Method for depigmenting keratin materials using resorcinol derivatives
The present invention relates to new compounds which are resorcinol derivatives and
to a method for cosmetic treatment, particularly for depigmenting and/or whitening the
skin, that employs such a compound.
At different periods in their life, certain people develop darker and/or more coloured
marks on their skin, and more particularly on the hands and face, which give 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 in order to treat pigmentary marks.
The mechanism of formation of the skin's pigmentation, in other words 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 participating in this sequence of reactions. In
particular it catalyses the reaction converting tyrosine into dopa
(dihydroxyphenylalanine), by virtue of its hydroxylase activity, and the reaction
converting dopa into 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 as being depigmenting if it acts directly on the vitality of
the epidermal melanocytes, where melanogenesis takes place, and/or if it interferes
with one of the steps in the biosynthesis of melanin, either by inhibiting one of the
enzymes involved in melanogenesis, or by inserting itself as a structural analogue of
one of the chemical compounds of the melanin synthesis chain; this chain may then
become blocked and may thus ensure depigmentation.
Arbutin and kojic acid are known as depigmenting agents for the skin.
Substances have been sought which exhibit an effective depigmenting action which in
particular is greater than that of arbutin and of kojic acid.
In this regard, the Applicant has found, surprisingly and unexpectedly, that certain
compounds derived from resorcinol exhibit good depigmenting activity even at low
concentration.
The invention accordingly provides new compounds of formula (I) as defined below.The invention also provides a composition comprising, in a physiologically acceptable
medium, at least one compound of formula (I) as defined below.
The invention likewise provides a non-therapeutic, cosmetic method for
depigmentation, lightening and/or whitening of keratin materials, more particularly the
skin, which comprises applying the composition described above.
The invention also provides for the non-therapeutic, cosmetic use of a compound of
formula (I) as a whitening, lightening and/or depigmenting agent for keratin materials,
more particularly the skin.
The compounds according to the invention allow effective depigmenting and/or
lightening, or even whitening, of the skin of human beings. They are intended more
particularly for application to the skin of individuals presenting 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 the body hair, eyelashes,
head hair and also the lips and/or the nails.
The new compounds accordi conform to formula (I) below:
in which:
denotes a hydrogen atom or an acetyl group;
A denotes a radical selected from:
a) -H;
b) - a C3-C8 cyclic or C3-C2o branched or C2-C2o unsaturated or C C20
saturated linear
alkyl group which is optionally interrupted by one or more heteroatoms or moieties
selected from N, O and -CO- or a combination thereof such as -NHCO-, -NHCONH-
and/or is optionally substituted by one or more identical or different groups selected
from:
i) -OR5ii) -SR5
iii) -NR6R7
iv) -CONHR6
v) -CONR6 R7
vi) -COORe
vii) -NHCONHR5
viii) -C(0)C |-C4alkyl
ix) a C5-C-1 2 (hetero)aryl group optionally containing one or more heteroatoms
selected from O, N and S and optionally substituted by one or more hydroxyls and/or
by one or more C C8 alkoxy radicals;
x) a saturated or unsaturated, non-aroamtic heterocycle having from 5 to 8 members
and comprising one or more heteroatoms selected from O, N and S which is optionally
substituted by one or more hydroxyls and/or by one or more C C8 alkoxy or C-|-
C4 alkyl radicals, it being possible for one of the members to be a carbonyl group;
c) - a C5-C-1 2 (hetero)aryl group optionally containing one or more heteroatoms
selected from O, N and S and optionally substituted by one or more hydroxyls and/or
by one or more radicals selected from C C8 alkoxy or C C8 alkyl groups;
d) -NR2 R3 ;
e) -OR4;
f) -C(0)N HR4 ;
g) (0 ) - -C 0 alkyl
where R2 and R3, which are identical or different, denote a radical selected from:
a) -H;
b) - a C3-C8 cyclic or C 3-C10
branched or C2-C 0 unsaturated or C1 -C10
linear saturated
alkyl group which is optionally interrupted by one or more heteroatoms or moieties
selected from N, O and -CO- or a combination thereof such as -NHCO-, -NHCONH-
and/or is optionally substituted by one or more identical or different groups selected
from -OR5;
c) a C5-C-1 2 (hetero)aryl group optionally containing one or more heteratoms selected
from O, N and S and optionally substituted by one or more hydroxyls and/or by one or
more C C8 alkoxy radicals;
it being possible for R2 and R3 to form , with the nitrogen which carries them, a
heterocycle which has from 5 to 8 members and may contain one or more heteroatoms
or moieties selected from N, O and -CO- and/or is optionally substituted by a C-|-C-|o
hydrocarbon chain optionally containing one or more radicals selected from hydroxyl or
C1 -C4 alkoxy;
R4 denotes a radical selected from:
a) -H
b) a C3-C8 cyclic or C 3-C10
branched or C1 -C10
linear saturated alkyl group which is
optionally substituted by one or more identical or different groups selected from:i) -COOR 6 ,
ii) a C5-C-1 2 (hetero)aryl radical which optionally contains one or more heteroatoms
selected from O, N and S and is optionally substituted by one or more hydroxyls and/or
by one or more C C8 alkoxy radicals;
c) a C5-C-1 2 (hetero)aryl group which optionally contains one or more heteroatoms
selected from O, N and S and is optionally substituted by one or more hydroxyls and/or
by one or more C C8 alkoxy radicals;
R5 is selected from H and a C3-C8 cyclic or C2-C 0 unsaturated or C 3-C10 branched or
C1-C10 linear saturated alkyl hydrocarbon group;
R5 and R7, which are identical or different, are selected from H, a C3-C8 cyclic or
C2-C 0 unsaturated or C 3-C10 branched or C1-C10 linear saturated alkyl hydrocarbon
group; a (C C )alkyl-C5 (hetero)aryl group optionally containing a nitrogen atom, more
particularly a benzyl group;
R5 and R7 may form, with the nitrogen which carries them, a heterocycle which has
from 5 to 8 members and may contain one or more heteroatoms or moieties selected
from N, O and -CO- and/or is optionally substituted by a C-| -C-| Q hydrocarbon chain;
h) a radical of formula (II):
in which:
X denotes C3-C8 cyclic or C 3-C10 branched or C1-C10 linear saturated hydrocarbon
chain or a C6-C 2 arylene group such as phenylene, or a C C alkylene-C 6-C8
cycloalkylene-CrC alkylene group or a C C alkylene-phenylene-C C alkylene
group, which is optionally substituted by one or more identical or different radicals
selected from -OH, -COOR5 where R5 denotes H or a C3-C8 cyclic or C2-C 0
unsaturated or C3-C10 branched or C C2o linear saturated alkyl hydrocarbon group;
denotes a hydrogen atom or an acetyl group;
and, when A denotes a radical of formula (II), all of the radicals R-| in the compounds of
formula (I) are identical;and also their salts, their solvates, their optical isomers and their racemates.
