WO2011078204A1 - Prophylactic or therapeutic agent for hyperlipemia, and anti-fatigue agent - Google Patents

Prophylactic or therapeutic agent for hyperlipemia, and anti-fatigue agent Download PDF

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WO2011078204A1
WO2011078204A1 PCT/JP2010/073088 JP2010073088W WO2011078204A1 WO 2011078204 A1 WO2011078204 A1 WO 2011078204A1 JP 2010073088 W JP2010073088 W JP 2010073088W WO 2011078204 A1 WO2011078204 A1 WO 2011078204A1
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carnosine
fatigue
agent
alanine
acetyl
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PCT/JP2010/073088
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French (fr)
Japanese (ja)
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正治 嶋津
一良 矢澤
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浜理薬品工業株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a prophylactic or therapeutic agent for hyperlipidemia containing a carnosinase inhibitor and L-carnosines, and an anti-fatigue agent.
  • Reactive oxygen and free radicals are thought to cause damage to cells, cause peroxidation, and promote aging as one of the causes of the decline in structure and function of human and other mammalian tissues with aging .
  • natural antioxidants in various body tissues or cells or in body fluids including plasma and blood flow
  • L-carnosine ( ⁇ -alanyl-L-histidine) represented by the following formula (I) is a non-protein fraction of vertebrate skeletal muscle (eg, Non-Patent Documents 1 and 2), olfactory epithelium and olfactory bulb It has been found to be one of the most abundant (1-20 mM) nitrogenous compounds present in such other tissues (eg, Non-Patent Document 3) and lens (Non-Patent Document 4).
  • Non-Patent Documents 5, 6, 7 L-carnosine related natural products such as N-acetyl-L-carnosine, L-anserine ( ⁇ -alanyl-L-3-methylhistidine) and its N-acetyl derivative, L-valenine ( ⁇ - Alanyl-L-1-methylhistidine), L-homocarnosine ( ⁇ -aminobutyryl-L-histidine) and its N-acetyl derivative, calcinin ( ⁇ -alanylhistamine) (for example, Non-Patent Documents 5, 6, 7)
  • Non-Patent Document 8 Have interesting differences in their distribution, activity and metabolic transformation (eg, Non-Patent Document 8), but are present in millimolar concentrations in tissues such as skeletal muscle, heart and brain of several mammals. (For example, Non-Patent Document 9).
  • L-carnosine and related natural substances are the most important natural antioxidants, such as lipids and proteins (including enzymes), DNA and other essential polymers in the lipid layer and aqueous environment of cell membranes or biological membranes. It is known that these water-soluble molecules have an action of protecting them from being damaged by reactive oxygen species and lipid peroxides (Non-Patent Documents 9, 10, 11, 12).
  • Non-patent Documents 13 and 14 Various antioxidant enzymes such as SOD (superoxide dismutase) or catalase react with the substrate only in an aqueous environment.
  • SOD superoxide dismutase
  • catalase catalase react with the substrate only in an aqueous environment.
  • L-carnosine and related natural substances have an action of capturing hydroxyl radicals, superoxide and singlet oxygen and suppressing lipid peroxidation (for example, Non-patent Documents 13 and 14). .
  • L-carnosine and its naturally occurring related compounds protect commercially available enzymes such as SOD from cells and tissues and antioxidant systems such as glutathione and ceruloplasmin from inactivation.
  • Water soluble L-carnosine enhances the antioxidant action of lipid soluble ⁇ -tocopherol upon lipid peroxidation in liver microsomes. Therefore, L-carnosine is the main protector of the liver cytochrome P-450 system.
  • L-carnosine is the only antioxidant known to clearly protect cellular chromosomes from oxidative damage.
  • ischemic diseases eg cerebral infarction, transient cerebral ischemic attack, stroke, angina pectoris, myocardial infarction, etc.
  • onset and progression of cataracts eg., cataracts, cataracts, and aging of muscles and skin.
  • L-carnosine is also known to improve brain neurodegenerative diseases (eg, Alzheimer's disease, dementia, epilepsy, etc.).
  • Non-Patent Document 15 L-carnosine supplementation is considered a useful method for the prevention and treatment of these diseases.
  • L-carnosine is the best anti-glycation agent discovered so far, and is known to inhibit so-called Maillard reaction, ie, advanced glycation reactions such as direct glycation of proteins and cross-linking of proteins. ing. Therefore, L-carnosine is not only diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, but also aging of vascular tissues (eg arteriosclerosis, retinopathy etc.), skin aging (eg wrinkles) or It can be expected to prevent aging of various tissues such as aging of the lens (for example, cataract).
  • Maillard reaction ie, advanced glycation reactions such as direct glycation of proteins and cross-linking of proteins. ing. Therefore, L-carnosine is not only diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, but also aging of vascular tissues (eg arteriosclerosis, retinopathy etc.), skin aging (eg wrinkles) or It can be expected
  • Non-Patent Documents 16 and 17 Recently, it has been reported that acrylamide, which is a carcinogenic and toxic substance, is formed in various foods by the Maillard reaction during cooking (for example, Non-Patent Documents 16 and 17). The addition of L-carnosine to foods or foods before cooking is considered to be an effective means for suppressing such acrylamide formation.
  • L-carnosine has a membrane stabilization and tissue repair action, and is effective in the prevention and treatment of gastrointestinal ulcerative diseases (eg, gastric ulcer, duodenal ulcer) or skin ulcerative diseases. It turns out. It is also effective in treating wounds and burns.
  • gastrointestinal ulcerative diseases eg, gastric ulcer, duodenal ulcer
  • skin ulcerative diseases eg, skin ulcerative diseases. It turns out. It is also effective in treating wounds and burns.
  • L-carnosine and related natural products have an anti-ischemic action not only on the brain but also on the heart.
  • L-carnosine has been found to increase cardiac contractility by enhancing cardiac cell calcium response.
  • L-carnosine injection has proven effective for emergency treatment of ischemic stroke.
  • L-carnosine plays an important role in buffering the acid balance in muscle when a large amount of H + is produced in conjunction with lactic acid accumulation by intense exercise. Therefore, L-carnosine plays a role in preventing muscle fatigue that leads to improvement in exercise performance. L-carnosine prevents muscle cell membranes from being oxidized under the acidic conditions of muscle movement. According to a recent report, L-carnosine concentration in muscle is highly correlated with average physical fitness (eg, Non-patent Document 18). L-carnosine has been shown to dramatically improve fatigue recovery from exercise (however, it does not mean increased exercise capacity, i.e., promotes motility, but rather facilitates an anabolic response to exercise) ). Carnosine has been shown to quickly restore muscle contraction ability after fatigue.
  • L-carnosine seems to be a real substrate of nitric oxide synthase (NOS).
  • L-carnosine supplementation may stimulate the synthesis of nitric oxide (NO), an endogenous vasorelaxant, to lower blood pressure and prevent ischemic diseases such as angina. Expected.
  • L-carnosine is effective as a scavenger for acetaldehyde, which is a major product of ethanol metabolism when alcoholic beverages (eg, whiskey, cognac, vodka, beer, liquor, wine, etc.) are consumed (for example, non-patent literature) 19). Therefore, L-carnosine protects the liver, brain or muscle from acetaldehyde toxicity. In addition, L-carnosine is effective in treating and preventing mucosal fistula and peptic ulcer exacerbated by alcohol consumption because it has a healing effect on wounds.
  • alcoholic beverages eg, whiskey, cognac, vodka, beer, liquor, wine, etc.
  • Chronic alcoholic skeletal muscle disorder is characterized by selective atrophy of type II fibers, affecting up to 2/3 of all alcohol abusers.
  • L-carnosine prevents fiber atrophy. That is, L-carnosine protects the brain not only from lipid peroxidation but also from damage caused by excessive alcohol consumption.
  • L-carnosine has an immunostimulatory action and protects the immune system from immunosuppression by hydrocortisone, antitumor agents or many other immunosuppressive agents.
  • L-carnosine has the following advantages to maintain health and youth.
  • L-carnosine and its related compounds increase the number of cell divisions (limit of Hayflick) and may be useful for prolonging survival or longevity (for example, Non-patent Document 20).
  • L-carnosine has a connective tissue rejuvenation effect and wound healing effect. In the tissue culture system supplemented with L-carnosine, the cells remained young and their survival was extended. This ability of L-carnosine to increase cell survival was also applicable to senescent cells, and in some experiments, addition of L-carnosine extended cell survival by 67%. Proven in an in vivo test using mice, mice administered with L-carnosine survived an average of 20% longer than control mice, and are more than twice as healthy as control mice over time. I kept it. In humans, L-carnosine blood levels decrease with age, and L-carnosine levels in muscle decrease by 63% between the ages of 10 and 70 years.
  • exogenous carnosine is easily excreted in urine or decomposed by an enzyme called carnosinase even when locally administered to the eye, and thus does not accumulate in tissues.
  • This carnosinase is present in plasma, an aqueous humor of the anterior chamber of the eye, liver, kidney or other tissues, but not in muscle (for example, Non-Patent Documents 21 and 22), but is present in the lens. (For example, nonpatent literature 23 and 24).
  • L-carnosine related natural substances such as N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-valenine, L-homocarnosine, N-acetyl-L-homocarnosine or carcinine
  • the degradation rate is slower than that of L-carnosine, it can be a substrate that is hydrolyzed or inactivated by carnosinase (for example, Non-Patent Document 25).
  • L-carnosine and / or related natural substances in the body due to aging or malnutrition causes various dysfunctions of the body in humans and other mammals. Supplementation with L-carnosine or related natural substances is therefore considered useful for the treatment or prevention of such dysfunctions or diseases derived therefrom.
  • excessive supplementation with L-carnosine and / or related natural substances has implications for the treatment of these diseases, improvement of exercise capacity, prevention of aging, skin treatment, improvement of quality of life (QOL), etc. It is thought that there is.
  • L-carnosine has already been used in several countries as a dietary supplement or as a cosmetic product, as described above, L-carnosine is easily hydrolyzed by an enzyme called sonocarnase (there are two forms, serotype and tissue type). These products are not considered very effective because they are broken down into ⁇ -alanine and L-histidine and completely lose the physiological activity of L-carnosine. Because carnosinase is widely distributed in the lumen of the small intestine, plasma and other tissues of humans and other mammals, the above purpose, ie, disease, regardless of the method of oral, parenteral or topical administration.
  • the present invention aims to find a novel use by combining a carnosinase inhibitor and L-carnosine, and further, a novel prophylactic or therapeutic agent for hyperlipidemia comprising a carnosinase inhibitor and L-carnosine, Another object of the present invention is to provide a novel anti-fatigue agent containing a carnosinase inhibitor and L-carnosines.
  • ⁇ -alanine represented by the following formula (II) N-alkanoyl- ⁇ -alanine derivative represented by the following formula (III)
  • the N-alkanoyl-L-carnosine derivative represented by the following formula (IV) is safe and inexpensive, and has an effect of reducing the plasma lactic acid concentration or free fatty acid concentration in combination with L-carnosines. I found out.
  • R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.
  • R 2 represents a hydrogen atom or a lower alkyl group
  • R 3 represents an alkyl group having 2 or more carbon atoms.
  • compositions comprising a carnosinase inhibitor and L-carnosine are useful for the prevention or treatment of hyperlipidemia, and a composition comprising a carnosinase inhibitor and L-carnosine.
  • the present invention was completed by finding that the product exhibits an anti-fatigue effect.
  • a prophylactic or therapeutic agent for hyperlipidemia comprising a carnosinase inhibitor and L-carnosines
  • Carnosinase inhibitor is ⁇ -alanine represented by the following formula (II), N-alkanoyl- ⁇ -alanine derivative represented by the following formula (III), N-
  • the high fat according to [1] above which is at least one selected from alkanoyl-L-carnosine derivatives, ⁇ -amino acid derivatives, thiol-type reducing agents, and hydrophobic vitamins having a branched hydrocarbon chain
  • Preventive or therapeutic agent for blood pressure (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.) (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
  • L-carnosine is L-carnosine, N-acetyl-L-
  • Preventive or therapeutic agent [5] The above-mentioned [1], further comprising at least one selected from cellulose derivatives, gelatin, dextrin, lactose, starch and polyvinylpyrrolidone in order to increase the absorption of the carnosinase inhibitor and / or L-carnosine.
