SALICYLIC ACID-SPHINGOID BASE DERIVATIVES AND USES THEREOF

Abstract: The present invention discloses novel compounds which are derivatives of salicylic acid and a sphingoid base of formula (1), wherein salicylic acid and the sphingoid base are coupled via an amide linkage. The present invention further describes topical use of said novel compounds.

Description: Salicylic acid-sphingoid base derivatives and uses thereof Field of the invention The present invention relates to topical application, especially of a salicylic acid derivative which is in the form of a derivative of a sphingoid base. Background of the invention Salicylic acid (2-hydroxybenzoic acid) is applied in topical compositions principally for its keratinolytic properties. In addition, salicylic acid is used topically in the treatment of fungal skin infections. Cosmetic application includes the use as an antiageing agent. Since salicylic acid is readily absorbed through the skin and excreted slowly in the urine, systemic poisoning may occur, especially after prolonged application of compositions containing high concentrations of salicylic acid. Therefore, salicylic acid preferably is not used in one or more of the following conditions: for prolonged periods, in high concentrations, on large areas of the body, or on inflamed or broken skin. However, it is desirable to avail of a salicylic acid formulation which is suitable for application also in the above conditions. Now, it has been found that the use of certain salicylic acid derivatives instead of the unmodified compound enables application of salicylic acid in the above conditions. Description of the invention The present invention discloses novel compounds which are formed by the coupling of the carboxyl group of salicylic acid to the amino group of a sphingoid base via an amide linkage. The sphingoid base used for coupling of salicylic acid via an amide linkage has a general structure according to Formula 1 : wherein: A is CH 2 -CH 2 , CH=CH or C(H)OH-CH 2 , and R is a straight chain or branched alkyl group having 10 to 22 carbon atoms which may optionally contain one or more double bonds and/or may optionally be substituted with one or more hydroxyl groups. Preferably A is C(H)0H-CH 2 and/or R is a straight chain alkyl group having 12 to 18 carbon atoms. More preferably A is C(H)0H-CH 2 and/or R is a straight chain alkyl group having 13 carbon atoms. Optionally, one or more glycosyl moieties, or phosphate or sulphate groups, may be attached to the primary hydroxyl group . Normally, sphingoid bases are an important constituent of ceramides. Ceramides form the largest polar lipid class of the epidermal lipids of the stratum corneum (20-40%) and are a structurally heterogenous group of sphingolipids containing the sphingoid bases sphinganine, sphingosine or phytosphingo- sine in amide linkage with fatty acids (both hydroxy- and non-hydroxy-fatty acids) . Ceramides are supposed to have an essential role in structuring and maintaining the water impermeability barrier of the skin. Ceramides are applied in topical compositions, e.g. to maintain and/or improve the structure and flexibility of the skin. In the salicylic acid-sphingoid base derivative the sphingoid base functions as a carrier for salicylic acid. Due to the sphingoid base structure, the salicylic acid- sphingoid base derivative will penetrate deeper into the skin than the unmodified salicylic acid. This implies that salicylic acid as carried by the sphingoid base will be targeted to sites localised deeper within the skin, e.g. the lower layers of the stratum corneum, the mitotically active epidermal cells in the stratum granulosum and/or stratum germinativum and/or stratum spinosum, and/or the dermis. Moreover, the salicylic acid-sphingoid base derivative will penetrate into the inner layers of the skin more efficiently than salicylic acid as such. When the salicylic acid-sphingoid base derivative according to the invention enters the stratum corneum, salicylic acid may be liberated as a result of in si tu enzymatic hydrolysis by an esterase, e.g. a lipase, or an amidase, e.g. a ceramidase or a protease, all of which are present in the mammalian epidermis [see 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. 9-59 , Academic Press, San Diego] . A very advantageous aspect of the in si tu enzymatical hydrolysis is that salicylic acid is released from the sphingoid base carrier in a controlled way and at the targeted site in the skin. The sphingoid base thus may function as a carrier as well as a controlled release means for salicylic acid as coupled to said sphingoid base. Controlled release is particularly advantageous to ensure an even dosage of a compound which displays a very high biological activity, i.e. to minimize the chance for overdosage of said compound. Consequently, the present invention provides the advantage that, as a result of its incorporation into a sphingoid base, much lower concentrations of salicylic acid are needed in topical compositions to reach