(3-alkylthio)propenoic acid-derived compounds and their application in cosmetics

Abstract

The present invention relates to compounds of general formula (I): ##STR00001##
wherein Y, R.sub.1, R.sub.2 and R.sub.3 are as defined in the specification. The invention also relates to cosmetic or dermocosmetic composition containing such compounds. The compounds according to the invention are useful as photoprotective agents.

Claims

1. A compound represented by the following general formula (I): ##STR00009## wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.2 is a hydrogen atom, or a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is: a C.sub.1-C.sub.18 alkyl group, a C.sub.3-C.sub.18 alkene group, or a C.sub.3-C.sub.4 alkyne group, said alkyl, alkene and alkyne groups being linear or branched and optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group; or the side chain of an amino acid selected from the group consisting of tyrosine, hydroxyproline, serine, homoserine, isoserine, threonine, homothreonine and isothreonine; provided that said compound is not one of the following compounds: 2-cis-entadamide A, isopenangin, N-ethyl-cis-3-butylmercaptoacrylamide and N-ethyl-cis-3-methylmercaptoacrylamide.

2. The compound according to claim 1, represented by the following general formula (II): ##STR00010## wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is a C.sub.1-C.sub.4 alkyl group, a C.sub.3-C.sub.4 alkene group, or a C.sub.3-C.sub.4 alkyne group, said alkyl, alkene and alkyne groups being linear or branched and optionally substituted with a hydroxyl, a hydroxyphenyl or dihydroxyphenyl group.

3. The compound according to claim 1, wherein Y is S.

4. The compound according to claim 1, wherein R.sub.1 is a methyl group.

5. The compound according to claim 1, wherein R.sub.3 is an ethyl group substituted by a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

6. The compound according to claim 1, which is (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide.

7. A cosmetic or dermocosmetic composition useful for photoprotection, which comprises as main active ingredient a compound of formula (IIIa), a compound of formula (IIIb), or a mixture thereof, in combination with any additive physiologically compatible with skin or appendages: ##STR00011## wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.2 is a hydrogen atom, or a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is: a C.sub.1-C.sub.18 alkyl group, a C.sub.3-C.sub.18 alkene group, or a C.sub.3-C.sub.4 alkyne group, said alkyl, alkene or alkyne groups being linear or branched and optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group; or the side chain of an amino acid selected from the group consisting of tyrosine, hydroxyproline, serine, homoserine, isoserine, threonine, homothreonine and isothreonine; and wherein the amount of main active ingredient is in the range from 0.001% to 0.1% by weight based on the total weight of the composition.

8. The cosmetic or dermocosmetic composition according to claim 7, which comprises, as main active ingredient, a compound of formula (IVa), a compound of formula (IVb), or a mixture thereof: ##STR00012## wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is a linear or branched C.sub.1-C.sub.4 alkyl group optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

9. The cosmetic or dermocosmetic composition according to claim 7, wherein in the compound of formula (IIIA) or (IIIb) Y is S, R.sub.1 is a methyl group and R.sub.3 is an ethyl group substituted by a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

10. The cosmetic or dermocosmetic composition according to claim 7, wherein the main active ingredient is (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide or (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide.

11. The cosmetic or dermocosmetic composition according to claim 7, which further comprises an organic or inorganic sun filter that is active in the UV-A and/or UV-B, selected from the group consisting of: anthranilates, cinnamic derivatives, dibenzoylmethane derivatives, salicylic derivatives, camphor derivatives, triazine derivatives, benzophenone derivatives, beta,beta-diphenylacrylate derivatives, benzotriazole derivatives, benzalmalonate derivatives, benzimidazole derivatives, imidazolines, bis-benzoazolyl derivatives, benzoxazole derivatives, p-aminobenzoic acid (PABA) derivatives, methylene bis-(hydroxyphenyl benzotriazole) derivatives, filter polymers, filter silicones, dimers derived from alpha-alkylstyrene, 4,4-diarylbutadienes, metal oxide pigments or nanopigments, coated or uncoated, and mixtures thereof.

