CN101434557A - Derivative of short chain 2-hydroxy carboxylic acid of ceramide - Google Patents
Derivative of short chain 2-hydroxy carboxylic acid of ceramide Download PDFInfo
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- CN101434557A CN101434557A CNA2007101681683A CN200710168168A CN101434557A CN 101434557 A CN101434557 A CN 101434557A CN A2007101681683 A CNA2007101681683 A CN A2007101681683A CN 200710168168 A CN200710168168 A CN 200710168168A CN 101434557 A CN101434557 A CN 101434557A
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Abstract
The invention relates to a compound, which is analog sphingosine base selected from sphingosine which is connected to 2-hydroxy-carboxyl with a chain length of 2 to 14 carbon atoms by amides and sphingosine, and the condition is that the compound is not glycolyl Sphingosine, 2-hydroxy butyryl group sphingosine or 2-hydroxy decanoyl dihydro sphingosine. The invention also relates to a preparation method of the compound, cosmetics or medical composition containing the compound, therapeutic application of the compound and the application of the compound as cosmetics.
Description
The present invention relates to new compound, promptly active ceramide derivatives.Especially, the present invention relates to the ceramide derivatives of 2 (α)-hydroxycarboxylic acids system.The invention describes the method that obtains these compounds.The invention still further relates to the topical application of these compounds.
Background of invention
Stratum corneum is made up of the keratinocyte (being called corneal cell) of end differentiation and the lipid that mainly is arranged in double-deck intercellular substance; This arrangement is called as " brick and mortar (bricks and mortar) " model (Schurer, N.Y. and Elias, P.M.in ＂ Thebiochemistry and function of stratum corneum lipids ＂, Adv.Lip.Research, (1991), the 24th volume, pp.27-57, Academic Press, San Diego).Therefore think that stratum corneum is two chamber systems, lipid be mutually only continuous system (Elias, P.M., J.Contr.Rel. (1991), 15, pp.199-208).The thin board type bilayer interacts by Van der Waals and hydrogen bond is stabilized in aqueous environment, that is: hydrophilic water layer be present between the double-layer of lipoid (people such as Rehfeld, J.Invest.Dermatol. (1988), 91,499-505).
Have been found that when (AHA ' when s) locally applying on the skin, it reduces cuticular corneal cell force of cohesion, thereby causes that corneal cell comes off (synonym: peel, peel off), causes more smooth, glossy and softish skin more with the 2-hydroxycarboxylic acid.In addition, it is reported that AHA ' s and related compound alleviate with endogenous and/or exogenous aging relevant skin, nail and hair change levies the marquis.Known AHA ' s also strengthens cell renewal and collagen synthetic (Berardesca, E. and Distante F., in:Proceedings of 10
ThSymposium of the BelgianAssociation of Dermato-Cosmetic Sciences, pp.11-23,1994; Smith, people such as W.P., Cosm.and Toilet. (1994), 109,41-48).
A shortcoming using AHA ' s is these compounds needs high relatively level (from 2-10%) being used for topical application of compositions.Known AHA ' s can stimulate or shouting pain people's skin once in a while.It is necessary to the exploitation for example improved four the step system, wherein the amount of AHA increases the AHA that makes skin can adapt to increasing amount gradually.
Also described AHA ' s do not show strong water retention capacity (Berardesca and Distante, op.cit.).
Ceramide is formed the 20-40% of whole skin lipids and is present in the cuticular intercellular lipid layer.Think that they have vital role in the water opacity barrier of formation and maintenance skin.
In order to make topical application effective, ceramide (and common sphingolipid) must be able to infiltrate in the stratum corneum to arrive the lipid layer of opacity barrier.Show (Potts, R.O. and Guy, R.H., in Dermal and Transdermal Drug Delivery, APV-paperback Band 31, Gurny, R. and Teubner, A. edits, 1993) permeability coefficient (K at compound
p) and hydrophobicity (octanol/water partition ratio, K
Oct) between have positive correlation.From cuticular natural ceramide is lipophilic compound, and when the outer time spent, it does not have the optimum balance that can finely infiltrate through skin between water and lipolyse.
