WO2009133586A1 - Remedy for alzheimer's disease - Google Patents

Remedy for alzheimer's disease 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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formula
alzheimer
disease
compound
extract
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PCT/JP2008/001115
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French (fr)
Japanese (ja)
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門田重利
アワレスレス
手塚康弘
東田千尋
宮崎真
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有限会社アンティアンティ
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Priority to PCT/JP2008/001115 priority Critical patent/WO2009133586A1/en
Priority to PCT/JP2009/001906 priority patent/WO2009133686A1/en
Publication of WO2009133586A1 publication Critical patent/WO2009133586A1/en

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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

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  • 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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Abstract

A novel drug to be used in treating or preventing neurodegenerative diseases such as Alzheimer's disease. A remedy for treating Alzheimer's disease containing, as the active ingredient, an extract obtained by extracting Rosa damascena (a plant belonging to Rosaceae) flower with an organic solvent which is also a drug having an effect of preventing atrophy of nerve cells caused by amyloid β. Furthermore, a drug or a remedy for Alzheimer's disease containing a compound of the formula (1), which is isolated from the above-described extract, as the active ingredient which is also a drug having an effect of preventing atrophy of nerve cells caused by amyloid β. Formula (1)

Description

アルツハイマー病の治療医薬Therapeutic drugs for Alzheimer's disease
　本発明はバラ科植物ローザ・ダマセナ（Rosa damascena）の花から有機溶媒により抽出した抽出物を有効成分とするアルツハイマー病の治療・予防医薬に関する。また、本発明は当該抽出物から単離した化合物を有効成分とする医薬及びアルツハイマー病の治療・予防医薬に関する。 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.
　アルツハイマー病の原因物質であるアミロイドベータ（Amiloid β）により出現する、神経細胞における樹状突起の萎縮や軸策の萎縮などを再構築する薬剤として、従来、人参、黄耆、菖蒲、茯苓からなる処方（例えば、特許文献１参照。）、ウィタノシド類とその代謝物ソミノン、およびアストラガロシド代謝物（例えば、特許文献２参照。）、帰脾湯（例えば、特許文献３参照。）などが報告されている。
ＷＯ　２００６／０６８１５５　Ａ１ 特開２００６－１７６４２８号公報 特開２００７－２３０９３８号公報 As a drug that reconstructs dendritic atrophy and axillary atrophy in nerve cells that appear due to amyloid beta, the causative agent of Alzheimer's disease, it has traditionally consisted of ginseng, jaundice, acupuncture, and acupuncture Prescription (for example, refer to Patent Document 1), withanosides and its metabolite sominone, and astragaloside metabolite (for example, refer to Patent Document 2), Kiyoto (for example, refer to Patent Document 3), and the like are reported. Has been.
WO 2006/068155 A1 JP 2006-176428 A JP 2007-230938 A
　本発明は例えばアルツハイマー病など神経変性疾患の治療や予防に使用する新規の医薬を得ることを課題とする。 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.
　本発明のその他の課題は、本発明の説明により明らかになる。 Other problems of the present invention will become apparent from the description of the present invention.
　本発明の一の態様にかかる医薬は、
　式（１）
Figure JPOXMLDOC01-appb-I000001
　　　　　　　　　　　　　　　　　　　　　　　　　　　　（１）
で示される化合物、または式（１）化合物の医学的に許容される塩またはエステルを有効成分とする。 The medicament according to one aspect of the present invention is:
Formula (1)
Figure JPOXMLDOC01-appb-I000001
(1)
Or a medically acceptable salt or ester of the compound represented by formula (1) as an active ingredient.
　本発明の好ましい実施態様において、前記医薬はアルツハイマー病の治療・予防医薬であってもよい。 In a preferred embodiment of the present invention, the medicament may be a therapeutic / preventive medicament for Alzheimer's disease.
　本発明のその他の好ましい実施態様において、前記医薬はアミロイドベータ（Amiloid β）により出現する神経細胞の萎縮を防止する医薬であってもよい。 In another preferred embodiment of the present invention, the medicament may be a medicament for preventing neuronal atrophy caused by amyloid beta.
