WO2001003689A1

WO2001003689A1 - Antianxiety drugs

Info

Publication number: WO2001003689A1
Application number: PCT/JP2000/004712
Authority: WO
Inventors: Yuji Maruyama; Hisashi Kuribara; Yoshimasa Ichio
Original assignee: Tsumura & Co.
Priority date: 1999-07-13
Filing date: 2000-07-13
Publication date: 2001-01-18
Also published as: AU6015300A; JP2001026537A

Abstract

Antianxiety drugs containing as the active ingredient 5-(2-propenyl)-5'-propyl-1,1'-biphenyl-2,2'-diol or pharmaceutically acceptable salts thereof.

Description

Description Anxiolytics Technical field

The present invention relates to a medicament as an anxiolytic using a reduced magnolol. Background art

The general clinical effects of anxiolytics are anxiety as a psychological disorder that causes neurosis and psychosomatic disorders--a level of tension that can lead to sleep and a loss of consciousness. To mitigate and improve. Currently, benzodiazepines are widely used as anxiolytics, but their side effects such as physical dependence and central muscle relaxation have been pointed out as serious problems.

In other words, in the treatment of patients with anxiety such as neurosis in the foreground, drugs are only an aid, and it is desirable to use the minimum required amount for the shortest possible time. With regard to benzodiazepines, reports of drug dependence, abuse, and long-term unresponsiveness have been added. Therefore, there has been a need for a drug that does not exhibit amnesia, tolerance, dependence, etc., in addition to benzodiazepine drugs, which has side effects such as hypnotic action and muscle relaxation action.

The present inventors have previously reported that honokiol (Honokiol: 3 ′, 5—di1-2—propinyl1-1, 1 ′) was used as a substance having an anxiolytic effect from a herbal medicine, Saiboku-to. — Biphenyl 2,4'-diol) and magnolol (Magnolol: 5, 5'-di-2-di-propyl-1,1'-biphenyl-1,2,2'-diol) A patent application has been filed (Japanese Patent Application No. 9-11466744).

Compounds obtained by reduction of honokiol (a) 3 ', 5-jeep mouth pill-1, 1'-biphenyl-1, 2, 4'-diol, compound (b) 3-propyl-5' — (2—Propenyl) — 1, 1, 1-biphenyl — 2 ', 4 — Diol and compound (c) 5 ′ 1-Propyl 1 3 — (2—Propenyl) 1 1 , 1'-biphenyl-1 ', 4diol was found to have better anxiolytic effects than magnolol and honokiol, especially the compound (c) 5' It is said that pyr-3- (2-propenyl) 1-1,1'-biphenyl-1-2 ', 4-diol (hereinafter, this compound is referred to as "honokiol reduced form (c)") is superior. After obtaining the knowledge, a patent application was filed (PCTZ JP 98/001114).

Magnolol and honokiol are 200 to 500 times more than Saibokuto, and the above compounds (a) to (c) obtained by reducing honokiol are more effective. Within the effective dose range, it is excellent in that there are no side effects of the benzodiazepine compound such as muscle relaxation, sedation, hypnosis, dependence, amnesia, etc. In addition, there is a demand for a compound having a more excellent anxiolytic effect. Further studies have shown that the reduced honokiol (c) partially acts on the benzodiazepine receptor as well as the benzodiazepine receptor. It has been found that there is a problem that side effects may occur when used in combination. Disclosure of the invention

Therefore, the present invention provides honokiol, magnolol and honokiol reductants, without the side effects of benzodiazepine drugs. Another object of the present invention is to provide a drug having a better anxiolytic effect than honokiol reductant (C).

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a compound obtained by reducing one of two double bonds possessed by magnolol, that is, 5- (2-propidinyl) -one 5'-Propyl 1'-Bifene2,2'-diol has anxiolytic activity equivalent to that of the honokiol reduced form (c), is more immediate, and Since the drug exerts its effects without acting on the benzodiazepine receptor and GABA (ferraminobutyric acid) receptor, it has been found that it has no side effects like benzodiazepine drugs. The invention has been reached.

