Process for depigmenting keratin materials using thiopyridinone
compounds
The present invention relates to a cosmetic treatment process in particular for
depigmenting and/or whitening the skin, that employs at least one compound of
thiopyridinone type.
At various periods in their life, certain people develop darker and/or more
coloured marks on their skin, and more especially on the hands, which gives the
skin a heterogeneous appearance. These marks are due in particular to a high
concentration of melanin in the keratinocytes located at the surface of the skin.
The use of harmless topical depigmenting substances which exhibit good
efficacy is especially desirable with a view to treating pigmentary marks.
The mechanism of formation of skin pigmentation, i.e. of the formation of
melanin, is particularly complex and involves, schematically, the following
principal steps:
Tyrosine —> Dopa —> Dopaquinone —> Dopachrome —> Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC
1.14.18.1 ) is the essential enzyme involved in this series of reactions. It
catalyzes in particular the reaction converting tyrosine to Dopa
(dihydroxyphenylalanine) by virtue of its hydroxylase activity, and the reaction
converting Dopa to dopaquinone by virtue of its oxidase activity. This tyrosinase
acts only when it is in the mature form, under the action of certain biological
factors.
A substance is acknowledged to be depigmenting i f it acts directly on the vitality
of epidermal melanocytes, where melanogenesis takes place, and/or i f it
interferes with one of the steps of melanin biosynthesis, either by inhibiting one
of the enzymes involved in melanogenesis, or by being inserted as a structural
analogue of one of the chemical compounds of the melanin synthesis chain,
which chain may then be blocked and thus ensure depigmentation.
Arbutin, niacinamide and kojic acid are known as skin depigmenting agents.
Substances have been sought which exhibit an effective depigmenting action, in
particular greater than that of arbutin, niacinamide and kojic acid.
In this regard, the applicant has found, surprisingly and unexpectedly, that
certain thiopyridinone compounds exhibit good depigmenting activity, even at
low concentration.
The subject of the invention is therefore a nontherapeutic cosmetic process for
depigmenting, lightening and/or whitening keratin materials, in particular theskin, which comprises the application of a cosmetic composition comprising, in
a physiologically acceptable medium, at least one compound of formula (I) as
defined hereinafter.
The invention also relates to the nontherapeutic cosmetic use of a compound of
formula (I) as a whitening, lightening and/or depigmenting agent for keratin
materials, in particular the skin.
The compounds used according to the invention allow effective depigmenting
and/or lightening, or even whitening, of the skin of human beings. They are in
particular intended to be applied to the skin of individuals exhibiting brownish
pigmentation marks or senescence marks, or to the skin of individuals who wish
to combat the appearance of a brownish colour arising from melanogenesis.
They may also allow depigmentation and/or lightening of body hair, the
eyelashes, head hair and also the lips and/or the nails.
The compounds used according to the invention therefore correspond to
formula (I) or ( ) below:
(I)
( )
in which:
i and R2, which may be identical or different, denote a radical chosen from:
a) a hydrogen atom;
b) a saturated linear C1-C20 or branched C3-C20 or unsaturated C2-C20 alkyl
group, optionally interrupted with one or more heteroatoms chosen from N, S
and O, and/or optionally substituted with one or more groups, which may be
identical or different, chosen from:
iv) -CONHR3
v) -COOR3 ;vi) a C5-C12 aryl group optionally substituted with one or more
hydroxyls and/or with one or more d-Cs alkoxy radicals;
c) a saturated d-Cs alkyl group substituted with a C5-C12 aryl radical
optionally substituted with one or more hydroxyls and/or with one or more d-Cs
alkoxy radicals;
d) a phenyl group optionally substituted with one or more hydroxyls and/or
with one or more d-Cs alkoxy radicals;
R3 denoting a hydrogen atom or a saturated linear C 1-C5 or branched C3-C5 or
unsaturated C2-C5 hydrocarbon-based group,
R denoting a hydrogen atom; a saturated linear C 1-C5 or branched C3-C5
hydrocarbon-based group; or an acetyl group;
it being possible for i and R2 to form, with the nitrogen atom which bears
them, a ring chosen from pyrrolidine, pyrroline, piperidine, piperazine,
morpholine, thiomorpholine and azepine;
and also the salts thereof, the solvates thereof and the optical isomers thereof,
and the racemates thereof.
The compound ( ) is the tautomer form of the compound (I) when a tautomeric
equilibrium exists according to the following scheme:
The salts of the compounds of formula (I) or ( ) comprise the conventional
nontoxic salts of said compounds, such as those formed from acid or from base.
As salts of the compound of formula (I) or ( ) , when it comprises a
quaternizable nitrogen atom), mention may be made of:
a) the salts obtained by addition of the compound (I) or ( ) with an inorganic
acid, in particular chosen from hydrochloric acid, boric acid, hydrobromic acid,
hydrioic acid, sulphuric acid, nitric acid, carbonic acid, phosphoric acid and
tetrafluoroboric acid;
b) or the salts obtained by addition of the compound (I) or ( ) with an organic
acid, in particular chosen from acetic acid, propionic acid, succinic acid, fumaric
acid, lactic acid, glycolic acid, citric acid, gluconic acid, salicylic acid, tartaric
acid, terephthalic acid, methylsulphonic acid, ethylsulphonic acid, benzene-
sulphonic acid, toluenesulphonic acid and triflic acid.Mention may also be made of the salts obtained by addition of the compound of
formula (I) or ( ) (when it comprises an acid group) with an inorganic base, such
as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium
hydroxide, magnesium hydroxide, lithium hydroxide, and sodium, potassium or
calcium carbonates or hydrogen carbonates, for example;
or with an organic base, such as a primary, secondary or tertiary alkylamine, for
example triethylamine or butylamine. This primary, secondary or tertiary
alkylamine may comprise one or more nitrogen and/or oxygen atoms and may
therefore comprise, for example, one or more alcohol functions; mention may in
particular be made of 2-amino-2-methylpropanol, ethanolamine,
triethanolamine, 2-dimethylaminopropanol, 2-amino-2-(hydroxymethyl)-1 ,3-
propanediol and 3-(dimethylamino)propylamine.