The salts of the compounds of formula (I) include conventional non-toxic salts of said
compounds, such as those formed from acid or from base.
Salts of the compound of formula (I) (when it comprises a quaternizable nitrogen atom),
include the following:
a) salts obtained by addition of the compound (I) with a mineral acid, selected more
particularly from hydrochloric, boric, hydrobromic, hydroic, sulphuric, nitric, carbonic,
phosphoric and tetrafluoroboric acids;
b) or the salts obtained by addition of the compound (I) with an organic acid, more
particularly selected from acetic, propionic, succinic, fumaric, lactic, glycolic, citric,
gluconic, salicylic, tartaric, terephthalic, methylsulphonic, ethylsulphonic, benzene
sulphonic, toluene sulphonic and triflic acids.
Also included are the salts obtained by addition of the compound of formula (I) (when it
comprises an acidic group) with a mineral base, such as aqueous sodium hydroxide
and potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium
hydroxide, lithium hydroxide, and sodium, potassium or calcium carbonates or
hydrogencarbonates, 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; included more particularly are 2-amino-2-
methylpropanol, ethanolamine, triethanolamine, 2-dimethylamino propanol, 2-amino-2-
(hydroxymethyl)-l ,3-propanediol and 3-(dimethylamino)propylamine.
Also included are the salts of amino acids such as, for example, lysine, arginine,
guanidine, glutamic acid and aspartic acid.
The salts of the compounds of formula (I) (when it comprises an acidic group) may
advantageously be selected from alkali metal salts or alkaline earth metal salts such as
sodium, potassium, calcium and magnesium salts; and ammonium salts.
The salts of the compounds of formula (I) (when it comprises a quaternizable nitrogen
atom) may advantageously be selected from halides such as chloride and bromide;
and from 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. Examples include the solvates resulting from
the presence of water or of linear or branched alcohols such as ethanol or isopropanol.The optical isomers are more particularly enantiomers and diastereoisomers.
The linear or branched groups may preferably be selected 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.
The saturated linear or branched alkyl groups may more preferably be selected from
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
The C - 4 alkoxy groups may preferably be selected from methoxy, ethoxy, propoxy
and butoxy and more preferably methoxy.
The compounds of formula (I) preferably have the following meanings:
denotes a hydrogen atom or an acetyl group;
A denotes a radical selected from:
a) - H
b) - a C3-C8 cyclic or C3-C 6 branched or C2-C 6 unsaturated or C 6 linear saturated
alkyl group which is optionally interrupted by one or more heteroatoms or moieties
selected from N, O, -CO- and -NHC(O)- and/or is optionally substituted by one or more
identical or different groups selected from:
i) -OH,
ii) C1-C4 alkoxy,
iii) -COORe,
iv) -CONR5R7 where R5 and R7, which are identical or different, denote H or a C3-C8
cyclic or C2-C8 unsaturated or C3-C8 branched or C C8 linear saturated alkyl group;
v) a phenyl group which is optionally substituted by one or more hydroxyls and/or by
one or more C C alkoxy radicals;
vi) a non-aromatic saturated or unsaturated heterocycle having from 5 to 8 members,
comprising one or more heteroatoms selected from O, N and S, it being possible for
one of the members to be a carbonyl group;
c) a C5-C-12 a r
y oup such as phenyl which is optionally substituted by one or more
identical or different radicals selected from OH, C-1-C4 alkoxy and C C4 alkyl;
d) -NR2R3, where R2 and R3, which are identical or different, denote:
i) H;
ii) a C3-C8 cyclic or C2-C8 unsaturated or C3-C8 branched or C C8 linear saturated alkyl
group which is optionally interrupted by an oxygen atom and/or is optionally substituted
by a hydroxyl group or a C C alkoxy group such as methoxy;iii) a C5-C-12 a r
y r up which is optionally substituted by one or more hydroxyls and/or
by one or more C C alkoxy radicals;
it being possible for R2 and R3 to form, with the nitrogen which carries them, a
heterocycle having from 5 to 8 members, said heterocycle being able to contain one or
more oxygen atoms and/or being optionally substituted by a C-1-C5 hydrocarbon chain
optionally containing one or more radicals selected from hydroxyl or C C alkoxy;
e) -OR4
f) -C(0)NHR 4 ,
where R4 denotes a radical selected from -H, a C3-C8 branched or C C8 linear
saturated alkyl group which is optionally substituted by one or more identical or
different groups selected from:
i) -COOR5, where R5 is as defined above;
ii) a C5-C-12 y radical,
g) a radical of formula (II)
in which X denotes a C3-C8 cyclic or C3-C6 branched or C C6 linear saturated
hydrocarbon chain or a C6-C 2 arylene group such as phenylene, which is optionally
substituted by one or more identical or different radicals selected from OH or a C C6
alkyl group,
R denotes a hydrogen atom or an acetyl group;
and also their salts, their solvates, their optical isomers and their racemates.
The compounds of formula (I) preferentially have the following meanings:
R denotes a hydrogen atom or an acetyl group;
A denotes a radical selected from:
a) H
b) a C3-C8 cyclic or C3-C 6 branched or C2-C 6 unsaturated or C 6 linear saturated
alkyl group which is optionally interrupted by one or more heteroatoms selected from Nand O and/or is optionally substituted by one or more identical or different groups
selected from:
i) -OH
ii) C - 4 alkoxy,
iii) -CONH 2 ;
iv) -COOR5, where R5 denotes H or a C3-C4 cyclic or C2-C unsaturated or C3-C
branched or C C linear saturated alkyl group;
v) a phenyl group which is optionally substituted by one or more hydroxyls and/or by
one or more C C alkoxy radicals;
vi) a saturated or unsaturated, non-aromatic heterocycle having from 5 to 8 members,
comprising one or more nitrogen atoms, it being possible for one of the members to be
a carbonyl moiety;
c) a C5-C-12 a r
y oup such as phenyl;
d) -NR2R3, where R2 and R3, which are identical or different, denote H or a C3-C8
cyclic or C2-C6 unsaturated or C3-C6 branched or C C6 linear saturated alkyl group; or
a C5-C-12 a r
y group such as phenyl;
it being possible for R2 and R3 to form, with the nitrogen which carries them, a
heterocycle having from 5 to 8 members, it being possible for said heterocycle to
contain an oxygen atom and/or being optionally substituted by a C- -C hydrocarbon
chain optionally containing one or more radicals selected from hydroxyl or C C alkoxy;
e) -OR4, where R4 denotes H or a C3-C6 branched or C C6 linear saturated alkyl group
which is optionally substituted by one or more identical or different groups selected
from:
i) -COOH,
ii) a C5-C-12 a r
y radical such as phenyl;
f) a radical of formula (II)
in which X denotes a C3-C8 cyclic or C3-C6 branched or C C6 linear saturated
hydrocarbon chain or a C6-C 2 arylene group such as phenylene, which is optionally
substituted by one or more hydroxyl radicals;and also their salts, their solvates, their optical isomers and their racemates.
