WO2007037258A1 - Agent thérapeutique destiné au trouble déficitaire de l’attention avec hyperactivité - Google Patents

Agent thérapeutique destiné au trouble déficitaire de l’attention avec hyperactivité Download PDF

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Publication number
WO2007037258A1
WO2007037258A1 PCT/JP2006/319144 JP2006319144W WO2007037258A1 WO 2007037258 A1 WO2007037258 A1 WO 2007037258A1 JP 2006319144 W JP2006319144 W JP 2006319144W WO 2007037258 A1 WO2007037258 A1 WO 2007037258A1
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WO
WIPO (PCT)
Prior art keywords
attention deficit
hyperactivity disorder
methamphetamine
cloperastine
therapeutic agent
Prior art date
Application number
PCT/JP2006/319144
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English (en)
Japanese (ja)
Inventor
Kazuo Takahama
Fumio Soeda
Yoshiko Fujieda
Tetsuya Shirasaki
Original Assignee
Kumamoto University
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 Kumamoto University filed Critical Kumamoto University
Priority to JP2007537635A priority Critical patent/JP5109132B2/ja
Publication of WO2007037258A1 publication Critical patent/WO2007037258A1/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for attention deficit hyperactivity disorder.
  • ADHD Attention deficitHyperactivity disorder
  • GIRK G protein-coupled inward rectifying K ion
  • JP 2000-264849 A discloses prevention of frequent urinary / urinary incontinence comprising a non-narcotic cough reflex inhibitor having a morphinan skeleton such as cloperastine or calamiphen hydrochloride. A composition is described.
  • Patent Document 1 JP 2000-264849 A
  • an object of the present invention is to provide an effective therapeutic agent for attention deficit'hyperactivity disorder.
  • a therapeutic agent for attention deficit / hyperactivity disorder comprising cloperastine, calamiphen, tipipedin, or a salt thereof.
  • a method for treating attention deficit / hyperactivity disorder comprising administering cloperastine, calamiphen, tipipedin, or a salt thereof to a patient.
  • the therapeutic agent for attention deficit 'hyperactivity disorder of the present invention is a compound having an action of suppressing an activation current of a G protein-coupled inward rectifying force-ium ion channel (GIRK channel), cloperastine, calamiphene, It contains pepidin or a salt thereof as an active ingredient.
  • GIRK channel G protein-coupled inward rectifying force-ium ion channel
  • cloperastine cloperastine
  • calamiphene It contains pepidin or a salt thereof as an active ingredient.
  • GIRK channel G protein-coupled inward rectifier potassium ion channel
  • NMDA N-methyl-D-aspartate
  • a compound having no action of suppressing current can be used as an active ingredient. like this Specific examples of such compounds include those commercially available as non-narcotic central antitussives.
  • the GIRK channel activation current is a membrane current resulting from the flow of potassium ions across the cell membrane due to the activation of the GIRK channel.
  • This channel is conjugated to various neurotransmitter receptors such as serotonin (5-HT) and noradrenaline, such as 5-HT
  • the glycine receptor activation current refers to a membrane current resulting from the flow of chloride ions across the cell membrane due to the activity of the glycine receptor. Therefore, glycine receptor activation current can be induced by glycine.
  • the aspartate current is an inward membrane current that flows due to the activation of NMDA receptor, which is one of excitatory amino acid receptors, aspartate. .
  • the primary screening of the therapeutic agent for attention deficit / hyperactivity disorder of the present invention preferably comprises GIRK channel activation current, and optionally glycine receptor activation current, and NMDA receptor activation current.
  • GIRK channel activation current preferably comprises GIRK channel activation current, and optionally glycine receptor activation current, and NMDA receptor activation current.
  • NMDA receptor activation current preferably comprises GIRK channel activation current, and optionally glycine receptor activation current, and NMDA receptor activation current.
  • FIG. 9 is a schematic diagram showing an example of a system for measuring membrane current in the present invention.
  • 1 is -Europe
  • 2 is a glass electrode for patch clamping
  • 3 is a Y tube through which the test solution flows
  • 4 is a Y tube test solution outlet
  • 5 is a suction for replacing the test solution in the tube
  • 6 is a culture dish
  • 7 is a reflux inlet
  • 8 is a reflux outlet
  • 9 is an amplifier
  • 10 is a ground wire.
  • FIG. 10 is an enlarged view of the main part of FIG. 9, 11 is a Y-tube, 12 is a jet port, 13 is -euron, and 14 is a recording electrode for measuring the membrane current.