  • anti-fatigue agent according to any one of [13]
  • the anti-fatigue agent according to any one of [8] to [12] which is characterized by About.
  • the present invention includes the following inventions.
  • a method for preventing or treating hyperlipidemia comprising a step of administering an effective amount of a carnosinase inhibitor and L-carnosine to a mammal.
  • Carnosinase inhibitors and L-carnosines for use in the prevention or treatment of hyperlipidemia.
  • An anti-fatigue method comprising a step of administering an effective amount of a carnosinase inhibitor and L-carnosine to a mammal.
  • Carnosinase inhibitors and L-carnosines for use in anti-fatigue.
  • the present invention it is possible to provide a prophylactic or therapeutic agent for hyperlipidemia that reduces the free fatty acid concentration in plasma.
  • the action of reducing the free fatty acid concentration in the plasma of the present invention is effective in preventing or treating hyperlipidemia, and is effective in preventing or treating a disease associated with an increase in the free fatty acid concentration in plasma.
  • the anti-fatigue agent which suppresses the increase in the lactic acid concentration in plasma or reduces the lactic acid concentration in plasma can be provided.
  • the anti-fatigue agent of the present invention has excellent fatigue reduction and fatigue recovery promoting effects, and an endurance improving effect.
  • the preventive or therapeutic agent for hyperlipidemia and the anti-fatigue agent of the present invention are composed of components that are safe for the human body, they can be used safely as a pharmaceutical composition or a functional food even when ingested over a long period of time. is there.
  • the prophylactic or therapeutic agent for hyperlipidemia of the present invention comprises a carnosinase inhibitor and L-carnosines.
  • a carnosinase inhibitor used in the preventive or therapeutic agent for hyperlipidemia of the present invention a known carnosinase inhibitor can be used without limitation, and among them, ⁇ -alanine represented by the following formula (II), An N-alkanoyl- ⁇ -alanine derivative represented by the formula (III) and an N-alkanoyl-L-carnosine derivative represented by the following formula (IV) are safe to the human body, inexpensive, This is preferable in that it is practically used in combination with carnosines.
  • R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.
  • R 2 represents a hydrogen atom or a lower alkyl group
  • R 3 represents an alkyl group having 2 or more carbon atoms.
  • R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.
  • the lower alkyl group include linear or branched lower alkyl groups, and specifically include a methyl group having 1 to 6 carbon atoms, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec-butyl group, tert-butyl group, heptyl group, hexyl group and the like.
  • R 3 represents an alkyl group having 2 or more carbon atoms.
  • alkyl group having 2 or more carbon atoms examples include linear or branched alkyl groups having 2 or more carbon atoms, and specifically include, for example, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl, sec-butyl, tert-butyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl Group, nonadecyl group, eicosyl group and the like.
  • the carbon number is preferably 30 or less.
  • N-alkanoyl- ⁇ -alanine derivatives represented by the above formula (III) include N-formyl- ⁇ -alanine, N-acetyl- ⁇ -alanine, N-propionyl- ⁇ -alanine, N-butyryl- ⁇ -alanine, N- (2-methylpropionyl) - ⁇ -alanine, N-pentanoyl- ⁇ -alanine, N-hexanoyl- ⁇ -alanine, N-heptanoyl- ⁇ -alanine, or esters thereof (eg, methyl esters , Lower alkyl esters such as ethyl ester) and the like. Of these, N-acetyl- ⁇ -alanine is preferred.
  • the N-alkanoyl- ⁇ -alanine derivative is a known compound or is produced from ⁇ -alanine represented by the above formula (II) by a method known per se using a known acylating agent or esterifying agent. can do.
  • N-alkanoyl-L-carnosine derivative represented by the above formula (IV) examples include N-propionyl-L-carnosine, N- (2-methylpropionyl) -L-carnosine, N-butyryl-L-carnosine. N- (2-methylpropionyl) -L-carnosine, N-pentanoyl-L-carnosine, N-hexanoyl-L-carnosine, N-heptanoyl-L-carnosine or esters thereof (for example, methyl ester, ethyl ester, etc.) Lower alkyl ester) and the like.
  • the above N-alkanoyl-L-carnosine derivative is a known compound or can be produced from L-carnosine represented by the formula (I) by a method known per se using a known acylating agent or esterifying agent. can do.
  • carnosinase inhibitors represented by the above formulas (II), (III) and (IV)
  • the compounds described below can also be used as carnosinase inhibitors to achieve the object of the present invention.
  • examples of such compounds include ⁇ -amino acid derivatives (for example, ⁇ -aminobutyrylhistamine), thiol-type reducing agents (for example, unitythiol, dithiothreitol, 2-mercaptoethanol, etc.), prolinase substrates (for example, L-proline-containing peptides such as L-Pro-L-His and derivatives thereof).
  • hydrophobic vitamins having branched hydrocarbon chains such as vitamin A and vitamin E can be used as carnosinase inhibitors.
  • L-carnosine used in the preventive or therapeutic agent for hyperlipidemia of the present invention include, for example, L-carnosine, L-anserine, L-valenin, L-homocarnosine, carcinin or acyl derivatives thereof (for example, N-acetyl-L-carnosine, N-acetyl-L-anserine, N-acetyl-L-homocarnosine, etc.).
  • the acyl derivative can be produced by a method known per se using a known acylating agent.
  • the dosage form of the prophylactic or therapeutic agent for hyperlipidemia of the present invention depends on the purpose of use, for example, preparations for oral administration such as tablets, capsules, granules, troches, powders, syrups, etc., or injections, Examples include preparations for parenteral administration such as drops and suppositories. These preparations are made of excipients (eg lactose, sucrose, glucose, mannitol, sorbitol, corn starch, potato starch, crystalline cellulose, gum arabic, dextran, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, calcium carbonate, phosphoric acid.
  • excipients eg lactose, sucrose, glucose, mannitol, sorbitol, corn starch, potato starch, crystalline cellulose, gum arabic, dextran, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, calcium carbonate, phosphoric acid.
  • lubricant eg stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica etc.
  • binder eg hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol etc.
  • disintegration Agents for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch, carboxymethyl starch sodium, Bridge additives such as polyvinyl pyrrolidone), stabilizers (eg, methyl paraben, propyl paraben, benzyl alcohol, etc.), flavoring agents (eg, commonly used sweeteners, acidulants, fragrances, etc.), and diluents. It can be produced according to a method known per se.
  • preparations for intravascular administration such as injections and drops are preferably prepared using an aqueous medium that is isotonic with body fluids.
  • an injection can be prepared as a solution, suspension or dispersion together with an appropriate auxiliary agent according to a conventional method using an aqueous medium selected from a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. .
  • Suppositories for enteral administration can be prepared using a carrier such as cacao butter, hydrogenated fat or hydrogenated carboxylic acid, for example.
  • the prophylactic or therapeutic agent for hyperlipidemia of the present invention has a function of reducing the free fatty acid concentration in plasma of mammals including humans. And by this action of reducing the free fatty acid concentration in plasma, it can be used not only for the prevention or treatment of hyperlipidemia, but also as a preventive or therapeutic agent for diseases associated with an increase in free fatty acid in plasma.
  • diseases related to free fatty acid include metabolic syndrome, obesity, diabetes, hypertension, hypercholesterolemia, fatty liver, heart failure, angina, myocardial infarction, arteriosclerosis and the like.
  • the prevention according to the present invention includes not only completely suppressing the onset of the disease but also suppressing the progression of the disease, and the treatment includes not only resolving the disease but also improving the disease.
  • the anti-fatigue agent of the present invention contains a carnosinase inhibitor and L-carnosines.
  • the carnosinase inhibitor and L-carnosine used in the anti-fatigue agent of the present invention are the same as the carnosinase inhibitor and L-carnosine used in the above-mentioned preventive or therapeutic agent for hyperlipidemia.
  • Anti-fatigue in the present invention means less fatigue, less fatigue, and recovery from fatigue.
  • fatigue is fatigue caused by an increase in plasma lactic acid concentration, and the anti-fatigue effect is to suppress the increase in plasma lactic acid concentration, or to reduce the plasma lactic acid concentration, This includes not declining athletic ability.
  • the dosage form and production method of the anti-fatigue agent of the present invention are the same as the dosage form and production method of the prophylactic or therapeutic agent for hyperlipidemia described above.
  • the dosage of the prophylactic or therapeutic agent for hyperlipidemia of the present invention and the anti-fatigue agent varies depending on the type of disease, symptoms, age, administration method, etc.
  • the dosage is The carnosinase inhibitor may be in the range of about 50-1500 mg / day, and the L-carnosines may be in the range of about 50-1000 mg / day.
  • the carnosinase inhibitor is in the range of about 100-1000 mg / day.
  • L-carnosine is preferably in the range of about 100 to 600 mg / day.
  • count of administering the daily required amount may be administered once and may be divided and administered in several times.
  • the agent for preventing or treating hyperlipidemia of the present invention and anti-fatigue agent are administered to other mammals, the dose may be the same as the above-mentioned human dose or about 1 to 10 times. preferable.
  • the prophylactic or therapeutic agent for hyperlipidemia and the anti-fatigue agent of the present invention include a cellulose derivative (eg, hydroxypropylcellulose), gelatin, etc. in order to increase the absorption of carnosinase inhibitor and / or L-carnosine. It preferably contains at least one selected from dextrin, lactose, starch and polyvinylpyrrolidone.
  • the preventive or therapeutic agent for hyperlipidemia and the anti-fatigue agent of the present invention are composed of ingredients that are safe for the human body, so that they can be safely taken over a long period of time, and functional foods other than the above-described pharmaceutical composition. It can also be widely used as a raw material for health supplements, foods and drinks, and the like.
  • Example 1 swimming experiment using mice ⁇ -alanine and L-carnosine (Hamari Pharmaceutical Co., Ltd.) were used as carnosinase inhibitors and L-carnosines as test substances.
  • mice A swimming test using mice evaluated the effects of carnosinase inhibitors, L-carnosines, and the combined use of carnosinase inhibitors and L-carnosines.
  • Sld ddY male mice (5 weeks old) were purchased from CLEA Japan, and acclimated in the test environment for 1 week, and then animals that showed normal growth were subjected to the test. The mice were divided into 4 groups as shown in Table 1 below with 15 animals per group so that the body weight and swimming time were equal. Samples were administered by oral gavage once a day using a sonde 5 days a week. The sample dose was 0.3 ml each time, and each component was contained in each sample as shown in Table 1 below.
  • mice were allowed to swim with a weight of 10% of the body weight, and the time until the head was submerged for 5 seconds under the surface of the water was measured to determine the swimming time.
  • the body weight and swimming time of each mouse were measured every week, and the glucose concentration, lactic acid concentration, and free fatty acid concentration in plasma were measured 5 weeks after the start of the experiment.
  • mice were allowed to swim for 15 minutes with a 5% body weight after fasting for 14 hours, and blood was collected from the tail before, during and after exercise. Measured.
  • FIGS. In the figure, the values are shown as mean ⁇ SE of each group. 1, 2 and 4, * indicates p ⁇ 0.05 with respect to the A group, and in FIGS. 1 and 4 *** indicates that p ⁇ 0.005 with respect to the A group.
  • Statistical differences between control (Group A) and B, C, D groups were evaluated using T-test (T test).
  • FIG. 1 is a graph showing the free fatty acid concentration in the plasma of a mouse that has been swimming
  • FIG. 2 is a graph showing the lactic acid concentration in the plasma of a mouse that has been swimming
  • FIG. It is a graph which shows glucose concentration. From FIG.
  • FIG. 4 is a graph showing changes in the swimming time of mice
  • FIG. 5 is a graph showing changes in body weight. From FIG. 4, in the fourth week, group C (***) to which ⁇ -alanine (900 mg / kg) was administered, and D to which L-carnosine (600 mg / kg) and ⁇ -alanine (900 mg / kg) were administered. It can be seen that the swimming time of the mice in the group (*) was significantly higher than that in the control group A. From FIG. 5, it can be seen that no significant change was observed in any group with respect to body weight.
