The present invention relates to novel resorcinol-based compounds and to a
cosmetic treatment process, in particular for depigmenting and/or bleaching the
skin, employing such a compound.
At different periods in their lives, some people witness the appearance on the
skin and more especially on the hands and face of darker and/or more highly
coloured blemishes which give the skin a heterogeneous appearance. These
blemishes are due in particular to a high concentration of melanin in the
keratinocytes situated at the surface of the skin.
The use of inoffensive topical depigmenting substances which are highly
effective is very particularly sought after with a view to treating pigment
blemishes.
The mechanism of formation of the pigmentation of the skin, that is to say of the
formation of melanin, is particularly complex and involves, schematically, the
following main stages:
Tyrosine —> Dopa —> Dopaquinone —> Dopachrome —> Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC
1.14.1 8.1 ) is the essential enzyme involved in this sequence of reactions. In
particular, it catalyses the conversion reaction of tyrosine to give Dopa
(dihydroxyphenylalanine), by virtue of its hydroxylase activity, and the
conversion reaction of Dopa to give dopaquinone, by virtue of its oxidase
activity. This tyrosinase only acts when it is in the maturation state under the
effect of certain biological factors.
A substance is recognized as 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 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 in the sequence for the synthesis
of melanin, which sequence can then be blocked and thus ensure
depigmentation.
Arbutin and kojic acid are known as agents for depigmenting the skin.
Substances have been sought which have efficient depigmenting action, in
particular superior to that of arbutin and kojic acid.
In this regard, the Applicant Company has discovered, surprisingly and
unexpectedly, that some resorcinol-based compounds show good depigmenting
activity, even at low concentration.
A subject of the invention is thus novel compounds of formula (I) as defined
below.
Another subject of the invention is a composition comprising, in a
physiologically acceptable medium, at least one compound of formula (I) as
defined below.
Another subject of the invention is a non-therapeutic cosmetic process for
depigmenting, lightening and/or bleaching keratin materials, in particular the
skin, comprising the application of the composition described above.
The invention also relates to the non-therapeutic cosmetic use of a compound
of formula (I) as an agent for bleaching, lightening and/or depigmenting keratin
materials, in particular the skin.
The compounds according to the invention make it possible to effectively
depigment and/or lighten, indeed even to bleach, human skin. They are in
particular intended to be applied to the skin of individuals exhibiting brownish
pigmentation blemishes or blemishes due to ageing or to the skin of individuals
desiring to combat the appearance of a brownish colour originating from
melanogenesis.
They can also make it possible to depigment and/or lighten bodily hair, the
eyelashes or head hair, and also the lips and/or the nails.
The novel compounds according to the invention thus correspond to formula (I)
below:
in which:
• R denotes a hydrogen atom or an acetyl group;
• Y denotes a radical chosen from OR' and NAR";
' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-C20
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms
or groups chosen from N, O, -CO- or a combination thereof such as
-NHCO- or -NHCONH-, and/or optionally substituted with one or more
identical or
different groups chosen from:
i) -OR5
ii) -SR5
iii) -NR6R7
iv) -CONHR6
v) -CONR6R7
vi) -COOR6
vii) -NHCONHR6
viii) -C(O)-(C1 -C4)alkyl
ix) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
R5 being chosen from H, a saturated linear C 1-C1 0 or branched C3-C1 0
or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based group;
R6 and R7, which may be identical or different, being chosen from H, a
saturated linear C1-C1 0 or branched C3-C1 0 or unsaturated C2-C1 0 or
cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group;
R6 and R7 possibly forming, with the nitrogen atom that bears them, a 5-
to 8-membered heterocycle which may contain one or more heteroatoms
or groups chosen from
N, O and-CO- and/or optionally substituted with a C 1-C1 0 hydrocarbonbased
chain;
A denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-
C20 or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms
or groups chosen from N, O, -CO- or a combination thereof such as
-NHCO- or -NHCONH-, and/or optionally substituted with one or more
identical or
different groups chosen from:
i) - OR 5
ii) -SR1 5
iii) -NR1 6R1 7
iv) -CONHR1 6
v) -CONR1 6R 7
vi) -COOR1 6
vii) -NHCONHR1 6
viii) -C(O)-(C1 -C4)alkyl
ix) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy
and C 1-C8 alkyl groups;
xi) -NH-C=NH(NH 2) (guanidine group)
d) -NR1 2R1 3;
e) -OR14;
f) -C(O)NHR14;
g) C(O)-(C1-C1 0)alkyl
R12 and R13, which may be identical or different, denoting a radical
chosen from:
a) -H;
b) a saturated linear C 1-C1 0 or unsaturated C2-C1 0 or branched C3-C1 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more groups, which may be identical or different, chosen from -OR5;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals; R 12 and
R 3 possibly forming, with the nitrogen that bears them, a 5- to 8-
membered heterocycle, which may contain one or more heteroatoms or
groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain optionally containing one or more
radicals chosen from hydroxyl and C 1-C4 alkoxy;
R14 denoting a radical chosen from:
a) -H;
b) a saturated linear C 1-C1 0 or branched C3-C1 0 or cyclic C3-C8 alkyl
group, optionally substituted with one or more groups, which may be
identical or different,
chosen from:
i) -COOR1 6;
ii) a C5-C 2 (hetero)aryl radical, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C -C8 alkoxy radicals;
c) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
R15 being chosen from H, a saturated linear C 1-C 0 or branched C3-
C 10 or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based
group;
R16 and R17, which may be identical or different, being chosen from H
and a saturated linear C 1-C1 0 or branched C3-C1 0 or unsaturated C2-
C 10 or cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group; an acetyl radical;
R16 and R17 possibly forming, with the nitrogen that bears them, a 5- to
8-membered heterocycle, which may contain one or more heteroatoms
or groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain;
' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-C20
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more identical or different groups chosen from:
i) -OR25
ii) -SR25
iii) -NR26R27
iv) -CONHR26
v) -CONR26R27
vi) -COOR26
vii) -NHCONHR26
viii) -C(O)-(C1 -C4)alkyl
ix) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
R25 being chosen from H, a saturated linear C 1-C1 0 or branched C3-
C 10 or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based
group;
R26 and R27, which may be identical or different, being chosen from H, a
saturated linear C1-C1 0 or branched C3-C1 0 or unsaturated C2-C1 0 or
cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group; R26 and R27 possibly forming, with the
nitrogen that bears them, a 5- to 8-membered heterocycle, which may
contain one or more heteroatoms or groups chosen from N, O and -COand/
or optionally substituted with a C1-C1 0 hydrocarbon-based chain;
it being understood that A and R" may form, with the nitrogen atom that bears
them, a saturated or unsaturated 5- to 8-membered heterocycle, which may
contain one or more heteroatoms or groups chosen from N, O and -CO- and/or
optionally substituted with a C1-C1 0 hydrocarbon-based chain or C1-C1 0
hydroxyalkyl or CO2T, T denoting a hydrogen atom or a saturated linear C1-
C 10 or branched C3-C1 0 alkyl radical,
and the salts thereof, the solvates thereof, the optical isomers thereof and the
racemic mixtures thereof, alone or as a mixture.
When a radical ( 1 ) may be substituted with one or more radicals (2) as specified
previously, preferentially, the said radical ( 1 ) may be substituted with 1 to 3
radicals (2) as specified previously.
When a cyclic radical ( 1') optionally contains one or more heteroatoms or
groups as specified previously, preferentially, the said cyclic radical ( 1')
optionally contains 1 to 3 heteroatoms or groups as specified previously.
The salts of the compounds of formula (I) comprise conventional non-toxic salts
of the said compounds, such as those formed from acid or base.
Mention may be made, as salts of the compound of formula (I) (when it
comprises a quaternizable nitrogen atom), of:
a) the salts obtained by addition of the compound (I) to a mineral acid, chosen
in particular from hydrochloric, boric, hydrobromic, hydriodic, sulfuric, nitric,
carbonic, phosphoric or tetrafluoroboric acid;
b) or the salts obtained by addition of the compound (I) to an organic acid,
chosen in particular from acetic, propionic, succinic, fumaric, lactic, glycolic,
citric, gluconic, salicylic, tartaric, terephthalic, methylsulfonic, ethylsulfonic,
benzenesulfonic, toluenesulfonic or triflic acid.