  • the whole cell patch clamp method and the nystatin perforated patch clamp method are known.
  • the recording electrode is brought into contact with the acutely isolated raphe nucleus-euron, and a negative pressure is applied inside the electrode to form a gigaohm seal, and then a negative pressure is applied to the tip of the electrode.
  • the membrane current due to extracellular administration such as serotonin can be recorded by breaking the cell membrane and penetrating the cell and the cell.
  • Nystatin perforated patch recording and its applications s to analyze of intracellular mechanisms. Jpn.J.
  • Physiol., 44, 433—473 is a nystatin perforated patch clamp method.
  • the nystatin in the electrode forms a perforation in the cell membrane, and the membrane current can be recorded while maintaining the intracellular environment. I'll do it.
  • a batch clamp amplifier for recording the membrane potential and the membrane current.
  • the obtained current waveform is observed with an oscilloscope or the like and analyzed with a personal computer. If necessary, the current waveform is recorded on a recording medium such as a flexible disk, CD-R / RW, DVD, or MO. If necessary, record the membrane current and membrane potential on magnetic tape and draw them on a recorder. It is preferable to use a notch clamp analysis system for the analysis.
  • the determination of whether or not the GIRK channel or the like can suppress the active current is expressed, for example, by expressing the current amplitude as a mean value standard error and statistically comparing between the presence and absence of the drug. .
  • the risk factor is p ⁇ 0.05, the difference is considered significant.
  • the compound having an action of suppressing the GIRK channel activation current preferably, having an action of suppressing the activity of the G protein-conjugated inward rectifier potassium ion channel (GIRK channel)
  • GIRK channel preferably, having an action of suppressing the activity of the G protein-conjugated inward rectifier potassium ion channel (GIRK channel)
  • NMDA N-methyl-D-aspartate
  • cloperastine As, for example, cloperastine, calamiphen, ebrazinone, ethandis nolephonic acid, tipepidine hibenzate, isoaminyl, memorphane, oxerazine, pentoxyberine, eprazinone, benproperin, guaifenesin, their hydrochlorides, phosphates, citrates Salt or fendizoate. These may be used as a mixture.
  • cloperastine or its hydrochloride or phendizoate, calamiphen hydrochloride, caramifen ethanedisulfonate, eprazinone hydrochloride, tipepidine hibenzate, tipepidine citrate, isoamyl kenate
  • cloperastine is most preferred.
  • Cloperastine which can be exemplified as a particularly preferred compound in the present invention, is a compound represented by the following structural formula (1) (1- [2-[(4-chlorophenol) phenylmethoxy] ethyl] piperidine) It has a boiling point of 424 ° C and a molecular weight of 330, and is known as a central antitussive with mild antihistamine action.
  • Caramifen which is preferred in the present invention and can be exemplified as a compound, is a compound represented by the following structural formula (2), which is also known as a central antitussive.
  • Tipepidine which is preferred in the present invention and can be exemplified as a compound, is a compound represented by the following structural formula (3), which is also known as a central antitussive. [0029] [Chemical 3]
  • the attention deficit / hyperactivity disorder therapeutic agent of the present invention is administered orally (including sublingual administration) or parenterally.
  • drug forms include tablets, capsules, fine granules, pills, troches, infusions, injections, suppositories, ointments, patches and the like.
  • physiological saline can be used as a main component, and other water-soluble additives and chemicals can be blended as necessary.
  • Additives added to such water include nutrients such as alkali metals such as potassium and magnesium, lactic acid, various amino acids, fat, glucose such as glucose, fructose, and sucrose, vitamins A and B And vitamins such as C and D, phosphate ions, chloride ions, hormones, plasma proteins such as albumin, polymer polysaccharides such as dextrin and hydroxyethyl starch, and the like.
  • concentration of the compound in such aqueous solution, a child and a range of 10- 7 M of 10- 5 M concentration is preferred.
  • the therapeutic agent containing the compound of the present invention can also be administered to a living body as a solid agent.
  • solid agents include powders, fine granules, granules, microcapsules, tablets and the like. Among such solid preparations, it is preferable that they are in the form of tablets, which are preferably easy to swallow.
  • Known fillers and binders for forming tablets with the compound for example, Oligosaccharides can be used. It is preferable that the tablet has a diameter of 2 to: LOmm and a thickness of 1 to 5 mm.
