WO2001036451A1 - Dérivés de vitamine e - Google Patents

Dérivés de vitamine e Download PDF

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Publication number
WO2001036451A1
WO2001036451A1 PCT/JP2000/008096 JP0008096W WO0136451A1 WO 2001036451 A1 WO2001036451 A1 WO 2001036451A1 JP 0008096 W JP0008096 W JP 0008096W WO 0136451 A1 WO0136451 A1 WO 0136451A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
tocopheryl
yloxycarbonyl
vitamin
glutathione
Prior art date
Application number
PCT/JP2000/008096
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English (en)
Japanese (ja)
Inventor
Kazumi Ogata
Takahiro Sakaue
Masahito Iemura
Original Assignee
Senju Pharmaceutical Co., Ltd.
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 Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO2001036451A1 publication Critical patent/WO2001036451A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel and useful vitamin E derivative, a method for producing the same and a use thereof. More specifically, a novel vitamin E derivative in which vitamin E maleic acid (or fumaric acid) and glutathione are S-bonded, and a tributophan or tryptophan derivative is further acid-bonded to this compound;
  • the present invention relates to a cerebral metabolism improving agent, an antioxidant, an anti-inflammatory agent and a UV erythema inhibitor containing the same.
  • Melatonin also known as N-acetyl-5-0-methylcetotonin or N-acetyl-5-methoxytryptamine
  • N-acetyl-5-0-methylcetotonin or N-acetyl-5-methoxytryptamine is used in the pineal gland to convert 5-hydric xytryptophan, serotonin, and N-acetylseminonine from tryptophan to tryptophan. It is a kind of brain hormone that is biosynthesized through the process.
  • melatonin has the ability to scavenge active oxygen (hydroxyl radical scavenging ability) and is said to be useful for preventing aging.
  • melatonin has been reported to be effective in suppressing erythema of the skin by ultraviolet (UV) irradiation in the skin area (Haut GmbH 1999 Jan; 50 (1): 5-11). In addition, melatonin has been reported to play an important role in protection against carrageenan-induced local inflammation (FASEB J 1999 Nov; 13 (14): 1930-8), and melatonin may suppress acute inflammatory response. (J Biol Regul Homeost Agents 1997 Oct-Dec; ll (4): 157-9).
  • the present invention relates to a novel vitamin E derivative, that is, a vitamin E derivative in which vitamin E maleic acid (or fumaric acid) and glucanthione are S-bonded, and 0-methylserotonin, 5-hydroxytryptophan, tryptophan or tryptophan.
  • the present invention provides a compound having an amide bond to Yumin.
  • an object of the present invention is to provide a cerebral metabolism improving agent, an antioxidant, an anti-inflammatory agent, and an ultraviolet erythema inhibitor containing these compounds.
  • the present invention relates to (1) the following formula [wherein and R 2 are the same or different and each represent a hydrogen atom or a methyl group, R 3 represents an S-bonded glutathione, and R 4 represents an amino Shows bound 0-methylcepatonin, 5-hydroxytritophan, tributophan or trypamine. ] Or a pharmacologically acceptable salt thereof,
  • R t and R 2 are the same or different and each represent a hydrogen atom or a methyl group
  • R 3 represents an S-linked glutathione
  • R 4 represents an amino-bonded 0- Indicates methylserotonin, 5-hydroxytributophan, tributofan or trimin.
  • a cerebral metabolism-improving agent comprising a vitamin E derivative represented by the formula or a pharmacologically acceptable salt thereof,
  • the present invention provides a compound represented by the following formula (1) wherein R and R 2 are the same or different and each represent a hydrogen atom or a methyl group, R 3 represents S-linked glutathione, and R 4 represents amino. Indicates bound 0-methylcetotonin, 5-hydroxytryptophan, tributofan or tryptamine.
  • a method for improving brain metabolism which comprises administering to a mammal, including a human, an effective amount of a vitamin E derivative or a pharmaceutically acceptable salt thereof represented by the formula:
  • a method for treating inflammation comprising administering to a mammal, including a human, an effective amount of a vitamin E derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, and
  • this compound forms an S bond between vitamin E maleic acid (or fumaric acid) and gluyuthione, and further binds these to serotonin, 0-methylserotonin, 5-octylidoxytributophan, and tributofan.
  • vitamin E maleic acid or fumaric acid
  • gluyuthione binds these to serotonin, 0-methylserotonin, 5-octylidoxytributophan, and tributofan.
  • tribamine is amino-bonded.
  • This compound is known to be used as a cerebral metabolism improving agent, an antioxidant, an anti-inflammatory agent, an antiallergic agent, etc., as described in the above publication and Japanese Patent Application Laid-Open No. 2000-191528, but it suppresses ultraviolet erythema. Its use as an agent is not yet known.
  • the present compound whether it is free or a pharmacologically acceptable salt thereof, can be appropriately used for the purpose of the present invention.
  • the pharmacologically acceptable salts include alkali metal salts such as sodium salt and potassium salt and alkaline earth metal salts such as calcium salt and magnesium salt. Any other salts may be used as long as they are pharmacologically acceptable.