Mention may also be made of the salts obtained by addition of the compound of
formula (I) (when it comprises an acid group) to an mineral base, such as
sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium
hydroxide, magnesium hydroxide, lithium hydroxide, and the carbonates or
hydrogen carbonates of sodium, of potassium or of calcium, for example;
or to an organic base, such as a primary, secondary or tertiary alkylamine, for
example triethylamine or butylamine. This primary, secondary or tertiary
alkylamine can contain one or more nitrogen and/or oxygen atoms and can thus
contain, for example, one or more alcohol functional groups; mention may in
particular be made of 2-amino-2-methylpropanol, ethanolamine,
triethanolamine, 2-(dimethylamino)propanol, 2-amino-2-(hydroxymethyl)-1 ,3-
propanediol or 3-(dimethylamino)propylamine.
Mention may also be made of the salts of amino acids, such as, for example,
lysine, arginine, guanidine, glutamic acid or aspartic acid.
Advantageously, the salts of the compound of formula (I) (when it comprises an
acid group) can be chosen from alkali metal or alkaline-earth metal salts, such
as sodium, potassium, calcium or magnesium; or ammonium salts.
Advantageously, the salts of the compound of formula (I) (when it comprises a
quaternizable nitrogen atom) can be chosen from halides, such as chloride or
bromide, citrate, acetate, succinate, phosphate, lactate or tartrate.
The acceptable solvates of the compounds described in the present invention
comprise conventional solvates, such as those formed during the preparation of
the said compounds due to the presence of solvents. Mention may be made, by
way of example, of the solvates due to the presence of water or of linear or
branched alcohols, such as ethanol or isopropanol.
The optical isomers are in particular enantiomers and diastereoisomers.
In the context of the present invention:
a "(Cx-Cy)alkyl group" denotes an alkyl group comprising from x to y carbon
atoms. Such an alkyl group can be linear and saturated and can typically
include from 1 to 20 carbon atoms or also from 1 to 10 carbon atoms. It can
also be linear and unsaturated and can typically include from 2 to 20 carbon
atoms or also from 2 to 10 carbon atoms. It can also be branched and can
typically include from 3 to 20 carbon atoms or also from 3 to 10 carbon atoms.
An alkyl group can also be cyclic; it is then a cycloalkyl group, which can
typically include from 3 to 8 carbon atoms.
Unless otherwise indicated, a "(Cx-Cy)alkyl group" denotes a linear and
saturated alkyl group comprising from x to y carbon atoms.
Preferentially, the saturated or branched linear alkyl groups may be chosen
from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl, 2-ethylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,
pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
More preferentially, the saturated or branched linear alkyl groups may be
chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,
hexyl, heptyl, 2-ethylhexyl and octyl.
The cycloalkyl group may be chosen from: cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl.
- A "(Cx-Cy)alkoxy group" denotes a linear and if appropriate branched group
of formula -O(C x-Cy)alkyl which can typically include from 1 to 8 carbon atoms
or also from 1 to 4 carbon atoms.
The alkoxy group may be chosen from methoxy, ethoxy, propoxy and butoxy
and can more particularly be a methoxy group.
- A "saturated or unsaturated non-aromatic heterocycle group" denotes a
monocyclic or bicyclic carbocyclic 5- to 8-membered group containing one to
three heteroatoms or groups chosen from N, O, S and -C(O)-.
A heterocycle group may be chosen from piperidyl, morpholinyl, piperazinyl and
pyrrolidinyl. Preferentially, it is the piperidyl or morpholinyl ring.
- An "aryl group" denotes an unsaturated or partially unsaturated monocyclic or
bicyclic carbocyclic group including from 5 to 12 carbon atoms.
The aryl radicals may be chosen from phenyl, naphthyl, indenyl, fluorenyl and
anthracenyl. Preferably, it is the phenyl group.
- A "heteroaryl group" denotes a fused or non-fused, 5- to 22-membered
monocyclic or polycyclic group, comprising from 1 to 6 heteroatoms chosen
from nitrogen, oxygen and sulfur, and at least one ring of which is aromatic;
preferentially, a heteroaryl radical is chosen from acridinyl, benzimidazolyl,
benzobistriazolyl, benzopyrazolyl, benzopyridazinyl, benzoquinolyl,
benzothiazolyl, benzotriazolyl, benzoxazolyl, pyridyl, tetrazolyl, dihydrothiazolyl,
imidazopyridyl, imidazolyl, indolyl, isoquinolyl, naphthimidazolyl, naphthxazolyl,
naphthpyrazolyl, oxadiazolyl, oxazolyl, oxazolopyridyl, phenazinyl,
phenoxazolyl, pyrazinyl, pyrazolyl, pyrilyl, pyrazoyltriazyl, pyridyl,
pyridinoimidazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl,
thiazolopyridyl, thiazoylimidazolyl, thiopyrylyl, triazolyl, xanthyl and the
ammonium salt thereof;
The term "5- to 8-membered heterocycle which may contain one or more
heteroatoms or groups chosen from N and O" means in particular, in a nonlimiting
manner, piperidine, morpholine, piperazine, imidazole and pyrrolidine
rings. Preferentially, it is a piperidine or morpholine ring.
Preferably, the compounds of formula (I) have the following meanings:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' and NAR";
R' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C 0 or unsaturated C2-C 0 or branched C 0 or
cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more groups - OR 5; R15 being chosen from H and a saturated linear
C 1-C4 alkyl hydrocarbon-based group;
c) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
A denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-C20
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more identical or
different groups chosen from:
i) - OR 5
ii) -SR1 5
iii) -NR1 6R1 7
iv) -CONHR1 6
vi) -COOR1 6
ix) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
d) -NR1 2R1 3;
e) -OR14;
R12 and R13, which may be identical or different, denoting a radical
chosen from:
a) -H;
b) a saturated linear C 1-C4 alkyl group;
c) a phenyl group optionally substituted with one or more hydroxyls
and/or with one or more C 1-C8 alkoxy radicals;
R12 and R13 possibly forming, with the nitrogen that bears them, a 5- to
8-membered heterocycle, which may contain one or more heteroatoms
or groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain optionally containing one or more
radicals chosen from hydroxyl and C 1-C4 alkoxy;
R14 denoting a radical chosen from:
a) -H;
b) a saturated linear C 1-C1 0 alkyl group optionally substituted with one
or more identical or different phenyl radicals, the said phenyl radicals
being
optionally substituted with one or more hydroxyls and/or with one or more
C 1-C8 alkoxy radicals;
R15 being chosen from H, a saturated linear C 1-C 0 or branched C3-
C 10 or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based
group;
R16 and R17, which may be identical or different, being chosen from H
and a saturated linear C 1-C1 0 or branched C3-C1 0 or unsaturated C2-
C 10 or cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group; an acetyl radical;
R16 and R17 possibly forming, with the nitrogen that bears them, a 5- to
8-membered heterocycle, which may contain one or more heteroatoms
or groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C 0 hydrocarbon-based chain;
otes a radical chosen from:
a) -H;
b) a linear saturated C 1-C 0 or branched C3-C 0 alkyl group, optionally
substituted with one or more identical or different groups -OR25;
R25 being chosen from H and a saturated linear C 1-C1 0 alkyl
hydrocarbon-based group;
it being understood that A and R" may form, with the nitrogen atom that bears
them, a saturated or unsaturated 5- to 8-membered heterocycle, which may
contain one or more heteroatoms or groups chosen from N, O and -CO- and/or
optionally substituted with a C1-C4 hydrocarbon-based chain or C1-C4
hydroxyalkyl or CO2T, T denoting a hydrogen atom or a saturated linear C 1-C6
or branched C3-C6 alkyl radical,
and the salts thereof, the solvates thereof, the optical isomers thereof and the
racemic mixtures thereof, alone or as a mixture.
