WO1999036380A1 - Agents anxiolytiques contenant des derives de biphenyle comme ingredient actif - Google Patents

Agents anxiolytiques contenant des derives de biphenyle comme ingredient actif Download PDF

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Publication number
WO1999036380A1
WO1999036380A1 PCT/JP1998/000114 JP9800114W WO9936380A1 WO 1999036380 A1 WO1999036380 A1 WO 1999036380A1 JP 9800114 W JP9800114 W JP 9800114W WO 9936380 A1 WO9936380 A1 WO 9936380A1
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WIPO (PCT)
Prior art keywords
group
compound
hydroxyl
represent
lower alkyl
Prior art date
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PCT/JP1998/000114
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English (en)
Japanese (ja)
Inventor
Yuji Maruyama
Hisashi Kuribara
Masahide Tanaka
Original Assignee
Tsumura & Co.
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Publication date
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Priority to PCT/JP1998/000114 priority Critical patent/WO1999036380A1/fr
Publication of WO1999036380A1 publication Critical patent/WO1999036380A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a drug such as an anxiolytic agent utilizing a bifujyl derivative having an excellent anxiolytic action, and a novel biphenyl derivative.
  • honokiol (Honokio 1; 3 ′, 5—di 2 —propinole 1, 1′-bihue) is a substance having an anxiety-inhibiting effect from a herbal medicine, Saiboku-to. 2,5'-diol and magnolol (Magno 1 o 1; 5,5'-di-2-propininole 1,1'-bihuen 2,2'-diol) And filed a patent application earlier (Japanese Patent Application No. 9-11466744).
  • Magnolol and Honolulu are 200-500 times more than Saiboku-tou,
  • the natural honokiol reductant is superior in that it has a higher potency and within the effective amount, there is no side effect of the benzodiazepine compound such as muscle relaxation, sedation, hypnosis, dependence and amnesia.
  • the medicinal properties are not yet sufficient, and there has been a demand for providing a compound having a better anxiolytic effect.
  • an object of the present invention is to provide a drug that does not exhibit the side effects of a benzodiazepine drug and has a more excellent anxiolytic effect than honokiol, magnolol and a natural honokiol reduced product.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, obtained by reacting a halogenated metal-substituted phenol compound with a halogen or pseudohalogen-substituted phenol compound in the presence of a palladium catalyst.
  • a halogenated metal-substituted phenol compound with a halogen or pseudohalogen-substituted phenol compound in the presence of a palladium catalyst.
  • some of the biphenyl compounds had significantly more anxiolytic effects than honokiol and natural honokiol reductants. It was also found that some of these compounds were not described in the literature.
  • the present invention has been completed based on these findings. Disclosure of the invention
  • An object of the present invention is to provide the following formula (I)
  • R 1 and R 2 each represent a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkenyloxy group, Group, aryl group, aralkyl group, aryloxy group, arylalkoxy group, lower alkylthio group, lower alkoxycarbonyl group, nitro group or cyano group, and R 3 and R 4 are a hydrogen atom and a hydroxyl group protection, respectively.
  • R 5 represents a lower alkyl group which may be substituted with a hydroxyl group or an alkoxy group, or a lower alkenyl group which may be substituted with a hydroxyl group or an alkoxy group.
  • n and m represent numbers from 0 to 2. However, 3 ', 5—di-2-propenyl-1, 1'-biphenylenol 2,4'-diol and 5— (2propyl) 3'propynole 1, 1'-biphenyl2, 4'—excluding diol)
  • anxiolytic agent comprising a biphenyl derivative represented by the following formula:
  • Another object of the present invention is to provide the following formula (II)
  • R! 'And R 2 ' represent a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group or a lower alkenyloxy group, respectively, and R 3 and each represent a hydrogen atom, a hydroxyl protecting group.
  • R 3 and each represent a hydrogen atom, a hydroxyl protecting group.
  • FIG. 1 is a transition curve showing the increasing rate of the anxiolytic effect depending on the dose of the test compound.
  • a lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, Xyl groups and the like can be exemplified.
  • the lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl, aryl, 2-butenyl, 3-butenyl, 1-methylarinole, 2 —Pentenyl, 2-hexenyl and the like.
  • the lower alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, and specific examples thereof include ethynyl, 1-propynyl, 2-propynyl and the like.
  • a lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, Pentyloxy, hexyloxy and the like can be exemplified.