12. The cosmetic or dermocosmetic composition according to claim 7, which further comprises one or several active ingredients selected from the group consisting of: deglycation agents, agents that increase the synthesis of collagen or elastin or prevent their degradation, agents that increase the synthesis of glycosaminoglycans or proteoglycans or prevent their degradation, agents that increase the cell proliferation, depigmenting or pro-pigmenting agents, antioxidant or anti-radical or anti-pollution agents, moisturizing agents, agents that stimulate lipolysis, draining or detoxifying agents, anti-inflammatory agents, penetration enhancer agents, desquamative agents, soothing and/or anti-irritating agents, astringent agents, agents that act on the microcirculation, and mixtures thereof.

13. A method of photoprotection against sun radiation, which comprises applying to skin a cosmetic or dermocosmetic composition comprising, as main active ingredient, a compound of formula (IIIa), a compound of formula (IIIb), or a mixture thereof, in combination with any additive physiologically compatible with skin or appendages: ##STR00013## wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.2 is a hydrogen atom, or a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is: a C.sub.1-C.sub.18 alkyl group, a C.sub.3-C.sub.18 alkene group, or a C.sub.3-C.sub.4 alkyne group, said alkyl, alkene or alkyne groups being linear or branched and optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group; or the side chain of an amino acid selected from the group consisting of tyrosine, hydroxyproline, serine, homoserine, isoserine, threonine, homothreonine and isothreonine.

14. The method according to claim 13, which comprises applying to skin a cosmetic or dermocosmetic composition comprising, as main active ingredient, a compound of formula (IVa), a compound of formula (IVb), or a mixture thereof in combination with any additive physiologically compatible with skin or appendages: ##STR00014## wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is a linear or branched C.sub.1-C.sub.4 alkyl group optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

15. The method according to claim 13, wherein in the compound of formula (IIIa) or (IIIb) Y is S, R.sub.1 is a methyl group and R.sub.3 is an ethyl group substituted by a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

16. The method according to claim 13, wherein the main active ingredient is (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide or (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide.

17. The method according claim 13, wherein the cosmetic or dermocosmetic composition comprises from 0.001% to 0.1% by weight of main active ingredient based on the total weight of the composition.

18. The method according to claim 13, wherein the cosmetic or dermocosmetic composition further comprises an organic or inorganic sun filter that is active in the UV-A and/or UV-B, selected from the group consisting of: anthranilates, cinnamic derivatives, dibenzoylmethane derivatives, salicylic derivatives, camphor derivatives, triazine derivatives, benzophenone derivatives, beta,beta-diphenylacrylate derivatives, benzotriazole derivatives, benzalmalonate derivatives, benzimidazole derivatives, imidazolines, bis-benzoazolyl derivatives, benzoxazole derivatives, p-aminobenzoic acid (PABA) derivatives, methylene bis-(hydroxyphenyl benzotriazole) derivatives, filter polymers, filter silicones, dimers derived from alpha-alkylstyrene, 4,4-diarylbutadienes, metal oxide pigments or nanopigments, coated or uncoated, and mixtures thereof.

19. The method according to claim 13, wherein the cosmetic or dermocosmetic composition further comprises one or several active ingredients selected from the group consisting of: deglycation agents, agents that increase the synthesis of collagen or elastin or prevent their degradation, agents that increase the synthesis of glycosaminoglycans or proteoglycans or prevent their degradation, agents that increase the cell proliferation, depigmenting or pro-pigmenting agents, antioxidant or anti-radical or anti-pollution agents, moisturizing agents, agents that stimulate lipolysis, draining or detoxifying agents, anti-inflammatory agents, penetration enhancer agents, desquamative agents, soothing and/or anti-irritating agents, astringent agents, agents that act on the microcirculation, and mixtures thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The invention has therefore for first object a family of pure cis or (Z)-isomers conjugates obtained by a coupling reaction between (Z)-3-(alkylthio)propenoic acid and primary or secondary alkylamines or a selection of hydroxylated and non-ionizable polar amino acids, characterized in that said family is represented by the following general formula (I):

(2) ##STR00002##
wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.2 is a hydrogen atom, or a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is: a C.sub.1-C.sub.18 alkyl group, a C.sub.3-C.sub.18 alkene group, a C.sub.3-C.sub.4 alkyne group, said alkyl, alkene or alkyne groups being linear or branched and optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group; or the side chain of an amino acid chosen from tyrosine, hydroxyproline, serine and its homoserine and isoserine analogues, threonine and its homothreonine and isothreonine analogues.