　また、本発明のさらにその他の好ましい実施態様にあって、前記医薬はアミロイドベータ（Amiloid β）により出現する神経細胞の死滅を防止する医薬であってもよい。 In still another preferred embodiment of the present invention, the medicament may be a medicament for preventing the death of nerve cells that appear due to amyloid beta.
　本発明のその他の態様は、式（１）化合物を含有するアルツハイマー病治療用組成物である。本発明のさらに他の態様は式（１）化合物を用いるアルツハイマー病治療方法であり、また、アルツハイマー病の治療のために使用する式（１）化合物である。これら本発明の態様にあって、式（１）化合物には、式（１）化合物の医学的に許容される塩またはエステルが含まれる。 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. In these embodiments of the present invention, the compound of formula (1) includes a medically acceptable salt or ester of the compound of formula (1).
　本発明の他の態様にかかるアルツハイマー病の治療・予防医薬は、
　バラ科植物ローザ・ダマセナ（Rosa damascena）の花を有機溶媒で抽出して得られた抽出物を有効成分とする。 The therapeutic / preventive medicament for Alzheimer's disease according to another embodiment of the present invention is as follows:
The active ingredient is an extract obtained by extracting the flower of Rosa damascena with an organic solvent.
　本発明において、有機溶媒は例えば、クロロホルム、ヘキサン、ジエチルエーテル、酢酸エチルなど公知の有機溶媒を使用することができる。 In the present invention, known organic solvents such as chloroform, hexane, diethyl ether, and ethyl acetate can be used as the organic solvent.
　本発明のその他の態様にかかる医薬は、
　バラ科植物ローザ・ダマセナ（Rosa damascena）の花を有機溶媒で抽出して得られた抽出物を有効成分とする、アミロイドベータ（Amiloid β）により出現する神経細胞の萎縮を防止する医薬である。 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.
　また、本発明のさらにその他の好ましい実施態様において、当該抽出物を有効成分とする医薬は、アミロイドベータ（Amiloid β）により出現する神経細胞の死滅を防止する医薬であってもよい。 In still another preferred embodiment of the present invention, 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.
　本発明のその他の態様は、当該抽出物を含有するアルツハイマー病治療用組成物である。本発明のさらに他の態様は当該抽出物を用いるアルツハイマー病治療方法であり、また、アルツハイマー病の治療のために使用する当該抽出物である。 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.
　以上説明した本発明、本発明の好ましい実施態様、これらに含まれる構成要素は可能な限り組み合わせて実施することができる。 The present invention described above, preferred embodiments of the present invention, and components included in these can be implemented in combination as much as possible.
　本発明にかかる式（１）化合物は、神経細胞にアミロイドベータ（Amiloid β）が作用して出現する当該細胞の萎縮や死滅を防止するので、アルツハイマー病などの神経変性疾患の治療または予防に有効である。 The compound of formula (1) according to the present invention prevents atrophy and death of the cells that appear when amyloid beta (Amiloid β) acts on nerve cells, and is therefore effective in the treatment or prevention of neurodegenerative diseases such as Alzheimer's disease. It is.
　また、本発明にかかる抽出物を有効成分とする医薬は、アルツハイマー病の治療または予防に有効である。 In addition, a medicament comprising the extract according to the present invention as an active ingredient is effective for treating or preventing Alzheimer's disease.
ローザ・ダマセナ（Rosa damascena）抽出物の分画操作の説明図である。It is explanatory drawing of the fractionation operation of a Rosa damascena extract. 式（１）化合物の１Ｈ－ＮＭＲスペクトルである。1 is a 1 H-NMR spectrum of a compound of formula (1). 式（１）化合物の１３Ｃ－ＮＭＲスペクトルである。3 is a 13 C-NMR spectrum of a compound of formula (1). 式（１）化合物のＥＩ－ＭＳスペクトルである。2 is an EI-MS spectrum of a compound of formula (1). ローザ・ダマセナ（Rosa damascena）抽出物の樹状突起萎縮抑制作用試験結果を示すグラフである。It is a graph which shows the dendritic atrophy inhibitory effect test result of Rosa damascena extract. ローザ・ダマセナ（Rosa damascena）抽出物の神経細胞死滅抑制作用試験結果を示すグラフである。It is a graph which shows the neuronal cell killing inhibitory test result of Rosa ダ damascena extract. ローザ・ダマセナ（Rosa damascena）抽出物画分の樹状突起萎縮抑制作用試験結果を示すグラフである。It is a graph which shows the dendritic-atrophy suppression test result of a Rosa damascena extract fraction. ローザ・ダマセナ（Rosa damascena）抽出物画分の軸策萎縮抑制作用試験結果を示すグラフである。It is a graph which shows the axon atrophy suppression test result of a Rosa damascena extract fraction. 式（１）化合物の樹状突起萎縮抑制作用試験結果を示すグラフである。It is a graph which shows the dendritic atrophy suppression test result of a compound of Formula (1).
