| PATENT ASSIGNEE'S COUNTRY | Netherlands |
| UPDATE | 04.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 25.04.00 |
| PATENT TITLE |
Phytosphingosine-based ceramide I analogs |
| PATENT ABSTRACT | Novel phytosphingosine-based analogs of ceramide I, methods for the preparation of these novel compounds, cosmetic and pharmaceutical compositions containing such compounds, and methods for the use thereof are described. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 05.05.98 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | Motta, S., et al., "Ceramide Composition of the Psoriatic Scale" Biochem Biophys Acta (1993) 1182(2):147-151. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of the formula: ##STR17## wherein A is C.sub.15-35 straight chain alkyl group which may optionally contain one or two double bonds, B is a C.sub.12-20 straight chain acyl group which may optionally contain one or two double bonds and X is 13. 2. The compound of claim 1 wherein A is a C.sub.22-31 group which may optionally contain one or two double bonds. 3. The compound of claim 1 wherein B is stearoyl, oleoyl or lineoyl. 4. The compound of claim 1 wherein B is lineoyl. 5. The compound of claim 1 wherein said compound is selected from the group consisting of N-(27-stearoyloxy-heptacosanoyl)-phytosphingosine, N-(27-lineoyloxy-heptacosanoyl)-phytosphingosine, N-(27-oleoyloxy-heptacosanoyl)-phytosphingosine, N-(27-lineoyloxy-heptacosanoyl)-phytosphingosine, N-(23-stearoyloxy-tricosanoyl)-phytosphingosine, N-(23-lineoyloxy-tricosanoyl)-phytosphingosine, and N-(23-oleoyloxy-tricosanoyl)-phytosphingosine. 6. The compound of claim 1 prepared from an acyloxy-alkanoic acid of the general formula B--O--A--COOH by chemically coupling to a moiety having the formula CH.sub.3 --(CH.sub.2).sub.X --(CHOH).sub.2 --CH(CH.sub.2 OH)--NH.sub.2 or to an activated acid of said moiety wherein A is C.sub.15-35 straight chain alkyl group which may optionally contain one or two double bonds, B is a C.sub.12-20 straight chain acyl group which may optionally contain one or two double bonds and X is 13. 7. The compound of claim 6 wherein said acyloxy-alkanoic acid of the general formula B--O--A--COOH is prepared by a method wherein a .sub..omega. -hydroxy alkanoic acid of the formula HO--A--COOH in which the carboxyl group is protected is coupled to an alkanoic acid of the formula B--OH, wherein A is C.sub.15-35 straight chain alkyl group which may optionally contain one or two double bonds and B is a C.sub.12-20 straight chain acyl group which may optionally contain one or two double bonds. 8. The compound of claim 7 wherein said .sub..omega. -hydroxy alkanoic acid of the formula HO--A--COOH is prepared by a method wherein protected acid chlorides are coupled with enamines prepared from cyclic ketones, followed by ring opening and reduction. 9. A cosmetic composition for topical application comprising from 0.001% to 25% of at least one compound according to claim 1 in a cosmetically acceptable excipient. 10. A pharmaceutical composition for topical application comprising from 0.001% to 25% of at least one compound according to claim 1 in a pharmaceutically acceptable excipient. 11. A method of treating mammalian skin comprising applying a cosmetic composition comprising a compound according to claim 1 to said skin. 12. A method according to claim 11 wherein said composition is used for the restoration of moisture to said mammalian skin. 13. A method of treating mammalian skin comprising applying a pharmaceutical composition comprising a compound according to claim 1. 14. A method according to claim 13 for the treatment of atopic eczema in mammals. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
The present invention relates to novel compounds related to natural ceramide I for use in cosmetic and pharmaceutical formulations. BACKGROUND OF THE INVENTION Ceramides are the main lipid component in the upper layer of the skin, the stratum corneum. The stratum corneum has an important barrier function: external compounds are generally kept outside and the loss of moisture is limited. The addition of ceramides to skin cosmetic products improves the barrier function of the skin, restores lost moisture and has been found to have "anti-wrinkle" effects. Moreover, ceramides have also found use in pharmaceutical preparations for example for the treatment of atopic eczema (Kerscher et al. (1991) Eur. J. Dermatol., 1, 39-43). European Patent Application