The invention discloses the ceramide derivatives of 2 (α)-hydroxycarboxylic acids system.Ceramide derivatives of the present invention is connected to the ceramide of following 2-hydroxyl carboxylic compound and the sphingoid bases of phytosphingosine (sphingoid base) is formed by being selected from acid amides:
1. 2-oxyacetic acid (oxyacetic acid)
2. 2 hydroxy propanoic acid (lactic acid)
3. 2-methyl-2 hydroxy propanoic acid (methyllactic acid)
4. 2-hydroxybutyric acid
5. 2-hydroxypentanoic acid
6. 2-hydroxycaproic acid
7. 2-hydroxyl enanthic acid
8. 2-Hydroxyoctanoic acid (Alpha-hydroxy is sad)
9. 2-hydroxyl n-nonanoic acid
10. 2-hydroxydecanoic acid
11. 2-hydroxyl undeeanoic acid
12. 2-hydroxyl dodecanoic acid
13. being described ceramide derivatives, 2-hydroxy tetradecanoic acid (Alpha-hydroxy lauric acid), condition be not glycolyl ceramide, 2-maloyl group ceramide or 2-hydroxy decanoyl ceramide.
The present invention also provides the method for these compounds of preparation.
In another aspect of this invention, described compound is used to prepare makeup and/or pharmaceutical composition.
Comprise compound compositions of the present invention and be suitable for local the use.Especially, comprise structure or the state that compound compositions of the present invention can be used for improving skin.
Detailed Description Of The Invention
The present invention relates to new compound, promptly active ceramide derivatives.Especially, the invention discloses the ceramide derivatives of 2 (α)-hydroxycarboxylic acids system.
Ceramide forms the maximum polar lipid class of epidermis lipid.These ceramides form the sphingolipid of structure heterology, and it comprises the sphingoid bases that is connected with acid amides with (hydroxyl and non-hydroxyl) paraffinic acid.
Ceramide derivatives of the present invention is connected to following 2-hydroxy carboxylic acid compound's ceramide and the sphingoid bases of vegetative nerve sphingosine is formed by being selected from acid amides:
1. 2-oxyacetic acid (oxyacetic acid)
2. 2 hydroxy propanoic acid (lactic acid)
3. 2-methyl-2 hydroxy propanoic acid (methyllactic acid)
4. 2-hydroxybutyric acid
5. 2-hydroxypentanoic acid
6. 2-hydroxycaproic acid
7. 2-hydroxyl enanthic acid
8. 2-Hydroxyoctanoic acid (Alpha-hydroxy is sad)
9. 2-hydroxyl n-nonanoic acid
10. 2-hydroxydecanoic acid
11. 2-hydroxyl undeeanoic acid
12. 2-hydroxyl dodecanoic acid
13. being described ceramide derivatives, 2-hydroxy tetradecanoic acid (Alpha-hydroxy lauric acid), condition be not glycolyl ceramide, 2-maloyl group ceramide or 2-hydroxy decanoyl ceramide.Ceramide
By AHA ' s is connected on the sphingoid bases, form derivative.These quite lipophilic ceramide derivatives are than in easier the penetrating to the skin of hydrophilic AHA ' s.Thereby the concentration of the required AHA ' s of topical application can be far below the concentration when using as free acid in cosmetic formulations in the time of in being included in the ceramide main chain.
In addition, integrate AHA ' s in the ceramide structure and have advantage: the compound that obtains has the acidity lower than corresponding free AHA ' s also therefore may than its low stimulation.Therefore, the AHA-ceramide derivatives of the present invention of relative high density be can use and skin irritation and inflammation do not caused.
Should also be noted that and have three class ceramides in the mammal skin: ceramide 4, ceramide 5 and ceramide 6II (always have the different ceramide of seven classes, Wertz, P.W. wait people (1985), J.Inv.Derm.84,410-412), be actually the combination of sphingoid bases and alpha-hydroxy carboxylic acid compounds.Yet the AHA ' s that produces on these physiology is in the scope of 16-30 carbon atom; There is not to find to be lower than the kind of 16 carbon atoms.The present invention be more particularly directed to comprise the purposes that the short chain alpha hydroxy acid is the ceramide derivatives of C2-C14 acid.
The present invention also provides the method for these C2-C14 alpha-hydroxy carboxylic acid compounds ceramide derivatives of preparation.2 (α)-hydroxycarboxylic acid ceramide derivatives of the present invention prepare by following reactions steps:
-will have required chain length carboxylic acid in 2-position bromination,
-2-bromine carboxylic acid is converted into the 2-alcohol acid,
-with described 2-alcohol acid acidylate,
-by in the presence of alkali, in organic solvent, reacting, the 2-acyloxycarboxylic acid is converted into mixed acid anhydride with alkyl sulfonyl chloride or alkaryl SULPHURYL CHLORIDE,
-prepare N-2-acyloxy amido alcohol by described mixed acid anhydride and amino alcohol (sphingoid bases is an amino alcohol) or its reactant salt,
-by described N-2-acyloxy amido alcohol alkaline hydrolysis is obtained ceramide derivatives of the present invention.
