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WO2013081226A1 - Nouveaux dérivés de phytospingosine et leur procédé de préparation - Google Patents

Nouveaux dérivés de phytospingosine et leur procédé de préparation Download PDF

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Publication number
WO2013081226A1
WO2013081226A1 PCT/KR2011/009339 KR2011009339W WO2013081226A1 WO 2013081226 A1 WO2013081226 A1 WO 2013081226A1 KR 2011009339 W KR2011009339 W KR 2011009339W WO 2013081226 A1 WO2013081226 A1 WO 2013081226A1
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WIPO (PCT)
Prior art keywords
phytosphingosine
hydroxy acid
omega hydroxy
omega
group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2011/009339
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English (en)
Korean (ko)
Inventor
박장서
김진욱
이은옥
장혜원
박성진
이수철
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LCS BIOTECH CO Ltd
Original Assignee
LCS BIOTECH 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 LCS BIOTECH CO Ltd filed Critical LCS BIOTECH CO Ltd
Priority to KR1020147014620A priority Critical patent/KR101689234B1/ko
Priority to PCT/KR2011/009339 priority patent/WO2013081226A1/fr
Publication of WO2013081226A1 publication Critical patent/WO2013081226A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • the technology disclosed herein relates to novel phytosphingosine derivatives and methods for their preparation.
  • Ceramide is a substance present in large quantities in the human body and is known as a substance that controls cell death.
  • the skin tissue plays an important role as a material constituting about 40% of the skin barrier.
  • the stratum corneum or skin barrier which constitutes the outermost layer of the skin, consists of dead corneocytes and intercellular lipids, which protects the skin from external stimuli and It is a skin barrier that prevents evaporation and is known to play a key role in skin health. Keratinocytes, keratinocytes, migrate to the surface of the skin through differentiation of Stratum spinosum and Stratum granulosum during growth differentiation.
  • the keratinocyte internal lipid composition decreases phospholipids and increases the content of ceramide, cholesterol, and fatty acids.
  • the increase in ceramide leads to the death of keratinocytes, and the dead keratinocytes and intercellular lipids make up the stratum corneum.
  • Ceramide is a substance in which fatty acid is amide-bound to sphingoslipid base skeletons such as sphingosine, phytosphingosine, and sphinginine, and is classified into various ceramides according to the type of fatty acid and spingo base. To date, seven to nine ceramides have been identified in the skin, and research on their function is being actively conducted.
  • ceramides In addition to forming lipid bilayers and responsible for moisturizing the skin, ceramides play a role in contributing to the solubility of cholesterol, reducing the fluidity of biological membranes, affecting skin cell differentiation and growth, and signaling in the skin. The mediating point is mentioned. Because of the usefulness of ceramides, many ceramide derivatives have been developed so far. Korean Unexamined Patent Publication No. 10-2003-0065991 also discloses a novel ceramide derivative.
  • an object of the present invention is to provide a method for preparing a derivative of phytosphingosine.
  • the omega hydroxy acid derivative of phytosphingosine according to the present invention is an omega hydroxy acid derivative of phytosphingosine combined with an omega hydroxy acid and phytosphingosine.
  • the omega hydroxy acid derivative of phytosphingosine may be a carboxyl group of the omega hydroxy acid and an amine group of phytosphingosine are bonded by an amide bond.
  • the omega hydroxy acid may have 4 to 28 carbon atoms.
  • the omega hydroxy acid may have 12 to 20 carbon atoms.
  • the omega hydroxy acid may have 14 to 18 carbon atoms.
  • the omega hydroxy acid derivatives of the phytosphingosine may have a structure of the formula (1).
  • a method for preparing an omega hydroxy acid derivative of phytosphingosine comprises the steps of: replacing a hydroxy group of omega hydroxy acid with an acetoxy group; Combining the omega hydroxy acid substituted with the acetoxy group with phytosphingosine; And replacing the acetoxy group with a hydroxy group from an omega hydroxy acid substituted with an acetoxy group bonded with the phytosphingosine.
  • the step of replacing the hydroxy group of the omega hydroxy acid with an acetoxy group may include reacting the omega hydroxy acid with an acetic hydride.
  • the omega hydroxy acid may have 4 to 28 carbon atoms.
  • the omega hydroxy acid may have 12 to 20 carbon atoms.
  • the omega hydroxy acid may have 14 to 18 carbon atoms.
  • the omega hydroxy acid derivative of the phytosphingosine may have a structure of the following formula (1).
  • Another aspect of the invention is a liposome comprising an omega hydroxy acid derivative of phytosphingosine mentioned above.
  • novel omega hydroxy acid derivatives of phytosphingosine can be obtained.
  • the omega hydroxy acid derivatives of the novel phytosphingosine can be used to prepare liposomes with much higher stability than other conventional ceramides or lipids.
  • NMR data of an omega hydroxy acid derivative of phytosphingosine prepared according to a method for preparing an omega hydroxy acid derivative of phytosphingosine according to an aspect of the present invention.