Preferentially, = H for the compounds of formula (I).
A number of embodiments of compounds of formula (I) are described below:
= H and A = H (compound 1) .
= H and A = C3-C 6 branched or C 6 saturated linear alkyl group (such as
compounds 2-9).
= H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by one or two hydroxyl groups and is optionally substituted by a group
-SR5, where R5 = H or C C alkyl (such as compounds 12-1 9) .
= H and A = phenyl or benzyl group (such as compounds 10 and 11) .
R = H and A = C3-C8 branched or C C8 alkyl group which is substituted by a phenyl
group which is optionally substituted by one or more hydroxyl groups and/or C C
alkoxy group (such as compounds 20-22).
= H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by a -COOH group, which is optionally substituted by a group SR5, where
R5 = H or Ci-C alkyl (such as compounds 23-31 ) .
= H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by a group -COOR5, where R5 denotes a C-1 -C alkyl group, and is
optionally substituted by a hydroxyl group and/or a group -SR5, where R5 = H or C C
alkyl and/or phenyl which is optionally substituted by one or more hydroxyls, or an
imidazole radical (such as compounds 32-45) .
= H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by a -CON H2 group, which is optionally substituted by a hydroxyl or phenyl
group which is optionally substituted by one or more hydroxyls, or a group-COORs,
where R5 denotes a C-1 -C alkyl group (such as compounds 46-51 ) .= H and A = group -OR4, where R4 denotes H, a C3-C6 branched or C C6 linear
saturated alkyl group which is optionally substituted by a -COOH group or a phenyl
group (such as compounds 55-59) .
= H and A = -NR2R3, where R2 and R3, which are identical or different, denote H
or a C3-C6 branched or C C6 linear saturated alkyl group or a phenyl group;
it being possible for R2 and R3 to form, with the nitrogen which carries them, a
heterocycle which has 5 or 6 members and may contain an oxygen atom, said
heterocycle being optionally substituted by a C-1 -C hydrocarbon chain optionally
containing one or more radicals selected from hydroxyl or C C alkoxy (such as
compounds 60-64) .
= H and A = C3-C6 branched or C2-C6 linear alkyl group interrupted by a -CON H-
group and substituted by a COOH group (such as compound 52).
= H and A = C5-C6 cyclic alkyl group interrupted by a -CON H- group (such as
compound 53).
= H and A = C5-C6 cyclic alkyl group interrupted by an oxygen atom (such as
compound 54).
R = H and A = radical of formula ( II) as described above in which X denotes a C5-C8
cyclic or C3-C6 branched or C C6 linear saturated hydrocarbon chain or a phenylene
group, which is optionally substituted by one or more hydroxyl groups (such as
compounds 65-73) .
Among the compounds of formula (I) it is preferred to use the following compounds:4 o 3-(2,4-dihydroxybenzyl)-1-
propylpyrrolidine-2,5-dione
5 O 3-(2,4-dihydroxybenzyl)-1-
isopropylpyrrolidine-2,5-dione
6 O
3-(2,4-dihydroxybenzyl)-1-
isobutylpyrrolidine-2,5-dione
7 3-(2,4-dihydroxybenzyl)-1-
butylpyrrolidine-2,5-dione
8 4-[(1-butyl-2,5-dioxopyrrolidin-3-
yl)methyl]benzene-1 ,3-diyl
diacetate
9 3-(2,4-dihydroxybenzyl)-1-
tetradecylpyrrolidine-2,5-dione
10 3-(2,4-dihydroxybenzyl)-1-
phenylpyrrolidine-2,5-dione
11 0 3-(2,4-dihydroxybenzyl)-1-
benzylpyrrolidine-2,5-dioneand also their salts, their solvates, their optical isomers and their racemates.
Among these compounds, more particular preference is given to the following
compounds:and also their salts, their solvates, their optical isomers and their racemates.
The invention likewise provides a process for preparing the above-described
compounds of formula (I), which comprises the following steps:
- A) reacting resorcinol (A1) with itaconic acid (B) or its anhydride (Β') or one of its
esters of formula (B1)
B1
in which R denotes H or a C3-C5 branched or C- -C linear alkyl group, to form a
compound C of formula (III), then
- B) reacting the compound C of formula (III), optionally in activated form, with a
compound of formula (IV) A-NH2, in which A has the same meaning described above
for the compounds of formula (I), optionally in the presence of a basic or acidic catalyst,
optionally with heating to a temperature of between 15°C and 200°C,
- C) optionally carrying out an acetylation reaction.
The invention likewise provides the compounds C of formula (III):in which R denotes H or a C3-C5 branched or C-1-C5 linear alkyl group.
These compounds of formula (III) are synthesis intermediates in the preparation
process described above.
The compounds of formula (I) may thus be obtained in accordance with reaction
scheme I below:
(I)
Scheme I
A) by reacting resorcinol in the presence of itaconic acid (B) or its anhydride (Β') or one
of its esters of formula (B1) described above, to give the compound C (III) (schemes I I
and III), particularly in the presence of an organic solvent which may be selected from
toluene, tetrahydrofuran, heptane, isooctane, methyltetrahydrofuran, methyl ethyl
ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate, isododecane
and mixtures thereof,
particularly at a temperature of between 15 and 200°C, optionally in the presence of a
catalyst (acidic or basic) as described in the following publications: Synthesis of 7-
hydroxycoumarins by Pechmann reaction using Nafion resin/silica nanocomposites as
catalysts: Laufer MC, Hausmann H, Holderich WF, J of catalysis, 2003, 218, 315-320;
Synthesis of 7-hydroxycoumarins catalysed by solid acid catalysts: Hoefnagel A,
Gunnewegh E, Downing R, van Bekkum H, J Chem Soc Chem Commun, 1995, 225-
226; more particularly in the presence of an acidic catalyst such as methanesulphonic
acid, triflic acid, para-toluenesulphonic acid and sulphonic resins as Dowex® resins or
Amberlyst® resins (sold by Aldrich).A1 B1 C
Scheme III
B) then reacting the compound C (III) with a compound of formula (IV) A-NH2, where A
has the same meaning described above for the compounds of formula (I), optionally in
the presence of an organic solvent, more particularly tetrahydrofuran, dioxane,
dimethylformamide, dimethyl sulphoxide;
optionally in the presence of a catalyst selected from Lewis or Bronsted acid catalysts
or basic catalysts, such as potassium carbonate, triethylamine or
diisopropylethylamine;
optionally with heating at a temperature of between 15°C and 200°C, more particularly
between 30°C and 150°C.
This gives the compounds (I) for which R-| = H (schemes I and V).
C) and optionally carrying out an acetylation reaction to give the compounds (I) for
which R-| = acetyl.