  • Example 2 Preparation of oral capsule preparation (Part 1) An oral capsule preparation was produced in a manner known per se. The following components are contained in one gelatin or HMPC capsule. L-carnosine 100mg ⁇ -Alanine 150mg
  • Example 3 Preparation of oral capsule preparation (2) An oral capsule preparation was produced in a manner known per se. The following components are contained in one gelatin or HMPC capsule. L-carnosine 50mg ⁇ -Alanine 100mg Citric acid 100mg
  • the prophylactic or therapeutic agent for hyperlipidemia of the present invention is useful for reducing the free fatty acid concentration in the plasma of mammals, and the anti-fatigue agent of the present invention reduces the lactic acid concentration in plasma and has excellent fatigue. Useful for reducing, promoting fatigue recovery and improving endurance.

Abstract

Disclosed are: a prophylactic or therapeutic agent for hyperlipemia, which contains a carnosinase inhibitor and L-carnosines; and an anti-fatigue agent which contains a carnosinase inhibitor and L-carnosines. The free fatty acid concentration in the plasma of a mammal can be decreased by the combined use of a carnosinase inhibitor and L-carnosines. In addition, the lactic acid concentration in the plasma can be decreased by the combined use of a carnosinase inhibitor and L-carnosines, thereby reducing fatigue, enhancing recovery from fatigue and improving endurance. Preferable examples of the carnosinase inhibitor may include β-alanine, N-alkanoyl-β-alanine derivatives, N-alkanoyl-L-carnosine derivatives and the like, and preferable examples of the L-carnosines may include L-carnosine, N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-balenine, L-homocarnosine, N-acetyl-L-homocarnosine, carcinine and the like.

Description

高脂血症の予防または治療剤、および抗疲労剤Preventive or therapeutic agent for hyperlipidemia, and anti-fatigue agent
　本発明は、カルノシナーゼ阻害剤およびＬ－カルノシン類を含む高脂血症の予防または治療剤、ならびに抗疲労剤に関する。 The present invention relates to a prophylactic or therapeutic agent for hyperlipidemia containing a carnosinase inhibitor and L-carnosines, and an anti-fatigue agent.
　ヒトおよび他の哺乳動物組織の構造および機能が加齢と共に低下する原因の一つとして、細胞にダメージを与え、また過酸化を引き起こし、老化を進めるのが活性酸素・フリーラジカルと考えられている。その老化および細胞の障害による病状の発症を予防する、またはできるだけ少なくするため、すなわち長寿のためには、種々の体組織又は細胞内、あるいは血漿および血流を含む体液において、天然抗酸化剤（フリーラジカル捕捉剤）を高濃度に維持して、該抗酸化剤を器官、組織および細胞に供給することが重要である。 Reactive oxygen and free radicals are thought to cause damage to cells, cause peroxidation, and promote aging as one of the causes of the decline in structure and function of human and other mammalian tissues with aging . In order to prevent or minimize the onset of pathological conditions due to its aging and cellular damage, i.e. for longevity, natural antioxidants (in various body tissues or cells or in body fluids including plasma and blood flow) It is important to maintain a high concentration of free radical scavengers and to supply the antioxidant to organs, tissues and cells.
　以下の式（Ｉ）で示されるＬ－カルノシン（β－アラニル－Ｌ－ヒスチジン）は、脊椎動物の骨格筋の非蛋白画分（例えば、非特許文献１、２）、嗅覚上皮および嗅覚球のような他組織（例えば、非特許文献３）および水晶体（非特許文献４）に存在し、最も豊富（１－２０ｍＭ）な窒素系化合物の一つであることが分かっている。 L-carnosine (β-alanyl-L-histidine) represented by the following formula (I) is a non-protein fraction of vertebrate skeletal muscle (eg, Non-Patent Documents 1 and 2), olfactory epithelium and olfactory bulb It has been found to be one of the most abundant (1-20 mM) nitrogenous compounds present in such other tissues (eg, Non-Patent Document 3) and lens (Non-Patent Document 4).
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　いくつかの他のＬ－カルノシン関連天然物、例えば、Ｎ－アセチル－Ｌ－カルノシン、Ｌ－アンセリン（β－アラニル－Ｌ－３－メチルヒスチジン）及びそのＮ－アセチル誘導体、Ｌ－バレニン（β－アラニル－Ｌ－１－メチルヒスチジン）、Ｌ－ホモカルノシン（γ－アミノブチリル－Ｌ－ヒスチジン）及びそのＮ－アセチル誘導体、カルシニン（β－アラニルヒスタミン）（例えば、非特許文献５、６、７）等は、その分布、活性および代謝性変換に興味ある違いがあるが（例えば、非特許文献８）、数種の哺乳動物の骨格筋、心臓および脳等の組織にミリモル濃度で存在していることが報告されている（例えば、非特許文献９）。 Several other L-carnosine related natural products such as N-acetyl-L-carnosine, L-anserine (β-alanyl-L-3-methylhistidine) and its N-acetyl derivative, L-valenine (β- Alanyl-L-1-methylhistidine), L-homocarnosine (γ-aminobutyryl-L-histidine) and its N-acetyl derivative, calcinin (β-alanylhistamine) (for example, Non-Patent Documents 5, 6, 7) Have interesting differences in their distribution, activity and metabolic transformation (eg, Non-Patent Document 8), but are present in millimolar concentrations in tissues such as skeletal muscle, heart and brain of several mammals. (For example, Non-Patent Document 9).
　上記したＬ－カルノシン及びその関連天然物質は、最も重要な天然抗酸化剤として、細胞膜あるいは生体膜の脂質層及び水性環境において、脂質及び蛋白質（酵素を含む）、ＤＮＡ及びその他の必須高分子等の水溶性分子が、活性酸素種および脂質過酸化物により損傷を受けるのを保護する作用を有することが知られている（非特許文献９、１０、１１、１２）。 The aforementioned L-carnosine and related natural substances are the most important natural antioxidants, such as lipids and proteins (including enzymes), DNA and other essential polymers in the lipid layer and aqueous environment of cell membranes or biological membranes. It is known that these water-soluble molecules have an action of protecting them from being damaged by reactive oxygen species and lipid peroxides (Non-Patent Documents 9, 10, 11, 12).
　ＳＯＤ（スーパーオキサイドジスムターゼ）あるいはカタラーゼ等の種々の抗酸化酵素は、水性環境下のみでその基質と反応する。また、Ｌ－カルノシン及びその関連天然物質は、水酸基ラジカル、スーパーオキサイド及び一重項酸素を捕捉し、脂質の過酸化を抑制する作用を有することを示している（例えば、非特許文献１３，１４）。 Various antioxidant enzymes such as SOD (superoxide dismutase) or catalase react with the substrate only in an aqueous environment. In addition, L-carnosine and related natural substances have an action of capturing hydroxyl radicals, superoxide and singlet oxygen and suppressing lipid peroxidation (for example, Non-patent Documents 13 and 14). .
　Ｌ－カルノシン類の生理学的な性質については、以下に更に詳細に説明する。
　１）Ｌ－カルノシン及びその天然に存在する関連化合物は、市販されている細胞及び組織由来のＳＯＤのような酵素及びグルタチオンやセルロプラスミンのような抗酸化システムを不活性化から保護している。水溶性のＬ－カルノシンは、肝臓ミクロソームにおいて脂質過酸化の際、脂質可溶性のα－トコフェロールの抗酸化作用を増強させる。それ故、Ｌ－カルノシンは肝臓チトクロームＰ－４５０の系の主要な保護物質である。Ｌ－カルノシンは細胞染色体を酸化による障害から明らかに保護することが知られている唯一の抗酸化剤である。こうした抗酸化作用は、動脈硬化、虚血性疾患（例えば脳梗塞、一過性脳虚血発作、脳卒中、狭心症、心筋梗塞等）、白内障の発症と進行、及び筋肉及び皮膚の老化の予防に有用である。また、Ｌ－カルノシンは脳の神経変性疾患（例えば、アルツハイマー病、痴呆、てんかん等）を改善することも知られている。最近、Ｌ－カルノシン、グルタチオン、スパーオキサイドジスムターゼ（ＳＯＤ）のような抗酸化系における機能不全は、後シナプスのグルタミン酸受容体（ＮＭＤＡおよびＡＭＰＡ）の過剰刺激を齎し、精神***病、パーキンソン氏病、ハンチントン舞踏病、筋萎縮性側索硬化症等の発症及び進行に繋がると推測されている（例えば、非特許文献１５）。Ｌ－カルノシンの補填は、こうした疾患の予防及び治療に有用な方法と考えられる。 The physiological properties of L-carnosine will be described in more detail below.
1) L-carnosine and its naturally occurring related compounds protect commercially available enzymes such as SOD from cells and tissues and antioxidant systems such as glutathione and ceruloplasmin from inactivation. Water soluble L-carnosine enhances the antioxidant action of lipid soluble α-tocopherol upon lipid peroxidation in liver microsomes. Therefore, L-carnosine is the main protector of the liver cytochrome P-450 system. L-carnosine is the only antioxidant known to clearly protect cellular chromosomes from oxidative damage. These antioxidant effects prevent arteriosclerosis, ischemic diseases (eg cerebral infarction, transient cerebral ischemic attack, stroke, angina pectoris, myocardial infarction, etc.), onset and progression of cataracts, and aging of muscles and skin. Useful for. L-carnosine is also known to improve brain neurodegenerative diseases (eg, Alzheimer's disease, dementia, epilepsy, etc.). Recently, dysfunction in antioxidant systems such as L-carnosine, glutathione, superoxide dismutase (SOD) has led to overstimulation of post-synaptic glutamate receptors (NMDA and AMPA), resulting in schizophrenia, Parkinson's disease, It is speculated that it will lead to the onset and progression of Huntington's disease, amyotrophic lateral sclerosis, etc. (for example, Non-Patent Document 15). L-carnosine supplementation is considered a useful method for the prevention and treatment of these diseases.
　２）Ｌ－カルノシンはこれまでに発見された最も優れた抗グリケーション剤であって、所謂メイラード反応、すなわち蛋白質の直接的グリケーション及び蛋白質の架橋といったアドバンスドグリケーション反応を阻害することが知られている。そのため、Ｌ－カルノシンは、糖尿病性網膜症、糖尿病性腎症、糖尿病性神経症のみならず、脈管系組織の老化（例えば動脈硬化症、網膜症等）、皮膚の老化（例えばしわ）あるいは水晶体の老化（例えば白内障）等の種々の組織の老化を防止することが期待できる。最近、発癌性および毒性物質であるアクリルアミドが、調理中にメイラード反応により種々の食品の中に形成されることが報告されている（例えば、非特許文献１６，１７）。Ｌ－カルノシンを調理前の食品あるいは食料に添加することは、そのようなアクリルアミドの生成を抑制する有力な手段となると考えられる。 2) L-carnosine is the best anti-glycation agent discovered so far, and is known to inhibit so-called Maillard reaction, ie, advanced glycation reactions such as direct glycation of proteins and cross-linking of proteins. ing. Therefore, L-carnosine is not only diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, but also aging of vascular tissues (eg arteriosclerosis, retinopathy etc.), skin aging (eg wrinkles) or It can be expected to prevent aging of various tissues such as aging of the lens (for example, cataract). Recently, it has been reported that acrylamide, which is a carcinogenic and toxic substance, is formed in various foods by the Maillard reaction during cooking (for example, Non-Patent Documents 16 and 17). The addition of L-carnosine to foods or foods before cooking is considered to be an effective means for suppressing such acrylamide formation.
　３）Ｌ－カルノシンは膜安定化および組織修復作用を有しており、消化管の潰瘍性疾患（例えば、胃潰瘍、十二指腸潰瘍）あるいは皮膚の潰瘍性疾患の予防及び治療に効果的であることが判明している。また、傷や火傷の治療にも効果がある。 3) L-carnosine has a membrane stabilization and tissue repair action, and is effective in the prevention and treatment of gastrointestinal ulcerative diseases (eg, gastric ulcer, duodenal ulcer) or skin ulcerative diseases. It turns out. It is also effective in treating wounds and burns.
　４）Ｌ－カルノシンおよびその関連天然物は、脳のみならず心臓に対して抗虚血作用を有している。Ｌ－カルノシンは、心臓細胞のカルシウム応答を高めることにより、心臓の収縮力を増大させることが判明している。Ｌ－カルノシン注射は、虚血性発作の緊急治療に効果的であることが証明されている。 4) L-carnosine and related natural products have an anti-ischemic action not only on the brain but also on the heart. L-carnosine has been found to increase cardiac contractility by enhancing cardiac cell calcium response. L-carnosine injection has proven effective for emergency treatment of ischemic stroke.
