The present invention relates to compounds of general formula (I):

##STR00001##
wherein X is selected from the group consisting of O or S and R is a linear or branched, saturated or unsaturated aliphatic group with from 2 to 23 carbon atoms (C2 to C23), or a cyclic group, and which can contain substituents selected from the group consisting of hydroxy, alkoxy, amino, carboxyl, cyano, nitro, alkylsulfonyl or halogen atoms, a method of obtaining them, cosmetic or pharmaceutical compositions containing them and the use thereof for treating, caring for and/or cleaning skin, hair and/or nails, preferably those conditions, disorders or pathologies of the skin, hair and/or nails which require regulating melanogenesis.

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Patent
   RE46228
Priority
Jun 15 2007
Filed
Feb 07 2014
Issued
Dec 06 2016
Expiry
Apr 11 2028
Inventors
Ferrer Mon…
Assg.orig
Lipotec, S…
Assg.curr
Lipotec, S…
Entity
Large
Referenced by
1
References
22
Maint.:
all paid
Preparation of 6-sub…
(Prophetic)">Example 2
Preparation of a Cos…
(Prophetic)">Example 3
Preparation of Lipos…
(Prophetic)">Example 4
Preparation of a Com…
(Prophetic)">Example 5
Preparation of a Nai…
(Prophetic)">Example 6
Preparation of a Com…
Example 7
Comparative Activity…
(Prophetic)">Example 8
Comparative Activity…
(Prophetic)">Example 9
Comparative Assay of…
Example 10
Assay of the Photopr…
0. 28. A compound of general formula (I)
##STR00015##
or its cosmetically or pharmaceutically acceptable salt, wherein
R is
##STR00016##
 and
X is selected from the group consisting of O and S.
22. A method for treating skin pigmentation disorders or pathologies in a subject in need of such treatment, comprising applying to said subject a cosmetic or pharmaceutical composition comprising a compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts according to claim 1 8.
20. A method of regulating the pigmentation of the skin, hair or nails in a subject in need of such regulating, comprising applying to said subject a cosmetic or pharmaceutical composition comprising a compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts according to claim 1 8.
23. A method for reducing or delaying the signs of aging or photoaging in a subject in need of such delaying or reducing, comprising applying to said subject a cosmetic or pharmaceutical composition comprising a compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts according to claim 1 8.
1. A compound of general formula (I)
##STR00009##
or its cosmetically or pharmaceutically acceptable salts salt, wherein
R is a linear or branched, saturated or unsaturated aliphatic group containing 2 to 23 carbon atoms, or a cyclic group, and which can contain substituents selected from the group consisting of hydroxy, alkoxy, amino, carboxyl, cyano, nitro, alkylsulfonyl or halogen atoms; and X is selected from the group consisting of O and S.
2. A The compound according to claim 1, wherein X is O.
3. The compound composition according to claim 1 8, wherein R is a saturated or unsaturated aliphatic group, containing 2 to 23 carbon atoms.
4. The compound according to claim 2 or 3 1, wherein
##STR00010##
is selected from the group consisting of tert-butanoyl, hexanoyl, 2-methylhexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.
5. The compound composition according to claim 1 8, wherein R is an alicyclic cyclic group, an aromatic cyclic group or a heterocyclic cyclic group.
6. The compound composition according to claims 2 or 5 claim 8, wherein
##STR00011##
is selected from the group consisting of —CO—(CH2)0_6_phenyl —CO—(CH2)0-6-phenyl, —CO—(CH2)0_6_(1-naphthyl) —CO—(CH2)0-6-(1-naphthyl), —CO—(CH2)0_6_(2-naphthyl) —CO—(CH2)0-6-(2-naphthyl), —CO—(CH2)0_6_—CH(phenyl)2 —CO—(CH2)0-6-CH(phenyl)2, —CO-(2-fluorophenyl), —CO—cyclohexyl, c˜-lipoyl α-lipoyl, L-prolyl, D-prolyl, biotinyl —CO-(4-imidazolyl), —CO-(2-pyridyl), —CO-(2-thienyl), —CO-(2-furyl) and —CO-(3-furyl).
7. A process of obtaining a compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts salt according to claim 1, wherein 6-hydroxy-7-methoxy -2,2-dimethylchromane is reacted with the compound of general formula (II)
##STR00012##
wherein X is selected from the group consisting of O and S;
R is a linear or branched, saturated or unsaturated aliphatic group with from 2 to 23 carbon atoms, or a cyclic group, and which can contain substituents selected from the group consisting of hydroxy, alkoxy, amino, carboxyl, cyano, nitro, alkylsulfonyl and halogen atoms, or a cyclic group; and Z is a free OH group, a reactive derivative thereof or a halogen.
8. A cosmetic or pharmaceutical composition comprising:
a cosmetically or pharmaceutically effective amount of at least one compound of general formula (I)
##STR00013##
 or its cosmetically or pharmaceutically acceptable salts according to claim 1, comprises salt, wherein
R is a linear or branched, saturated or unsaturated aliphatic group containing 2 to 23 carbon atoms, or a cyclic group, and which can contain substituents selected from the group consisting of hydroxy, alkoxy, amino, carboxyl, cyano, nitro, alkylsulfonyl or halogen atoms; and
