WO2009133586A1 - Remède pour la maladie d’alzheimer - Google Patents

Remède pour la maladie d’alzheimer Download PDF

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Publication number
WO2009133586A1
WO2009133586A1 PCT/JP2008/001115 JP2008001115W WO2009133586A1 WO 2009133586 A1 WO2009133586 A1 WO 2009133586A1 JP 2008001115 W JP2008001115 W JP 2008001115W WO 2009133586 A1 WO2009133586 A1 WO 2009133586A1
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WIPO (PCT)
Prior art keywords
formula
alzheimer
disease
compound
extract
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Application number
PCT/JP2008/001115
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English (en)
Japanese (ja)
Inventor
門田重利
アワレスレス
手塚康弘
東田千尋
宮崎真
Original Assignee
有限会社アンティアンティ
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.)
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Application filed by 有限会社アンティアンティ filed Critical 有限会社アンティアンティ
Priority to PCT/JP2008/001115 priority Critical patent/WO2009133586A1/fr
Priority to PCT/JP2009/001906 priority patent/WO2009133686A1/fr
Publication of WO2009133586A1 publication Critical patent/WO2009133586A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/738—Rosa (rose)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • 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

Definitions

  • the present invention relates to a therapeutic / preventive drug for Alzheimer's disease comprising an extract extracted from a flower of the Rosaceae Rosa Rosamasasena with an organic solvent as an active ingredient.
  • the present invention also relates to a medicament comprising a compound isolated from the extract as an active ingredient and a medicament for treating / preventing Alzheimer's disease.
  • An object of the present invention is to obtain a new medicine used for the treatment and prevention of neurodegenerative diseases such as Alzheimer's disease.
  • the medicament according to one aspect of the present invention is: Formula (1) (1) Or a medically acceptable salt or ester of the compound represented by formula (1) as an active ingredient.
  • the medicament may be a therapeutic / preventive medicament for Alzheimer's disease.
  • the medicament may be a medicament for preventing neuronal atrophy caused by amyloid beta.
  • the medicament may be a medicament for preventing the death of nerve cells that appear due to amyloid beta.
  • Another aspect of the present invention is a composition for treating Alzheimer's disease containing a compound of formula (1).
  • Yet another embodiment of the present invention is a method for treating Alzheimer's disease using a compound of formula (1), and a compound of formula (1) used for the treatment of Alzheimer's disease.
  • the compound of formula (1) includes a medically acceptable salt or ester of the compound of formula (1).
  • the therapeutic / preventive medicament for Alzheimer's disease is as follows:
  • the active ingredient is an extract obtained by extracting the flower of Rosa damascena with an organic solvent.
  • organic solvents such as chloroform, hexane, diethyl ether, and ethyl acetate can be used as the organic solvent.
  • the medicament according to another aspect of the present invention is: It is a medicine for preventing atrophy of nerve cells appearing due to amyloid beta, comprising as an active ingredient an extract obtained by extracting a flower of Rosa damascena with an organic solvent.
  • the medicament containing the extract as an active ingredient may be a medicament for preventing the death of nerve cells that appear due to amyloid beta.
  • Another aspect of the present invention is a composition for treating Alzheimer's disease containing the extract. Still another embodiment of the present invention is a method for treating Alzheimer's disease using the extract, and the extract used for treating Alzheimer's disease.
  • the compound of formula (1) according to the present invention prevents atrophy and death of the cells that appear when amyloid beta (Amiloid ⁇ ) acts on nerve cells, and is therefore effective in the treatment or prevention of neurodegenerative diseases such as Alzheimer's disease. It is.
  • Amyloid beta amyloid beta
  • a medicament comprising the extract according to the present invention as an active ingredient is effective for treating or preventing Alzheimer's disease.
  • FIG. 1 is a 1 H-NMR spectrum of a compound of formula (1).
  • 3 is a 13 C-NMR spectrum of a compound of formula (1).