　５）激しい運動による乳酸の蓄積と連動して大量のＨ＋が生成されるとき、Ｌ－カルノシンは筋肉中の酸バランスを緩衝する重要な役割を果たしている。従って、Ｌ－カルノシンは運動実行能力の改善に繋がる筋肉疲労の防止という役割を果たしている。Ｌ－カルノシンは、筋肉細胞膜が筋肉運動の酸性条件下、酸化されるのを防止している。最近の報告によると、筋肉中のＬ－カルノシン濃度は、平均体力と大いに相関している（例えば、非特許文献１８）。Ｌ－カルノシンは運動による疲労回復を劇的に改善することが証明されている（しかしながら、運動能力の増大、即ち、動作性の助長を意味するのではなく、むしろ運動に対する同化応答を容易ならしめるものである）。カルノシンは疲労後の筋肉収縮能力を迅速に回復させることが証明されている。 5) L-carnosine plays an important role in buffering the acid balance in muscle when a large amount of H + is produced in conjunction with lactic acid accumulation by intense exercise. Therefore, L-carnosine plays a role in preventing muscle fatigue that leads to improvement in exercise performance. L-carnosine prevents muscle cell membranes from being oxidized under the acidic conditions of muscle movement. According to a recent report, L-carnosine concentration in muscle is highly correlated with average physical fitness (eg, Non-patent Document 18). L-carnosine has been shown to dramatically improve fatigue recovery from exercise (however, it does not mean increased exercise capacity, i.e., promotes motility, but rather facilitates an anabolic response to exercise) ). Carnosine has been shown to quickly restore muscle contraction ability after fatigue.
　６）最近、Ｌ－カルノシンが一酸化窒素合成酵素（ＮＯＳ）の本当の基質のようであると言われている。Ｌ－カルノシンの補給は、内因性の血管緊張緩和物質である一酸化窒素（ＮＯ）の合成を刺激して、血圧を下げたり、狭心症のような虚血性疾患を予防したりすることが期待されている。 6) Recently, it is said that L-carnosine seems to be a real substrate of nitric oxide synthase (NOS). L-carnosine supplementation may stimulate the synthesis of nitric oxide (NO), an endogenous vasorelaxant, to lower blood pressure and prevent ischemic diseases such as angina. Expected.
　７）Ｌ－カルノシンは、アルコール飲料（例えばウイスキー、コニャック、ウオッカ、ビール、酒、ワイン等）を消費したときのエタノール代謝の主要産物であるアセトアルデヒドの捕捉剤として有効である（例えば、非特許文献１９）。従って、Ｌ－カルノシンは肝臓、脳あるいは筋肉をアセトアルデヒドの毒性から保護している。また、傷を治癒させる作用があるため、Ｌ－カルノシンは、アルコール消費によって増悪する粘膜の糜爛や消化性潰瘍の治療および予防に有効である。 7) L-carnosine is effective as a scavenger for acetaldehyde, which is a major product of ethanol metabolism when alcoholic beverages (eg, whiskey, cognac, vodka, beer, liquor, wine, etc.) are consumed (for example, non-patent literature) 19). Therefore, L-carnosine protects the liver, brain or muscle from acetaldehyde toxicity. In addition, L-carnosine is effective in treating and preventing mucosal fistula and peptic ulcer exacerbated by alcohol consumption because it has a healing effect on wounds.
　８）慢性のアルコール性骨格筋障害は、ＩＩ型繊維の選択的萎縮に特徴があり、全アルコール濫用者の２／３までが影響を受けている。Ｌ－カルノシンは、繊維の萎縮を予防する。すなわちＬ－カルノシンは脂質過酸化のみならず過度のアルコール摂取によって起こる障害からも脳を保護している。 8) Chronic alcoholic skeletal muscle disorder is characterized by selective atrophy of type II fibers, affecting up to 2/3 of all alcohol abusers. L-carnosine prevents fiber atrophy. That is, L-carnosine protects the brain not only from lipid peroxidation but also from damage caused by excessive alcohol consumption.
　９）Ｌ－カルノシンは、免疫賦活作用を有し、ハイドロコーチゾン、抗腫瘍剤あるいはその他の多くの免疫抑制剤による免疫抑制から免疫系を保護している。 9) L-carnosine has an immunostimulatory action and protects the immune system from immunosuppression by hydrocortisone, antitumor agents or many other immunosuppressive agents.
　１０）健康と若さを保つためにＬ－カルノシンは次のような利点を有している。Ｌ－カルノシンおよびその関連化合物は、細胞***回数（ヘイフリックの限界）を増やし、生存期間の延長あるいは長寿に有用かも知れない（例えば、非特許文献２０）。Ｌ－カルノシンは、結合組織の若返り効果および傷の治療効果を有している。Ｌ－カルノシンを添加した組織培養系において、細胞は若い外観を保ち、その生存期間が延長した。このＬ－カルノシンが有する細胞生存期間を増大させるという能力は、老化細胞に対しても当てはまり、ある実験ではＬ－カルノシン添加により細胞の生存期間が６７％延長された。マウスを用いたｉｎ　ｖｉｖｏ試験でも証明され、Ｌ－カルノシンを投与されたマウスは、コントロールのマウスに比べ平均２０％長く生存し、年を取ってもコントロールのマウスよりも２倍以上健康な状態を保っていた。ヒトにおいては、Ｌ－カルノシン血中濃度は加齢と共に下がり、筋肉中のＬ－カルノシン濃度は、１０歳から７０歳までの間に６３％減少する。 10) L-carnosine has the following advantages to maintain health and youth. L-carnosine and its related compounds increase the number of cell divisions (limit of Hayflick) and may be useful for prolonging survival or longevity (for example, Non-patent Document 20). L-carnosine has a connective tissue rejuvenation effect and wound healing effect. In the tissue culture system supplemented with L-carnosine, the cells remained young and their survival was extended. This ability of L-carnosine to increase cell survival was also applicable to senescent cells, and in some experiments, addition of L-carnosine extended cell survival by 67%. Proven in an in vivo test using mice, mice administered with L-carnosine survived an average of 20% longer than control mice, and are more than twice as healthy as control mice over time. I kept it. In humans, L-carnosine blood levels decrease with age, and L-carnosine levels in muscle decrease by 63% between the ages of 10 and 70 years.
　一方、外因性のカルノシンは、代表的な例として眼に局所投与した場合でも尿中に容易に***されるか、またはカルノシナーゼと呼ばれる酵素で分解されるので、組織には蓄積されない。このカルノシナーゼは、血漿、前方眼房の房水、肝臓、腎臓あるいは他の組織中に存在し、筋肉中には存在しないが（例えば、非特許文献２１、２２）、水晶体には存在している（例えば、非特許文献２３、２４）。Ｎ－アセチル－Ｌ－カルノシン、Ｌ－アンセリン、Ｎ－アセチル－Ｌ－アンセリン、Ｌ－バレニン、Ｌ－ホモカルノシン、Ｎ－アセチル－Ｌ－ホモカルノシンまたはカルシニン等のＬ－カルノシン関連天然物質は、加水分解速度がＬ－カルノシンよりも遅いけれども、カルノシナーゼにより加水分解または不活化される基質となり得る（例えば、非特許文献２５）。 On the other hand, exogenous carnosine, as a typical example, is easily excreted in urine or decomposed by an enzyme called carnosinase even when locally administered to the eye, and thus does not accumulate in tissues. This carnosinase is present in plasma, an aqueous humor of the anterior chamber of the eye, liver, kidney or other tissues, but not in muscle (for example, Non-Patent Documents 21 and 22), but is present in the lens. (For example, nonpatent literature 23 and 24). L-carnosine related natural substances such as N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-valenine, L-homocarnosine, N-acetyl-L-homocarnosine or carcinine Although the degradation rate is slower than that of L-carnosine, it can be a substrate that is hydrolyzed or inactivated by carnosinase (for example, Non-Patent Document 25).
　上述したように、老化あるいは栄養失調等で体の中にＬ－カルノシンおよび／またはその関連天然物質が不足すると、ヒトおよびその他の哺乳動物においては、体の様々な機能不全をもたらす。Ｌ－カルノシンまたはその関連天然物質の補給は、それ故、こうした機能不全あるいはそれから派生する疾患の治療または予防に有用であると考えられる。また、Ｌ－カルノシンおよび／またはその関連天然物質を過剰に補給することにより、こうした疾患の治療、運動能力の改善、老化の防止、皮膚の治療、生活の質（ＱＯＬ）の向上等に意義があるものと考えられる。Ｌ－カルノシンは栄養補助食品として、あるいは化粧品として数ケ国においてすでに使用されているが、上述したようにＬ－カルノシンはいわゆるカルノシナーゼという酵素（血清型および組織型の二形態がある）により容易に加水分解されてβ－アラニンおよびＬ－ヒスチジンになり、Ｌ－カルノシンの生理的活性を完全に失うので、これらの製品は非常に有効であるとは考えられない。カルノシナーゼはヒトおよびその他の哺乳動物の小腸の内腔、血漿およびその他の組織中に広く分布しているので、経口的、非経口的あるいは局所的な投与方法に関係なく、上記した目的、即ち疾患の治療、運動能力の改善、老化の防止、皮膚の手入れ（スキンケア）、ＱＯＬの改善等を達成するためには、大過剰のＬ－カルノシンを投与して該酵素を飽和させ、投与したＬ－カルノシンが完全に加水分解されるのを防止することが推奨されている。
　また、Ｌ－カルノシンまたはその関連天然物質を分解することなく目標器官へ効果的に送達させる安全な方法としてカルノシナーゼ阻害剤の併用が有効であることが報告されている（特許文献１）。ベスタチンが強力な組織カルノシナーゼ阻害剤（非特許文献２６）であること、および内因性組織Ｌ－カルノシンの蓄積はベスタチン処理により増大することは公知であったが、Ｌ－カルノシンとベスタチンとをｉｎ　ｖｉｖｏで同時に投与したときも、ベスタチンがＬ－カルノシンの標的器官への効果的な送達を支援し、さらにベスタチンとＬ－カルノシンの併用に抗癌作用があることが報告されている（特許文献１）。 As described above, a lack of L-carnosine and / or related natural substances in the body due to aging or malnutrition causes various dysfunctions of the body in humans and other mammals. Supplementation with L-carnosine or related natural substances is therefore considered useful for the treatment or prevention of such dysfunctions or diseases derived therefrom. In addition, excessive supplementation with L-carnosine and / or related natural substances has implications for the treatment of these diseases, improvement of exercise capacity, prevention of aging, skin treatment, improvement of quality of life (QOL), etc. It is thought that there is. Although L-carnosine has already been used in several countries as a dietary supplement or as a cosmetic product, as described above, L-carnosine is easily hydrolyzed by an enzyme called sonocarnase (there are two forms, serotype and tissue type). These products are not considered very effective because they are broken down into β-alanine and L-histidine and completely lose the physiological activity of L-carnosine. Because carnosinase is widely distributed in the lumen of the small intestine, plasma and other tissues of humans and other mammals, the above purpose, ie, disease, regardless of the method of oral, parenteral or topical administration. In order to achieve treatment, improvement of exercise capacity, prevention of aging, skin care (skin care), improvement of QOL, etc., a large excess of L-carnosine is administered to saturate the enzyme, and the administered L- It is recommended to prevent carnosine from being fully hydrolyzed.
Further, it has been reported that a combined use of a carnosinase inhibitor is effective as a safe method for effectively delivering L-carnosine or its related natural substance to a target organ without degrading (Patent Document 1). Although it was known that bestatin is a potent tissue carnosinase inhibitor (Non-patent Document 26) and that the accumulation of endogenous tissue L-carnosine is increased by treatment with bestatin, L-carnosine and bestatin are in vivo. It has been reported that bestatin supports effective delivery of L-carnosine to target organs, and that the combination of bestatin and L-carnosine has an anticancer effect even when administered simultaneously in (Patent Document 1). .