More preferentially, the compounds of formula (I) have the following meanings:
· R denotes a hydrogen atom;
• Y denotes a radical chosen from OR' and NAR";
R' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C1 0 or unsaturated C2-C1 0 or branched C3-C1 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
oxygen atoms, and/or optionally substituted with one or more hydroxyl,
methoxy or ethoxy groups;
A denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C1 0 or unsaturated C2-C1 0 or branched C3-C1 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
oxygen atoms, and/or optionally substituted with one or more identical or
different groups chosen from:
i) - OR 5
ii) -NR1 6R1 7
vi) -COOR1 6
ix) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals;
c) a phenyl group optionally substituted with one or more radicals chosen
from hydroxyl and/or methoxy and/or ethoxy;
d) -NR1 2R1 3;
e) -OR14;
R12 and R13, which may be identical or different, denoting a radical chosen
from:
a) -H;
b) a saturated linear C 1-C4 alkyl group;
c) a phenyl group optionally substituted with one or more hydroxyls
and/or with one or more C 1-C8 alkoxy radicals;
R14 denoting a radical chosen from:
a) -H;
b) a saturated linear C 1-C4 alkyl group optionally substituted with a
phenyl radical;
R15 being chosen from H and a saturated linear C 1-C4 or branched C3-C4
alkyl hydrocarbon-based group;
R16 and R17, which may be identical or different, being chosen from H and a
saturated linear C1-C1 0 or branched C3-C1 0 or unsaturated C2-C1 0 or cyclic
C3-C8 alkyl hydrocarbon-based group; a (C1 -C4)alkyl(hetero)(C6)aryl group
optionally containing a nitrogen atom, especially a benzyl group; an acetyl
radical;
R16 and R17 possibly forming, with the nitrogen that bears them, a 5- to 8-
membered heterocycle, which may contain one or more heteroatoms or groups
chosen from N, O and -CO- and/or optionally substituted with a C 1-C1 0
hydrocarbon-based chain;
R" denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C 0 or branched C3-C 0 alkyl group, optionally
substituted with one or more identical or different groups -OR25; R25
being chosen from H and a saturated linear C 1-C4 alkyl hydrocarbonbased
group;
it being understood that A and R" may form, with the nitrogen atom that bears
them, a saturated or unsaturated 5- to 8-membered heterocycle, which may
contain one or more heteroatoms or groups chosen from N, O and -CO- and/or
optionally substituted with a C1-C4 hydrocarbon-based chain or C1-C4
hydroxyalkyl or CO2T, T denoting a hydrogen atom or a saturated linear C1-C6
or branched C3-C6 alkyl radical;
and the salts thereof, the solvates thereof, the optical isomers thereof and the
racemic mixtures thereof, alone or as a mixture.
The particularly preferred products are chosen from:

2-(2,4-dihydroxybenzyl)-4-hydroxy-
N-[2-(4-hydroxy-3-
methoxyphenyl)-
ethyl]butyramide
OH
HO
ethyl N-[2-(2,4-dihydroxybenzyl)-4-
hydroxybutanoyl]prolinate
OH
2-(2,4-dihydroxybenzyl)-N-(2,3-
dihydroxypropyl)furfurylbutanamide
HO
ethyl N-[2-(2,4-dihydroxybenzyl)-4-
hydroxybutanoyl]valinate
OH
2-(2,4-dihydroxybenzyl)-N-(2,3-
dihydroxypropyl)phenylbutanamide
0 OH
2-(2,4-dihydroxybenzyl)-N-(2,3-
dihydroxypropyl)oxybutanamide
OH
0 OH 2-(2,4-dihydroxybenzyl)-N-(2,3-
dihydroxypropyl)benzyloxybutanamide
OH
0 OH
2-(2,4-dihydroxybenzyl)-N-(2,3-
dihydroxypropyl)butyric acid
hydrazide
OH
I 0 OH
2-(2,4-dihydroxybenzyl)-N-(2,3-
dihydroxypropyl)butyric acid N' ,N'-
dimethylhydrazide
OH
0 OH
2-(2,4-dihydroxybenzyl)-4-hydroxyethyl
butanoate
OH
I 0 OH
2-(2,4-dihydroxybenzyl)-4-hydroxyisopropyl
butanoate
OH
0 OH
2-(2,4-dihydroxybenzyl)-4-hydroxybutyl
butanoate
OH
0 OH
2-(2,4-dihydroxybenzyl)-4-hydroxyhexyl
butanoate
OH
0 OH
2-(2,4-dihydroxybenzyl)-4-hydroxybutyhc
acid 2,3-dihydroxypropyl
ester
OH
0
0 O acetic acid 5-acetoxy-2-(4-
acetoxy-
2-propylcarbamoylbutyl)phenyl
ester
0
0 OH
ethyl N-[2-(2,4-dihydroxybenzyl)-4-
1 OH hydroxybutanoyl]methioninate

and the salts thereof, the solvates thereof, the optical isomers thereof and the
racemic mixtures thereof, alone or as a mixture.
Among these compounds, the most particularly preferred compounds in the
context of the present invention are the following: compounds 1 to 6, 12 to 25,
3 1, 33 and 59, and salts thereof, solvates thereof, isomers thereof and racemic
mixtures thereof, taken alone or as a mixture.
The compounds of the invention of formula (I) may be prepared according to the
following synthetic routes:
Resorcinol (A1 ) is reacted with itaconic acid (B) or its anhydride (B') or one of its
esters of formula (B1 )
B1
in which R denotes H or a linear C1-C6 or branched C3-C6 alkyl group,
to form a compound C, and this compound is then activated to form a
heterocycle of formula (III), which is then subjected to a reduction step to form
the intermediate (IV) which gives access to the compounds (V).
The intermediate of formula (IV) may also be accessed directly by reacting
resorcinol (A1 ) with tulipaline (3-methylenedihydrofuran-2-one) (A2).
This step makes it possible to arrive directly at the compounds of formula (I) by
reaction of derivatives YH. One variant consists in treating (IV) with an alcohol
ROH to give the compounds (V), which, by reaction with YH, lead to (I).
To obtain the other compounds of formula (I),
compound C (R other than H) is reacted with a derivative YH = NHR"A in which
A, R' and R" have the same meaning as described previously for the
compounds of formula (I), optionally in the presence of a basic or acidic
catalyst, optionally by heating to a temperature of between 15 and 200°C. This
leads to the compounds of formula (VI), which, when subjected to a selective
reduction of ester versus amide, makes it possible to obtain the compounds (I).
The final step is optionally an acetylation reaction (compounds of formula (I) for
which R = acetyl).
The reaction of resorcinol (A1 ) in the presence of itaconic acid (B) or its
anhydride (B') or one of its esters of formula (B1 ) which are described above, in
order to form the compound C, is especially performed in the presence of an
organic solvent which may be chosen from toluene, tetrahydrofuran, heptane,
isooctane, methyltetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone,
dioxane, ethyl acetate, isopropyl acetate, isododecane and mixtures thereof, in
particular at a temperature of between 15 and 200°C, optionally in the presence
of a catalyst (acidic or basic) as described in the publications: Synthesis of 7-
hydroxycoumarins via the Pechmann reaction using Nafion resin/silica
nanocomposites as catalysts: Laufer MC, Hausmann H and Holderich WF, J. of
Catalysis, 2003, 2 18, 3 15-320; Synthesis of 7-hydroxycoumarins catalysed by
solid acid catalysts: Hoefnagel A, Gunnewegh E, Downing R and van Bekkum
H, J. Chem. Soc, Chem. Commun., 1995, 225-226; in particular in the
presence of an acid catalyst, such as methanesulfonic acid, triflic acid, paratoluenesulfonic
acid or sulfonic resins, such as the Dowex® products or the
Amberlyst® products (sold by the company Aldrich).