In another aspect of this invention, the ceramide of AHA system is used to prepare makeup and/or pharmaceutical composition.
Special makeup and/or pharmaceutical preparation comprise the known composition of one of skill in the art.Described composition comprises the vehicle that activeconstituents can be delivered to skin.Vehicle comprises water, solid and liquid.These are divided into tenderizer, propelling agent, solvent, wetting Agent for Printing Inks, thickening material, penetration enhancer and powder.
Tenderizer comprises alkyl higher fatty acid, oil and higher alcohols.
Propelling agent comprises propane, butane, Trimethylmethane, dme, chlorine fluoroalkane (chlorofluoroalkane), carbonic acid gas, Nitrous Oxide.
Solvent comprises ethanol, methylene dichloride, Virahol, ether, DMSO.
Wetting Agent for Printing Inks comprises glycerine, gelatin, sorbyl alcohol.
Penetration enhancer comprises solvent, oil, tensio-active agent.
Powder comprises chalk, talcum, starch, natural gum.
The combination of described composition can account for 10 to 99% of composition.
Comprise compound compositions of the present invention and be fit to local the use.The amount that is fit to the activeconstituents of topical application or its mixture by the weight of composition from 0.001% to 10%, preferably from 0.005% to 2%, most preferably in from 0.01% to 1% the scope.
Especially, comprise structure and the state that compound compositions of the present invention can be used for improving skin.Described thus improvement comprises the protection that strengthens skin and avoid stimulating, the protection that strengthens the skin anti-inflammatory, the dehydration of minimizing skin, minimizing skin irritation, quickening skin exfoliation, increases the slipperiness of skin.
Comprise compound compositions of the present invention by topical application, find that the ceramide of AHA system has multi-functional effect.
Compound of the present invention on the one hand, has showed the effect of short chain AHA ' s really.They show owing to reducing the corneal cell cohesion increases skin peeling (coming off), and reduces the roughness of skin.
On the other hand, the effect that the ceramide of AHA of the present invention system shows the same ceramide of skin surprisingly that is: is strengthened and is kept cuticular lipid layer barrier.This ability of avoiding stimulating by the ceramide protection skin of AHA system obtains proof.
Ceramide 6 derivatives of the present invention by preparing several 2-of comprising hydroxycarboxylic acids, promptly N-(2-hydroxyl propionyl)-, N-(2-hydroxy capryloyl base)-and N-(2-hydroxy decanoyl)-phytosphingosine carry out illustration.
The phytosphingosine that uses can effectively obtain by the deacetylation of Tetraacetylphytospingosine, and Tetraacetylphytospingosine self can particularly pass through by microbial fermentation
Hansenula ciferriFermentation is a large amount of to be obtained.
The make-up composition that comprises these compounds and the topical application of these compositions have been described.
Experiment
Measuring apparatus
Roughness
(OFR 01 to use the pin type instrument; Romano GmbH, Cologne Germany) measures roughness by technology of profiling (profilometry).The silicon die of preparation palmar forearm test zone.Use dental material Silasoft
(Detax-K.Huber K.G., Karlsruhe Germany) make die.Measure roughness R
zThe parameter mean degree of depth of (DIN 4768/1).By convention, sweep length is divided into three equidimension zones, determines that in each zone the climax is to the distance between the lowest trough.The mean value of these five distances is R
z
See through the epidermis fluid loss
With Tewameter (Courage ﹠amp; Khazaka, Cologne Germany) sees through the measurement of epidermis fluid loss (TEWL).Tewameter be a kind of by A.Fick at 1885 the devices of finding based on the measurement skin surface moisture evaporation of diffusion principle.
The colour of skin
With Minolta Chromameter CR 300 (Minolta, Ahrensburg, Germany) by colorimetry according to the Commission International de l ' eclairage (CIE) system, measure the colour of skin, regulate the non-linear color sensitivity that color is recorded to human eye in view of the above.Has green-red (a
*), Huang-indigo plant (b
*) and L
*Express color in the three-dimensional coordinate system of axle (brightness).Illuminate skin and the fluorescence that transmits by photoreceiver record and analyzing by the hernia photoflash lamp.Colorimetry is sensitive and accurately be used to characterize skin irritant redness.On the skin of inflammation, observe a
*The just variation of redward on the axle.Each value all is the mean value of three records.
