EP3328829A1 - Ceramide dimer, method for the production thereof, and use of same - Google Patents
Ceramide dimer, method for the production thereof, and use of sameInfo
- Publication number
- EP3328829A1 EP3328829A1 EP16744380.3A EP16744380A EP3328829A1 EP 3328829 A1 EP3328829 A1 EP 3328829A1 EP 16744380 A EP16744380 A EP 16744380A EP 3328829 A1 EP3328829 A1 EP 3328829A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- atoms
- ceramide
- carboxylic acid
- mercapto
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- 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
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
Definitions
- the invention relates to ceramide dimers of two ceramides in which the amino alcohols are linked amide-like via a dicarboxylic acid.
- the dicarboxylic acids receive at least one sulfur atom in the chain.
- the invention relates to a method for producing the ceramide dimers.
- the ceramide dimers are used as active ingredients for stabilizing the skin barrier in cosmetic and pharmaceutical preparations.
- the barrier function of human skin is realized by the highly ordered structure of the lipids of the stratum corneum (SC).
- SC lipids form lipid bilayers and consist of the free fatty acids, cholesterol and its derivatives as well as the ceramides.
- Ceramides play a key role here.
- a lack of ceramides in the human stratum corneum is responsible for various skin diseases (Sahle FF, Gebre-Mariam T, Dobner B, Wohlrab J, Neubert RHH, Skin Diseases Associated with the Depletion of Stratum Corneum Lipid and Stratum Corneum Lipid Substitution Therapy. Skin Pharmacology and Physiology (2015); 28: 42-55).
- ceramides have been supplied externally via topical formulations to remedy ceramide deficits in the SC, but they are subject to considerable metabolite.
- ceramide dimers for the stabilization of the skin barrier, whose hydrophilic head groups, such as e.g. the amino alcohols sphingosine and phytosphingosine are linked together via a long-chain dicarboxylic acid.
- This long-chain dicarboxylic acid consists either of a chain of CH 2 groups or of a chain of CH 2 groups which is interrupted by a defined number of ether groups (EP 2 266 950 A1).
- ceramide dimer having the features of claim 1 and the method for producing the ceramide dimer having the features of claim 10.
- Claim 9 discloses uses according to the invention.
- the other dependent claims show advantageous developments.
- a ceramide dimer of two ceramides is provided, which via a dicarboxylic acid having a carbon chain with 4-40 carbon atoms (optionally 10 to 40 carbon atoms, preferably 20-30 carbon atoms) in each case via an amide bond with two as hydrophilic head group acting amino alcohols is formed, wherein the carbon chain of the dicarboxylic acid by at least one sulfur atom (optionally 1-5 S atoms, preferably 1 to 3 S atoms, in particular 1 to 2 S atoms) is substituted.
- the dicarboxylic acid is preferably an ⁇ , ⁇ -dicarboxylic acid, ie the dicarboxylic acid has a carboxyl group at the beginning and at the end of its carbon chain.
- the invention thus also relates to bipolar ceramide dimers in which the amino alcohols sphingosine and phytosphingosine are linked together by a long-chain dicarboxylic acid.
- the amino alcohols sphingosine and phytosphingosine are linked together by a long-chain dicarboxylic acid.
- Sphingosine and phytosphingosine can be terminally substituted by other polar groups.
- the additional hydrophilic groups increase the polarity and thus the bipolar character of the compounds, resulting in a stronger water-binding capacity.
- the dicarboxylic acid in the chain consists of CH 2 groups, which is interrupted by a defined number of thioether groups.
- Dicarboxylic acid with a chain length of 4-40 carbon atoms is the bipolar character of these ceramides possible.
- the membrane-spanning property of these compounds enhances the stability of the stratum corneum lipid bilayers and thus the barrier function of the stratum corneum.
- Thioether group may preferably be built up from at least two building blocks by one or more alkylation steps.
