CN101434558A - Salicylic acid-sphingoid base derivative and uses thereof - Google Patents
Salicylic acid-sphingoid base derivative and uses thereof Download PDFInfo
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- CN101434558A CN101434558A CNA2007101681698A CN200710168169A CN101434558A CN 101434558 A CN101434558 A CN 101434558A CN A2007101681698 A CNA2007101681698 A CN A2007101681698A CN 200710168169 A CN200710168169 A CN 200710168169A CN 101434558 A CN101434558 A CN 101434558A
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- ointment
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Abstract
The invention relates to a compound which is a derivative of salicylic acid-analog sphingosine base, wherein, the salicylic acid is coupled to the analog sphingosine base in Formula (1) by amido links, while A is CH2-CH2, CH=CH or C (H) OH-CH2 and R is a linear chain with 10 to 22 carbon atoms or branched alkyl and optionally contains one or more double bonds and/or is optionally replaced with one or more hydroxyl groups. And optionally, one or more glycosyl parts, or acid ester or sulfuric acid ester groups can be connected to a primary hydroxyl. The invention also relates to a preparation method of the compound, cosmetic composition and dermatology composition containing the compound, and applications of the compound as medicines and cosmetics.
Description
The present invention relates to topical application, particularly the topical application of the salicyclic acid derivatives of the form of sphingoid bases (sphingoid base) derivative.
Background of invention
Mainly due to Whitfield's ointment (2 hydroxybenzoic acid) dissolving keratic (keratinolytic) character, it is applied in the topical compositions.In addition, Whitfield's ointment is used by local in the treatment of dermatophytid infection.Cosmetic applications comprises as antidotal agent.
Because Whitfield's ointment is easy to absorb through skin, and slowly drains in urine, therefore systemic toxicity may take place, particularly after long-term application contains the composition of high density bigcatkin willow acid.
Therefore, Whitfield's ointment had better not be used for following one or more situations: long-term, high density, use in the big area of health, and use on inflammation or damaged skin.
Yet, expect the utilization of such Whitfield's ointment preparation, it also is applicable to above-mentioned situation.
At present, found to use some salicyclic acid derivatives to replace the compound of unmodified in above-mentioned situation, to use Whitfield's ointment.
Summary of the invention
The invention discloses by salicylic carboxyl is coupled to the new compound of the amino formation of sphingoid bases via amido linkage.
Be used for having formula according to formula 1 via the salicylic sphingoid bases of amido linkage coupling:
Wherein:
A is CH
2-CH
2, CH=CH or C (H) OH-CH
2, and
R is the straight or branched alkyl with 10 to 22 carbon atoms, and it can randomly contain one or more pairs of keys and/or can randomly be replaced by one or more hydroxyls.
Preferably, A is C (H) OH-CH
2And/or R is the straight chained alkyl with 12 to 18 carbon atoms.More preferably, A is C (H) OH-CH
2And/or R is the straight chained alkyl with 13 carbon atoms.
Randomly, one or more glycosyl parts or phosphoric acid ester or sulfate group can randomly be connected on the primary hydroxyl group.
Usually, sphingoid bases is the important component of ceramide.Ceramide forms the polar lipid class (20-40%) of the maximum of stratum corneum epidermis lipid, and is the structure heterology group of the sphingolipid that contains the sphingoid bases dihydrosphingosine, ceramide or the phytosphingosine that are connected with acid amides with lipid acid (hydroxyl and non-hydroxyl lipid acid).Ceramide is considered to have vital role in the water opacity barrier of structure and maintenance skin.Ceramide is applied in the topical compositions, for example for keeping and/or improving skin texture and elasticity.
In Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant, sphingoid bases works as salicylic carrier.