the desired effect. Undesirable side effects of salicylic acid as coupled to a sphingoid base are thereby absent or reduced to a substantially lower level as compared to the effects of the unmodified compound. The enzymatic hydrolysis of the compounds of the present invention which occurs in the skin will release salicylic acid as well as the sphingoid base. Sphingoid bases are also known for their biological activity. For instance, sphingoid bases can be beneficial to the skin by acting as an important physiological regulator of growth and differentiation of epidermal cells (Hannun, Y.A. and Bell, R.M. , Science 1989, 243, pp. 500-507) . The present invention further provides a method for preparing salicylic acid derivatives of sphingoid bases, wherein salicylic acid is coupled to a sphingoid base via an amide linkage. Said salicylic acid-sphingoid base derivatives can be prepared by various synthesis methods known in the art. Salicylic acid can be coupled to a sphingoid base either enzymatically or chemically. Chemically, the acid can be coupled either as such using a coupling reagent, e.g. EEDQ (N-ethoxycarbonyl -2 -ethoxy- 1 , 2 -dihydroquinoline) , HOBT (hydroxybenzotriazole) and/or a carbodiimide, or as an activated acid e.g. a mixed anhydride (see WO93/20038) or acid halogenide. Optionally, the salicylic acid-sphingoid base derivative may be further purified by treatment with a concentrated base to hydrolyse any diacyl compounds formed, i.e. to hydrolyze any ester bond which might be formed between the primary hydroxyl group of the sphingoid base and salicylic acid. In a preferred embodiment of the invention, coupling of salicylic acid and a selected sphingoid base via an amide linkage occurs in the presence of HOBT and diisopropyl- carbodiimide or dicyclohexyl - carbodiimide , using tetrahydrofuran as a solvent. The sphingoid base to which salicylic acid is coupled can be any sphingoid base according to Formula (1) , including sphingoid bases selected from the group of sphingosines, 6- hydroxy-sphingosines, phytosphingosines and sphinganines , optionally with one or more glycosyl moieties, or phosphate or sulphate groups, attached to the primary hydroxyl group. In another preferred embodiment of the invention, the sphingoid base to which salicylic acid is coupled is phytosphingosine . Phytosphingosine is obtainable efficiently by deacetylation of tetra-acetylphytosphingosine (TAPS) , which in turn can be obtained in large amounts by microbial fermentation, especially by fermentation of Pichia ciferri . Phytosphingosine as obtained by fermentation of Pichia ciferri has a structure according to Formula (1) , wherein A is C(H)OH-CH 2 and R is a straight chain alkyl group having 13 carbon atoms . Another aspect of the invention relates to the use of the salicylic acid-sphingoid base derivatives of the invention in the preparation of cosmetic and/or pharmaceutical (dermatological) compositions for topical use. Specific cosmetic and/or dermatological preparations include the usual components. The composition comprises a vehicle to enable the active ingredient to be conveyed to the skin. Vehicles include water, solids and liquids. These are classified as emollients, emulsifiers, surfactants, solubilizers , propellants, solvents, hu ectants, thickeners and powders. Emollients include alkyl higher fatty acids, natural oils, higher fatty alcohols, glyceryl and isopropyl esters, mineral oils, silicones, fatty alcohol esters. Emulsifiers comprise compounds having a HLB (hydrophilic/lipophilic balance) value which is in the lower as well as in the higher ranges, i.e. compounds which are able to form a water-in-oil as well as compounds which are able to form an oil-in-water emulsion, respectively. Typically, if a water-in-oil emulsion is required, the HLB value of the emulsifier or mixture of emulsifiers varies between about 1 and 7. For an oil-in-water emulsion, said HLB value is higher than about 7. Propellants include propane, butane, isobutane, dimethyl ether, chlorofluoroalkanes, carbon dioxide, nitrous oxide. Solvents include ethyl alcohol, methylene chloride, isopropanol, ethyl ethers, DMSO, propylene glycol, butylene glycol . Humectants include proteins and protein hydrolysates, arnino acids, sorbitol, glycerin, other polyols. Thickeners include polysaccharides, gums and carboxylic grou -containing polymers Powders including chalk, talc, starch. The combination of the said components can account for about 5 to about 99% of the composition. The composition containing the compounds of the invention may further include additional active ingredients, e.g. ingredients which may increase the efficacy of the salicylic acid-sphingoid base derivative in a certain application. The compositions containing the compounds of the invention are suitable for topical use. The amount of salicylic acid-sphingoid base derivative as present in a composition suitable for topical application ranges 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% by weight of the