X is selected from the group consisting of O and S or its cosmetically or pharmaceutically acceptable salt; and
at least one cosmetically or pharmaceutically acceptable excipient or adjuvant, and
wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salt is present at from 0.00000001% to 20% by weight of the composition.
9. The cosmetic or pharmaceutical composition according to claim 8, wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts salt are incorporated in a cosmetically or pharmaceutically acceptable sustained release system or carrier selected from the group consisting of liposomes, millicapsules, microcapsules, nanocapsules, sponges, vesicles, micelles, millispheres, microspheres, nanospheres, lipospheres, microemulsions, nanoemulsions, milliparticles, microparticles and nanoparticles.
10. The cosmetic or pharmaceutical composition according to claim 8, wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts salt are adsorbed on a cosmetically or pharmaceutically acceptable organic polymer or solid mineral support selected from the group consisting of talc, bentonite, silica, starch and maltodextrin.
11. The cosmetic or pharmaceutical composition according to claim 8, wherein it has a formulation selected from the group consisting of creams, oil and/or silicone in water emulsions, water in oil and/or silicone emulsions, water/oil or silicone/water type emulsions, oil or silicone/water/oil or silicone type emulsions, oils, milks, balsams, foams, lotions, hydroalcoholic solutions, gels, liniments, serums, soaps, shampoos, ointments, mousses, salves, powders, bars, pencils, sprays or aerosols, capsules, including gelatin capsules, tablets, including sugar-coated tablets, powders, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, jellies and gelatin.
12. The cosmetic or pharmaceutical composition according to claim 8, wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts salt are incorporated in solid accessories selected from the group consisting of towelettes, hydrogels, adhesive patches, non-adhesive patches and face masks.
13. The cosmetic or pharmaceutical composition according to claim 8, wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts salt are incorporated in makeup products selected from the group consisting of under eye concealers, makeup bases, makeup removal lotions and makeup removal milks.
14. The cosmetic or pharmaceutical composition according to claim 8, wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts salt are incorporated in fabrics.
15. The cosmetic or pharmaceutical composition according to claim 8, wherein it further comprises an additional cosmetically or pharmaceutically effective amount of at least one active agent selected from the group consisting of a depigmenting or whitening agent, an anti-stretch mark agent, an anti-wrinkle agent, an antioxidant agent, an anti-glycation agent, an NO-synthase inhibitor, an anti-ageing agent, an agent capable of reducing or eliminating bags under the eyes, an exfoliating agent, emulsifying agents, emollients, organic solvents, liquid propellants, skin conditioners, wetting agents, moisture retaining substances, alpha hydroxy acids, moisturizers, vitamins, pigments or colorants, dyes, gelling polymers, thickeners, surfactants, softeners, an agent stimulating dermal or epidermal molecule synthesis and/or for preventing or inhibiting their degradation, an agent stimulating collagen synthesis, an agent stimulating decorin synthesis, an agent stimulating elastin synthesis, an agent stimulating laminin synthesis, an agent inhibiting collagen degradation, an agent inhibiting elastin degradation, an agent stimulating fibroblast and/or keratinocyte proliferation or for stimulating keratinocyte differentiation, agents stimulating lipid synthesis and synthesis of components of the stratum corneum, agents stimulating glycosaminoglycan synthesis, DNA repair agents, DNA protecting agents, agents stimulating defensin synthesis, agents stimulating chaperone synthesis, anti-pruritus agents, agents for treating sensitive skin, astringent agents, sebum production regulating agents, anti-cellulite agents, agents stimulating lipolysis, agents intended to improve the dermal-epidermal junction, a dermorelaxing agent, a reaffirming firming agent, an anti-atmospheric contamination and/or free radical scavenger, an agent acting on capillary circulation and/or microcirculation, a calming agent, an anti-inflammatory agent, an antimicrobial agent, an antifungal agent, bactericides, an agent acting on cell metabolism, a chelating agent and/or an organic or mineral photoprotective agent active against ultraviolet A and/or B rays, and mixtures thereof.