  • 2 is an EI-MS spectrum of a compound of formula (1). It is a graph which shows the dendritic atrophy inhibitory effect test result of Rosa damascena extract. It is a graph which shows the neuronal cell killing inhibitory test result of Rosa ⁇ damascena extract. It is a graph which shows the dendritic-atrophy suppression test result of a Rosa damascena extract fraction. It is a graph which shows the axon atrophy suppression test result of a Rosa damascena extract fraction. It is a graph which shows the dendritic atrophy suppression test result of a compound of Formula (1).
  • the compound of formula (1) is contained in a flower of Rosaceae Rosama damascena.
  • Rosa damascena may also be called Rose ⁇ otto, Persian pink rose, Demask Rose, Summer damask, Rosa Damasquena, etc.
  • the compound of formula (1) is contained in the flower of Rosa damascena.
  • the flower usually includes a flower that has been blossomed and a bud before flowering, more preferably a bud, more preferably a pod picked during 1 day before flowering to 10 days before flowering, most preferably from 1 day before flowering. A cocoon picked during the three days before flowering.
  • the flowers and buds are used as they are, or more preferably after air drying. Air-drying is done by leaving the picked flowers and buds in a place with good wind and moisture for a week to 10 days.
  • the compound of the formula (1) can be extracted and isolated from the flowers of Rosa damascena and / or air dried mushrooms as follows. Flowers and / or buds are extracted with an organic solvent (for example, chloroform) to obtain an organic solvent fraction. Further, these compounds are isolated from the organic solvent fraction by chromatography (column chromatography, HPLC, thin layer chromatography, etc.). As the separation and purification means, other known means such as solvent extraction and recrystallization may be used.
  • an organic solvent for example, chloroform
  • the compound of formula (1) may be obtained by synthesis or semi-synthesis by a known method.
  • an ester means a compound in which a carboxylic acid group (—COOH) moiety in the compound of formula (1) is bonded to an alcoholic and / or phenolic hydroxy group, and a water molecule is eliminated.
  • —COOH carboxylic acid group
  • a water molecule is eliminated.
  • the medically acceptable ester those known in the medical and pharmaceutical fields can be used without limitation.
  • the salt may be any salt derived from inorganic and organic bases, and is a compound in which the hydrogen ion of the carboxylic acid group (—COOH) in the compound of formula (1) is substituted with, for example, a metal ion.
  • a metal ion As the medically acceptable salt, those known in the medical and pharmaceutical fields can be used without limitation. For example, alkali metal, alkaline earth metal, and amine salts can be used.
  • the medicament according to the present invention can be administered orally, parenterally or transdermally.
  • a form usually used for administration of pharmaceuticals can be used without limitation.
  • various preparations such as tablets or coated tablets, capsules, solutions, syrups, powders, suppositories and the like may be combined with excipients, adjuvants, additives and the like.
  • the dose of the compound of formula (1) is not constant depending on the patient's symptoms or the dosage form of the preparation, but is usually 0.01 mg to 1000 mg / person / day. However, it is also contemplated to determine an appropriate dosage by first administering a small amount and then increasing until the intended effect is achieved.
  • MLC Medium pressure liquid chromatography
  • BW-820MH silica gel (Fuji Silysia Chemical Co., Japan) (Column size: 4.0 ⁇ 15 cm)).
  • Thin layer chromatography was performed using precoated plates of silica gel 60F 254 or RP-18F 254 plates (thickness 0.25 or 0.50 mm, Merck, Germany).
  • FIG. 1 is an explanatory diagram of the fractionation operation of Rosa damascena extract.
  • 16 g of the extract was subjected to MPLC using a silica gel column and initially using hexane as a solvent and subsequently using a mixture of methanol and CHCl 3 as a solvent to obtain 9 fractions.
  • the fourth fraction ((DNP-4, 350 mg)) was thin-layered TLC with a developing solution containing 10% ethyl acetate in hexane (10% EtOAc-hexane), and 5 sub-fractions (4-1 , 60 mg; 4-2, 75 mg; 4-3, 80 mg; 4-4, 55 mg; 4-5, 40 mg).
  • Sub-fraction 4-3 was further purified by normal-phase preparative TLC with 2% MeOH-CHCl 3 and Acetone-benzene. (1: 9)) was repeatedly purified to obtain DNP-931 (27.0 mg). DNP-931 was a colorless amorphous solid.