The compounds B 1 for which R is other than H may be obtained conventionally by
selective esterification in acidic medium of itaconic acid with one or more alcohols of
formula ROH (where R has the meanings described above), as described in the
literature (Selective esterification of non-conjugated carboxylic acids in the presence of
conjugated or aromatic carboxylic acids over active carbon supported
methanesulphonic acid; Feng, Ze Wang; Zhao, Xin Qi; Bi, Hua, Science in China,
Series B: Chemistry (2008), 1(10), 990-992 / An efficient and regiospecific esterification
of dioic acids using PTSA; Devi, A. Rama; Rajaram, S. Indian Journal of Chemistry,
Section B: Organic Chemistry Including Medicinal Chemistry (2000), 39B(4), 294-296 /
A simple method for the preparation of monomethyl esters of dicarboxylic acids byselective esterification of the nonconjugated carboxyl group in the presence of an
aromatic or conjugated carboxyl group; Ram, Ram N.; Meher, Nabin Kumar; Journal of
Chemical Research, Synopses (2000), (6), 282-283.).
According to one particular embodiment of step (B) of the synthesis process, when the
group R of the compound C denotes H, the compound of formula (I) may be obtained
by activating the acid C in accordance with known techniques for activating acids,
described in particular in Comprehensive Organic Transformation by R. Larock,
published by Wiley VCH, in the chapter Interconversion of nitriles, carboxylic acids and
derivatives.
Acid activation techniques include the following:
- the intermediate formation of acid chloride (for example using thionyl or oxalyl
chloride, or 1-chloro-N,N,2-trimethyl-1-propenamine),
- the intermediate formation of mixed anhydride (for example using a C2-C5 alkyl
chloroformate, such as isobutyl chloroformate (scheme IV), in the presence of a base
such as, for example, triethylamine or diisopropylethylamine;
- the intermediate formation of carbamimidate or of acylphosphonate (for example
using carbodiimides or diethyl cyanophosphate; 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 -
2217).
Scheme IVScheme V
The compounds of formula (I) for which denotes an acetyl group may be obtained
by acetylating compounds of formula (I) for which R-| = H.
The acetylation reaction may be carried out with acetic anhydride or acetyl chloride,
especially in the presence of an aprotic solvent such as toluene, pyridine or
tetrahydrofuran.
The acetylation reaction may be selective, by employing protective groups on the
functions which are not to be acetylated, then carrying out a deprotection reaction,
according to the known techniques of organic synthesis.
All of these steps may also employ protection/deprotection strategies which are in
common use in organic chemistry, as compiled in the work "Protecting Groups in
Organic Synthesis", Greene, Wuts, Wiley Interscience.
According to one particular embodiment of the preparation process, the compounds of
formula (I) for which A denotes a group of formula (II) as described above may be
prepared by reacting the compound C (III) in the presence of a diamine of formula (V)
H2N-X-NH2 according to the reaction scheme below:
Scheme VIThe reaction may take place in the presence or absence of a solvent, more particularly
tetrahydrofuran, dioxane, dimethylformamide or dimethylsulphoxide.
The reaction may take place in the presence of a catalyst selected from Lewis or
Bronsted acid catalysts or basic catalysts, such as potassium carbonate, triethylamine
and diisopropylethylamine.
The reaction may be carried out at a temperature of between 0°C and 200°C, more
particularly between 30°C and 150°C.
The compounds of formula (I) according to the invention are employed especially in the
cosmetics sector.
The composition according to the invention comprises, in a physiologically acceptable
medium, a compound of formula (I) as described above.
A physiologically acceptable medium is a medium which is compatible with the keratin
materials of human beings such as the skin of the face or body, the lips, the mucous
membranes, the eyelashes, the nails, the scalp and/or the hair.
The compound (I) may be present in the composition according to the invention in an
amount which may be between 0.01% and 10% by weight, preferably between 0.1% to
5% by weight, in particular from 0.5% to 3% by weight, relative to the total weight of the
composition.
The composition according to the invention is advantageously a cosmetic composition:
it may comprise adjuvants which are commonly employed in the cosmetics sector.
Included in particular are water; organic solvents, especially C2-C5 alcohols; oils,
especially hydrocarbon oils, silicone oils; waxes, pigments, fillers, dyes, surfactants,
emulsifiers; active cosmetic ingredients, UV filters, polymers, thickeners, preservatives,
fragrances, bactericides, odour absorbers and antioxidants.
These optional cosmetic adjuvants may be present in the composition in a proportion of
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 their proportions, will
be selected by the skilled person such that the advantageous properties of the
compounds according to the invention are not, or not substantially, adversely affected
by the intended addition.
Active agents which it will be advantageous to introduce into the composition
according to the invention are at least one compound selected from desquamating
agents; calmatives, organic or inorganic light stabilizers, moisturizers; depigmenting or
propigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents stimulatingthe synthesis of dermal or epidermal macromolecules and/or preventing their
degradation; agents stimulating fibroblast and/or keratinocyte proliferation or
stimulating keratinocyte differentiation; muscle relaxants and/or dermal decontractants;
tensioning agents; anti-pollution agents and/or free-radical scavengers; agents acting
on the microcirculation; agents acting on the energy metabolism of the 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 especially 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 them; ceramides;
hydroxy acids such as salicylic acid and 5-n-octanoylsalicylic acid; resveratrol;
oligopeptides and pseudodipeptides and acyl derivatives thereof; manganese and
magnesium salts, in particular the gluconates; and mixtures thereof.
The term "desquamating agent" means 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-octanoylsalicylic acid); -
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
other proteases (trypsin, chymotrypsin-like). These include 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); 2-
oxothiazolidine-4-carboxylic acid (procysteine) derivatives; 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 and preferably ranging
from 0.1% to 10% by weight relative to the total weight of the composition.
Calmatives that may be used in the composition according to the invention include the
following: pentacyclic triterpenes and extracts of plants (e.g.: Glycyrrhiza glabra)
containing them, for instance β-glycyrrhetinic acid and salts and/or derivatives thereof(glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate or 3-stearoyl-
oxyglycyrrhetic acid), ursolic acid and its salts, oleanolic acid and its salts, betulinic
acid and its salts, an extract of Paeonia suffruticosa and/or lactiflora, salicylic acid salts
and in particular zinc salicylate, the phycosaccharides from the company Codif, an
extract of Laminaria saccharina, canola oil, bisabolol and camomile extracts, allantoin,
Sepivital EPC (phosphoric diester of vitamins 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, a Pygeum extract, an extract of Boswellia serrata, an extract of
Centipeda cunninghami, an extract of Helianthus annuus, an extract of Linum
usitatissimum, tocotrienols, extracts of Co/a nitida, piperonal, an extract of clove, an
extract of Epilobium Angustifolium, Aloe vera, an extract of Bacopa monieri,
phytosterols, cortisone, hydrocortisone, indomethacin and betamethasone.