Decortication
Use dansyl chloride that stratum corneum is dyeed.In the day before yesterday that begins this research, with dansyl chloride with 5% (weight) uniform mixing in Vaseline and be administered to the palmar forearm of the volunteer under semiclosed band.After 24 hours, remove cover plate and under the mobile tap water, wipe all excessive materials.Under the UV irradiation, use following fluorescence to extract scale and estimate fluorescence intensity and homogeneity by the evaluator who trained:
0: no fluorescence extracts
1: hypofluorescence extracts
2: medium fluorescence extracts
3: hyperfluorescence extracts
4: fluorescence extracts fully.
Use half scale when needing.
Test method
Comprise in the test that two groups every group 5 age 19-55 year has the volunteer of healthy skin.
Relative humidity in 22 ± 1 ℃ temperature and 60 ± 10% is measured.Before measuring, all make experimenter's customary environment condition 20 minutes.Test is carried out at the palmar forearm.In all six zones, measure initial untreated skin to find baseline value.Use five kinds of test products then, a zone keeps not handling.The dosage of using is about 2mg/cm
2Afterwards 7 days be in and use morning and night.Daily the last time using assessed observed value in back two hours during the 7th day treatment.Then the test site of two forearms is handled with the aqueous solution of 5% sodium lauryl sulphate (SDS) and used air-locked dressing to induce skin irritation.Remove dressing after two hours, water leniently washs this zone and air-dry.After 1 hour, after the same day is steadily fixed, measure.
In whole research, using of other makeup is limited to pilot region.
Evaluation time
-before beginning to handle;
-Di used back two hours in 7 days for the last time;
-stimulate (sealing following 2 hours) after 1 hour with SDS.
*Propylene glycol (with) Phenoxyethanol (with) methyl p-hydroxybenzoate (with) propylparaben (with) ethyl p-hydroxybenzoate (with) butyl p-hydroxybenzoate
Embodiment 1
N-[(S)-and 2-hydroxyl propionyl] phytosphingosine (Cer6/OH-C3) synthetic
A. (S)-2-acetoxyl group propionic acid
With Dien-Rodney Stark device with (S)-2 hydroxy propanoic acid (120ml; 135g; 1.5mol), acetate (500ml), toluene (100ml) and the vitriol oil (1ml) heating under refluxing.In water trap (trap), collect during the water, add more toluene (2x100ml) and acetate (200ml).After adding sodium acetate (4g), the underpressure distillation reaction mixture, thus obtain (S)-2-acetoxyl group propionic acid of 99.2g at 116-130 ℃/0.2mmHg.
B.N-[(S)-and 2-acetoxyl group propionyl] phytosphingosine
At 31 ℃, in the stirred solution of ethyl acetate (250ml), dripping (S)-2-acetoxyl group propionic acid (24.38g at Tosyl chloride (32.4g) under the nitrogen; 184mmol), the mixture of triethylamine (60ml) and ethyl acetate (90ml).After 20 minutes, under nitrogen, mixture was added to phytosphingosine vitriol (51g 45 ℃ of stirrings in about 10 minutes; About 63mmol) in the suspension of the stirring of ethyl acetate (165ml) and triethylamine (30ml) (39 ℃).Add entry (150ml) 50 ℃ of stirrings after 2 hours.Separate each layer and in organic layer, add the water of 150ml.Behind HCl (36%) adjusting pH to 2.5, isolate organic layer, use sodium chloride solution washing (100ml; 20% solution) and in rotatory evaporator in vacuum-evaporation to dry.The methyl alcohol that then adds 100ml also evaporates methyl alcohol again.After resistates is dissolved in the hot methanol of 200ml, solution is cooled to 1 ℃ and use independently strainer to filter to keep low temperature.After the cold methanol with 50ml washs also vacuum-drying, obtain the N-[(S of 31.31g)-2-acetoxyl group propionyl] phytosphingosine.
PMR composes (360MHz; DMSO-d6; Numerical value is represented with ppm).
δ：0.84(t，3H)；1.23(22H)；1.29(d，3H)；1.43(m，4H)；2.04(s，3H)；3.36(m，2H)；3.51(m，2H)；3.87(m，1H)；4.30(d，1H)；4.48(t，1H)；4.62(d，1H)；4.96(q，1H)；7.60(d，1H)。
C.N-[(S)-and 2-hydroxyl propionyl] phytosphingosine
To N-[(S)-2-acetoxyl group propionyl] add NaOH solution (NaOH of 1.23g is in the water of 1.23ml) in the stirring the mixture of phytosphingosine (10.23g) and methyl alcohol (50ml).
