WO2019208700A1 - Dipeptide et composition pharmaceutique le contenant - Google Patents

Dipeptide et composition pharmaceutique le contenant Download PDF

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Publication number
WO2019208700A1
WO2019208700A1 PCT/JP2019/017656 JP2019017656W WO2019208700A1 WO 2019208700 A1 WO2019208700 A1 WO 2019208700A1 JP 2019017656 W JP2019017656 W JP 2019017656W WO 2019208700 A1 WO2019208700 A1 WO 2019208700A1
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WO
WIPO (PCT)
Prior art keywords
asp
pro
leu
val
ile
Prior art date
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PCT/JP2019/017656
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English (en)
Japanese (ja)
Inventor
耕太郎 山田
英知 櫻井
佐藤　健司
晃佳 江島
修 中川西
孝一 丹野
Original Assignee
ゼリア新薬工業株式会社
国立大学法人京都大学
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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Publication date
Application filed by ゼリア新薬工業株式会社, 国立大学法人京都大学 filed Critical ゼリア新薬工業株式会社
Priority to KR1020207030150A priority Critical patent/KR20210003108A/ko
Priority to SG11202010069SA priority patent/SG11202010069SA/en
Priority to CN201980027959.5A priority patent/CN112041328B/zh
Priority to JP2020515565A priority patent/JPWO2019208700A1/ja
Publication of WO2019208700A1 publication Critical patent/WO2019208700A1/fr
Priority to JP2023067139A priority patent/JP2023089192A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/31—Foods, ingredients or supplements having a functional effect on health having an effect on comfort perception and well-being