(3) The skilled person can easily identify the side chain of the above-mentioned amino acids. These amino acids are represented by one of the following formulae:

(4) ##STR00003##
which correspond to tyrosine (R.sub.4=4-hydroxyphenyl), serine (R.sub.4═—CH.sub.2—OH) and its homoserine (R.sub.4═—CH.sub.2—CH.sub.2—OH) and isoserine (R.sub.5═H, R.sub.6═OH) analogues, threonine (R.sub.4═—CH(OH)—CH.sub.3) and its homothreonine (R.sub.4═—CH.sub.2—CH(OH)—CH.sub.3) and isothreonine (R.sub.5═CH.sub.3, R.sub.6═OH) analogues. These amino acids can also be defined by a registration number in a data bank (hydroxyproline, CAS n.sup.o 51-35-4).

(5) According to a preferred embodiment of the invention, the (Z)-isomer conjugates of the invention are represented by the formula (II) here-below:

(6) ##STR00004##
wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is a C.sub.1-C.sub.4 alkyl group, a C.sub.3-C.sub.4 alkene group, a C.sub.3-C.sub.4 alkyne group, said alkyl, alkene or alkyne groups being linear or branched and optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

(7) Advantageously, the (Z)-isomer conjugates of formula (I) or (II) are as such that Y═S.

(8) Advantageously, the (Z)-isomer conjugates of formula (I) or (II) are such that R.sub.1 is a methyl group.

(9) Advantageously, the (Z)-isomer conjugates of formula (I) or (II) are such that R.sub.3 is an ethyl group substituted by a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group. Thus as an example of alkylamines involved in the coupling reaction with cis-3-methylthiopropenoic acid (Z-TMPA), ethanolamine, tyramine, a catecholamine like dopamine, adrenaline or noradrenaline, can be mentioned.

(10) As non-exhaustive examples of (Z)-isomer conjugates of formula (I) or (II), the following compounds can be mentioned, the photo-isomerization-induced product (trans-isomer) of which naturally occurs in plants: (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide.

(11) To date and to the knowledge of the applicant, the (Z)-isomer conjugates of formula (I) are new with the exception of the 2-cis-entadamide A, isopenangin, N-ethyl-cis-3-butylmercaptoacrylamide and N-ethyl-cis-3-methylmercaptoacrylamide compounds.

(12) The conjugates of formula (I) can be synthesized by the following production process developed by the applicant: i/ stereoselective preparation of (Z)-3-thiocyanatopropenoic acid by reaction of propiolic acid with potassium thiocyanate; ii/ alkylation reaction at low temperature of (Z)-3-thiocyanatopropenoic acid according to i/ using alkyl iodide, preferably methyl iodide, and then formation of the resulting (Z)-3-(alkylthio)propenoic acid synthon, preferably (Z)-3-methylthiopropenoic acid; iii/ coupling reaction at room temperature between (Z)-3-(alkylthio)propenoic acid according to ii/, preferably (Z)-3-methylthiopropenoic acid, and a primary or secondary alkylamine or a polar amino acid, preferably a linear or branched primary alkylamine, and even more preferably ethanolamine or tyramine, and formation of the resulting conjugated derivatives, preferably (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide and (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide. The coupling reaction is carried out with a coupling agent well-known to the skilled person, preferably N,N′-dicyclohexylcarbodiimide, and with a carboxylic function activator of the (Z)-3-alkylthiopropenoic acid synthon that is also well known to the skilled person, preferably hydroxybenzotriazole.

(13) These (Z)-isomer conjugates are obtained in powdered solid form, are soluble in alcoholic medium, and are stable both in powder form and in solution over a period exceeding 28 days.