Stirring at room 1 hour and after reaction mixture is filtered and uses the rotatory evaporator vacuum concentration with HCl (36%) adjusting pH to 7.Resistates and water (100ml) are stirred, leach, wash with water and drying, obtain the N-[(S of 8.33g)-2-hydroxyl propionyl] phytosphingosine.According to the NMR purity assay is 93%; The 4-nitrotoluene is as interior mark).
PMR composes (360MHz; DMSO-d6; Numerical value is represented with ppm; δ DMSO:2.49).δ: 0.84 (t, 3H); 1.23 (22H); 1.42 (m, 2H); 1.55 (m, 2H); About 3.3 (2H); 3.51 (m, 2H); 3.93 (m, 2H); 4.38 (d, 1H); 4.60 (t, 1H); 4.70 (d, 1H); 5.51 (d, 1H); 7.31 (d, 1H).
Embodiment 2
Synthesizing of N-(2-hydroxy capryloyl base) phytosphingosine (Cer6/OH-C8)
A.2-bromine is sad
With sad (288g; Purity 99%; 2mol) and the mixture of phosphorus trichloride (10ml) under slight suction, stir to remove acid vapour and 60 ℃ of heating by water jet pump.Added bromine (100ml) then through 1 hour.
Mixture was stirred 1 day at 60 ℃.After stirred overnight at room temperature, continue to stir 1 day in 70 ℃.Add more bromine (25ml) and continue to stir and spend the night at 70 ℃.Add more phosphorus trichloride (10ml) and more bromine (10ml) in second day and continue stirring.Added more bromine (15ml) near 1 o'clock and continue to stir and spend the night in 60 ℃.By TLC assessment be converted into the 2-bromine sad be 80%.
Follow suction with mixture heating up to 110 ℃ to remove excessive bromine and to stir with 1 premium on currency.Separating organic layer also stirs with 1 premium on currency again.Sad organic layer former state is used to prepare the 2-Hydroxyoctanoic acid will to comprise the 2-bromine.
B.2-Hydroxyoctanoic acid
The solution stirring of the sodium hydroxide of the sad 200g with in 2 liters water of the 2-bromine that will in embodiment 2a, prepare and under nitrogen in 80 ℃ of heating.When stopping to spume, mixture was stirred 2 hours at 95 ℃, be cooled to 80 ℃ of 36% hcl acidifyings of also using 350ml.
Extract this mixture with toluene (500ml) after being cooled to 30 ℃.The evaporation extract obtains the oil of 327g.It is dissolved in (700ml) and filtered while hot in the hot hexane.Hexane wash strainer with 50ml heat.
Chlorine liquid is stirred the throw out be cooled to 7 ℃ and leach formation, wash also with cold hexane (250 and 200ml)
VacuumDrying obtains the title product of 201.24g.
C.2-acetoxyl group is sad
Diacetyl oxide (40ml) add stirred and the mixture of ice-cold 2-Hydroxyoctanoic acid (30g) and pyridine (80ml) in.After stirred overnight at room temperature, add entry (100ml) and continue to cool off and stirred 1 hour in room temperature simultaneously.
Use 36% hydrochloric acid of 90ml that mixture is acidified to pH=1 and uses toluene (100ml and 50ml) extraction.
The toluene extraction liquid that merges is used 1M HCl, water (2 x 100ml) and the salt water washing of 50ml.After the filtration with toluene solution
VacuumEvaporation obtains the title compound of 39.9g.
D.N-(2-acetoxyl group capryloyl) ceramide
With 2-acetoxyl group sad (8.80g), exsiccant ethyl acetate (25ml) and triethylamine (13ml) in 45 ℃ of Tosyl chloride stirred solutions in the 50ml ethyl acetate that in 10 minutes, add to 7g.Stir after 30 minutes, this suspension was added in 5 minutes in the suspension of the stirring of phytosphingosine vitriol (12g) in ethyl acetate (50ml) and triethylamine (6.5ml).At 46 ℃ of water that continue to stir 1 hour and added 100ml.Regulate pH to 6.2 and isolate organic layer and with the water washing of 100ml and evaporate and obtain oil with 36% hydrochloric acid.Handle with 25ml methyl alcohol.Obtain the solid of 18.57g behind the evaporation methyl alcohol.This raw material with 1.06g
VacuumDrying obtains the exsiccant title compound of 0.98g.