Definitions

  • the present invention relates to a dipeptide and a pharmaceutical or food composition containing the same.
  • ⁇ ⁇ Fatigue generally has fatigue and malaise as the main symptom, but as a result, it leads to a decline in athletic ability, sleep disorder, reduced motivation, and the like. In the case of short-term fatigue, recovery is achieved by rest, sleep, nutritional supplementation, etc., but in the case of chronic fatigue, long-term general fatigue, fatigue, slight fever, etc. are difficult to recover.
  • Patent Document 1 amino acid compositions
  • Patent Document 2 L-carnitine
  • Patent Document 3 ascorbic acid and the like
  • liver hydrolyzate has an AMPK activation action and an anti-fatigue effect
  • JP-A-9-124473 JP 2001-046021 A JP-A-6-327435 International Publication No. 2015/022927
  • liver hydrolyzate is said to contain a lot of amino acids and peptides, but the actual active ingredient is not known. Therefore, the subject of this invention is providing the component which has a new fatigue prevention improvement effect.
  • the present inventor studied to develop a new agent for improving fatigue prevention, searched for indigestible peptides that migrated into the blood by administering liver hydrolyzate to animals, and used various columns for liver hydrolyzate. As a result of fractionating peptides and evaluating their efficacy, a dipeptide derived from a specific D-form amino acid, not an L-form amino acid, was found, and the dipeptide was found to have an effect of improving fatigue prevention. completed.
  • the present invention provides the following [1] to [9].
  • the dipeptide of the present invention is derived from a D-form amino acid, it is indigestible, is present in blood for a long time, and has an effect of improving fatigue prevention. Therefore, it is useful as a pharmaceutical and food composition for improving fatigue prevention. is there.
  • the anti-fatigue effect of a hydrophobic peptide fraction is shown.
  • the anti-fatigue effect of a hydrophobic pyroglutamyl peptide fraction is shown.
  • the anti-fatigue effect of a hydrophilic peptide fraction is shown.
  • the anti-fatigue effect of a hydrophilic pyroglutamyl peptide fraction is shown.
  • the anti-fatigue effect of Asp-Leu (D ⁇ ) is shown.
  • the anti-fatigue effect of Asp-Leu (D ⁇ ) is shown.
  • the anti-fatigue effect of Asp-Val (D ⁇ ) is shown.
  • the anti-fatigue effect of Asp-Val (D ⁇ ) is shown.
  • the anti-fatigue effect of Asp-Phe (D ⁇ ) is shown.
  • the anti-fatigue effect of Asp-Phe (D ⁇ ) is shown.
  • the dipeptides of the present invention are (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val -(D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D ) Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val
  • the dipeptide of the present invention can be produced by an ordinary liquid phase peptide synthesis method or solid phase peptide synthesis method using (D) amino acid as a raw material.
  • an amino acid protected with a functional group other than an ⁇ -amino group and an amino acid protected with a functional group other than a carboxy group or an amino acid protected with a functional group other than a carboxy group are condensed and protected. It can be produced by removing the group.
  • examples of the protecting group for the amino group of an amino acid include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a fluorenylmethoxycarbonyl group, and the like.
  • Examples of the protecting group for the carboxy group include a tert-butyl group and a benzyl group.
  • a method using N, N′-dicyclohexylcarbodiimide, dicyclohexylurea or other condensing agent, an active ester method such as nitrophenol or N-hydroxysuccinimide, a mixed acid anhydride method, or the like can be used.
  • the protecting group is removed, but in the case of the solid phase method, the bond between the C-terminus of the peptide and the resin is further cleaved.
  • the peptides of the present invention are purified according to conventional methods.
  • the dipeptide of the present invention can be an acid addition salt or a base salt.
  • Acid addition salts include inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfone Examples thereof include salts of organic acids such as acids, benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid.
  • the base salt include alkali metal salts such as sodium, potassium and lithium, and alkaline earth metal salts such as calcium and magnesium.
  • the peptide of the present invention can be a solvate.
  • solvates include solvates such as water (in the case of hydrates), methanol, ethanol, and isopropanol.
  • the dipeptide of the present invention is indigestible, has high blood migration after oral administration, is excellent in sustainability, and has an effect of improving fatigue prevention.
  • the fatigue prevention / improvement actions include motor function sustaining action, motor function improving action, anti-fatigue action, anti-stress action, fatigue reduction action, chronic fatigue prevention action, fatigue recovery action, plow prevention / improvement action, Examples include prevention / improvement of putting on, prevention / improvement of breathlessness, and prevention / improvement of muscle pain. Therefore, the composition containing the dipeptide of the present invention is useful as a pharmaceutical composition or a food composition.
  • the pharmaceutical composition of the present invention can be administered by oral administration, transdermal administration, enteral administration, intravenous administration, etc., and oral administration is more preferred.
  • oral administration examples include liquids, tablets, powders, fine granules, granules, capsules and the like, but liquids and tablets are preferable, and liquids are more preferable.
  • a solubilizing agent such as a nonionic surfactant, a corrigent, a sweetener, a stabilizer, a pH adjuster, water, ethanol, propylene glycol, glycerin and the like can be used.
  • a coating agent such as hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer may be used.
  • active ingredients can also be mix
  • Other active ingredients include vitamin B 1 ; thiamine, thiamine nitrate, thiamine hydrochloride, fursultiamine, bisbenchamine, benhotiamine, thiamine disulfide, dicetiamine, thiamine propyl disulfide and their derivatives, vitamin B 2 types; riboflavin and Derivatives and their salts, vitamin B 3 classes; niacin, nicotinic acid, nicotinic acid amides and derivatives and their salts, vitamin B 5 classes; panthenol, pantothenic acid and derivatives and their salts, vitamin B 6 classes; pyridoxine and derivatives and their salts, vitamin B 12 compound; cyanocobalamin and derivatives and salts thereof, other vitamins vitamin a, vitamin C, vitamin E, vitamin K, vitamin P, dichloroacetate diisopropylamine, taurine, con Droitin sulf
  • composition of the present invention can also be used as functional foods such as pharmaceuticals, quasi drugs, foods for specified health use, sports drinks, rehabilitation drinks, pet foods and the like.
  • the content of the dipeptide in the pharmaceutical composition or food composition of the present invention varies depending on the administration form, but is usually preferably 0.001 to 10% by mass, more preferably 0.001 to 5% by mass.
  • the daily dose of the dipeptide in the pharmaceutical composition or food composition of the present invention is preferably 10 mg to 1000 mg, more preferably 20 mg to 800 mg, and even more preferably 50 mg to 800 mg.
  • Example 1 (fraction of liver hydrolyzate) (1) Fractionation of Peptide and Pyroglutamyl Peptide A strong cation exchange resin (AG50) was packed in Econo Column (2.5 ⁇ 20 cm), and the resin was equilibrated with 10 mM HCl. 1 g of liver hydrolyzate (Sample A) was dissolved in 20 mL of 10 mM HCl. This solution was added onto the resin, and 20 mL of the flow-through fraction was collected (flow-through fraction 1). Subsequently, 20 mL of 10 mM HCl is added onto the resin and a 20 mL flow-through fraction is collected. This operation was repeated 19 times (through fractions 2 to 20).
  • AG50 strong cation exchange resin
  • the absorbance (230 nm) of the flow-through fractions 1 to 20 was measured to confirm peptide elution. Subsequently, 20 mL of 50% ammonia solution was added onto the resin, and 20 mL of the adsorbed fraction was collected. This operation was repeated 20 times (adsorption fractions 1 to 20). Absorbance (230 nm) of adsorbed fractions 1 to 20 was measured to confirm peptide elution.
  • the flow-through fraction (pyroglutamyl peptide fraction) and the adsorbed fraction (peptide fraction) were concentrated under reduced pressure using an evaporator.
  • Example 2 (1) Quantitative experiment of indigestible peptide in liver hydrolyzate 1) 2.5 mg of liver hydrolyzate was dissolved in 1 mL of 50 mM Tris-HCl. 2) Pancreatin (0.1 mg), leucine aminopeptidase (2.45 unit), and carboxypeptidase (7.7 unit) were added to 1) and subjected to an enzymatic reaction (37 ° C., 24 h). 3) The enzyme was removed by ultrafiltration (10K). 4) 3) was passed through a strong cation exchange resin (AG50) packed in a spin column, and the flow-through fraction was collected (pyroglutamyl peptide fraction).
  • AG50 strong cation exchange resin
  • Example 3 (Synthesis of dipeptide) 1) Reagents are added to the eggplant type flask in the following order and allowed to react with stirring (4 ° C., over night). (I) H-Leu-OtBu ⁇ HCl (Ii) DMF (Iii) TEA (Iv) Boc-Asp (OtBu) -OH (L ⁇ form) (V) HOBt (Vi) EDL / HCl In the case of other isomers, the following protected amino acids are used. Boc-D-Asp (OtBu) -OH (D ⁇ form) Boc-Asp-OtBu (L ⁇ form) Boc-D-Asp-OtBu (D ⁇ form) 2) Remove DMF with an evaporator.
  • Example 4 ⁇ Test method ⁇ (1) Animals used In experiments, ddY male mice (Japan SLC) weighing 28 to 32 g (26 g at the time of delivery) were used, and room temperature was 22 ⁇ 2 ° C., humidity was 55 ⁇ 5%, and brightness was 12 until they were used in the experiment. The animals were reared in a constant environment of a time cycle (light period; 7:00 to 19:00, dark period 19:00 to 7:00). During breeding, a plastic cage (length 30 cm ⁇ width 20 cm ⁇ height 13 cm) was used, and solid feed and tap water were freely ingested except for the experiment.
  • Example 5 Animals used For experiments, ddY male mice (Japan SLC) weighing 28 to 32 g (26 g at the time of delivery) were used, and room temperature was 22 ⁇ 2 ° C., humidity was 55 ⁇ 5%, and the brightness was 12 hours until the experiment. The animals were reared in a constant environment of a cycle (light period; 7:00 to 19:00, dark period 19:00 to 7:00). During breeding, a plastic cage (length 30 cm ⁇ width 20 cm ⁇ height 13 cm) was used, and solid feed and tap water were freely ingested except for the experiment.
  • the dipeptide was dissolved in physiological saline and 0.1 mL per 10 g body weight was administered intraperitoneally (ip). As the administration schedule, physiological saline or dipeptide is administered i. p. After 3 hours of forced walking, a physiological saline solution or dipeptide is applied to the observation cage for 15 minutes after i. p. Administered. (3) Forced walking load As the forced walking load, a mouse was placed in an electric rotating basket having a diameter of 37 ⁇ depth of 35.5 cm, and forced walking was tried at a speed of 1 rotation / 25 seconds for 3 hours.

