DE4420736C1 - New pseudo-ceramide cpds. - Google Patents

Abstract

The invention concerns pseudoceramides of formula I (I) in which R<1>CO stands for a hydroxyacyl group having 3 to 8 carbon atoms and 2 to 7 hydroxy groups, and R<2> and R<3> can be identical or different and stand for hydrogen, a linear or branched alkyl group having 1 to 50 carbon atoms, or a group of formula II (II), in which R<4> stands for an alkylene group having 1 to 18 carbon atoms, which can contain a further ester group, COO-R<6>, in which R<6> is a linear or branched alkyl group having 1 to 50 carbon atoms, and R<5> is a linear or branched alkyl group having 6 to 50 carbon atoms, provided that at least two of the groups R<2>, R<3>, R<5> and R<6> are long-chain groups having 6 to 50 carbon atoms, or at least one of the groups R<2>, R<3>, R<5> and R<6> is a branched alkyl group, the branches comprising at least 6 carbon atoms. The compounds are suitable as "synthetic barrier lipids" for preparing skin-care products.

Description

Field of the Invention

The invention relates to pseudoceramides that are available by reacting sugar acids or their lactones with fat alcohol esters of amino acids, a process for their preparation of pseudoceramides, skin care products containing the Pseudoceramides and the use of the pseudoceramides for Manufacture of skin care products.

State of the art

It plays out for the elasticity and the appearance of the skin balanced water balance in the individual skin layers ne important role. In the dermis and in the boundary layer of the Epidermis near the basement membrane is the level of bound Water greatest. The skin's elasticity is crucial the collagen fibrils in the dermis, the speci fish conformation of collagen by the incorporation of water molecules is reached. Destruction of the lipid barrier in the Stratum corneum (SC), for example, by surfactants leads to egg an increase in transepidermal water loss, causing the aqueous environment of the cells is disturbed. Because that in deeper Layers of water bound to the skin only via vessels over the body perfluid, but not from outside,  it becomes clear that the preservation of the barrier function of the stratum Corneum is essential for the overall condition of the skin. [see. S.E. Friberg et al., C.R. 23rd CED Congress, Barcelona, 1992, 5.29].

Ceramides are lipophilic amides of long-chain fatty acids, which are generally derived from sphingosine or phytosphingosine deduce. This class of bodywork has considerable importance gene solids since they were used in the intercellular Space between the corneocytes as key components for the Structure of the lipid bilayer, i.e. the permeability barrier, in the Stratum corneum of human skin. Ceramides have molecular weights of well below 1000, so that at external supply in a cosmetic formulation that Reaching the site of action is possible. The external application of ceramides leads to the restoration of the lipid barrier, causing the described disorders of skin function can be counteracted causally. [see. R.D. Petersen, Cosm. Toil. 107, 45 (1992)].

The use of ceramides is due to their lack of ver availability has so far set limits. It has therefore already Ver given, ceramide-analogous structures, so-called "synthetic barrier lipids (SBL)" or "pseudoceramides" too synthesize and use for skin care. [see. G. Imokawa et al., J. Soc. Cosiet. Chem. 40, 273 (1989)].

For example, in the European Disclosure publications EP-A O 277 641 and EP-A O 227 994 (Kao) Ceramidana loge of the following structure proposed:

From European laid-open publications EP-A 0 482 860 and EP-A-0 495 624 (Unilever) are structures related to ceramide known formula:

For the protection of skin and hair are used in the European Patent application EP-A 0 455 429 (Unilever) also sugar deri vate of the following composition proposed:

Here Ra stands for hydrogen or an unsaturated one Fatty acyl residue, z for numbers from 7 to 49, A for a hydroxy alkyl and Z for a sugar or phosphate residue.

Notwithstanding these attempts, success is with these Can achieve substances, so far unsatisfactory; especially the performance of natural ceramides will not he enough. Furthermore, the synthesis sequences are technically complex and therefore costly as to the importance of the substances additionally relativized.

The object of the present invention is new lei to develop high-strength ceramide-analogous structures that characterized by the simplest possible synthesis. A white Another task is to base new pseudoceramides on to produce non-animal raw materials.  