E.N-(2-hydroxy capryloyl base) phytosphingosine
Stir N-2-(R, S)-mixture of acetoxyl group capryloyl phytosphingosine (26g) and methyl alcohol (80ml).The sodium hydroxide of 1.6g that adds prepared fresh then in the water of 1.6g solution and in this mixture of stirring at room 3 hours.
With in the acetate of 1ml and after, mixture is filtered (with the methanol wash strainer of 30ml).Add the water of 80ml then and continue stirring 5 minutes.
Leach throw out and also with the water washing of methanol=1/1 of 50ml and 2 x 100ml
Very EmptyDry to obtain the title compound of 22.01g.
PMR composes (360MHz; CDCl
3-d6, pyridine-d5,2 (dr.) DCOOD; T:323 ° of K; Numerical value is represented with ppm).
δ：0.92(t，6H)；1.3-2.0(m，36H)；3.95(m，2H)；4.1-4.2(m，2H)；4.35(m，1H)；4.64(m，1H)；8.13(2xd，1H)。
Embodiment 3
Synthesizing of N-(2-hydroxyl certain herbaceous plants with big flowers acyl group) phytosphingosine
A.2-bromine capric acid
With capric acid (430g; 2.5mol) and phosphorus trichloride (13ml; 0.15mol) mixture 60 ℃ of heating.In 10 minutes, add bromine (155ml then; 3.0mol), simultaneous temperature remains on 60 ℃ and use water jet pump to keep low vacuum to remove HBr smog.
Spend the night to reaction mixture 60 ℃ and 90 ℃ of continuously stirring and to decolour.With the mixture cooling, dilution with toluene and water (3x0.25L and 2x0.25L are at pH=2) washing with 1L for the separation that obtains, add some ether (1L) then.After organic layer usefulness S-WAT drying, concentrate in 90 ℃ of decompressions (0.5mm Hg), obtain the title compound of 595g.
B.2-hydroxydecanoic acid
Mixture in 85 to 90 ℃ of stirrings under nitrogen with the solution of the sodium hydroxide of 2-bromine capric acid (by the preparation of the capric acid of 175g) and the 80g in 1 liter water.Add more sodium hydroxide (25g) and continue and stirred 2.5 hours.
Then with mixture with 36% the hcl acidifying of 125ml and with the toluene extraction of 450ml.With the extraction liquid evaporation, obtain the oil of 210g.Begin crystallization after the hexane dilution with 900ml.Stir and leach precipitation after 0.5 hour,, obtain the title product of 101.10g with hexane wash and the drying of 250ml.
C.2-acetoxyl group capric acid
Diacetyl oxide (20ml) is slowly added in the mixture of the 2-hydroxydecanoic acid (15.34g) that stirs and pyridine (40ml), water-bath is at room temperature simultaneously cooled off.Stir the water that adds 50ml after 2 hours and also regulate pH to 2 with 36% hydrochloric acid.With toluene extraction mixture and with the salt acid elution extraction liquid that dilutes, concentrate the title compound that obtains 19.39g.
D.N-(2-acetoxyl group decanoyl) phytosphingosine
With the mixture of 2-acetoxyl group capric acid (19.0g), dry ethyl acetate (45ml) and triethylamine (24ml) at 45 ℃ of Tosyl chloride (13g) solution in ethyl acetate (90ml) that added to stirring through 20 minutes.Stir the suspension of phytosphingosine vitriol (19g) in ethyl acetate (100ml) and triethylamine (12ml) that after 0.5 hour this suspension was added to stirring in 10 minutes.At 46 ℃ of water that continue to stir 1 hour and added 200ml.Regulate pH to acidity with 36% hydrochloric acid of 9ml, isolate organic layer, with the water washing of 100ml and evaporate and obtain oil.Its methyl alcohol with 100ml is handled and evaporation.Solid is handled and leached to resistates with the methyl alcohol of 50ml.The methyl alcohol of filter cake and 100ml is stirred, leach the title compound that also vacuum-drying obtains 16.66g once more.
E.N-(2-hydroxy decanoyl) phytosphingosine
The mixture heating up of N-(2-acetoxyl group decanoyl) phytosphingosine (16g) and methyl alcohol (80ml) is obtained solution and is cooled to room temperature.The solution of sodium hydroxide that adds the 1.6g in the water of 1.6g of prepared fresh then, and with mixture stirring at room 2.5 hours.With in the acetate of 1.5ml and after, follow stirring to add the water of 100ml in batches.Leach precipitation and also with methanol=1/1 of 50ml and 2 x 100ml water washings
VacuumDrying obtains the title compound of 13.41g.
