US20020045765A1 - Tocopherol derivatives and method for preparation thereof - Google Patents

Tocopherol derivatives and method for preparation thereof Download PDF

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Publication number
US20020045765A1
US20020045765A1 US09/756,179 US75617901A US2002045765A1 US 20020045765 A1 US20020045765 A1 US 20020045765A1 US 75617901 A US75617901 A US 75617901A US 2002045765 A1 US2002045765 A1 US 2002045765A1
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tocopherol
derivatives
organic solvent
tocopherol derivatives
present
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US6410752B1 (en
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Kil Joong Kim
Duck Hee Kim
Ho Sik Rho
Jae Won You
Chun Ja Nam
Jong Eoun Hong
Hak Hee Kang
Ih Seop Chang
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Amorepacific Corp
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Pacific Corp
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Assigned to PACIFIC CORPORATION reassignment PACIFIC CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHANG, IH S., HONG, JONG E., KANG, HAK H., KIM, DUCK H., KIM, KIL J., NAM, CHUN J., RHO, HO S., YOU, JAE W.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/678—Tocopherol, i.e. vitamin E
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention is related to tocopherol derivatives and their salts, and to method for preparation thereof.
  • tocopherol one of liposoluble-type vitamins, has bioactive functions including a protective function against activity of free radicals which are harmful to human body, promotion of cell growth, and induction of collagen biosynthesis, anti-allergy effects and anti-inflammatory effects. Therefore, tocopherol has also been used as a cosmetic source because of its bioactivities.
  • the unstable, liposoluble and water-insoluble properties of tocopherol have limited the uses of tocopherol as a cosmetic source.
  • tocopherol derivatives have been developed in order to improve its stability.
  • U.S. Pat. No. 4,564,686 disclosed that compounds produced by phosphatic esterification between tocopherol and ascorbic acid could improve the stability of tocopherol.
  • the traditionally known tocopherol derivatives could improve only the stability of tocopherol. And they were materials combined simply through the esterification between tocopherol and compounds with similar physiological activities.
  • tocopherol derivatives introduced with compounds with other physiological activities have still not been developed.
  • tocopherol derivatives into which compounds with other physiological activities may be introduced, so that other bioactivities and improved stability of tocopherol can be obtained thereby.
  • the tocopherol derivatives introduced with 3-aminopropane phosphate could be hydrolyzed through biological enzymes in a living body, and the tocopherol-hydrolyzed products, tocopherol and 3-aminopropane phosphate, can perform different physiological activitives.
  • these tocopherol derivatives have both hydrophilic and hydrophobic groups, thus show improved stability in aqueous mediums. And these tocopherol derivatives also show a much more improved anti-oxidative effect than tocopherol.
  • an object of the present invention is to provide the tocopherol derivatives represented by the following formula (I), and their salts:
  • R 1 , R 2 and R 3 are H or methyl group, and at least one positions selected from group consisting of the R 1 , R 2 and R 3 positions are methyl group; and,
  • A is CH 2 —CH(CH 3 )— or CH ⁇ C(CH 3 )—
  • the other object of the present invention is to provide a method for preparing the above tocopherol derivatives.
  • the tocopherol derivatives is prepared by reacting tocopherol with phosphorous oxychloride in an equivalent ratio of 1: 1 ⁇ 1.3, in presence of an organic base, in an organic solvent; reacting the tocopherol dichlorophosphate produced by the above reaction with 3-aminopropanol in presence of an organic base, in an organic solvent; and, hydrolyzing the above products.