  • FIG. 2 shows the 1 H-NMR spectrum of the compound of formula (1)
  • FIG. 3 shows the 13 C-NMR spectrum of the compound of formula (1)
  • FIG. 4 shows the EI-MS spectrum of the compound of formula (1).
  • the 1 H-NMR spectrum shows signals specific to unsaturated fatty acids, and the proton positions are olefinic protons at ⁇ H 5.30-5.43 ppm, allylic protons at ⁇ H 2.34 ppm, methylenes at ⁇ H 1.20-1.37 ppm, methyl group at ⁇ H was 0.88 ppm.
  • the 13 C-NMR spectrum showed acid carbonyl at ⁇ C 179.6 ppm, ten olifenic carbons ( ⁇ C 132.0, 130.3, 130.2, 128.28, 128.26, 128.1, 127.9, 127.8 and 127.1 ppm,).
  • DNP-931 was identified as a fatty acid of C37: 5 ( ⁇ 23, 26, 29, 31, 34), that is, a compound of formula (1).
  • a ⁇ 25-35: Active partial peptide of amyloid beta (Sigma, Saint Louis, MO, USA) Fluorescence microscope: AX-80 (Olympus, Tokyo, Japan) Image analysis software: Neuroocyte Ver. 1.5 (Toyobo, Osaka Japan) Calcein AM (Dojindo, Kumamoto, Japan) S14G Humanin: Cell death antagonist (Phoeni, CA, USA) DHA: cis-4,7,10,13,16,19-docosahexaenoic acid (Tokyo Kasei Kogyo Co. Ltd.
  • GA1 ginkgoic acid A (uses the substance isolated by the inventors)
  • GA2 ginkgoic acid B (using the substance isolated by the inventors)
  • NGF Nerve growth factor (Austral Biologicals, CA, USA)
  • RE Rose chloroform (CHCl 3 ) extract
  • FIG. 5 to FIG. 9 The data in FIG. 5 to FIG. 9 are shown as an average value ⁇ standard error.
  • An asterisk in FIGS. 5 to 9 represents a significant difference test result. Significance test was performed using Student's test or one-way ANOVA of analysis of variance followed by Dunnett's test of post-hoc test. The significance level was 5%.
  • Alexa Fluor 568-labeled goat anti-rabbit IgG was used (dilution ratio 300 times; Molecular Probes, Carlsbad, USA). The cells were observed with a fluorescence microscope to obtain a fluorescence image. The average length of dendrites per nerve cell was measured using Neuroocyte Ver. 1.5.
  • the primary antibody used was a rabbit polyclonal antibody against MAP2, a dendritic marker protein (dilution factor 500 times; Chemicon, Temecula, USA) and a mouse monoclonal antibody against phosphorylated NF-H, an axon marker protein.
  • a dendritic marker protein diclonal antibody against MAP2
  • secondary antibodies Alexa Fluor 568-labeled goat anti-rabbit IgG and Alexa Fluor 488-labeled goat anti-mouse IgG were used (dilution ratio 300 times; Molecular Probes, Carlsbad, USA). Cells were observed with a fluorescence microscope to obtain fluorescence images. The average length of dendrites and axons per nerve cell was measured using Neuroocyte Ver. 1.5.
  • Results are shown in FIG. 7 and FIG.
  • DNP-4 and F-5 were the fractions that showed a more prominent effect than the protrusion extension effect of Rose chloroform extract.
  • DNP-4 showed significant effects on dendrite and axon length extension.
  • DNP-931 0.1 ⁇ M, 1 ⁇ M, DNP-932: 2.5 ⁇ g / ml, 5 ⁇ g / ml, DNP-4 extract: 2.5 ⁇ g / ml, 5 ⁇ g / ml, DHA: 0.1 ⁇ M, 1 ⁇ M, GA1: 0.1 ⁇ M, 1 ⁇ M , GA2: 0.1 ⁇ M, 1 ⁇ M, NGF: 0.1 ⁇ g / ml Using the same reagent and the same method as in Activity Test 1, the average length of dendrites per nerve cell was measured.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Neurosurgery (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne un nouveau médicament destiné à être utilisé dans le traitement ou la prévention de maladies neurodégénératives telles que la maladie d’Alzheimer. La présente invention concerne en outre un remède pour traiter la maladie d’Alzheimer contenant, en tant que principe actif, un extrait obtenu par extraction de fleur de Rosa damascena (une plante appartenant aux rosacées) avec un solvant organique qui est également un médicament ayant un effet de prévention de l’atrophie des cellules nerveuses causée par l’amyloïde β. De plus, la présente invention concerne un médicament ou un remède pour la maladie d’Alzheimer contenant un composé de formule (1), qui est isolé de l’extrait décrit ci-dessus, en tant que principe actif qui est également un médicament ayant un effet de prévention de l’atrophie des cellules nerveuses causée par l’amyloïde β. Formule (1)
PCT/JP2008/001115 2008-04-28 2008-04-28 Remède pour la maladie d’alzheimer WO2009133586A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/JP2008/001115 WO2009133586A1 (fr) 2008-04-28 2008-04-28 Remède pour la maladie d’alzheimer
PCT/JP2009/001906 WO2009133686A1 (fr) 2008-04-28 2009-04-27 Médicaments destinés au traitement de la maladie d’alzheimer