The calmatives are generally present in the composition according to the invention in
proportions ranging from 0.01% to 15% by weight and preferably ranging from 0.1% to
10% by weight relative to the total weight of the composition.
The organic light stabilizers are selected especially from anthranilates; cinnamic
derivatives; dibenzoylmethane derivatives; salicylic derivatives; camphor derivatives;
triazine derivatives such as those described in patent applications US 4 367 390,
EP 863 145, EP 5 17 104, EP 570 838, EP 796 851 , EP 775 698, EP 878 469,
EP 933 376, EP 507 691 , EP 507 692, EP 790 243, EP 944 624; benzophenone
derivatives; β ,β-diphenylacrylate derivatives; benzotriazole derivatives; benzalmalonate
derivatives; benzimidazole derivatives; imidazolines; bis-benzazolyl derivatives as
described in patents EP 669 323 and US 2 463 264; p-aminobenzoic acid (PABA)
derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives as described in
patent applications US 5 237 071, US 5 166 355, GB 2 303 549, DE 197 26 184 and
EP 893 119; screening polymers and screening silicones such as those described
especially in patent application WO 93/04665; oc-alkylstyrene-based dimers, such as
those described in patent application DE 198 55 649.
The inorganic light stabilizers may be selected especially from pigments or
nanopigments (average size of the primary particles: generally between 5 nm and
100 nm and preferably between 10 nm and 50 nm) of coated or uncoated metal oxides,
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 of cerium oxide, which
are all well-known UV light stabilizers. Standard coating agents are, moreover, alumina
and/or aluminium stearate. Such coated or uncoated metal oxide nanopigments are
described in particular in patent applications EP 518 772 and EP 518 773.The light stabilizers are generally present in the composition according to the invention
in proportions ranging from 0.1% to 20% by weight and preferably ranging from 0.2% to
15% by weight relative to the total weight of the composition.
The composition according to the invention may be in any of the formulation forms
normally used in the cosmetics sector, and especially 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 emulsion (for example
W/O/W or 0/W/O), an aqueous gel, a dispersion of oil in an aqueous phase with the
aid of spherules, these spherules possibly being polymeric nanoparticles such as
nanospheres and nanocapsules or, better still, lipid vesicles of ionic and/or nonionic
type; 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,
especially an oil-in-water emulsion, is preferably used.
The composition according to the invention may constitute a skincare composition, and
especially a cleansing, protecting, treatment or care cream for the face, the hands, the
feet, the major anatomical folds or the body (for example day creams, night creams,
makeup-removing creams, foundation creams or antisun creams); a fluid foundation, a
makeup-removing milk, a protective or care body milk or an antisun milk; or a skincare
lotion, gel or mousse, such as a cleansing lotion.
The invention is illustrated in greater detail by the non-limiting examples that follow.
Example 1: Synthesis of compound 10
a) Synthesis of (7-hydroxy-2-oxo-3,4-dihydro-2H-chromen-3-yl) acetic acid (C1)
C 1
In a round-bottomed flask equipped with a Dean-Stark apparatus, 10 g of resorcinol
and 11.8 g of itaconic acid were dissolved in 150 ml of a toluene/dioxane mixture
(volume ratio 1/1) in the presence of Amberlyst 15 resin from Aldrich. The reaction
mixture was heated at 100°C for 3 hours. After cooling, the crude reaction product wasfiltered and the filtrate was concentrated under vacuum. The crude product was
recrystallized hot from ethyl acetate. This gave 10 g of a white powder, which
corresponds to the expected product (50% yield).
Melting point: 174-175°C
b) Synthesis of compound 10:
A solution of 450 mg (2 mmol) of (7-hydroxy-2-oxo-3,4-dihydro-2H-chromen-3-yl) acetic
acid (obtained according to step a) described above, in 15 ml of tetrahydrofuran (THF)
was admixed with 223 mg (2.2 mmol) of triethylamine and 0.3 g (2.2 mmol) of isobutyl
chloroformate. After reaction, this solution was added to 250 mg (2.2 mmol) of
phenylamine (or aniline = amine A-NH2 with A = phenyl) in 15 ml of THF. Following
stirring at 20°C, the reaction mixture was concentrated under vacuum and then in THF
at 40°C in the presence of potassium carbonate after which, following filtration,
concentration of the filtrate and purification by chromatography on a silica column,
0.18 g (30% yield) of the expected compound 10 was obtained.
The NMR and mass spectra are in accordance with the structure of the expected
product.
Example 2: Synthesis of compound 1 1
The procedure described in Example 1 b) above was repeated, using benzylamine.
This gave 0.35 g (56% yield) of compound 11.
The NMR and mass spectra are in accordance with the structure of the expected
product.
Example 3: Synthesis of compound 7
a) Synthesis of ethyl (7-hydroxy-2-oxo-3,4-dihydro-2H-chromen-3-yl)acetate (C2):C2
100 ml of toluene were admixed with 4.4 g (0.04 mol) of resorcinol and 6.32 g
(0.04 mol) of the ethyl monoester of itaconic acid, and also 8.8 g of Amberlyst 15 resin
from Aldrich. The reaction mixture was stirred for 2 hours and then filtered off to
cooling. The filtrate was concentrated and purified by flash chromatography on a silica
column (eluent CH2CI2: MeOH = 50:1), to give, following recrystallization from a 3/1
hexane/ethyl acetate mixture, 4.6 g (46% yield) of the expected lactone C2 in the form
of a white solid.
Melting point: 102-103°C
The NMR and mass spectra are in accordance with the structure of the expected
product.
b) Synthesis of compound 7 :
A solution of 5.5 g (22 mmol) of ethyl (7-hydroxy-2-oxo-3,4-dihydro-2H-chromen-3-
yl)acetate (compound C2) in 50 ml of THF was admixed with 1.6 g (22 mmol) of butyl
amine (amine A-NH2 with A = C4H9) and 3 g (22 mmol) of potassium carbonate. The
mixture was stirred at 40°C for 12 hours. Following filtration and concentration of the
filtrate, the crude product was purified by chromatography on a silica column to give 5 g
(82% yield) of the expected compound 7 .
Melting point: 122-123°C
The NMR and mass spectra are in accordance with the structure of the expected
product.
Examples 4 to 25: Synthesis of compounds
The procedure of Example 3 b) above was repeated, using a different amine as
specified in the table below:
Example / Reactant
Structure Yield Analyses
Compound A-NH?