The compounds (B1 ) may be obtained in a known way by selective
esterification in an acidic medium of itaconic acid with one or more alcohols of
formula ROH, as described in the literature (Selective esterification of nonconjugated
carboxylic acids in the presence of conjugated or aromatic
carboxylic acids over active carbon supported methanesulfonic acid; Feng, Ze
Wang, Zhao, Xin Qi and Bi, Hua, Science in China, Series B: Chemistry (2008),
1( 10), 990-992 / An efficient and regiospecific estenfication of dioic acids using
PTSA; Devi, A. Rama and 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 by
selective esterification of the nonconjugated carboxyl group in the presence of
an aromatic or conjugated carboxyl group; Ram, Ram N. and Meher, Nabin
Kumar, Journal of Chemical Research, Synopses (2000), (6), 282-283).
According to a specific embodiment of the process of synthesis, when the R
group of the compound C denotes H, the compound of formula (I) may be
obtained by activation of the acid C according to the known acid activation
methods, described especially in Comprehensive Organic Transformations by
R. Larock, published by Wiley VCH, in the chapter Interconversion of nitriles,
carboxylic acids and derivatives.
Compound C in acid form is then esterified in the presence of ethanol under
standard conditions of heating (between 15 and 100°C) and of acid catalysis to
give a carboxylic acid ethyl ester derivative (A3), which, when activated
according to the known acid activation methods, described especially in
Comprehensive Organic Transformations by R. Larock, published by Wiley
VCH, in the chapter Interconversion of nitriles, carboxylic acids and derivatives,
leads to the heptacyclic lactone of formula (III). This lactone, subjected to a
reduction with hydride, gives the compound of formula (IV) after acidic work-up.
This reduction may be performed between -30 and +60°C in protic or aprotic
solvents (tetrahydrofuran, dioxane, ethanol, methanol) with metal hydride
donors, such as sodium borohydride, sodium triacetoxyborohydride or
diisobutylaluminium hydride.
The reaction of resorcinol (A1 ) in the presence of tulipaline (3-methylenedihydrofuran-
2-one) (A2), and leading to compound (IV), is especially performed
in the presence of an organic solvent which may be chosen from toluene,
tetrahydrofuran, heptane, isooctane, methyltetrahydrofu ran, methyl ethyl
ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate and
isododecane, and mixtures thereof, especially at a temperature of between 15
and 200°C, optionally in the presence of a catalyst (acidic or basic) as
described in the publications: Synthesis of 7-hydroxycoumarins by Pechmann
reaction using Nafion resin/silica nanocomposites as catalysts: Laufer MC,
Hausmann H and Holderich WF, J. of Catalysis, 2003, 2 18, 3 15-320; Synthesis
of 7-hydroxycoumarins catalysed by solid acid catalysts: Hoefnagel A,
Gunnewegh E, Downing R and van Bekkum H, J. Chem. Soc, Chem.
Commun., 1995, 225-226; in particular in the presence of an acid catalyst, such
as methanesulfonic acid, triflic acid, para-toluenesulfonic acid or sulfonic resins,
such as the Dowex® products or the Amberlyst® products (sold by the
company Aldrich).
The reaction of the compound of formula (IV) with a compound of formula YH
is optionally performed in the presence of an organic solvent, in particular
tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2-
methyltetrahydrofuran, dichloromethane, toluene, methanol or ethanol,
optionally in the presence of a catalyst chosen from acid catalysts of Lewis or
Bronsted type or basic catalysts, such as potassium carbonate, triethylamine or
diisopropylethylamine;
optionally by heating to a temperature of between 15°C and 200°C, in particular
between 30°C and 150°C.
It should be noted that the lactone (IV) may be in equilibrium with the ethyl ester
form (IV) in the presence of ethanol. The acyclic ester can then react with YH
compounds in order to result in the compounds (I).
Alternatively, if R is other than H, the compounds of formula (I) may be obtained
by opening the lactone C with derivatives YH, for example and especially the
amines (YH = NHR"A), having the same meaning as described previously for
the compounds of formula (I), optionally in the presence of a protic or aprotic
organic solvent, especially tetrahydrofuran, dioxane, dimethylformamide,
dimethyl sulfoxide, 2-methyltetrahydrofuran, dichloromethane, methanol or
ethanol;
optionally in the presence of a catalyst chosen from acid catalysts of Lewis or
Bronsted type or basic catalysts, such as potassium carbonate, triethylamine or
diisopropylethylamine;
optionally by heating to a temperature of between 15°C and 200°C, in particular
between 30°C and 150°C.
The compounds (VI) for which R = ethyl are thus obtained. These compounds
are then subjected to a reduction with hydride to give the compounds I after
acidic work-up. This reduction may be performed at between -30 and +60°C in
protic or aprotic solvents (tetrahydrofuran, dioxane, ethanol, methanol) with
metal hydride donors, such as sodium borohydride, sodium
triacetoxyborohydride or diisobutylaluminium hydride.
The compounds of formula (I) for which R denotes an acetyl group may be
obtained by acetylation of compounds of formula (I) for which R = H.
The acetylation reaction may be carried out with acetic anhydride or acetyl
chloride, in particular 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 functional groups which must not be acetylated and by then carrying out a
deprotection reaction, according to the known techniques of organic synthesis.
Mention may be made, as acid activation methods, of:
- the intermediate formation of acid chloride (for example by using thionyl or
oxalyl chloride, or 1-chloro-N,N,2-trimethyl-1 -propenamine),
- the intermediate formation of a mixed anhydride (for example by using a C2-C6
alkyl chloroformate, such as isobutyl chloroformate, in the presence of a base,
for instance triethylamine or diisopropylethylamine, ;
- the intermediate formation of carbamimidate or of acylphosphonate (for
example by 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 1-2217).
All of these steps may also resort to protection/deprotection strategies normally
used in organic chemistry and compiled in the book Protecting Groups in
Organic Synthesis, Greene and Wuts, Wiley Interscience, as a function of the
nature of the radicals R', A and R".
In addition, when the final compounds (I) bear a free carboxylic acid on the
radical A or R", these compounds may be obtained by saponification using
mineral bases, for instance NaOH or LiOH, in the presence of protic or aprotic
solvents, for instance ethanol or tetrahydrofuran or water, at temperatures
ranging between 0 and 100°C. The salts obtained are then re-acidified in the
presence of conventional mineral or organic acids, for instance hydrochloric
acid or citric acid.
The compounds of formula (I) according to the invention have a very particular
application in the cosmetics field.
The composition according to the invention comprises, in a physiologically
acceptable medium, a compound of formula (I) as described above.
The term "physiologically acceptable medium" is understood to mean a medium
that is compatible with human keratin materials, such as bodily skin or facial
skin, the lips, mucous membranes, the eyelashes, the nails, the scalp and/or
the hair.
Compound (I) may be present in the composition according to the invention in
an amount that may be between 0.01 % and 10% by weight, preferably between
0.1 % and 5% by weight and especially 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 can comprise adjuvants normally employed in the cosmetics
field.
Mention may especially be made of water, organic solvents, in particular C2-C6
alcohols, oils, especially hydrocarbon-based oils or silicone oils, waxes,
pigments, fillers, dyes, surfactants, emulsifiers, cosmetic active agents, UV
screening agents, polymers, thickeners, preserving agents, fragrances,
bactericides, odour absorbers or antioxidants.
These optional cosmetic adjuvants may be present in the composition in a
proportion of 0.001 % to 80% by weight and especially 0.1 % to 40% by weight
relative to the total weight of the composition. In any case, these adjuvants, and
the proportions thereof, will be chosen by a person skilled in the art so that the
advantageous properties of the compounds according to the invention are not,
or not substantially, adversely affected by the envisaged addition.