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Abstract

L'invention concerne un nouvel ingrédient ayant des effets de prévention et de récupération de la fatigue. Ce dipeptide est choisi parmi : (D)Ile-(D)Pro, (D)Leu-(D)Pro, (D)Pro-(D)Ile, D)Pro-(D)Leu, (D)Val-(D)Pro, (D)Pro-(D)Val, (D)Leu-(D)Hyp, (D)Ile-(D)Hyp, (D)Val-(D)Hyp, (D)Asp-(D)Ile, (D)Asp-(D)Val, (D)Asp-(D)Leu, (D)Asp-(D)Phe, (D)Ile-(L)Pro, (D)Leu-(L)Pro, (D)Pro-(L)Ile, (D)Pro-(L)Leu, (D)Val-(L)Pro, (D)Pro-(L)Val, (D)Leu-(L)Hyp, (D)Ile-(L)Hyp, (D)Val-(L)Hyp, (D)Asp-(L)Ile, (D)Asp-(L)Val, (D)Asp-(L)Leu, et (D)Asp-(L)Phe.
PCT/JP2019/017656 2018-04-26 2019-04-25 Dipeptide et composition pharmaceutique le contenant WO2019208700A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1020207030150A KR20210003108A (ko) 2018-04-26 2019-04-25 디펩티드 및 이것을 함유하는 의약 조성물
SG11202010069SA SG11202010069SA (en) 2018-04-26 2019-04-25 Dipeptide and pharmaceutical composition containing same
CN201980027959.5A CN112041328B (zh) 2018-04-26 2019-04-25 二肽和含有该二肽的药物组合物
JP2020515565A JPWO2019208700A1 (ja) 2018-04-26 2019-04-25 ジペプチド及びこれを含有する医薬組成物
JP2023067139A JP2023089192A (ja) 2018-04-26 2023-04-17 ジペプチド及びこれを含有する医薬組成物

