tract, as in the case of oral administration.
Therefore, both drugs have different kinetics, and it is suggested that magnolol reductants may be effective for anxiety neurosis and panic disorder, which appear in the acute phase. It was suggested that side effects such as dependence formation, muscle relaxation and resistance development were unlikely to occur. There were no significant changes in spontaneous movement.

Example 4 Examination of Combination Effect with Diazepam: 7-week-old STD-dd
Magnolol reduced form 1m to Y male male mice (10 per group)
g / kg orally, and diazepam 1 mg / kg 1 hour and 10 minutes before administration at which the onset of the anxiolytic effect is maximized.
And 0.5 mg / kg were orally administered, respectively. Next, similarly to Test Example 1, the anti-anxiety effect was measured using the improved elevated plus maze apparatus, and the degree of the effect of the combined use was evaluated and compared with each control group. In addition, spontaneous locomotor activity was measured.

Table 4 shows the results.

[0036]

[Table 4] As a result, the magnolol reduced product was diazepam (1 mg).
/ Kg) itself anxiolytic effect level (28.2 ± 8.3)
On the other hand, the result of the combination was 32.8 ± 8.45 with respect to 0), and no statistically useful combination effect was observed. Also, when the dose of diazepam was halved (0.5 mg / kg),
The result of the combined use was 33.8 ± 5.31 for the single anxiolytic level (23.8 ± 6.20), and no combined effect was observed. In addition, no significant change was found in the locomotor activity in any of the above administrations.

Example 5 Examination of Combination Effect with Flumazenil (Benzodiazepine Receptor Antagonist): Seven-week-old male STD-ddY mouse (1
Magnolol reductant (1 mg / kg) was orally administered to the group (10 mice), and flumazenil (0.3 mg / kg) was intraperitoneally administered 1 hour and 10 minutes after administration at which the anxiolytic effect was maximized. Next, similarly to Test Example 1, the anti-anxiety effect was measured using the improved elevated plus maze apparatus, and the degree of the effect of the combined use was evaluated and compared with each control group. Spontaneous locomotor activity was measured for each experiment. Note that honokiol reductants and diazepam were used as comparative drugs.

Table 5 shows the results.

[0039]

[Table 5] As a result, the anxiolytic effect level of the reduced magnolol itself (10.2 ± 1.86) was 15.2 ± 1.
At 4.68, no statistically useful combination effect was observed. On the other hand, in the case of honokiol reductants, a single level 1
1.7 ± 3.48 compared to 3.6 ± 1.4.
5. In the case of diazepam, the level of single use was 19.4 ± 2.8, whereas the result of the combination was 7.4 ± 3.0, showing a significant decrease. In addition, no significant change was observed in the locomotor activity. Therefore, it was shown that the reduced magnolol exhibited an anxiolytic effect without the intervention of the benzodiazepine receptor.

Example 6 Examination of Combination Effect with Bicuculline (GABA Receptor Antagonist): Seven-week-old STD-ddY male mice (10 mice per group)
Was orally administered with 1 mg / kg of a reduced magnolol, and 0.1 mg / kg of bicuculline was subcutaneously administered 1 hour and 10 minutes before the administration at which the anxiolytic effect was maximized. Next, similarly to Test Example 1, the anti-anxiety effect was measured using the improved elevated plus maze apparatus, and the degree of the effect of the combined use was evaluated and compared with each control group. Spontaneous locomotor activity was measured for each experiment. Note that honokiol reductants and diazepam were used as comparative drugs.

Table 6 shows the results.

[0042]

[Table 6] As a result, the anxiolytic effect level (15.8 ± 4.73) of the reduced magnolol itself was 9.8 ±.
At 2.95, no statistically useful combination effect was observed. On the other hand, for diazepam, a single level of 28.2 ±
Compared with 8.30, the result of the combination was 8.4 ± 1.78, showing a significant decrease. In addition, no significant change was observed in the locomotor activity. Therefore, the reduced magnolol is GA
It has been shown that an anxiolytic effect is expressed without using the BA receptor.

EXAMPLE 7 Examination of Action on Hypnotic (Hexobarbital):
As an experimental animal, a 7-week-old male STD-ddY mouse (1
1 hour before administration of hexobarbital, the magnolol reductant 0.5, 1.0, 2.0 mg / kg
Was orally administered, and the effect on sleep was examined. Hexobarbital was administered intraperitoneally at 100 mg / kg. The sleep effect was represented by the time from the loss of the righting reflex to the recovery as sleep time. On the other hand, for comparison, a group (five animals per group) to which diazepam 1 mg / kg was orally administered in advance and 10 minutes after administration, hexobarbital 100 mg / kg was intraperitoneally administered was used. Further, in the group in which the reduced form of magnolol and diazepam were used in combination (the reduced form of magnolol was administered 1 hour before and the administration of diazepam 10 minutes before), 100 mg of hexobarbital was similarly used.
/ Kg was administered intraperitoneally and the prolongation of sleep time was compared with that of diazepam alone.

Table 7 shows the results.