　式（１）化合物はバラ科植物ローザ・ダマセナ（Rosa damascena）の花に含まれている。また、ローザ・ダマセナ（Rosa damascena）は、Rose otto、Persian pink rose、Demask Rose、Summer damask、ロサ・ダマスケナなどと呼称することもある。 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.
　式（１）化合物はローザ・ダマセナ（Rosa damascena）の花に含まれる。花は通常開花した花と開花前の蕾を含み、より好ましくは蕾であり、さらに好ましくは開花前１日間～開花前１０日間の間に摘み取った蕾であり、もっとも好ましくは開花前１日間～開花前３日間の間に摘み取った蕾である。花や蕾は、そのまま使用するか、より好ましくは風乾の後に使用する。風乾は、摘み取った花や蕾を、風とおしの良い場所に1週間～１０日間放置して行う。 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.
　式（１）化合物はローザ・ダマセナ（Rosa damascena）の花及び／または蕾の風乾物から、次のようにして抽出、単離することができる。花及び／または蕾を有機溶媒（例えばクロロホルム）で抽出し有機溶媒画分を得る。さらに、その有機溶媒画分からクロマトグラフィー（カラムクロマトグラフィー、ＨＰＬＣ、薄層クロマトグラフィーなど）を用いてこれら化合物を単離する。分離精製手段は、その他の公知の手段、例えば溶媒抽出、再結晶などを用いてもよい。 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.
　式（１）化合物は公知の方法で合成あるいは半合成して得てもよい。 The compound of formula (1) may be obtained by synthesis or semi-synthesis by a known method.
　本発明においてエステルとは、式（１）化合物中のカルボン酸基（－ＣＯＯＨ）部分が、アルコール性及び／またはフェノール性のヒドロキシ基と結合し、水分子が脱離した化合物を意味する。医学的に許容されるエステルは、医学・薬学の分野で公知のものが制限なく使用できる。 In the present invention, 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. As the medically acceptable ester, those known in the medical and pharmaceutical fields can be used without limitation.
　塩は、無機及び有機の塩基から誘導されるいかなる塩でもよく、式（１）化合物中のカルボン酸基（－ＣＯＯＨ）の水素イオンが、例えば金属イオンと置換した化合物である。医学的に許容される塩は、医学・薬学の分野で公知のものが制限なく使用できる。例えば、アルカリ金属、アルカリ土類金属、アミンの塩が使用出来る。 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. 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.
　本発明にかかる医薬は経口、非経口、又は経皮投与することができる。投与形態は、通常医薬の投与に用いられる形態が制限なく使用可能である。例えば、賦形剤、補助剤、添加剤などと組み合わせて、各種の製剤、例えば、錠剤もしくは被覆錠、カプセル、溶液、シロップ、粉末、座薬などにすればよい。 The medicament according to the present invention can be administered orally, parenterally or transdermally. As the dosage form, a form usually used for administration of pharmaceuticals can be used without limitation. For example, 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.
　式（１）化合物の投与量は、患者の症状によりあるいは製剤の剤型などにより一定ではないが、通常、０．０１ｍｇ～１０００ｍｇ／人／日である。しかしながら、最初に小量を投与し、次いで、意図した効果が達成されるまで増量することにより、適当な投与量を決定することも意図されている。 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.
