RESORCINOL DERIVATIVES AND THEIR COSMETIC APPLICATION
The present invention relates to novel compounds derived from resorcinol and
to a cosmetic treatment method, in particular for depigmenting and/or whitening 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
fo o wing main stages :
Tyrosine —> Dopa —> Dopaquinone —> Dopachrome —> Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC
1.14.18.1) 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 stages of the biosynthesis of melanin, either by inhibiting one of the enzymes
involved in melanogenesis or by being inserted as 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 depigmenting agents for the skin.
Substances have been sought which exhibit an effective 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 compounds derived from resorcinol exhibit a good depigmenting
activity, even at low concentration.
A subject-matter of the invention is thus novel compounds of formula (I) as
defined below.
Another subject-matter of the invention is a composition comprising, in a
physiologically acceptable medium, at least one compound of formula (I) as defined
below.
Another subject-matter of the invention is a non-therapeutic cosmetic method
for depigmenting, lightening and/or whitening keratinous substances, in particular the skin,
comprising the application of the composition described above.
More preferably, it is the method for depigmenting, lightening and/or
whitening the skin.
The invention also relates to the non-therapeutic cosmetic use of a compound
of formula (I) as whitening, lightening and/or depigmenting agent for keratinous
substances, in particular the skin.
The compounds according to the invention make it possible to effectively
depigment and/or lighten, indeed even to whiten, the skin of human beings. 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 non-scalp hair, the
eyelashes or the hair, and also the lips and/or the nails.
A subject-matter of the invention is thus novel compounds of formula (I) as
follows:
in which:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci -C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR5,
ii) -SR5,
iii) -NR6R7,
iv) - C(0)NHR6,
v) - C(0)NR6R7,
vi) - C(0)OR6,
vii) -NHC (0)NHR6,
viii) -C(0 )(Ci-C 4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci -C8 )alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group;
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from
• H, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3 -Cs)cycloalkyl group;
R6 and R7, which are identical or different, being chosen from
• H,
• an acetyl radical, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group,
a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C 4)alkyl
group, such as a benzyl group, or a pyridyl(Ci-C 4)alkyl group;
it being possible for R6 and R7 to form, with the nitrogen which carries them, a
saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle
to be optionally substituted by a (Ci-Cio)alkyl group;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
v) -C(0)NR16R17,
vi) -C(0)OR16,
vii) -NHC(0)NHR16,
viii) -C(0)(Ci-C 4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group,
x) a saturated or unsaturated nonaromatic (C3 -Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci-C 8)alkoxy group and a (Ci-C4)alkyl group; and
xi) -NH-C=NH(NH2) (guanidine group);
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
d) -NR12R13;
e) -OR14;
f -C(0)NHR14; and
g) -C(0)(Ci-Cio)alkyl;
R12 and R13, which are identical or different, denoting a radical chosen from:
· -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2 -Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different -OR 15 groups, and
• an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group and a (Ci-Cs)alkoxy group,
it being possible for R12 and R13 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl
optionally being substituted by one to three groups chosen from a hydroxyl group and a
(Ci-C4)alkoxy group;
R14 denoting a radical chosen from:
· -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally substituted by one to three identical or different groups chosen
from:
vi) -C(0)OR16, and
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
• an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an
unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl
group;
R16 and R17, which are identical or different, being chosen from H; an acetyl
radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C 4)alkyl
group, such as a benzyl group, or a pyridyl(Ci-C 4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C -C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR25,
ii) -SR25,
iii) -NR26R27,
iv) -C(0)NHR26,
v) -C(0)NR26R27,
vi) -C(0)OR26,
vii) -NHC(0)NHR26,
viii) -C(0)(Ci-C 4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci -C8)alkoxy group and a (Ci -C4)alkyl group; and
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R25 being chosen from H, a saturated linear (Ci-Cio )alkyl group, an
unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl
group;
R26 and R27, which are identical or different, being chosen from H, a
saturated linear (Ci-Cio )alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C -
Cio)alkyl group or a (C -C8)cycloalkyl group; a phenyl(Ci -C4)alkyl group, such as a benzyl
group, or a pyridyl(Ci -C4)alkyl group;
it being possible for R26 and R27 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio )alkyl group;
it being understood that A and R" can form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a group chosen from (Ci-Cio )alkyl, hydroxy(Ci-
Cio)alkyl and C(0 )OT, T denoting a group chosen from H, a saturated linear (Ci-Cio )alkyl
group and a branched (C -Cio)alkyl group;
and their salts, their solvates and their optical isomers, their racemates, alone or
as mixtures.