- At least one of the amino alcohols contains or consists of a sphingosine molecule, wherein the sphingosine molecule or the ceramide particularly preferably a sphingosine, phytosphingosine, sphinganine or 6-hydroxysphingosine main body according to one of the general Formulas I to IV have:
- R straight-chain or branched dicarboxylic acid radical having 4-40 C atoms (optionally 10 to 40 C atoms, preferably 20-30 C atoms), wherein the carbon chain of the dicarboxylic acid residue is substituted by at least one sulfur atom, i. the dicarboxylic acid residue contains at least one thioether group.
- dicarboxylic acid is substituted with one or more sulfur atoms in the chain according to one of the general formulas V or VI:
- Ri sphingoid basic body according to one of the formulas I to IV;
- Ri ' sphingoid basic body according to one of the formulas I to IV;
- R 2 H or OH
- R 2 ' H or OH
- R 3 straight-chain or branched C 1 -C 8 -alkyl radical
- R 3 ' straight-chain or branched C 1 -C 8 -alkyl radical
- R 4 ' straight-chain or branched C 2 -C 20 -alkyl radical
- n at least 1.
- the head group of the ceramide dimer has at least one further hydrophilic group.
- This at least one further hydrophilic group is preferably selected from the group consisting of amino acids, in particular serine, threonine, lysine, arginine, histidine, asparagine, aspartic acid, glutamine, glutamic acid, tyrosine and
- Polyols especially ethanediol, propanediol or Gly
- Sugar in particular glucose or galactose
- Amino sugars or sugar derivatives with dissociable carboxyl group in particular glucuronic acid or galacturonic acid
- organic acids in particular succinic acid, malic acid or
- Inorganic acids in particular phosphoric or sulfuric acid,
- the at least one further hydrophilic group is either via the hydroxyl group or the hydroxymethylene group of
- the ceramide dimers may be provided for use as drugs.
- skin diseases preferably diseases in which a disorder of the composition of the stratum corneum lipids of the skin is present, particularly preferred diseases in which a disturbance of the composition of the stratum corneum- lipids of the skin with respect to the content of ceramides, a Hydroxyceramides and / or sphingosines.
- the ceramide dimers according to the invention can be used for the preparation of a cosmetic preparation, in particular as a colloidal preparation, preferably as a cream, ointment, lotion, suspension, gel, spray, cosmetic oil, nanoparticle, nanocapsule, microemulsion or liposomes.
- a process for the preparation of a ceramide dimer according to the invention comprising the coupling of a first and a second carboxylic acid group of a dicarboxylic acid whose carbon chain is substituted by at least one sulfur atom, with the amino group of each sphingoid body, wherein two amide bonds formed become.
- the two amide bonds thus combine chemically kova- lent the a- and ⁇ -position of the carboxylic acid with the position of the amino group of the sphingoid basic body.
- the dicarboxylic acid is prepared prior to coupling by a process comprising the steps of: a) reacting at least one ⁇ , ⁇ -diol having 2 to 20 carbon atoms or an ⁇ , ⁇ -dihalide having 2 to 20 C atoms, preferably with thiourea, to an ⁇ , ⁇ -dithiol, in particular to octane-l, 8-dithiol;
- Dithiols especially to form dipotassium octane-l, 8-dithiolate; and c) reaction of the alkali salt of the ⁇ , ⁇ -dithiol with two ⁇ -functionalized carboxylic acids each having 2 to 20 carbon atoms, preferably with the addition of a condensing agent and an auxiliary base or an activator, in particular to 12,21-dithiadotriacontanedioic acid.
- dicarboxylic acid may be provided prior to coupling by a process comprising the steps of:
- dicarboxylic acid may be provided prior to coupling by a method comprising the following steps:
- Halogenated carboxylic acid having 2 to 20 carbon atoms preferably with the addition of a condensing agent and an auxiliary base or an activator, in particular to 16-thiahentriacontanedioic acid.
- a condensing agent preferably with the addition of a condensing agent and an auxiliary base or an activator, in particular to 16-thiahentriacontanedioic acid.