  • a lower alkenyloxy group means a straight-chain or branched alkenyloxy group having 2 to 6 carbon atoms, and specifically, bieroxy, aryloxy and the like.
  • aryl groups include groups such as phenyl and naphthyl.
  • aralkyl group include, for example, benzyl, 2-phenyl, and 1-phenethyl group.
  • aryloxy group include, for example, a phenoxy group. Are benzyloxy, phenethyloxy and the like.
  • a lower alkylthio group is a straight-chain or branched alkylthio group having 1 to 6 carbon atoms, specifically, methylthio, ethylthio, propylthio, isopropylthio, butynolethio, t.ert-butylthio, pentinorethio, and hexyl. Examples thereof include a luthio group.
  • the lower alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbo. Examples thereof include quinole, butoxycanoleboninole, tert-butoxycanoleboninole, pentinoleoxycarbonyl, and hexyloxycarbonyl group.
  • the anti-anxiety agent of the present invention some of the compounds of the formula (I) used as an active ingredient are known, and some of them are commercially available. it can.
  • a compound according to the purpose can be appropriately synthesized by a force-ring method described in Japanese Patent Publication No. Hei 7-130556.
  • the bifuunil derivative of the formula (II), which is a novel compound is synthesized by force-rolling the phenolic compounds (III) and (IV) as raw materials according to the following formula as follows.
  • R ′ and R 2 ′′ are each a protected hydroxyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkoxy group or lower R 3 'and R each represent a hydroxyl protecting group, a lower alkyl group or a lower alkenyl group;
  • M et represents zinc, magnesium or zirconium;
  • X and Y each represent a halogen atom;
  • R, R 2 ', R 3 , R-, n and m have the same meanings as defined above
  • the phenolic compound (III), which is one of the raw materials, can be obtained, for example, by halogenating compound (V) to give compound (VI) according to the following formula, and then protecting the hydroxyl group.
  • a hydroxyl group-protecting group such as a methoxymethyl group, a methyl group, a benzyl group, or a methoxymethyloxy group.
  • the funool compound (IV) is prepared, for example, according to the following formula. That is, after reacting aryl bromide with the hydroxyl group of the halogen-substituted phenol (VII) to give aryloxyhalogenobenzene (VIII), the aryl group is rearranged to give the aryl-substituted halogenophenol.
  • the reaction between the compound (VII) and aryl bromide is carried out by potassium carbonate or the like.
  • the reaction is carried out by heating to about 60 ° C in a solvent such as dimethylformamide (DMF) in the presence of dimethylformamide (DMF) to transfer the aryl group of compound (VIII) to compound (IX).
  • the reaction is carried out by reacting boron trichloride at a temperature of about 15 ° C. in a solvent such as dichloromethane.
  • compound (IX) In the reaction of converting compound (IX) to compound (IV), after protecting the hydroxyl group, tetrahydrofuran, 1,4-dioxane, ether, In a solvent such as dimethoxetane, compound (IX) is allowed to react with 11.5 equivalents of n-butyllithium or 2 to 3 equivalents of t-butyllithium at a temperature of 160 ° C or lower, and This is done by adding 12 equivalents of metal halide and raising the temperature to room temperature. Since the compound (IV) thus obtained is easily decomposed by water, oxygen and the like, it is desirable to use it for the reaction with the compound (III) without isolation and purification.
  • the biphenyl derivative ( ⁇ ) obtained by the above reaction can be used as a drug such as an anxiolytic or its intermediate material after removal of the protecting group or purification if necessary. it can.
  • the synthetic honokiol derivative or a pharmaceutically acceptable salt thereof has extremely excellent anxiolytic effect compared to honokiol and its natural honokiol reduced form, and has side effects (dependency, Tolerance is not recognized, so it is very promising as a drug such as an anxiolytic.
  • the anti-anxiety agent of the present invention is obtained by formulating a bifurnyl derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof together with a conventional pharmaceutical carrier, and comprises tablets, capsules, granules, Oral preparations such as fine granules, powders, and liquid preparations, and parenteral preparations such as injections, infusions, and suppositories may be used.
  • oral preparation In order to achieve the intended effect as an oral preparation, it depends on the patient's age, weight, and degree of illness, but usually the adult bifuunil derivative (I) 0.1 mg to 100 mg per day It is appropriate to take mg in several divided doses.