  • the tocopherol derivatives according to the present invention can be hydrolyzed by biological enzymes in a living body to produce tocopherol and 3-aminopropane phosphate. And they can induce physiological activities including recovery of injured skin, prevention from aging of bio-membrane, etc. Also, the tocopherol derivatives according to the present invention have improved stability, safety to skin and anti-oxidant effect superior to preceding tocopherol and its derivatives.
  • the tocopherol derivatives according to the invention are materials which can be hydrolyzed by biological enzymes, thereby can release tocopherol and 3-aminopropane phosphate. They have effects including prevention of biolipids oxidation and promotion of collagen biosynthesis, and they are also safe to skin and can provide improved effects such as an increase in elasticity of skin and prevention of skin aging. Moreover, the tocopherol derivatives according to the present invention have excellent anti-oxidant effect and stability in both water and lipid media by possessing both hydrophilic and lipophilic groups. Therefore, the tocopherol derivatives of the invention may have various usages such as cosmetic composition.
  • R 1 , R 2 and R 3 are H or methyl group, and at least one positions selected from group consisting of the R 1 , R 2 and R 3 positions are methyl group; and,
  • A is CH 2 —CH(CH 3 )— or CH ⁇ C(CH 3 )—
  • the method for preparing the tocopherol derivatives of the above general formula (I) comprises the following steps:
  • step (A) it is preferable that the reaction of tocopherol with phosphorus oxychloride is carried out in an equivalent ratio 1:1 ⁇ 1.3. In case that this ratio is lower than 1:1, the object product cannot be obtained. While, in case that the ratio is higher than 1: 1.3, excessive by-products as well as the object product are obtained.
  • step (B) an intermediate complex of tocopherol and phosphorus oxychloride is produced with a yield of 95% or more, and ditocopherol phosphate as a by-product, 2:1 complex of tocopherol and phosphorus oxychloride is produced with a yield of 3% or less.
  • ditocopherol phosphate may be removed simply by step (B) and (C), and through a purification step, triethylamine hydrochloride salt is removed though filtration of the reaction solution.
  • the organic base employed in this step may include, but not limited thereto, pyridine and triethylamine. Among them, triethylamine may be preferable.
  • the organic solvent employed in this step may include, but not limited thereto, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether and other inert solvents. Among them, tetrahydrofuran may be preferable.
  • reaction time is preferably 1 ⁇ 3 hours.
  • step (B) the reaction between tocopherol dichlorophosphate and 3-aminopropanol is carried out at a temperature of ⁇ 10 ⁇ 30° C., in an equivalent ratio 1:1 ⁇ 1.3, in organic solvent in the presence of organic base.
  • the above reaction produces 2-tocopherol-tetrahydro-2H-1,3,2-oxazaphosphorin P-Oxide represented by formula (III).
  • the mole ratio of 3-aminopropanol to tocopherol dichlorophosphate (II) is lower than 1.0, the yield of the step (B) reaction decreases. In contrast, the by-product increase if the ratio is larger than 1.3.
  • the ratio of tocopherol dichlorophosphate to 3-aminopropanol is preferably 1: 1. ⁇ 3.
  • the reaction rate may be slow at a temperature of ⁇ 10° C. or less, and the production of by-products is increased at 30° C. or more.
  • the reaction is preferably carried out at a temperature of ⁇ 10 ⁇ 30° C., more preferably 0 ⁇ 15° C.
  • the organic solvent and organic base employed in this step is the same as those of the step (A).
  • the filtrate of the reaction solution is concentrated under reduced pressure, thereafter the obtained residue may be hydrolyzed by using acid catalysts such as hydrochloric acid and sulfuric acid for adjusting hydrolysis conditions.
  • acid catalysts such as hydrochloric acid and sulfuric acid for adjusting hydrolysis conditions.
  • the P-N bond can be hydrolyzed through adjusting pH to 1 ⁇ 5, preferably 2 ⁇ 4 by the addition of acidic solution to 2-tocopherol-tetrahydro-2H-1,3,2-oxazaphosporin P-oxide(III) solution, thereafter maintaining in a temperature of 5 ⁇ 100° C., and stirring.