composition. The compositions containing the salicylic acid-sphingoid base derivatives of the invention may be used in any of the fields where topical application of salicylic acid is desired. For instance, the compositions of the invention are advantageously used in the treatment of hyperkeratotic and scaling skin conditions, such as psoriasis, ichtiosis, seborrhoeic dermatitis, atopic dermatitis, acne, and the like. The compositions of the invention further are particularly useful in those applications wherein salicylic acid may act synergistically with a spingoid base, e.g. in applications wherein an antimicrobial, especially an antifungal, or an antiinflammatory efficacy is desired. Example 1 Synthesis of N-salicyloyl-phytosphingosine A mixture of 50 grams of phytosphingosine, 25 grams of salicylic acid (Acros) , 430 ml of tetrahydrofuran (Merck) and 22.5 grams of 1-hydroxybenzotriazol (Acros) was stirred under nitrogen. All solids were rinsed into the flask with 50 ml of tetrahydrofuran. The temperature was 15°C. Next 30 ml of diisopropyl -carbodiimide (Sigma) was added over a period of 14 minutes causing the temperature to go up to 31°C. After stirring at 35°C for 1.5 hours 25 ml of water was added (suspension => clear solution) and the mixture was distilled off until the liquid temperature reached 80°C (440 ml distillate) . After cooling 500 ml of methanol was added followed by 125 ml of water and the mixture was cooled to 0°C in 1 hour while stirring gently. After stirring at 0°C for 1 hour the mixture was filtered off with suction. The filtercake was washed with a cold (5°C) mixture of 250 ml of methanol and 100 ml of water to give 270 g of cake. The cake was heated with 450 ml of methanol to 63 °C. The pH was adjusted from 3.7 to 10.7 with 17.3 grams of 50% w/w NaOH. After stirring for 1.5 hour at ca 63 °C (pH=10.7) the pH was adjusted with acetic acid to 6.7 ( 15 g) . The mixture was filtered while hot and the residue was washed with 50 ml of methanol. To the filtrate 200 ml of methanol and 100 ml of water were successively added, the mixture was cooled while stirring and crystallisation started at ca. 27°C. The mixture was further cooled to 0°C in about 1 hour. After stirring at 0°C for 1 hour the precipitate was filtered off and washed with a cold mixture of 300 ml of methanol and 100 ml of water. The wet filtercake weighted 195 grams. The wet cake was dried overnight at 35°C (ventilated) and under vacuum at 40°C to give 54 grams of N-salicyloyl-phytosphingosine .

Claims: Claims 1. A compound which is a salicylic acid-sphingoid base derivative wherein salicylic acid is coupled to a sphingoid base having a general structure according to Formula 1 wherein: A is CH 2 -CH 2 , CH=CH or C(H)OH-CH 2 , R is a straight chain or branched alkyl group having 10 to 22 carbon atoms which may optionally contain one or more double bonds and/or may optionally be substituted with one or more hydroxyl groups , and optionally, one or more glycosyl moieties, or phosphate or sulphate groups, may be attached to the primary hydroxyl group . via an amide linkage. 2. The compound of claim 1, wherein A is C(H)OH-CH 2 . 3. The compound of claims 1 or 2 , wherein R is a straight chain alkyl group having 12 to 18 carbon atoms, preferably a straight chain alkyl group having 13 carbon atoms. 4. A process for the preparation of the compounds of any one of the claims 1 to 3 , wherein salicylic acid is coupled to the sphingoid base either as such, using a coupling reagent, e.g. EEDQ (N-ethoxycarbonyl -2 -ethoxy- 1 , 2 - dihydroquinoline) , HOBT (hydroxybenzotriazole) and/or a carbodiimide, or as an activated acid e.g. a mixed anhydride or acid halogenide. 5. The process of claim 4, wherein salicylic acid is coupled to the sphingoid base using a coupling reagent, e.g. EEDQ (N-ethoxycarbonyl-2 -ethoxy- 1, 2-dihydroquinoline) , HOBT (hydroxybenzotriazole) and/or a carbodiimide. 6. The process of claim 5, wherein the coupling reagent is HOBT and diisopropyl-carbodiimide or dicyclohexyl- carbodiimide. 7. A cosmetic composition comprising the compound of any one of the claims 1 to 3. 8. A dermatological composition comprising the compound of any one of the claims 1 to 3. 9. The composition of claims 7 or 8 , wherein the salicylic acid-sphingoid base derivative is present in a concentration varying 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% by weight of the composition. 10. The compound of any one of the claims 1 to 3 for use as a pharmaceutical. 11. Use of the compound of any one of the claims 1 to 3 as a cosmetic .

Inventors: BRAND ERNST JACOB, LAMBERS JOHANNES WILHELMUS JAC, WEBER PIETER GIJSBERT, BRAND, ERNST, JACOB, LAMBERS, JOHANNES, WILHELMUS, JACOBUS, WEBER, PIETER, GIJSBERT
Applicants: BRAND ERNST JACOB, GIST BROCADES BV, LAMBERS JOHANNES WILHELMUS JAC, WEBER PIETER GIJSBERT, BRAND, ERNST, JACOB, GIST-BROCADES B.V., LAMBERS, JOHANNES, WILHELMUS, JACOBUS, WEBER, PIETER, GIJSBERT
Application year: 1998
Main classification: C07C235
IPC codes: A61K8, A61Q19, C07C235