Description of the invention

The invention relates to pseudoceramides of the formula I.

wherein
R¹ CO represents a hydroxyacyl radical with 3 to 8 carbon atoms and 2 to 7 hydroxy groups,
and
R² and R³ may be the same or different and represent hydrogen, a linear or branched alkyl group having 1 to 50 carbon atoms, or a group of the formula II

-R⁴-COO-R⁵ (II)

wherein R⁴ for an alkylene group with 1 to 18 carbon atoms men who have another ester group, COO-R⁶, wherein R⁶ is a li linear or branched alkyl group with 1 to 50 carbon atoms men is, may contain, and R⁵ is a linear or ver is a branched alkyl group having 6 to 50 carbon atoms, with the proviso that at least two of the groups R², R³, R⁵ and R⁶ represent long-chain radicals having 6 to 50 carbon atoms represent or at least one of the groups R², R³, R⁵ and R⁶ a branched alkyl group, the branches being at least have at least 6 carbon atoms.

Surprisingly, it was found that the Er pseudoceramides to be used the natural barrier Strengthen the function of the skin, firm the skin and prevent it protect drying. The fabrics are the natural skin lipi based on the dermatological and ecotoxicologically  conceivable and can be homogeneously cosmetic in the oil phase Incorporate funds. They are colored white or ivory-like, odor-free, hydrolysis-resistant in the area of the skin pH and color stable against atmospheric oxygen. The invention Pseudoceramides can be based on vegetable fatty alcohols and Sugar, i.e. without the use of unwanted animal raw materials fabrics are manufactured.

Particularly preferred are pseudoceramides of the formula I in which R¹ is a pentahydroxyhexyl radical and R² is a hydrogen atom when R³ is an R _18-36 guerbetalkyl radical, a C _18-36 guerbetalkoxycarbonyl-C _1-6 alkyl radical or a group R⁴-COOR⁵ , in the R⁴ for the groups

stands
and R⁵ and R⁶ each represent a C _12-18 alkyl group; or
R² is a C _12-18 alkyl radical and R³ is one of the groups -CH₂-CO₂R⁶ or -CH₂-CH₂-CO₂R⁶, in which R bedeutet is a C _12-18 alkyl radical; or R² and R³ represent a C _12-18 alkyl radical.

The groups R², R³, R⁵ and R⁶ are preferably selected so that at least two of the groups have long-chain residues with 6 to 50 Represent carbon atoms or at least one of the groups R², R³, R⁵ and R⁶ is a branched alkyl group, the Branches have at least 6 carbon atoms. By such a selection of the groups can have a molecular structure are obtained that the compounds of the invention hydrophilic hydroxyalkyl residue and two lipophilic alkyl residues included, which ensures a good installation of the connections in the Bilayer structure of the horny layer lipids and thus one Improvement in barrier properties is achieved.  

Manufacturing process

Another object of the invention relates to a method for the preparation of pseudoceramides of the formula I.

wherein
R 1 CO represents a hydroxyacyl radical having 3 to 8 carbon atoms and 2 to 7 hydroxy groups,
and
R² and R³ may be the same or different and represent hydrogen, a linear or branched alkyl group having 1 to 50 carbon atoms, or a group of the formula II

-R⁴-COO-R⁵ (II)

wherein R⁴ for an alkylene group with 1 to 18 carbon atoms men who have another ester group, COO-R⁶, wherein R⁶ is a li linear or branched alkyl group with 1 to 50 carbon atoms men is, may contain, and R⁵ is a linear or ver is a branched alkyl group having 6 to 50 carbon atoms, with the proviso that at least two of the groups R², R³, R⁵ and R⁶ represent long-chain radicals having 6 to 50 carbon atoms represent or at least one of the groups R², R³, R⁵ and R⁶ a branched alkyl group, the branches being at least have at least 6 carbon atoms, wherein one has a compound with the general formula III

R¹COOR⁷ (III)

wherein R¹ has the meaning given above and R⁷ represents an alkyl group having 1 to 4 carbon atoms,
or the lactone with the formula (IV)

where m represents the numbers 0 to 3 and n represents the numbers 2 or 3,
aminolysis with an amine of the general formula (V)

HNR²R³ (V)

wherein R² and R³ have the meaning given above, submits.