Mention may also be made of amino acids such as, for example, lysine,
arginine, guanidine, glutamic acid or aspartic acid.
Advantageously, the salts of the compounds of formula (I) or ( ) (when it
comprises an acid group) may be chosen from alkali metal salts or alkaline
earth metal salts, such as sodium, potassium, calcium or magnesium salts; and
ammonium salts.
Advantageously, the salts of the compounds of formula (I) or ( ) (when it
comprises a quaternizable nitrogen atom) can be chosen from halides such as
chloride or bromide; and citrates, acetates, succinates, phosphates, lactates
and tartrates.
The acceptable solvates of the compounds described in the present invention
comprise conventional solvates such as those formed during the preparation of
said compounds as a result of the presence of solvents. By way of example,
mention may be made of the solvates resulting from the presence of water or of
linear or branched alcohols such as ethanol or isopropanol.
The optical isomers are in particular enantiomers and diastereoisomers.
Preferentially, the linear or branched groups can be chosen from: methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
octadecyl, nonadecyl and eicosyl.
More preferentially, the saturated linear or branched alkyl groups can be chosen
from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl and octyl.
Preferentially, the C 1-C4 alkoxy groups can be chosen from methoxy, ethoxy,
propoxy and butoxy, and even more preferentially methoxy.The compounds of formula (I) can be obtained, in a known manner, by reacting
2-mercaptonicotinic acid and an amine of formula HNR-1R2 (Ri and R2 having
the meanings described above), in particular in the presence of a base such as
carbonyldiimidazole.
The compounds of formula (I) can also be obtained, in a known manner, by
reacting 2-mercaptonicotinic acid or 2-chloronicotinic acid with an amine of
formula HNR-|R2 (Ri and R2 having the meanings described above), in
particular in the presence of an agent for activating carboxylic acids according
to the conventional methods for activating acids (described, for example, in
Comprehensive Organic Transformation by R. Larock, published by Wiley VCH,
in the chapter Interconversion of nitriles, carboxylic acids and derivatives). Use
is preferably made of an agent for activating carboxylic acids which makes it
possible to form an acid chloride (for example, using thionyl chloride or oxalyl
chloride, or 1-chloro-N,N,2-trimethyl-1 -propenamine) or to form a mixed
anhydride (using alkyl chloroform ates), or carbodiimides or diethyl
cyanophosphate are used to form carbamimidates or acylphosphonates
(Phosphorus in organic synthesis-XI, Amino acids and peptides-XXI, Reaction
of diethyl phosphorocyanidate with carboxylic acids. A new synthesis of
carboxylic esters and amides, Tetrahedron, 32, 1976, 221 1-2217).
When 2-chloronicotinic acid is used as starting reagent, the chloroamide
obtained is then used in an exchange reaction between chlorine and sulphur by
means of reagents such as NaSH, thiourea, sodium thiosulphate or thioacetic
acid (in basic medium).
Compounds of formula (I) or ( ) are described in the following documents:
EP-A-298752, WO03/014062, EP-A-298752, FR-A-2349591 , EP-A-2555450,
WO 03/014062 and WO 2008/012532, and in the publications
- article A. Monge, V. Martinez-Merino; Synthesis of 2-substituted 3-
Oxoisothiazolo[5,4-b]pyridines; J . heterocyclic. Chem, 22, 1353 ( 1985).
- article A. Dunn, R. Norrie; Synthesis of pyrido-1 ,3-thiazines; Zeitschrift fur
chemie 1988, vol 28, n° 6 , p 212/214.
- S. Andreae; J . Parkt. Chem. 339 (1997) 152-1 58;
- S. Gorsuch; Biorganic & Medicinal Chemistry 17(2009) 467-474.
- A. Monge et al; J . Heterocyclic Che. 25, 23 ( 1988).
- M. Pregnolato; I I Farmaco 55 (2000) 669-679.
Preferably, the compounds of the formula (I) or ( ) have the following meanings:
Ri denotes a radical chosen from:
a) a hydrogen atom;
b) a saturated linear - oor branched C 3-C10 or unsaturated C2-Cio alkyl
group, optionally substituted with one or more OR3 groups;
R2 denotes a radical chosen from:a) a saturated linear - o or branched C3-C10 or cyclic C3-C7 alkyl group,
optionally interrupted with one or more oxygen atoms, preferably one, and/or
optionally containing one or more groups, which may be identical or different,
chosen from:
iii) -CONHR3,
b) a phenyl group optionally substituted with one or more hydroxyls and/or
with one or more C1-C3 alkoxy radicals;
c) a saturated C1-C5 alkyl group substituted with a phenyl radical optionally
substituted with one or more hydroxyls or with one or more C1-C3 alkoxy
radicals;
R3 denoting a hydrogen atom or a saturated linear C1-C5 or branched C3-C5
hydrocarbon-based group;
R denoting a hydrogen atom or a saturated linear C1-C5 or branched C3-C5
hydrocarbon-based group;
and the salts thereof, the solvates thereof and the optical isomers thereof, and
the racemates thereof.