　以下に実施例により本発明をさらに説明する。この発明の実施例に記載されている原材料、化合物の抽出法などは、この発明の範囲をそれらのみに限定する趣旨のものではなく、単なる説明例にすぎない。 The present invention will be further described below with reference to examples. The raw materials, compound extraction methods, and the like described in the examples of the present invention are not intended to limit the scope of the present invention only, but are merely illustrative examples.
（抽出物と式（１）化合物の調整）
　抽出物の調整と式（１）化合物の調整及び同定に使用した機器、方法は以下のとおりである。ＮＭＲスペクトルは、tetramethylsilane (TMS)を内部標準物質として使用し、JEOL JNM-LA400（日本電子株式会社、日本）で測定した。電子イオン化質量分析（ＥＩ－ＭＳ）は、JEOL JMS-700T（日本電子株式会社、日本）を使用して行い、イオン化電圧70 eV、直接導入法（direct inlet system）で測定した。中圧液体クロマトグラフィー（Medium pressure liquid chromatograph (MPLC)）は、シリカゲルカラム（BW-820MH silica gel （富士シリシア化学株式会社、日本）(Column size: 4.0×15 cm)）を用いて、BUCHI MPLC 装置（BUCHI Labortechnik、 スイス）で行った。薄層クロマトグラフィーは、silica gel 60F254 またはRP-18F254 plates （厚さ0.25 あるいは 0.50 mm、メルク社、ドイツ）のプレコートプレートを使用して行った。 (Preparation of extract and compound of formula (1))
The equipment and method used for the preparation of the extract and the preparation and identification of the compound of formula (1) are as follows. NMR spectra were measured with JEOL JNM-LA400 (JEOL Ltd., Japan) using tetramethylsilane (TMS) as an internal standard. Electron ionization mass spectrometry (EI-MS) was performed using JEOL JMS-700T (JEOL Ltd., Japan), and measurement was performed with an ionization voltage of 70 eV and a direct inlet system. Medium pressure liquid chromatography (MPLC) is a BUCHI MPLC instrument using a silica gel column (BW-820MH silica gel (Fuji Silysia Chemical Co., Japan) (Column size: 4.0 × 15 cm)). (BUCHI Labortechnik, Switzerland). 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).
　図１はローザ・ダマセナ（Rosa damascena）抽出物の分画操作の説明図である。 FIG. 1 is an explanatory diagram of the fractionation operation of Rosa damascena extract.
　２００５年に摘み取り風乾したRosa damascenaの蕾を購入した。Rosa damascenaの蕾４００ｇにCHCl3 1リットル( L)を加え、超音波振動を与えながら１．５時間抽出し、溶液と残渣を分離した。残渣に同様の抽出処理を２回行った。３回の抽出液を合わせて、CHCl3を留去（エバポレーション）して、１８ｇの抽出物を得た。 In 2005, I bought Rosa damascena cocoons that were picked and air-dried. To 400 g of Rosa damascena jar, 1 liter (L) of CHCl 3 was added and extracted for 1.5 hours while applying ultrasonic vibration to separate the solution and the residue. The same extraction treatment was performed twice on the residue. Three extracts were combined and CHCl 3 was distilled off (evaporation) to obtain 18 g of extract.
　当該抽出物１６ｇを、シリカゲルカラムを用い当初ヘキサンを溶媒に使用し、引き続いてメタノールとCHCl3 混合液を溶媒に使用してMPLCを行い、９画分を得た。第４の画分（(DNP-4, 350 mg)）をヘキサン中に１０％の酢酸エチルを含む（10% EtOAc-hexane）展開液で薄層ＴＬＣし、５つのサブ画分(4-1, 60 mg; 4-2, 75 mg; 4-3, 80 mg; 4-4, 55 mg; 4-5, 40mg)を得た。 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).
　サブ画分4-3を、さらに、順層分取薄層クロマトグラフィー（normal-phase preparative TLC with 2% MeOH-CHCl3  and Acetone-benzene (1:9)）で繰り返し精製し、DNP-931 (27.0 mg)を得た。DNP-931は無色の不定形固体であった。 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.
　図２に式（１）化合物の１Ｈ－ＮＭＲスペクトル、図３に式（１）化合物
の１３Ｃ－ＮＭＲスペクトル、図４に式（１）化合物のＥＩ－ＭＳスペクトルを示す。 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), and FIG. 4 shows the EI-MS spectrum of the compound of formula (1).
