WO2017085844A1 - Inhibiteur de bêta-sécrétase contenant de la turmérone comme ingrédient actif et préparation pharmaceutique et aliment/boisson contenant ledit inhibiteur - Google Patents

Inhibiteur de bêta-sécrétase contenant de la turmérone comme ingrédient actif et préparation pharmaceutique et aliment/boisson contenant ledit inhibiteur Download PDF

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Publication number
WO2017085844A1
WO2017085844A1 PCT/JP2015/082611 JP2015082611W WO2017085844A1 WO 2017085844 A1 WO2017085844 A1 WO 2017085844A1 JP 2015082611 W JP2015082611 W JP 2015082611W WO 2017085844 A1 WO2017085844 A1 WO 2017085844A1
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WIPO (PCT)
Prior art keywords
turmerone
secretase
inhibitor
secretase inhibitor
food
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PCT/JP2015/082611
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English (en)
Japanese (ja)
Inventor
秀秋 松田
村田　和也
晋一 松村
百合 吉岡
Original Assignee
学校法人近畿大学
稲畑香料株式会社
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Application filed by 学校法人近畿大学, 稲畑香料株式会社 filed Critical 学校法人近畿大学
Priority to JP2017551474A priority Critical patent/JP6998212B2/ja
Priority to PCT/JP2015/082611 priority patent/WO2017085844A1/fr
Publication of WO2017085844A1 publication Critical patent/WO2017085844A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/12—Ketones