That is, the present invention provides 5- (2-propenyl) -5′-propyl—1,1′-biphenyl-1,2,2′-diol or a pharmaceutically acceptable salt thereof as an active ingredient. It provides anxiolytics. BEST MODE FOR CARRYING OUT THE INVENTION

5- (2-Propenyl) —5′-propyl—1,1,1′-bifuren 2,2′—diol (hereinafter referred to as “magnolol reduced product”) of the present invention is commercially available. Magnolol can be obtained by derivatization or by the following synthesis method.

OMe OH OH 麵

(1) 2 — Promote 1 (Methoxymethoxy) 1 4 — (2 —Probenyl) Synthesis of benzene (4)

4 — (2 — Propenyl) anisol (1) is dissolved in dichloromethane and cooled in ice water. Boron tribromide is added dropwise, and the mixture is stirred for 40 minutes under ice cooling. Pour the reaction mixture into ice water, neutralize with saturated aqueous sodium bicarbonate, dilute with water, and extract with dichloromethane. Dry the organic layer with magnesium sulfate Thereafter, the solvent is distilled off under reduced pressure, and the residue is dried to obtain 4- (2-probenyl) phenol (2). Used in the following bromination reaction without further purification.

4 Dissolve 1- (2-propanol) phenol (2) in dichloromethane, add NBS (N-Bromsk Shinimid) at 0 ° C, and stir for 2 hours . The residue obtained by distilling off the solvent was purified by silica gel column chromatography (dichloromethane Z hexane = 1 Z 4) to give 2-bromo-1- 4 — (2-pro (Vinyl) vinyl (3) can be obtained.

Dissolve 2-bromo-1- (2-propenyl) phenol (3) and diisopropylpropylamine in dichloromethane, add chloromethyl methyl ether dropwise, and add 1 at room temperature. Stir for 6 hours. Dilute the reaction with dichloromethane and treat with hydrochloric acid (pH = 1). The organic layer is washed with saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Purification of the residue by silica gel column chromatography (ether Z hexane = 110) yielded 2-bromo 1-(methoxymethoxy) 14-(2-propenyl) benzene. (4) can be obtained.

(2) Synthesis of 2-bromo-1- (methoxymethoxy) -1-4-propylbenzene (7)

4-Dissolve propylphenol (5) in dichloromethane, add NBS at 0 ° C, and stir for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (dichloromethane / hexane = 14) to obtain 2-promo 4-propanol. (6) can be obtained.

2—Bromo-4-propyl phenol (6) and diisopropinoletylamine are dissolved in dichloromethan to give chloromethylinolemethilene. After the dropwise addition, the mixture is stirred at room temperature for 16 hours. Dilute the reaction with dichloromethane and treat with hydrochloric acid (pH = 1). The organic layer is washed with saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Purification of the residue by silica gel column chromatography (ether / hexane = 1/1/10) yields 2-promo- 1- (methoxymethoxy) -14-propylbenzene (7). .

(3) Synthesis of 5-(2-probenyl) 1 5 '-propyl-1, 1'-biphenyl-2,2 '-diol (reduced magnolol) (9)

2,2'-Bis (methyoxymethoxy) -1-5- (2-propenyl) -5'-Propyl-1,1,1'-Bifenyl (8)

2 — Promo 1 — (Methoxy methoxy) 1 4 1 Propylbenzene

Dissolve (7) in anhydrous THF (tetrahydrofuran), add n-butyllithium at 178 ° C under a stream of argon, and stir for 25 minutes. Next, after adding zinc chloride, the mixture is stirred at room temperature for 30 minutes. To this, 4-aryl 2-promote 1-(methoxy methoxy) benzene and tetrakis triphenylphosphine dissolved in anhydrous THF. Add radium and heat to reflux for 15 hours. The reaction solution is quenched with water, extracted with ethyl acetate, and washed with water and saturated saline. After drying the organic layer with magnesium sulfate, the solvent is distilled off under reduced pressure. Purification of the residue by silica gel column chromatography (ether Z hexane = 110) yielded 2,2'-bis (meth- oxymethoxy) 15- (2-propionyl) -one. 5'-Propyl-1,1'-biphenyl (8) can be obtained.