  • vitamin E which is a component of the present compound
  • any one of H, ⁇ , r, and (5-tocophere) can be used as appropriate.
  • Biyumin E is an antioxidant and has recently been used in cataracts. It has been suggested to be effective.
  • Gluythione a component of this compound, is an SH compound and is known to have an anticataract effect and a liver damage inhibitory effect.
  • serotonin, 0-methylcetotonin, 5-hydroxytryptophan, tryptophan, and trypamine, the other components of the compound are precursors to melatonin, a hormone in the brain, as described above. is there.
  • This compound can be appropriately synthesized, for example, by the following synthesis method or according to the method.
  • Maleic acid (or fumaric acid) monotocopherol which is a starting compound of the present compound, can be synthesized by the method described in the above-mentioned International Publication No. W099 / 33818 or according to the method. That is, in the presence of maleic anhydride and alkali carbonates (such as sodium carbonate and potassium carbonate) or alkali acetates (such as sodium acetate and potassium acetate), tocopherol is treated with a nonpolar solvent such as acetone, acetonitrile, or tetrahedrofuran (THF). To react for about 1 to 3 hours by heating in a neutral solvent to obtain maleic acid (or fumaric acid) Can be.
  • a nonpolar solvent such as acetone, acetonitrile, or tetrahedrofuran (THF).
  • the maleic acid (or fumaric acid) monotocopherol thus obtained is combined with serotonin, 0-methylserotonin, 5-hydroxytryptophan, triptophan or trypamine, in a solvent such as chloroform or tetrahydrofuran. Condensation in the presence of an amine (pyridine, triethylamine, etc.) by the mixed acid anhydride method with chloroethyl carbonate, etc., yields the corresponding acid amide of maleic acid (or fumaric acid) monotocopherol.
  • the present compound can be obtained by subjecting these compounds to an addition reaction with glucan thione at room temperature for about 3 to 6 hours and under heating for 1 to 3 hours.
  • the reaction solvent in this case include water or a solvent miscible with water, for example, alcohol, acetonitrile, dioxane, and the like, and a mixed solution with water is preferable.
  • the present compound thus obtained may be obtained as a pharmacologically acceptable salt by a known method.
  • This compound can be separated in vivo into vitamin E and glutathione by cleavage of the S bond in the compound, and cleavage into the acid amide bond in the compound to the corresponding tributophan and tributane derivatives. Be expected.
  • the present compound has a strong cerebral metabolism improving action, an antioxidant action (radical scavenger action), an ultraviolet erythema inhibitory action and an anti-inflammatory action.
  • Specific diseases targeted by the agent for improving cerebral metabolism of the present invention include cerebrovascular disorders such as cerebral infarction and stroke.
  • Specific diseases targeted by the anti-inflammatory agent of the present invention include hemorrhoids, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, osteoarthritis, lumbago, gout attacks, acute otitis media, cystitis , Prostatitis, toothache, uveitis, sinusitis and the like.
  • This compound has antioxidant action (radical scavenger action) as described above. It can be added to cosmetics such as creams, lotions, lotions, etc. for the purpose of absorbing ultraviolet rays and beautiful skin, or stabilizing (antioxidant) other cosmetic ingredients. Further, the present compound can be incorporated into cosmetics as an ultraviolet erythema inhibitory component. When the present compound is incorporated into cosmetics, components usually used in cosmetics can be appropriately added.
  • the power varies depending on the type of the compound, the type of cosmetic to be blended, the purpose of blending, etc. Usually about 0.001 to 5 (w / w)%, preferably about 0.005 to 2 (w / w). /. It is better to mix them.
  • the present compound is appropriately used orally or parenterally as an agent for improving brain metabolism or an anti-inflammatory agent.
  • the form of the preparation it can be prepared by any known method such as a solid preparation such as tablets, granules, powders and capsules or a liquid preparation such as injections. Excipients, binders, thickeners, dispersants, resorption promoters, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, and stabilizing agents commonly used in these formulations Various additives such as agents and pH adjusters may be used as appropriate.
  • the dosage of the compound used as a cerebral metabolism improving agent or anti-inflammatory agent varies depending on the type of the compound used, the weight and age of the patient, the type and condition of the disease to be treated, the administration method, etc. However, for example, in the case of injections, it is preferable to administer about lmg to about 30mg once daily for adults, and for oral administration, it is recommended to administer about lmg to about 100mg once a day for adults several times a day.
  • the present compound When the present compound is used as a cerebral metabolism improving component, an antioxidant component, an ultraviolet erythema inhibitory component or an anti-inflammatory component, one or more of the present compounds can be appropriately combined and contained according to the purpose and necessity. .