- reaction of the alkali thiolate with acid to form a thiol, preferably in 2N hydrochloric acid.
- step c) preferably takes place with heating for 5 to 20 hours.
- the coupling in the process according to the invention is preferably carried out with the addition of a coupling reagent, more preferably in combination with an auxiliary base and / or an activator, whereby in particular ⁇ , ⁇ '-bis [(3S, 4R) -l, 3,4-trihydroxyoctadec (2S) -2-yl] -12,21-dithiado-tria-contan- diamide is formed.
- the carboxylic acid is an ⁇ , ⁇ -dicarboxylic acid, preferably an ⁇ , ⁇ -dicarboxylic acid having a) 4-40 C atoms, preferably 10 to 40 C atoms, particularly preferably 20 to 35 C atoms. Atoms, in particular 25-30 C atoms; and or 1-5 S atoms, preferably 1 to 3 S atoms, in particular 1 to 2 S atoms.
- the ceramide dimers according to the invention are preferably preparable by the process according to the invention.
- Fig. 1 shows a first compound according to the invention with two
- Fig. 2 shows a second compound according to the invention with a
- starting materials for the compound shown in Fig. 1 serve ⁇ , ⁇ -diols and ⁇ , ⁇ - dibromides of different chain length, which are converted into ⁇ , ⁇ -dithiols.
- the dithiols are then reacted in the form of their sodium and potassium salts with ⁇ -functionalized carboxylic acid derivatives.
- the commercially available 11-bromoundecanoic acid is used.
- Bis-tosylate and bis-mesylate of octane-l, 8-diol can be obtained.
- the compound shown in Fig. 2 is prepared from 15-bromo- or 15-hydroxypentadecanoic acid and potassium sulfide.
- the binding of the dicarboxylic acids according to the invention to the sphingosine and phytosphingosine bodies or their derivatives is carried out by using pybop as condensing agent and an auxiliary base.
- a second method involves the use of EEDQ. as activating reagent. example
- Washed diethyl ether and the ether phases are combined with the dithiol phase, concentrated and dried over phosphorus pentoxide.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102015214295.7A DE102015214295A1 (en) | 2015-07-28 | 2015-07-28 | Ceramide dimer, process for its preparation and its use |
PCT/EP2016/067818 WO2017017104A1 (en) | 2015-07-28 | 2016-07-26 | Ceramide dimer, method for the production thereof, and use of same |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3328829A1 true EP3328829A1 (en) | 2018-06-06 |
Family
ID=56550880
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16744380.3A Withdrawn EP3328829A1 (en) | 2015-07-28 | 2016-07-26 | Ceramide dimer, method for the production thereof, and use of same |
Country Status (4)
Country | Link |
---|---|
US (1) | US10745349B2 (en) |
EP (1) | EP3328829A1 (en) |
DE (1) | DE102015214295A1 (en) |
WO (1) | WO2017017104A1 (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5863886A (en) * | 1997-09-03 | 1999-01-26 | Rhodia Inc. | Nonionic gemini surfactants having multiple hydrophobic and hydrophilic sugar groups |
EP2266950A1 (en) | 2009-06-23 | 2010-12-29 | Hans Uwe Wolf | Ceramide dimers and their use as medicine or cosmetic preparation |
-
2015
- 2015-07-28 DE DE102015214295.7A patent/DE102015214295A1/en not_active Withdrawn
-
2016
- 2016-07-26 US US15/748,058 patent/US10745349B2/en active Active
- 2016-07-26 WO PCT/EP2016/067818 patent/WO2017017104A1/en active Application Filing
- 2016-07-26 EP EP16744380.3A patent/EP3328829A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
US20180237387A1 (en) | 2018-08-23 |
DE102015214295A1 (en) | 2017-02-02 |
WO2017017104A1 (en) | 2017-02-02 |
US10745349B2 (en) | 2020-08-18 |
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