WO1998013330A1 - Esters d'acides gras insatures - Google Patents

Esters d'acides gras insatures Download PDF

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Publication number
WO1998013330A1
WO1998013330A1 PCT/GB1997/002502 GB9702502W WO9813330A1 WO 1998013330 A1 WO1998013330 A1 WO 1998013330A1 GB 9702502 W GB9702502 W GB 9702502W WO 9813330 A1 WO9813330 A1 WO 9813330A1
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WO
WIPO (PCT)
Prior art keywords
acid
fatty acid
ester
fatty acids
preparation
Prior art date
Application number
PCT/GB1997/002502
Other languages
English (en)
Inventor
David Frederick Horrobin
Mehar Singh Manku
Austin Mcmordie
Original Assignee
Scotia Holdings Plc
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 Scotia Holdings Plc filed Critical Scotia Holdings Plc
Priority to AU42159/97A priority Critical patent/AU4215997A/en
Publication of WO1998013330A1 publication Critical patent/WO1998013330A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds

Definitions

  • the invention relates to esters of unsaturated fatty acids. Glvcerides
  • fatty acids play many important roles as components of membrane structure, as factors in cell signalling systems and as regulators of gene function.
  • the fatty acids are usually taken in the diet in the form of triglycerides, phospholipids and cholesterol esters.
  • the triglycerides are particularly important vehicles for fatty acids.
  • During the process of digestion the fatty acids at the 1 and 3 positions of the triglyceride are split off by pancreatic lipase, leaving a monoacylglycerol with the fatty acid in the 2 position.
  • This monoacylglycerol may be reconverted by acylation to a diglyceride or triglyceride. or the fatty acid may migrate spontaneously to the 1 or 3 positions. Such migration may possibly be enzyme assisted but may also occur non-enzymically since it can occur in vitro in the absence of enzymes.
  • the 2-monoacylglycerides are important vehicles for the absorption of fatty acids in the small intestine and may be particularly important vehicles for transferring fatty acids into lymphatics which can then take their contents to the blood stream while by-passing the liver.
  • the 2-monoacylglycerides may also have specific biological activities of their own in membranes and in cell signalling systems although as yet these activities are ill-defined.
  • Glycerol has hydroxyl groups in conventionally numbered 1, 2 and 3 positions to which fatty acids may become attached. If the 2-position is occupied by a fatty acid, that fatty acid may migrate to the 1 or 3 positions, thus changing the properties of the monoester, or other fatty acids may be added to the 1 and 3 positions.
  • 2-propanol is related in structure to glycerol, but has no hydroxyl groups at the 1 and 3 positions.
  • the isopropyl esters of fatty acids are therefore analogous to the monoglycerides with the fatty acid in the two position. However such isopropyl esters cannot be converted to di and tri-glycerides, nor can their structure be changed by internal migration of the fatty acid to the 1 or 3 positions.
  • the isopropyl esters therefore provide novel vehicles for the carriage of fatty acids in biological systems and in particular for their unchanged absorption via the lymphatic system.
  • the isopropyl esters may be used as delivery systems whereby unsaturated fatty acids may be effectively delivered to the body, particularly by oral and topical but also by other routes.
  • the fatty acids delivered topically in this way are particularly effectively transported across the skin.
  • the invention provides the isopropyl esters of fatty acids with 16-26 carbon atoms and two to six double bonds in either the cis or the trans configuration, as such and when for use for example in food, cosmetic and therapeutic applications, all as claimed herein.
  • fatty acids include all cis linoleic acid, conjugated linoleic acid, columbinic acid, parinaric acid and all the essential fatty acids of the n-3 and n-6 series, as shown in Table 1. TABLE 1 n-6 EFAs n-3 EFAs
  • LA Linoleic acid
  • ALA Linolenic acid
  • GLA ⁇ -Linolenic acid