Output connections

As starting compounds for the production of pseudoceramides the invention are C₁-C₄ alkyl esters of polyhydroxycarboxylic acid ren and their lactones suitable. As polyhydroxycarboxylic acids come especially those with 3 to 8 carbon atoms and 2 up to 7 hydroxy groups, d. H. so-called sugar acids in Be dress. Typical examples of this are glyceric acid, glucon acid, heptagluconic acid, mannonic acid and galactonic acid. Especially more preferred are the corresponding lactones such as D-delta Gluconolactone, D-gamma-heptagluconolactone, L-mannonic acid gam ma-lactone, D-galactonic acid-delta-lactone and glyceric acid methyl ester used.

The esters or lactones with the formulas III and IV are in in a manner known per se with amino compounds having the formula V subjected to aminolysis. The reaction is preferred in Ge presence of a solvent such as a lower alkyl alcohol, preferably methanol, at temperatures between 20 ° C and 65 ° C  carried out, it may be advantageous to take the amine Add stirring to the suspension / solution of the ester or lactone.

As amino compounds with the sugar acids or Lactone derivatives for the production of the verb according to the invention primary implementations and secondary alkyl amines and naturally occurring or syn theoretical amino acids. As examples of which he Amines used according to the invention can name compounds in which R² and R³ are linear or branched Alkyl radical having 1 to 50 carbon atoms. As examples for these amines can fatty amines, especially difatty alkyl amines, such as dihexadecylamine, dioctadecylamine, didodecylamine, Didecylamine, dioctylamine and Guerbetamine can be called. Technical fatty amines in particular are those plant-based such as coconut amine, palm kernel amine or oleyl amine as well as the Guerbetamine.

The esters of natural and synthetic amino acids which come under the formula V, such as, for example, amino mono- or dicarboxylic acids, can also be used as further amino compounds. As preferred examples of suitable amino acids on which these esters are based, 2-amino fatty acids, glycine, alanine, NC _8-22- alkyl-β-alanine, L-, D, L-aspartic acid, L-, D, L-glutamic acid or aminomalonic acid be used. Mixtures of amino acids can also be used.

The amino acids can with the alcohols R⁶OH, wherein R⁶ 6 to Has 50 carbon atoms, be esterified, wherein amino acid reester are preferred, which have two long carbon chains point. In particular linear primary alcohols come as alcohols fetch and branched primary alcohols. Examples for linear alcohols, the native fatty alcohols on plants Licher basis, such as B. lauryl alcohol, myristyl alcohol, cetyl  alcohol, stearyl alcohol, behen alcohol, oleyl alcohol, Elai dyl alcohol, ricinol alcohol, linoleyl alcohol, linolenyl alcohol and their technical mixtures, such as coconut oil alcohol, Tallow oil fatty alcohol, palm and palm kernel fatty alcohol or also Peanut fatty alcohol.

Typical examples of branched primary alcohols are 2-ethylhexanol, Isotridecyl alcohol, isopalmityl alcohol and iso stearyl alcohol. Are particularly preferred as starting materials Guerbet alcohols with 12 to 36 carbon atoms, which one passes through Condensation of linear fatty alcohols in the presence of basic Receives catalysts. Typical examples are 2-hexyl decanol, 2-octyldodecanol, 2-decyltetradecanol, 2-dodecylhexa decanol, 2-tetradecyloctadecanol and 2-hexadecyleicosanol.

Skin care products

The pseudoceramides can be found in skin care products in Men gene from 1 to 50, preferably from 1 to 30, in particular from 2 to 10 wt .-% - based on the agent - contain and both as "water-in-oil" and "oil-in-water" emulsions present; further customary auxiliaries and additives can be found in Contain amounts of 5 to 95, preferably 10 to 80 wt .-% his. Furthermore, the formulations can contain water in an amount have up to 99 wt .-%, preferably 5 to 80 wt .-%.