　しかしながら、カルノシナーゼ阻害剤およびＬ－カルノシン類を併用して摂取することが高脂血症の予防または治療に有効であること、また、カルノシナーゼ阻害剤およびＬ－カルノシン類を併用して摂取すると抗疲労効果が得られることについては全く知られていなかった。 However, taking carnosinase inhibitor and L-carnosine in combination is effective for the prevention or treatment of hyperlipidemia, and taking carnosinase inhibitor and L-carnosine in combination helps prevent fatigue It was not known at all that an effect could be obtained.
国際公開２００４－０６４８６６号公報International Publication No. 2004-064866
　本発明は、カルノシナーゼ阻害剤とＬ－カルノシン類との併用による新規な用途を見出すことを目的とし、さらに、カルノシナーゼ阻害剤およびＬ－カルノシン類を含む新規な高脂血症の予防または治療剤、ならびに、カルノシナーゼ阻害剤およびＬ－カルノシン類を含む新規な抗疲労剤を提供することを目的とする。 The present invention aims to find a novel use by combining a carnosinase inhibitor and L-carnosine, and further, a novel prophylactic or therapeutic agent for hyperlipidemia comprising a carnosinase inhibitor and L-carnosine, Another object of the present invention is to provide a novel anti-fatigue agent containing a carnosinase inhibitor and L-carnosines.
　本発明者らは、カルノシナーゼ阻害剤について精力的な研究を続けた結果、下記式（ＩＩ）で表されるβ－アラニン、下記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体、下記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体が安全かつ安価であって、Ｌ－カルノシン類との併用において血漿中の乳酸濃度、または遊離脂肪酸濃度を減少させる効果があることを知見した。 As a result of intensive research on carnosinase inhibitors, the present inventors have found that β-alanine represented by the following formula (II), N-alkanoyl-β-alanine derivative represented by the following formula (III), The N-alkanoyl-L-carnosine derivative represented by the following formula (IV) is safe and inexpensive, and has an effect of reducing the plasma lactic acid concentration or free fatty acid concentration in combination with L-carnosines. I found out.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。）
Figure JPOXMLDOC01-appb-C000009
 (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.)
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は炭素数２以上のアルキル基を表す。）
Figure JPOXMLDOC01-appb-C000010
 (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
　さらに、本発明者らは、カルノシナーゼ阻害剤とＬ－カルノシン類とを含む組成物が高脂血症の予防または治療に有用であること、また、カルノシナーゼ阻害剤とＬ－カルノシン類とを含む組成物が抗疲労作用を奏することを見出し、本発明を完成した。 Furthermore, the present inventors have found that a composition comprising a carnosinase inhibitor and L-carnosine is useful for the prevention or treatment of hyperlipidemia, and a composition comprising a carnosinase inhibitor and L-carnosine. The present invention was completed by finding that the product exhibits an anti-fatigue effect.
　すなわち、本発明は、
［１］カルノシナーゼ阻害剤およびＬ－カルノシン類を含む高脂血症の予防または治療剤、
［２］カルノシナーゼ阻害剤が、下記式（ＩＩ）で表されるβ－アラニン、下記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体、下記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体、γ－アミノ酸誘導体、チオール型還元剤、および分岐状炭化水素鎖を有する疎水性ビタミンから選ばれる少なくとも１種であることを特徴とする前記［１］に記載の高脂血症の予防または治療剤、
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
 （式中、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。）
Figure JPOXMLDOC01-appb-C000013
 （式中、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は炭素数２以上のアルキル基を表す。）
［３］Ｌ－カルノシン類が、Ｌ－カルノシン、Ｎ－アセチル－Ｌ－カルノシン、Ｌ－アンセリン、Ｎ－アセチル－Ｌ－アンセリン、Ｌ－バレニン、Ｌ－ホモカルノシン、Ｎ－アセチル－Ｌ－ホモカルノシンおよびカルシニンから選ばれる一種以上であることを特徴とする前記［１］または［２］に記載の高脂血症の予防または治療剤、
［４］Ｎ－アルカノイル－β－アラニン誘導体が、低級アルキル基でエステル化されていてもよいＮ－アセチル－β－アラニンであることを特徴とする前記［２］に記載の高脂血症の予防または治療剤、
［５］カルノシナーゼ阻害剤および／またはＬ－カルノシン類の吸収を上げるために、さらにセルロース誘導体、ゼラチン、デキストリン、乳糖、でんぷんおよびポリビニルピロリドンから選ばれる少なくとも１種を含むことを特徴とする前記［１］～［４］のいずれかに記載の高脂血症の予防または治療剤、
［６］高脂血症の予防または治療が血漿中の遊離脂肪酸濃度を低下させることによるものである前記［１］～［５］のいずれかに記載の高脂血症の予防または治療剤、
［７］高脂血症の予防または治療がメタボリックシンドローム、肥満、糖尿病、高血圧、高コレステロール血症、脂肪肝、心不全、狭心症、心筋梗塞、または動脈硬化の予防または治療である前記［１］～［６］のいずれかに記載の高脂血症の予防または治療剤、
［８］カルノシナーゼ阻害剤およびＬ－カルノシン類を含むことを特徴とする抗疲労剤、
［９］カルノシナーゼ阻害剤が、下記式（ＩＩ）で表されるβ－アラニン、下記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体、下記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体、γ－アミノ酸誘導体、チオール型還元剤、および分岐状炭化水素鎖を有する疎水性ビタミンから選ばれる少なくとも１種であることを特徴とする前記［８］に記載の抗疲労剤、
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
 （式中、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。）
Figure JPOXMLDOC01-appb-C000016
 （式中、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は炭素数２以上のアルキル基を表す。）
［１０］Ｌ－カルノシン類が、Ｌ－カルノシン、Ｎ－アセチル－Ｌ－カルノシン、Ｌ－アンセリン、Ｎ－アセチル－Ｌ－アンセリン、Ｌ－バレニン、Ｌ－ホモカルノシン、Ｎ－アセチル－Ｌ－ホモカルノシンおよびカルシニンから選ばれる少なくとも１種であることを特徴とする前記［８］または［９］に記載の抗疲労剤、
［１１］Ｎ－アルカノイル－β－アラニン誘導体が、低級アルキル基でエステル化されていてもよいＮ－アセチル－β－アラニンであることを特徴とする前記［９］に記載の抗疲労剤、
［１２］カルノシナーゼ阻害剤および／またはＬ－カルノシン類の吸収を上げるために、さらにセルロース誘導体、ゼラチン、デキストリン、乳糖、でんぷんおよびポリビニルピロリドンから選ばれる少なくとも１種を含むことを特徴とする前記［８］～［１１］のいずれかに記載の抗疲労剤、
［１３］抗疲労が血漿中の乳酸濃度を低下させる作用によることを特徴とする前記［８］～［１２］のいずれかに記載の抗疲労剤、および
［１４］抗疲労が持久力を増強させる作用によることを特徴とする前記［８］～［１２］のいずれかに記載の抗疲労剤、
に関する。 That is, the present invention
[1] A prophylactic or therapeutic agent for hyperlipidemia comprising a carnosinase inhibitor and L-carnosines,
[2] Carnosinase inhibitor is β-alanine represented by the following formula (II), N-alkanoyl-β-alanine derivative represented by the following formula (III), N- The high fat according to [1] above, which is at least one selected from alkanoyl-L-carnosine derivatives, γ-amino acid derivatives, thiol-type reducing agents, and hydrophobic vitamins having a branched hydrocarbon chain Preventive or therapeutic agent for blood pressure,
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
 (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.)
Figure JPOXMLDOC01-appb-C000013
 (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
[3] L-carnosine is L-carnosine, N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-valenine, L-homocarnosine, N-acetyl-L-homocarnosine And a prophylactic or therapeutic agent for hyperlipidemia according to the above [1] or [2], which is one or more selected from calcinin,
[4] The hyperlipidemic condition according to [2], wherein the N-alkanoyl-β-alanine derivative is N-acetyl-β-alanine which may be esterified with a lower alkyl group. Preventive or therapeutic agent,
[5] The above-mentioned [1], further comprising at least one selected from cellulose derivatives, gelatin, dextrin, lactose, starch and polyvinylpyrrolidone in order to increase the absorption of the carnosinase inhibitor and / or L-carnosine. ] To a prophylactic or therapeutic agent for hyperlipidemia according to any of [4],
[6] The prophylactic or therapeutic agent for hyperlipidemia according to any one of the above [1] to [5], wherein the prevention or treatment of hyperlipidemia is by reducing the concentration of free fatty acid in plasma,
[7] The prevention or treatment of hyperlipidemia is prevention or treatment of metabolic syndrome, obesity, diabetes, hypertension, hypercholesterolemia, fatty liver, heart failure, angina pectoris, myocardial infarction, or arteriosclerosis [1] ] To a prophylactic or therapeutic agent for hyperlipidemia according to any of [6],
[8] An anti-fatigue agent comprising a carnosinase inhibitor and L-carnosines,
[9] The carnosinase inhibitor is a β-alanine represented by the following formula (II), an N-alkanoyl-β-alanine derivative represented by the following formula (III), an N— represented by the following formula (IV): The anti-fatigue according to [8] above, which is at least one selected from alkanoyl-L-carnosine derivatives, γ-amino acid derivatives, thiol-type reducing agents, and hydrophobic vitamins having a branched hydrocarbon chain Agent,
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
 (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.)
Figure JPOXMLDOC01-appb-C000016
 (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
[10] L-carnosine is L-carnosine, N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-valenine, L-homocarnosine, N-acetyl-L-homocarnosine And the anti-fatigue agent according to the above [8] or [9], which is at least one selected from calcinin,
[11] The anti-fatigue agent according to the above [9], wherein the N-alkanoyl-β-alanine derivative is N-acetyl-β-alanine which may be esterified with a lower alkyl group,
[12] The above-mentioned [8], further comprising at least one selected from cellulose derivatives, gelatin, dextrin, lactose, starch and polyvinylpyrrolidone in order to increase the absorption of carnosinase inhibitor and / or L-carnosines. ] To [11] the anti-fatigue agent according to any one of
[13] The anti-fatigue agent according to any one of [8] to [12] above, wherein anti-fatigue is due to an action of lowering plasma lactic acid concentration, and [14] anti-fatigue enhances endurance The anti-fatigue agent according to any one of [8] to [12], which is characterized by
About.
　また、本発明には以下の各発明も含まれる。
［１５］哺乳動物に対して、カルノシナーゼ阻害剤およびＬ－カルノシン類の有効量を投与する工程を包含することを特徴とする高脂血症の予防または治療方法。
［１６］高脂血症の予防または治療剤を製造するための、カルノシナーゼ阻害剤およびＬ－カルノシン類の使用。
［１７］高脂血症の予防または治療に使用するための、カルノシナーゼ阻害剤およびＬ－カルノシン類。
［１８］哺乳動物に対して、カルノシナーゼ阻害剤およびＬ－カルノシン類の有効量を投与する工程を包含することを特徴とする抗疲労方法。
［１９］抗疲労剤を製造するための、カルノシナーゼ阻害剤およびＬ－カルノシン類の使用。
［２０］抗疲労に使用するための、カルノシナーゼ阻害剤およびＬ－カルノシン類。 The present invention includes the following inventions.
[15] A method for preventing or treating hyperlipidemia, comprising a step of administering an effective amount of a carnosinase inhibitor and L-carnosine to a mammal.
[16] Use of a carnosinase inhibitor and L-carnosine for producing a prophylactic or therapeutic agent for hyperlipidemia.
[17] Carnosinase inhibitors and L-carnosines for use in the prevention or treatment of hyperlipidemia.
[18] An anti-fatigue method comprising a step of administering an effective amount of a carnosinase inhibitor and L-carnosine to a mammal.
[19] Use of a carnosinase inhibitor and L-carnosines for producing an anti-fatigue agent.
[20] Carnosinase inhibitors and L-carnosines for use in anti-fatigue.