Because the structure of sphingoid bases, Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant can deeper infiltrate skin than the Whitfield's ointment of unmodified.This means the Whitfield's ointment that is loaded with by sphingoid bases can target to the skin darker position, location, for example: the mitotically active epidermic cell in cuticular bottom, granular layer and/or malpighian layer and/or the spinous layer, and/or corium.In addition, compare with Whitfield's ointment itself, Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant can more effective infiltration skin inner layer.
When Whitfield's ointment of the present invention-quasi-sheath ammonia alcohol alkali derivant entering angle matter layer, as result by the esterase in-situ enzymolysis, can discharge Whitfield's ointment, described esterase is lipase, Ntn hydrolase such as Sialidase or proteolytic enzyme for example, all these enzymes all are present in the mammalian epidermis [sees Wertz, P.H. and Downing, D.T.FEBS (1990), 268,110-112; Hassler, D.F. and Bell, R.M. (1993) in " Ceramidases:Enzymology and metabolic roles ", Adv.Lip.Research 26, pp.49-59, Academic Press, San Diego].To be Whitfield's ointment discharge from the sphingoid bases carrier in check mode with at the targeting moiety of skin in a very favorable aspect of in-situ enzymolysis.
Therefore, described sphingoid bases can play carrier, also can be used as the salicylic sustained release instrument that is coupled to described sphingoid bases and works.Sustained release is particularly conducive to the steady dosage of guaranteeing to show very high bioactive compound, minimizes the excessive possibility of described compound that is:.
Therefore, advantage provided by the invention is: be incorporated into the result of sphingoid bases as it, reach the required Whitfield's ointment concentration of expectancy effect in the topical compositions and reduce greatly.Therefore compare with the effect of the compound of unmodified, the salicylic side effect of not expecting that is coupled to sphingoid bases does not exist or is reduced to quite low level.
The enzymolysis that compound of the present invention takes place in skin can discharge Whitfield's ointment and sphingoid bases.Sphingoid bases also is celebrated because of their biological activity.For example: sphingoid bases by serving as epidermic cell growth and the important physiological regulation agent of differentiation, can to skin beneficiating (Hannun, Y.A. and Bell, R.M., Science 1989,243, pp.500-507).
The present invention also provides the method for the salicyclic acid derivatives of preparation sphingoid bases, and wherein Whitfield's ointment is coupled to sphingoid bases by amido linkage.Described Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant can be by many synthetic method preparations known in the art.Whitfield's ointment can be coupled to sphingoid bases by enzyme process or chemical method.Chemically; can or use coupling agent; as: EEDQ (N-ethoxycarbonyl-2-oxyethyl group-1; the 2-dihydroquinoline), HOBT (hydroxybenzotriazole) and/or carbodiimide; with described sour coupling; perhaps with described acid as activatory acid, as mixed acid anhydride (seeing WO93/20038) or acyl halide (acid halogenide) coupling.
Randomly, described Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant also can be handled diacyl compound with any formation of hydrolysis (that is: any ester bond that may form of hydrolysis) by concentrated base and obtain purifying between the primary hydroxyl group of sphingoid bases and Whitfield's ointment.
In a preferred embodiment of the present invention, under the existence that is coupled at HOBT and DIC or dicyclohexylcarbodiimide of the sphingoid bases of Whitfield's ointment and selection by amido linkage, use tetrahydrofuran (THF) to take place as solvent.
The salicylic sphingoid bases of coupling can be any sphingoid bases according to formula (1), comprise the sphingoid bases that is selected from ceramide, 6-hydroxyl sphingosine, phytosphingosine and D-sphinganine, it randomly has one or more glycosyl part or phosphoric acid ester or sulfate groups that are connected to primary hydroxyl group.
In another preferred embodiment of the present invention, the salicylic sphingoid bases of coupling is a phytosphingosine.Phytosphingosine can pass through deacetylated effective acquisition of Tetraacetylphytospingosine (TAPS), and TAPS can pass through microbial fermentation again, particularly obtains by Pichia ciferri fermentation is a large amount of.The phytosphingosine that obtains by Pichia ciferri fermentation has the structure according to formula (1), and wherein A is C (H) OH-CH
2And R is the straight chained alkyl with 13 carbon atoms.