As active agents, it will be advantageous to introduce, into the composition
according to the invention, at least one compound chosen from: desquamating
agents; calmatives; organic or mineral photoprotective agents; moisturizers;
depigmenting agents; antiglycation agents; NO-synthase inhibitors; agents
which stimulate the synthesis of dermal or epidermal macromolecules and/or
which prevent their decomposition; agents which stimulate the proliferation of
fibroblasts and/or keratinocytes or which stimulate the differentiation of
keratinocytes; muscle relaxants and/or dermo-decontracting agents; tensioning
agents; antipollution agents and/or free-radical scavengers; agents which act on
the capillary circulation; agents which 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 phytohormones; marine
extracts, such as algal extracts; bacterial extracts; sapogenins such as
diosgenin and extracts of wild yam containing the same; ceramides; hydroxy
acids, such as salicylic acid and 5-n-octanoylsalicylic acid; resveratrol;
oligopeptides and pseudodipeptides and acylated derivatives thereof;
manganese salts and magnesium salts, in particular gluconates; and mixtures
thereof.
The term "desquamating agent" is understood to mean any compound capable
of having an effect:
- either directly on desquamation by promoting exfoliation, such as b-hydroxy
acids, in particular salicylic acid and its derivatives (including 5-(noctanoyl)
salicylic acid); c -hydroxy acids, such as glycolic, citric, lactic, tartaric,
malic or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid;
Saphora japonica extract; or resveratrol;
- or on the enzymes involved in desquamation or decomposition of the
corneodesmosomes, such as glycosidases, stratum corneum chymotryptic
enzyme (SCCE) or indeed even other proteases (trypsin, chymotrypsin-like).
Mention may be made of agents which chelate mineral salts: EDTA; N-acylN
,N' ,N'-ethylenediaminetriacetic acid; aminosulfonic compounds, in particular
N-(2-hydroxyethyl)piperazine-N-2-ethanesulfonic acid (HEPES); 2-
oxothiazolidine-4-carboxylic acid (procysteine) derivatives; derivatives of
a-amino acids of glycine type (such as described in EP 0 852 949, and also
sodium methyl glycine diacetate, sold by BASF under the trade name Trilon M);
honey; or sugar derivatives, such as O-octanoyl-6-D-maltose and Nacetylglucosamine.
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.
As calmatives that may be used in the composition according to the invention,
mention may be made of: pentacyclic triterpenes and extracts of plants (for
example Glycyrrhiza glabra) comprising the same, such as b-glycyrrhetinic acid
and its salts and/or its derivatives (glycyrrhetinic acid monoglucuronide, stearyl
glycyrrhetinate, 3-(stearoyloxy)glycyrrhetic acid), ursolic acid and its salts,
oleanolic acid and its salts, betulinic acid and its salts, a Paeonia suffruticosa
and/or lactiflora extract, salicylic acid salts and in particular zinc salicylate,
phycosaccharides from the company Codif, a Laminaria saccharina extract,
canola oil, bisabolol, 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 or fish oil, plankton extracts,
capryloyi glycine, Seppicalm VG (sodium palmitoylproline and Nymphaea alba)
from SEPPIC, a Pygeum extract, a Boswellia serrata extract, a Centipeda
cunninghamii extract, a Helianthus annuus extract, a Linum usitatissimum
extract, tocotrienols, Co/a nitida extracts, piperonal, a clove extract, an
Epilobium angustifolium extract, aloe vera, a Bacopa moniera extract,
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 photoprotective agents are chosen in particular 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
and EP 944 624; benzophenone derivatives; b,b-diphenylacrylate derivatives;
benzotriazole derivatives; benzalmalonate derivatives; benzimidazole
derivatives; imidazolines; bis-benzazolyl derivatives, such as described in
patents EP 669 323 and US 2 463 264; p-aminobenzoic acid (PABA)
derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives, such as
described in patent applications US 5 237 071 , US 5 166 355, GB 2 303 549,
DE1 97261 84 and EP 893 119; screening polymers and screening silicones,
such as those described in particular in patent application WO-93/04665; c -
alkylstyrene-based dimers, such as those described in patent application
DE1 9855649; and merocyanin derivatives, such as those described in patent
applications WO 201 1 1371 9 and FR 2 957 251 .
The mineral photoprotective agents may be chosen in particular from coated or
non-coated metal oxide pigments or nanopigments (mean size of the primary
particles generally of between 5 nm and 100 nm, preferably between 10 nm and
50 nm), for instance titanium oxide (amorphous or crystallized in rutile and/or
anatase form), iron oxide, zinc oxide, zirconium oxide or cerium oxide
nanopigments, which are all well-known UV photoprotective agents.
Conventional coating agents are furthermore alumina and/or aluminium
stearate. Such coated or non-coated metal oxide nanopigments are described
in particular in patent applications EP 5 18 772 and EP 5 18 773.
The photoprotective agents 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 galenical form
normally used in the cosmetics field and in particular in the form of an aqueous
or aqueous/alcoholic solution, which is optionally gelled, a dispersion of the
lotion type, optionally comprising two phases, an oil-in-water or water-in-oil or
multiple (W/O/W or O/W/O, for example) emulsion, an aqueous gel, a
dispersion of oil in an aqueous phase using 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 an
aqueous or oily gel. These compositions are prepared according to the usual
methods. Use is preferably made, according to this invention, of a composition
in the form of an emulsion, in particular an oil-in-water emulsion.
The composition according to the invention can constitute a composition for
caring for the skin and in particular a cleansing, protecting, treating 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, make-up-removing
creams, foundation creams or anti-sun creams); a fluid foundation; a make-upremoving
milk, a protective or care body milk or an anti-sun milk; or a lotion, gel
or mousse for caring for the skin, such as a cleansing lotion.
The invention is illustrated in more detail by the following non-limiting examples.
Method 1 for obtaining the compounds (I):
a) Synthesis of 3-(2,4-dihydroxybenzyl)dihydrofuran-2(3H)-one of formula (IV)
To a solution of 11 g of resorcinol and 10 g of 3-methylenedihydrofuran-2-one
(CAS 547-65-9) in 100 ml of a 50/50 toluene/isooctane mixture are added 20 g
of Amberlyst 15 resin from Aldrich. The reaction mixture is heated at 120°C for
72 hours with, if necessary, addition of further resin. After cooling, 100 ml of
methyltetrahydrofuran are added and the reaction medium is stirred for 1 hour.
The mixture is filtered and the filtrate is concentrated under vacuum before
purifying on a column of silica (eluent: 60/40 heptane/ethyl acetate) to give a
colourless oil which may solidify, corresponding to compound IV (14% yield).
The 1H NMR and mass spectra are in accordance with the structure of the
expected product (IV).
b) Compound IV is reacted with compound YH, used as reagent and solvent
when YH is liquid, for example when YH is an amine (3 equivalents), and the
reaction medium is then maintained at 60°C for 2 hours.
In the case where YH is solid, methyltetrahydrofuran can be added in a
sufficient amount to dissolve the reaction medium.
At the end of the reaction, the reaction medium is concentrated under vacuum.
The crude product is dissolved in methyltetrahydrofuran, washed with a 0.1 N
hydrochloric acid solution and then washed with water. The organic phase is
collected, dried over magnesium sulfate and concentrated under vacuum. The
crude product is purified on a chromatography column to give the expected
product.
Method 2 for obtaining the compounds (I):
a) Production of the lactone (III) in acid form
10 g of resorcinol and 11.8 g of itaconic acid were dissolved in 150 ml of
a toluene/dioxane mixture (1/1 ratio by volume) in the presence of
Amberlyst 15 resin from Aldrich in a round-bottomed flask equipped with
a Dean and Stark apparatus. The reaction medium was heated at 100°C
for 3 hours. After cooling, the crude reaction product was filtered and the
filtrate was concentrated under vacuum. The crude product was
recrystallized under hot conditions from ethyl acetate. 10 g of a white
powder corresponding to the expected product were obtained (yield of
50%).
Melting point: 174-1 75°C. The 1H NMR and mass spectra are in
accordance with the structure of the expected product
b) Production of the heptacyclic lactone III
11 -a III
Compound I I ( 1 .6 mmol) in acid form is refluxed in ethanol (5 ml) for 2
hours. After concentrating under vacuum, the residue is purified on a
column of silica (eluent: 1/1 heptane/ethyl acetate) to give 300 mg of a
colourless oil (70% yield) characterized by NMR and MS as compound IIa
: 2-(2,4-Dihydroxybenzyl)succinic acid 1-ethyl ester. This synthesis may
be extrapolated to a larger scale enabling the intermediate to be
accumulated in larger amount.