Preferentially, the compounds of formula (I) or ( ) have the following meanings:
Ri denotes a hydrogen atom or a linear Ci-C 4 alkyl radical optionally substituted
with one or more hydroxyl groups;
R2 denotes a radical chosen from:
a) a saturated linear C1-C10 or branched C3-C10 or cyclic C 5-C7 alkyl group,
optionally interrupted with an oxygen atom and/or optionally containing a
-CONH2 group and/or optionally substituted with one or more hydroxyl groups;
b) a phenyl group;
c) a saturated C1-C5 alkyl group substituted with a phenyl radical optionally
substituted with one or more hydroxyl or C1-C3 alkoxy radicals;
and also the salts thereof, the solvates thereof and the optical isomers thereof,
and the racemates thereof.
More preferentially, the compounds of formula (I) or ( ) have the following
meanings:
Ri denotes a hydrogen atom or a Ci-C 4 hydroxyalkyl group;
R2 denotes a saturated linear C1-C10 or branched C3-C10 or cyclic C5-C6 alkyl
hydrocarbon-based group, optionally interrupted with an oxygen atom and/or
optionally containing a -CONH2 group and/or optionally substituted with a
hydroxyl group; a phenyl group; or a saturated C1-C5 alkyl group substituted
with a phenyl radical itself optionally substituted with one or more hydroxyl or
C1-C3 alkoxy radicals;and also the salts thereof, the solvates thereof and the optical isomers thereof,
and the racemates thereof.
The subject of the invention is also the novel compounds of formulae (la) and
(la') corresponding to those of formula (I) or ( )
in which:
- when R 1 denotes a hydrogen atom, then R2 denotes a radical chosen from
unsaturated C2-C20 alkyls, cyclic C7 alkyl radicals, saturated linear C1-C20 or
branched C3-C20 alkyls, substituted with one or more identical or different -OR3
groups, and (Ci-C2o)alkylaryls substituted with one or more identical or different
-OR3 groups, R3 denoting a hydrogen atom or a saturated linear C1-C5 or
branched C3-C5 or unsaturated C2-C5 hydrocarbon-based group;
- when Ri denotes a saturated linear -C o or branched C3-C10 or unsaturated
C2-C10 alkyl group, optionally substituted with one or more -OR3 groups, then R2
denotes a radical chosen from:
a) a saturated branched C3-C12 or cyclic C3-C7 alkyl group, optionally interrupted
with one or more oxygen atoms, preferably one, and/or optionally containing
one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or an optionally hydroxylated, saturated linear C-i-
C 5 or branched C3-C5 hydrocarbon-based group;
and also the salts thereof, the optical isomers thereof and the racemates
thereof.
Preferably, for the novel compounds of the formulae (la) and (la'):
- when R1 denotes a hydrogen atom, then R2 denotes a radical chosen from
unsaturated C2-C20 alkyls, saturated linear C1-C20 or branched C3-C20 alkyls,
substituted with one or more identical or different -OR3 groups, and (C-i-
Ce)alkylphenyls substituted with one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or a saturated linear C1-C5 or branched C3-C5 or
unsaturated C2-C5 hydrocarbon-based group;
- when R1 denotes a saturated linear C1-C12 or branched C3-C10 or unsaturated
C2-C10 alkyl group, optionally substituted with one or more -OR3 groups, then R2
denotes a radical chosen from:
a) a saturated branched C3-C12 or cyclic C3-C7 alkyl group, optionally interrupted
with one or more oxygen atoms, preferably one, and/or optionally containing
one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or an optionally hydroxylated, saturated linear C-i-
C 5 or branched C3-C5 hydrocarbon-based group,
and also the salts thereof, the optical isomers thereof and the racemates
thereof.
Preferably, for the novel compounds of formulae (la) and (la'):- when R denotes a hydrogen atom, then R2 denotes a radical chosen from
saturated linear C1-C20 or branched C3-C20 alkyls, substituted with one or more
identical or different -OR3 groups, and (Ci-C6)alkylphenyls substituted with one
or more identical or different -OR3 groups, R3 denoting a hydrogen atom or a
saturated linear C1-C5 or branched C3-C5 or unsaturated C2-C5 hydrocarbon-
based group;
- when R denotes a saturated linear -C o or branched C3-C10 or unsaturated
C2-C10 alkyl group, optionally substituted with one or more -OR3 groups, then R2
denotes a radical chosen from:
a) a saturated branched C3-C12 or cyclic C3-C7 alkyl group, optionally interrupted
with one or more oxygen atoms, preferably one, and/or optionally containing
one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or an optionally hydroxylated, saturated linear C-i-
C 5 or branched C3-C5 hydrocarbon-based group.