Definitions

  • the present invention relates to a ⁇ -secretase inhibitor containing a rhizome-derived compound of turmeric (Curcuma longa) as an active ingredient, and a pharmaceutical preparation and food and drink containing the inhibitor.
  • a ⁇ -secretase inhibitor containing a rhizome-derived compound of turmeric (Curcuma longa) as an active ingredient, and a pharmaceutical preparation and food and drink containing the inhibitor.
  • Alzheimer's disease a typical disease of senile dementia, is a degenerative disease characterized by brain atrophy, deposition of senile plaques, and formation of neurofibrillary tangles. Dementia symptoms are caused by neuronal loss. Is considered to be caused (Non-Patent Document 1).
  • ⁇ -amyloid which is the main component of senile plaques, has a cytotoxic action and is considered to cause neuronal cell death in Alzheimer's disease (non-patent documents 2 to 5).
  • ⁇ -amyloid is produced from the amyloid precursor protein (APP) by the action of an enzyme called ⁇ -secretase. Therefore, compounds having an inhibitory action on this ⁇ -secretase are considered to be useful for the prevention of Alzheimer's disease.
  • Patent Document 1 research on compounds having an inhibitory action on ⁇ -secretase has been actively conducted.
  • Patent Document 2 As an example of the search for a highly safe ⁇ -secretase inhibitor, the invention described in Patent Document 2 by the present inventors can be mentioned.
  • ⁇ -secretase inhibitors are extracted from natural products generally used as spices such as pepper, sesame seeds and turmeric.
  • Patent Document 2 further specifies a compound having ⁇ -secretase inhibitory activity among compounds contained in the extract.
  • ⁇ -secretase inhibitors that have higher inhibitory activity and are cheaper.
  • Patent Document 3 describes a method of treating a patient suffering from Alzheimer's disease using an extract from Spice. Specifically, the use of curcuminoid, turmeric, polysaccharides and / or turmeric extract containing turmerin is described. However, although Patent Document 3 describes that turmeric extract inhibits amyloid aggregation, it has a problem that the specific action mechanism has not been clarified.
  • Patent Document 4 describes an acetylcholinesterase inhibitor containing an AR turmerone derivative to be used for the treatment of Alzheimer's disease.
  • a substance having acetylcholinesterase inhibitory activity is useful for symptomatic treatment for alleviating the accumulation of ⁇ -amyloid, but has a problem that it is not effective for preventing Alzheimer's disease.
  • JP 2008-137914 A JP, 2013-189385, A Japanese Patent Application Publication No. 2009-530305 JP, 2011-225478, A
  • the present inventors in Japanese Patent Application No. 2015-146208, sesamolin extracted from sesame, galangal and hijasu respectively, ethyl 4-methoxycinnamate and pipetalin
  • the present invention proposes a pharmaceutical preparation and food and drink having a ⁇ -secretase inhibitor containing as an active ingredient.
  • the invention described in Japanese Patent Application No. 2015-146208 specifies the above three compounds as compounds having ⁇ -secretase inhibitory activity, and shows specific inhibitory activity by calculating the IC 50 value of each compound.
  • ⁇ -secretase inhibitors that have higher inhibitory activity and are cheaper.
  • the present invention provides a ⁇ -secretase inhibitor which is useful for the prevention of Alzheimer's disease, is highly safe, and has a further high inhibitory activity on ⁇ -secretase activity, and a pharmaceutical preparation and food and drink containing the inhibitor. It is.
  • the invention according to claim 1 relates to a ⁇ -secretase inhibitor containing, as an active ingredient, one or more compounds selected from the group consisting of AR-turmerone, ⁇ -turmerone and ⁇ -turmerone.
  • the invention according to claim 2 relates to the ⁇ -secretase inhibitor according to claim 1, characterized in that AR-turmerone, ⁇ -turmerone and ⁇ -turmerone are extracted from turmeric rhizomes.
  • the invention according to claim 3 relates to a pharmaceutical preparation comprising the ⁇ -secretase inhibitor according to claim 1 or 2.
  • the invention according to claim 4 relates to a food or drink containing the ⁇ -secretase inhibitor according to claim 1 or 2.
  • the first aspect of the present invention since it has a still higher inhibitory activity on ⁇ -secretase activity, it is possible to prevent or stop the progression of senile dementia such as Alzheimer's disease.
  • the compound obtained from the extract of the rhizome of turmeric (Curcuma longa) is used as an active ingredient, the safety to the human body is high, and senile dementia such as Alzheimer's disease, etc. It is possible to provide ⁇ -secretase inhibitors that can prevent or halt the progression. Furthermore, since the method of extracting a compound from turmeric is simple, it can be manufactured at low cost.
  • the pharmaceutical preparation contains a ⁇ -secretase inhibitor having an excellent inhibitory action on ⁇ -secretase activity
  • the ⁇ -secretase inhibitor is ingested in accordance with the condition and condition of the user. It is possible to prevent or stop the progression of senile dementia such as Alzheimer's disease.
  • the ⁇ -secretase inhibitor since it is a food and drink containing a ⁇ -secretase inhibitor having an excellent inhibitory effect on ⁇ -secretase activity, the ⁇ -secretase inhibitor can be easily taken on a daily basis. And prevent the progression of senile dementia such as Alzheimer's disease.
  • ⁇ -secretase inhibitor according to the present invention, and the pharmaceutical preparation and food and drink containing the inhibitor will be described.
  • the ⁇ -secretase inhibitor of the present invention contains, as an active ingredient, one or more compounds selected from the group consisting of AR-turmerone, ⁇ -turmerone and ⁇ -turmerone.
  • AR-turmerone is CAS number 532-65-0, and has a structure shown in the following formula (Formula 1).
  • ⁇ -turmerone is CAS number 82508-15-4 and has a structure shown in the following formula (Formula 2).
  • ⁇ -turmerone is CAS No. 82508-14-3 and has a structure shown in the following formula (Formula 3).
  • Turmeric (English name: Turmeric, Scientific name: Curcuma longa) is a monocotyledonous plant of the ginger family Turmeric genus. It is a perennial herb native to India and having a developed rhizome, which is used as a raw material and dye for curry powder.
  • AR-turmerone, ⁇ -turmerone and ⁇ -turmerone are preferably extracted from the rhizome of turmeric with hexane. The reason is that, by extracting the turmeric rhizome with hexane, it is possible to elute more AR-turmerone, ⁇ -turmerone and ⁇ -turmerone.
  • the above compounds may be used singly or in combination of two or more. As described in detail in the following examples, since the above compounds have strong ⁇ -secretase inhibitory activity, the ⁇ -secretase inhibitors of the present invention containing them as an active ingredient can be used for various uses. it can.
  • the ⁇ -secretase inhibitor of the present invention when used as a pharmaceutical preparation, it is used as a preventive agent for senile dementia in mammals (particularly human), particularly as a prophylactic agent for Alzheimer's disease.
  • the beta-secretase inhibitor of the present invention can be tablet, powder, fine granule, granule, coated tablet, capsule, syrup, troche, inhalant, suppository, injection, ointment according to a conventional method. It can be formulated into pharmaceutical preparations such as eye ointments, eye drops, nasal drops, ear drops, buffs, lotions and the like.