　ＥＩ－ＭＳ測定の結果、分子量（実験値）は540.4898であった。分子式C37H64O2,の理論値分子量は540.4906である。 As a result of EI-MS measurement, the molecular weight (experimental value) was 540.4898. The theoretical molecular weight of the molecular formula C 37 H 64 O 2 is 540.4906.
　１Ｈ－ＮＭＲスペクトルは不飽和脂肪酸に固有のシグナルを示し、また、プロトンの位置はolefinic protons  at δH 5.30-5.43 ppm, allylic protons at δH 2.34 ppm, methylenes at δH 1.20-1.37 ppm,  methyl group at δH 0.88 ppmであった。 The 1 H-NMR spectrum shows signals specific to unsaturated fatty acids, and the proton positions are olefinic protons at δ H 5.30-5.43 ppm, allylic protons at δ H 2.34 ppm, methylenes at δ H 1.20-1.37 ppm, methyl group at δ H was 0.88 ppm.
　１３Ｃ－ＮＭＲスペクトルは、acid carbonyl at δC 179.6 ppm, ten olifenic carbons (δC 132.0, 130.3, 130.2, 128.28, 128.26, 128.1, 127.9, 127.8 and 127.1 ppm,)を示した。  The 13 C-NMR spectrum showed acid carbonyl at δ C 179.6 ppm, ten olifenic carbons (δ C 132.0, 130.3, 130.2, 128.28, 128.26, 128.1, 127.9, 127.8 and 127.1 ppm,).
　また、ＥＩ－ＭＳによるフラグメントの解析を行い、DNP-931は、C37:5 (Δ 23, 26, 29, 31, 34) の脂肪酸、すなわち式（１）化合物と同定した。 Also, the fragment was analyzed by EI-MS, and DNP-931 was identified as a fatty acid of C37: 5 (Δ 23, 26, 29, 31, 34), that is, a compound of formula (1).
（活性試験）
　活性試験に使用した試薬類、抽出物、ポジティブコントロールとして使用した薬剤などの略号、化合物名、製造元などは以下のとおりである。 (Activity test)
Abbreviations, compound names, manufacturers, etc. of reagents and extracts used for activity tests, drugs used as positive controls, etc. are as follows.
Aβ（25-35)：アミロイドベータの活性部分ペプチド（Sigma, Saint Louis, MO,USA）
蛍光顕微鏡：AX-80（Olympus, Tokyo, Japan）
画像解析ソフトウエア：Neurocyte Ver. 1.5 (Toyobo, Osaka Japan) 
Calcein AM（Dojindo, Kumamoto, Japan）
S14G Humanin：細胞死拮抗因子（Phoeni, CA, USA）
DHA：cis-4,7,10,13,16,19-docosahexaenoic acid（Tokyo Kasei Kogyo Co. Ltd. Tokyo, Japan）
GA1：ginkgoic acid A（発明者らが単離した物質を使用） 
GA2：ginkgoic acid B（発明者らが単離した物質を使用）
NGF：Nerve growth factor（神経成長因子）（Austral Biologicals, CA, USA）
RE：Roseクロロホルム（CHCl3）抽出物 Aβ (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. Tokyo, Japan)
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
　図５～図９のデータは平均値±標準誤差で示した。図５～図９中のアスタリスクは有意差検定結果を示した。有意差検定はStudent's t-testあるいは分散分析のone way ANOVAを行った後、post hoc testのDunnett's testを行った。有意水準は５％とした。 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%.