Another aspect of the present invention relates to Whitfield's ointment of the present invention-quasi-sheath ammonia alcohol alkali derivant and is used for the local makeup that use and/or the purposes of medicine (dermatology) composition in preparation.
Concrete makeup and/or dermatological preparation comprise common component.
Described composition comprises the vehicle that can make activeconstituents be delivered to skin.Vehicle comprises water, solid and liquid.These are divided into tenderizer, emulsifying agent, tensio-active agent, solubilizing agent, propelling agent, solvent, wetting Agent for Printing Inks, thickening material and powder.
Tenderizer comprises alkyl higher fatty acid, natural oils, high fatty alcohol, glycerine and isopropyl ester, mineral oil, silicone resin, aliphatic alcohol ester.
Emulsifying agent comprises the compound that has in HLB (hydrophile/lipophile balance) value of low and higher range, can form the compound and the compound that can form emulsion oil-in-water of water-in-oil emulsion respectively that is:.Typically, water-in-oil emulsion if desired, the HLB value of the mixture of emulsifying agent or emulsifying agent is between about 1 to 7.For emulsion oil-in-water, described HLB value is higher than about 7.
Propelling agent comprises propane, butane, Trimethylmethane, dme, fluorine alkyl chloride, carbonic acid gas, Nitrous Oxide.
Solvent comprises ethanol, methylene dichloride, Virahol, ether, DMSO, propylene glycol, butyleneglycol.
Wetting Agent for Printing Inks comprises protein and proteolytic ferment, amino acid, sorbyl alcohol, glycerine, other polyvalent alcohols.
Thickening material comprises polysaccharide, natural gum and carboxylic polymkeric substance.
Powder comprises chalk, talcum, starch.
The combination of described composition can account for about 5% to about 99% of described composition.
Contain compound compositions of the present invention and also can comprise other activeconstituents, for example: the composition that in certain is used, improves described Whitfield's ointment-sphingoid bases usefulness.
Contain compound compositions of the present invention and be suitable for local the use.Be present in the weight of the amount of the Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant that is suitable in the topical application of compositions by composition, from 0.0001% to 25%, preferably from 0.001% to 5%, more preferably from 0.005% to 2%, most preferably in from 0.01% to 1% the scope.
The composition that contains Whitfield's ointment of the present invention-quasi-sheath ammonia alcohol alkali derivant can be used for the salicylic arbitrary field of requirement topical application.For example, composition of the present invention is used for the treatment of the skin disorder of Hyperkeratotic and decortication valuably, as: psoriatic, ichtiosis, seborrheic dermatitis, atopic dermatitis, acne etc.
Composition of the present invention also therein Whitfield's ointment can work synergistically with sphingoid bases those are particularly useful in using, for example:, particularly expect in the using of antimycotic or anti-inflammatory usefulness antibiotic.
Embodiment 1
Synthesizing of N-salicylyl phytosphingosine
The mixture of the I-hydroxybenzotriazole (Acros) of the tetrahydrofuran (THF) of the Whitfield's ointment (Acros) of the phytosphingosine of stirring 50g, 25g, 430ml and 22.5g under nitrogen.Tetrahydrofuran (THF) with 50ml washes into flask with all solids.Temperature is 15 ℃.Then, the DIC (Sigma) through 14 fens clock time adding 30ml causes that temperature is increased to 31 ℃.After 1.5 hours, add water (suspension=〉 settled solution of 25ml 35 ℃ of stirrings), and distillating mixture reaches 80 ℃ (440ml distillates) until fluid temperature.
After the cooling, add the ethanol of 500ml,, in 1 hour, follow mild stirring that mixture is cooled to 0 ℃ succeeded by the water of 125ml.0 ℃ stir 1 hour after, the suction filtration mixture.With cold (5 ℃) mixture washing leaching cake of the water of the methyl alcohol of 250ml and 100ml, obtain the filter cake of 270g.