Preferably, for the novel compounds of formulae (la) and (la'):
Ri denotes a hydrogen atom and R2 denotes a radical chosen from:
a) a saturated linear C1-C10 or branched C3-C10 or cyclic C 5-C7 alkyl group,
substituted with one or more hydroxyl groups, and optionally interrupted with an
oxygen atom, or
Ri denotes a linear C1-C4 alkyl radical optionally substituted with one or more
hydroxyl groups; and R2 denotes a radical chosen from:
a) a saturated linear d-C-io or branched C3-C10 or cyclic C 5-C7 alkyl group,
substituted with one or more hydroxyl groups, and optionally interrupted with an
oxygen atom.
Preferentially, for the novel compounds of formulae (la) and (la'):
Ri denotes a hydrogen atom and R2 denotes a saturated linear d-C-io or
branched C3-C10 or cyclic C5-C6 alkyl hydrocarbon-based group, optionally
interrupted with an oxygen atom and optionally substituted with a hydroxyl
group, or
Ri denotes a C1-C4 hydroxyalkyl group;
R2 denotes a saturated linear d-C-io or branched C3-C10 or cyclic C5-C6 alkyl
hydrocarbon-based group, optionally interrupted with an oxygen atom and
optionally substituted with a hydroxyl group.
Among the compounds of formula (I), the following compounds are preferably
used:Structure Chemical name CAS No.
N-methyl-2-thioxo-1 ,2-
dihydropyridine-3- 9 859-74-
carboxamide 4
N-ethyl-2-thioxo-1 ,2-
dihydropyridine-3- 9 859-75-
carboxamide 5
N-isopropyl-2-thioxo-
1,2-dihydropyridine-3- 9 1859-76-
carboxamide 6
N-propyl-2-thioxo-1 ,2-
dihydropyridine-3- 330667-
carboxamide 56-6
N-(2-methylpropyl)-2-
thioxo-1 ,2-
1100027-
dihydropyridine-3-
79-9
carboxamide
H
N-butyl-2-thioxo-1 ,2-
dihydropyridine-3- 65282-55-
carboxamide 5
0
N-pentyl-2-thioxo-1 ,2-
dihydropyridine-3- 330667-
carboxamide 57-7
H
O
N-octyl-2-thioxo-1 ,2-
dihydropyridine-3- 9 1859-77-
carboxamide 7H carboxamide
Among these compounds, the following compounds are more particularly
preferred:N-(2-hydroxyethyl)-2-
19 thioxo-1 ,2-
dihydropyridine-3-
s carboxamide
H
N,N-bis(2-hydroxyethyl)-
20 2-thioxo-1 ,2-
dihydropyridine-3-
carboxamide
H OH
O N-(2,3-dihydroxypropyl)-
2 1 2-thioxo-1 ,2-
dihydropyridine-3-
S H OH carboxamide
H
O r O N-ethyl-N-(2-
23 hydroxyethyl)-2-thioxo-
1,2-dihydropyridine-3-
carboxamide
I
H
O
27 N,N-diethyl 2-
mercaptonicotinamide
H
and also the salts thereof, the optical isomers thereof and the solvates thereof.
Compounds 1 and 10 are described in application EP-A-298752 as synthesis
intermediates.
Compounds 2 to 8 , 11 and 12 are described in FR-A-2555450.
Compound 14 is described in the article A. Monge, V. Martinez-Merino;
Synthesis of 2-substituted 3-Oxoisothiazolo[5,4-b]pyridines; J . heterocyclic.
Chem, 22, 1353 ( 1985).
Compounds 4 , 6 , 7 and 15 are described in the article A. Dunn, R. Norrie;
Synthesis of pyrido-1 ,3-thiazines; Zeitschrift fur chemie 1988, vol 28, n° 6 , p
212/214.
Compound 14 is described in the article A. Monge, V. Martinez-Merino;
Synthesis of 2-substituted 3-Oxoisothiazolo[5,4-b]pyridines; J . heterocyclic.
Chem, 22, 1353 ( 1985).
Compound 18 is described in WO-A-03/0 14062.
Compound 27 is described in EP 298752.Compounds 2 , 7 , 12, 16, 2 1 and 27 are the most particularly preferred.
The compounds of formula (I) and/or ( ) according to the invention are of quite
particular use in the cosmetics field.
The composition used according to the invention comprises a compound of
formula (I) and/or ( ) as described above, in a physiologically acceptable
medium.
The compound (I) and/or ( ) can be present in the composition used according
to the invention in an amount which can be between 0.01 and 10% by weight,
preferably between 0.1 and 5% by weight, in particular from 0.5 to 3% by
weight, relative to the total weight of the composition.
The term "physiologically acceptable medium" is understood to mean a medium
that is compatible with keratin materials of human beings, such as the skin of
the body or of the face, the lips, the mucous membranes, the eyelashes, the
nails, the scalp and/or the hair.
The composition used according to the invention may thus comprise all the
adjuvants which are commonly employed in the cosmetics field.
Mention may in particular be made of water; organic solvents, in particular C2-C6
alcohols; oils, in particular hydrocarbon-based oils, silicone oils; waxes,
pigments, fillers, dyes, surfactants, emulsifiers; cosmetic active agents, UV
screens, polymers, thickeners, preservatives, fragrances, bactericides, odour
absorbers and antioxidants.
These optional cosmetic adjuvants may be present in the composition in a
proportion of from 0.001 to 80% by weight, in particular 0.1 to 40% by weight,
relative to the total weight of the composition. In any event, these adjuvants,
and also the proportions thereof, will be chosen by those skilled in the art in
such a way that the advantageous properties of the compounds according to
the invention are not, or not substantially, impaired by the envisaged addition.
