WO2004045628A1 - Inhibiteur d'agregation plaquettaire comprenant de l'anhydrofructose et son derive - Google Patents

Inhibiteur d'agregation plaquettaire comprenant de l'anhydrofructose et son derive Download PDF

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Publication number
WO2004045628A1
WO2004045628A1 PCT/JP2003/014621 JP0314621W WO2004045628A1 WO 2004045628 A1 WO2004045628 A1 WO 2004045628A1 JP 0314621 W JP0314621 W JP 0314621W WO 2004045628 A1 WO2004045628 A1 WO 2004045628A1
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WO
WIPO (PCT)
Prior art keywords
platelet aggregation
formula
anhydro
fructose
group
Prior art date
Application number
PCT/JP2003/014621
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English (en)
Japanese (ja)
Inventor
Ikuro Maruyama
Kazuyo Yamaji
Susumu Hizukuri
Original Assignee
Nihon Starch Co., Ltd.
Biomedical Technology Hybrid, Ltd.
Hizukuri, Fumiko
Hizukuri, Kazuko
Hizukuri, Kaoru
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.)
Filing date
Publication date
Application filed by Nihon Starch Co., Ltd., Biomedical Technology Hybrid, Ltd., Hizukuri, Fumiko, Hizukuri, Kazuko, Hizukuri, Kaoru filed Critical Nihon Starch Co., Ltd.
Priority to AU2003302079A priority Critical patent/AU2003302079A1/en
Publication of WO2004045628A1 publication Critical patent/WO2004045628A1/fr