  • Excipients binders, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption accelerators, surfactants, pH adjusters, preservatives, anti-oxidants which are usually used for formulation.
  • An oxidizing agent and the like can be used, and in general, components and amounts to be used as raw materials of pharmaceutical preparations are appropriately selected and formulated by a standard method.
  • the form thereof is not particularly limited, and it may be a commonly used method, and may be orally or parenterally administered.
  • the dose of the pharmaceutical preparation according to the present invention can be appropriately selected as a pharmaceutically effective amount according to the degree of symptoms, age, sex, body weight, administration form, specific type of disease and the like.
  • oral administration for example, in the case of oral administration, it is usually appropriate for an active ingredient amount of about 0.001 to 1000 mg / kg in adults, and if it is divided into once a day several times Good.
  • the beta-secretase inhibitor of the present invention is a food additive such as various beverages such as soft drinks, dairy products (processed milk, yogurt), confectionery products (jelly, chocolate, biscuit, gum, tablets) or supplements. It can also be blended with various beverages such as soft drinks, dairy products (processed milk, yogurt), confectionery products (jelly, chocolate, biscuit, gum, tablets) or supplements. It can also be blended with various beverages such as soft drinks, dairy products (processed milk, yogurt), confectionery products (jelly, chocolate, biscuit, gum, tablets) or supplements. It can also be blended with various beverages such as soft drinks, dairy products (processed milk, yogurt), confectionery products (jelly, chocolate, biscuit, gum, tablets) or supplements. It can also be blended with various beverages such as soft drinks, dairy products (processed milk, yogurt), confectionery products (jelly, chocolate, biscuit, gum, tablets) or supplements. It can also be blended with various beverages such as soft drinks, dairy products (processed milk, yogurt), confectionery products (jelly, chocolate, biscuit, gum,
  • the addition amount thereof is not particularly limited, and may be appropriately determined according to the type of food.
  • the dry weight of the above-mentioned extract may be added so that the content is in the range of about 0.0005 to 50% by weight.
  • the food and drink contain, in addition to the ⁇ -secretase inhibitor of the present invention, excipients, flavoring agents, coloring agents, preservatives, thickeners, stabilizers, gelling agents, antioxidants, etc. It is also good.
  • the excipients include, but are not limited to, for example, powders such as fine particle silicon dioxide, sucrose fatty acid ester, crystalline cellulose, sodium carboxymethylcellulose, calcium hydrogen phosphate, wheat starch, rice starch, corn starch , Potato starch, dextrin, cyclodextrin and other starches, crystalline cellulose, lactose, glucose, sugar, reduced maltose, starch syrup, fructooligosaccharide, galactooligosaccharide, soybean oligosaccharide, isomaltooligosaccharide, xylooligosaccharide, maltoligosaccharide, milk and fruit Examples thereof include saccharides such as oligosaccharides, and sugar
  • the flavoring agent examples include, but are not limited to, for example, bontan extract which is a fruit juice extract, lychee extract, apple juice, orange juice, orange juice, yuzu extract, peach flavor, ume flavor, acesulfame K which is a sweetening agent, erythritol, oligosaccharides And mannose, xylitol, isomerized saccharides, green tea which is a tea component, oolong tea, banaba tea, tonka tea, iron kannon tea, castorine tea, blowfish tea, amacha tea, macomo tea, kelp tea, yoghurt flavor and the like.
  • bontan extract which is a fruit juice extract, lychee extract, apple juice, orange juice, orange juice, yuzu extract, peach flavor, ume flavor, acesulfame K which is a sweetening agent, erythritol, oligosaccharides And mannose, xylit
  • ⁇ -secretase inhibition rate (%) 100 ⁇ [(area value of peak from each extract / peak area value from control) ⁇ 100]
  • the hexane extract was analyzed using GCMS under the following conditions. ⁇ Column; Intertcap Pure Wax (0.25 id ⁇ 0.25 ⁇ m ⁇ 60 m) Injection volume: 1.0 ⁇ l -Temperature rising; holding at 50 ° C for 2 minutes, 2.5 ° C heating / minute to 240 ° C-Vaporization room temperature: 250 ° C ⁇ Carry gas flow rate: Helium 1.2 ml / min ⁇ Split ratio: 1/80 From the results of GCMS analysis, the compound was estimated to be AR-turmerone, ⁇ -turmerone and ⁇ -turmerone by attached library search (wiley7n and NIST08). The hexane extract contained 9.9% AR-turmerone, 30.4% ⁇ -turmerone, and 11.5% ⁇ -turmerone.
  • the hexane extract was fractionated under the following HPLC conditions. ⁇ Column; L-column ODS (20 id ⁇ 250 mm) ⁇ Mobile phase: water: acetonitrile (20: 80, v / v) ⁇ Flow rate: 18.9 ml / min ⁇ Column temperature; Room temperature ⁇ Detection; UV 243 nm ⁇ Injection volume: 10 ⁇ l As active ingredients of the hexane extract, colorless oily substances were obtained from the fractions of RT 7.5, 10.5 and 11.0 respectively.
  • ⁇ -turmerone and ⁇ -turmerone have been known as substances which are difficult to separate, but it should be noted that they could be extracted by such a simple method as described above.
  • the enzyme inhibitory activity of the standard products of the above-identified compounds was examined in the same manner as above (measurement of ⁇ -secretase inhibition rate), and each standard product was examined.
  • IC50 value it was as follows.
  • the above-mentioned IC50 value showed that AR-turmerone, ⁇ -turmerone and ⁇ -turmerone have ⁇ -secretase inhibitory activity.
  • This IC50 value is the IC50 value of sesamoline, pipetalin and ethyl 4-methoxycinnamate which the inventors previously found and described in Japanese Patent Application No. 2015-146208 (sesamoline: 0.14 mM, ethyl 4-methoxycinnamate: 0 AR-turmerone, ⁇ -turmerone and ⁇ -turmerone were found to have very high ⁇ -secretase inhibitory activity, which is significantly lower compared to 676 mM and pipetalin: 0.304 mM). Further, since the extraction method of the present invention is simple as compared with the extraction method described in Japanese Patent Application No. 2015-140208, the production cost can be suppressed to 1/10 or less.
  • the present invention can be suitably used for a pharmaceutical preparation for preventing Alzheimer's disease, and can be suitably used for additives of various foods and drinks such as soft drinks, dairy products, confectioneries or supplements. it can.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne une préparation pharmaceutique et un aliment/boisson contenant un inhibiteur de β-sécrétase qui est tout à fait sans danger et qui présente un meilleur effet inhibiteur sur l'activité de la β-sécrétase. L'invention concerne un inhibiteur de β-sécrétase qui contient un ou plusieurs composés choisis dans un groupe composé d'AR-turmérone, d'α-turmérone, de β-turmérone comme ingrédients actifs.
PCT/JP2015/082611 2015-11-19 2015-11-19 Inhibiteur de bêta-sécrétase contenant de la turmérone comme ingrédient actif et préparation pharmaceutique et aliment/boisson contenant ledit inhibiteur WO2017085844A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2017551474A JP6998212B2 (ja) 2015-11-19 2015-11-19 ターメロンを有効成分とするβ‐セクレターゼ阻害剤、及び該阻害剤を含む飲食品
PCT/JP2015/082611 WO2017085844A1 (fr) 2015-11-19 2015-11-19 Inhibiteur de bêta-sécrétase contenant de la turmérone comme ingrédient actif et préparation pharmaceutique et aliment/boisson contenant ledit inhibiteur