5 — (2 — propyl) 1 5 '— propyl 1, 1' — biphenyl — 2, 2 '— diol (reduced magnolol) (9)

2, 2'-bis (methoxymethoxy) 1-5 — (2-propenyl) Dissolve 5'-propyl-11,1'-biphenyl (8) in methanol, add concentrated hydrochloric acid, and heat to reflux for 30 minutes. After cooling, the reaction mixture is extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and brine. After drying the organic layer with magnesium sulfate, the solvent is distilled off under reduced pressure. Purification of the residue by silica gel column chromatography (ethyl acetate / hexane = 1/5) yielded 5 — (2 — propyl) 1 5 '— propyl-1, 1, 1 — biphenyl-1 2 , 2'-diol (9) can be obtained.

The reduced magnolol or the pharmaceutically acceptable salt thereof obtained in this way is extremely excellent in anti-insecure action compared to honokiol or the reduced honokiol, and has a minor effect on benzodiazepine drugs. Since no action (dependence, tolerance) is recognized, it is promising as a drug such as an anxiolytic.

This reduced magnolol can be used as a pharmaceutical product or its intermediate material after further purification as necessary. In some cases, it can also 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 the above-mentioned reduced magnolol or a pharmaceutically acceptable salt thereof, the anxiolytic agent is formulated together with a conventional pharmaceutical carrier, and tablets, capsules, granules, Oral preparations, such as fine granules, powders, and liquid preparations, and parenteral preparations, such as injections, drops, and suppositories, may be used. To achieve the desired effect as an oral preparation, the magnolol reductant is usually 0.1 to 100 mg / day for an adult, depending on the patient's age, weight, and degree of disease. It is appropriate to take several doses.

Pharmaceutical carriers can be selected according to the dosage form and dosage form of the preparation, and in the case of oral preparations, for example, starch, lactose, sucrose, mannite, carboquin methyl cellulose, corn starch, inorganic salts It is manufactured according to a conventional method using the method described above. In the preparation of an oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity enhancer, a flavoring agent, a coloring agent, a fragrance, and the like can be further blended. . The following are specific examples of these.

Binder

Starch, dextrin, arabic gum powder, gelatin, hydroxypropyl starch, methylcellulose, carboxymethylcellulose sodium starch, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyro Redon, Macro goal.

Disintegrant

Starch, hydroxypropyl pilstarch, carboxymethylcellulose sodium sodium, potassium oleboxime cellulose cellulose, carboxymethylcellulose, low-substituted hydroxypropyl propylenolose.

Surfactant

Sodium leuryl sulfate, soy lecithin, sucrose fatty acid ester, polysorbate 80 o

Lubricant

Talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

Flowability enhancer

Light gay anhydride, dried aluminum hydroxide gel, synthetic aluminum acid magnesium, magnesium gay acid.

It can also be administered as a liquid for oral use, as a suspension, emulsion, syrup or elixir. A coloring agent may be blended.

On the other hand, in order to achieve the desired effect as a parenteral drug, Depending on age, body weight, and degree of disease, usually about 0.1 g to 100 mg per day as a magnolol reducer in adults, intravenous injection, intravenous injection by drip, subcutaneous injection It is appropriate to administer by intramuscular injection or the like.

This parenteral preparation can be manufactured according to a conventional method. Generally, diluents include distilled water for injection, physiological saline, aqueous solution of glucose, vegetable oil for injection, sesame oil, laccase oil, soybean oil, corn oil, Propylene glycol, polyethylene glycol and the like can be used. In addition, fungicides, preservatives and stabilizers may be added, if necessary. In addition, from the viewpoint of stability, this parenteral preparation can be filled and frozen in vials and the like, and the water can be removed by a conventional freeze-drying technique. it can. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.