(14) The above-mentioned conjugates (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide and (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide have the following physico-chemical and spectral characteristics: (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide

(15) Rf=0.40 (CHCl.sub.3/MeOH, 90:10);

(16) m.p.=112° C.;

(17) .sup.1H NMR (CD.sub.3OD): δ=2.32 ppm (s, 3H, CH.sub.3), 3.31 (t, 2H, J=6 Hz, CH.sub.2—NH), 3.60 ppm (t, 2H, J=6 Hz, CH.sub.2—OH), 5.89 ppm (d, 1H, J=10 Hz, CH═), 6.93 ppm (d, 1H, J=10 Hz, CH═);

(18) .sup.13C NMR (CD.sub.3OD): δ=19.2 ppm (CH.sub.3), 42.8 ppm (N—CH.sub.2), 61.8 ppm (CH.sub.2—O), 115.9 ppm (═CH), 148.6 ppm (═CH—S), 169.2 ppm (C═O). (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide

(19) Rf=0.35 (toluene/acetone/acetic acid, 100:50:2);

(20) m.p.=132° C.;

(21) .sup.1H NMR (CD.sub.3OD): δ=2.31 ppm (s, 3H, CH.sub.3—S), 2.69 (t, 2H, J=7.5 Hz, CH.sub.2-Ph), 3.35 ppm (t, 2H, J=7.5 Hz, CH.sub.2—N), 5.83 ppm (d, 1H, J=10 Hz, CH═), 6.90 ppm (d, 1H, J=10 Hz, CH═), 6.70 ppm (d, 2H, J=8.5 Hz, C.sub.Ph—H), 7.02 ppm (d, 2H, J=8.5 Hz, C.sub.Ph—H); .sup.13C NMR (CD.sub.3OD): δ=19.2 ppm (CH.sub.3—S), 35.9 ppm (CH.sub.2-Ph), 42.2 ppm (CH.sub.2—N), 116 ppm (CH═), 116.2 ppm (phenol), 130.7 ppm (phenol), 131.3 ppm (phenol), 148.4 ppm (═CH), 156.9 ppm (phenol), 169 ppm (C═O).

(22) According to a second aspect, the invention also covers a composition for cosmetic or dermocosmetic use, intended for photoprotection, in particular of skin or appendages. This composition comprises as main active ingredient a compound of general formula (III) below in combination with any physiologically acceptable additive with skin or appendages:

(23) ##STR00005##
wherein: Y, R.sub.1, R.sub.2 and R.sub.3 are as defined here-above for the compounds of formula (I).

(24) Advantageously, the cosmetic or dermocosmetic composition according to the invention comprises, as main active ingredient, a compound of general formula (IV):

(25) ##STR00006##
wherein: Y═S or SO; R.sub.1 is a linear or branched C.sub.1-C.sub.4 alkyl group; R.sub.3 is a linear or branched C.sub.1-C.sub.4 alkyl group, optionally substituted with a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group.

(26) The general formula (III) includes both the Z-isomers of formula (IIIa), the E-isomers of formula (IIIb), and mixtures of these isomers, preferably the racemate:

(27) ##STR00007##

(28) Similarly, the general formula (IV) includes both the Z-isomers of formula (IVa), the E-isomers of formula (IVb), and mixtures of these isomers, preferably the racemate:

(29) ##STR00008##

(30) In the context of the present invention, the term “main active ingredient” is intended to mean an active substance capable of opposing the harmful effects of sun radiation.

(31) Advantageously, the amount of compound of general formula (III) or (IV) in the described compositions is in the range from 0.001% to 0.1% by weight based on the total weight of the composition, preferably from 0.005 to 0.05% % by weight.

(32) The recommended molar concentration of the compound of general formula (III) or (IV) in the described compositions is advantageously in the range from 0.05 to 5 mM, preferably from 0.25 to 2.5 mM as in the illustrative tests hereafter.

(33) Advantageously, the compound of general formula (III) or (IV) is such that Y═S.

(34) Advantageously, the compound of general formula (III) or (IV) is such that R.sub.1 is a methyl group.