  • SA Stearidonic acid
  • DHA Docosahexaenoic acid
  • the acids which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. z,z octadeca - 9,12 - dienoic acid or z,z,z,z,z,z docosa- 4, 7, 10, 13, 16, 19 - hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2n-6 or 22:6n-3 are convenient.
  • Initials e.g., EPA and shortened forms of the name e.g. eicosapentaenoic acid are used as trivial names in some of the cases.
  • esters may be used for a variety of purposes, but particularly as pharmaceuticals, as foods, as nutritional supplements, as food additives and as agents to be used in all forms of skin and hair care.
  • they When administered to humans or animals, they may be given in doses of from lmg to lOOg per day, preferably lOmg to 30g per day and very preferably lOOmg to 5g per day.
  • skin care agents or other vehicles When incorporated into foods, skin care agents or other vehicles they may be used in concentrations from 0.01 to 50%) preferably 0.5 to 20%, by weight.
  • They may be formulated in capsules, tablets, emulsions, liquids, creams, ointments, skin patches, pessaries, suppositories or any other vehicle for oral, topical, enteral or parenteral administration known to those skilled in the art.
  • Isopropyl esters of bioactive fatty acids may be prepared by any reasonable method of ester synthesis and especially:
  • z,z,z-octadeca-6, 9, 12-trienoic acid 5g, 17.96mmol
  • concentrated sulphuric acid 0.5ml
  • 2-propanol 50ml
  • the mixture was diluted with hexane (25ml) and neutralised with saturated sodium hydrogen carbonate solution.
  • the organic phase was washed with water (2X12ml). dried with magnesium sulphate, filtered, concentrated under reduced pressure and purified by column chromatography to yield z,z,z-octadeca-6, 9, 12-trienoic acid, isopropyl e.ster as a pale yellow oil.
  • z,z,z,z,z,z-eicosa-5, 8, 11,14, 17-pentaenoyl chloride 5g, 15.58mmol
  • 2-propanol 50ml
  • the mixture was concentrated under reduced pressure and purified by column chromatography to yield z,z,z,z,z-eicosa-5, 8, 1 1, 14, 17-pentaenoic acid, isopropyl ester as a yellow oil.
  • Part 2 z,z,z,z,z-eicosa-5, 8, 1 1, 14, 17-pentaenoic acid, isopropyl ester (ester of EPA and isopropanol)
  • Cesium z,z,z,z,z-eicosa-5, 8, 1 1,14, 17-pentaenoate (7.18g 16.53 mmol) and 2-iodopropane (5.62g, 33.06mmol) were heated to 50°C in tetrahydrofuran (55ml) and 1 , 3-dimethyl-3, 4, 5, 6-tetrahydro-2(lH)-pyrimidinone (55ml) with stirring for 3 days under an atmosphere of nitrogen.
  • the mixture was diluted with water (50ml) and a 1 : 1 solution of ethyl acetate and hexane (100ml).
  • the aqueous phase was extracted with ethyl acetate/hexane (1 : 1, 2X250ml).
  • the combined organic phases were washed with saturated sodium chloride solution (2X50ml) and water (50ml), dried with magnesium sulphate, filtered, concentrated under reduced pressure and purified by column chromatography to yield z,z,z,z,z-eicosa-5, 8, 1 1, 14, 17-pentaenoic acid, isopropyl ester as a yellow oil.
  • isopropyl esters of the n-6 EFAs other than GLA, of the n-3 EFAs other than EPA, and of conjugated linoleic acid, parinaric acid and columbinic acid are prepared.
  • Capsules hard or soft gelatin, containing 400mg of the isopropyl ester of linoleic acid, alphalinolenic acid, ga ma-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, or any of the other fatty acids specified.
  • Emulsions for oral or intravenous administration containing 10% by weight of the isopropyl ester of a fatty acid as mentioned in Example 8, suitable natural, synthetic and semi-synthetic emulsifiers, such as phospholipids and galactolipids, known to those skilled in the field being used.
  • suitable natural, synthetic and semi-synthetic emulsifiers such as phospholipids and galactolipids, known to those skilled in the field being used.
  • Galactolipid emulsifiers may in particular be those of our PCT patent application SE 97/001 15 (WO 95/20943)
  • Creams or ointments for topical application prepared as per se known to those skilled in the field and containing 1% by weight of the isopropyl ester of a fatty acid as mentioned in Example 8.