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to the use or use of 1,5-anhydro-D-fructose and its derivatives on pharmaceutical or functional foods.
  • 1,5-anhydro D-fructoses L1,5—anhydro-D-fructoses are derived from polysaccharides such as starch and glycogen. It is a unique sugar that is produced by the glucan lyase reaction and exists in various plants, including mammals, and has a double bond in the molecule.
  • 1,5-AF is generated from daricogen by the 1,4-glucan lyase by the anhydrofructose pathway, and then 1,5-anhydro by the 1,5-AF-specific reductase. Reduced to D-glucitol (hereinafter abbreviated as 1,5-AG).
  • 1,5—AG is considered the end product of 1,5—AF, but in diabetes; , 5-—It is known that the blood concentration of AG decreases, and it is used as a marker for diabetes. Considering such conversion processes, it has been proposed to use 1,5-AF and its similar cyclic ethers for the treatment of patients with impaired glucose tolerance (eg, diabetes) (eg, WO 01 / 51058 A1).
  • 1,5-AF has radical scavenger-like activity, and that 1,5-AF significantly oxidizes LDL in the oxidation reaction of low-density lipoprotein (LDL) by copper ions.
  • LDL low-density lipoprotein
  • the present invention provides pharmaceutical preparations and articles (intended for application to an individual, particularly to mammals including humans) which exhibit additional useful physiological activities or effects. Aim.
  • the present inventors have studied the more detailed mechanism of action of 1,5-AF in the above-mentioned LDL oxidation system and other systems, and found that 1,5-AF and certain derivatives thereof were human platelets. Has been found to be able to significantly suppress aggregation. Therefore, the present invention is based on such findings, and comprises a pharmaceutically acceptable carrier, diluent or excipient, and 1,5-anhydro-D-fructoses as active ingredients and the following:
  • a platelet aggregation inhibitor comprising one or more members selected from the group consisting of the derivatives represented by the general formula (I) is provided.
  • AF represents a 1,5-anhydro-D-fructose residue
  • G Represents a group of the formula G— (G) n — or RCO—, where G is a glucose residue and (G) n is
  • N is an integer from 0 to 20
  • m is an integer from 0 to 3
  • RCO is a group derived from a fatty acid of 2 to 20 carbon atoms
  • G— (G) n — or RCO— is a glucosidic bond (at least one site selected from the 3-, 4- and 6-positions) of the AF via a hydroxyl group. 1 ⁇ 3, 1 ⁇ 4 or 1-6) or at least one ester bond.
  • the invention relates to 1,5-anhydro-D-fructoses and the general A pharmaceutical or functional food for inhibiting platelet aggregation of one or more active ingredients selected from the group consisting of 1,5-anhydro-D-fructose derivatives represented by the formula (I) For use in preparation.
  • the present invention provides a method for administering 1,5-anhydro-D-fructoses and 1,5-anhydro-D-fructoses to an individual in need thereof (for example, humans and non-human mammals) at a dose sufficient to inhibit platelet aggregation.
  • Platelet aggregation comprising administering to the individual one or more active ingredients selected from the group consisting of 1,5-anhydro-D-fructoses derivatives represented by the general formula (I).
  • the present invention relates to a method for preventing or treating a disease associated with the disease.
  • FIG. 1 is a graph showing the inhibitory effect of 1,5-AF on platelet aggregation measured by the experimental method described in Examples.
  • thrombin is a result when the platelet inhibitor according to the present invention is not included, and +1, 5-AF indicates 1,5-AF as the blood cell inhibitor. It is the result of the case where it is open.
  • the active ingredient 1,5-AF according to the present invention is, for example, van hydrofructose which is known to exist as several tautomers as shown by the following formula.
  • 1,5-AF is hydrated in an aqueous solution and exists as a hydrated form represented by the following formula. It has also been suggested that in non-aqueous solutions, it may exist as a dimer represented by the following formula (J. Carbohydrate Chemistry, 1998,] 7, 1027-1 1035).
  • 1,5-AF is present in mammals and various plants, but can be chemically synthesized from glucose or synthesized using enzymes (for example, J. Appl. Glycosci., Vol. 46). 439-444, 1999).
  • 1,5-anhydro-D-fructoses 1,5-AF
  • isomers, hydrates and structural isomers having any of the above-mentioned forms are referred to. It is used in a concept that includes the body. ' Therefore, in general formula (I): X—AF, the AF representing 1,5-anhydro-D—fructoses residue is the 3-position or 4-position in 1,5-AF, excluding the dimer described above. Or a sugar residue in a state in which a hydrogen atom or the hydroxyl has been removed from the hydroxyl group at position 6.
  • G-, 1-G-glucose residues include, but are not limited to, water from 1-hydroxyl groups and / or 1-2 hydroxyl groups at 4-, 6-, or 3-positions.
  • N in the above formula can be theoretically any integer, but considering the use of the present invention, 0 to 20, preferably 0 to 11, more preferably 0 to 6, particularly preferably 0 to 2
  • m is 0-3, preferably 0 [ie (G) n has no branches].
  • Examples of the 1,5-AF derivative represented by are not limited. Can be obtained by reacting a mixture of 1,5-AF and 3-cyclodextrin described in JP 2001-20449 OA with a cyclodextrin synthase, Consists of 5-AF residue and 1-10 glucose residues, each with a degree of polymerization of 2-11, reducing end is 1,5-AF residue and non-reducing end is glucose residue
  • Each of the 1,5-AF saccharide derivatives can be isolated, or a mixture of any two or more saccharide derivatives having a degree of polymerization.
  • the 1,5-AF derivative is represented by the 3,5-anhydro-D-fructose residue 3 Position, position 4 or position 6 (preferably position 6)
  • the hydroxyl group is a fatty acid-derived acyl group having 2 to 20 carbon atoms in an ester bond.
  • T-syl groups can be straight or branched and can be derived from saturated or unsaturated aliphatic or carboxylic acids, for example, acetyl, propionyl, petyloyl, decanoyl, dodecanoyl, hexadecanoyl, 9 Hexadecenoyl, Octadecanoyl, 9,12-Octadecadienol, 9,12,15-Octadecatrienoyl, 5,8,11,14-Icosatetraenoyl And so on.
  • saturated or unsaturated aliphatic or carboxylic acids for example, acetyl, propionyl, petyloyl, decanoyl, dodecanoyl, hexadecanoyl, 9 Hexadecenoyl, Octadecanoyl, 9,12-Octadecadienol, 9,12,15-Octadecatrienoyl
  • acyl derivatives can be produced by a chemical synthesis method
  • an acyl derivative derived from a higher fatty acid can be produced, for example, by a synthesis method using a lipase as described in WO 00/56574. Can be manufactured. In some cases, it is preferable to use the acyl derivative thus produced as an active ingredient of the present invention.
  • platelet aggregation is an essential event for clot formation.
  • blood clots have the effect of preventing blood from leaking out of the vascular system, ie, stopping blood.
  • this hemostatic function is activated in the blood vessels, which leads directly to serious conditions (eg, myocardial infarction, cerebral infarction, etc.).