(35) Advantageously, the compound of general formula (III) or (IV) is such that R.sub.3 is an ethyl group substituted by a hydroxyl, a hydroxyphenyl or a dihydroxyphenyl group. Thus as an example of corresponding primary or secondary alkylamines involved in the coupling reaction with Z-TMPA and E-TMPA acids, mention can be made of ethanolamine, tyramine, a catecholamine like dopamine, adrenaline or noradrenaline.

(36) Very particularly in the compositions according to the invention, the compound of general formula (III) or (IV) is respectively a (Z)-isomer conjugate of formula (IIIa) or (IVa) derived from (Z)-3-(alkylthio)propenoic acid.

(37) Most preferably, the compositions according to the invention comprise, as main ingredient, (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide or (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide.

(38) The compositions according to the invention are suitable for topical cutaneous administration, presented under all forms normally used for such an administration. By way of non-limiting information, compositions can be in the form of suspensions, lotions, creams, aqueous or hydroalcoholic gels, powders and various emulsions that can be possibly microemulsions or nanoemulsions, etc.

(39) The compositions according to the invention can contain as physiologically acceptable additive at least one additive known by the skilled person and compatible in cosmetic or dermocosmetic areas, chosen among oils, waxes, silicone elastomers, surfactants, co-surfactants, thickeners and/or gellants, humectants, emollients, organic or inorganic sun filters, photostabilizing agents, preservatives with the exception of aldehyde donor preservatives, dyes, matifying agents, tensors, sequestering agents, perfumes, etc, and mixtures thereof.

(40) Said organic or inorganic sun filters are active in the UV-A and/or UV-B, and are chosen among anthranilates, cinnamic derivatives, dibenzoylmethane derivatives, salicylic derivatives, camphor derivatives, triazine derivatives, benzophenone derivatives, beta,beta-diphenylacrylate derivatives, benzotriazole derivatives, benzalmalonate derivatives, benzimidazole derivatives, imidazolines, bis-benzoazolyl derivatives, benzoxazole derivatives, p-aminobenzoic acid (PABA) derivatives, methylene bis-(hydroxyphenyl benzotriazole) derivatives, filter polymers, filter silicones, dimers derived from alpha-alkylstyrene, 4,4-diarylbutadienes, metal oxide pigments or nanopigments (titanium, zinc, iron, zirconium and cerium oxides), coated or uncoated, and mixtures thereof.

(41) The compositions according to the invention can further comprise one or several additional active ingredients, the skilled person however ensuring that the possible additional active compounds as well as their proportions are chosen in such a way that the advantageous properties acknowledged for the compositions according to the invention are not affected. These additional active ingredients can be chosen, without the list being limited, among deglycation agents, agents that increase the synthesis of collagen or elastin or prevent their degradation, agents that increase the synthesis of glycosaminoglycans or proteoglycans or prevent their degradation, agents that increase cell proliferation, depigmenting or pro-pigmenting agents, antioxidant or anti-radical or anti-pollution agents, moisturizing agents, agents that stimulate lipolysis, draining or detoxifying agents, anti-inflammatory agents, penetration enhancer agents, desquamative agents, soothing and/or anti-irritating agents, astringent agents, agents that act on the microcirculation, etc, and mixtures thereof.

(42) The compositions according to the invention can also further comprise at least a skin tanning and/or browning agent.

(43) Another object of the invention relates to the use, in a cosmetic or dermocosmetic composition, of a compound of formula (III) or (IV) such as previously defined, as a photoprotective agent against sun radiation.

(44) Another object of the invention relates to a method of photoprotection against sun radiation which comprises the application of a cosmetic or dermocosmetic composition such as previously defined and containing a compound of formula (III) or (IV). In one embodiment the method comprises topically applying the cosmetic or dermocosmetic composition of the invention to skin.

(45) Preferably in the above-mentioned use and method, the compound of formula (III) or (IV) is respectively a (Z)-isomer conjugate of formula (IIIa) or (IVa) derived from (Z)-3-(alkylthio)propenoic acid, especially (Z)—N-(2-hydroxyethyl)-3-(methylthio)propenamide or (Z)—N-(4-hydroxyphenethyl)-3-(methylthio)propenamide.