  • the vertical axis represents Relative absorbance representing the absorbance after the addition of deoxycholic acid to the initial absorbance before the addition of deoxycholic acid
  • the horizontal axis represents the molar ratio (DOC / Lipid) of deoxycholic acid (DOC) to lipid. ratio).
  • omega hydroxy acid refers to an acid having a linear aliphatic organic acid having n carbon atoms and having a carboxylic acid at one position and a hydroxy group at the n position.
  • N may be 4 or more, 6 or more, 8 or more, 10 or more, 12 or more, 14 or more, or 16 or more.
  • n may be 28 or less, 26 or less, 24 or less, 22 or less, 20 or less, 18 or less, or 16 or less.
  • n may be 8 to 24.
  • n may be 12 to 20.
  • n may be from 14 to 18.
  • n may be 16. It is more stable if n is in the said range.
  • Omega hydroxy acids may be saturated fatty acids containing only single bonds or unsaturated fatty acids containing one or more double bonds.
  • Phytosphingosine is a type of sphingolipids present in living organisms and means a compound having the formula:
  • Omega hydroxy acid having 16 carbon atoms is a linear aliphatic organic acid having 16 carbon atoms, and means an acid having a carboxylic acid at 1 position and a hydroxy group at 16 position.
  • 16-hydroxyhexadecanoic acid having the following formula as having no double bond:
  • the hydroxy group of the omega hydroxy acid is substituted with an acetoxy group.
  • any one can be used as a reactant of the present substitution reaction.
  • an acetion hydride is mentioned.
  • the omega hydroxy acid substituted with the acetoxy group is then combined with phytosphingosine.
  • the carboxyl group of acetoxy omega hydroxy acid and the amine group of phytosphingosine react to combine the two compounds by amide bond.
  • the acetoxy group is again substituted with a hydroxy group from an omega hydroxy acid substituted with an acetoxy group bonded to phytosphingosine by the amide bond.
  • any reagent can be used as long as it can replace the acetoxy group with a hydroxyl group.
  • a basic solvent is mentioned. Strongly basic solvents can be used for the reaction efficiency. For example, NaOH aqueous solution, KOH aqueous solution, etc. are mentioned.
  • Liposomes comprising 16-hydroxyhexadecanoic phytosphingosine prepared by Example 1 were prepared. Hydrogenated purified soybean lecithin was used to eliminate unsaturation to prepare liposomes. The general composition of the phospholipids of purified soy lecithin is shown in Table 1 below.
  • Example 2 The hydrogenated lecithin and 16-hydroxyhexadecanoicphytosphingosine prepared in Example 1 were mixed in a molar ratio of 30: 1 and dissolved in ethanol. The solvent was evaporated from the obtained solution to form a thin film. Liposomes of a certain size were then prepared by hydration and sonication at 60 ° C. above the phase transition temperature of the lipids (HPC 90 + Y3J).
  • Liposomes were prepared in the same manner as in Example 2, except that the lipid consisting of the hydrogenated lecithin was used to compare the liposomes prepared by Example 2 (HPC only).
  • Liposomes were prepared in the same manner as in Example 2, except that ceramide 3 (oleic acid) was used instead of the 16-hydroxyhexadecanoic phytosphingosine to compare the liposome prepared by Example 2 (HPC). 90 + Y3O).
  • Liposomes were prepared in the same manner as in Example 2, except that ceramide 3 (stearic acid) was used instead of the 16-hydroxyhexadecanoic phytosphingosine to compare the liposomes prepared in Example 2 ( HPC 90 + Y3S).
  • ceramide 3 stearic acid
  • Liposomes were prepared in the same manner as in Example 2, except that oleic acid was used instead of the 16-hydroxyhexadecanoic phytosphingosine to compare the liposome prepared by Example 2 (HPC 90 + OA). .
  • Liposomes were prepared in the same manner as in Example 2, except that stearic acid was used instead of the 16-hydroxyhexadecanoicphytosphingosine to compare the liposomes prepared by Example 2 (HPC 90 + SA ).
  • liposomes were prepared in the same manner as in Example 2, except that 16-hydroxyhexadecanoic acid was used instead of 16-hydroxyhexadecanoicphytosphingosine. (HPC 90 + JA).
  • Example 2 In order to evaluate the stability of liposomes prepared according to Example 2 and Comparative Examples 1-6, the degree of dissolution of liposomes by adding deoxycholic acid, a powerful solubilizer, to the prepared liposomes was measured at 490 nm with a spectrophotometer. Absorbance was measured. The results are shown in FIG. FIG. 2 shows how the relative absorbance, which represents the absorbance after addition of deoxycholic acid to the initial absorbance, changes as the ratio of deoxycholic acid (DOC) to lipid (DOC / Lipid ratio) increases. . As shown in Figure 2, liposomes containing 16-hydroxyhexadecanoicphytosphingosine according to Example 2 had the highest stability.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un nouveau dérivé acide oméga-hydroxylique de phytospingosine et son procédé de préparation. En particulier, cette invention concerne un dérivé acide oméga-hydroxylique de phytospingosine obtenu par combinaison d'un groupe carboxylique d'acide oméga-hydroxylique ayant un certain nombre de carbone et d'un groupe amine de phytospingosine par l'intermédiaire d'une liaison amide.
PCT/KR2011/009339 2011-12-02 2011-12-02 Nouveaux dérivés de phytospingosine et leur procédé de préparation Ceased WO2013081226A1 (fr)