  • Platelet aggregation as referred to in the present invention, generally refers primarily to the process leading to such disease states. Without being bound by theory, the present invention contemplates the generation of trace thrombin at the site of vascular injury, thereby activating platelets and subsequently inhibiting platelet aggregation. ing.
  • the present invention provides a means for preventing or treating thrombus formation.
  • the active ingredients described above are used to dissolve blood clots.
  • the active ingredient according to the present invention could also be used to prevent pathological thrombus as well as to prevent the occurrence of reinfarction following thrombus dissolution and to accelerate the rate of thrombolysis.
  • the platelet inhibitor of the present invention when used as a pharmaceutical preparation, it contains, in addition to the active ingredient, a pharmaceutically acceptable carrier, diluent or excipient known in the art. It can be included by known blending methods. Depending on the choice of one or more carriers, the formulation containing them may be administered parenterally (eg, intravenous, intraarterial, intramuscular or subcutaneous), oral, topical It can be in the form of administration by implantation or the like. It can also be in the form of functional foods (including beverages).
  • a pharmaceutically acceptable carrier diluent or excipient known in the art. It can be included by known blending methods.
  • the formulation containing them may be administered parenterally (eg, intravenous, intraarterial, intramuscular or subcutaneous), oral, topical It can be in the form of administration by implantation or the like. It can also be in the form of functional foods (including beverages).
  • Formulations for parenteral administration may be in unit dosage form (eg, in ampoules) or in multi-dose containers with an added stock. These compositions may be in the form of a suspending agent, solution, or oily [particularly in the case of the compound represented by the general formula (Ib)] or an emulsifier in an aqueous excipient. And may optionally contain pharmaceutical agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredients may be in powder form for constitution with a suitable excipient (eg, sterile pyrogen-free water).
  • a suitable excipient eg, sterile pyrogen-free water
  • a simple treatment such as removing cyclodextrin synthase and adding an isotonic agent if necessary
  • the above preparation for parenteral administration or the oral administration preparation (including food) described below can be obtained. Good.
  • Such forms of preparation are also within the scope of the present invention.
  • Formulations for oral administration according to the present invention include, for example, a binder (eg, pregelatinized starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose): a filler (eg, lactose, microcrystalline cellulose). Or calcium phosphate); lubricants (eg, magnesium stearate, talc, or gayne); disintegrants (eg, sodium starch glycolate); or wetting agents (eg, sodium lauryl sulfate)
  • a binder eg, pregelatinized starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose
  • a filler eg, lactose, microcrystalline cellulose. Or calcium phosphate
  • lubricants eg, magnesium stearate, talc, or gayne
  • disintegrants eg, sodium starch glycolate
  • wetting agents eg, sodium lauryl sulfate
  • Liquid preparations for oral administration or for parenteral administration as described above may take the form of, for example, solutions, syrups or suspensions, or they may be prepared with water or other suitable liquid prior to use. It can be provided as a dry product for reconstitution with excipients.
  • Such liquid preparations may include, for example, suspending agents (eg, sorbitol syrup, methylcellulose, or hydrogenated edible fat); particularly, for derivatives of formula (I-b), emulsifiers (eg, lecithin or Acacia) or non-aqueous excipients (eg, almond oil, oily esters, or ethyl alcohol): and pharmaceutically acceptable preservatives (eg, methyl or propyl p-hydroxybenzoic acid, or sorbic acid) It can be prepared by a conventional method using the excipient used.
  • suspending agents eg, sorbitol syrup, methylcellulose, or hydrogenated edible fat
  • emulsifiers eg, lecithin or Acacia
  • non-aqueous excipients eg, almond oil, oily esters, or ethyl alcohol
  • pharmaceutically acceptable preservatives eg, methyl or propyl p-hydroxybenzoic acid, or sorbic acid
  • preparations containing 1,5-AF include red algae [Gracilaria chor da ⁇ ogonori (Gracilaria verrucosa) etc.] ⁇ mushroom (Morchella hortensis) ⁇ or liver of constant temperature animals, etc.
  • red algae Gramilaria chor da ⁇ ogonori (Gracilaria verrucosa) etc.
  • mushroom Muschella hortensis
  • Such oral dosage forms may be in the form of food or beverages.
  • the active ingredient of the present invention may further be used as a depot preparation.
  • Such long acting formulations may be administered by implantation or implantation (for example, subcutaneously or intracerebrally) or by intramuscular injection.
  • these compounds may be suitable polymerizable or hydrophobic materials (eg, acceptable emulsifiers in oils) ) Can be prepared.
  • the formulation of the present invention is not limited because the optimal dose varies depending on the dosage form or route of administration, or the condition to be prevented or treated, but is usually, but not limited to : preferably determined by professional judgment.
  • a dose of 0.0001 to 3000 mg, preferably 0.01 to 100 mg, more preferably 0.1 to lmg, based on the active ingredient, per kg of the patient's body weight is generally obtained. It can be.
  • Such dosages may also be administered at a suitable frequency of administration, for example 1 to 10, preferably 1 to 2 times per day, or once at appropriate intervals (every few days).
  • the action and effect of the present invention can be evaluated by the following experiment widely recognized by those skilled in the art in evaluating the platelet aggregation inhibitory effect (also, Freedman et al., Circulation, 1996; _4-2434). -2440).
  • Platelet aggregation was examined using platelets collected from the blood of normal subjects. Blood collected in a 3.8% sodium citrate blood collection tube was centrifuged (350 g, 15 minutes, room temperature) to obtain platelet-rich plasma (PRP). Further centrifugation was performed (2000 g, 15 minutes, room temperature) to obtain Platelet poor plasma (PPP).
  • PRP platelet-rich plasma
  • PPP Platelet poor plasma
  • the platelet aggregation ability was examined using PRP. Aggregation of 200 ⁇ L of PRP is induced by adenosine 5'-diphosphate (ADP) or thrombin, and the turbidity is optically measured using a platelet aggregometer (Hema Tracer TM Model 801, Mko Bioscience, Tokyo) ]. At that time, PPP was used as a control.
  • ADP adenosine 5'-diphosphate
  • thrombin thrombin
  • 1,5-AF is a sugar and is basically a substance that exists in the body
  • 1,5-AF and its derivatives are useful as antithrombotic agents. Can be considered
  • the derivative of 1,5-AF may be a compound of the formula (I-a) and (I-b) provided in accordance with the present invention.
  • the hydroxyl group at the reducing site of the compound is in a free state (ie, has no substituent), it exhibits almost the same effect as 1,5-AF described above.
  • a means for significantly suppressing platelet aggregation in an individual is provided. Therefore, it can be used in the medical industry or industries providing functional foods.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