Examples of other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, all of which can be produced according to a conventional method.

Next, the present invention will be further described with reference to examples, but the present invention is not limited by these examples.

Example 1

Anti-anxiety effect

The anti-anxiety effect of the reduced magnolol was investigated using the following Maruyama Ichigurihara type / improved elevated cross maze device. The test method and the results are shown below. As a comparative drug, honokiol reductant (c) (hereinafter simply referred to as honokiol reductant) was used.

Test method

1. Laboratory animals

As experimental animals, 7-week-old male STD-ddY mice (10 per group) Per animal). Mice were placed in solid cages (30 (W) X 20 (D) XI 5 (H) cm) covered with pad chips and solid feed (MF: Oriental Yeast Co., Ltd.). ), Tokyo, Japan) and tap water. The animal rearing room had a 14-hour light period and a 10-hour dark period (light period: 5:00 am to 7:00 pm). The room temperature was adjusted to 23 ± 1 ° C and the humidity was adjusted to 55 ± 3%. The experimental drug was orally administered 1 hour before the start of the experiment (3 hours before the start of the experiment for the reduced form of honokiol).

2. Experimental equipment

The modified elevated plus maze has four arms (6 (W) x 30 (D) cm each) orthogonal to each other, and the intersection consists of a gray opaque floor platform (9 x 9 cm). ing. The two closed arms have black opaque side walls (10 (H) cm) and the floor is gray opaque. The two open arms perpendicular 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 was measured by a large-sized ambulometer (AMB-10; Ohara Medical Industry Co., Ltd., Tokyo, Japan) having a measuring cage made of acryl resin with a diameter of 20 cm. . This device 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 time spent in the open arm was measured over the next 5 minutes. If four forelimbs and four hindlimbs completely came out of the platform from the platform, it was judged to be a transition to the open arm.

Immediately after the 5-minute elevated plus maze experiment was completed, the mouse was placed in the ambibulometer, and the locomotor activity was measured for 5 minutes thereafter. Specified.

These experiments were performed between 9 am and 1 pm.

B

The results obtained are shown in Table 1.

table 1

* To-tween-180 As evident from these results, the reduced magnolol exhibited the same anxiolytic effect as the reduced honokiol.

Example 2

Examination of the change with time of the anxiolytic effect by oral administration

Using 7-week-old STD-ddY male mice (10 mice per group) as experimental animals, 1 mgZ kg of magnolol reduced product and 1 mgZ kg of honokiol reduced product were orally administered, respectively. Similarly, an anxiolytic effect at 0.5, 1, 2, 3, 6, 8, and 12 hours after administration was measured using a modified elevated plus maze apparatus.

Table 2 shows the obtained results. Table 2

* Tween-80 gffi As can be seen from the results, the honokiol reduced form shows the maximum effect 3 hours after administration, whereas the magnolol reduced form reaches the maximum 1 hour after administration. Was.

Example 3

Examination of the time course of the anxiolytic effect by intraperitoneal administration

In order to confirm the difference in the expression of the effect in Example 2, the time-dependent change by intraperitoneal administration was examined. A 7-week-old male STD-ddY mouse (10 mice per group) was used as an experimental animal. Magnolol reductants and honokiol reductants were administered intraperitoneally at 1 mgZ kg each as in Test Example 1. Using an improved elevated plus maze device, the anxiolytic effect was measured for 15, 30, 60, 120 and 180 minutes after administration. Table 3 shows the results. ¾ _ 3