EXAMPLES

Example 1

(46) For illustrative purposes, four formulation examples of composition according to the invention are mentioned hereafter, containing a conjugate derived from cis-3-methylthiopropenoic acid of the above-mentioned general formula (I):

(47) TABLE-US-00001 Formula A (cream) (Z)-N-(2-hydroxyethyl)-3-(methylthio)propenamide 0.008%    Hydrogenated polyisobutene 7% Isobutyl myristate 7% Cetyl palmitate 7% Ethylene glycol monostearate 5% Sorbitan laurate 2% Polysorbate 20 2% Carbomer (acrylate/acrylamide copolymer & mineral oil) 0.3%   Phenoxyethanol 0.5%   Water qsp 100%

(48) TABLE-US-00002 Formula B (gel) (Z)-N-(4-hydroxyphenethyl)-3-(methylthio)propenamide 0.011%  Carbomer (acrylate/acrylamide copolymer & mineral oil) 1.5% Sodium benzoate 0.2% Sorbic acid   1% 1,3-butanediol  10% Glycerin   5% Sodium hydroxide 0.13%  Phenoxyethanol 0.9% Water qsp 100%

(49) TABLE-US-00003 Formula C (lotion) (E)-N-(4-hydroxyphenethyl)-3-(methylthio)propenamide 0.031%  Chlorphenesin 0.2% Phenonip (parabens - butyl, ethyl, isobutyl, methyl, propyl 0.6% parahydroxybenzoates, and phenoxyethanol) Xamhan gum 0.3% Glycerin 2.5% Triethanolamine 0.03%  Water qsp 100%

(50) TABLE-US-00004 Formula D (emulsion) (Z)-N-(2-hydroxyethyl)-3-(methylthio)propenamide 0.018%    Hydrogenated polydecene 8% Capric/caprylic triglycerides 2% Ethoxydiglycol oleate 8% Glyceryl stearate 2% Dimethicone 1% Polyethylene glycol-100 stearate and glyceryl stearate 5% Propyl paraben 0.3%   Stearyl alcohol 1% EDTA (ethylene diamine disodium salt dihydrate 0.2%   acid tetraacetic acid) Glycerin 3% Xanthan gum 0.4%   Wheat germ oil 1% Macadamia seed oil 1% Polyethylene glycol-8 & tocopherol & ascorbyl palmitate & 0.07%   ascorbic acid & citric acid Triethanolamine 0.35%   Water qsp 100%
(In all the examples the % are % by weight).

Example 2

(51) Merely by way of information, the invention is hereafter illustrated by the following tests which are mentioned above in the description of the invention (tests 1 to 5).

(52) Test 1: Evidence of the Antioxidant Potential of the Compounds of Formula (IIIc) and (IIIb) Against Squalene Hydroperoxidation by Singlet Oxygen

(53) Principle: the aim is to demonstrate a possible scavenging effect (“quenching”) of the compounds according to the invention on squalene hydroperoxides generated by the action of dissolved molecular oxygen on squalene in the presence of a photosensitizing agent (methylene blue).

(54) Experimentally, a squalene solution at 5 g/100 mL, a methylene blue solution at 5 mM and a solution of the compound according to the invention (from 1 to 5 mM) or a control compound (methylthiopropylamido acetyl methionine-AMDM) were prepared after being dissolved in 100 mL of methanol (HPLC grade). Then in a UV-B oven, each solution was poured in equal parts into an uncovered Petri dish, in order to be submitted to a radiation dose (1D) of 1.42 J.Math.cm.sup.−2. At the end of the radiation, volumes of the solutions were recovered, adjusted to 20 mL with methanol prior to analysis by HPLC assay and after removal of methylene blue. The “quenching,” rate was then deduced from the following equation:

(55) $\%\mathrm{protection}=\frac{\begin{array}{c}\mathrm{amount}\mathrm{of}\mathrm{oxidized}\mathrm{squalene}\left(\mathrm{control}\right)-\\ \mathrm{amount}\mathrm{of}\mathrm{oxidized}\mathrm{squalene}\left(\mathrm{test}\right)\end{array}}{\mathrm{amount}\mathrm{of}\mathrm{oxidized}\mathrm{squalene}\left(\mathrm{control}\right)\times 100}$
The results are gathered in table 1 below:

(56) TABLE-US-00005 TABLE 1 Compound % squalene protection Control (AMDM, 1 mM) 3 Control (AMDM, 5 mM) 15 (Z)-N-(2-hydroxyethyl)-3- 24 (methylthio)propenamide (1 mM) (Z)-N-(2-hydroxyethyl)-3- 25 (methylthio)propenamide (5 mM) (Z)-N-(4-hydroxyphenethyl)-3- 35 (methylthio)propenamide (1 mM) (Z)-N-(4-hydroxyphenethyl)-3- 44 (methylthio)propenamide (5 mM) (E)-N-(2-hydroxyethyl)-3- 71 (methylthio)propenamide (1 mM) (E)-N-(4-hydroxyphenethyl)-3- 30 (methylthio)propenamide (1 mM)

(57) The results in table 1 show that the compounds according to the invention are capable of opposing efficiently the photo-induced oxidation of squalene into hydroperoxides.

(58) Test 2: Evidence of the Absence of Cytotoxic Potential of the Oxidation by-Products of the (Z)-Isomer Conjugates of Formula (I)

(59) Experimentally, the test was carried out on a cell line of immortalized keratinocytes “HaCaT” maintained by subculture in a complete culture medium “DMEM” (with 10% foetal calf serum) in a humid atmosphere at 37° C. and 5% CO.sub.2. HaCaT cells were seeded in 24-well plates at the rate of 1.Math.10.sup.5 cells per well.

(60) Sulfoxide and sulfone derivatives of (Z)-isomer conjugates of formula (I) were synthesized after a stoichiometric exposure to hydrogen peroxide (H.sub.2O.sub.2), then purified and finally quantified.

(61) 500 μl of sulfoxide and sulfone oxidation by-products from the conjugates according to the invention were added in each well, at the concentration of 2.5 mM in PBS. After removal of the medium, the HaCaT keratinocytes cell viability was measured using the “MTT method” (MTT standing for (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (solution at 500 μg/ml) and by spectrophotometry (absorbance at 550 nm). Expressed as the average values obtained from three independent experiments, the results are gathered in table 2 below, in comparison with those obtained for the non-irradiated cells.

(62) TABLE-US-00006 TABLE 2 Compound % cell viability Control (non-irradiated cells) 100 (Z)-N-(2-hydroxyethyl)-3- 94.3 (methylthiosulfinyl)propenamide (2.5 mM) (Z)-N-(2-hydroxyethyl)-3- 93.1 (methylthiosulfonyl)propenamide (2.5 mM) (Z)-N-(4-hydroxyphenethyl)-3- 95.6 (methylthiosulfinyl)propenamide (2.5 mM) (Z)-N-(4-hydroxyphenethyl)-3- 95.0 (methylthiosulfonyl)propenamide (2.5 mM)

(63) The results in table 2 show the absence of toxicity of the oxidation by-products of the (Z)-isomer conjugates of formula (I).

(64) Test 3: Evidence of the Ability of the (Z)-Isomer Conjugates of Formula (I) to Make Viable a Keratinocyte Cell Line Exposed to UV-B Cytotoxic Doses

(65) Experimentally, the study was also carried out on a cell line of immortalized keratinocytes “HaCaT” seeded in 24-well plates at a rate of 8000 cells per square centimeter, namely 15200 cells per welkin 0.5 ml culture medium (with 10% foetal calf serum).

(66) 500 μl of the conjugate according to the invention were added in each well at a concentration from 0.05 to 0.5 mM in PBS. The cells in the presence of active ingredient were then exposed to ultraviolet radiations (UV-B) at the moderate dose of 100 mJ.Math.cm−.sup.2, and then placed into a medium without active ingredient for 24 hours. After removal of the medium, the HaCaT keratinocytes cell viability was also measured using the “MTT method” (solution at 250 μg/ml) and by spectrophotometry (absorbance at 570 nm). Gathering the average values obtained from three independent experiments, the results are presented in table 3 below, in comparison with those obtained for two controls, the non-irradiated cells and the non-treated irradiated cells with the conjugates according to the invention.