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 an inorganic 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 inorganic base, such as sodium
hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium
hydroxide, lithium hydroxide, and the carbonates or hydrogencarbonates 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
comprise one or more nitrogen and/or oxygen atoms and can thus comprise, 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 saturated and
linear alkyl group comprising from x to y carbon atoms.
Preferably, the branched or saturated linear alkyl groups can 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 preferably, the branched or saturated linear alkyl groups can be chosen
from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2-
ethylhexyl and octyl.
The cycloalkyl group can 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 -0(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 can be chosen from methoxy, ethoxy, propoxy and butoxy
and can more particularly be a methoxy group.
- A "saturated or unsaturated nonaromatic heterocycle group" denotes a
monocyclic or bicyclic carbocyclic group having from 5 to 8 ring members and comprising
from one to three heteroatoms or groups chosen from N, O, S and -C(O)-.
A heterocycle group can be chosen from piperidyl, morpholinyl, piperazinyl
and pyrrolidinyl. Preferably, 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 can be chosen from phenyl, naphthyl, indenyl, fluorenyl and
anthracenyl. Preferably, it is the phenyl group.
- A "heteroaryl group" denotes a fused or nonfused poly- or monocyclic
group comprising from 5 to 22 ring members and from 1 to 6 heteroatoms chosen from a
nitrogen, oxygen or sulfur atom, at least one ring of which is aromatic.
The heteroaryl radicals can be chosen from furyl, acridinyl, benzimidazolyl,
benzobistriazolyl, benzopyrazolyl, benzopyridazinyl, benzoquinolyl, benzothiazolyl,
benzotriazolyl, benzoxazolyl, pyridinyl, tetrazolyl, dihydrothiazolyl, imidazopyridinyl,
imidazolyl, indolyl, isoquinolyl, naphthoimidazolyl, naphthooxazolyl, naphthopyrazolyl,
oxadiazolyl, oxazolyl, oxazolopyridyl, phenazinyl, phenooxazolyl, pyrazinyl, pyrazolyl,
pyrazoyltriazyl, pyridyl, pyridinoimidazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl,
thiazolyl, thiazolopyridinyl, thiazoylimidazolyl, thiopyrylyl, triazolyl, xanthyl and its
ammonium salt.
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' or NAR";
R' denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different -OR5 groups; and
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from H and a saturated linear (Ci-C4)alkyl group;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
vi) -C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group;
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
d) -NR12R13; and
e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H;
• a saturated linear (Ci-C4)alkyl group; and
• a phenyl group, optionally substituted by one to three groups chosen from a
hydroxyl group and a (Ci-C 8)alkoxy group; and
it being possible for R12 and R13 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio )alkyl group, the said (Ci-Cio)alkyl
optionally being substituted by one to three groups chosen from a hydroxyl group and a
(Ci -C4)alkoxy group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-Cio)alkyl group which can optionally be substituted by
one to three identical or different groups chosen from a saturated linear (Ci-Cio)alkyl
group, optionally substituted by one or more phenyl radicals, it being possible for the said
phenyl radicals to be optionally substituted by one to three identical or different groups
chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an
unsaturated (C2 -Cio)alkyl group, a branched (C3-Cio)alkyl group and a (C3-Cs)cycloalkyl
group;
R16 and R17, which are identical or different, being chosen from
• H;
• an acetyl radical; and
· a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group,
a branched (C3-Cio)alkyl group or a (C3-C8 )cycloalkyl group; and a phenyl(Ci -C4)alkyl
group, such as a benzyl group, or a pyridyl(Ci -C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group or a branched (C3 -Cio)alkyl group, it
being possible for the said groups to be optionally substituted by one to three identical or
different -OR25 groups;
R25 being chosen from H or a linear (Ci-Cio )alkyl group;
it being understood that A and R" can form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a group chosen from (Ci -C4)alkyl, hydroxy(Ci-
C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci -C6 )alkyl
group and a branched (C3-C )alkyl group;
and their salts, their solvates and their optical isomers, their racemates, alone or
as mixtures.