　本発明によれば、血漿中の遊離脂肪酸濃度を低下させる高脂血症の予防または治療剤を提供することができる。本発明の血漿中の遊離脂肪酸濃度を低下させる働きは、高脂血症の予防または治療に有効であり、血漿中の遊離脂肪酸濃度の上昇に関連する疾患の予防または治療に有効である。
　また、本発明によれば、血漿中の乳酸濃度の増加を抑制もしくは血漿中の乳酸濃度を低下させる抗疲労剤を提供することができる。これらの働きにより、本発明の抗疲労剤は、優れた疲労軽減、疲労回復の促進作用を有し、持久力の向上作用を有する。
　本発明の高脂血症の予防または治療剤、および抗疲労剤は、人体に安全な成分から成るため、長期にわたって摂取しても安心で、医薬組成物または機能性食品として広く適用が可能である。 According to the present invention, it is possible to provide a prophylactic or therapeutic agent for hyperlipidemia that reduces the free fatty acid concentration in plasma. The action of reducing the free fatty acid concentration in the plasma of the present invention is effective in preventing or treating hyperlipidemia, and is effective in preventing or treating a disease associated with an increase in the free fatty acid concentration in plasma.
Moreover, according to this invention, the anti-fatigue agent which suppresses the increase in the lactic acid concentration in plasma or reduces the lactic acid concentration in plasma can be provided. By these functions, the anti-fatigue agent of the present invention has excellent fatigue reduction and fatigue recovery promoting effects, and an endurance improving effect.
Since the preventive or therapeutic agent for hyperlipidemia and the anti-fatigue agent of the present invention are composed of components that are safe for the human body, they can be used safely as a pharmaceutical composition or a functional food even when ingested over a long period of time. is there.
遊泳させたマウスの血漿中の遊離脂肪酸濃度を示すグラフである。It is a graph which shows the free fatty acid density | concentration in the plasma of the mouse | mouth made to swim. 遊泳させたマウスの血漿中の乳酸濃度を示すグラフである。It is a graph which shows the lactate density | concentration in the plasma of the mouse | mouth made to swim. 遊泳させたマウスの血漿中のグルコース濃度を示すグラフである。It is a graph which shows the glucose level in the plasma of the mouse | mouth made to swim. マウスの遊泳時間の変化を示すグラフである。It is a graph which shows the change of the swimming time of a mouse | mouth. マウスの体重の変化を示すグラフである。It is a graph which shows the change of the body weight of a mouse | mouth.
　本発明の高脂血症の予防または治療剤はカルノシナーゼ阻害剤およびＬ－カルノシン類を含むものである。
　本発明の高脂血症の予防または治療剤で用いられるカルノシナーゼ阻害剤としては、公知のカルノシナーゼ阻害剤を制限なく用いることができるが、中でも下記式（ＩＩ）で表されるβ－アラニン、下記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体、下記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体が人体に対して安全であり、安価であって、Ｌ－カルノシン類との併用において実用的である点で好ましい。 The prophylactic or therapeutic agent for hyperlipidemia of the present invention comprises a carnosinase inhibitor and L-carnosines.
As the carnosinase inhibitor used in the preventive or therapeutic agent for hyperlipidemia of the present invention, a known carnosinase inhibitor can be used without limitation, and among them, β-alanine represented by the following formula (II), An N-alkanoyl-β-alanine derivative represented by the formula (III) and an N-alkanoyl-L-carnosine derivative represented by the following formula (IV) are safe to the human body, inexpensive, This is preferable in that it is practically used in combination with carnosines.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
 （式中、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。）
Figure JPOXMLDOC01-appb-C000018
 (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.)
Figure JPOXMLDOC01-appb-C000019
 （式中、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は炭素数２以上のアルキル基を表す。）
Figure JPOXMLDOC01-appb-C000019
 (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
　上記式（ＩＩＩ）および（ＩＶ）において、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。低級アルキル基としては、例えば、直鎖状または分岐状の低級アルキル基等が挙げられ、具体的には炭素数１～６のメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ヘプチル基、ヘキシル基等が挙げられる。
　上記式（ＩＶ）において、Ｒ３は炭素数２以上のアルキル基を表す。炭素数２以上のアルキル基としては、例えば、炭素数２以上の直鎖状または分岐状のアルキル基等が挙げられ、具体的には、例えば、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基、ヘプタデシル基、オクタデシル基、ノナデシル基、エイコシル基等が挙げられる。その炭素数は３０以下であることが好ましい。 In the above formulas (III) and (IV), R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group. Examples of the lower alkyl group include linear or branched lower alkyl groups, and specifically include a methyl group having 1 to 6 carbon atoms, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec-butyl group, tert-butyl group, heptyl group, hexyl group and the like.
In the above formula (IV), R 3 represents an alkyl group having 2 or more carbon atoms. Examples of the alkyl group having 2 or more carbon atoms include linear or branched alkyl groups having 2 or more carbon atoms, and specifically include, for example, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl, sec-butyl, tert-butyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl Group, nonadecyl group, eicosyl group and the like. The carbon number is preferably 30 or less.
　上記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体としては、例えば、Ｎ－ホルミル－β－アラニン、Ｎ－アセチル－β－アラニン、Ｎ－プロピオニル－β－アラニン、Ｎ－ブチリル－β－アラニン、Ｎ－（２－メチルプロピオニル）－β－アラニン、Ｎ－ペンタノイル－β－アラニン、Ｎ－ヘキサノイル－β－アラニン、Ｎ－ヘプタノイル－β－アラニン、またはそれらのエステル（例えば、メチルエステル、エチルエステル等の低級アルキルエステル）等が挙げられる。中でもＮ－アセチル－β－アラニンが好ましい。上記Ｎ－アルカノイル－β－アラニン誘導体は、公知化合物であるか、公知のアシル化剤あるいはエステル化剤を使用するそれ自体公知の方法で、上記式（ＩＩ）で表されるβ－アラニンから製造することができる。 Examples of N-alkanoyl-β-alanine derivatives represented by the above formula (III) include N-formyl-β-alanine, N-acetyl-β-alanine, N-propionyl-β-alanine, N-butyryl- β-alanine, N- (2-methylpropionyl) -β-alanine, N-pentanoyl-β-alanine, N-hexanoyl-β-alanine, N-heptanoyl-β-alanine, or esters thereof (eg, methyl esters , Lower alkyl esters such as ethyl ester) and the like. Of these, N-acetyl-β-alanine is preferred. The N-alkanoyl-β-alanine derivative is a known compound or is produced from β-alanine represented by the above formula (II) by a method known per se using a known acylating agent or esterifying agent. can do.
　上記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体としては、例えば、Ｎ－プロピオニル－Ｌ－カルノシン、Ｎ－（２－メチルプロピオニル）－Ｌ－カルノシン、Ｎ－ブチリル－Ｌ－カルノシン、Ｎ－（２－メチルプロピオニル）－Ｌ－カルノシン、Ｎ－ペンタノイル－Ｌ－カルノシン、Ｎ－ヘキサノイル－Ｌ－カルノシン、Ｎ－ヘプタノイル－Ｌ－カルノシンまたはそれらのエステル（例えばメチルエステル、エチルエステル等の低級アルキルエステル）等が挙げられる。上記、Ｎ－アルカノイル－Ｌ－カルノシン誘導体は、公知化合物であるか、公知のアシル化剤あるいはエステル化剤を使用するそれ自体公知の方法により、式（Ｉ）で表されるＬ－カルノシンから製造することができる。 Examples of the N-alkanoyl-L-carnosine derivative represented by the above formula (IV) include N-propionyl-L-carnosine, N- (2-methylpropionyl) -L-carnosine, N-butyryl-L-carnosine. N- (2-methylpropionyl) -L-carnosine, N-pentanoyl-L-carnosine, N-hexanoyl-L-carnosine, N-heptanoyl-L-carnosine or esters thereof (for example, methyl ester, ethyl ester, etc.) Lower alkyl ester) and the like. The above N-alkanoyl-L-carnosine derivative is a known compound or can be produced from L-carnosine represented by the formula (I) by a method known per se using a known acylating agent or esterifying agent. can do.
　上記式（ＩＩ）、（ＩＩＩ）および（ＩＶ）で表されるカルノシナーゼ阻害剤の他に、以下に記載する化合物等もカルノシナーゼ阻害剤として本発明の目的達成のために使用できる。そのような化合物としては、例えば、γ－アミノ酸誘導体（例えば、γ－アミノブチリルヒスタミン等）、チオール型還元剤（例えば、ユニチオール、ジチオスレイトール、２－メルカプトエタノール等）、プロリナーゼ基質（例えば、Ｌ－Ｐｒｏ－Ｌ－Ｈｉｓ等のＬ－プロリン含有ペプチドおよびその誘導体等）等が挙げられる。
　さらに、例えば、ビタミンＡ、ビタミンＥ等の分岐状炭化水素鎖を有する疎水性ビタミン類をカルノシナーゼ阻害剤として使用することもできる。 In addition to the carnosinase inhibitors represented by the above formulas (II), (III) and (IV), the compounds described below can also be used as carnosinase inhibitors to achieve the object of the present invention. Examples of such compounds include γ-amino acid derivatives (for example, γ-aminobutyrylhistamine), thiol-type reducing agents (for example, unitythiol, dithiothreitol, 2-mercaptoethanol, etc.), prolinase substrates (for example, L-proline-containing peptides such as L-Pro-L-His and derivatives thereof).
Furthermore, for example, hydrophobic vitamins having branched hydrocarbon chains such as vitamin A and vitamin E can be used as carnosinase inhibitors.
　本発明の高脂血症の予防または治療剤で用いられるＬ－カルノシン類としては、例えば、Ｌ－カルノシン、Ｌ－アンセリン、Ｌ－バレニン、Ｌ－ホモカルノシン、カルシニンまたはそれらのアシル誘導体（例えば、Ｎ－アセチル－Ｌ－カルノシン、Ｎ－アセチル－Ｌ－アンセリン、Ｎ－アセチル－Ｌ－ホモカルノシン等）等が挙げられる。アシル誘導体は、公知のアシル化剤を使用してそれ自体公知の方法で製造することができる。 Examples of L-carnosine used in the preventive or therapeutic agent for hyperlipidemia of the present invention include, for example, L-carnosine, L-anserine, L-valenin, L-homocarnosine, carcinin or acyl derivatives thereof (for example, N-acetyl-L-carnosine, N-acetyl-L-anserine, N-acetyl-L-homocarnosine, etc.). The acyl derivative can be produced by a method known per se using a known acylating agent.
　本発明の高脂血症の予防または治療剤の剤型は使用目的に応じて、例えば、錠剤、カプセル剤、顆粒剤、トローチ剤、散剤、シロップ剤等の経口投与用製剤、あるいは注射剤、点滴剤、坐剤等の非経口投与用製剤等が挙げられる。これらの製剤は、賦形剤（例えば、乳糖、白糖、ブドウ糖、マンニトール、ソルビトール、トウモロコシデンプン、バレイショデンプン、結晶性セルロース、アラビアゴム、デキストラン、プルラン、軽質無水珪酸、合成珪酸アルミニウム、炭酸カルシウム、燐酸水素カルシウム等）、滑沢剤（例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、タルク、コロイドシリカ等）、結合剤（例えば、ヒドロキシプロピルセルロース、ヒドロキプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール等）、崩壊剤（例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチ、カルボキシメチルスターチナトリウム、架橋ポリビニルピロリドン等）、安定剤（例えば、メチルパラベン、プロピルパラベン、ベンジルアルコール等）、矯味矯臭剤（例えば、通常使用される甘味料、酸味料、香料等）、希釈剤等の添加剤を用いて自体公知の方法に従って製造することができる。 The dosage form of the prophylactic or therapeutic agent for hyperlipidemia of the present invention depends on the purpose of use, for example, preparations for oral administration such as tablets, capsules, granules, troches, powders, syrups, etc., or injections, Examples include preparations for parenteral administration such as drops and suppositories. These preparations are made of excipients (eg lactose, sucrose, glucose, mannitol, sorbitol, corn starch, potato starch, crystalline cellulose, gum arabic, dextran, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, calcium carbonate, phosphoric acid. Calcium hydrogen etc.), lubricant (eg stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica etc.), binder (eg hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol etc.), disintegration Agents (for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch, carboxymethyl starch sodium, Bridge additives such as polyvinyl pyrrolidone), stabilizers (eg, methyl paraben, propyl paraben, benzyl alcohol, etc.), flavoring agents (eg, commonly used sweeteners, acidulants, fragrances, etc.), and diluents. It can be produced according to a method known per se.