Compound ll-a (2 g) is dissolved in 20 ml of dichloromethane, followed
by addition of 1.25 eq. of EDCI ( 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide), 1.25 eq. of HOBT
(hydroxybenzotriazole) and 3 eq. of triethylamine. The reaction medium
is stirred at room temperature for 2 hours. After concentrating under
vacuum, the crude product is purified on a column of silica (2/1
heptane/ethyl acetate) to give compound III in the form of a pale yellow
oil (44% yield). The 1H NMR and mass spectra are in accordance with
the structure of the expected product (III).
c)Synthesis of compound (IV) from (III):
To a solution of 0.34 mmol of III in 2 ml of tetrahydrofuran are added 1.1
eq. (0.37 mmol) of sodium borohydride at room temperature. After
stirring for 1 hour, the reaction is stopped by addition of 1N hydrochloric
acid. The mixture is then extracted three times with ethyl acetate. The
organic phase is dried over sodium sulfate and then concentrated to
dryness under vacuum. The crude product is purified on a column of
silica (heptane/ethyl acetate) to give compound IV in the form of a very
pale yellow pasty solid (60% yield). The 1H NMR and mass spectra are in
accordance with the structure of the expected product (IV).
d) Compound (IV) is added to compound YH, used as reagent and solvent,
for example an amine (3 equivalents), and the reaction medium is then
maintained at 60°C for 2 hours.
In the case where YH is solid, methyltetrahydrofuran is added in a sufficient
amount to dissolve the reaction medium.
At the end of the reaction, the medium is concentrated under vacuum. The
crude product is dissolved in methyltetrahydrofuran, washed with a 0.1 N
hydrochloric acid solution and then washed with water. The organic phase is
collected, dried over sodium sulfate and concentrated under vacuum. The
crude product is purified on a chromatography column to give the expected
product.
Method 3 for obtaininq the compounds (I): in the case where YH is a secondary
amino derivative, for example
a) Synthesis of ethyl 7-hydroxy-2-oxo-3,4-dihydro-2H-chromen-3-yl)acetate (II
in ethyl ester form):
4.4 g (0.04 mol) of resorcinol and 6.32 g (0.04 mol) of itaconic acid ethyl
half-ester, and also 8.8 g of Amberlyst 15 resin from Aldrich, were added
to 100 ml of toluene. The reaction mixture was refluxed and stirred for 2
hours and then filtered after cooling. The filtrate was concentrated and
purified by chromatography on a column of silica (eluent: 50/1
CH2Cl2/MeOH) to give, after recrystallization from a 3/1 hexane/ethyl
acetate mixture, 4.6 g (46% yield) of the expected lactone in the form of a
white solid.
Melting point: 02-1 03°C
The 1H NMR and mass spectra are in accordance with the structure of
the expected product.
b) Synthesis of the acyclic amido-ethyl ester:
To a solution of 2 g (8 mmol) of ethyl(7-hydroxy-2-oxo-3,4-dihydro-2Hchromen-
3-yl)acetate are added 20 ml of the secondary amine as
reagent and solvent. The mixture is heated at 80°C for 3 hours. After
concentrating under vacuum, the crude reaction product is purified by
chromatography on a column of silica (eluent: 30/1
dichloromethane/methanol) to give the desired compound.
c) Reduction of the ester function:
The amido-ethyl ester (4.27 mmol) obtained previously is dissolved in 30
ml of tetrahydrofuran. 3 equivalents of lithium aluminium hydride are
added at room temperature. After stirring for 3 hours, methanol is added
and the reaction medium is then concentrated under vacuum. The crude
reaction product is then purified on a column of silica (eluent:
dichloromethane/methanol) to give the desired product (I).
Example 1: synthesis of compound 1: Method 1 starting with compound (IV)
12 g of compound IV and 6 equivalents of ethyl phenylalaninate (67 g) are
placed in a round-bottomed flask. The reaction medium is heated at 140°C for 3
hours. After cooling, the reaction medium is filtered. The filtrate is taken up in
ethyl acetate and washed twice with 1N hydrochloric acid. After drying the
organic phase over sodium sulfate and concentrating under vacuum, an
orange-coloured oil is obtained ( 18 g). This oil is taken up in diisopropyl ether to
give, after precipitation and filtration, 12.6 g (52% yield) of a pale yellow solid
corresponding to compound 1, in the form of a mixture of two diastereoisomers
in a 52/48 ratio determined by 1H NMR.
The 1H NMR and mass spectra are in accordance with the structure of the
expected mixture of diastereoisomers.
Example 2: synthesis of compound 3 : Method 2 starting with compound IV
3.3 g of compound IV and 4.4 equivalents of ethyl glycinate ( 1 .5 g) are placed in
a round-bottomed flask. The reaction medium is heated at 130°C for 2 hours.
After cooling, the reaction medium is diluted in methanol and filtered. The filtrate
is concentrated under vacuum to give, after purification on a column of silica
(eluent: 40/1 dichloromethane/methanol), 260 mg of a white solid corresponding
to compound 3 (25% yield).
The 1H NMR and mass spectra are in accordance with the structure of the
expected product
m.p.: 5 1-54°C
Example 3: synthesis of compound 9 : saponification of compound 3
800 mg of compound 3 are placed in 15 ml of tetrahydrofuran, and 4.5 ml of 2N
lithium hydroxide solution are added dropwise. After stirring for 2 hours, the
reaction is acidified to pH 2 with 1N hydrochloric acid. After concentrating under
vacuum, the residue is purified by column chromatography on silica (eluent:
1/30 methanol/dichloromethane) to give the acid compound 4 in the form of a
white solid. (Yield = 44%).
The 1H NMR and mass spectra are in accordance with the structure of the
expected product
m.p.: 55-60°C
Example 4: synthesis of compound 24: method 3
A mixture of 2 g of compound I I (ethyl ester form) and 20 ml of diethylamine is
heated at 80°C for 3 hours. After cooling, the mixture is concentrated under
vacuum. The crude product obtained is purified by chromatography on a column
of silica (eluent: 30/1 dichloromethane/methanol). The desired amido-ester is
thus obtained in the form of a white solid in a yield of 43%.
1.37 g of this product are then placed in 30 ml of tetrahydrofuran, and 0.47 g (3
equivalents) of LiAIH is added portionwise. After stirring at room temperature
for 3 hours, cold methanol is added to the reaction medium. The medium is
concentrated under vacuum and the residue is then purified on a column of
silica (30/1 dichloromethane/methanol), to give 192 mg of a white solid
corresponding to compound 24 ( 15% yield).
The 1H NMR and mass spectra are in accordance with the structure of the
expected product.
m.p.: 128-1 30°C
Examples 5 to 32: Synthesis of the compounds (including those
mentioned previously)
The same procedure was carried out as in the examples described above,
using a different amine specified in the table below:

Example 33: Example of separation of the diastereoisomers and
characterization of the latter
Compound 1 is subjected to a preferential crystallization in hot dichloromethane
(20 volumes w/w). A diastereoisomer precipitates out ( 1-a) during the
temperature decrease. The second one is present in the filtrate ( 1-b).
Another method consists in and performing a separation using a preparative
HPLC system.
Instrument: SFC-80 (Thar, Waters)
Column: Chiralpak OJ-H 30*250 mm 5 urn (Daicel)
Column temperature: 40°C
Mobile phase: CO2/ Ethanol = 85/1 5
Flow: 80 g/min
Back pressure: 100 bar
Cycle time of stack injection: 4.4 min
Load per injection: 23 mg
Retention time of the first diastereoisomer ( 1-a): 3.07 min
Retention time of the second diastereoisomer ( 1-b): 3.95 min
The 1H NMR and mass spectra are in accordance with the structures of the 2
expected products. Product 1 indeed corresponds to mixtures of 1-a and 1-b.
Example 34: Demonstration of the activity with regard to constitutive
melanogenesis
A biological test demonstrated the depigmenting activity of the compounds I .