  • 2-tocopherol-tetrahydro-2H-1,3,2-oxazaphosporin P-oxide can be hydrolyzed through filtrating its solution, concentrating the filtrate, adjusting the pH of the residue by adding an acidic solution, and thereafter reacting the results at a temperature of 5 ⁇ 100° C., preferably 10 ⁇ 40° C., for 1 ⁇ 10 hours, preferably for about 2 hours.
  • the reaction rate decreases when the reaction is carried out at a temperature of 5° C. or less, while its P—O bond gets broken at a temperature of 100° C. or more.
  • the hydrolysis is not completed when the reaction time is carried out for less than 1 hour, while P—O bond is broken at reaction times of more than 10 hours.
  • Tocopherol derivatives are produced through mixing the solution obtained by the step (C) with a organic solvent, removing the impurities by washing several times with water, drying the solution with anhydrous sodium sulfate or magnesium sulfate and removing the solvent.
  • the organic solvent employed in this step is same with those employed in step (A).
  • the tocopherol derivatives provided in the method of the invention can also be employed in the form of their salts obtained by neutralization with an alkali or a base.
  • a neutralizing agent may include, but not limited thereto, salts of alkali metals including sodium and potassium; the salts of the alkali earth metals including calcium and magnesium; the salts of amine or ammonium including triethylamine.
  • tocopherol derivatives should be used as cosmetic ingredient, their safety in the living body is very important.
  • the present invention thus examined whether the tocopherol derivatives of the invention have toxicity and cause irritation to the body or not.
  • the product of Preparation Example 1 was dissolved in squalene to produce 10% of solution sample, and the sample was employed in safety experiments.
  • mice 1 ml/kg of the sample was administrated to total ten (10) mice (male and female were separately five (5) mice). As a result, no death of mice was observed. And the difference in the body weight after administration was also insignificant.
  • mice and rabbits Acute dermal toxicity test in mice and rabbits : 0.2 ml/kg of the sample was administrated percutaneously once to a total often (10) mice (five male and five female). After two weeks of observation, no mice administered with the sample exhibited abnormal symptoms or changes in body weight. When the same experiment was performed on rabbits, No abnormal symptom and change of body weight were observed in rabbit administrated with the sample.
  • Human patch test Human patch test was carried out for thirty (30) healthy women aged 20 ⁇ 28 according to CTFA Guideline(The Cosmetic Toiletry and Fragrance Association, INC., Washington, D. C. 20036, 1991). As a result, primary irritation response was not observed.
  • the tocopherol derivatives according to the present invention are materials safe for skin application.
  • tocopherol derivatives of preparation example 1 did not change in color, but tocopherol as a control increase in coloration at four (4) months or more. And quantitative analysis by NMR Spectroscopy indicated that preparation example 1 was more stable.
  • Fibroblast cells of infant were inoculated on 24-wells(10 5 cells/well). They were washed with PBS once. And then, preparation example 1 and 3-aminopropane phosphate as a control were treated by the concentration shown Table 3, and were incubated at CO 2 incubator for 24 hours. Each supernatant was collected, and the variation of procollagen was measured by using procol GmbH type (I) ELISA kit. The results are shown in Table 3. The value of biosynthesis activity was calculated by comparing to 100, the value of none-treated sample. TABLE 3 Biosynthesis Concentration (%) activity (%) 3-aminopropane phosphate 10 ⁇ 4 146 Preparation example 1 10 ⁇ 6 141
  • the tocopherol derivatives according to the present invention have excellent biosynthesis activity of collagen.
  • ageing and oxidation of bio-membrane may be prevented.
  • the tocopherol derivatives according to the present invention were assayed whether they may be hydrolyzed by biological enzyme in living body into tocopherol and 3-aminopropane phosphate.
  • the phosphodiesterase was used as biological enzyme, and 1% aqueous solution of 1:9 mixture of preparation example 1 and Tween 20 was prepared to use as an assay sample.