EP 0 373 038 describes the therapeutic use of N-acyllysosphingolipids, wherein the acyl group has a chain length of 2-24 carbon atoms and is substituted by one or more polar groups. In particular, ceramide I, described in European Patent 0 097 059 (Unilever/Conopco) is commonly found in commercial cosmetic preparations. The structure of ceramide I was investigated by Wertz et al. ((1985) J. Invest. Dermatol., 84(8), 410-412--see also Wertz and Downing (1983) J. Lipid Res., 24, 759-765; Wertz et al. (1983) Biochim. Biophys. Acta, 753, 350-355; Kerscher et al. (1991); supra, p. 41) and is depicted below: ##STR1## Several references postulate that ceramide I has a unique function in relation to other known ceramides. It appears that ceramide I, with its characteristic acyl-ceramide structure, acts as a sort of "molecular rivet" whereby the extracellular lipid bilayers of the stratum corneum are bound to one another, thus maintaining the skin's characteristic barrier function (permeability-regulating) and its moisture-retaining properties (see Melton et al. (1987) Biochim. Biophys. Acta, 921(2), 191-197; Wertz and Downing (1988) Lipids, 23(5), 415-418; Brooks and Idsen (1991) Int. J. Cosmet. Sci., 13, 103-113; Wertz et al. (1983) Biochim. Biophys. Acta, 753, 350-355; and Kerscher et al. (1991) supra). The analysis of the ceramide composition in the skin disorder psoriasis, a skin disorder which is characterized by an impaired barrier function, showed a significantly decreased content of ceramide I, as compared to normal human stratum corneum, Motta et al., Biochimica et Biophysica Acta, 1182, pp. 147-151 1993). However, it has also been found that sphingosine-based ceramides such as natural ceramide I are broken down in the skin by the action of ceramidases to liberate sphingosine. Free sphingosine inhibits the activity of protein kinase C and in this way may affect cell division. It has been proposed that the effects of free sphingosine may be an important factor in the modulation of epidermal cell proliferation in order to balance the rate in which cells are lost from the skin surface (Downing, D. T. (1992) J. Lipid Res., 33, 301-313). Nevertheless, as mentioned above, natural ceramide I is commonly found in cosmetic preparations containing ceramides. Thus, the application of ceramide I-containing cosmetics to the skin may lead to the accumulation of an excess of free sphingosine due to the subsequent action of the ceramidases endogenous to the statum corneum. As a result, the fine balance of epidermal cell modulation may be upset. On the other hand, the presence of phytosphingosine could not been demonstrated in the skin, despite efforts to locate it (Wertz and Downing (1990) J. Invest. Dermatol., 94(2), 159-161; Wertz and Downing (1989) Biochim. Biophys. Acta, 1002(2), 213-217). This may indicate that the ceramidases which degrade sphingosine-based ceramides are not active on phytosphingosine-based ceramides. Another drawback of the use of natural ceramide I in cosmetics is that this ceramide is difficult to obtain in a cost-effective way in the quantities needed for application in cosmetic preparations. Isolation from natural sources is laborious and expensive, resulting in only small amounts of pure ceramide I. A solution to this problem may be the chemical synthesis of ceramide I from its constituents sphingosine and an acyloxyalkanoic acid. However, this is not a very realistic option, because the sphingosine constituent is not easily obtainable in the amounts necessary for larger scale synthesis reactions. Accordingly, it would be desirable to develop analogs of natural ceramide I which would maintain their efficacy as "molecular rivets" of the extracellular lipid bilayers of the stratum corneum, thus maintaining and enhancing the skin's barrier and moisture-retaining functions without upsetting the balance of epidermal cell modulation which could result from an excess of sphingosine in the epidermis. In addition, it would be most desirable to obtain such analogs of natural ceramide I in a cost-effective way. SUMMARY OF THE INVENTION The present invention provides phytosphingosine-based analogues of ceramide I wherein the sphingosine backbone of ceramide I is replaced by a phytosphingosine backbone. The present invention further provides methods for the preparation of the novel phytosphingosine-containing ceramide I analogues. Also disclosed are methods for the preparation of acyloxy-alkanoic acids and .omega.