DE4424530A1 - Pseudoceramides - Google Patents

Abstract

New pseudoceramides have the formula (I), in which R<1>CO stands for a branched, saturated and/or unsaturated acyl residue with 8 to 50 carbon atoms, R<2> stands for hydrogen or an optionally hydroxy-substituted alkyl residue with 1 to 30 carbon atoms, R<3> stands for a hydroxyalkyl residue with 2 to 12 carbon atoms and 1 to 10 hydroxyl groups or for a glycosyl residue, provided that the sum of the carbon atoms of residues R<1> and R<2> be at least 16. These new pseudoceramides are suitable as synthetic barrier lipids for skin care products.

Description

Field of the Invention

The invention relates to pseudoceramides that are available by reacting branched fatty acids, their acid chlorides or anhydrides with amines, a process for the preparation of the Pseudoceramides, skin care products containing the pseudo ceramides and the use of pseudoceramides for their manufacture treatment 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 are shaped 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, P. 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 genes have been extracted since they were 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 delivery in a cosmetic formulation chen of the site of action is possible. The external application from Ceramids leads to the restoration of the lipid barrier, causing the described disorders of skin function can be counteracted. [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. Cosmet. Chem. 40, 273 (1989)].

For example, in the European Disclosure publications EP-A 0 277 641 and EP-A 0 227 994 (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 fatty acyl radical, z for numbers from 7 to 49, R ^b for a hydroxyalkyl and Z for a sugar or phosphate radical.

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.

in the R¹CO for a branched, saturated and / or unsung saturated acyl radical with 8 to 50 carbon atoms, R² for What serstoff or an optionally hydroxy-substituted Alkyl radical with 1 to 30 carbon atoms, R³ for a Hy hydroxyalkyl radical having 2 to 12 carbon atoms and 1 to 10 Hydroxyl groups or a glycosyl radical, with the measure be that the sum of the carbon atoms of the radicals R¹ and R² is at least 16.

Pseudoceramides of the formula I are particularly preferred R¹CO for the branched acyl residue of a guerbet acid with 12 up to 36 carbon atoms, R² for hydrogen or a methyl group, R³ for a hydroxyalkyl radical with 6 carbon atoms and 5 hydroxyl groups or a glucosyl radical.

Manufacturing process

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

in the R¹CO for a branched, saturated and / or unsung saturated acyl radical with 8 to 50 carbon atoms, R² for What serstoff or an optionally hydroxy-substituted Al  kylrest with 1 to 30 carbon atoms, R³ for a Hy Droxyalkylrest with 2 to 12 carbon atoms and 1 to 10 Hy droxyl groups or a glycosyl radical, with the proviso that that the sum of the carbon atoms of the radicals R¹ and R² min is at least 16, characterized in that one

• a) branched carboxylic acids of the formula II, where R¹CO has the meaning given above,
  in a manner known per se by means of chlorine compounds in their acid chlorides or in their mixed anhydrides and
• b) the resulting acid chlorides or mixed anhydrides are condensed with hydroxyalkylamines or glucosylamines of the formula III, wherein R² and R³ have the meanings given above.

Output connections

In the sense of the method according to the invention come as branch te, saturated and / or unsaturated carboxylic acids with 8 up to 50 carbon atoms. examples for this are 2-ethylhexane carboxylic acid, isotridecyl carboxylic acid, isopalmitin acid and isostearic acid. Are special as starting materials prefers the so-called Guerbet acids with 12 to 36 carbons suitable atoms. The acids used according to the invention can in a manner known per se from the corresponding ver  branched alcohols with 8 to 50 carbon atoms, in particular Guerbet alcohols are obtained. The Guerbet alcohol le is obtained by condensing linear fatty alcohols in Presence of basic catalysts. Typical examples of Guerbet alcohols are 2-hexyldecanol, 2-octyldodecanol, 2-de cyltetradecanol, 2-dodecylhexane decanol, 2-tetradecyloctadeca nol and 2-hexadecyleicosanol.

To create a link between the carboxylic acids and the polyhy To be able to produce droxyalkylamines, the free carb oxyl group first in a manner known per se using chlorine compounds in the acid chloride or in the mixed acid transferred reanhydride.