（活性試験１）
　SDラット（胎生18日齢）の大脳皮質神経細胞を初代培養した。8 well culture slide上に1.7 4 X 105 cells/cm2の密度で細胞をまき、3日後に10μM Aβ(25-35)を処置した。同時に抽出物を処置しさらに5日後に免疫染色を行った。抽出物の濃度は以下の通りである。Roseクロロホルム抽出物: 0.5, 5μg/ml。1次抗体は樹状突起のマーカータンパク質であるMAP2に対するウサギポリクローナル抗体（希釈倍率500倍；Chemicon, Temecula, USA）を用いた。2次抗体はAlexa Fluor 568標識ヤギ抗ウサギIgGを用いた（希釈倍率300倍；Molecular Probes, Carlsbad, USA）。蛍光顕微鏡により細胞を観察し蛍光画像を取得した。神経細胞あたりの樹状突起の平均長をNeurocyte Ver. 1.5を用いて計測した。 (Activity test 1)
Cerebral cortical neurons of SD rats (fetal 18 days old) were cultured in primary culture. Cells were seeded on an 8-well culture slide at a density of 1.74 × 10 5 cells / cm 2 and treated with 10 μM Aβ (25-35) 3 days later. At the same time, the extract was treated and further immunostained 5 days later. The concentration of the extract is as follows. Rose chloroform extract: 0.5, 5 μg / ml. The primary antibody used was a rabbit polyclonal antibody against MAP2, which is a dendritic marker protein (dilution factor 500 times; Chemicon, Temecula, USA). As the secondary antibody, 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.
　結果を図５に示す。Aβ(25-35)処置すなわちVehicle群では有意に樹状突起の長さが減少した。Roseクロロホルム抽出物を共存させることによって、いずれの用量でも有意に樹状突起の萎縮が抑制された。 The results are shown in FIG. In Aβ (25-35) treatment, Vehicle group, the length of dendrites was significantly reduced. By coexisting with the Rose chloroform extract, dendritic atrophy was significantly suppressed at any dose.
（活性試験２）
　SDラット（胎生18日齢）の大脳皮質神経細胞を初代培養した。8 well culture slide上に1.45 X 105 cells/cm2の密度で細胞をまき、2日後に10μM Aβ(25-35)を処置した。同時に抽出物および化合物を処置しさらに5日後に、6μM calcein AMを加え、４０分間３７℃でインキュベート後固定し、蛍光顕微鏡にて蛍光画像を取得した。細胞内へのcalcein AMの取り込みを、ATTO Densitograph（ATTO,Tokyo, Japan）によって定量し、細胞生存率とした。 (Activity test 2)
Cerebral cortical neurons of SD rats (fetal 18 days old) were cultured in primary culture. Cells were seeded on an 8-well culture slide at a density of 1.45 × 10 5 cells / cm 2 and treated with 10 μM Aβ (25-35) two days later. At the same time, the extract and the compound were treated, and further 5 days later, 6 μM calcein AM was added, incubated at 37 ° C. for 40 minutes and fixed, and a fluorescence image was obtained with a fluorescence microscope. The uptake of calcein AM into the cells was quantified by ATTO Densitograph (ATTO, Tokyo, Japan) and used as the cell viability.
　結果を図６に示す。Vehicle群では有意に低い細胞生存率が確認された。一方、Roseクロロホルム抽出物処置群において、Vehicle群と比して高い細胞生存率が確認された。ポジティブコントロールのS14G Humaninでも有意に細胞生存率が高かった。 The results are shown in FIG. A significantly low cell viability was confirmed in the Vehicle group. On the other hand, in the Rose chloroform extract treatment group, a higher cell survival rate was confirmed as compared with the Vehicle group. The positive control S14G 高 か っ Humanin also had a significantly higher cell viability.
(活性試験３)
　SDラット（胎生19日齢）の大脳皮質神経細胞を初代培養した。8 well culture slide上に1.45 X 105 cells/cm2の密度で細胞をまき、3日後に10μM Aβ(25-35)を処置した。同時に化合物を処置しさらに5日後に免疫染色を行った。抽出物の濃度は5μg/ml、NGFの濃度は 0.1μg/ ml。1次抗体は樹状突起のマーカータンパク質であるMAP2に対するウサギポリクローナル抗体（希釈倍率500倍；Chemicon, Temecula, USA）および軸索のマーカータンパク質であるリン酸化型NF-Hに対するマウスモノクローナル抗体を用いた。2次抗体はAlexa Fluor 568標識ヤギ抗ウサギIgGとAlexa Fluor 488標識ヤギ抗マウスIgGを用いた（希釈倍率300倍；Molecular Probes, Carlsbad, USA）。蛍光顕微鏡により細胞を観察し蛍光画像を取得した。神経細胞あたりの樹状突起と軸索の平均長をNeurocyte Ver. 1.5を用いて計測した。 (Activity test 3)
Cerebral cortical neurons of SD rats (embryonic day 19) were primary cultured. Cells were seeded on an 8-well culture slide at a density of 1.45 × 10 5 cells / cm 2 and treated with 10 μM Aβ (25-35) 3 days later. The compound was treated at the same time and immunostaining was performed after another 5 days. Extract concentration is 5 μg / ml and NGF concentration is 0.1 μg / ml. 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. . As 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.