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  • Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
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KR1020000050330A KR100365070B1 (ko) 2000-08-29 2000-08-29 토코페롤 유도체 및 그의 제조방법

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050089495A1 (en) * 2001-12-13 2005-04-28 West Simon M. Transdermal transport of compounds
US20090004166A1 (en) * 2004-08-03 2009-01-01 Simon Michael West Carrier For Enternal Administration
US20090239827A1 (en) * 2005-03-03 2009-09-24 Esra Ogru Compounds having lipid lowering properties
US20100076094A1 (en) * 2000-11-14 2010-03-25 Simon Michael West Formulation containing phosphate derivatives of electron transfer agents
US20100209459A1 (en) * 2004-03-03 2010-08-19 Simon Michael West Alkaloid formulations
US20100261670A1 (en) * 2000-11-14 2010-10-14 Simon Michael West Complexes of phosphate derivatives
US8008345B2 (en) 2001-07-27 2011-08-30 Vital Health Sciences Pty. Ltd. Dermal therapy using phosphate derivatives of electron transfer agents
US8652511B2 (en) 2010-03-30 2014-02-18 Phosphagenics Limited Transdermal delivery patch
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100376088B1 (ko) * 2001-03-09 2003-03-28 주식회사 태평양 3-아미노프로필코질포스페이트 및 그의 염을 함유한미백화장료 조성물
KR100401959B1 (ko) * 2001-06-02 2003-10-17 주식회사 태평양 토코페롤 유도체를 사용하여 레시틴을 안정화하는 방법
KR100394770B1 (ko) * 2001-06-05 2003-08-14 주식회사 태평양 토코페롤 유도체를 이용하여 나노유화입자를 안정화시키는방법 및 나노유화입자를 함유하는 피부 외용제 조성물
KR100456427B1 (ko) * 2001-12-14 2004-11-10 주식회사 태평양 3-아미노프로필토코페릴 포스페이트를 함유한나노유화입자 및 그의 제조방법, 및 이를 함유하는피부외용제 조성물
EP1589964B1 (en) * 2003-01-17 2011-11-23 Vital Health Sciences Pty Ltd. Compounds having anti-proliferative properties
KR101056879B1 (ko) * 2005-06-08 2011-08-12 (주)아모레퍼시픽 세사몰 유도체 또는 그의 염, 그의 제조방법, 및 이를함유하는 피부외용제 조성물
US10434204B2 (en) 2011-07-15 2019-10-08 Soclean, Inc. Technologies for sanitizing mist humidifiers
CA2924126C (en) 2013-09-13 2023-05-02 The Board Of Trustees Of The University Of Arkansas Preparation and use of a composition for prevention and mitigation of the effects of radiation
US20160324914A1 (en) 2015-05-05 2016-11-10 Tocol Pharmaceuticals, Llc Use of rice bran oil distillate extract for prevention and mitigation of the effects of radiation

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JPS59219295A (ja) * 1983-05-30 1984-12-10 Senjiyu Seiyaku Kk リン酸ジエステルまたはその塩およびそれらの製造法
US4977282A (en) * 1984-04-17 1990-12-11 Henkel Corporation Production of d-alpha-tocopherol from natural plant sources
FR2679904A1 (fr) * 1991-08-01 1993-02-05 Lvmh Rech Utilisation d'un phosphate de tocopherol, ou de l'un de ses derives, pour la preparation de compositions cosmetiques, ou pharmaceutiques et compositions ainsi obtenues.
JP4115524B2 (ja) * 1995-10-17 2008-07-09 昭和電工株式会社 高純度トコフェロールリン酸エステル類、その製造方法、その分析方法並びに化粧料
JPH1045783A (ja) * 1996-07-29 1998-02-17 Showa Denko Kk ヒドロキシクロマン誘導体リン酸エステルの製造方法

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100076094A1 (en) * 2000-11-14 2010-03-25 Simon Michael West Formulation containing phosphate derivatives of electron transfer agents
US8173145B2 (en) 2000-11-14 2012-05-08 Vital Health Sciences Pty. Ltd. Formulation containing phosphate derivatives of electron transfer agents
US20100261670A1 (en) * 2000-11-14 2010-10-14 Simon Michael West Complexes of phosphate derivatives
US8008345B2 (en) 2001-07-27 2011-08-30 Vital Health Sciences Pty. Ltd. Dermal therapy using phosphate derivatives of electron transfer agents
US20050089495A1 (en) * 2001-12-13 2005-04-28 West Simon M. Transdermal transport of compounds
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US8529947B2 (en) 2004-03-03 2013-09-10 Vital Health Sciences Pty. Ltd. Alkaloid formulations
US20100209459A1 (en) * 2004-03-03 2010-08-19 Simon Michael West Alkaloid formulations
US20090004166A1 (en) * 2004-08-03 2009-01-01 Simon Michael West Carrier For Enternal Administration
US20090239827A1 (en) * 2005-03-03 2009-09-24 Esra Ogru Compounds having lipid lowering properties
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US8652511B2 (en) 2010-03-30 2014-02-18 Phosphagenics Limited Transdermal delivery patch
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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KR20020029443A (ko) 2002-04-19
JP4330279B2 (ja) 2009-09-16
KR100365070B1 (ko) 2002-12-16
FR2813191B1 (fr) 2003-06-20
JP2002088091A (ja) 2002-03-27
US6410752B1 (en) 2002-06-25
FR2813191A1 (fr) 2002-03-01

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