As chlorine compounds for the production of acid chlorides preferably phosphorus trichloride or thionychloride used. Usually, the carboxylic acids and Chlorine compounds in a molar ratio of 1: 0.4 to 1: 2.5 deploy. The chlorination is preferably carried out in the presence of solvent at -10 to 60 ° C in the absence of water carried out. Gasoline, for example, comes as a solvent fractions, toluene, ethyl acetate, 1,2-dimethoxyethane, tert-Bu tylmethyl ether or tetrahydrofuran. But you can also work in the melt without solvents. After Ab at the end of the reaction, the impurities, e.g. B. un terphosphorous acid separated, unreacted chlorine distilled off or - if it is only a small amount Amounts act - leave in the reaction mixture.

In a variant of the method according to the invention, the Carboxylic acids with chlorinated carbonic acid alkyl esters in an inert Solvents are converted to the mixed anhydrides. The reaction preferably takes place in the presence of an acid catchers such as triethylamine, tributylamine or sodium or Ka lium carbonate instead, the reactants in about molar  Amounts at temperatures from -10 to 60 ° C, preferably 0 to 10 ° C can be used. Following implementation is recommended it is possible to filter off the salts formed. In this together Hang on to the publication of C. Bersena in J. Org.Chem.27, 3489 (1962). For the following Reaction can either be the solution obtained or else its evaporated residue can be used.

As hydroxyalkylamines, which with the acid chlorides or the An hydrides are reacted, for example N-alkylsorbitylamines and especially N-alkylglucosylamines Formula V into consideration

in which R² is preferably an alkyl radical having 8 to 22 and in particular 12 to 18 carbon atoms.

In a further preferred embodiment of the invention are glucamine or N-alkylglucamine of the formula VI puts,  

in the R⁴ preferably for hydrogen or an alkyl radical with 1 to 4 carbon atoms, especially for an alkyl rest with 1 to 2 carbon atoms. The N-alkylgluca Mine are usually by reductive amination of Glu cose made with fatty amines. In addition, both the glucosylamines as well as the glucamines, for example derived from maltose, fructose or palatinose. As examples be N-methyl-glucamine and N- (2-hydroxyethyl) -glucamine called. Diethanol also comes as further hydroxyalkylamines amine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymes thyl-1,3-propanediol and 2,3-dihydroxypropylamine.

Usually you can acid chlorides or mixed Anhy dride and the hydroxyalkylamines or glucosylamines in the molar Use a ratio of 1: 0.9 to 1: 1.1. The condens sationsreaktion is preferably at temperatures in the range from 20 to 60 ° C in the presence of alkaline catalysts carried out, the reaction times typically 1 to Can be 10 hours. Soda, potash can be used as acid scavengers or tertiary amines such as. B. triethylamine can be used. Tetrahydrofu, for example, is recommended as a solvent ran. The products can then be recrystallized for example from lower alcohols or column chromatography be cleaned. The condensation of amine compounds with acid chlorides is generally known and is used in described for example in EP-A-0 265 818 (CP Stockhausen) ben.  

Skin care products

Another object of the invention relates to skin care with tel, containing pseudoceramides of the formula I.

The agents according to the invention can contain the pseudoceramides 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 Lich molecular weight from 10,000 to 50,000. Additional additive 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, Po lyglycols with an average molecular weight of 200 to 600; Buffers such as B. lactic acid / TEA or lactic acid right / NaOH; mild surfactants such as B. alkyl oligoglucosides, fatty al alcohol ether sulfates, fatty acid isethionates, taurides and sarco sinates, 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 ceramides, 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 also dissolved and given in squalene or squalane if with the other ingredients mentioned together with volatile or non-volatile silicone compounds as what water-free or almost water-free single-phase systems formu be lated. Other examples of ingredients and typical 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 a "synthetic bar rier lipids "for the manufacture of skin care products in which they in amounts from 1 to 50, preferably from 1 to 30, in particular Special from 2 to 10 wt .-% - based on the agent - contain can be. But also special formulations that Liquid crystalline, lamellar structures are the Er maintaining the barrier function of the skin 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 fatty acids and their salts, 10% by weight up to 50% by weight of cholesterol, phytosterols and / or cholesteryl sulfate, 5 wt .-% to 30 wt .-% triglycerides (triolein) and Wax esters, and 2% to 20% by weight phospholides such as Leci thine or cephaline. Typical examples of the like formulations are skin creams, soft creams, nutritional creams, Sunscreen creams, night creams, skin oils, care lotions and Body aerosols.