-hydroxy alkanoic acids. The compounds of the present invention are used in pharmaceuticals. In addition, the compounds of the present invention are used in cosmetics. The present invention provides cosmetic and pharmaceutical preparations for topical application which restore and enhance the skin's barrier and moisture-retaining functions. The compounds of the present invention may be present in the compositions of the present invention in a range of from 0.001% to 25% in such cosmetic and pharmaceutical formulations. Preferably the compounds of the present invention are present in the range of 0.005% to 5%, more preferably 0.02% to 2% and most preferably about 0.5%. DETAILED DESCRIPTION OF THE INVENTION The present invention describes novel analogs of ceramide I wherein the sphingosine backbone of the natural compound is replaced by a phytosphingosine backbone. The novel compounds of the present invention have the general formula: ##STR2## wherein A is a C.sub.10 or greater straight chain alkyl group which may optionally contain one or two double bonds and B is a hydrogen atom or a C.sub.5-25 straight chain acyl group which may optionally contain one or two double bonds. X is an integer from 10-25, inclusive. Preferred compounds of the present invention are those wherein A is a C.sub.15-35, straight chain alkyl group which may optionally contain one or two double bonds, more preferably a C.sub.22-31 group which may optionally contain one or two double bonds and B is a C.sub.12-20 straight chain acyl group which may optionally contain one or two double bonds and even more preferred wherein B is stearoyl, oleoyl or lineoyl. Examples of such compounds are N-(27-stearoyloxy-heptacosanoyl)-phytosphingosine, N-(27-lineoyloxy-heptacosanoyl)-phytosphingosine, N-(27-oleoyloxy-heptacosanoyl)-phytosphingosine, N-(23-stearoyloxy-tricosanoyl)-phytosphingosine, N-(23-lineoyloxy-tricosanoyl)-phytosphingosine, N-(23-oleoyloxy-tricosanoyl)-phytosphingosine. Most preferred compounds are those wherein A is as defined above and B is lineoyl. It should also be understood that the value of X in the phytosphingosine moiety, is preferably 13, but is intended to include analogs wherein the saturated alkyl chain tail, which extends from the 4-OH position, is from 11 to 26 carbons in total length (i.e. X is 10-25), such as is described by Wertz et al. ((1985) supra, p. 411). The phytosphingosine-based ceramide I analogs may be prepared by various chemical synthesis methods known to the skilled artisan such as the selective acylation method of Smeets and Weber (WO 93/20038) or a method analogous to that of Mori and Nishio (1991) Liebigs Ann. Chem., 253-257. The choice of the synthesis method is not critical to the present invention. The compounds of the present invention may be prepared via an amidation reaction of a straight chain acyloxy-alkanoic acid of the general formula: ##STR3## wherein A and B are as previously defined, with phytosphingosine. The coupling between either an acyloxy-alkanoic acid or an .omega.-hydroxy alkanoic acid and phytosphingosine can be carried out either enzymatically or chemically. Numerous methods are available to a person skilled in the art for the chemical coupling between either an acyloxy-alkanoic or an .omega.-hydroxy alkanoic acid and phytosphingosine. These include methods wherein the acid can be coupled either as such using coupling reagents, e.g. EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) and/or HOBT (hydroxybenzotriazole), or N-hydroxysuccinimide, or a carbodiimide, or as an activated acid e.g. a mixed anhydride or acid halogenide. A preferred chemical synthesis method using a mixed anhydride in the coupling reaction, is the selective acylation method published by Smeets and Weber (supra). The coupling reaction is performed via a two-step method, the first step comprising the formation of a mixed anhydride via the reaction of a saturated straight chain acyloxy-alkanoic acid (Formula 3), or a salt thereof, with a sulfonyl chloride in organic solvent and in the presence of an organic base, followed by a second step wherein the mixed anhydride formed in the first step is reacted with phytosphingosine. Both steps may be optionally performed in a single reaction vessel ("one-pot process"). Phytosphingosine is obtainable efficiently by deacetylation of tetra-acetylphytosphingosine (TAPS). The deacetylation may be chemical, e.g. by base catalyzed hydrolysis