(67) TABLE-US-00007 TABLE 3 % cell Compound viability Control (non-irradiated cells) 100 Control + UV-B irradiation = 100 mJ/cm.sup.2 46 (Z)-N-(2-hydroxyethyl)-3-(methylthio)propenamide (0.1 mM) 64 (Z)-N-(2-hydroxyethyl)-3-(methylthio)propenamide (0.25 mM) 85 (Z)-N-(2-hydroxyethyl)-3-(methylthio)propenamide (0.5 mM) 94 (Z)-N-(4-hydroxyphenethyl)-3-(methylthio)propenamide 70 (0.1 mM) (Z)-N-(4-hydroxyphenethyl)-3-(methylthio)propenamide 93 (0.25 mM) (Z)-N-(4-hydroxyphenethyl)-3-(methylthio)propenamide 100 (0.5 mM) (Z)-N-ethyl-3-(methylthio)propenamide (0.5 mM) 86

(68) The results in table 3 show a dose-dependent cell viability for the compounds according to the invention, with a keratinocyte photoprotection starting at 0.1 mM and with a complete or nearly complete photoprotection at 0.5 mM.

(69) Test 4: Evidence of the Ability of the (Z)-Isomer Conjugates of Formula (I) to Absorb Ultraviolet Radiation by Photo-Isomerization

(70) Principle: the aim is to check whether the conjugates according to the invention are able to isomerize under UV-B irradiation.

(71) Experimentally, 2 ml of a squalene solution at 5 g/100 mL and 2 mL of a solution of compound according to the invention at the concentration of 25 mM in methanol were introduced into a 20 mL measuring cylinder, and then supplemented with methanol up to 20 mL. The preparation thus obtained was poured into a Petri dish onto which an irradiation dose of 1 J.Math.cm.sup.−2 was applied in a UV-B oven. At the end of the irradiation, the solutions were collected and analyzed by HPLC dosage. Volumes were previously standardized with methanol.

(72) Chromatographic profiles were thus obtained, and the formation of the E-isomer was investigated. An isomerization rate was then determined by comparison with a control profile. The results obtained are gathered in table 4 below:

(73) TABLE-US-00008 TABLE 4 Compound % isomerization (Z)-N-(2-hydroxyethyl)-3-(methylthio)propenamide 62 (2.5 mM) (Z)-N-(4-hydroxyphenethyl)-3- 95 (methylthio)propenamide (2.5 mM) (Z)-N-ethyl-3-(methylthio)propenamide (2.5 mM) 60 (Z)-N-(2-hydroxyethyl)-3- 64 (methylthiosulfinyl)propenamide (2.5 mM)

(74) The results in table 4 show that the compounds according to the invention are capable of absorbing radiation efficiently due to the production of their trans-configuration stereoisomer.

(75) Test 5: Evidence of the Ability of the (Z)-Isomer Conjugates of Formula (I) to Oppose the Trans-Urocanic Acid Photo-Induced Isomerization

(76) Principle: the aim is to check whether the conjugates according to the invention are capable of opposing the trans-urocanic acid photo-isomerization.

(77) Experimentally, the study was carried out almost identically as in tests 1 and 4 above. Beforehand, it was checked that under defined experimental conditions, trans-urocanic acid generates a significant amount of cis-urocanic acid that can be measured by HPLC analysis. The irradiation dose (1D) was 31 mJ.Math.cm.sup.−2 for a compound concentration of 5 mM. The results are gathered in table 5 below:

(78) TABLE-US-00009 TABLE 5 % inhibition of (E)- Compound urocanic acid (Z)-N-(2-hydroxyethyl)-3- 75 (methylthio)propenamide (5 mM) (Z)-N-(4-hydroxyphenethyl)-3- 78 (methylthio)propenamide (5 mM)

(79) The results in table 5 show that the compounds according to the invention are efficient at a low or moderate dose to protect trans-urocanic acid against UV-B irradiation.