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JP2018-084925 2018-04-26
JP2018084925 2018-04-26

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KR (1) KR20210003108A (fr)
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SG (1) SG11202010069SA (fr)
TW (1) TWI828681B (fr)
WO (1) WO2019208700A1 (fr)

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KR20220101269A (ko) 2021-01-11 2022-07-19 주식회사 엘지에너지솔루션 가압 트레이 및 이를 포함하는 전지 셀의 활성화 장치

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JPH08198768A (ja) * 1995-01-20 1996-08-06 Osamu Mimura 糖尿病治療剤
WO2005012334A1 (fr) * 2003-08-01 2005-02-10 Calpis Co., Ltd. Peptide biologiquement non biodegradable, inhibiteur de l'enzyme de conversion de l'angiotensine, medicament et aliment fonctionnel
JP2011152075A (ja) * 2010-01-27 2011-08-11 Tottori Univ Ｄ−，ｌ−ペプチドの立体選択的合成法
WO2012105711A1 (fr) * 2011-02-04 2012-08-09 学校法人早稲田大学 Procédé pour produire un composé organique
WO2012165546A1 (fr) * 2011-05-31 2012-12-06 味の素株式会社 Procédé pour produire un peptide
JP2013040111A (ja) * 2011-08-11 2013-02-28 Okayama Prefecture ジペプチジルペプチダーゼ−ｉｖ阻害剤及びその製造方法
JP2013543850A (ja) * 2010-11-08 2013-12-09 上海医薬工業研究院 新規な化合物、その製造方法および用途
WO2017034011A1 (fr) * 2015-08-27 2017-03-02 アサヒグループホールディングス株式会社 Agent de prolifération des bactéries intestinales bénéfiques

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JP4526047B2 (ja) 1995-11-08 2010-08-18 雪印乳業株式会社 体力増強剤
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
JP2001046021A (ja) 1999-08-10 2001-02-20 Itoham Foods Inc 体力増強・疲労回復用素材及びそれを用いた食品
JP5645360B2 (ja) * 2006-04-21 2014-12-24 株式会社明治 ジペプチドを有効成分として含有する組成物
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Publication number Priority date Publication date Assignee Title
JPH04501056A (ja) * 1988-08-12 1992-02-27 カールバイオテック　リミテッド　アクティーゼルスカブ ジペプチドまたは構造関連化合物の酵素的製造方法
JPH08198768A (ja) * 1995-01-20 1996-08-06 Osamu Mimura 糖尿病治療剤
WO2005012334A1 (fr) * 2003-08-01 2005-02-10 Calpis Co., Ltd. Peptide biologiquement non biodegradable, inhibiteur de l'enzyme de conversion de l'angiotensine, medicament et aliment fonctionnel
JP2011152075A (ja) * 2010-01-27 2011-08-11 Tottori Univ Ｄ−，ｌ−ペプチドの立体選択的合成法
JP2013543850A (ja) * 2010-11-08 2013-12-09 上海医薬工業研究院 新規な化合物、その製造方法および用途
WO2012105711A1 (fr) * 2011-02-04 2012-08-09 学校法人早稲田大学 Procédé pour produire un composé organique
WO2012165546A1 (fr) * 2011-05-31 2012-12-06 味の素株式会社 Procédé pour produire un peptide
JP2013040111A (ja) * 2011-08-11 2013-02-28 Okayama Prefecture ジペプチジルペプチダーゼ−ｉｖ阻害剤及びその製造方法
WO2017034011A1 (fr) * 2015-08-27 2017-03-02 アサヒグループホールディングス株式会社 Agent de prolifération des bactéries intestinales bénéfiques

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CN112041328A (zh) 2020-12-04
TWI828681B (zh) 2024-01-11
SG11202010069SA (en) 2020-11-27
CN112041328B (zh) 2024-06-21
TW201945387A (zh) 2019-12-01
JPWO2019208700A1 (ja) 2021-04-30
KR20210003108A (ko) 2021-01-11
JP2023089192A (ja) 2023-06-27

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