WO2009133686A1 - Médicaments destinés au traitement de la maladie d’alzheimer - Google Patents

Médicaments destinés au traitement de la maladie d’alzheimer Download PDF

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Publication number
WO2009133686A1
WO2009133686A1 PCT/JP2009/001906 JP2009001906W WO2009133686A1 WO 2009133686 A1 WO2009133686 A1 WO 2009133686A1 JP 2009001906 W JP2009001906 W JP 2009001906W WO 2009133686 A1 WO2009133686 A1 WO 2009133686A1
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formula
medicament
compound
disease
nmr
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PCT/JP2009/001906
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English (en)
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
豊岡尚樹
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有限会社アンティアンティ
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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 compound isolated from a flower of Rosaceae Rosa damascena, a pharmaceutical comprising a similar compound as an active ingredient, and a therapeutic / preventive pharmaceutical for 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: A linear fatty acid having 28 to 45 carbon atoms or a medically acceptable salt or ester of the linear fatty acid is used 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 according to another aspect of the present invention is: A linear fatty acid having 28 to 37 carbon atoms or a medically acceptable salt or ester of the linear fatty acid is used 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 according to another aspect of the present invention is: A compound selected from the group consisting of the following formulas (1) and (2) or a medically acceptable salt or ester of the compound is used as an active ingredient.
  • a compound selected from the group consisting of the following formulas (1) and (2) or a medically acceptable salt or ester of the compound is used 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 according to still another aspect of the present invention contains a compound represented by the following formula (3) or a medically acceptable salt or ester of the compound of the formula (3) as an active ingredient.
  • Formula (3) Formula (3)
  • 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.
  • linear fatty acid according to the present invention and salts and esters thereof prevent the atrophy of the cells that appear when amyloid beta (Amiloid ⁇ ) acts on the nerve cells, treatment of neurodegenerative diseases such as Alzheimer's disease or Effective for prevention.
  • Amyloid beta amyloid beta
  • FIG. 1 is an explanatory diagram of a fractionation operation of an extract of Rosa damascena.
  • FIG. 2 is a 1 H-NMR spectrum of the compound of formula (1).
  • FIG. 3 is a 13 C-NMR spectrum of the compound of formula (1).
  • FIG. 4 is an EI-MS spectrum of the compound of formula (1).
  • FIG. 5 is a graph showing the results of a dendritic atrophy suppression test of Rosa damascena extract.
  • FIG. 6 is a graph showing the results of a test for inhibiting neuronal cell death of an extract of Rosa damascena.
  • FIG. 7 is a graph showing the dendritic atrophy suppression test results of the Rosa damascena extract fraction.
  • FIG. 1 is an explanatory diagram of a fractionation operation of an extract of Rosa damascena.
  • FIG. 2 is a 1 H-NMR spectrum of the compound of formula (1).
  • FIG. 3 is a 13 C-NMR spectrum of
  • FIG. 8 is a graph showing the results of a test for suppressing axon atrophy of a Rosa damascena extract fraction.
  • FIG. 9 is a graph showing the results of a dendritic atrophy suppression test of the compound of formula (1).
  • FIG. 10 is an explanatory view (No. 1) showing a synthesis route of linear fatty acids.
  • FIG. 11 is an explanatory diagram (No. 2) showing a synthetic pathway for linear fatty acids.
  • FIG. 12 is an explanatory diagram (No. 3) showing a synthetic pathway for linear fatty acids.
  • FIG. 13 is a 1 H-NMR spectrum of the compound of formula (2).
  • FIG. 14 is an IR spectrum of the compound of formula (2).
  • FIG. 15 is a 1 H-NMR spectrum of the compound of formula (3).
  • FIG. 16 is an IR spectrum of the compound of formula (3).
  • FIG. 17 is a graph showing the dendritic atrophy suppression test results of the synthesized linear fatty acid compound.
  • the compound of formula (1) is a straight-chain and long-chain fatty acid.
  • 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.
  • Formula (2), Formula (3) and other linear fatty acids according to the present invention can be obtained by synthesis.
  • a straight chain fatty acid is a fatty acid having no carbon chain branching in the molecule.
  • the linear fatty acid may be a saturated fatty acid or an unsaturated fatty acid.
  • an ester means a compound in which a carboxylic acid group (—COOH) moiety of a linear fatty acid is bonded to an alcoholic and / or phenolic hydroxy group and a water molecule is eliminated.
  • —COOH carboxylic acid group
  • a linear fatty acid is bonded to an alcoholic and / or phenolic hydroxy group and 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 a hydrogen ion of a carboxylic acid group (—COOH) of a linear fatty acid is substituted with, for example, a metal ion.
  • a metal ion a compound in which a hydrogen ion of a carboxylic acid group (—COOH) of a linear fatty acid is substituted with, for example, a metal ion.
  • a metal ion those known in the medical and pharmaceutical fields can be used without limitation.