Examples of suitable carrier oils are: mine ral oils, vegetable oils, silicone oils, fatty acid esters, dialkyl ethers, Fatty alcohols and Guerbet alcohols. As emulsifiers can for example: sorbitan esters, monoglycerides, Polysorbates, polyethylene glycol mono / difatty acid ester, highly eth  oxylated fatty acid esters as well as high molecular silicone compound applications such as B. Dimethylpolysiloxane with an average molecular weight from 10,000 to 50,000. Further addition substances can be: preservatives such as B. p-Hydroxy benzoic acid esters; Antioxidants such as B. butylated hydroxytoluene, Tocopherol: humectants, such as. B. glycerin, sorbitol. 2-pyrrolidine-5-carboxylate, Dibutyl phthalate, gelatin, Polyglycols with an average molecular weight of 200 to 600; Buffers such as B. lactic acid / TEA or milk acid / NaOH; mild surfactants such as B. alkyl oligoglucosides, fat alcohol ether sulfates, fatty acid isothionates, taurides and sar cosinates, ether carboxylic acids, sulfosuccinates, protein hydrolyzates or fatty acid condensates, sulfotriglycerides, short-chain Glucamides; Phospholipids, waxes such as B. beeswax, ozoke rit wax, paraffin wax; Plant extracts, e.g. B. from Aloe vera; Thickeners; Dyes and perfumes, as well as sun protection medium, such as B. ultrafine titanium dioxide or organic matter fe such as p-aminobenzoic acid and its esters, ethylhexyl-p-meth oxycinnamic acid ester, 2-ethoxyethyl-p-methoxycinnamic acid ester, Bu tylmethoxydibenzoylmethan and their mixtures.

In a preferred embodiment of the invention, the Pseudoceramides with conventional ceramides, further pseudo ceramic cholesterol, cholesterol fatty acid esters, fatty acid ren, triglycerides, cerebrosides, phospholipids and the like Substances are mixed, whereby liposomes can arise.

In a further preferred embodiment of the invention can the pseudoceramides with accelerators, esp especially with essential oils, such as eucalyptol, Menthol and the like can be mixed.

In a third preferred embodiment, the pseu doceramide finally also dissolved in squalene or squalane and possibly together with the other ingredients mentioned  with volatile or non-volatile silicone compounds as water-free or almost water-free single-phase systems be formulated. More examples of ingredients and ty Chemical compositions can be found, for example, in WO 90/01323 (Bernstein) and S.E. Friberg, J. Soc. Cosmet. Chem. 41, 155 (1990).  

Industrial applicability

In the sense of the invention as "synthetic barrier lipids" Adding pseudoceramides strengthen the natural barrier function of the skin against external stimuli. They improve Fe increase the firmness, suppleness and elasticity of the skin the moisture content and protect the skin from dehydration; at the same time, the finest wrinkles are smoothed.

Another object of the invention therefore relates to the Ver Use of pseudoceramides of the formula I as "synthetic barrier lipids "for the manufacture of skin care products, in de in amounts of 1 to 50, preferably 1 to 30, in particular from 2 to 10% by weight, based on the composition, can be included. But also special formulations that Liquid-crystalline, lamellar structures are used for Maintaining the skin's barrier function is particularly advantageous. These formulations can be based on the composition the horny layer lipids as main components 5% by weight to 50 % By weight of a compound of the formula I, 25% by weight to 75 % By weight of saturated and unsaturated fatty acids, their Alkali salts or mixtures of the fatty acids and their salts, 10 % By weight to 50% by weight of cholesterol, phytosterols and / or choles steryl sulfate, 5% to 30% by weight triglycerides (triolein) and wax esters, and 2% to 20% by weight phospholides, such as Lecithins or cephalins. Typical examples of such formulations are skin creams, soft creams, Nutrient creams, sunscreen creams, night creams, skin oils, Care lotions and body aerosols.

The following examples are intended to be the subject of the invention explain in more detail without restricting it.  

Examples ND-gluconoyl-L-aspartic acid di-C _16/18 alkyl ester

58.2 g (0.1 mol) of L-aspartic acid-di. Were added to the stirred suspension of 17.8 g (0.1 mol) of D-5-glucono lactone in 150 ml of methanol at 65 ° C. in the course of 10 minutes -C _16/18 alkyl ester added in portions and the mixture was heated to boiling for a further 1.5 hours. The solvent was then largely distilled off under reduced pressure. In almost quantitative yield (74 g), ND-gluconoyl-L-aspartic acid di-C _16/18 alkyl ester was obtained as a colorless waxy substance with an unsharp melting point between 60 ° C. and 80 ° C. The compound can be purified by recrystallization from n-hexane, but is already very pure as a crude product (DC control).