Priority Applications (2)

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KR1020147014620A KR101689234B1 (ko) 2011-12-02 2011-12-02 신규 파이토스핑고신 유도체 및 그 제조방법
PCT/KR2011/009339 WO2013081226A1 (fr) 2011-12-02 2011-12-02 Nouveaux dérivés de phytospingosine et leur procédé de préparation

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107567457A (zh) * 2015-03-31 2018-01-09 爱茉莉太平洋股份有限公司 植物鞘氨醇衍生物及含有其的组合物
JP2024503368A (ja) * 2021-01-06 2024-01-25 エボニック オペレーションズ ゲーエムベーハー ヒドロキシ置換スフィンゴ脂質
JP7788458B2 (ja) 2021-01-06 2025-12-18 エボニック オペレーションズ ゲーエムベーハー ヒドロキシ置換スフィンゴ脂質

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011881A1 (fr) * 1993-10-28 1995-05-04 Gist-Brocades N.V. Analogues de ceramide i a base de phytosphingosine
KR100423102B1 (ko) * 2001-08-13 2004-03-16 주식회사 참 존 항암활성을 가지는 파이토스핑고신 유도체

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
JP3594962B2 (ja) * 1992-04-03 2004-12-02 コスモフェルム ベースローテン フェンノートシャップ アミノアルコールの選択的ｎ‐アシル化

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011881A1 (fr) * 1993-10-28 1995-05-04 Gist-Brocades N.V. Analogues de ceramide i a base de phytosphingosine
KR100423102B1 (ko) * 2001-08-13 2004-03-16 주식회사 참 존 항암활성을 가지는 파이토스핑고신 유도체

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MOON, BYUNG SEOK ET AL.: "Synthesis of novel phytosphingosine derivatives and their preliminary biological evaluation for enhancing radiation therapy.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS., vol. 17, 2007, pages 6643 - 6646, XP022325953, DOI: doi:10.1016/j.bmcl.2006.09.063 *
ZYTOVSKA J ET AL.: "Influence of phytosphingosine-type ceramides on the structure of DMPC membrane.", CHEMISTRY AND PHYSICS OF LIPIDS., vol. 138, 2005, pages 69 - 80 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107567457A (zh) * 2015-03-31 2018-01-09 爱茉莉太平洋股份有限公司 植物鞘氨醇衍生物及含有其的组合物
CN107567457B (zh) * 2015-03-31 2020-07-03 爱茉莉太平洋股份有限公司 植物鞘氨醇衍生物及含有其的组合物
JP2024503368A (ja) * 2021-01-06 2024-01-25 エボニック オペレーションズ ゲーエムベーハー ヒドロキシ置換スフィンゴ脂質
JP7788458B2 (ja) 2021-01-06 2025-12-18 エボニック オペレーションズ ゲーエムベーハー ヒドロキシ置換スフィンゴ脂質

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KR101689234B1 (ko) 2016-12-23
KR20140097263A (ko) 2014-08-06

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