Abstract

L'invention concerne des esters isopropyle d'acides gras possédant de 16 à 26 atomes de carbone et de 2 à 6 liaisons doubles soit dans la configuration cis, soit dans la configuration trans.
PCT/GB1997/002502 1996-09-26 1997-09-17 Esters d'acides gras insatures WO1998013330A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42159/97A AU4215997A (en) 1996-09-26 1997-09-17 Esters of unsaturated fatty acids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9620248.6 1996-09-26
GBGB9620248.6A GB9620248D0 (en) 1996-09-26 1996-09-26 Esters of unsaturated fatty acids

Publications (1)

Publication Number Publication Date
WO1998013330A1 true WO1998013330A1 (fr) 1998-04-02

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/002502 WO1998013330A1 (fr) 1996-09-26 1997-09-17 Esters d'acides gras insatures

Country Status (3)

Country Link
AU (1) AU4215997A (fr)
GB (1) GB9620248D0 (fr)
WO (1) WO1998013330A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1037624A1 (fr) * 1997-12-12 2000-09-27 Purdue Research Foundation Methodes et compositions de traitement du diabete
FR2803749A1 (fr) * 2000-01-18 2001-07-20 Pharmascience Lab Utilisation d'au moins un ester gras pour la preparation d'une composition destinee a inhiber l'activite de la 5 alpha-reductase, en pharmacie notamment en dermatologie, en cosmetique et en tant qu'additif alimentaire
US6551602B1 (en) * 1999-07-30 2003-04-22 Conopco, Inc. Skin care composition containing conjugated linoleic acid and a phenolic compound
US7015249B1 (en) 1997-12-12 2006-03-21 Purdue Research Foundation Methods and compositions for treating diabetes
FR2940281A1 (fr) * 2008-12-22 2010-06-25 Fabre Pierre Dermo Cosmetique Ester de diol et d'acide gras polyinsature comme agent anti-acne
US8809560B2 (en) 2011-05-17 2014-08-19 Board Of Trustees Of The University Of Arkansas Trans-, trans-conjugated linoleic acid compositions and use thereof
US9062276B2 (en) 2012-12-03 2015-06-23 Board Of Trustees Of The University Of Arkansas Conjugated linoleic acid rich vegetable oil production from linoleic rich oils by heterogeneous catalysis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05306223A (ja) * 1991-07-03 1993-11-19 Takeda Chem Ind Ltd 抗真菌性外用組成物
WO1995000107A1 (fr) * 1993-06-22 1995-01-05 Aminco, Inc. Protection du cuir chevelu et de la peau lors de l'application de produits traitants sur les cheveux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05306223A (ja) * 1991-07-03 1993-11-19 Takeda Chem Ind Ltd 抗真菌性外用組成物
WO1995000107A1 (fr) * 1993-06-22 1995-01-05 Aminco, Inc. Protection du cuir chevelu et de la peau lors de l'application de produits traitants sur les cheveux