The following example is intended to illustrate the subject matter of the invention explain without restricting him to it.

example C _32/36 Guerbet Acid N-methylsorbitylamide

A solution of 140.3 g (0.25 mol) of C _32/36 Guerbet acid in 500 ml of gasoline (60-95 ° C.) was mixed with 20.6 g (0.15 mol) of phosphorus tri chloride, 1 hour at room temperature, 4 hours at 35 ° C. and left overnight at room temperature. The clear solution is decanted from the resinous phosphorous acid and the solution is concentrated. 58.0 g (0.1 mol) of the pasty acid chloride were dissolved in 400 ml of toluene and, with vigorous stirring, slowly to a solution of 23.4 g (0.12 mol) of N-methyl glucamine in 50 ml of water 100 ml of toluene were added, dropwise, until the pH of the low-viscosity emulsion had dropped from 11.2 to 9.0. In addition, 16.8 g (0.42 mol) of sodium hydroxide in 38 ml of water were added dropwise so slowly that the pH did not drop below 7.9. The mixture was then left to react for 4.5 hours. 4.5 hours. After standing overnight, the mixture was heated to 60.degree. C. for better phase separation, the toluene phase was separated off and the aqueous phase was extracted three more times with 200 ml of toluene each time. The combined toluene phases were evaporated and dried in an oil pump vacuum. 79 g of an almost colorless waxy mass were obtained as a residue. The nitrogen content was 90% of theory.

The substance was in tert. Butyl methyl ether dissolved and as aqueous emulsion by adding hydrochloric acid until neutral weakly acidic. The organic phase was removed separates and evaporated. It became a waxy substance hold.

Claims (10)

1. pseudoceramides of the formula I, in the R¹CO for a branched, saturated and / or unsaturated acyl radical having 8 to 50 carbon atoms, R² for hydrogen or an optionally hydroxysubstituted alkyl radical with 1 to 30 carbon atoms, R³ for a hydroxyalkyl radical with 2 to 12 carbon atoms and 1 to 10 hydroxyl groups or one Glycosylrest stands, with the proviso that the sum of the carbon atoms of the radicals R¹ and R² is at least 16. 2. Pseudoceramides according to claim 1, characterized in that that in formula I R¹CO for the branched acyl group ner Guerbet acid with 12 to 36 carbon atoms, R² for Hydrogen or a methyl group, R³ for a hydroxy alkyl radical with 6 carbon atoms and 5 hydroxyl groups or a glucosyl residue. 3. Process for the preparation of pseudoceramides of the formula I. in the R¹CO for a branched, saturated and / or unsaturated acyl radical having 8 to 50 carbon atoms, R² for hydrogen or an optionally hydroxysubstituted alkyl radical with 1 to 30 carbon atoms, R³ for a hydroxyalkyl radical with 2 to 12 carbon atoms and 1 to 10 hydroxyl groups or one Glycosylrest, with the proviso that the sum of the carbon atoms of the radicals R¹ and R² is at least 16, characterized in that

• a) branched carboxylic acids of the formula II, wherein R¹CO has the meaning given above, in a conventional manner by means of chlorine compounds in their acid chlorides or mixed anhydrides and
• b) the resulting acid chlorides or mixed anhydrides are condensed with hydroxyalkylamines or glucosylamines of the formula III, wherein R² and R³ have the meanings given above.

4. The method according to claim 3, characterized in that branched carboxylic acids of the Guerbet acid type Uses 12 to 36 carbon atoms. 5. The method according to any one of claims 3 or 4, characterized ge indicates that as hydroxylalkylamine Glucosyla mine, glucamine or 2-amino-2-hydroxymethyl-1,3-propane uses diol.   6. The method according to any one of claims 3 to 5, characterized ge indicates that phosphorus tri chloride, thionyl chloride or chlorinated carbonate starts. 7. The method according to any one of claims 3 to 6, characterized ge indicates that the carboxylic acid with the formula II and the chlorine compounds in a molar ratio of 1: 0.9 up to 1: 1.1. 8. The method according to any one of claims 3 to 7, characterized ge indicates that the acid chlorides or the mixture ten anhydrides and the hydroxylalkylamines in the molar Ratio 1: 0.9 to 1: 1.1 implemented. 9. Skin care agent containing pseudoceramides according to claim 1. 10. Use of pseudoceramides according to claim 1 as Be part of "synthetic barrier lipids" for production of skin care products.