16. The cosmetic or pharmaceutical composition according to claim 15, wherein the active agent is a desquamating agent selected from the group consisting of alpha hydroxy acids, beta hydroxy acids, urea and derivatives thereof, gentisic acid, cinnamic acid, jasmonic acid and derivatives thereof, oligofucoses, resveratrol, N-acetylglucosamine, Saphorajaponica extract, detergents and enzymes.
17. The cosmetic or pharmaceutical composition according to claim 15, wherein the active agent is an organic or mineral photoprotective agent active against ultraviolet A and/or B rays.
18. The cosmetic or pharmaceutical composition according to claim 15, wherein the active agent is a whitening or depigmenting agent selected from the group consisting of 6-hydroxy-7- methoxy-2,2-dimethylchromane, arbutin and isomers thereof, kojic acid and derivatives thereof, vitamin C and derivatives thereof including, 6-O-palmitoylascorbic acid, magnesium salt of ascorbic acid-2-phosphate (MAP), sodium salt of ascorbic acid-2-phosphate (NAP), ascorbyl glucoside and ascorbyl tetraisopalmitate (VCIP), retinol and derivatives thereof including, tretinoin and isotretinoin, idebenone, hydroxybenzoic acid and derivatives thereof, flavonoids, soy extract, yeast extract, lemon extract, orange extract, ginkgo extract, cucumber extract, geranium extract, bearberry extract, carob bean extract, cinnamon extract, marjoram extract, rosemary extract, clove extract, soluble licorice extract, blackberry leaf extract, niacinamide, liquiritin, resorcinol and derivatives thereof, hydroquinone, α-tocopherol, Y-tocopherol, azelaic acid, resveratrol, mercury salts, linoleic acid, α-lipoic acid, dihydrolipoic acid, alpha hydroxy acids, beta hydroxy acids, ellagic acid, ferulic acid, cinnamic acid, oleanolic acid, aloesin and derivatives thereof, dithiaoctanediol, gluconic acid, beta- carotene, serine protease inhibitors, including tryptase, trypsin and PAR-2 inhibitors, diacetylboldine, undecylenoyl phenylalanine, nonapeptide-1, amino ethyl phosphoric acid, Achillea millefolium extract, Alchemilla vulgaris extract, Aloe vera extract, Azadirachta indica extract, Arctostaphylos uva ursi leaf extract, Osmunda japonica extract, Artocarpus incisus extract, Bidens pylosa extract, Brassica napus extract, Broussonetia papyrifera extract, Chlorella vulgaris extract, Cimicifiiga racemosa extract, Emblica officinalis extract, Glycyrrhiza glabra extract, extract of Glycyrrhiza uralensis, Ilex purpurea extract, Ligusticum lucidum extract, Ligusticum wallichii extract, Malva sylvestris extract, Melissa officinalis leaf extract, Mentha piperita leaf extract, Mitracarpus scaber extract, Morinda citrifolia extract, Morus alba extract, Morus bombycis extract, Naringi crenulata extract, Pisum sativum extract, Primula veris extract, Prunus domesticus extract, Pseudostellariae radix extract, Rumex crispus extract, Rumex occidentalis extract, Sapindus mukurossi extract, Saxifraga sarmentosa extract, Scutellaria galericulata extract, Sedum sarmentosum Bunge extract, Stellaria medica extract, Triticum Vulgare extract, Uva ursi extract, Veronica officinalis extract, Withania somnifera extract and leukocyte extract.
19. A method for treating, caring for, or cleaning skin, hair or nails in a subject in need of such treatment comprising applying to said subject a cosmetic or pharmaceutical composition comprising a compound of general formula (I)
##STR00014##
or its cosmetically or pharmaceutically acceptable salts according to claim 1 salt,
wherein
R is a linear or branched, saturated or unsaturated aliphatic group containing 2 to 23 carbon atoms, or a cyclic group, and which can contain substituents selected from the group consisting of hydroxy, alkoxy, amino, carboxyl, cyano, nitro, alkylsulfonyl or halogen atoms; and
X is selected from the group consisting of O and S.
21. A method for whitening or lightening the skin in a subject in need of such whitening or lightening comprising applying to said subject a cosmetic or pharmaceutical composition comprising a compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts according to claim 1 8.
24. A method for photoprotecting skin, hair or nails in a subject in need of such photoprotecting, comprising applying to said subject a cosmetic or pharmaceutical composition comprising a compound of general formula (I) or its cosmetically or pharmaceutically acceptable salts according to claim 1.
25. The method according to any one of claims 19-24 wherein said applying comprises topical or transdermal application of said composition.
0. 26. The compound according to claim 1, wherein R is CH3(CH2)14—.
0. 27. The compound according to claim 1, wherein the compound is 7-methoxy-6-palmitoyl-2,2-dimethylchromane.
0. 29. The cosmetic or pharmaceutical composition according to claim 8, wherein the compound of general formula (I) or its cosmetically or pharmaceutically acceptable salt is present at between 0.00001% and 10% by weight of the composition.
0. 30. The composition according to claim 3, wherein
##STR00017##
is selected from the group consisting of tert-butanoyl, hexanoyl, 2-methylhexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.