　結果を図７と図８に示す。Aβ(25-35)処置すなわちVehicle群では有意に樹状突起および軸索の長さが減少した。Roseクロロホルム抽出物による突起伸展効果より、さらに顕著な効果を示したフラクションは、DNP-4とF-5だった。特にDNP-4は樹状突起および軸索の長さ伸展に有意な効果を示した。 Results are shown in FIG. 7 and FIG. In Aβ (25-35) treatment, Vehicle group, the length of dendrites and axons was significantly reduced. DNP-4 and F-5 were the fractions that showed a more prominent effect than the protrusion extension effect of Rose chloroform extract. In particular, DNP-4 showed significant effects on dendrite and axon length extension.
（活性試験４）
　SDラット（胎生19日齢）の大脳皮質神経細胞を初代培養した。8 well culture slide上に1.45 X 105 cells/cm2の密度で細胞をまき、3日後に10μM Aβ(25-35)を処置した。同時に化合物などを処置しさらに5日後に免疫染色を行った。化合物などの濃度は以下の通りである。DNP-931: 0.1μM, 1μM, DNP-932: 2.5μg/ml, 5μg/ml, DNP-4抽出物：2.5μg/ml, 5μg/ml, DHA: 0.1μM, 1μM , GA1: 0.1μM, 1μM, GA2: 0.1μM, 1μM, NGF: 0.1 μg/ml　活性試験１と同一の試薬、同一の方法を用いて、神経細胞あたりの樹状突起の平均長を計測した。 (Activity test 4)
Cerebral cortical neurons of SD rats (embryonic day 19) were primary cultured. Cells were seeded on an 8-well culture slide at a density of 1.45 × 10 5 cells / cm 2 and treated with 10 μM Aβ (25-35) 3 days later. At the same time, the compounds were treated and further immunostained 5 days later. The concentrations of compounds and the like are as follows. DNP-931: 0.1μM, 1μM, DNP-932: 2.5μg / ml, 5μg / ml, DNP-4 extract: 2.5μg / ml, 5μg / ml, DHA: 0.1μM, 1μM, GA1: 0.1μM, 1μM , GA2: 0.1 μM, 1 μM, NGF: 0.1 μg / ml Using the same reagent and the same method as in Activity Test 1, the average length of dendrites per nerve cell was measured.
　結果を図９に示す。処置化合物などの略号の上に記載したアルファベットＬとＨは、Ｌが低濃度、Ｈが高濃度での処置を示している。Aβ(25-35)処置すなわちVehicle群では有意に樹状突起の長さが減少した。DNP-4フラクションおよび、DNP-4から単離したDNP-931に樹状突起伸展効果が認められた。溶媒投与群と、2つの用量のDNP-931投与群とのone way ANOVAによる有意差検定の結果は、F(2, 9) = 3.720, P = 0.066 であった。 The results are shown in FIG. Alphabets L and H described above abbreviations such as treatment compounds indicate treatments where L is a low concentration and H is a high concentration. In Aβ (25-35) treatment, Vehicle group, the length of dendrites was significantly reduced. The DNP-4 fraction and DNP-931 isolated from DNP-4 showed a dendritic extension effect. The results of one-way ANOVA significant difference test between the vehicle administration group and the two doses of DNP-931 administration group were F (2, 9) = 3.720, P = 0.066.

Claims (5)

  1. 　式（１）
    Figure JPOXMLDOC01-appb-I000002
    　　　　　　　　　　　　　　　　　　　　　　　　　　　（１）
    で示される化合物、または式（１）化合物の医学的に許容される塩またはエステルを有効成分とする医薬。     Formula (1)
    Figure JPOXMLDOC01-appb-I000002
    (1)
    Or a medically acceptable salt or ester of the compound represented by formula (1) as an active ingredient.