  • a therapeutic agent containing the compound may be mixed with other therapeutic agents.
  • additives can be blended in the solid agent.
  • additive agents include stabilizers, surfactants, solubilizers, plasticizers, sweeteners, antioxidants, flavoring agents, coloring agents, preservatives, inorganic fillers, and the like. it can.
  • surfactants include key-on interfaces such as higher fatty acid sarcophagus, alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate salts, acyl N methyl taurate salts, alkyl ether phosphate ester salts, and N acyl amino acid salts.
  • Activating agents Salts such as alkyltrimethyl ammonium, dialkyldimethyl ammonium chloride, benzalkonium chloride, etc.
  • Thion surfactant alkyldimethylaminoacetic acid betaine, alkylamidodimethylaminoacetic acid betaine
  • Nonionic surfactants such as amphoteric surfactants such as 2-hydroxyquinole N force noreboxy N-hydroxyimidazole-betaine, polyoxyethylene-type, polyhydric alcohol ester-type, ethylenoxide propylene oxide block copolymer, etc.
  • Examples of the inorganic filler to be blended for the purpose of improving swallowability and the like include talc, my strength, titanium dioxide and titanium dioxide.
  • Examples of the stabilizer include adipic acid and ascorbic acid.
  • Examples of the solubilizing agent include surfactants such as sucrose fatty acid ester and stearyl alcohol, asunargin, arginine and the like.
  • Examples of sweeteners include aspartame, amateur, kanso, wiki and the like.
  • suspending agent carboxyvinyl polymer, etc., as the antioxidant, ascorbic acid, etc., as the flavoring agent, sugar flavor, etc., as the pH adjusting agent, sodium taenoate, etc. Can be mentioned.
  • the therapeutic agent for attention deficit 'hyperactivity disorder of the present invention is usually 1 to 40 mg at a time, preferably 10 mg
  • the agent of the present invention can be used for the treatment of attention deficit hyperactivity disorder.
  • Attention deficitHyperactivity disorder is a disproportionate attention to age or development and Z or shock. It is a behavioral disorder characterized by mobility and hyperactivity, which impedes social activities and academic functions. In addition, it appears before the age of seven, the condition continues, and it is estimated that the central nervous system is dysfunctional for some reason.
  • Attention deficit 'Hyperactivity disorder has the following characteristics: (1) Attention deficit (difficult to listen to the end, difficult to distract, often distracted, work to the end ), (2) Hyperactivity (can't sit still, talk without thinking of the other person's position and situation, etc.), and (3) Impulsiveness (difficult to wait for turn) ), Etc.).
  • diagnostic criteria for attention deficit 'hyperactivity disorder the diagnostic criteria (according to DSM-IV) that it is necessary to meet the following A. B. C. D. E. can be mentioned.
  • haloperidol is clinically used for sedation in cases of intense impulsivity such as violence against others, but haloparidol suppresses the increase in spontaneous movement by methamphetamine.
  • Methylfedate an existing therapeutic agent for attention deficit / hyperactivity disorder, does not suppress the increase in gait-induced gait, but the therapeutic agent for attention deficit / hyperactivity disorder of the present invention. Has also suppressed the gait increase in gait induced by methamphetamine, so methylphenidate, a treatment for existing attention deficit / hyperactivity disorder, is ineffective !, and can treat attention deficit / hyperactivity disorder There is sex.
  • methylfedate inhibits the increase in gait induced by 6-hydroxydopamine. Therefore, the attention deficit 'hyperactivity disorder therapeutic drug of the present invention is effective for the attention deficits in which methylfdate is effective. Even if it is a dysfunction!
  • mice Four-week-old ddY male mice were purchased, handled for one week, and used for experiments at the age of five weeks.
  • Figure 1 shows the time schedule of the experiment.
  • mice were given saline or cloperastine (5, 10, 20 mg / kg), tipepidine (10, 20, 40 mg / kg), calamiphen (20, 40 mg / kg), methylfedate (10 mg). / kg) was administered subcutaneously.
  • methamphetamine 0.5 mg / kg was administered subcutaneously, and immediately an open field test was performed for 30 minutes. This open field test was used to measure the amount of walking, which is one of the search behaviors of mice, and to evaluate hyperactivity.
  • the mouse was placed in an open field, and the walking amount was measured for 10 minutes. Thereafter, physiological saline or cloperastine (20 mg / kg), tipepidine (20 mg / kg), and methyl fade (10 mg / kg) were subcutaneously administered, and immediately an open field test was conducted for 10 minutes. In the same way as in Experiment 1, after the test was completed, the effect of the drug on the cooperative movement of the mouse was evaluated using a treadmill (rotor rod).