(Partly Prophetic)

Preparation of 6-substituted 7-methoxy-2,2-dimethylchromanes

6-hydroxy-7-methoxy-2,2-dimethylchromane (5.0 g; 24.0 mmol, 1 equiv.) was reacted with 1 equiv. of the corresponding carboxylic or thiocarboxylic acid in the presence of DMAP (2.0 mmol, 0.083 equiv.) and DCC (24.0 mmol, 1 equiv.) in dichloromethane at room temperature, performing controls by thin layer chromatography. When it was observed that the reaction stopped progressing the formed dicyclohexylurea was filtered and evaporated to dryness. The obtained compounds were purified by silica column chromatography by eluting with n-hexane and ethyl acetate and were characterized by ESI-MS. In the table below, examples where no experimental molecular weight is given are prophetic examples.

##STR00006## Theo- retical MW Experi- mental MW
X = O 264.32 264.39
R = CH3CH2—
X = O 306.40 306.35
R = CH3(CH2)4
X = O 334.45 334.40
R = CH3(CH2)6
X = O 348.48 348.54
R = CH3(CH2)7
X = O 362.50 362.48
R = CH3(CH2)8
X = O 376.53 376.57
R = CH3(CH2)9
X = O 390.56 390.51
R = CH3(CH2)10
X = O 418.61 418.53
R = CH3(CH2)12
X = O 446.66 446.62
R = CH3(CH2)14
X = O 474.72 474.79
R = CH3(CH2)16
X = O 502.77 502.83
R = CH3(CH2)18
X = O 530.82 530.88
R = CH3(CH2)20
X = O 558.88 558.85
R = CH3(CH2)22
X = O 454.64 454.59
R = CH3(CH2)4(CH═CHCH2)4CH2CH2
X 444.65 444.63
R = cis CH3(CH2)5CH═CH(CH2)7
X 472.70 472.67
R = cis CH3(CH2)10CH═CH(CH2)4
X = O 556.86 556.92
R = cis CH3(CH2)7CH═CH(CH2)13
X = O 468.67 468.71
R =
CH3CH2CH═CHCH2CH═CHCH2CH═CH(CH2)7
X = O 474.72 474.77
R = CH3CH(CH3)(CH2)14
X = O 470.68 470.63
R = CH3(CH2)4CH═CHCH2CH═CH(CH2)7
X = O 472.70 472.76
R = trans CH3(CH2)7CH═CH(CH2)7
X = O 472.70 472.67
R = cis CH3(CH2)7CH═CH(CH2)7
X = O 528.81 528.89
R = cis CH3(CH2)7CH═CH(CH2)11
X = O 488.70 488.75
R = CH3(CH2)5CH(OH)CH2CH═CH(CH2)7
X = O 374.51 374.56
R = CH2═CH(CH2)8
X = O 292.37 292.28
R = (CH3)3—C 
X = O 320.42 320.41
R = CH3—(CH2)3—CH(CH3) 
X = O 318.41 318.22
R = cyclohexyl
X = O 312.36 312.44
R = C6H5
X = O 330.35 330.42
R = 2 fluorophenyl
X = O 326.39 326.33
R = C6H5—CH2
X = O 362.42 362.18
R = 1-naphthyl
X = O 362.42 362.44
R = 2-naphthyl
X = O 396.57 396.63
R = ##STR00007##
X = O 434.55 434.52
R = ##STR00008##
X = O 302.33 302.39
R = 4-imidazolyl
X = O 313.35 313.43
R = 2-pyridyl
X = O 318.39 318.41
R = 2-thienyl
X = O 302.32 302.27
R = 2-furyl
X = O 302.32 302.35
R = 3-furyl
X = O 305.37 305.42
R = (R)-2-pyrrolidinyl
X = O 305.37 305.39
R = (S)-2-pyrrolidinyl
X = S 342.45 342.47
R = C6H5—CH2
X = S 308.44 308.51
R = tert butyl
X = S 384.53 384.52
R = (4-tert-butyl)phenyl
X = S 344.43 344.47
R = (2-hydroxy)phenyl