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Application Number Priority Date Filing Date Title
PCT/JP2008/001115 WO2009133586A1 (fr) 2008-04-28 2008-04-28 Remède pour la maladie d’alzheimer

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PCT/JP2009/001906 WO2009133686A1 (fr) 2008-04-28 2009-04-27 Médicaments destinés au traitement de la maladie d’alzheimer

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CA3239555A1 (fr) * 2021-12-03 2023-06-08 Tadaomi NAKA Procede d'attenuation du stress oxydatif

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JPH0733655A (ja) * 1990-01-18 1995-02-03 Efamol Holdings Plc 医薬組成物
JPH08143454A (ja) * 1994-11-17 1996-06-04 Kanagawa Kagaku Kenkyusho:Kk 神経成長因子産生増強剤
JPH11180879A (ja) * 1997-09-22 1999-07-06 L'oreal Sa バラ科植物エキスの用途
JP2004250445A (ja) * 2003-01-31 2004-09-09 Yakult Honsha Co Ltd グリケーション阻害剤及びその利用
JP2007291031A (ja) * 2006-04-26 2007-11-08 Shiseido Co Ltd 抗酸化香料組成物及びこれを含有する皮膚外用剤

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IT1320180B1 (it) * 2000-12-29 2003-11-26 Hunza Di Marazzita Maria Carme Preparazioni nutrizionali e terapeutiche dotate di attivita'antiossidante ed in grado di controllare gli eccessi ponderali e
US7649103B2 (en) * 2002-06-17 2010-01-19 Medestea Research And Production S.R.L. Long chain unsaturated oxygenated compounds and their use in the therapeutical, cosmetic and nutraceutical field
WO2008103926A1 (fr) * 2007-02-22 2008-08-28 Innlabs, Llc Préparation de vitamine c

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* Cited by examiner, † Cited by third party
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JPH0733655A (ja) * 1990-01-18 1995-02-03 Efamol Holdings Plc 医薬組成物
JPH08143454A (ja) * 1994-11-17 1996-06-04 Kanagawa Kagaku Kenkyusho:Kk 神経成長因子産生増強剤
JPH11180879A (ja) * 1997-09-22 1999-07-06 L'oreal Sa バラ科植物エキスの用途
JP2004250445A (ja) * 2003-01-31 2004-09-09 Yakult Honsha Co Ltd グリケーション阻害剤及びその利用
JP2007291031A (ja) * 2006-04-26 2007-11-08 Shiseido Co Ltd 抗酸化香料組成物及びこれを含有する皮膚外用剤

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CHOI, S.J. ET AL.: "Protective effect of Rosa laevigata against amyloid beta peptide-induced oxidative stress", AMYLOID, vol. 13, no. 1, 2006, pages 6 - 12 *
DUNPHY, P.J.: "Location and biosynthesis of monoterpenyl fatty acyl esters in rose petals", PHYTOCHEMISTRY, vol. 67, no. 11, 2006, pages 1110 - 1119, XP028059752, DOI: doi:10.1016/j.phytochem.2006.03.023 *
SHAHRIARI, S. ET AL.: "In vivo antioxidant potentials of Rosa damascene petal extract from Guilan, Iran, comparable to a-tocopherol", INTERNATIONAL JOURNAL OF PHARMACOLOGY, vol. 3, no. 2, 2007, pages 187 - 190 *
STOYANOVA-IVANOVA, B. ET AL.: "Composition, structure and biogenesis of the ketones in rose flower wax", PHYTOCHEMISTRY, vol. 8, no. 8, 1969, pages 1549 - 1552 *
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UDDIN, S. ET AL.: "CNS depressant effect of the crude ethanolic extract of the flowering tops of Rosa damascena", IRANIAN JOURNAL OF PHARMACOLOGY AND THERAPEUTICS, vol. 5, no. 2, 2006, pages 171 - 174 *
VINOKUR, Y. ET AL.: "Rose petal tea as an antioxidant-rich beverage: cultivar effects", JOURNAL OF FOOD SCIENCE, vol. 71, no. 1, 2006, pages S42 - S47 *

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