The following compounds were obtained in an analogous manner as colorless wax-like substances:
ND-gluconoyl-L-aspartic acid dioctadecyl ester
ND-gluconoyl-L-glutamic acid dioctadecyl ester
ND-heptagluconoyl-L-glutamic acid octadecyl / docosyl-1: 1 mixed ester
ND-Gluconoylglycine-C- _32/36 Guerbet _alkyl ester
ND-Gluconoy IL-alanine-C _24/28 Guerbet alkyl ester

Claims (9)

1. Pseudoceramides with the general formula I wherein
R 1 CO represents a hydroxyacyl radical having 3 to 8 carbon atoms and 2 to 7 hydroxyl groups,
and
R² and R³ may be the same or different and represent hydrogen, a linear or branched alkyl group having 1 to 50 carbon atoms, or a group having the formula II-R⁴-COO-R⁵ (II) wherein R⁴ is an alkylene group having 1 to 18 carbon atoms which can contain a further ester group, COO-R⁶, in which R⁶ is a linear or branched alkyl group having 1 to 50 carbon atoms, and R⁵ is a linear or branched alkyl group having 6 to 50 carbon atoms,
with the proviso that at least two of the groups R², R³, R⁵ and R⁶ represent long-chain radicals with 6 to 50 carbon atoms or at least one of the groups R², R³, R⁵ and R⁶ is a branched alkyl group, the branches having at least 6 carbon atoms. 2. Pseudoceramides according to claim 1, characterized in that R¹ is a pentahydroxyhexyl radical and R² is a hydrogen atom when R³ is an R _18-36 - Guerbetalkylrest, a C _18-36- Guerbetalkoxycarbonyl-C _1-6 - alkyl radical or a group R⁴ -COOR⁵, in the R⁴ for the groups and R⁵ and R⁶ each represent a C _12-18 alkyl group; or R² is a C _12-18 alkyl radical and R³ is one of the groups -CH₂-CO₂R⁶ or -CH₂-CH₂-CO₂R⁶, in which R bedeutet is a C _12-18 alkyl radical; or
R² and R³ represent a C _12-18 alkyl radical. 3. Process for the preparation of a compound of formula I. wherein
R 1 CO represents a hydroxyacyl radical having 3 to 8 carbon atoms and 2 to 7 hydroxyl groups,
and
R² and R³ may be the same or different and represent hydrogen, a linear or branched alkyl group having 1 to 50 carbon atoms, or a group having the formula II-R⁴-COO-R⁵ (II) wherein R⁴ is an alkylene group having 1 to 18 carbon atoms which can contain a further ester group, COO-R⁶, in which R⁶ is a linear or branched alkyl group having 1 to 50 carbon atoms, and R⁵ is a linear or branched alkyl group having 6 to 50 carbon atoms,
with the proviso that at least two of the groups R², R³, R⁵ and R⁶ represent long-chain radicals with 6 to 50 carbon atoms or at least one of the groups R², R³, R⁵ and R⁶ is a branched alkyl group, the branches having at least 6 carbon atoms , in which a compound having the general formula IIIR¹COOR⁷ (III) in which R¹ has the meaning given above and R¹ represents an alkyl group having 1 to 4 carbon atoms, or the lactone having the formula IV where m represents the numbers 0 to 3 and n represents the numbers 2 or 3,
subject to aminolysis with an amine of the general formula VHNR²R³ (V) wherein R² and R³ have the meaning given above. 4. The method according to claim 3, characterized in that one as a compound with the formula III a Zuckersäuremethyl ester used. 5. The method according to claim 3, characterized in that one as a compound with the formula IV D-delta-glycono lactone uses. 6. The method according to any one of claims 3 to 5, characterized ge indicates that as a compound with formula V one  Amino acid ester uses two long carbon has chains. 7. The method according to any one of claims 3 to 5, characterized ge indicates that as a compound of formula V. Difettalkylamin uses. 8. The method according to any one of claims 3 to 5, characterized characterized in that as a compound of formula V uses a Guerbet fatty alkyl amine. 9. Use of pseudoceramides according to claim 1 as Be part of "synthetic barrier lipids" for production of skin care products.