L'invention concerne un inhibiteur d'agrégation plaquettaire, notamment un inhibiteur d'agrégation plaquettaire d'un type nouveau, qui comprend, en tant que principe actif, de la 1,5-anyhdro-D fructose ou un dérivé défini de celle-ci.
PCT/JP2003/014621 2002-11-18 2003-11-18 Inhibiteur d'agregation plaquettaire comprenant de l'anhydrofructose et son derive WO2004045628A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003302079A AU2003302079A1 (en) 2002-11-18 2003-11-18 Platelet aggregation inhibitor comprising anhydrofructose and its derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-333502 2002-11-18
JP2002333502A JP2006016301A (ja) 2002-11-18 2002-11-18 アンヒドロフルクトースおよびその誘導体の血小板凝集抑制剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006306814A (ja) * 2005-04-28 2006-11-09 Nihon Starch Co Ltd 抗炎症剤

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012001515A (ja) * 2010-06-21 2012-01-05 Toyama Univ グリコーゲン分解酵素阻害剤
JP2020100601A (ja) * 2018-12-25 2020-07-02 国立大学法人 鹿児島大学 一酸化窒素合成酵素活性化剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050532A2 (fr) * 1997-05-06 1998-11-12 Danisco A/S Procede de preparation d'un antioxydant
WO2000056745A1 (fr) * 1999-03-19 2000-09-28 Danisco A/S 1,5-anhydro-d-fructose substituee par un groupe hydrophobe, servant d'anti-oxydant et/ou d'emulsifiant
JP2001204490A (ja) * 2000-01-26 2001-07-31 進 ▲桧▼作 構成糖に１，５−ｄ−アンヒドロフルクトースを含有する糖鎖

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050532A2 (fr) * 1997-05-06 1998-11-12 Danisco A/S Procede de preparation d'un antioxydant
WO2000056745A1 (fr) * 1999-03-19 2000-09-28 Danisco A/S 1,5-anhydro-d-fructose substituee par un groupe hydrophobe, servant d'anti-oxydant et/ou d'emulsifiant
JP2001204490A (ja) * 2000-01-26 2001-07-31 進 ▲桧▼作 構成糖に１，５−ｄ−アンヒドロフルクトースを含有する糖鎖

Non-Patent Citations (5)

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Title
KAWASHIMA YASUKO ET AL.: "Kessen shiketsu kiko to kassei sanso", HEMATOLOGY FRONTIER, vol. 11, no. 6, 2001, pages 728 - 729, XP002986479 *
SAMAL A.B. ET AL.: "The role of active oxigen species inaggregation and deaggregation of platelets", BIOKHIMIYA, vol. 55, no. 5, 1990, pages 786 - 790, XP002986480 *
SCHOENE N.W. ET AL.: "Genistein inhibits reactive oxigen species (ROS) production, shape change, and aggregation in rat platelets", NUTR. RES., vol. 20, no. 1, 2000, pages 47 - 57, XP002986481 *
SUMI H.: "Hakko daizu no kassei sanso shokyokei, tokuni SOD-zai toshite no natto", THE FOOD INDUSTRY, vol. 41, no. 14, 1998, pages 49 - 55, XP002955073 *
YAMAJI K. ET AL.: "Antioxidant effects of 1,5-anhydro-D-fructose, a new natural sugar, in vitro", PLANTA MED., vol. 68, 2002, pages 16 - 19, XP002986478 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006306814A (ja) * 2005-04-28 2006-11-09 Nihon Starch Co Ltd 抗炎症剤

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