  • Figure 3 shows the results for cloperastine.
  • methamphetamine 0.5 mg / kg
  • the amount of walking was significantly increased compared to the group receiving saline.
  • subcutaneous administration of 10 or 20 mg / kg cuperastatin significantly suppressed the increase in gait due to methamphetamine.
  • the influence of the rotarod on the cooperative movement of the mouse was evaluated, but in all groups, the influence was not recognized in the cooperative movement ability.
  • FIG. 4 shows the results of tipepidine.
  • the gait volume was significantly increased by subcutaneous administration of methamphetamine.
  • subcutaneous administration of tipepidine 20 and 40 mg / kg significantly suppressed the increase in gait due to methamphetamine.
  • the effect of the rotarod on the cooperative movement of the mouse was evaluated, but in all groups, the influence was not recognized in the cooperative movement.
  • FIG. 5 shows the results of caramifen.
  • FIG. 6 shows the results of methyl fed-date.
  • methamphetamine administration significantly increased walking volume.
  • subcutaneous administration of methyl phosphate-date at 10 mg / kg further increased the gait increase due to methamphetamine.
  • the effect of the rotarod on the cooperative ability of mice was evaluated, but the cooperative ability was normal in all groups.
  • Figure 7 shows the results for cloperastine and tipepidine.
  • the 6-OHDA exposure group had a significant increase in walking volume for 10 minutes before drug administration.
  • Forced force with no significant change in gait of 6-OHDA-exposed mice by subcutaneous administration of saline.
  • FIG. 8 shows the results of methyl fed-date.
  • Subcutaneous administration of methyl fedate at 10 mg / kg significantly decreased the walking amount of 6-OHDA-exposed mice compared to the control group.
  • all the groups that evaluated the effect of the rotarod on the coordinated movement of the mice were not affected by the coordinated movement.
  • the present invention relates to a therapeutic agent for attention deficit hyperactivity disorder.
  • a compound having an action of suppressing an active current of a G protein-coupled inward rectifying force ryu ion channel (GIRK channel) represented by cloperastin is a model of attention deficit and hyperactivity disorder. It is effective in the treatment of attention deficit / hyperactivity disorder and has the effect of suppressing hyperactivity in animals treated with 6-hydroxydopamine and methamphetamine-induced hyperactivity.
  • FIG. 1 shows the schedule for Experiment 1.
  • cloperastine 5, 10, 20 mg / kg
  • tipepidine 10, 20, 40 mg / kg
  • caramiphen 20, 40 mg / kg
  • methylphenida te 10 mg / kg
  • Figure 2 shows the schedule for Experiment 2. Cloperastine (20 mg / kg) as the test substance, Tipepidine (20 mg / kg) and methylphenidate (10 mg / kg) were used.
  • FIG. 3 shows the effect of cloperastine on methamphetamine-induced gait increase.
  • SS saline— saline
  • SM saline— methamphetamine
  • M 5 cloperastine 5 mg / kg— metha mphetamine
  • CM10 cloperastine 10 mg / kg-methamphetamine
  • CM20 cloperastin e 20 mg / kg-methamphetamine
  • walking amount is open field Displays the number of times the mouse has crossed the boundary line of 30 minutes.
  • FIG. 4 shows the effect of tipepidine on methamphetamine-induced gait increase.
  • SS s aline- saline
  • SM saline-methamphetamine
  • TM10 tipepidine 10 mg / kg-methamph etamine
  • TM20 tipepidine 20 mg / kg-methamphetamine
  • TM40 tipepidine 40 mg / kg-methamphetamine Is displayed as the number of times the mouse crosses over 30 minutes.
  • FIG. 5 shows the effect of caramiphen on methamphetamine-induced gait increase.
  • SS saline-saline
  • SM saline-methamphetamme
  • CaM20 caramiphen 20 mg / g-methamphetamine
  • CaM40 caramiphen 40 mg / kg-methamphetamine, walking is o ⁇ Displayed as the number of crossings in 30 minutes.
  • FIG. 6 shows the effect of methylphenidate on methamphetamine-induced gait increase.
  • SS saline-saiine
  • SM saline-methamphetamine
  • MM10 methylphenidate 10 mg / kg-methamphetamine
  • FIG. 7 shows the effects of cloperastine and tipepidine on 6-hydroxydonamine-induced gait increase. Walking amount is displayed as the number of times the mouse crosses the border of the open field section in 10 minutes.
  • FIG. 8 shows the effect of methylphenidate on 6-hydroxydopamine-induced gait increase. Walking amount is displayed as the number of times the mouse crosses the border of the open field section in 10 minutes.
  • FIG. 9 is a schematic view showing an example of an apparatus used in the notch clamp method.
  • FIG. 10 is an enlarged view of a main part of the apparatus used in the patch clamp method of FIG.