Example 2 (Prophetic)
Preparation of a Cosmetic Composition Containing 7-methoxy-6-palmitoyl-2,2-dimethylchromane

The following formulation was is prepared as described in the present invention:

The components of Phase A were are weighed in a large enough reactor and the mixture is heated to 70° C. to melt the waxes. The components of Phase B are weighed in a suitable container for the entire content. The components of Phase C are added to Phase B and heated to 70° C. under intense stirring. Then Phase A is slowly added to the preceding mixture under stirring and the mixture is maintained under stirring for 30 minutes at 70° C. It is left to cool under gentle stirring and when the mixture is at room temperature, xanthan gum and fragrance are added, the mixture is homogenized and the pH is corrected with triethanolamine if needed.

The cream that is obtained has a pH between 5.5 and 6.

INGREDIENT (INCI Nomenclature) % BY WEIGHT
PHASE A
MINERAL OIL 3.00
7-methoxy-6-palmitoyl-2,2-dimethylchromane 0.10
POLYACRYLAMIDE, C13-14 2.00
ISOPARAFFIN, LAURETH-7
ETHYLHEXYL SALICILATE 1.00
BUTYL METHOXYD1BENZOYLMETHANE 1.00
ETHYLHEXYL METHOXYCINNAMATE 7.50
DIMETHICONE 1.00
CETEARYL ALCOHOL 2.00
SODIUM STEAROYL LACTYLATE 1.50
POLYGLYCERYL-3 STEARATE 1.50
1 METHYLENE BIS-BENZOTRIAZOLYL
TETRAMETHYLBUTYLPHENOL, 3.00
AQUA (WATER), DECYL GLUCOSIDE,
PROPYLENE GLYCOL, XANTHAN GUM
SQUALANE 3.00
GLYCERYL STEARATE 2.00
PHASE B
DISODIUM EDTA 0.30
AQUA (WATER) 55.82
PHENOXYETHANOL, METHYLPARABEN, 0.47
ETHYLPARABEN, BUTYLPARABEN,
PROPYLPARABEN, ISOBUTYLPARABEN
IMIDAZOLIDINYL UREA 0.10
PHASE C
TITANIUM DIOXIDE 2.00
GLYCERINE 4.00
PHASE D
XANTHAN GUM 0.35
PHASE E
PARFUME (FRAGRANCE) 0.20
PHASE F
TRIETHANOLAMINE QSF

Example 3 (Prophetic)
Preparation of Liposomes Containing 7-methoxy-6-palmitoyl-2,2-dimethylchromane

Dipalmitoylphosphatidylcholine (DPPC), cholesterol and 7-methoxy-6-palmitoyl-2,2-dimethylchromane are weighed and dissolved in chloroform. The solvent is evaporated under vacuum until obtaining a thin phospholipid layer, and this is hydrated by treating at 55° C. with an aqueous solution containing Phenonip®, obtaining the MLV liposomes. The ULV liposomes are obtained by submerging the MLV liposomes in an ultrasound bath at 55° C. for 8 2-minute cycles at 5 minute intervals. To reduce the size even more, it can be passed through an extrusion system under high pressure.