* As can be seen from the results, the effect of the reduced form of magnolol began to appear 15 minutes after intraperitoneal administration, reached its maximum at 30 minutes, and then declined for 2 hours. Later he returned to control levels. On the other hand, in the case of the honokiol reductant, the effect was similarly observed after 15 minutes, and after 30 minutes, the effect was insignificant, but once decreased, reached a maximum at 60 minutes, and then gradually decreased. And decreased to 75% of the peak after 3 hours. This indicates that the reduced form of magnolol, as in the case of oral administration, is more effective than the reduced form of honokiol when it is transferred to the blood without passing through the gastrointestinal tract. It became clear. Therefore, both drugs have different kinetics, and it is suggested that magnolol reductants may be effective for anxiety neurosis and panic disorder that appear in the acute phase, and that the retention time in the body is short. This suggests that side effects such as dependence formation, muscle relaxation and resistance development are unlikely to occur during repeated use. As for spontaneous movement, significant changes were observed.

Example 4

Examination of the combined effect with Jazebam 7-week-old STD-dd Y male mice (10 mice per group) were orally administered 1 mg Z kg of magnesium reduced form, and 1 hour after administration at which the anti-anxiety effect was maximized. 0 minutes before, 1 mg / kg and 0.5 mg / kg of diazebam were orally administered, respectively. Next, as in Test Example 1, the anxiolytic effect was measured using the improved elevated plus maze device, and the degree of the effect of the combined use was evaluated based on comparison with each control group. In addition, the spontaneous locomotion was measured respectively.

Table 4 shows the obtained results.

Table 4

* Tween-80 and distilled water for injection were used. As a result, the reduced magnolol reduced the anti-anxiety effect level of diazebam (lmg Z kg) itself (28.2 ± 8.30). Was 32.8 ± 8.45, and no statistically useful combination effect was observed. In addition, when the dose of diazebam was increased to 1 Z 2 (0.5 mg / kg), the single anxiolytic level (23.8 ± 6.20) was not increased. On the other hand, the result of the combination was 33.8 ± 5.31, and no combination effect was observed. No significant change in locomotor activity was observed in any of the above administrations.

Example 5

Examination of combination effect with flumazenil (benzodiazepine receptor antagonist)

7-week-old STD-dd Y male mice (10 mice per group) were orally administered 1 mg Z kg of the reduced magnolol, and 10 hours after administration at which the anxiolytic effect was maximized. One minute before, 0.3 mg Z kg of flumazenil was intraperitoneally administered. Next, as in Test Example 1, the anxiolytic effect was measured using an improved elevated plus-maze device, and the degree of the effect of the combined use was evaluated based on comparison with each control group. Spontaneous locomotor activity was measured for each experiment. As comparative drugs, honokiol reductants and jazebam were used.

Table 5 shows the obtained results.

¾ 5

* 1: Tween-80 is used * 2: Distilled water for injection is used As a result, the result of combined use is 1 against the anti-anxiety effect level of the magnolol reductant itself (10.2 ± 1.86) The value was 5.2 ± 4.68, and no statistically useful combination effect was observed. On the other hand, in the case of the honokiol reduced form, the result of the combined use was 3.6 ± 1.45 compared with the single level of 11.7 ± 3.48, and in the case of diazepam, the single level of 19.4 ± Sat 2.8 was used. In contrast, the result of the combination was 7.4 ± 3.0, indicating a significant decrease. No significant changes were found in locomotor activity. Thus, it was shown that the reduced form of magnolol exerts an anxiolytic effect without mediated by the benzodiazepine receptor.

Example 6

Examination of combination effect with bicuculline (GABA receptor antagonist)

7-week-old STD — dd Y male mice (10 mice per group) 1 mg Z kg of the reduced product was orally administered, and 0.1 mg Z kg of bicucliline was subcutaneously administered 1 hour and 10 minutes before the administration at which the anxiolytic effect was maximized. Next, as in Test Example 1, the anxiolytic effect was measured using the improved elevated plus-maze device, and the degree of expression of the combined effect was evaluated by comparison with each control group. Spontaneous locomotor activity was measured for each experiment. Honokiol reductants and diazepam were used as comparative drugs.