NMR /
4 NH3 37 MS in
Compound accordExample 26: Preparation of compound 69
A 25 ml round-bottomed flask was charged with 1 g (0.004 mol) of ethyl (7-hydroxy-2-
oxo-3,4-dihydro-2H-chromen-3-yl)acetate (compound C2), 0.829 g (0.06 mol) of
potassium carbonate and 0.120 g (0.02 mol) of ethylene diamine in 10 ml oftetrahydrofuran. The reaction mixture was heated at 40°C for 12 hours. Following
filtration of the salts, the filtrate was concentrated under vacuum and then taken up in
ethyl acetate. The precipitate thus obtained was filtered. It was purified on a silica
column (eluent dichloromethane/methanol 95/5) to give 0.35 g (33% yield) of a white
powder corresponding to the expected product.
Melting point: 125°C
The NMR and mass spectra are in accordance with the structure of the expected
product.
Example 27: Demonstration of the activity on constitutive melanogenesis
A biological test demonstrated the depigmenting activity of compounds 1, 7 , 12 and 32.
The modulatory effect of compound 1 on melanogenesis was measured by the method
described in patent FR-A-2 734 825 and also in the article by R. Schmidt, P. Krien and
M. Regnier, Anal. Biochem., 235(2), 113-18,1996. This test is carried out on a co-
culture of keratinocytes and melanocytes.
For the compound tested, the following parameters were ascertained:
- the cytotoxicity, by estimation of the incorporation of leucine,
- the inhibitory activity on melanin synthesis, by estimating the ratio of incorporation
of thiouracil to the incorporation of leucine, relative to 100% of the control (the
control corresponds to the test carried out without compound tested). The IC50
values (concentration for which 50% of the synthesis of melanin is inhibited) were
ascertained.
The test was also carried out with arbutin and kojic acid, which are known
depigmenting compounds.
The results are collated in the table below:Compounds 1, 7 , 12 and 32 according to the invention therefore demonstrate their
efficacy in inhibiting melanogenesis and, furthermore, are more effective than arbutin
and kojic acid.
Example 28
A depigmenting gel for the skin is prepared, comprising (% by weight):
Compound 7 (Example 3) 2%
Carbomer (Carbopol 981 from Lubrizol) 1%
Preservative qs
Water qs 100%
When applied to the skin, the composition eliminates brown marks.
A similar composition is prepared with compound 1 (Example 15) or compound 32
(Example 5) or compound 12 (Example 6).CLAIMS
1. Compounds of formu
in which:
denotes a hydrogen atom or an acetyl group;
A denotes a radical selected from:
a) -H;
b) - a C3-C8 cyclic or C3-C2obranched or C2-C2ounsaturated or C C20
saturated linear
alkyl group which is optionally interrupted by one or more heteroatoms or moieties
selected from N, O and -CO- or a combination thereof such as -NHCO-, -NHCONH-
and/or is optionally substituted by one or more identical or different groups selected
from:
i) -OR5
ii) -SR5
iii) -N
iv) -CONHR 6
v) -CONR 6 R7
vi) -COOR 6
vii) -NHCONHRg
viii) -C(0)C-i-C4alkyl
ix) a C5-C-12 (hetero)aryl group optionally containing one or more heteroatoms
selected from O, N and S and optionally substituted by one or more hydroxyls and/or
by one or more C C8 alkoxy radicals;
x) a saturated or unsaturated, non-aromatic heterocycle having from 5 to 8 members
and comprising one or more heteroatoms selected from O, N and S which is optionally
substituted by one or more hydroxyls and/or by one or more C C8 alkoxy or C-|-
C4 alkyl radicals, it being possible for one of the members to be a carbonyl group;
c) - a C5-C-12 (hetero)aryl group optionally containing one or more heteroatoms
selected from O, N and S and optionally substituted by one or more hydroxyls and/or
by one or more radicals selected from C C8 alkoxy or C C8 alkyl groups;
d) -NR2 R3 ;
e) -OR4;f) -C(0)NHR 4 ;
g) (0 ) -C oalkyl
where 2 and R3, which are identical or different, denote a radical selected from:
a) -H;
b) - a C3-C8 cyclic or C 3-C1 0 branched or C2-C 0 unsaturated or C1-C1 0 linear saturated
alkyl group which is optionally interrupted by one or more heteroatoms or moieties
selected from N, O and -CO- or a combination thereof such as -NHCO-, -NHCONH-
and/or is optionally substituted by one or more identical or different groups selected
from -OR5;
c) a C5-C-1 2 (hetero)aryl group optionally containing one or more heteratoms selected
from O, N and S and optionally substituted by one or more hydroxyls and/or by one or
more C C8 alkoxy radicals;
it being possible for R2 and R3 to form, with the nitrogen which carries them, a
heterocycle which has from 5 to 8 members and may contain one or more heteroatoms
or moieties selected from N, O and -CO- and/or is optionally substituted by a C-|-C-| o
hydrocarbon chain optionally containing one or more radicals selected from hydroxyl or
CrC 4 alkoxy;
R4 denotes a radical selected from:
a) -H
b) a C3-C8 cyclic or C 3-C1 0 branched or C1-C1 0 linear saturated alkyl group which is
optionally substituted by one or more identical or different groups selected from:
i) -COOR 6 ,
ii) a C5-C-1 2 (hetero)aryl radical which optionally contains one or more heteroatoms
selected from O, N and S and is optionally substituted by one or more hydroxyls and/or
by one or more C C8 alkoxy radicals;
c) a C5-C-1 2 (hetero)aryl group which optionally contains one or more heteroatoms
selected from O, N and S and is optionally substituted by one or more hydroxyls and/or
by one or more CrC 8 alkoxy radicals;
R5 is selected from H and a C3-C8 cyclic or C2-C 0 unsaturated or C 3-C1 0 branched or
C1-C1 0 linear saturated alkyl hydrocarbon group;
Rg and R7, which are identical or different, are selected from H, a C3-C8 cyclic or
C2-C1 0 unsaturated or C3-C1 0 branched or C1-C1 0 linear saturated alkyl hydrocarbon
group; a (CrC )alkyl-C5 (hetero)aryl group optionally containing a nitrogen atom, more
particularly a benzyl group;
Rg and R7 may form, with the nitrogen which carries them, a heterocycle which has
from 5 to 8 members and may contain one or more heteroatoms or moieties selected
from N, O and -CO- and/or is optionally substituted by a C-| -C-| Q hydrocarbon chain;h) a radical of formula (II):
in which:
X denotes C3-C8 cyclic or C 3-C10
branched or C1 -C10
linear saturated hydrocarbon
chain or a C6-C 2 arylene group such as phenylene, or a C C alkylene -C6-C8
cycloalkylene -CrC alkylene group or a C C alkylene-phenylene -C C alkylene
group, which is optionally substituted by one or more identical or different radicals
selected from -OH, -COORg where Rg denotes H or a C3-C8 cyclic or C2-C 0
unsaturated or C 3-C10
branched or C C20
linear saturated alkyl hydrocarbon group;
R denotes a hydrogen atom or an acetyl group;
and, when A denotes a radical of formula (II), all of the radicals R-| in the compounds of
formula (I) are identical;
and also their salts, their optical isomers and their racemates.