　非経口投与用製剤のうち注射剤や点滴剤等の血管内投与用製剤は、好ましくは体液と等張の水性媒体を用いて調製することができる。例えば、注射剤は、塩溶液、ブドウ糖溶液または塩溶液とブドウ糖溶液の混合物等から選ばれる水性媒体を用い、常法に従って適当な助剤とともに溶液、懸濁液または分散液として調製することができる。 Among the preparations for parenteral administration, preparations for intravascular administration such as injections and drops are preferably prepared using an aqueous medium that is isotonic with body fluids. For example, an injection can be prepared as a solution, suspension or dispersion together with an appropriate auxiliary agent according to a conventional method using an aqueous medium selected from a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. .
　腸内投与のための坐剤は、例えば、カカオ脂、水素化脂肪または水素化カルボン酸等の担体を用いて調製することができる。 Suppositories for enteral administration can be prepared using a carrier such as cacao butter, hydrogenated fat or hydrogenated carboxylic acid, for example.
　本発明の高脂血症の予防または治療剤は、ヒトを含む哺乳動物の血漿中の遊離脂肪酸濃度を低下させる働きがある。そして、この血漿中の遊離脂肪酸濃度を低下させる働きにより、高脂血症の予防または治療だけでなく、血漿中の遊離脂肪酸の上昇に関連する疾患の予防または治療剤として用いることもできる。遊離脂肪酸に関連する疾患としては、例えば、メタボリックシンドローム、肥満、糖尿病、高血圧、高コレステロール血症、脂肪肝、心不全、狭心症、心筋梗塞、動脈硬化等が挙げられる。
　本発明にいう予防は、疾患の発症を完全に抑えることのほか、疾患の進行を抑制することを含み、治療は、疾患が完快することのほか、疾患が改善することを含む。 The prophylactic or therapeutic agent for hyperlipidemia of the present invention has a function of reducing the free fatty acid concentration in plasma of mammals including humans. And by this action of reducing the free fatty acid concentration in plasma, it can be used not only for the prevention or treatment of hyperlipidemia, but also as a preventive or therapeutic agent for diseases associated with an increase in free fatty acid in plasma. Examples of the disease related to free fatty acid include metabolic syndrome, obesity, diabetes, hypertension, hypercholesterolemia, fatty liver, heart failure, angina, myocardial infarction, arteriosclerosis and the like.
The prevention according to the present invention includes not only completely suppressing the onset of the disease but also suppressing the progression of the disease, and the treatment includes not only resolving the disease but also improving the disease.
　本発明の抗疲労剤はカルノシナーゼ阻害剤およびＬ－カルノシン類を含むものである。
　本発明の抗疲労剤で用いられるカルノシナーゼ阻害剤およびＬ－カルノシン類は、上記した高脂血症の予防または治療剤で用いられるカルノシナーゼ阻害剤およびＬ－カルノシン類と同様である。
　本発明における抗疲労とは、疲れにくいこと、疲労を軽減すること、疲労から回復することを意味する。また、疲労とは血漿中の乳酸濃度が上昇することに起因する疲労であって、抗疲労作用には血漿中の乳酸濃度の上昇を抑制すること、または血漿中の乳酸濃度を減少させること、運動能力が低下しないことが含まれる。
　本発明の抗疲労剤の剤型および製造方法は上記した高脂血症の予防または治療剤の剤型および製造方法と同様である。 The anti-fatigue agent of the present invention contains a carnosinase inhibitor and L-carnosines.
The carnosinase inhibitor and L-carnosine used in the anti-fatigue agent of the present invention are the same as the carnosinase inhibitor and L-carnosine used in the above-mentioned preventive or therapeutic agent for hyperlipidemia.
Anti-fatigue in the present invention means less fatigue, less fatigue, and recovery from fatigue. In addition, fatigue is fatigue caused by an increase in plasma lactic acid concentration, and the anti-fatigue effect is to suppress the increase in plasma lactic acid concentration, or to reduce the plasma lactic acid concentration, This includes not declining athletic ability.
The dosage form and production method of the anti-fatigue agent of the present invention are the same as the dosage form and production method of the prophylactic or therapeutic agent for hyperlipidemia described above.
　本発明の高脂血症の予防または治療剤、および抗疲労剤の投与量は、疾患の種類、症状、年齢、投与方法等によって異なるが、例えば、経口投与用製剤の場合には投与量が、カルノシナーゼ阻害剤が約５０～１５００ｍｇ／日の範囲であり、Ｌ－カルノシン類が約５０～１０００ｍｇ／日の範囲であればよく、中でも、カルノシナーゼ阻害剤が約１００～１０００ｍｇ／日の範囲であり、Ｌ－カルノシン類が約１００～６００ｍｇ／日の範囲であることが好ましい。また、投与する回数としては、一日の必要量を１回で投与しても良いし、数回に分けて投与してもよい。
　本発明の高脂血症の予防または治療剤、および抗疲労剤のその他の哺乳動物に投与する場合は、上記したヒトの投与量と同じであるか、あるいは１～１０倍程度であることが好ましい。 The dosage of the prophylactic or therapeutic agent for hyperlipidemia of the present invention and the anti-fatigue agent varies depending on the type of disease, symptoms, age, administration method, etc. For example, in the case of a preparation for oral administration, the dosage is The carnosinase inhibitor may be in the range of about 50-1500 mg / day, and the L-carnosines may be in the range of about 50-1000 mg / day. Among them, the carnosinase inhibitor is in the range of about 100-1000 mg / day. L-carnosine is preferably in the range of about 100 to 600 mg / day. Moreover, as the frequency | count of administering, the daily required amount may be administered once and may be divided and administered in several times.
When the agent for preventing or treating hyperlipidemia of the present invention and anti-fatigue agent are administered to other mammals, the dose may be the same as the above-mentioned human dose or about 1 to 10 times. preferable.
　また、本発明の高脂血症の予防または治療剤、および抗疲労剤は、カルノシナーゼ阻害剤及び／又はＬ－カルノシン類の吸収を上げるために、セルロース誘導体（例えば、ヒドロキシプロピルセルロース等）、ゼラチン、デキストリン、乳糖、でんぷん及びポリビニルピロリドンから選ばれる少なくとも１種を含んでいることが好ましい。 In addition, the prophylactic or therapeutic agent for hyperlipidemia and the anti-fatigue agent of the present invention include a cellulose derivative (eg, hydroxypropylcellulose), gelatin, etc. in order to increase the absorption of carnosinase inhibitor and / or L-carnosine. It preferably contains at least one selected from dextrin, lactose, starch and polyvinylpyrrolidone.
　さらに、本発明の高脂血症の予防または治療剤、および抗疲労剤は、人体に安全な成分から成るため、長期にわたって摂取しても安心で、上記した医薬組成物以外にも機能性食品、健康補助食品、飲食品等の原料としても広く利用することができる。 Furthermore, the preventive or therapeutic agent for hyperlipidemia and the anti-fatigue agent of the present invention are composed of ingredients that are safe for the human body, so that they can be safely taken over a long period of time, and functional foods other than the above-described pharmaceutical composition. It can also be widely used as a raw material for health supplements, foods and drinks, and the like.
　以下、実施例で、本発明をさらに詳しく説明するが、本発明はこれらに限定されるものではない。 Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these.
〔実施例１〕マウスによる遊泳実験
　被験物質となるカルノシナーゼ阻害剤およびＬ－カルノシン類としては、β－アラニンおよびＬ－カルノシン（浜理薬品工業株式会社）を用いた。 [Example 1] Swimming experiment using mice β-alanine and L-carnosine (Hamari Pharmaceutical Co., Ltd.) were used as carnosinase inhibitors and L-carnosines as test substances.
　マウスを用いた遊泳試験により、カルノシナーゼ阻害剤、Ｌ－カルノシン類、およびカルノシナーゼ阻害剤とＬ－カルノシン類の併用の効果を評価した。
　Ｓｌｄ：ｄｄＹ雄性マウス（５週齢）を日本クレア株式会社より購入し、１週間試験環境で馴化させた後、順調な発育を示した動物を試験に供した。体重と遊泳時間が均等になるように１群１５匹で下記表１のようにマウスを４群に群分けした。サンプルの投与は週５日、１日１回ゾンデにて強制経口投与を行った。サンプルの投与量は毎回０．３ｍｌとし、各サンプル中に下記表１となるように各成分を含有させた。 A swimming test using mice evaluated the effects of carnosinase inhibitors, L-carnosines, and the combined use of carnosinase inhibitors and L-carnosines.
Sld: ddY male mice (5 weeks old) were purchased from CLEA Japan, and acclimated in the test environment for 1 week, and then animals that showed normal growth were subjected to the test. The mice were divided into 4 groups as shown in Table 1 below with 15 animals per group so that the body weight and swimming time were equal. Samples were administered by oral gavage once a day using a sonde 5 days a week. The sample dose was 0.3 ml each time, and each component was contained in each sample as shown in Table 1 below.
　マウスに体重の１０％の重りをつけて遊泳させ、頭部が水面下に５秒間水没するまでの時間を測定し、遊泳時間とした。一週間ごとに各マウスの体重と遊泳時間を測定し、実験開始から５週間後に血漿中のグルコース濃度、乳酸濃度、遊離脂肪酸濃度を測定した。血漿中のグルコース濃度、乳酸濃度、遊離脂肪酸濃度の測定は、１４時間の絶食後、マウスに体重の５％の重りをつけて１５分間遊泳させ、運動前、運動中、運動後に尾部より採血して測定した。 The mouse was allowed to swim with a weight of 10% of the body weight, and the time until the head was submerged for 5 seconds under the surface of the water was measured to determine the swimming time. The body weight and swimming time of each mouse were measured every week, and the glucose concentration, lactic acid concentration, and free fatty acid concentration in plasma were measured 5 weeks after the start of the experiment. For measurement of plasma glucose, lactate and free fatty acid concentrations, mice were allowed to swim for 15 minutes with a 5% body weight after fasting for 14 hours, and blood was collected from the tail before, during and after exercise. Measured.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　結果を図１～図５に示す。図中、値は各群の平均値±ＳＥを記載した。図１、２、４中、＊はＡ群に対してｐ＜０．０５であり、図１、４中、＊＊＊はＡ群に対してｐ＜０．００５であることを示す。コントロール（Ａ群）及びＢ、Ｃ、Ｄ群の間の統計的な差は、Ｔ－ｔｅｓｔ（Ｔ検定）を使用して評価した。
　図１は遊泳させたマウスの血漿中の遊離脂肪酸濃度を示すグラフであり、図２は遊泳させたマウスの血漿中の乳酸濃度を示すグラフであり、図３は遊泳させたマウスの血漿中のグルコース濃度を示すグラフである。
　図１より、Ｌ－カルノシン（６００ｍｇ／ｋｇ）を投与したＢ群（＊（２５分、４５分））、およびＬ－カルノシン（６００ｍｇ／ｋｇ）とβ－アラニン（９００ｍｇ／ｋｇ）を投与したＤ群（＊（１０分、４５分）、＊＊＊（２５分））のマウスの血漿中の遊離脂肪酸濃度がコントロールのＡ群のマウスと比較して有意に減少していることがわかる。
　図２より、Ｌ－カルノシン（６００ｍｇ／ｋｇ）とβ－アラニン（９００ｍｇ／ｋｇ）を投与したＤ群（＊（５分））のマウスの血漿中の乳酸濃度がコントロールのＡ群のマウスと比較して有意に減少していることがわかる。
　図３より、血漿中のグルコース濃度には有意な変化は見られなかったことがわかる。 The results are shown in FIGS. In the figure, the values are shown as mean ± SE of each group. 1, 2 and 4, * indicates p <0.05 with respect to the A group, and in FIGS. 1 and 4 *** indicates that p <0.005 with respect to the A group. Statistical differences between control (Group A) and B, C, D groups were evaluated using T-test (T test).
FIG. 1 is a graph showing the free fatty acid concentration in the plasma of a mouse that has been swimming, FIG. 2 is a graph showing the lactic acid concentration in the plasma of a mouse that has been swimming, and FIG. It is a graph which shows glucose concentration.
From FIG. 1, group B (* (25 minutes, 45 minutes)) administered with L-carnosine (600 mg / kg), and D administered with L-carnosine (600 mg / kg) and β-alanine (900 mg / kg). It can be seen that the free fatty acid concentration in the plasma of the mice of the group (* (10 minutes, 45 minutes), *** (25 minutes)) is significantly reduced compared to the mice of the control group A.