  • Pharmaceutical carriers can be selected according to the dosage form and dosage form of the preparation. In the case of oral preparations, for example, starch, lactose, sucrose, mannite, It is manufactured according to a conventional method using ropoxymethylcellulose, corn starch, inorganic salts and the like.
  • a binder In preparing the oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, and the like can be further added.
  • a binder In preparing the oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, and the like can be further added. The following are specific examples of these.
  • Starch dextrin, gum arabic, gelatin, hydroxypine pinorestarch, methinoresenololose, canolepo'ximetinoresenole sodium, sodium, hydroxypropionolecellulose, crystal cell mouth, ethyl senorelose , Polyvinylpyrrolidone, and macrogor.
  • Starch hydroxypropyl starch, carboxymethylcellulose sodium, potassium oleboxylmethylcellulose canolesum, potassium oleboxyl methylsenorellose, low-substituted hydroxypropyl pilcenorellose.
  • Talc roux, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.
  • It can also be administered as an oral liquid suspension, suspension, emulsion, syrup, and elixir. Flavoring agents and coloring agents may be added.
  • This parenteral preparation is manufactured according to a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, pro Pyrenglycol, polyethylene glycol and the like can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added.
  • this parenteral preparation can be frozen after filling into vials and the like, water can be removed by conventional freeze-drying technology, and the liquid preparation can be prepared from the freeze-dried product immediately before use. it can. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.
  • 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 ordinary methods.
  • the anxiolytic agent of the present invention has an excellent anxiolytic effect as shown in the test examples described below, has no side effects (dependency, tolerance) as observed with benzodiazepine drugs, and is safe. Therefore, it is extremely advantageous in the medical field.
  • Example 1 Example 1
  • 2-Bromo-4-propylpyrrole (14) 930 mg (4.33 mmo 1 e), chloromethinole methinolate (10 ml), 0.6 ml (7.9 mmo 1 e), A solution of 1.7 ml (9.8 mmo 1 e) of diisopropyrethylamine in 2 ml of dichloromethane was stirred at room temperature for 16 hours. The reaction solution was washed with 2N aqueous hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate.
  • MOMO represents a methoxymethoxy group
  • Ph represents a phenyl group
  • Me represents a methyl group
  • Bz represents a benzyl group
  • Et represents an ethyl group.
  • mice As an experimental animal, a 6-week-old standard ddY mouse was used. Six to ten mice were placed in a polycarbonate cage (30 (W) X 20 (D) XI 5 (H) cm) covered with a pad-tip bedding, and a solid feed (MF: Enthal yeast, Tokyo) and tap water. The animal breeding room has a 14-hour light period and a 10-hour dark period (light period: 5:00 am to 7:00 pm) and a room temperature of 22 ⁇ 2. C and humidity were adjusted to 50 ⁇ 2%. The test drug was administered only once 3 hours before the start of the experiment (1 hour before administration for honokiol and 10 minutes before administration for diazepam).
  • 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 platform (9 x 9 cm) .
  • the two closed arms have black opaque side walls (10 (H) cm) and the floor is gray opaque.
  • Two open arms orthogonal to the closed arm have no side walls and the floor is transparent It is.
  • the entire maze device was installed at a height of 40 cm.
  • the locomotor activity of the mice was measured with a large-sized ambulometer (AMB-10; Ohara Medical, Tokyo) having an acrylic resin measuring cage with a diameter of 20 cm.
  • AMB-10 Ohara Medical, Tokyo
  • the device selectively records only horizontal movements (relocation movements) of the mouse, not vertical movements.
  • 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 two forearms and one of the hind limbs (three in total) were completely on the open arm from the platform, it was judged that the shift to the open arm was made. -
  • mice were placed in an ambulometer and their locomotor activity was measured for 5 minutes.
  • Table 2 shows the results of single oral administration (single administration).
  • Administered drug (mg / kg) Residence time '(sec) Compound 50 0.2 2 3.7 ⁇ 5.4
  • Example 2 Using a 6-week-old standard Dod dd Y mouse (10 mice per group) as an experimental animal, the compound 5 obtained in Example 2 was orally administered at a dose of lmg / kg. The anxiolytic effect was measured at 1, 2, 3, 4, 6, 24, 48, and 72 hours after administration using an elevated plus maze device. Table 4 shows the results.
  • Example 2 Using a 6-week-old standard dd ⁇ (5 animals per group) as an experimental animal, the compound 5 obtained in Example 2 was orally administered 3 hours before administration of hexobarbital, and The effects were investigated. Hexobarbital was administered intravenously at 100 mg / kg. Also, for comparison, honokiol And the compound 13 obtained in Example 3 was used.