2. Compounds according to the preceding claim, wherein:
R denotes a hydrogen atom or an acetyl group;
A denotes a radical selected from:
a) - H
b) - a C3-C8 cyclic or C3-C 6 branched or C2-C 6 unsaturated or C C 6 linear saturated
alkyl group which is optionally interrupted by one or more heteroatoms or moieties
selected from N, O, -CO- and -NHC(O)- and/or is optionally substituted by one or more
identical or different groups selected from:
i) -OH,
ii) C1 -C4 alkoxy,
iii) -COORg,
iv) -CONRgR7 where Rg and R7, which are identical or different, denote H or a C3-C8
cyclic or C2-C8 unsaturated or C3-C8 branched or C C8 linear saturated alkyl group;
v) a phenyl group which is optionally substituted by one or more hydroxyls and/or by
one or more C C4 alkoxy radicals;vi) a saturated or unsaturated heterocycle having from 5 to 8 members, comprising one
or more heteroatoms selected from O, N and S, it being possible for one of the
members to be a carbonyl group;
c) a C5-C-12 a y group such as phenyl which is optionally substituted by one or more
identical or different radicals selected from OH, C-1-C4 alkoxy and C C alkyl;
d) -NR2R3, where 2 and R3, which are identical or different, denote:
i) H;
ii) a C3-C8 cyclic or C2-C8 unsaturated or C3-C8 branched or C C8 linear saturated alkyl
group which is optionally interrupted by an oxygen atom and/or is optionally substituted
by a hydroxyl group or a C C alkoxy group such as methoxy;
iii) a C5-C-12 a r
y group which is optionally substituted by one or more hydroxyls and/or
by one or more C C alkoxy radicals;
it being possible for R2 and R3 to form, with the nitrogen which carries them, a
heterocycle having from 5 to 8 members, said heterocycle being able to contain one or
more oxygen atoms and/or being optionally substituted by a C- -C hydrocarbon chain
optionally containing one or more radicals selected from hydroxyl or C C alkoxy;
e) -OR4
f) -C(0)NHR 4 ,
where R4 denotes a radical selected from -H, a C3-C8 branched or C C8 linear
saturated alkyl group which is optionally substituted by one or more identical or
different groups selected from:
i) -COORg, where Rg is as defined above;
ii) a C5-C-12 a yl radical,
radical of formula (II)
in which g denotes a C3-C8 cyclic or C3-C6 branched or C C6 linear saturated
hydrocarbon chain or a C6-C 2 arylene group such as phenylene, which is optionally
substituted by one or more identical or different radicals selected from OH or a C C6
alkyl group,denotes a hydrogen atom or an acetyl group.
3. Compounds according to either of the preceding claims, wherein:
denotes a hydrogen atom or an acetyl group;
A denotes a radical selected from :
a) H
b) a C3-C8 cyclic or C3-C 6 branched or C2-C 6 unsaturated or C 6 linear saturated
alkyl group which is optionally interrupted by one or more heteroatoms selected from N
and O and/or is optionally substituted by one or more identical or different groups
selected from:
i) -OH
ii) C -C4 alkoxy,
iii) -CON H2 ;
iv) -COORg, where Rg denotes H or a C3-C4 cyclic or C2-C unsaturated or C3-C
branched or C C linear saturated alkyl group;
v) a phenyl group which is optionally substituted by one or more hydroxyls and/or by
one or more C C alkoxy radicals;
vi) a saturated or unsaturated, non-aromatic heterocycle having from 5 to 8 members,
comprising one or more nitrogen atoms, it being possible for one of the members to be
a carbonyl moiety;
c) a C5-C-1 2 a r
y oup such as phenyl;
d) -NR2R3, where R2 and R3, which are identical or different, denote H or a C3-C8
cyclic or C2-C6 unsaturated or C3-C6 branched or C C6 linear saturated alkyl group; or
a C5-C-1 2 a r
y group such as phenyl;
it being possible for R2 and R3 to form , with the nitrogen which carries them, a
heterocycle having from 5 to 8 members, it being possible for said heterocycle to
contain an oxygen atom and/or being optionally substituted by a C-1 -C hydrocarbon
chain optionally containing one or more radicals selected from hydroxyl or C C alkoxy;
e) -OR4, where R4 denotes H or a C3-C6 branched or C C6 linear saturated alkyl group
which is optionally substituted by one or more identical or different groups selected
from:
i) -COOH ,
ii) a C5-C-1 2 a r
y radical such as phenyl;
f) a radical of formula ( II)in which X denotes a C3-C8 cyclic or C3-C6 branched or C C6 linear saturated
hydrocarbon chain or a C6-C 2 arylene group such as phenylene, which is optionally
substituted by one or more hydroxyl radicals.
4. Compounds according to any of the preceding claims, wherein R = H.
5. Compounds according to any of the preceding claims, wherein the compounds
have one of the following meanings:
a) R = H and A = H;
b) R = H and A = C3-C 6 branched or C 6 saturated linear alkyl group;
c) R = H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by one or two hydroxyl groups and is optionally substituted by a group
-SR5, where R5 = H or C C4 alkyl;
d) R = H and A = phenyl or benzyl group;
e) R = H and A = C3-C8 branched or C C8 alkyl group which is substituted by a
phenyl group which is optionally substituted by one or more hydroxyl groups and/or C
C4 alkoxy group;
f ) R = H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by a -COOH group, which is optionally substituted by a group SR5, where
R5 = H or C1-C4 alkyl;
g) R = H and A = C3-C8 branched or -C8 saturated linear alkyl group which is
substituted by a group -COORg, where Rg denotes a C- -C alkyl group, and is
optionally substituted by a hydroxyl group and/or a group -SR5, where R5 = H or C C4alkyl and/or phenyl which is optionally substituted by one or more hydroxyls, or an
imidazole radical;
h) R = H and A = C3-C8 branched or C C8 saturated linear alkyl group which is
substituted by a -CON H2 group, which is optionally substituted by a hydroxyl or phenyl
group which is optionally substituted by one or more hydroxyls, or a group-COORg,
where Rg denotes a C-1 -C alkyl group;
i) R = H and A = group -OR4, where R4 denotes H, a C3-C6 branched or C C6 linear
saturated alkyl group which is optionally substituted by a -COOH group or a phenyl
group;
j ) R = H and A = -NR2R3, where R2 and R3, which are identical or different, denote
H or a C3-C6 branched or C C6 linear saturated alkyl group or a phenyl group;
it being possible for R2 and R3 to form, with the nitrogen which carries them, a
heterocycle which has 5 or 6 members and may contain an oxygen atom, said
heterocycle being optionally substituted by a C-1 -C hydrocarbon chain optionally
containing one or more radicals selected from hydroxyl or C C alkoxy;
k) Ri = H and A = C3-C6 branched or C2-C6 linear alkyl group interrupted by a -CON H-
group and substituted by a COOH group;
I) Ri = H and A = C5-C6 cyclic alkyl group interrupted by a -CON H- group;
m) R = H and A = C5-C6 cyclic alkyl group interrupted by an oxygen atom;
n) R = H and A = radical of the formula ( I I) as described above in which X denotes a
C5-C8 cyclic or C3-C6 branched or C C6 linear saturated hydrocarbon chain or a
phenylene group, which is optionally substituted by one or more hydroxyl groups.