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Abstract

L’invention concerne un agent thérapeutique efficace destiné au trouble déficitaire de l’attention avec hyperactivité. L’agent thérapeutique comprend de la clopérastine, de la caramiphène, de la tipépidine ou un sel de celles-ci.
PCT/JP2006/319144 2005-09-28 2006-09-27 Agent thérapeutique destiné au trouble déficitaire de l’attention avec hyperactivité WO2007037258A1 (fr)

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JP2007537635A JP5109132B2 (ja) 2005-09-28 2006-09-27 注意欠陥・多動性障害の治療薬

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007139153A1 (fr) * 2006-05-31 2007-12-06 Kumamoto University Agent améliorant une fonction pour le dysfonctionnement cérébral provoqué par un produit chimique environnemental
JP2009227631A (ja) * 2008-03-25 2009-10-08 Kumamoto Univ 気分障害又は感情障害の治療薬
JP2011246446A (ja) * 2010-04-28 2011-12-08 Kumamoto Univ 脳機能障害修復剤
JP2012062272A (ja) * 2010-09-15 2012-03-29 Kumamoto Univ 中枢機能改善薬

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Publication number Priority date Publication date Assignee Title
JP2000264849A (ja) * 1999-01-12 2000-09-26 Takeda Chem Ind Ltd 頻尿・尿失禁治療組成物
JP2003514818A (ja) * 1999-11-18 2003-04-22 アストラゼネカ・アクチエボラーグ 新規使用および新規ｎ−アザビシクロ−アミド誘導体
WO2005084709A1 (fr) * 2004-03-04 2005-09-15 Kumamoto Technology & Industry Foundation Remede contre les troubles urinaires

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Publication number Priority date Publication date Assignee Title
JP2000264849A (ja) * 1999-01-12 2000-09-26 Takeda Chem Ind Ltd 頻尿・尿失禁治療組成物
JP2003514818A (ja) * 1999-11-18 2003-04-22 アストラゼネカ・アクチエボラーグ 新規使用および新規ｎ−アザビシクロ−アミド誘導体
WO2005084709A1 (fr) * 2004-03-04 2005-09-15 Kumamoto Technology & Industry Foundation Remede contre les troubles urinaires

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IKEDA K.: "Hattatsu Shogai Model Dobutsu no Kodo Yakuri Kaiseki ni yoru Byotai Kaimei to Chiryoyaku no Kaihatsu", 'HATTATSU SHOGAI NO BYOTAI KAIMEI NI MOTOZUITA CHIRYOHO NO KAIHATSU NI KANSURU KENKYU', HEISEI 16 NENDO KENKYU HAPPYOKAI PROGRAM. SHOROKUSHU, 2004, pages 18, XP003011029 *
TAKAHAMA K.: "Hankenko kara kenko e - Yori Sugureta", KOJI NOKINO SYMPOSIUM YOSHISHU, vol. 11TH, 2000, pages 23 - 26, XP003011030 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007139153A1 (fr) * 2006-05-31 2007-12-06 Kumamoto University Agent améliorant une fonction pour le dysfonctionnement cérébral provoqué par un produit chimique environnemental
JP2009227631A (ja) * 2008-03-25 2009-10-08 Kumamoto Univ 気分障害又は感情障害の治療薬
JP2011246446A (ja) * 2010-04-28 2011-12-08 Kumamoto Univ 脳機能障害修復剤
JP2012062272A (ja) * 2010-09-15 2012-03-29 Kumamoto Univ 中枢機能改善薬

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