  • the cerebral metabolism improving agent, anti-inflammatory agent and ultraviolet erythema inhibitor of the present invention include other cerebral metabolism improving agent, anti-inflammatory component, ultraviolet erythema inhibitor and other types of medicament, unless they are against the purpose of the present invention. Components may be appropriately contained.
  • the above THF solution was added at room temperature with stirring to a solution prepared by adding 0.5 g of sodium hydroxide and 3.5 g of glucanthione to 60 ml of an 80% methanol solution, followed by stirring for 30 minutes. After stirring for 2 hours, the solvent was distilled off, and ethanol was added to this to crystallize it and collected by filtration. Next, this was dissolved in 100 ml of water, and 5 ml of acetic acid was added. The precipitated white crystals were collected by filtration, washed with water, recrystallized from THF / ethanol, melting point 182 to 184: 6.6 g of the free acid of the target compound (decomposed) Get.
  • test substance was dissolved in methanol.
  • a male Hartley guinea pig weighing approximately 300 g purchased from SLC Japan Co., Ltd. It was used.
  • the back of the guinea pig was irradiated with ultraviolet light for 30 seconds by applying a light-shielding cloth having a small circular hole of 6 mm diameter.
  • An ultraviolet erythema device (TK-151 manufactured by Nyucom Co.) was used for ultraviolet irradiation.
  • the degree of erythema on the back was determined based on the following scoring table.
  • test substance was applied 20 L 15 minutes before UV irradiation.
  • test substance was dissolved in Phosphate Buffer Saline (PBS) (50 mM, H7.4) containing 10% ethanol (ethanol final concentration 1%).
  • PBS Phosphate Buffer Saline
  • Wistar rats purchased from Nippon SLC Co., Ltd. were decapitated under anesthesia, and then immediately opened to remove the brain.
  • the excised brain was washed with ice-cold PBS, and the water content was gently measured with filter paper.
  • Four times the volume of ice-cold PBS was added and homogenized in ice.
  • the homogenate was centrifuged at 0 "C and 1000 X g (2700 rpm) for 10 minutes, and the supernatant was used for the test.
  • Add 700 U of PBS to IOO I (containing 10% ethanol) add 200 1 of brain homogenate supernatant, and incubate for 30 minutes at 37.
  • Use PBS (containing 10% ethanol) for control and blank groups. The blank group was incubated for 30 minutes at 0.
  • the lipid peroxide production inhibition rate of each test substance was calculated according to the following equation.
  • Lipid peroxide production inhibition rate (%) [1— (C—A / B—A)] X100
  • the present compound has a stronger antioxidant effect than melatonin and is useful as a brain metabolism improving agent.
  • test substance was dissolved in methanol to a concentration of 0.5%.
  • mice Six-week-old male ddY mice purchased from Japan SLC, Inc. were used. First, after measuring the thickness of the pinna of the mouse, the compound was applied to the inside and outside of the pinna of the mouse by IOL. One hour later, a 10 L PMA acetate solution (100 g / mL) was applied to the inside and outside of the mouse pinna. Twenty-four hours later, the thickness of the pinna of the mouse was measured, and the pinna edema rate was calculated.
  • the above components are mixed by a conventional method to prepare a cosmetic cream.
  • the above ingredients are molded by a conventional method as a material for one tablet.
  • the above are mixed by a conventional method to prepare an injection.
  • R 3 Group evening thione
  • 1 4 Se compound of Rotonin is known.
  • A cerebral metabolism improving agents, antioxidants, anti It is useful as an inflammatory agent and UV erythema inhibitor.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Toxicology (AREA)
  • Biophysics (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention a trait à des agents améliorant le métabolisme cérébral, à des antioxydants, à des anti-inflammatoires ainsi qu'à des inhibiteurs de l'érythème dû aux ultraviolets, contenant des dérivés de la vitamine E, correspondant à la formule générale (I), ou à leurs sels acceptables du point de vue pharmaceutique. Dans cette formule, R1 et R2 représentent, chacun de manière indépendante, un hydrogène ou un méthyle, R3 représente un reste glutathion lié par une liaison S et R4 représente une sérotonine, O-méthylsérotonine, 5-hydroxytryptophan ou un reste tryptamine lié par une liaison amino.
PCT/JP2000/008096 1999-11-18 2000-11-16 Dérivés de vitamine e WO2001036451A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/328386 1999-11-18
JP32838699 1999-11-18

Publications (1)

Publication Number Publication Date
WO2001036451A1 true WO2001036451A1 (fr) 2001-05-25

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PCT/JP2000/008096 WO2001036451A1 (fr) 1999-11-18 2000-11-16 Dérivés de vitamine e

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033818A1 (fr) * 1997-12-24 1999-07-08 Senju Pharmaceutical Co., Ltd. Derives de vitamine e
JP2000191528A (ja) * 1998-12-25 2000-07-11 Senju Pharmaceut Co Ltd ビタミンｅ誘導体を含有してなる抗炎症剤または抗アレルギ―剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033818A1 (fr) * 1997-12-24 1999-07-08 Senju Pharmaceutical Co., Ltd. Derives de vitamine e
JP2000191528A (ja) * 1998-12-25 2000-07-11 Senju Pharmaceut Co Ltd ビタミンｅ誘導体を含有してなる抗炎症剤または抗アレルギ―剤

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