The modulating effect on melanogenesis of compound 1 was measured
according to the method described in patent FR-A-2 734 825, and in the article
by R. Schmidt, P. Krien and M. Regnier, Anal. Biochem., 235(2), 113-1 8, 1996.
This test is carried out on a coculture of keratinocytes and melanocytes.
For the test compound, the following were determined:
- the cytotoxicity, by estimating the incorporation of leucine,
- the inhibitory activity on melanin synthesis, by estimating the ratio of the
incorporation of thiouracil to the incorporation of leucine, relative to 100% for
the control (the control corresponds to the test performed without test
compound). The IC5o (concentration for which 50% of the synthesis of the
melanin is inhibited) values were determined.
The test was also carried out with arbutin and kojic acid, which are known
depigmenting compounds.
The results are collated in the following table:
The compounds according to the invention are thus shown to be effective in
inhibiting melanogenesis and are furthermore more effective than arbutin and
kojic acid.
TEST on pigmented reconstructed epidermis samples
Compositions comprising 300 mM of compound 1 in DMSO were applied to
samples of pigmented reconstructed epidermis (cf. EP 1 878 790). The control
is DMSO. The melanin was quantified by image analysis on histological slices
after staining with Fontana Masson dye. Each sample of coloured epidermis is
photographed over its entire length using a camera connected to a microscope.
The melanin is thresholded and the number of melanin pixels is measured in
each field using automated image analysis software. A non-parametric
statistical test is performed in order to determine the significance of the
measurements (Mann-Whitney test).
The pigmented reconstructed epidermis standard study model was published
by:
Regnier M, Duval C, Galey JB, Philippe M, Lagrange A, Tuloup R, Schmidt R,
Cellular and Molecular Biology, 1999, 45, 7, 969-980: "Keratinocyte-Melanocyte
co-cultures and pigmented reconstructed human epidermis: models to study
modulation of melanogenesis".
Significant depigmenting activity was evaluated at 300 mM for compound 1
(pValue < 0.05: significant depigmenting activity).
Example 35: Use of a cosmetic formulation
A depigmenting gel for the skin is prepared, comprising (% by weight):
Compound 1 (Example 1) 2%
Carbomer (Carbopol 981 from Lubrizol) 1%
Preserving agent qs
Water qs 100%
The composition, applied to the skin, makes it possible to attenuate brown
blemishes.
Similar compositions are prepared with compounds 5, 6 and 18.

WE CLAIMS:-
1. Compounds of formula (I):
in which:
• R denotes a hydrogen atom or an acetyl group;
· Y denotes a radical chosen from OR' and NAR";
R' denotes a radical chosen from:
a) -H;
b) a linear saturated C -C20 or unsaturated C2-C20 or branched C3-C20
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms
or groups chosen from N, O, -CO- or a combination thereof such as
-NHCO- or -NHCONH-, and/or optionally substituted with one or more
identical or
different groups chosen from:
i) -OR5
ii) -SR5
iii) -NR6R7
iv) -CONHR6
v) -CONR6R7
vi) -COOR6
vii) -NHCONHR6
viii) -C(O)-(C1 -C4)alkyl
ix) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
2013/189930 PCT/EP2013/062623
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy
and C 1-C8 alkyl groups;
R5 being chosen from H, a saturated linear C 1-C1 0 or branched C3-C1 0
or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based group;
R6 and R7, which may be identical or different, being chosen from H, a
saturated linear C1-C1 0 or branched C3-C1 0 or unsaturated C2-C1 0 or
cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group;
R6 and R7 possibly forming, with the nitrogen atom that bears them, a 5-
to 8-membered heterocycle which may contain one or more heteroatoms
or groups chosen from
N, O and-CO- and/or optionally substituted with a C 1-C1 0 hydrocarbonbased
chain;
A denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-
C20 or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms
or groups chosen from N, O, -CO- or a combination thereof such as
-NHCO- or -NHCONH-, and/or optionally substituted with one or more
identical or
different groups chosen from:
i) -OR1 5
ii) -SR1 5
iii) -NR1 6R1 7
iv) -CONHR1 6
v) -CONR1 6R1 7
vi) -COOR1 6
vii) -NHCONHR1 6
viii) -C(O)-(C1 -C4)alkyl
89930 PCT/EP2013/062623
ix) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy
and C 1-C8 alkyl groups;
xi) -NH-C=NH(NH 2) (guanidine group)
d) -NR1 2R1 3;
e) -OR14;
f) -C(O)NHR14;
g) C(O)-(C1-C1 0)alkyl
R12 and R13, which may be identical or different, denoting a radical
chosen from:
a) -H;
b) a saturated linear C 1-C 0 or unsaturated C2-C 0 or branched C3-C 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more groups, which may be identical or different, chosen from -OR5;
c) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals; R2 and
R3 possibly forming, with the nitrogen that bears them, a 5- to 8-
membered heterocycle, which may contain one or more heteroatoms or
groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain optionally containing one or more
radicals chosen from hydroxyl and C 1-C4 alkoxy;
R14 denoting a radical chosen from:
a) -H;
b) a saturated linear C -C 0 or branched C3-C 0 or cyclic C3-
C8 alkyl group, optionally substituted with one or more groups, which
may be identical or different,
013/189930 PCT/EP2013/062623
chosen from:
i) -COOR1 6;
ii) a C5-C1 2 (hetero)aryl radical, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
R15 being chosen from H, a saturated linear C 1-C1 0 or branched C3-
C 10 or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based
group; R16 and R17, which may be identical or different, being chosen
from H and a saturated linear C 1-C1 0 or branched C3-C1 0 or
unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based group; a
(C1 -C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group;
R16 and R17, which may be identical or different, being chosen from H
and a saturated linear C 1-C1 0 or branched C3-C1 0 or unsaturated C2-
C 10 or cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group; an acetyl radical;
R16 and R17 possibly forming, with the nitrogen that bears them, a 5- to
8-membered heterocycle, which may contain one or more heteroatoms
or groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain;
' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-C20
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more identical or different groups chosen from:
i) -OR25
ii) -SR25
iii) -NR26R27
iv) -CONHR26
v) -CONR26R27
vi) -COOR26
2013/189930 PCT/EP2013/062623
vii) -NHCONHR26
viii) -C(0)-(C1 -C4)alkyl
ix) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
R25 being chosen from H, a saturated linear C 1-C1 0 or branched C3-
C 10 or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based
group;
R26 and R27, which may be identical or different, being chosen from H, a
saturated linear C1-C1 0 or branched C3-C1 0 or unsaturated C2-C1 0 or
cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group; R26 and R27 possibly forming, with the
nitrogen that bears them, a 5- to 8-membered heterocycle, which may
contain one or more heteroatoms or groups chosen from N, O and -COand/
or optionally substituted with a C1-C1 0 hydrocarbon-based chain;
it being understood that A and R" may form, with the nitrogen atom that bears
them, a saturated or unsaturated 5- to 8-membered heterocycle, which may
contain one or more heteroatoms or groups chosen from N, O and -CO- and/or
optionally substituted with a C1-C1 0 hydrocarbon-based chain or C1-C1 0
hydroxyalkyl or CO2T, T denoting a hydrogen atom or a saturated linear C 1-
C 10 or branched C3-C1 0 alkyl radical,
and the salts thereof, the solvates thereof, the optical isomers thereof and the
racemic mixtures thereof, alone or as a mixture.