Table 6 shows the obtained results.

Table 6

*: Tween-80 and distilled water for injection were used. As a result, the anxiolytic effect level of the magnolol reduced product itself (15.

In contrast, the result of the combination was 9.8 ± 2.95, whereas no statistically useful combination effect was observed. On the other hand, in jazebam, the level alone was 28.2 ± 8.30, but the result of the combination was 8.4 soil.

1.78, indicating a significant decrease. Spontaneous exercise is significant No significant change was observed. Therefore, it was shown that the reduced magnolol exhibited an anxiolytic effect without the mediation of the GABA receptor.

Example 7

Investigation of effects on sleeping pills (hexobarbital)

Using 7-week-old STD-ddY male mice (5 mice per group) as experimental animals, magnolol reductants 0.5, 1.0 and 2.0 mg 1 hour before administration of hexobarbital Each dose of Z kg was orally administered and its effect on sleep was examined. Hexobarbital was administered intraperitoneally at 10 O mg Z kg. The sleep effect was expressed 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 lazeZmg of diazepam was orally administered in advance and 100 mg of hexobarbital was administered intraperitoneally 10 minutes after administration was used. In addition, in the group in which the reduced form of magnolol and diazebam were used together (the reduced form of magnolol was administered 1 hour before, and the administration of diazepam 10 minutes before), similarly, hexobarbital 10 O mg / mg kg was administered intraperitoneally and the prolonged sleep time was compared to that of diazepam alone.

Table 7 shows these results.

Table 7 Dose

Drug administration Sleep time (seconds)

(mg / kg)

Against liquid, liquid * ¹ 2979.6 ± 315.8 Magno-roller 0.55 3228. 2 person 184.5

1. 0 3105.4 4 ± 331. 9

2.0 2863.4 ± 378.7 Control solution * ² 542.3.8 ± 480.7 Magnolol reduced form 0.5 4838.6 Sat 44.3

+ Jazepam (lmg / kg) 1.0 052.2.2 ± 851.6

2. 0 4621. 4 ± 951. 7

* 1: Use twine-80

氺 2: Jazepam 1 mg Z kg, twine 80

And use distilled water for injection

As is evident from these results, there was no correlation between the dose of magnolol reductant and the sleep time, and the sleep time of the group receiving the magnolol reductant was the sleep time of the control group. This is almost the same as 99.7 s, indicating that sleep time is not prolonged within the effective dose range (0.5 to 2.0 mg X kg) for the reduction of magnolol. I got it.

On the other hand, in the group to which the comparative jazebam was administered, the sleep time of the control group (297.9.6 seconds) was significantly prolonged to 542.3.8 seconds. In addition, there was no significant difference between the group administered diazepam and the reductant of magnolol and the group administered only diazepam.Therefore, the reductant of magnolol was induced by hexobarbital regardless of the presence or absence of diazebam. It was found that there was no effect to prolong sleep time.

Example 8 Examination of effects on memory impairment

Applying the improved elevated plus maze device used in Example 1, the following method was used to determine whether or not the magnolol reductant had an effect on memory input (learning acquisition) and memory output (memory retention). investigated.

experimental method

Memory input ability test: 7-week-old STD-dd Y male mice (10 mice per group) were orally administered with 1.0 and 5. OmgZkg of the reduced magnolol, respectively, and the maze device was opened. At the end of the arm, the robot was allowed to stand with the cross toward the tip of the cross, and the time required for the limb to completely enter the closed arm was measured. The same experiment was performed on the same animal 24 hours later. Dazepam 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. After 24 hours, the magnolol reduced forms 1.0 and 5. OmgZkg were orally administered, and 1 hour later, the same experiment was performed. Diazepam 1.0 and 2. OmgZkg were used as comparative drugs.

Table 8 shows the results.