  • 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 linear fatty acid and its salt and ester according to the present invention is not constant depending on the symptoms of the patient 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 Ltd., 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-layer 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.
  • DNP-931 is sometimes referred to as a compound of formula (1).
  • 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 a signal specific to unsaturated fatty acids, and the proton position is 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 C37: 537 ( ⁇ 23, 26, 29, 31, 34) fatty acid, that is, a compound of formula (1).
  • FIG. 10, FIG. 11 and FIG. 12 show a synthetic route for linear fatty acids and the like.
  • the alphanumeric characters attached to the chemical formulas indicating the molecular skeleton are code numbers indicating the synthetic compounds. The synthesis was performed as follows.
  • TBDPS form (X2, 800 mg, 1.45 mmol) in toluene (30 mL) at room temperature with imidazole (148 mg, 2.2 mmol), Ph 3 P (577 mg, 2.2 mmol), I 2 (479 mg, 1.89 mmol) Were sequentially added and stirred at room temperature for 15 h. The reaction was stopped with 10% Na 2 S 2 O 3 in satd.NaHCO 3 (aq), the organic layer was separated, the organic layer extracted with ethyl acetate was combined, dried over magnesium sulfate, filtered and the solvent was distilled off.
  • tert-Butylheptatriaconta-23,34-dienyloxydiphenylsilane (X7) NaN (SiMe3) 2 (1M in THF, 0.48 mL, 0.48 mmol) was added to a solution of Wittig reagent (A, 275 mg, 0.50 mmol) in THF (10 mL) at 0 ° C and stirred for 5 min, then aldehyde (X6, 73 mg , 0.14 mmol) in THF (5 mL) was added and stirred at room temperature for 15 h. The organic layer obtained by adding water to the reaction solution and stopping the reaction and extracting the organic layer with ether was combined and dried over magnesium sulfate.
  • TBDPS body was obtained by the same method.
  • Heptatriaconta-23,34-dien-1-ol (X8) TBAF (1M in THF, 0.3 mL, 0.3 mmol) was added to a solution of TBDPS (X7, 116 mg, 0.15 mmol) in THF (7 mL) at 0 ° C, and the reaction solution stirred at room temperature for 2 h was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (developing solvent: hexane: acetone 100: 1 to 90: 1) to obtain alcohol (X8, 69 mg, 75%) as a colorless oil.
  • Heptatriaconta-23,34-dienoic acid (X9) Jones reagent was added to a solution of alcohol (X8, 22 mg, 0.04 mmol) in acetone (10 mL), and the mixture was stirred at room temperature for 20 min. The residue obtained by separating the organic layer and evaporating the solvent was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (developing solvent: hexane: acetone 90: 1 to 50: 1). The carboxylic acid (X9, 16.1 mg, 71%) was obtained as a colorless solid.
  • X9 may be referred to as a compound of formula (2).
  • FIG. 13 shows the 1 H-NMR spectrum of the compound of formula (2)
  • FIG. 14 shows the IR spectrum of the compound of formula (2).
  • X15 may be referred to as a compound of formula (3).
  • FIG. 15 shows the 1 H-NMR spectrum of the compound of formula (3)
  • FIG. 16 shows the IR spectrum of the compound of formula (3).
  • 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
  • FIGS. 5 to 9 and FIG. 17 are shown as mean values ⁇ standard errors. An asterisk in these figures indicates a significant difference test result.
  • the 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). Cells were observed with a fluorescence microscope to obtain fluorescence images. 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.
  • DNP-931 is a compound of formula (1).
  • FIG. 17 the number of carbon atoms of the compound is displayed in parentheses after the compound code.
  • Tables 1 and 2 show compound codes, simple structural formulas, and carbon numbers for which activity tests were performed.
  • X9 is a compound of formula (2) and X15 is a compound of formula (3).
  • DNP-931 in which dendrite re-extension was observed in activity test 4 shown in FIG. 9, is a linear fatty acid having 37 carbon atoms.
  • dendrite re-extension was observed in five of the seven types of 37 straight chain fatty acids tested.
  • X21 and X22 are higher alcohols.

Abstract

La présente invention concerne de nouveaux médicaments utilisés dans le traitement ou la prévention de troubles neurologiques dégénératifs tels que la maladie d’Alzheimer. Il s’agit de médicaments destinés au traitement de la maladie d’Alzheimer, ainsi que de médicaments empêchant l’atrophie sénile induite par l’amyloïde β, dont l’ingrédient actif est un composé représenté par la formule (1) isolé dans des fleurs de la rose Rosa damascena. En outre, il s’agit de médicaments destinés à traiter la maladie d’Alzheimer, ainsi que de médicaments empêchant l’atrophie sénile induite par l’amyloïde β, dont l’ingrédient actif est un acide gras à chaîne longue droite.
PCT/JP2009/001906 2008-04-28 2009-04-27 Médicaments destinés au traitement de la maladie d’alzheimer WO2009133686A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023100938A1 (fr) * 2021-12-03 2023-06-08 日本水産株式会社 Procédé d'atténuation du stress oxydatif

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Publication number Priority date Publication date Assignee Title
WO2023100938A1 (fr) * 2021-12-03 2023-06-08 日本水産株式会社 Procédé d'atténuation du stress oxydatif

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