FIG. 2 shows that the plasma lactic acid concentration of the mice of Group D (* (5 minutes)) administered with L-carnosine (600 mg / kg) and β-alanine (900 mg / kg) is compared with that of the control Group A mice. It can be seen that the number is significantly decreased.
FIG. 3 shows that no significant change was observed in the plasma glucose concentration.
　図４はマウスの遊泳時間の変化を示すグラフであり、図５は体重の変化を示すグラフである。
　図４より、４週目において、β－アラニン（９００ｍｇ／ｋｇ）を投与したＣ群（＊＊＊）、およびＬ－カルノシン（６００ｍｇ／ｋｇ）とβ－アラニン（９００ｍｇ／ｋｇ）を投与したＤ群（＊）のマウスの遊泳時間が、コントロールのＡ群と比較して有意に高い値を示したことがわかる。
　図５より、体重に関してはいずれの群においても有意な変化は見られなかったことがわかる。 FIG. 4 is a graph showing changes in the swimming time of mice, and FIG. 5 is a graph showing changes in body weight.
From FIG. 4, in the fourth week, group C (***) to which β-alanine (900 mg / kg) was administered, and D to which L-carnosine (600 mg / kg) and β-alanine (900 mg / kg) were administered. It can be seen that the swimming time of the mice in the group (*) was significantly higher than that in the control group A.
From FIG. 5, it can be seen that no significant change was observed in any group with respect to body weight.
　以上の結果から、β－アラニンおよびＬ－カルノシンの併用摂取に血漿中の遊離脂肪酸濃度の上昇を抑制する作用、および血漿中の遊離脂肪酸濃度を下げる作用があることが確認され、またβ－アラニンおよびＬ－カルノシンの併用摂取に血漿中の乳酸濃度の上昇を抑制する作用、および血漿中の乳酸濃度を下げる作用があることが確認された。さらにβ－アラニンおよびＬ－カルノシンを併用摂取するとマウスの遊泳時間が延びることが確認された。 From the above results, it was confirmed that the combined use of β-alanine and L-carnosine has an effect of suppressing the increase in free fatty acid concentration in plasma and an effect of lowering the free fatty acid concentration in plasma. It has been confirmed that the combined use of L-carnosine has an effect of suppressing an increase in plasma lactic acid concentration and an effect of lowering plasma lactic acid concentration. Further, it was confirmed that when β-alanine and L-carnosine were taken together, the swimming time of the mice was extended.
〔実施例２〕経口カプセル製剤の作製（その１）
　経口カプセル製剤をそれ自体公知の方法で製造した。
　　１個のゼラチンまたはＨＭＰＣカプセル中に下記成分を含む。
　　　Ｌ－カルノシン　　　　　　　　　　　　　　　　１００ｍｇ
　　　β－アラニン　　　　　　　　　　　　　　　　　１５０ｍｇ [Example 2] Preparation of oral capsule preparation (Part 1)
An oral capsule preparation was produced in a manner known per se.
The following components are contained in one gelatin or HMPC capsule.
L-carnosine 100mg
β-Alanine 150mg
〔実施例３〕経口カプセル製剤の作製（その２）
　経口カプセル製剤をそれ自体公知の方法で製造した。
　　１個のゼラチンまたはＨＭＰＣカプセル中に下記成分を含む。
　　　Ｌ－カルノシン　　　　　　　　　　　　　　　　　５０ｍｇ
　　　β－アラニン　　　　　　　　　　　　　　　　　１００ｍｇ
　　　クエン酸　　　　　　　　　　　　　　　　　　　１００ｍｇ [Example 3] Preparation of oral capsule preparation (2)
An oral capsule preparation was produced in a manner known per se.
The following components are contained in one gelatin or HMPC capsule.
L-carnosine 50mg
β-Alanine 100mg
Citric acid 100mg
　本発明の高脂血症の予防または治療剤は、哺乳動物の血漿中の遊離脂肪酸濃度の減少に有用であり、本発明の抗疲労剤は、血漿中の乳酸濃度を減少させ、優れた疲労軽減、疲労回復の促進、持久力の向上に有用である。 The prophylactic or therapeutic agent for hyperlipidemia of the present invention is useful for reducing the free fatty acid concentration in the plasma of mammals, and the anti-fatigue agent of the present invention reduces the lactic acid concentration in plasma and has excellent fatigue. Useful for reducing, promoting fatigue recovery and improving endurance.

Claims (14)

  1. 　カルノシナーゼ阻害剤およびＬ－カルノシン類を含む高脂血症の予防または治療剤。 A prophylactic or therapeutic agent for hyperlipidemia containing a carnosinase inhibitor and L-carnosines.
  2. 　カルノシナーゼ阻害剤が、下記式（ＩＩ）で表されるβ－アラニン、下記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体、下記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体、γ－アミノ酸誘導体、チオール型還元剤、および分岐状炭化水素鎖を有する疎水性ビタミンから選ばれる少なくとも１種であることを特徴とする請求項１に記載の高脂血症の予防または治療剤。
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。）
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は炭素数２以上のアルキル基を表す。）     Carnosinase inhibitors include β-alanine represented by the following formula (II), N-alkanoyl-β-alanine derivative represented by the following formula (III), N-alkanoyl-L represented by the following formula (IV) The prevention of hyperlipidemia according to claim 1, characterized in that it is at least one selected from a carnosine derivative, a γ-amino acid derivative, a thiol-type reducing agent, and a hydrophobic vitamin having a branched hydrocarbon chain Or therapeutic agent.
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
     (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.)
    Figure JPOXMLDOC01-appb-C000003
     (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
  3. 　Ｌ－カルノシン類が、Ｌ－カルノシン、Ｎ－アセチル－Ｌ－カルノシン、Ｌ－アンセリン、Ｎ－アセチル－Ｌ－アンセリン、Ｌ－バレニン、Ｌ－ホモカルノシン、Ｎ－アセチル－Ｌ－ホモカルノシンおよびカルシニンから選ばれる一種以上であることを特徴とする請求項１または２に記載の高脂血症の予防または治療剤。 L-carnosines are from L-carnosine, N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-valenine, L-homocarnosine, N-acetyl-L-homocarnosine and carcinin The prophylactic or therapeutic agent for hyperlipidemia according to claim 1 or 2, wherein the agent is one or more selected.
  4. 　Ｎ－アルカノイル－β－アラニン誘導体が、低級アルキル基でエステル化されていてもよいＮ－アセチル－β－アラニンであることを特徴とする請求項２に記載の高脂血症の予防または治療剤。 3. The prophylactic or therapeutic agent for hyperlipidemia according to claim 2, wherein the N-alkanoyl-β-alanine derivative is N-acetyl-β-alanine optionally esterified with a lower alkyl group. .
  5. 　カルノシナーゼ阻害剤および／またはＬ－カルノシン類の吸収を上げるために、さらにセルロース誘導体、ゼラチン、デキストリン、乳糖、でんぷんおよびポリビニルピロリドンから選ばれる少なくとも１種を含むことを特徴とする請求項１～４のいずれかに記載の高脂血症の予防または治療剤。 5. The method according to claim 1, further comprising at least one selected from cellulose derivatives, gelatin, dextrin, lactose, starch and polyvinylpyrrolidone in order to increase the absorption of carnosinase inhibitors and / or L-carnosines. The prophylactic or therapeutic agent for hyperlipidemia according to any one of the above.
  6. 　高脂血症の予防または治療が血漿中の遊離脂肪酸濃度を低下させることによるものである請求項１～５のいずれかに記載の高脂血症の予防または治療剤。 6. The prophylactic or therapeutic agent for hyperlipidemia according to any one of claims 1 to 5, wherein the prophylactic or therapeutic treatment for hyperlipidemia is by reducing the concentration of free fatty acid in plasma.
  7. 　高脂血症の予防または治療がメタボリックシンドローム、肥満、糖尿病、高血圧、高コレステロール血症、脂肪肝、心不全、狭心症、心筋梗塞、または動脈硬化の予防または治療である請求項１～６のいずれかに記載の高脂血症の予防または治療剤。 The prevention or treatment of hyperlipidemia is prevention or treatment of metabolic syndrome, obesity, diabetes, hypertension, hypercholesterolemia, fatty liver, heart failure, angina pectoris, myocardial infarction, or arteriosclerosis. The prophylactic or therapeutic agent for hyperlipidemia according to any one of the above.
  8. 　カルノシナーゼ阻害剤およびＬ－カルノシン類を含むことを特徴とする抗疲労剤。 An anti-fatigue agent comprising a carnosinase inhibitor and L-carnosines.
  9. 　カルノシナーゼ阻害剤が、下記式（ＩＩ）で表されるβ－アラニン、下記式（ＩＩＩ）で表されるＮ－アルカノイル－β－アラニン誘導体、下記式（ＩＶ）で表されるＮ－アルカノイル－Ｌ－カルノシン誘導体、γ－アミノ酸誘導体、チオール型還元剤、および分岐状炭化水素鎖を有する疎水性ビタミンから選ばれる少なくとも１種であることを特徴とする請求項８に記載の抗疲労剤。
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒ１およびＲ２は独立して水素原子または低級アルキル基を表す。）
    Figure JPOXMLDOC01-appb-C000006
     （式中、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は炭素数２以上のアルキル基を表す。）     Carnosinase inhibitors include β-alanine represented by the following formula (II), N-alkanoyl-β-alanine derivative represented by the following formula (III), N-alkanoyl-L represented by the following formula (IV) 9. The anti-fatigue agent according to claim 8, wherein the anti-fatigue agent is at least one selected from a carnosine derivative, a γ-amino acid derivative, a thiol-type reducing agent, and a hydrophobic vitamin having a branched hydrocarbon chain.
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
     (In the formula, R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.)
    Figure JPOXMLDOC01-appb-C000006
     (In the formula, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an alkyl group having 2 or more carbon atoms.)
  10. 　Ｌ－カルノシン類が、Ｌ－カルノシン、Ｎ－アセチル－Ｌ－カルノシン、Ｌ－アンセリン、Ｎ－アセチル－Ｌ－アンセリン、Ｌ－バレニン、Ｌ－ホモカルノシン、Ｎ－アセチル－Ｌ－ホモカルノシンおよびカルシニンから選ばれる少なくとも１種であることを特徴とする請求項８または９に記載の抗疲労剤。 L-carnosines are from L-carnosine, N-acetyl-L-carnosine, L-anserine, N-acetyl-L-anserine, L-valenine, L-homocarnosine, N-acetyl-L-homocarnosine and carcinin The anti-fatigue agent according to claim 8 or 9, wherein the anti-fatigue agent is at least one selected.
  11. 　Ｎ－アルカノイル－β－アラニン誘導体が、低級アルキル基でエステル化されていてもよいＮ－アセチル－β－アラニンであることを特徴とする請求項９に記載の抗疲労剤。 10. The anti-fatigue agent according to claim 9, wherein the N-alkanoyl-β-alanine derivative is N-acetyl-β-alanine which may be esterified with a lower alkyl group.
  12. 　カルノシナーゼ阻害剤および／またはＬ－カルノシン類の吸収を上げるために、さらにセルロース誘導体、ゼラチン、デキストリン、乳糖、でんぷんおよびポリビニルピロリドンから選ばれる少なくとも１種を含むことを特徴とする請求項８～１１のいずれかに記載の抗疲労剤。 12. The method according to claim 8, further comprising at least one selected from cellulose derivatives, gelatin, dextrin, lactose, starch, and polyvinylpyrrolidone in order to increase the absorption of carnosinase inhibitors and / or L-carnosines. The anti-fatigue agent in any one.
  13. 　抗疲労が血漿中の乳酸濃度を低下させる作用によることを特徴とする請求項８～１２のいずれかに記載の抗疲労剤。 The anti-fatigue agent according to any one of claims 8 to 12, wherein the anti-fatigue is due to an action of lowering a lactic acid concentration in plasma.
  14. 　抗疲労が持久力を増強させる作用によることを特徴とする請求項８～１２のいずれかに記載の抗疲労剤。 The anti-fatigue agent according to any one of claims 8 to 12, wherein the anti-fatigue is due to an action of enhancing endurance.
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