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WO2001003689A1 - Anxiolytiques - Google Patents

Anxiolytiques Download PDF

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Publication number
WO2001003689A1
WO2001003689A1 PCT/JP2000/004712 JP0004712W WO0103689A1 WO 2001003689 A1 WO2001003689 A1 WO 2001003689A1 JP 0004712 W JP0004712 W JP 0004712W WO 0103689 A1 WO0103689 A1 WO 0103689A1
Authority
WO
WIPO (PCT)
Prior art keywords
magnolol
reduced
effect
honokiol
anxiolytic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2000/004712
Other languages
English (en)
Japanese (ja)
Inventor
Yuji Maruyama
Hisashi Kuribara
Yoshimasa Ichio
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tsumura and Co
Original Assignee
Tsumura and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tsumura and Co filed Critical Tsumura and Co
Priority to AU60153/00A priority Critical patent/AU6015300A/en
Publication of WO2001003689A1 publication Critical patent/WO2001003689A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to a medicament as an anxiolytic using a reduced magnolol.
  • anxiolytics 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.
  • 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.
  • honokiol Honokiol: 3 ′, 5—di1-2—propinyl1-1, 1 ′
  • Biphenyl 2,4'-diol Biphenyl 2,4'-diol
  • 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).
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the anxiolytic agent of the present invention 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.
  • a conventional pharmaceutical carrier such as a 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.
  • 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.
  • 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.
  • Starch dextrin, arabic gum powder, gelatin, hydroxypropyl starch, methylcellulose, carboxymethylcellulose sodium starch, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyro Redon, Macro goal.
  • Starch hydroxypropyl pilstarch, carboxymethylcellulose sodium sodium, potassium oleboxime cellulose cellulose, carboxymethylcellulose, low-substituted hydroxypropyl propylenolose.
  • Talc waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.
  • a coloring agent may be blended.
  • intravenous injection in order to achieve the desired effect as a parenteral drug, 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.
  • 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.
  • fungicides, preservatives and stabilizers may be added, if necessary.
  • 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.
  • parenteral preparations examples 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.
  • honokiol reductant (hereinafter simply referred to as honokiol reductant) was used.
  • mice 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).
  • 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.
  • 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. .
  • AMB-10 Ohara Medical Industry Co., Ltd., Tokyo, Japan
  • This device records only the horizontal movement (relocation movement) of the mouse, not the vertical movement.
  • 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.
  • the mouse was placed in the ambibulometer, and the locomotor activity was measured for 5 minutes thereafter. Specified.
  • mice 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • mice 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.
  • 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.
  • comparative drugs honokiol reductants and jazebam were used.
  • mice 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.
  • 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.
  • the sleep time of the control group (297.9.6 seconds) was significantly prolonged to 542.3.8 seconds.
  • the group administered diazepam and the reductant of magnolol there was no significant difference between the group administered diazepam and the reductant of magnolol and the group administered only diazepam.
  • 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.
  • 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.
  • mice 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.
  • An anxiolytic (tablet) was manufactured according to the following formulation and manufacturing method.
  • Prescription (1) Dextrin 54 g
  • 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.
  • An anxiolytic (granule) was manufactured according to the following formulation and manufacturing method. Prescription
  • 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.
  • Anxiolytics manufactured by the following formula and manufacturing method
  • One capsule contains 2 mg of reduced magnolol, and 1 to 6 capsules per adult per day are taken in several doses.
  • An anxiolytic (injection) was manufactured according to the following formulation and manufacturing method.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne des anxiolytiques renfermant comme principe actif du 5-(2-propényle)-5'-propyle-1, 1'-biphényle-2, 2'-diol ou des sels de ce composés acceptables au plan pharmaceutique.
PCT/JP2000/004712 1999-07-13 2000-07-13 Anxiolytiques Ceased WO2001003689A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60153/00A AU6015300A (en) 1999-07-13 2000-07-13 Antianxiety drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/198543 1999-07-13
JP11198543A JP2001026537A (ja) 1999-07-13 1999-07-13 抗不安剤

Publications (1)

Publication Number Publication Date
WO2001003689A1 true WO2001003689A1 (fr) 2001-01-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/004712 Ceased WO2001003689A1 (fr) 1999-07-13 2000-07-13 Anxiolytiques

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JP (1) JP2001026537A (fr)
AU (1) AU6015300A (fr)
WO (1) WO2001003689A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008542192A (ja) * 2005-02-23 2008-11-27 アービサー ジャック エル． 増殖の障害の治療用のホノキオール誘導体
WO2012013691A1 (fr) 2010-07-28 2012-02-02 Prous Institute For Biomedical Research, S.A. Dérivés biphényl diols substitués multicibles

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10338631A (ja) * 1997-06-04 1998-12-22 Tsumura & Co 抗不安剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10338631A (ja) * 1997-06-04 1998-12-22 Tsumura & Co 抗不安剤

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008542192A (ja) * 2005-02-23 2008-11-27 アービサー ジャック エル． 増殖の障害の治療用のホノキオール誘導体
WO2012013691A1 (fr) 2010-07-28 2012-02-02 Prous Institute For Biomedical Research, S.A. Dérivés biphényl diols substitués multicibles
EP2423181A1 (fr) 2010-07-28 2012-02-29 Prous Institute For Biomedical Research S.A. Dérivés de biphényldiol substitués à cible multiple

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Publication number Publication date
AU6015300A (en) 2001-01-30
JP2001026537A (ja) 2001-01-30

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