[0045]

[Table 7] As is clear from these results, no correlation was observed between the dose of the magnolol reduced form and the sleep time, and the sleep time of the group administered the magnolol reduced form was 2979. It is almost the same as 6 seconds, and the effective amount of the anxiolytic effect of the magnolol reduced form (0.5 to 2.0 mg)
/ Kg) range did not prolong sleep time.
On the other hand, in the group to which the comparative diazepam was administered, 5423.
The sleep time of the control group (2979.6 seconds) was significantly prolonged to 8 seconds. In addition, there was no significant difference between the diazepam and magnolol-reduced groups compared to the diazepam-only group, and therefore the magnolol reduced form had the effect of prolonging hexobarbital-induced sleep time with or without diazepam. Turned out not to be.

Example 8 Examination of Action on Memory Disorder: Applying the improved elevated plus-maze device used in Experimental Example 1, magnolol for memory input (learning acquisition) and memory output (memory retention) The presence or absence of the reductant's hindrance was examined by the following method. (Experimental method) Memory input ability test: STD-d at 7 weeks of age
The dY strain male mice (10 mice per group) were orally administered with 1.0 and 5.0 mg / kg of the reduced magnolol, respectively, and allowed to stand at the tip of the open arm of the maze device with the cruciform tip in place. The time to completely enter the closed arm was measured. The same experiment was performed on the same animal 24 hours later. Diazepam 1.0 and 2.0 mg / kg were used as comparative drugs. Memory output ability test: The above memory test was performed without giving a drug, and after 24 hours, the magnolol reduced form was 1.0 or 5.0.
mg / kg was orally administered, and the same experiment was performed 1 hour later. As a comparative drug, diazepam 1.0, 2.0 m
g / kg was used.

Table 8 shows the results.

[0048]

[Table 8] As is evident from the results, in memory input, diazepam was impaired at both doses of 1.0 and 2.0 mg / kg, but 1.0 and 5.0 mg / mg of reduced magnolol.
No impairing effect was observed at any dose of kg. No adverse effects were observed on the whole dose with respect to the magnolol reductant and diazepam in the memory output.

Example 9 Muscle Relaxation Test: The relaxant effect of the reduced magnolol was measured.
The following suspension test was used. (Test method) STD-dd at 7 weeks of age as an experimental animal
10. Using male Y mice (10 mice per group), 10.0 mg / kg of reduced magnolol and 10 reduced honokiol were used.
0 mg / kg was orally administered, and a suspension test was performed 1 hour after the administration in the magnolol reductant administration group and 3 hours after the administration in the honokiol reductant administration group. In the suspension test, a wire having a diameter of 1.6 mm and a length of 30 cm was placed horizontally at a height of 30 cm, and was held by the limb of the mouse, and the suspension time of 60 seconds was used as a measurement standard. Each animal was performed twice and the average value was measured. Those exceeding 60 seconds were recorded as 60 seconds.

Table 9 shows the results.

[0051]

[Table 9] As is clear from the results, the high dose (10.0 mg /
In the suspension test (kg), the honokiol-reduced group showed a slight reduction in the retention time, but the magnolol-reduced group did not show any muscle relaxant effect as in the control group.

Example 10 Tablets: Anxiolytics (tablets) according to the following formulation and manufacturing method
Was manufactured.

[Preparation] (1) Dextrin 54 g (2) Crystalline cellulose 32 g (3) Carboxymethylcellulose calcium 6 g (4) Polyethylene glycol 6000 6 g (5) Magnolol reductant 2 g Total 100 g [Preparation method] (1) to (5) were uniformly mixed and compression-molded with a tableting machine to obtain a tablet of 100 mg per tablet. Each tablet contains 2 reductants of magnolol.
mg, and take 1 to 6 tablets daily for adults in several doses.

Example 11 Condyle Granule: An anxiolytic (granule) was produced by the following formulation and manufacturing method.

[Procedure] (1) Dextrin 90 g (2) Polyethylene glycol 6000 2.5 g (3) Carboxymethylcellulose calcium 6 g (4) Light anhydrous silicic acid 0.5 g (5) Magnolol reductant 1 g Total 100 g Method] (1) to (5) were uniformly mixed according to the above-mentioned formulation, compression-molded by a compression molding machine, pulverized by a crusher, and sieved to obtain granules. 1 g of this granule contains 10 mg of a reduced magnolol, and 200 to 1000 mg of an adult is taken several times a day.

Example 12 Capsule: An anxiolytic (capsule) was produced according to the following formulation and production method.

[Procedure] (1) 98 g of anhydrous crystalline maltose (2) 1 g of light anhydrous silicic acid (3) 1 g of reduced magnolol 1 g 100 g [Production method] According to the above-mentioned recipe, (1) to (3) were uniformly prepared. After mixing, 200 mg was filled into a No. 2 capsule. Each capsule contains 2 mg of magnolol reductant
And take 1 to 6 capsules daily for adults.

Example 13 Injection: An anxiolytic (injection) was produced according to the following formulation and production method.

[Procedure] (1) 90.4 g of distilled water for injection (2) 5 g of soybean oil (3) 2.5 g of soybean phospholipid (4) 2 g of glycerin (5) 0.1 g of reduced magnolol 100 g Total amount 100 g [Production method] According to the above-mentioned formulation, (5) was dissolved in (2) and (3), and the solution of (1) and (4) was added thereto and emulsified to obtain an injection.

Claims (1)

[Claims] (1) 5- (2-propenyl) -5′-propyl-1,
An anti-anxiety agent comprising 1'-biphenyl-2,2'-diol or a pharmaceutically acceptable salt thereof as an active ingredient.