As active agents, it will be advantageous to introduce into the composition used
according to the invention at least one compound chosen from: desquamating
agents; calmatives; organic or inorganic photoprotective agents, moisturizers;
depigmenting or propigmenting agents; anti-glycation agents; NO-synthase
inhibitors; agents for stimulating the synthesis of dermal or epidermal
macromolecules and/or preventing degradation thereof; agents for stimulating
fibroblast and/or keratinocyte proliferation or stimulating keratinocyte
differentiation; muscle relaxants and/or dermo-decontracting agents; tensioning
agents; anti-pollution agents and/or free-radical scavengers; agents that act on
the microcirculation; agents that act on the energy metabolism of cells; and
mixtures thereof.Examples of such additional compounds are: retinol and derivatives thereof
such as retinyl palmitate; ascorbic acid and derivatives thereof such as
magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and
derivatives thereof such as tocopheryl acetate; nicotinic acid and precursors
thereof such as nicotinamide; ubiquinone; glutathione and precursors thereof
such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and in particular
plant proteins and hydrolysates thereof, and also plant hormones; marine
extracts such as algal extracts; bacterial extracts; sapogenins such as
diosgenin and wild yam extracts containing same; ceramides; hydroxy acids
such as salicylic acid and 5-n-octanoylsalicylic acid; resveratrol; oligopeptides
and pseudodipeptides and acyl derivatives thereof; manganese salts and
magnesium salts, in particular the gluconates; and mixtures thereof.
The term "desquamating agent" is intended to mean any compound capable of
acting:
- either directly on desquamation by promoting exfoliation, such as β-hydroxy
acids, in particular salicylic acid and derivatives thereof (including 5-n-octanoyl
salicylic acid); a-hydroxy acids, such as glycolic acid, citric acid, lactic acid,
tartaric acid, malic acid or mandelic acid; urea; gentisic acid; oligofucoses;
cinnamic acid; Saphora japonica extract; resveratrol;
- or on the enzymes involved in the desquamation or degradation of
corneodesmosomes, glycosidases, stratum corneum chymotryptic enzyme
(SCCE) or even other proteases (trypsin, chymotrypsin-like). Mention ay be
made of agents for chelating mineral salts: EDTA; N-acyl-N,N',N'-
ethylenediaminetriacetic acid; aminosulphonic compounds and in particular (N-2
hydroxyethylpiperazine-N-2-ethane)sulphonic acid (HEPES); derivatives of
2-oxothiazolidine-4-carboxylic acid (procysteine); derivatives of alpha-amino
acids of glycine type (as described in EP-0 852 949, and also sodium methyl
glycine diacetate sold by BASF under the trade name Trilon M); honey; sugar
derivatives such as O-octanoyl-6-D-maltose and N-acetylglucosamine.
The desquamating agents are generally present in the composition according to
the invention in proportions ranging from 0.01 to 15% by weight, preferably
ranging from 0.1 to 10% by weight, relative to the total weight of the
composition.
As calmatives that can be used in the composition according to the invention,
mention may be made of: pentacyclic triterpenes and extracts of plants (for
example Glycyrrhiza glabra) containing them, for instance β-glycyrrhetinic acid
and salts and/or derivatives thereof (glycyrrhetinic acid monoglucuronide,
stearyl glycyrrhetinate, 3-stearoyloxyglycyrrhetic acid), ursolic acid and salts
thereof, oleanolic acid and salts thereof, betulinic acid and salts thereof, an
extract of Paeonia suffruticosa and/or lactiflora, salicylic acid salts and in
particular zinc salicylate, phycosaccharides from the company Codif, an extractof Laminaria saccharina, canola oil, bisabolol and camomile extracts, allantoin,
Sepivital EPC (phosphoric diester of vitamin E and C) from SEPPIC, omega-3
unsaturated oils such as musk rose oil, blackcurrant oil, ecchium oil, fish oil,
plankton extracts, capryloylglycine, Seppicalm VG (sodium palmitoylproline and
Nymphea alba) from SEPPIC, an extract of Pygeum, an extract of Boswellia
serrata, an extract of Centipeda cunnighami, an extract of Helianthus annuus,
an extract of Linum usitatissimum, tocotrienols, extracts of Cola nitida,
piperonal, an extract of clove, an extract of Epilobium angustifolium, aloe vera,
an extract of Bacopa moniera, phytosterols, cortisone, hydrocortisone,
indomethacin and betamethasone.
The calmatives are generally present in the composition used according to the
invention in proportions ranging from 0.01 to 15% by weight, preferably ranging
from 0.1 to 10% by weight, relative to the total weight of the composition.
The organic photoprotective agents are in particular chosen from anthranilates;
cinnamic derivatives; dibenzoylmethane derivatives; salicylic derivatives,
camphor derivatives; triazine derivatives such as those described in patent
applications US4367390, EP863145, EP51 7 104, EP570838, EP796851 ,
EP775698, EP878469, EP933376, EP507691 , EP507692, EP790243 and
EP944624; benzophenone derivatives; β,β-diphenylacrylate derivatives;
benzotriazole derivatives; benzalmalonate derivatives; benzimidazole
derivatives; imidazolines; bis-benzoazolyl derivatives as described in patents
EP669323 and US 2,463,264; p-aminobenzoic acid (PABA) derivatives;
methylenebis(hydroxyphenylbenzotriazole) derivatives as described in
applications US5237071 , US51 66355, GB2303549, DE1 97261 84 and
EP8931 19 ; screening polymers and screening silicones such as those
described in particular in application WO-93/04665; and a-alkylstyrene-derived
dimers such as those described in patent application DE 19855649.