PMR composes (360MHz; CDCl
3-d6, pyridine-d5,2 DCOOD; T:323 ° of K; Numerical value is represented with ppm).
δ：0.92(t，6H)；1.3-2.0(m，36H)；3.95(m，2H)；4.1-4.2(m，2H)；4.35(m，1H)；4.64(m，1H)；8.13(2xd，1H)。
Embodiment 4
Measure the effect that ceramide 6 analogues polish healthy human skin with technology of profiling
Carrying out skin roughness with ceramide 6 analogue Cer6/OH-C3 and Cer6/OH-C8 measures.The results are shown in table 1 and 2 of these measurements.7 days and SDS value should be compared with 0 day corresponding initial value.
The reduction of finding roughness in the zone after handling 7 days with the prescription that comprises ceramide 6 analogues is far above placebo treatment.After the SDS stimulation, in untreated zone and roughness increase in the pretreated zone with placebo.In the zone of handling, only detect minimum variation with the prescription that comprises ceramide.
Table 1
Table 2
Embodiment 5
Measure the barrier function of the skin of strengthening by ceramide 6 analogues by TEWL
The prescription that use comprises ceramide 6 analogue Cer6/OH-C3 and Cer6/OH-C8 carries out the TEWL measurement.The results are shown in table 3 and 4 of these measurements.7 days and SDS value should be compared with 0 day corresponding initial value.
After the SDS stimulation, the increase of TEWL is pretreated far below contrast and placebo in 7 days zone of ceramide 6 analogue pre-treatment.This effect is dose-dependent.This shows with the ceramide 6 analogue pre-treatment of AHA system has protected skin to avoid the SDS-damage.Compare with 0 day TEWL value after 7 days, pre-treatment itself does not show significant difference.
Table 3
Table 4
Embodiment 6
Use colorimetry to measure the barrier function of the skin of strengthening by ceramide 6 analogues
The prescription that use comprises ceramide 6 analogue Cer6/OH-C3 and Cer6/OH-C8 carries out colour of skin measurement.The results are shown in table 5 and 6 of these measurements.7 days and SDS value should be compared with 0 day corresponding initial value.
After the SDS stimulation, the increase of the colour of skin is pretreated far below contrast and placebo in 7 days zone of ceramide 6 analogue pre-treatment.This effect is dose-dependent.This shows with the ceramide 6 analogue pre-treatment of AHA system has protected skin to avoid the SDS-damage.Compare with 0 day skin tone value after 7 days, pre-treatment itself does not show significant difference.
Table 5
Table 6
Embodiment 7
Measure the effect of ceramide 6 analogues by decortication to the human skin of health
The prescription that use comprises ceramide 6 analogue Cer6/OH-C3 and the Cer6/OH-C8 measurement of peeling.The results are shown in table 7 and 8 of these measurements.Handling the value of measuring the back at 7 days with SDS should compare with 0 day corresponding initial value.
Handling zone after 7 days and placebo with ceramide 6 analogues compares with untreated zone and demonstrating decortication and increase.In addition, after handling with SDS, obtain far below being untreated and using the fluorescence extraction value of the pretreated skin of placebo with the pretreated skin of ceramide 6 analogues.This shows the effect that ceramide 6 analogues are attacked the anti-SDS of human skin.
Table 7
Table 8
Claims (9)
1. compound; it is to be selected from by acid amides to be connected to the ceramide of the 2-hydroxyl carboxyl with 2 to 14 carbon atom chain lengths and the sphingoid bases of phytosphingosine, and condition is that described compound is not glycolyl ceramide, 2-maloyl group ceramide or 2-hydroxy decanoyl dihydrosphingosine.
2. according to the compound of claim 1, wherein said 2-hydroxyl carboxyl is 2-hydroxyacetyl, 2-hydroxyl propionyl, 2-methyl-2-hydroxyl propionyl, 2-maloyl group, 2-hydroxyl pentanoyl, 2-hydroxyl caproyl, 2-hydroxyl oenanthyl, 2-hydroxy capryloyl base, 2-hydroxyl nonanoyl, 2-hydroxy decanoyl, 2-hydroxyl undecanoyl, 2-hydroxyl lauroyl, 2-hydroxyl myristoyl.
3. according to the compound of claim 1, wherein said 2-hydroxyl carboxyl is 2-hydroxyacetyl, 2-hydroxyl propionyl, 2-hydroxy capryloyl base or 2-hydroxy decanoyl.