INGREDIENT (INCI Nomenclature) % BY WEIGHT
DIPALMITOYLPHOSPHATIDYLCHOLINE 8.0
7-methoxy-6-palmitoyl-2,2-dimethylchromane 1.0
CHOLESTEROL 3.0
PHENOXYETHANOL, METHYLPARABEN, 0.5
ETHYLPARABEN, BUTYLPARABEN,
PROPYLPARABEN, ISOBUTYLPARABEN
AQUA (WATER) 87.5

Example 4 (Prophetic)
Preparation of a Composition in the Form of a Liposome Gel Containing 7-methoxy-6-palmitoyl-2,2-dimethylchromane

The liposomes of example 3 are dispersed in water with preservatives (EDTA, imidazolidinyl urea and Phenonip®) under gentle stirring. Hispagel® 200 [INCI Aqua, Glycerin and Glyceryl polyacrylate] is added and it is gently stirred until a homogenous mixture is obtained.

INGREDIENT (INCI Nomenclature) % BY WEIGHT
LIPOSOMES CONTAINING 10.00
7-methoxy-6-palmitoyl-2,2-dimethylchromane (1%)
DISODIUM EDTA 0.15
IMIDAZOLIDINYL UREA 0.10
AQUA (WATER), GLYCERIN, 60.00
GLYCERYL POLYACRYLATE
AQUA (WATER) 29.25
PHENOXYETHANOL, METHYLPARABEN, 0.50
ETHYLPARABEN, BUTYLPARABEN,
PROPYLPARABEN, ISOBUTYLPARABEN

Example 5 (Prophetic)
Preparation of a Nail Polish Composition Containing 7-methoxy-6-palmitoyl-2,2-dimethylchromane

7-methoxy-6-palmitoyl-2,2-dimethylchromane is weighed with the acrylate copolymer and they are dissolved in ethanol by stirring vigorously. Acetone is added and it is conserved in a covered container to minimize evaporation.

INGREDIENT (INCI Nomenclature) % BY WEIGHT
ACRYLATES COPOLYMER 22.0
ETHYL ALCOHOL 65.4
ACETONE 12.5
7-methoxy-6-palmitoyl-2,2-dimethylchromane 0.1

Example 6 (Prophetic)
Preparation of a Composition to Depigment Body Hair Containing 7-methoxy-6-palmitoyl-2,2-dimethylchromane

Heat Phase A and Phase B separately at 70-75° C. Add A to B under intense stirring. Allow it to cool, maintaining stirring at room temperature, add Phase C and neutralize with triethanolamine until obtaining pH 6.5.

INGREDIENT (INCI Nomenclature) % BY WEIGHT
PHASE A
MINERAL OIL 10.00
PETROLATUM 1.00
BEESWAX (CERA ALBA) 2.00
7-methoxy-6-palmitoyl-2,2-dimethylchromane 0.50
CETEARETH-25 2.00
DIMETHICONE 0.20
C24-28 ALKYL METHICONE 0.10
CETEARYL ALCOHOL 2.00
PHASE B
DISODIUM EDTA 0.15
AQUA (WATER) QSF 100
PHENOXYETHANOL, METHYLPARABEN, 0.50
ETHYLPARABEN, BUTYLPARABEN,
PROPYLPARABEN, ISOBUTYLPARABEN
IMDDAZOLEDINYL UREA 0.10
CARBOMER 0.35
GLYCERINE 3.00
PHASE C
PARFUME (FRAGRANCE) 0.10
PHASE F
TRIETHANOLAMINE QSF

Example 7
Comparative Activity Assay of 7-methoxy-6-palmitoyl-2,2-dimethylchromane on the Action of Mushroom Tyrosinase In Vitro

The assay is performed in 96 well plates and the samples are performed in triplicate. The control sample contains 80 μL of buffer (150 mM HEPES), 10 μL of mushroom tyrosinase of 10 μg/μL and 10 μL of 10 mM L-Dopa substrate. The positive control further contains kojic acid at a concentration of 0.1 mM. The samples of 7-methoxy-6-palmitoyl-2,2-dimethylchromane and 6-hydroxy-7-methoxy-2,2-dimethylchromane (Lipochroman-6) contain instead of kojic acid, the compounds at a concentration of 1 mM. The samples thus prepared are incubated at 37° C. for 10 minutes. Then the plate containing the samples is cooled for 5 minutes on ice to stop the enzymatic reaction. To quantify the melanin produced it is measured in the plate reader at a length of 492 nm.

Table 1 measures the percentage of melanin formed normalized in relation to the control sample for the comparative sample with kojic acid and for the sample with 7-methoxy-6-palmitoyl-2,2-dimethylchromane and for the Lipochroman-6 sample.