The inorganic photoprotective agents can in particular be chosen from coated or
uncoated metal oxide pigments or nanopigments (average size of the primary
particles generally between 5 nm and 100 nm, preferably between 10 nm and
50 nm), for instance nanopigments of titanium oxide (amorphous or crystallized
in rutile and/or anatase form), of iron oxide, of zinc oxide, of zirconium oxide or
cerium oxide, which are all well-known UV photoprotective agents.
Conventional coating agents are, moreover, alumina and/or aluminium stearate.
Such coated or uncoated metal oxide nanopigments are in particular described
in patent applications EP51 8772 and EP51 8773.
The photoprotective agents are generally present in the composition used
according to the invention in proportions ranging from 0.1 to 20% by weight,
preferably ranging from 0.2 to 15% by weight, relative to the total weight of the
composition.The composition used according to the invention may be in any of the galenical
forms normally used in the cosmetics field, and in particular in the form of an
optionally gelled aqueous or aqueous-alcoholic solution, a dispersion, optionally
a two-phase dispersion, of the lotion type, an oil-in-water or water-in-oil or
multiple (W/O/W or 0/W/O) emulsion, an aqueous gel, a dispersion of oil in an
aqueous phase by means of spherules, it being possible for these spherules to
be polymeric nanoparticles such as nanospheres and nanocapsules or, better
still, lipid vesicles of ionic and/or nonionic type; or aqueous or oily gels. These
compositions are prepared according to the usual methods. According to this
invention, a composition in the form of an emulsion, in particular an oil-in-water
emulsion, is preferably used.
The composition used according to the invention may constitute a skincare
composition, and in particular a cleansing, protecting, treatment or care cream
for the face, for the hands, for the feet, for the major anatomical folds or for the
body (for example, day creams, night creams, makeup-removing creams,
foundation creams, antisun creams); a fluid foundation, a makeup-removing
milk, a protective or care body milk or an antisun milk; a skincare lotion, gel or
foam, such as a cleansing lotion.
The invention is illustrated in greater detail by the following nonlimiting
examples.
Examples 1 to 4: Demonstration of the activity on constitutive melanogenesis
A biological test demonstrated the depigmenting activity of 7 compounds of
formula (I) (compounds 2 , 7 , 12, 16, 19 , 2 1 and 27).
The modulatory effect of each compound on melanogenesis was measured
according to the method described in FR-A-2734825 and also in the article by
R.Schmidt, P. Krien and M. Regnier, Anal. Bichem., 235(2), 113-1 8,1996. This
test is carried out on a coculture of keratinocytes and melanocytes.
For the compounds tested, the following were determined:
- the cytotoxicity, by estimating leucine incorporation,
- the inhibitory activity on melanin synthesis, by estimating the ratio of
thiouracil incorporation to leucine incorporation, relative to 100% of the
control (the control corresponds to the test carried out without test
compound). The IC50 values (concentration for which 50% of the melanin
synthesis is inhibited) were determined.
The test was also carried out with arbutin, niacinamide and kojic acid, which are
known depigmenting compounds.
The results are collated in the following table:Cytotoxicity on
Compound IC50
coculture
Not attained
Arbutin Non-cytotoxic (or greater
than 500 µΜ)
Not attained
Kojic acid 100 µΜ (or greater
than 500 µΜ)
Niacinamide Non-cytotoxic Not attained
Compound 2
O
Non-cytotoxic 4.9 µΜ
/
H
Compound 12
Non-cytotoxic 37 µΜ
H
Compound 16
100 µΜ 25 µΜ
/
H
Compound 7
Non-cytotoxic 32 µΜ
Compound 27 Non-cytotoxic 29 µΜo
H
Compound 19
Non-cytotoxic 4 10 µΜ
Compound 2 1
Non-cytotoxic 128 µΜ
Compounds 2 , 7 , 12, 16, 19 , 2 1 and 27 therefore demonstrate their efficacy in
inhibiting melanogenesis and are, moreover, more effective than arbutin, kojic
acid and niacinamide.
Compound 2 is the most effective compound.
Example 5
A depigmenting gel for the skin is prepared, comprising (% by weight):
Compound 2 2%
Carbomer (Carbopol 981 from Lubrizol) 1%
preservative qs
water qs 100%
When applied to the skin, the composition makes it possible to fade out brown
marks.