6. Compounds according to any of the preceding claims, characterized in that
they are selected from the following compounds:
3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1 -methylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1 -ethylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1 -propylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1 -isopropylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1 -isobutylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1 -butylpyrrolidine-2,5-dione
4-[(1 -butyl-2,5-dioxopyrrolidin-3-yl)methyl]benzene-1 ,3-diyl diacetate3-(2,4-dihydroxybenzyl)- tetradecylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- phenylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- benzylpyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 2-hydroxyethyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 1-hydroxypropan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 1-hydroxy-3-methylpentan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 1-hydroxy-4-methylpentan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 1-hydroxy-3-methylbutan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 2,3-dihydroxypropyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 1,3-dihydroxypropan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- 1-hydroxy-4-(methylsulphanyl)butan-2-yl]pyrrolidine-2,5-
dione
3-(2,4-dihydroxybenzyl)- (1-hydroxy-3-phenylpropan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- [2-(4-hydroxyphenyl)ethyl]pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)- [2-(4-hydroxy-3-methoxyphenyl)ethyl]pyrrolidine-2,5-dione
[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]acetic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]propanoic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-methylpentanoic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-4-methylpentanoic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-methylbutanoic acid
4-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]butanoic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-sulphanylpropanoic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-4-(methylsulphanyl)butanoic acid
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-(4-hydroxyphenyl)propanoic acid
ethyl [3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]acetate
isopropyl [3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]acetate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]propanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-methylbutanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-(1 H-imidazol-4-
yl)propanoate
ethyl 4-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]butanoate
isopropyl 4-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]butanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-methylpentanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-4-methylpentanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-phenylpropanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-(4-
hydroxyphenyl)propanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-hydroxypropanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-sulphanylpropanoate
ethyl 2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-4-(methylsulphanyl)butanoate
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]acetamide
4-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]butanamide2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-phenylpropanamide
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-(4-hydroxyphenyl)propanamide
2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-3-hydroxypropanamide
ethyl 4-amino-2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]-4-oxobutanoate
N-{2-[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]propanoyl}alanine
3-(2,4-dihydroxybenzyl)-1-(2-oxoazepan-3-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(tetrahydrofuran-2-ylmethyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-hydroxypyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-methoxypyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-ethoxypyrrolidine-2,5-dione
{[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]oxy}acetic acid
3-(2,4-dihydroxybenzyl)-1-benzyloxypyrrolidine-2,5-dione
1-amino-3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(dimethylamino)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(morpholin-4-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-2'-(methoxymethyl)-1 ,1'-bipyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(phenylamino)pyrrolidine-2,5-dione
1,1 '-cyclohexane-1,3-diylbis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
1,1 '-(cyclohexane-1 ,3-diyldimethanediyl)bis[3-(2,4-dihydroxybenzyl)pyrrolidine-2, 5-
dione]
1,1'-propane-1,3-diylbis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
1,1'-(2-hydroxypropane-1,3-diyl)bis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
1,1'-ethane-1,2-diylbis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
1,1'-benzene-1 ,4-diylbis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
1,1 '-cyclohexane-1,4-diylbis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
1,1 '-cyclohexane-1,2-diylbis[3-(2,4-dihydroxybenzyl)pyrrolidine-2,5-dione]
ethyl 2,6-bis[3-(2,4-dihydroxybenzyl)-2,5-dioxopyrrolidin-1-yl]hexanoate
3-(2,4-dihydroxybenzyl)-1-(2-hydroxyethyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(1-hydroxypropan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(1-hydroxy-3-methylpentan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(1-hydroxy-4-methylpentan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(1-hydroxy-3-methylbutan-2-yl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(2,3-dihydroxypropyl)pyrrolidine-2,5-dione
3-(2,4-dihydroxybenzyl)-1-(1 ,3-dihydroxypropan-2-yl)pyrrolidine-2,5-dione.
7. Composition comprising, in a physiologically acceptable medium, a compound
of formula (I) according to any of the preceding claims.
8. Composition according to the preceding claim, characterized in that the
compound (I) is present in an amount of between 0.01% and 10% by weight, preferably
between 0.1% to 5% by weight, relative to the total weight of the composition.9. Composition according to either of Claims 7 and 8 , characterized in that it
comprises at least one adjuvant selected from the group consisting of water; organic
solvents, hydrocarbon oils, silicone oils, waxes, pigments, fillers, dyes, surfactants,
emulsifiers, active cosmetic ingredients, UV filters, polymers, thickeners, preservatives,
fragrances, bactericides, ceramides, odour absorbers and antioxidants.
10. Composition according to any of Claims 7 to 9 , characterized in that it
comprises at least one active ingredient selected from desquamating agents;
calmatives, organic or inorganic light stabilizers, moisturizers; depigmenting or
propigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents stimulating
the synthesis of dermal or epidermal macromolecules and/or preventing their
degradation; agents stimulating fibroblast and/or keratinocyte proliferation or
stimulating keratinocyte differentiation; muscle relaxants and/or dermal decontractants;
tensioning agents; anti-pollution agents and/or free-radical scavengers; agents acting
on the microcirculation; agents acting on the energy metabolism of the cells; and
mixtures thereof.
11. Non-therapeutic, cosmetic method for depigmenting, lightening and/or
whitening keratin materials, which comprises applying a composition according to any
of Claims 7 to 10.
12. Method according to the preceding claim for depigmenting, lightening and/or
whitening the skin.
13. Non-therapeutic, cosmetic use of a compound of formula (I) as defined in any
of Claims 1 to 6 as a whitening, lightening and/or depigmenting agent for keratin
materials.
14. Process for preparing compounds of formula (I) according to any of Claims 1 to
5 , which comprises the following steps:
- A) reacting with resorcinol with itaconic acid or its anhydride or one of its esters of
formula (B1)
B1
in which R denotes H or a C3-C5 branched or C- -C linear alkyl group, to form a
compound of formula (III)then
- B) reacting the compound of formula (III), optionally in activated form, with a
compound of formula (IV) A-NH2, in which A has the same meaning described for the
compounds of formula (I) in one of Claims 1 to 5 , optionally in the presence of a basic
or acidic catalyst, optionally with heating to a temperature of between 15°C and 200°C,
- C) optionally carrying out an acetylation reaction.
15. Intermediate comp
in which R denotes H or a C3-C5 branched or C- -C linear alkyl group.