TABLE 1
COMPOUND % MELANIN
Control 100.0
0.1 mM Kojic acid 44.5
1 mM Lipochroman-6 96.6
1 mM 7-methoxy-6-palmitoyl-2,2-dimethylchromane 63.0

Example 8 (Prophetic)
Comparative Activity Assay of 7-methoxy-6-palmitoyl-2,2-dimethylchromane on Endogenous Tyrosinase Extracted from Human Melanocytes

The human melanocytes are cultured in DMEM medium supplemented with 10% FBS, 1% penicillin/streptomycin and 100 nM PMA. The compound 7-methoxy-6-palmitoyl-2,2-dimethylchromane is dissolved in 1:1 DMSO:sterile water at a final concentration of 10 mM.

The endogenous tyrosine of the human melanocytes seeded at a confluence of 95% is extracted. The assay is performed after extracting and quantifying the enzymatic content. Such assay consists of incubating the tyrosinase enzyme for 30 minutes with Lipochroman-6 (1 mM), 7-methoxy-6-palmitoyl-2,2-dimethylchromane (1 mM) or with kojic acid (0.1 mM) as a comparative agent. To check the enzymatic activity after the treatment, the synthetic L-Dopa (10 mM) substrate is added, measuring absorbance at a wavelength of 475 nm one hour after having added L-Dopa. This measurement allows evaluating the melanin content produced.

Table 2 measures the percentage of melanogenesis in relation to a control sample, one hour after having added L-Dopa, for the comparative sample with kojic acid and for the samples with 7-methoxy-6-palmitoyl-2,2-dimethylchromane and with Lipochroman-6.

TABLE 2
%
COMPOUND MELANIN
Control 100.0
0.1 mM Kojic acid 31.0
1 mM Lipochroman-6 79.8
1 mM 7-methoxy-6-palmitoyl-2,2-dimethylchromane 57.0

Example 9 (Prophetic)
Comparative Assay of the Depigmenting Efficacy of 7-methoxy-6-palmitoyl-2,2-dimethylchromane in Human Melanocyte Cultures

The human melanocytes seeded in confluence are cultured for 5 days adding fresh medium daily containing 0.1 mM of kojic acid or of 7-methoxy-6-palmitoyl-2,2-dimethylchromane. The melanin content was is seen directly by means of microscopy using a 40 magnification lens. The depigmenting efficacy was is determined by counting the number of cells containing melanin and the total number of cells, and the obtained results were are normalized in relation to the whitening efficacy of a control sample.

TABLE 3
%
DEPIGMENTING
COMPOUND EFFICACY
Control 0.0
0.1 mM Kojic acid 30.2
0.1 mM 7-methoxy-6-palmitoyl-2,2-dimethylchromane 45.9

Example 10
Assay of the Photoprotecting Efficacy of 7-methoxy-6-palmitoyl-2,2-dimethylchromane in Human Keratinocyte Cultures

The human keratinocytes were maintained in culture for 24 hours in 96 well plates to form monolayers and the cells were pre-incubated in the dark with 150 μg/mL of 7-methoxy-6-palmitoyl-2,2-dimethylchromane or saline phosphate buffer (control) for one hour at 37° C. and humidified air with 5% CO2. The cells were then irradiated with a solar simulation lamp with an energy of 37 J/cm2 at room temperature for 150 minutes. A control plate was maintained in the dark for the same time at room temperature. The medium of the cells was replaced after the irradiation period with fresh medium and the cells were incubated for 24 additional hours. The cell viability was determined by means of the Neutral Red dye, measuring the optical density at 540 nm in a spectrophotometer.

The photoprotecting efficacy was determined by comparing the viability obtained in the cells treated with 7-methoxy-6-palmitoyl-2,2-dimethylchromane in relation to the response of the irradiated and non-irradiated control cells.

TABLE 4
CELL PHOTOPROTECTTNG
TREATMENT VIABILITY EFFICACY
Control 100% —
Irradiated control 13.8% —
150 μg/mL 7-methoxy- 49.1% 254.9%
6-palmitoyl-2,2-dimethylchromane

INVENTORS:

Ferrer Montiel, Antonio Vicente, Carreño Serraïma, Cristina, Almiñana Doménech, Nuria, Cebrián Puche, Juan, Messeguer Peypoch, Ángel

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