A similar composition is prepared with compound 3 or compound
compound 16.2012/080075 PCT/EP2011/072180
CLAIMS
1. Nontherapeutic cosmetic process for depigmenting, lightening and/or
whitening keratin materials, which comprises the application of a cosmetic
composition comprising, in a physiologically acceptable medium, at least one
compound of formula (I):
or its tautomer form of formula
in which:
i and R2, which may be identical or different, denote a radical chosen from:
a) a hydrogen atom;
b) a saturated linear C1-C20 or branched C3-C20 or unsaturated C2-C20 alkyl
group, optionally interrupted with one or more heteroatoms chosen from N, S
and O, and/or optionally substituted with one or more groups, which may be
identical or different, chosen from:
iv) -CONHR3
vi) a C 5-C12 aryl group optionally substituted with one or more
hydroxyls and/or with one or more d-Cs alkoxy radicals;
c) a saturated d-Cs alkyl group substituted with a C 5-C12 aryl radical
optionally substituted with one or more hydroxyls and/or with one or more d-Cs
alkoxy radicals;
d) a phenyl group optionally substituted with one or more hydroxyls and/or
with one or more d-Cs alkoxy radicals;
R3 denoting a hydrogen atom or a saturated linear C 1- C 5 or branched C3-C5 or
unsaturated C2- C 5 hydrocarbon-based group,
R denoting a hydrogen atom; a saturated linear C 1- C 5 or branched C3-C5
hydrocarbon-based group; or an acetyl group;2012/080075 PCT/EP2011/072180
it being possible for i and R2 to form, with the nitrogen atom which bears
them, a ring chosen from pyrrolidine, pyrroline, piperidine, piperazine,
morpholine, thiomorpholine and azepine;
and also the salts thereof, the optical isomers thereof and the racemates
thereof.
2 . Process according to claim 1, in which:
i denotes a radical chosen from:
a) a hydrogen atom;
b) a saturated linear - oor branched C3-C10 or unsaturated C2-C10 alkyl
group, optionally substituted with one or more OR3 groups;
R2 denotes a radical chosen from:
a) a saturated linear C1-C10 or branched C3-C10 or cyclic C3-C7 alkyl group,
optionally interrupted with one or more oxygen atoms, preferably one, and/or
optionally containing one or more groups, which may be identical or different,
chosen from:
iii) -CONHR3,
b) a phenyl group optionally substituted with one or more hydroxyls and/or
with one or more C1-C3 alkoxy radicals;
c) a saturated C1-C5 alkyl group substituted with a phenyl radical optionally
substituted with one or more hydroxyls and/or with one or more C1-C3 alkoxy
radicals;
R3 denoting a hydrogen atom or a saturated linear C1-C5 or branched C3-C5
hydrocarbon-based group;
R denoting a hydrogen atom or a saturated linear C1-C5 or branched C3-C5
hydrocarbon-based group.
3 . Process according to either of the preceding claims, in which:
Ri denotes a hydrogen atom or a linear Ci-C 4 alkyl radical optionally substituted
with one or more hydroxyl groups;
R2 denotes a radical chosen from:
a) a saturated linear C1-C10 or branched C3-C10 or cyclic C 5-C7 alkyl group,
optionally interrupted with an oxygen atom and/or optionally containing a
-CONH2 group and/or optionally substituted with one or more hydroxyl groups;
b) a phenyl group;
c) a saturated C1-C5 alkyl group substituted with a phenyl radical optionally
substituted with one or more hydroxyl or C1-C3 alkoxy radicals.
4 . Process according to one of the preceding claims, in which:
Ri denotes a hydrogen atom or a Ci-C 4 hydroxyalkyl group;2012/080075 PCT/EP2011/072180
R2 denotes a saturated linear - o or branched C3-C1 0 or cyclic C5-C6 alkyl
hydrocarbon-based group, optionally interrupted with an oxygen atom and/or
optionally containing a -CONH2 group and/or optionally substituted with a
hydroxyl group; a phenyl group; or a saturated C 1-C5 alkyl group substituted
with a phenyl radical itself optionally substituted with one or more hydroxyl or
C 1-C3 alkoxy radicals.
5 . Process according to one of the preceding claims, in which the compound of
formula (I) is chosen from the following compounds:
N-methyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-ethyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-isopropyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-propyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2-methylpropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-butyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-pentyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-octyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-nonyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N,N-dimethyl-2-mercaptonicotinamide;
N-cyclopentyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-cyclohexyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-cycloheptyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-phenyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-benzyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-[2-(4-methoxyphenyl)ethyl]-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(3-ethoxypropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2-amino-2-oxoethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N,N-bis(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2,3-dihydroxypropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(1 ,3-dihydroxypropan-2-yl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-ethyl-N-(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-[2-(2-hydroxyethoxy)ethyl]-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(3-hydroxypropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-[2-(2-hydroxyethoxy)ethyl]-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(3-methoxypropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
Ν,Ν-diethyl 2-mercaptonicotinamide;
Ethyl N-[(2-thioxo-1 ,2-dihydropyridin-3-yl)carbonyl]alaninate;
Ethyl N-[(2-thioxo-1 ,2-dihydropyridin-3-yl)carbonyl]phenyl alaninate;
N-[2-(dimethylamino)ethyl]-N-ethyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide.
6 . Process according to one of the preceding claims, in which the compound of
formula (I) is chosen from the following compounds:
N-methyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;2012/080075 PCT/EP2011/072180
N-ethyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide ;
N-isopropyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-propyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2-methylpropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-butyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-pentyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-cyclopentyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-cyclohexyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-cycloheptyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-benzyl-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-[2-(4-methoxyphenyl)ethyl]-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N,N-bis(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2,3-dihydroxypropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-ethyl-N-(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
Ν,Ν-diethyl 2-mercaptonicotinamide.
7 . Process according to one of the preceding claims, in which the compound of
formula (I) is present, alone or as a mixture, in the composition, in an amount of
between 0.01 and 10% by weight, preferably between 0.1 and 5% by weight, in
particular from 0.5 to 3% by weight, relative to the total weight of the
composition.