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PCT/JP2015/082611 WO2017085844A1 (fr) 2015-11-19 2015-11-19 Inhibiteur de bêta-sécrétase contenant de la turmérone comme ingrédient actif et préparation pharmaceutique et aliment/boisson contenant ledit inhibiteur

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007109210A2 (fr) * 2006-03-17 2007-09-27 Herbalscience Singapore Pte. Ltd. EXTRAITS ET PROCÉDÉS CONTENANT DE l'ESPÈCE CURCUMA
JP2013189385A (ja) * 2012-03-12 2013-09-26 Kinki Univ β‐セクレターゼ阻害剤及びβ‐セクレターゼ阻害剤を含む飲食品
US8859020B2 (en) * 2005-05-30 2014-10-14 Benny Antony Treatment of alzheimer's with a curcuminoid mixture and essential oil of turmeric having 45% Ar-turmerone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8859020B2 (en) * 2005-05-30 2014-10-14 Benny Antony Treatment of alzheimer's with a curcuminoid mixture and essential oil of turmeric having 45% Ar-turmerone
WO2007109210A2 (fr) * 2006-03-17 2007-09-27 Herbalscience Singapore Pte. Ltd. EXTRAITS ET PROCÉDÉS CONTENANT DE l'ESPÈCE CURCUMA
JP2013189385A (ja) * 2012-03-12 2013-09-26 Kinki Univ β‐セクレターゼ阻害剤及びβ‐セクレターゼ阻害剤を含む飲食品

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DOUGLAS R. SHYTLE ET AL.: "Optimized turmeric extracts have potent anti-amyloidogenic effects", CURRENT ALZHEIMER RESEARCH, vol. 6, 2009, pages 564 - 571, ISSN: 1567-2050 *
SUN YOUNG PARK ET AL.: "Anti-inflammatory effects of aromatic-turmerone through blocking of NF-KB, JNK, and p38 MAPK signaling pathways in amyloid beta-stimulated microglia", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 14, no. 1, 20 June 2012 (2012-06-20), pages 13 - 20, XP028425798, ISSN: 1567-5769 *

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