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ATARASHII GANKA, vol. 12, no. 4, 1995, pages 683 - 688 *
CHEM.ZVESTI, vol. 16, 1962, pages 82 - 88 *
CHEMICAL ABSTRACTS, vol. 121, no. 23, 5 December 1994, Columbus, Ohio, US; abstract no. 271293n, PINTO JULIA C. ET AL.: "Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid" page 33; column right; XP002047561 *
CHEMICAL ABSTRACTS, vol. 123, no. 5, 31 July 1995, Columbus, Ohio, US; abstract no. 47841y, SAKAI HIROYUKI ET AL.: "Effect of topical docosahexaenoic acid (DHA) isopropyl ester on retinal function in vitamin E-deficient rabbits" page 79; column left; XP002047560 *
CHEMICAL ABSTRACTS, vol. 59, no. 1, 8 July 1963, Columbus, Ohio, US; abstract no. 433e, STEFAN KOVAC: "The preparation of alkyl esters of cis,cis-delta 9,12-octadecadienoic acid and cis,cis,cis-delta 9,12,15-octadecatrienoic acid." page 263; column 433; XP002047559 *
DATABASE WPI Week 9351, 19 November 1993 Derwent World Patents Index; AN 93-408837, XP002047562 *
MOL.PHARMACOL., vol. 46, no. 3, 1994, pages 516 - 522 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1037624A1 (fr) * 1997-12-12 2000-09-27 Purdue Research Foundation Methodes et compositions de traitement du diabete
EP1037624A4 (fr) * 1997-12-12 2002-05-15 Purdue Research Foundation Methodes et compositions de traitement du diabete
US7015249B1 (en) 1997-12-12 2006-03-21 Purdue Research Foundation Methods and compositions for treating diabetes
US6551602B1 (en) * 1999-07-30 2003-04-22 Conopco, Inc. Skin care composition containing conjugated linoleic acid and a phenolic compound
FR2803749A1 (fr) * 2000-01-18 2001-07-20 Pharmascience Lab Utilisation d'au moins un ester gras pour la preparation d'une composition destinee a inhiber l'activite de la 5 alpha-reductase, en pharmacie notamment en dermatologie, en cosmetique et en tant qu'additif alimentaire
WO2001052837A2 (fr) * 2000-01-18 2001-07-26 Laboratoires Pharmascience Utilisation d'au moins un ester gras pour la preparation d'une composition destinee a inhiber l'activite de la 5 alpha reductase, en pharmacie notamment en dermatologie, en cosmetique et en tant qu'additif alimentaire
WO2001052837A3 (fr) * 2000-01-18 2002-06-20 Pharmascience Lab Utilisation d'au moins un ester gras pour la preparation d'une composition destinee a inhiber l'activite de la 5 alpha reductase, en pharmacie notamment en dermatologie, en cosmetique et en tant qu'additif alimentaire
JP2003520229A (ja) * 2000-01-18 2003-07-02 ラボラトワール ファルマシアンス ５α−レダクターゼ活性を阻害するように設計された組成物を調製するための少なくとも１つの脂肪酸エステルの薬理学、特定の皮膚科学、化粧品における使用および食品添加物としての使用。
US8318186B2 (en) 2000-01-18 2012-11-27 Laboratoires Expanscience Use of at least a fatty ester for preparing a composition designed to inhibit 5-α-reductase activity, in pharmacology, in particular dermatology, in cosmetics and as food additive
JP4948732B2 (ja) * 2000-01-18 2012-06-06 ラボラトワール エクスパンシアンス ５α−レダクターゼ活性を阻害するように設計された組成物を調製するための少なくとも１つの脂肪酸エステルの薬理学、特定の皮膚科学、化粧品における使用および食品添加物としての使用。
KR20110101152A (ko) * 2008-12-22 2011-09-15 삐에르화브르데르모-코스메띠끄 고도불포화 지방산 및 디올 에스테르 항-여드름 제제
WO2010072738A1 (fr) * 2008-12-22 2010-07-01 Pierre Fabre Dermo-Cosmetique Ester de diol et d'acide gras polyinsature comme agent anti-acne
JP2012513380A (ja) * 2008-12-22 2012-06-14 ピエール、ファブレ、デルモ‐コスメティーク 抗アクネ剤としての多価不飽和脂肪酸およびジオールエステル
FR2940281A1 (fr) * 2008-12-22 2010-06-25 Fabre Pierre Dermo Cosmetique Ester de diol et d'acide gras polyinsature comme agent anti-acne
AU2009331526B2 (en) * 2008-12-22 2013-10-24 Pierre Fabre Dermo-Cosmetique Polyunsaturated fatty acid and diol ester as an anti-acne agent
US8623916B2 (en) 2008-12-22 2014-01-07 Pierre Fabre Dermo-Cosmetique Polyunsaturated fatty acid and diol ester as an anti-acne agent
CN102256930B (zh) * 2008-12-22 2014-03-12 皮埃尔·法布尔皮肤化妆品公司 作为抗痤疮剂的多不饱和脂肪酸及二醇酯
KR101676055B1 (ko) 2008-12-22 2016-11-14 삐에르화브르데르모-코스메띠끄 고도불포화 지방산 및 디올 에스테르 항-여드름 제제
US8809560B2 (en) 2011-05-17 2014-08-19 Board Of Trustees Of The University Of Arkansas Trans-, trans-conjugated linoleic acid compositions and use thereof
US9062276B2 (en) 2012-12-03 2015-06-23 Board Of Trustees Of The University Of Arkansas Conjugated linoleic acid rich vegetable oil production from linoleic rich oils by heterogeneous catalysis

Also Published As

Publication number Publication date
GB9620248D0 (en) 1996-11-13
AU4215997A (en) 1998-04-17

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