  2. 　アルツハイマー病の治療・予防医薬である請求項１に記載した医薬。 The medicament according to claim 1, which is a therapeutic / preventive medicament for Alzheimer's disease.
  3. 　アミロイドベータ（Amiloid β）により出現する神経細胞の萎縮を防止する医薬である請求項１に記載した医薬。 The medicament according to claim 1, which is a medicament for preventing atrophy of nerve cells appearing by amyloid beta (Amiloid β).
  4. 　バラ科植物ローザ・ダマセナ（Rosa damascena）の花を有機溶媒で抽出して得られた抽出物を有効成分とするアルツハイマー病の治療・予防医薬。 A therapeutic / preventive drug for Alzheimer's disease comprising as an active ingredient an extract obtained by extracting the flower of Rosa Rosadamascena with an organic solvent.
  5. 　バラ科植物ローザ・ダマセナ（Rosa damascena）の花を有機溶媒で抽出して得られた抽出物を有効成分とする、アミロイドベータ（Amiloid β）により出現する神経細胞の萎縮を防止する医薬。 A pharmaceutical agent that prevents atrophy of nerve cells that appear due to amyloid beta (Amiloid β), comprising as an active ingredient an extract obtained by extracting a flower of the Rosaceae plant Rosa damascena with an organic solvent.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733655A (en) * 1990-01-18 1995-02-03 Efamol Holdings Plc Medicinal composition
JPH08143454A (en) * 1994-11-17 1996-06-04 Kanagawa Kagaku Kenkyusho:Kk Nerve growth factor production enhancer
JPH11180879A (en) * 1997-09-22 1999-07-06 L'oreal Sa Use of extract from rosaceae plant
JP2004250445A (en) * 2003-01-31 2004-09-09 Yakult Honsha Co Ltd Glycation inhibitor and its use
JP2007291031A (en) * 2006-04-26 2007-11-08 Shiseido Co Ltd Antioxidative perfume composition and skin care preparation containing the same

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1320180B1 (en) * 2000-12-29 2003-11-26 Hunza Di Marazzita Maria Carme NUTRITIONAL AND THERAPEUTIC PREPARATIONS EQUIPPED WITH ANTI-OXIDANT ACTIVITY AND ABLE TO CONTROL THE PONDERAL EXCESSES AND
ATE439127T1 (en) * 2002-06-17 2009-08-15 Medestea Res & Production S P LONG CHAIN UNSATURATED OXYGEN CONTAINING COMPOUNDS AND THEIR USE IN THE THERAPEUTIC, COSMETIC AND DIETARY FIELD
WO2008103926A1 (en) * 2007-02-22 2008-08-28 Innlabs, Llc Vitamin c preparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733655A (en) * 1990-01-18 1995-02-03 Efamol Holdings Plc Medicinal composition
JPH08143454A (en) * 1994-11-17 1996-06-04 Kanagawa Kagaku Kenkyusho:Kk Nerve growth factor production enhancer
JPH11180879A (en) * 1997-09-22 1999-07-06 L'oreal Sa Use of extract from rosaceae plant
JP2004250445A (en) * 2003-01-31 2004-09-09 Yakult Honsha Co Ltd Glycation inhibitor and its use
JP2007291031A (en) * 2006-04-26 2007-11-08 Shiseido Co Ltd Antioxidative perfume composition and skin care preparation containing the same

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Sekai Yuyo Shokubutsu Jiten", HEIBONSHA, 1989, pages 917 - 925 *
BRADLEY, F. ET AL.: "The effects of inhalation of essential oil odour from Rosa damascena Mill. on gerbils in two models of anxiety", PLANTA MEDICA, vol. 73, no. 9, 2007, pages 984 *
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 *
TSAI, P. ET AL.: "Comparison of NO-scavenging and NO-suppressing activities of different herbal teas with those of green tea", FOOD CHEMISTRY, vol. 103, no. 1, 2007, pages 181 - 187, XP005897903, DOI: doi:10.1016/j.foodchem.2006.08.013 *
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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