The methyl alcohol of filter cake and 450ml is heated to 63 ℃.50% w/w NaOH with 17.3g is adjusted to 10.7 with the pH value from 3.7.After about 63 ℃ (pH=10.7) stir 1.5 hours, regulate pH value to 6.7 with acetate (15g).The filtered while hot mixture is also used the methanol wash resistates of 50ml.In filtrate, add the methyl alcohol of 200ml and the water of 100ml in succession, follow the stirring cooling mixture, in the time of about 27 ℃, begin crystallization.Further mixture was cooled to 0 ℃ in about 1 hour.0 ℃ stir 1 hour after, leach precipitation and wash with the cold mixture of the water of the methyl alcohol of 300ml and 100ml.The heavy 195g of wet cake.Wet cake is in 35 ℃ of dried overnight (ventilation), and vacuumizes the N-salicylyl phytosphingosine that obtains 54g at 40 ℃.
Claims (11)
1. compound, it is Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant, wherein Whitfield's ointment is coupled to the sphingoid bases that has according to the formula of formula 1 via amido linkage
Wherein:
A is CH
2-CH
2, CH=CH or C (H) OH-CH
2,
R is the straight or branched alkyl with 10 to 22 carbon atoms, it can randomly contain one or more pairs of keys and/or can randomly be replaced by one or more hydroxyls, and randomly, one or more glycosyl parts or phosphoric acid ester or sulfate group can be connected on the primary hydroxyl group.
2. the compound of claim 1, wherein A is C (H) OH-CH
2
3. claim 1 or 2 compound, wherein R is the straight chained alkyl with 12 to 18 carbon atoms, preferably has the straight chained alkyl of 13 carbon atoms.
4. be used for preparing each the method for compound of claim 1 to 3; wherein or use coupling agent; as: EEDQ (N-ethoxycarbonyl-2-oxyethyl group-1; the 2-dihydroquinoline), HOBT (hydroxybenzotriazole) and/or carbodiimide are coupled to sphingoid bases with Whitfield's ointment itself; perhaps with Whitfield's ointment as activatory acid, as: mixed acid anhydride or acyl halide are coupled to class sheath amine alcohol alkali.
5. the method for claim 4 is wherein used coupling agent, as: EEDQ (N-ethoxycarbonyl-2-oxyethyl group-1,2-dihydroquinoline), HOBT (hydroxybenzotriazole) and/or carbodiimide are coupled to sphingoid bases with Whitfield's ointment.
6. the method for claim 5, wherein said coupling agent is HOBT and DIC or dicyclohexylcarbodiimide.
7. the make-up composition that comprises each compound in the claim 1 to 3.
8. the dermatological compositions that comprises each compound in the claim 1 to 3.
9. claim 7 or 8 composition, wherein the concentration of the described Whitfield's ointment-quasi-sheath ammonia alcohol alkali derivant of Cun Zaiing be described composition weight from 0.0001% to 25%, preferably from 0.001% to 5%, more preferably from 0.005 to 2%, most preferably from 0.01% to 1%.
10. each compound in the claim 1 to 3, it is as medicine.
11. each compound is as the purposes of makeup in the claim 1 to 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101681698A CN101434558A (en) | 2007-11-13 | 2007-11-13 | Salicylic acid-sphingoid base derivative and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101681698A CN101434558A (en) | 2007-11-13 | 2007-11-13 | Salicylic acid-sphingoid base derivative and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101434558A true CN101434558A (en) | 2009-05-20 |
Family
ID=40709213
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101681698A Pending CN101434558A (en) | 2007-11-13 | 2007-11-13 | Salicylic acid-sphingoid base derivative and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101434558A (en) |
-
2007
- 2007-11-13 CN CNA2007101681698A patent/CN101434558A/en active Pending
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Open date: 20090520 |