Table 8

* 1: Twist-80 with itffl * 2: Distilled distilled water As can be seen from the results, in memory entry, diazepam was impaired at both 1.0 and 2.0 mg Z kg doses. No disturbing effects were observed at any of the 1.0 and 5.0 mg Z kg doses of the reduced magnolol. No adverse effects were observed for the magnolol reductant or jazebam at the entire dose, even in memory output.

Example 9

Muscle relaxation action test

The muscle relaxation effect of the reduced magnolol was examined by the following suspension test. Test force method

Seven-week-old male STD-ddY mice (10 mice per group) were used as experimental animals, and 100 mg / kg of the reduced magnolol and 10.0 mg / kg of the reduced honokiol were used. Oral administration was performed, and a suspension test was performed 1 hour after administration in the group receiving the reduced magnolol and 3 hours after administration in the group receiving the honokiol reduced body. In the suspension test, a wire of 1.6 mm in diameter and 30 cm in length was placed horizontally at a height of 30 cm, and was placed in the limb of a mouse. The suspension time of 60 seconds was used as a measurement standard. The average was measured twice per animal, and the average value was recorded as 60 seconds if it exceeded 60 seconds.

Table 9 shows the obtained results.

Table 9

* Twin-80 used As is clear from the results, in the suspension test at a high dose (10. Omg Z kg), the retention time was slightly shortened in the honokiol reductant administration group. However, as in the control group, no muscular relaxation action was observed in the magnolol reduced body-administered group.

Example 10

Tablets

An anxiolytic (tablet) was manufactured according to the following formulation and manufacturing method. Prescription (1) Dextrin 54 g

(2) crystalline cellulose 32 g (3) carboxymethylcellulose calcium 6 g (4) polyethylene glycol 600 006 g (5) reduced magnolol 2 g

100 g total

Ingredients (1) to (5) were uniformly mixed in accordance with the above formula, and compression-molded with a tableting machine to obtain a tablet of 100 mg per tablet.

Each tablet contains 2 mg of reduced magnolol and 1 to 6 tablets per adult per day.

Example 1 1

Granules

An anxiolytic (granule) was manufactured according to the following formulation and manufacturing method. Prescription

(1) Dextrin 90 g

(2) Polyethylene glycol 6000 2.5 g

(3) Carboxymethyl cellulose canolesum 6 g

(4) 0.5 g of light gay anhydride

(5) Magnolol reductant 1 g

100 g Production method

Ingredients (1) to (5) were uniformly mixed according to the above 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 magnolol reductant, and take 200 to 100 mg per day for adults in several doses. You.

Example 1 2

Force capsules

Anxiolytics (capsules) manufactured by the following formula and manufacturing method

(1) Anhydrous crystalline maltose 98 g

(2) 1 g of light gay anhydride

(3) Magno-reductor 1

100 g total

Ingredients (1) to (3) were uniformly mixed according to the above formula, and 200 mg was filled in No. 2 capsule.

One capsule contains 2 mg of reduced magnolol, and 1 to 6 capsules per adult per day are taken in several doses.

Example 13

Injection

An anxiolytic (injection) was manufactured according to the following formulation and manufacturing method. Prescription

(1) 90.4 g of distilled water for injection

(2) 5 g of soybean oil

(3) 2.5 g of soybean lipid

(4) Glycerin 2 g

(5) Magnolol reduced product 0.1 total amount 100 g According to the above formula, the component (5) was dissolved in the components (2) and (3), and a solution of the components (1) and (4) was added thereto and emulsified to obtain an injection. Industrial applicability

Magnolol reductants show excellent anti-anxiety effects as shown in the above test examples. In addition, it is effective because it exerts its effects without acting on the benzodiazepine receptor and GABA receptor, so it has no side effects (dependency, tolerance) as seen with benzodiazepines and is a highly safe drug. Therefore, it is expected to be used as an anxiolytic.

Claims

The scope of the claims

1.5- (2-Probenyl) -1 5'-propyl-1,1, '-biphenyl-2,2'-diol or a pharmaceutically acceptable salt thereof as an active ingredient.