8 . Process according to one of the preceding claims, in which the composition
comprises at least one adjuvant chosen from the group made up of: water;
organic solvents, in particular -C6 alcohols and C2-C1 0 carboxylic acid esters;
carbon-based and/or silicone oils, of mineral, animal and/or plant origin; waxes,
pigments, fillers, dyes, surfactants, emulsifiers, co-emulsifiers; cosmetic or
dermatological active agents, UV screens, polymers, hydrophilic or lipophilic
gelling agents, thickeners, preservatives, fragrances, bactericides, ceramides,
odour absorbers and antioxidants.
9 . Process according to one of the preceding claims, in which the composition
comprises at least one active agent chosen from: desquamating agents;
calmatives; organic or inorganic photoprotective agents, moisturizers;
depigmenting or propigmenting agents; anti-glycation agents; NO-synthase
inhibitors, agents for stimulating the synthesis of dermal or epidermal
macromolecules and/or preventing degradation thereof; agents for stimulating
fibroblast and/or keratinocyte proliferation and/or stimulating keratinocyte
differentiation; muscle relaxants and/or dermo-decontracting agents; tensioning
agents; anti-pollution agents and free-radical scavengers; agents that act on the
microcirculation; agents that act on the energy metabolism of cells; and
mixtures thereof.2012/080075 PCT/EP2011/072180
10 . Process according to one of the preceding claims, for depigmenting,
lightening or whitening the skin.
11. Nontherapeutic cosmetic use of a compound of formula (I) as defined
according to any one of Claims 1 to 6 , as a whitening, lightening and/or
depigmenting agent for keratin materials.
12. Compounds of formula
or its tautomeric form of formula (I'a):
(I'a)
in which:
- when i denotes a hydrogen atom, then R2 denotes a radical chosen from
unsaturated C2-C20 alkyls, cyclic C7 alkyl radicals, saturated linear C1-C20 or
branched C 3-C20 alkyls, substituted with one or more identical or different -OR3
groups, and (Ci-C2o)alkylaryls substituted with one or more identical or different
-OR3 groups, R3 denoting a hydrogen atom or a saturated linear C1-C5 or
branched C3-C5 or unsaturated C2-C5 hydrocarbon-based group;
- when Ri denotes a saturated linear -C o or branched C 3-C10 or unsaturated
C2-C10 alkyl group, optionally substituted with one or more -OR3 groups, then R2
denotes a radical chosen from:
a) a saturated branched C 3-C12 or cyclic C 3-C7 alkyl group, optionally interrupted
with one or more oxygen atoms, preferably one, and/or optionally containing
one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or an optionally hydroxylated, saturated linear C-i-
C 5 or branched C3-C5 hydrocarbon-based group,
and also the salts thereof, the optical isomers thereof and the racemates
thereof.
13 . Compounds of formula (la) or (I'a) according to the preceding claim, for
which:
- when R denotes a hydrogen atom, then R2 denotes a radical chosen from
unsaturated C2-C20 alkyls, saturated linear C1-C20 or branched C 3-C20 alkyls,
substituted with one or more identical or different -OR3 groups, and (C-i-2012/080075 PCT/EP2011/072180
C 6)alkylphenyls substituted with one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or a saturated linear C1-C5 or branched C3-C5 or
unsaturated C2-C5 hydrocarbon-based group;
- when R denotes a saturated linear C1-C12 or branched C 3-C10 or unsaturated
C2-C10 alkyl group, optionally substituted with one or more -OR3 groups, then R2
denotes a radical chosen from:
a) a saturated branched C 3-C12 or cyclic C3-C7 alkyl group, optionally interrupted
with one or more oxygen atoms, preferably one, and/or optionally containing
one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or an optionally hydroxylated, saturated linear C-i-
C 5 or branched C3-C5 hydrocarbon-based group,
14. Compounds of formula (la) or (I'a) according to either of Claims 12 and 13,
for which:
- when R denotes a hydrogen atom, then R2 denotes a radical chosen from
saturated linear C1-C20 or branched C 3-C20 alkyls, substituted with one or more
identical or different -OR3 groups, and (Ci -C6 )alkylphenyls substituted with one
or more identical or different -OR3 groups, R3 denoting a hydrogen atom or a
saturated linear C1-C5 or branched C3-C5 or unsaturated C2-C5 hydrocarbon-
based group;
- when R denotes a saturated linear -C o or branched C 3-C10 or unsaturated
C2-C10 alkyl group, optionally substituted with one or more -OR3 groups, then R2
denotes a radical chosen from:
a) a saturated branched C 3-C12 or cyclic C3-C7 alkyl group, optionally interrupted
with one or more oxygen atoms, preferably one, and/or optionally containing
one or more identical or different -OR3 groups,
R3 denoting a hydrogen atom or an optionally hydroxylated, saturated linear C-i-
C 5 or branched C3-C5 hydrocarbon-based group.
15 . Compounds of formula (la) or (I'a) according to either of Claims 12 and 13,
chosen from:
N-(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N,N-bis(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(2,3-dihydroxypropyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(1 ,3-dihydroxypropan-2-yl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-(1 ,3-dihydroxypropan-2-yl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-ethyl-N-(2-hydroxyethyl)-2-thioxo-1 ,2-dihydropyridine-3-carboxamide;
N-[2-(2-hydroxyethoxy)ethyl]-2-thioxo-1 ,2-dihydropyridine-3-carboxamide.