2 . Compounds according to the preceding claim, in which
2013/189930 PCT/EP2013/062623
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' and NAR";
' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C1 0 or unsaturated C2-C1 0 or branched C3-C1 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more groups -OR5; R5 being chosen from H and a saturated linear C 1-
C4 alkyl hydrocarbon-based group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
A denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C20 or unsaturated C2-C20 or branched C3-C20
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
heteroatoms or groups chosen from N, O, -CO- or a combination thereof
such as -NHCO- or -NHCONH-, and/or optionally substituted with one or
more identical or
different groups chosen from:
i) -OR1 5
ii) -SR1 5
iii) -NR1 6R1 7
iv) -CONHR1 6
vi) -COOR1 6
ix) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals; one of the ring members
possibly being a carbonyl group;
c) a C5-C1 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more radicals chosen from C 1-C8
alkoxy and C1-C8 alkyl groups;
89930 PCT/EP2013/062623
d) -NR1 2R1 3;
e) -OR14;
R12 and R13, which may be identical or different, denoting a radical
chosen from:
a) -H;
b) a saturated linear C 1-C4 alkyl group;
c) a phenyl group optionally substituted with one or more hydroxyls
and/or with one or more C 1-C8 alkoxy radicals;
R12 and R13 possibly forming, with the nitrogen that bears them, a 5- to
8-membered heterocycle, which may contain one or more heteroatoms
or groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain optionally containing one or more
radicals chosen from hydroxyl and C 1-C4 alkoxy;
R14 denoting a radical chosen from:
a) -H;
b) a saturated linear C 1-C1 0 alkyl group optionally substituted with one
or more identical or different phenyl radicals, the said phenyl radicals
being
optionally substituted with one or more hydroxyls and/or with one or more
C 1-C8 alkoxy radicals;
R15 being chosen from H, a saturated linear C 1-C1 0 or branched C3-
C 10 or unsaturated C2-C1 0 or cyclic C3-C8 alkyl hydrocarbon-based
group;
R16 and R17, which may be identical or different, being chosen from H
and a saturated linear C 1-C1 0 or branched C3-C1 0 or unsaturated C2-
C 10 or cyclic C3-C8 alkyl hydrocarbon-based group; a (C1-
C4)alkyl(hetero)(C6)aryl group optionally containing a nitrogen atom,
especially a benzyl group; an acetyl radical;
R16 and R17 possibly forming, with the nitrogen that bears them, a 5- to
8-membered heterocycle, which may contain one or more heteroatoms
or groups chosen from N, O and -CO- and/or optionally substituted with a
C 1-C1 0 hydrocarbon-based chain;
otes a radical chosen from:
a) -H;
2013/189930 PCT/EP2013/062623
b) a linear saturated C 1-C1 0 or branched C3-C1 0 alkyl group, optionally
substituted with one or more identical or different groups -OR25;
R25 being chosen from H and a saturated linear C 1-C1 0 alkyl
hydrocarbon-based group.
3 . Compounds according to either of the preceding claims, in which:
· R denotes a hydrogen atom;
• Y denotes a radical chosen from OR' and NAR";
R' denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C1 0 or unsaturated C2-C1 0 or branched C3-C1 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
oxygen atoms, and/or optionally substituted with one or more hydroxyl,
methoxy or ethoxy groups;
A denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C1 0 or unsaturated C2-C1 0 or branched C3-C1 0
or cyclic C3-C8 alkyl group, optionally interrupted with one or more
oxygen atoms, and/or optionally substituted with one or more identical or
different groups chosen from:
i) - OR 5
ii) -NR1 6R1 7
vi) -COOR1 6
ix) a C5-C 2 (hetero)aryl group, optionally containing one or more
heteroatoms chosen from O, N and S, optionally substituted with one or
more hydroxyls and/or with one or more C 1-C8 alkoxy radicals;
x) a saturated or unsaturated non-aromatic 5- to 8-membered
heterocycle, comprising one or more heteroatoms chosen from O, N and
S, optionally substituted with one or more hydroxyls and/or with one or
more C 1-C8 alkoxy or C 1-C4 alkyl radicals;
c) a phenyl group optionally substituted with one or more radicals chosen
from hydroxyls and/or methoxy and/or ethoxy;
d) -NR1 2R1 3;
e) -OR14;
2013/189930 PCT/EP2013/062623
R12 and R13, which may be identical or different, denoting a radical chosen
from:
a) -H;
b) a saturated linear C 1-C4 alkyl group;
c) a phenyl group optionally substituted with one or more hydroxyls
and/or with one or more C 1-C8 alkoxy radicals;
R14 denoting a radical chosen from:
a) -H;
b) a saturated linear C 1-C4 alkyl group optionally substituted with a
phenyl radical;
R15 being chosen from H and a saturated linear C 1-C4 or branched C3-C4
alkyl hydrocarbon-based group;
R16 and R17, which may be identical or different, being chosen from H and a
saturated linear C1-C1 0 or branched C3-C1 0 or unsaturated C2-C1 0 or cyclic
C3-C8 alkyl hydrocarbon-based group; a (C1 -C4)alkyl(hetero)(C6)aryl group
optionally containing a nitrogen atom, especially a benzyl group; an acetyl
radical;
R16 and R17 possibly forming, with the nitrogen that bears them, a 5- to 8-
membered heterocycle, which may contain one or more heteroatoms or groups
chosen from N, O and -CO- and/or optionally substituted with a C 1-C1 0
hydrocarbon-based chain;
R" denotes a radical chosen from:
a) -H;
b) a linear saturated C 1-C1 0 or branched C3-C1 0 alkyl group, optionally
substituted with one or more identical or different groups -OR25; R25
being chosen from H and a saturated linear C 1-C4 alkyl hydrocarbonbased
group.
4 . Compound according to any one of the preceding claims, in which R = H.
5 . Compounds according to one of the preceding claims, chosen from
No. Structure
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and the salts thereof, the solvates thereof, the optical isomers thereof and the
racemic mixtures thereof, alone or as a mixture.
6 . Composition comprising, in a physiologically acceptable medium, a
compound of formula (I) according to any one of the preceding claims.
7 . Composition according to the preceding claim, characterized in that
compound (I) is present in a content of between 0.01 % and 10% by weight and
preferably between 0.1 % and 5% by weight relative to the total weight of the
composition.
8 . Composition according to either of Claims 6 and 7, characterized in that it
comprises at least one adjuvant chosen from the group formed by: water,
organic solvents, hydrocarbon-based oils, silicone oils, waxes, pigments, fillers,
dyes, surfactants, emulsifiers; cosmetic active agents, UV screening agents,
polymers, thickeners, preserving agents, fragrances, bactericides, ceramides,
odour absorbers and antioxidants.
9 . Composition according to any one of Claims 6 to 9, characterized in that it
comprises at least one active agent chosen from: desquamating agents;
calmatives; organic or mineral photoprotective agents; moisturizers;
depigmenting agents; antiglycation agents; NO-synthase inhibitors; agents
which stimulate the synthesis of dermal or epidermal macromolecules and/or
which prevent their decomposition; agents which stimulate the proliferation of
fibroblasts and/or keratinocytes or which stimulate the differentiation of
keratinocytes; muscle relaxants and/or dermo-decontracting agents; tensioning
agents; antipollution agents and/or free-radical scavengers; agents which act on
2013/189930 PCT/EP2013/062623
the capillary circulation; agents which act on the energy metabolism of cells;
and mixtures thereof.
10 . Non-therapeutic cosmetic process for depigmenting, lightening and/or
bleaching keratin materials, comprising the application of a composition
according to any one of Claims 6 to 9 .
11. Process according to the preceding claim, for depigmenting, lightening
and/or bleaching the skin.
12 . Non-therapeutic cosmetic use of a compound of formula (I) as defined
according to any one of Claims 1 to 5, as an agent for bleaching, lightening
and/or depigmenting keratin materials.
13 . Process for preparing the compounds of formula (I) according to one of
Claims 1 to 5, comprising the following stages:
2013/189930 PCT/EP2013/062623
comprising the following steps:
a) Reaction of resorcinol (A1 ) with itaconic acid (B) or with its
anhydride (B') or with one of its esters of formula (B1 )
B1
in which R denotes H or a linear C 1-C6 or branched C3-C6 alkyl group, to form
a compound C, and this compound is then activated to form a heterocycle of
formula (III), which is then subjected to a reduction step to form the intermediate
(IV) which gives access to the compounds (I).
14. Intermediate compounds of formulae (III) and (IV)
in which Z denotes H or a linear (Ci-Ce)alkyl group or a branched (C3-Ce)alkyl
group.