  • the sleep effect was expressed by the time from the loss of the righting reflex to the recovery as sleep time. Table 5 shows the results.
  • Compound 5 obtained in Example 2 was added to 6-week-old standard 1-dd Y mice (10 mice per group) at 0.2, 1.0, and 2.0 mg / kg, respectively.
  • the obtained compound 13 was orally administered at 2 mg Z kg, and 3 hours later, the suspension time of the suspension force was measured to examine the onset of muscle relaxation.
  • the muscle relaxant effect was measured using a 1.6-mm-diameter wire with a 10-cm-diameter ring fixed at 40 cm from the floor. It was measured as time. 6 0 seconds holding time per animal and a reference, are set to be c comparison was evaluated as 6 0 seconds those held anymore Jiazepamu 0. 5, 1. 0, S. Administered O mg Z kg The used mouse was used.
  • Table 7 shows the results when the anxiolytic effect is at a maximum.
  • Dazepam is the value 10 minutes after administration.
  • mice of the same strain used in Test Example 6 (10 mice per group) were orally administered with lmg Z kg of the compound 5 and diazebam obtained in Example 2, respectively.
  • the retention effect of the suspension force was measured over time in the same manner as in Test Example 6, and the onset of muscle relaxation was examined. The results are shown in Tables 8 and 9.
  • Compound 5 of the present invention showed that Compound 5 of the present invention was identical to the control in all groups. , And no muscle relaxation was observed. In contrast, diazepam showed a slight muscle relaxant effect.
  • An anxiolytic (tablet) was manufactured according to the following formulation and manufacturing method.
  • (1) to (5) were uniformly mixed and compression-molded with a tableting machine to obtain a tablet of 10 Omg per tablet.
  • An anxiolytic (granule) was manufactured according to the following formulation and manufacturing method.
  • (1) to (5) were uniformly mixed, compression-molded by a compression molding machine, pulverized by a crusher, and sieved to obtain granules.
  • An anxiolytic (capsule) was manufactured according to the following formulation and manufacturing method.
  • (1) to (3) were evenly mixed, and 200 mg was filled in a No. 2 capsule.
  • Pile anxiety agents were manufactured according to the following formulation and manufacturing method. [How]

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des agents anxiolytiques contenant en tant qu'ingrédient actif des dérivés de biphényle représentés par la formule générale (I) suivante: (I) dans laquelle R1 et R2 représentent chacun l'hydroxy, l'alkyle inférieur, l'alcényle inférieur, l'alcynyle inférieur, l'alcoxy inférieur, l'alcényloxy inférieur, l'aralkyle, l'aryloxy, l'arylalcoxy, l'alkylthio inférieur, l'alcoxycarbonyle inférieur, nitro ou cyano; R3 et R4 représentent chacun l'hydrogène, un groupe protecteur de l'hydroxy, l'alkyle inférieur ou l'alcényle inférieur; R5 représente l'alkyle inférieur éventuellement substitué par hydroxy ou alcoxy ou l'alcényle inférieur éventuellement substitué par hydroxy ou alcoxy; et n et m sont chacun un nombre de 0 et 2, à condition que 3',5-di-2-proényl-1,1'-biphényle-2,4'-diol et 5 (2-propényle)-3'-propyl-1,1,'-biphényl-2,4'-diol sont exclus de ces derniers. Ces agents anxiolytiques n'exercent pas d'effets secondaires observés dans les composés de benzodiazépine tel que relaxation musculaire, sédation, hypnose, dépendance ou de troubles de mémoire et présentent en effet anxiolytique supérieur à l'honokiol, au magnolol et aux dérivés réduits d'honokiol d'origine naturelle.
PCT/JP1998/000114 1998-01-14 1998-01-14 Agents anxiolytiques contenant des derives de biphenyle comme ingredient actif WO1999036380A1 (fr)

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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
KR100892596B1 (ko) 2007-02-12 2009-04-09 바이오스펙트럼 주식회사 바이페닐 다이올 유도체 및 이를 유효성분으로 포함하는조성물

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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
KR100892596B1 (ko) 2007-02-12 2009-04-09 바이오스펙트럼 주식회사 바이페닐 다이올 유도체 및 이를 유효성분으로 포함하는조성물

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