with potassium hydroxide, or enzymatical. After alkaline hydrolysis of TAPS, the resulting phytosphingosine may be purified according to any method known to a person skilled in the art. TAPS is obtainable efficiently in large amounts by microbial fermentation, especially by fermentation of Hansenula, more especially by fermentation of Hansenula ciferrii. The acyloxy-alkanoic acid of Formula 3 may be prepared by standard techniques known to the skilled artisan, such as a method analogous to that described by. Mori and Nishio (supra) or a manner analogous to that described by Heslinga and Pabon (1984) Recl. Trav. Chim. Pays-Bas, 103, 348-351. Again the choice of the synthesis method is not critical to the present invention. Preferably, the compounds of Formula 3 may be prepared by reacting an .omega.-hydroxy alkanoic acid (C.sub.10 or longer) with a selected C.sub.5-25 (optionally unsaturated) straight chain fatty acid wherein the acid moiety of the former starting material is preferably protected with a protecting group known to those skilled in the art. Suitable protecting groups are described in Greene, T. (1981) Protective Groups in Organic Synthesis (John Wiley & Sons; New York). For instance, silyl, allyl, t-butyl, benzyl can be used. It has to be kept in mind that the reagents and/or solvents as well as the reaction conditions should be chosen in such a way that they do not interfere with the protecting group and that the addition as well as the removal of the protecting group should not destroy the starting material or the compound to be synthesized. The .omega.-hydroxy alkanoic acids may be obtained from carnauba wax (Wertz et al. (1985), supra) or may be synthesized chemically by methods well within the knowledge of the skilled artisan such as a method analogous to that described by Schill, G. (1966) Chem. Ber., 99, 2689-2698. The present invention describes a novel and simple method to obtain various .omega.-hydroxy acids with different chain length, via the coupling of protected acid chlorides of variable chain length with enamines prepared from cyclic ketones of variable size, followed by ring opening and reduction. In this way, the .omega.-hydroxy alkanoic acid can be provided with any chain length that is desirable. In another embodiment, .omega.-hydroxy alkanoic acids may be obtained by hydrolysis of a cyclic lactone. The novel ceramide I analogs of the present invention have several advantages above natural ceramide I. The ceramide I analogs may be less susceptible to degradation by the ceramidases endogenous to the stratum corneum and, importantly, they are obtainable in a more cost-effective way. In addition, they have a higher oxidation stability, since the ceramide I analogs of the present invention lack the double bond which is present in the sphingosine moiety of natural ceramide I. Thus, the ceramide I analogs of the present invention may be applied beneficially in cosmetic and pharmaceutical preparations for topical use on the skin. Once obtained, the compounds of the present invention may be formulated in oil/water or water/oil compositions suitable for cosmetic or pharmaceutical use. In addition to the compounds of the present invention, which serve as the active ingredients in the cosmetic and pharmaceutical compositions of the present invention, other cosmetically and pharmaceutical excipients may be employed including diluents, dispersants, solvents, emollients. Perfume may also be optionally employed. Such vehicles are well-known to those skilled in the art and are described in detail in the literature, for example, in European Patent No. 0 097 059 which is incorporated herein by reference. The compounds of the present invention may be present in the compositions of the present invention in a range of from 0.001% to 25% in such cosmetic and pharmaceutical formulations. Preferably the compounds of the present invention are present in the range of 0.005% to 5%, more preferably 0.02% to 2% and most preferably about 0.5%. The compositions of the present invention may optionally contain more than one of the herein described phytosphingosine-based ceramide I analogs. The cosmetic and pharmaceutical compositions of the present invention may be applied topically to mammalian skin and are useful, inter alia, in restoring moisture to the skin and in the treatment of atopic eczema. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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