4. preparation is according to the method for each compound in the claim 1 to 3, and it may further comprise the steps:
-with the carboxylic acid of 2 to 14 carbon atoms of chain length in 2-position bromination,
-2-bromine carboxylic acid is converted into the 2-alcohol acid,
-with described 2-alcohol acid acylations,
-by in the presence of alkali, in organic solvent, reacting, the 2-acyloxycarboxylic acid is converted into mixed acid anhydride with alkyl sulfonyl chloride or alkylaryl SULPHURYL CHLORIDE,
-with described mixed acid anhydride and amino alcohol or its reactant salt,
-by alkaline hydrolysis with the hydrolysis of N-2-acyl-oxygen acyl group amido alcohol.
5. comprise makeup or pharmaceutical composition according to each compound in the claim 1 to 3.
6. according to the composition of claim 5, it comprises weight concentration by described composition from 0.001% to 10%, and preferably from 0.005% to 2%, the described compound in from 0.01% to 1% scope most preferably.
7. according to each compound in the claim 1 to 3, during it is used for the treatment of.
8. according to each compound in the claim 1 to 3, it is as makeup.
9. purposes according to Claim 8 is used for improving the structure and the state of skin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101681683A CN101434557A (en) | 2007-11-13 | 2007-11-13 | Derivative of short chain 2-hydroxy carboxylic acid of ceramide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101681683A CN101434557A (en) | 2007-11-13 | 2007-11-13 | Derivative of short chain 2-hydroxy carboxylic acid of ceramide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101434557A true CN101434557A (en) | 2009-05-20 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101681683A Pending CN101434557A (en) | 2007-11-13 | 2007-11-13 | Derivative of short chain 2-hydroxy carboxylic acid of ceramide |
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| CN (1) | CN101434557A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675088A (en) * | 2012-05-28 | 2012-09-19 | 温州市工业科学研究院 | Preparation method of alpha-hydroxy-cyclohexanecarboxylic acid |
| CN102690184A (en) * | 2011-03-24 | 2012-09-26 | 江南大学 | Method for synthesizing alpha-hydroxycarboxylic acid metallic soap by hydrolysis of alpha-halogenated carboxylic acid |
| CN115304509A (en) * | 2022-08-05 | 2022-11-08 | 深圳市迪克曼生物科技有限公司 | Ceramide compound containing chain carboxylic acid and preparation method and application thereof |
| CN115894278A (en) * | 2022-11-01 | 2023-04-04 | 深圳市迪克曼生物科技有限公司 | Linolenic acid-derived ceramide, and preparation method and application thereof |
| CN116459179A (en) * | 2023-03-20 | 2023-07-21 | 上海科黛生物科技有限公司 | Novel ceramide composition and preparation method and application thereof |
| WO2024078483A1 (en) * | 2022-10-10 | 2024-04-18 | 深圳市迪克曼生物科技有限公司 | Novel ceramide, preparation method therefor, and use thereof |
-
2007
- 2007-11-13 CN CNA2007101681683A patent/CN101434557A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690184A (en) * | 2011-03-24 | 2012-09-26 | 江南大学 | Method for synthesizing alpha-hydroxycarboxylic acid metallic soap by hydrolysis of alpha-halogenated carboxylic acid |
| CN102690184B (en) * | 2011-03-24 | 2014-04-30 | 江南大学 | Method for synthesizing alpha-hydroxycarboxylic acid metallic soap by hydrolysis of alpha-halogenated carboxylic acid |
| CN102675088A (en) * | 2012-05-28 | 2012-09-19 | 温州市工业科学研究院 | Preparation method of alpha-hydroxy-cyclohexanecarboxylic acid |
| CN115304509A (en) * | 2022-08-05 | 2022-11-08 | 深圳市迪克曼生物科技有限公司 | Ceramide compound containing chain carboxylic acid and preparation method and application thereof |
| WO2024078483A1 (en) * | 2022-10-10 | 2024-04-18 | 深圳市迪克曼生物科技有限公司 | Novel ceramide, preparation method therefor, and use thereof |
| CN115894278A (en) * | 2022-11-01 | 2023-04-04 | 深圳市迪克曼生物科技有限公司 | Linolenic acid-derived ceramide, and preparation method and application thereof |
| CN116459179A (en) * | 2023-03-20 | 2023-07-21 | 上海科黛生物科技有限公司 | Novel ceramide composition and preparation method and application thereof |
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Open date: 20090520 |