More preferably, the compounds of formula (I) have the following meanings:
R denotes a hydrogen atom;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio )alkyl group, an unsaturated (C2 -Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three oxygen atoms, it being possible for the
said groups to be optionally substituted by one to three identical or different groups chosen
from hydroxyl, methoxy and ethoxy;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-Cio )alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three oxygen atoms, it being possible for the
said groups to be optionally substituted by one or more identical or different groups chosen
from:
i) -OR15,
ii) -SR15, preferably SMe,
iii) -NR16R17,
vi) - C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci -C8)alkoxy group, preferably an imidazole
or indole radical or a phenyl radical optionally substituted by one to three groups chosen
from a hydroxyl group and a (Ci -C8)alkoxy group, particularly preferably an imidazolyl,
indolyl or phenyl group, and
x) a saturated or unsaturated nonaromatic, preferably saturated, (C -
C )cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen
from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci -C4)alkyl group;
c) a phenyl group optionally substituted by one to three groups chosen from
hydroxyl, methoxy and ethoxy;
d) -NR12R13; and
e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H,
• a saturated linear (Ci -C4)alkyl group, and
• a phenyl group, optionally substituted by one to three groups chosen from a
hydroxyl group and a (Ci -C8)alkoxy group;
R12 and R13 preferably denoting a hydrogen atom or a (Ci -C4)alkyl group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-C4)alkyl group, optionally substituted by a phenyl
radical, such as the benzyl group;
R15 being chosen from H, a saturated linear (Ci -C4)alkyl group and a branched
(C -C4)alkyl group;
R16 and R17, which are identical or different, being chosen from H; an acetyl
radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2 -Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-C8 )cycloalkyl group; and a phenyl(Ci -C4)alkyl
group, such as a benzyl group, or a pyridyl(Ci -C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle comprising one to three
heteroatoms or groups chosen from N, O and -C(O)-, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-Cio)alkyl group or a
(C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted
by one to three identical or different -OR25 groups;
R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group;
it being understood that A and R" can form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a group chosen from (Ci -C4)alkyl, hydroxy(Ci-
C4)alkyl and C(0 )OT, T denoting a group chosen from H, a saturated linear (Ci -C6 )alkyl
group and a branched (C -C )alkyl group, the said heterocycle preferably being a
piperidinyl or morpholinyl group;
and their salts, their solvates and their optical isomers, their racemates, alone or
as mixtures.
Preferably, R = H for the compounds of formula (I).
Several embodiments of compounds of formula (I) are described below:
a) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, optionally substituted by a
i) hydroxyl;
According to this embodiment, the particularly preferred compounds are the
compounds 1, 10, 12, 13, 17, 19, 20, 24, 26 and 27.
b) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, interrupted by an oxygen atom and
optionally substituted by a
i) hydroxyl;
According to this embodiment, the particularly preferred compounds are the
compounds 44, 45 and 46.
c) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by
vi) one or two identical C(0)OR16 groups,
and optionally substituted by a group chosen from
ii) -SR15,
ix) phenyl, optionally being substituted by a hydroxyl, and
ix) a heteroaryl,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl hydrocarbon group
and a branched (C3 -Cio)alkyl group, and
R15 being a saturated linear (Ci-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the
compounds 5, 6, 7, 15, 16, 22, 38, 40, 41, 42 and 47.
d) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by a group chosen from
iii) -NR16R17,
ix) phenyl, optionally being substituted by a hydroxyl and/or a (Ci-Cs
ix) a heteroaryl having from 5 to 12 ring members, comprising an oxygen
atom,
x) a saturated heterocycle having from 5 to 8 ring members, comprising one or
two oxygen atoms, optionally substituted by one or two (Ci-C4)alkyl radicals,
xii) a (C3-Cs)cycloalkyl,
R16 and R17, which are identical or different, being chosen from H, a saturated
linear (Ci-Cio)alkyl group and an acetyl;
According to this embodiment, the particularly preferred compounds are the
compounds 21, 25, 28, 34, 35, 48, 49 and 51.
e) R = H, Y = -NAR", R" = H,
A = branched (C3-Cio)alkyl, optionally substituted by a group chosen from
i) hydroxyl,
vi) a COOR16 group,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl group and a
branched (C3-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the
compounds 2, 3, 4, 8, 9, 14, 18 and 23.
f) R = H, Y = -NAR", R" = H, and
A = cyclic (C3-Cs)alkyl or
A = phenyl optionally substituted by a hydroxyl;
According to this embodiment, the particularly preferred compounds are the
compounds 11, 36 and 37.
g) R = H, Y = -NAR", and
A and R' ' form, with the nitrogen atom which carries them, a saturated 5- to 8-
membered heterocycle, optionally comprising an oxygen atom and optionally being
substituted by a C(0)OT group, T denoting a saturated linear (Ci-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the
compounds 29, 32 and 39.
h) R = H, Y = -NAR", and
A denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one
or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR16,
R16 being a saturated linear (Ci-Cio)alkyl group; and
R" denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by
one or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR26,
R26 being a saturated linear (Ci-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the
compounds 30, 31, 33 and 50.
j) R = acetyl, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl;
According to this embodiment, the particularly preferred compound is the
compound 43.
k) R = H, Y = -NAR", R" = H, and
A = -NR12R13 or
A = -OR14,
R12 and R13, which are identical, denoting a radical chosen from:
a) - H and
b) a saturated linear (Ci-Cio)alkyl group;
R14 denoting a radical chosen from:
a) -H,
b) a saturated linear (Ci-Cio)alkyl group substituted by a phenyl;
According to this embodiment, the particularly preferred compounds are the
compounds 52, 53, 54 and 55.
1) R = H, Y = -OR',
R' = saturated linear (Ci-Cio)alkyl or a branched (C3 -Cio)alkyl group,
optionally interrupted by an oxygen atom and optionally substituted by one or two
i) hydroxyIs.
According to this embodiment, the particularly preferred compounds are the
compounds 56 and 6 1.
Examples of compounds of formula (I) of the invention are collated in Table I
below.
Table I
The numbers of the table correspond to the numbers used in the examples
below.

Their salts, their solvates, their isomers and their racemates also form part of
the invention, taken alone or as mixtures.
Among these compounds, the most particularly preferred compounds in the
context of the present invention are the following: compounds 1 to 37, 39, 44 and 56, and
their salts, their solvates, their isomers and their racemates, taken alone or as mixtures.
The compounds of the invention can be prepared according to the following
Scheme 1:
Scheme 1
Acetylation
The process according to this Scheme 1 comprises the following stages:
a) reaction of resorcinol (Al) with itaconic acid (B) or its anhydride (B')
of its esters of formula (Bl)
B1
in which Ri denotes H or a linear (Ci -C6 )alkyl group or a branched (C3-
C )alkyl group, in order to form a compound C,
b) reduction of this compound C, in order to result in the intermediate (III),
then
c) reaction of the intermediate (III) with a derivative YH, in which Y is as
defined above, in order to access the compounds (I).
An alternative form consists in treating (III) with an alcohol ROH, in order to
result in the compounds (IV), which, by reaction with YH, result in the compounds of
formula (I).
The final stage is optionally an acetylation reaction (compounds of formula (I)
for which R = acetyl).
Another subject-matter of the invention is the compound of formula (III) and
the compound of formula (IV)
in which R denotes H or a linear (Ci-C )alkyl group or a branched (C3 -C )alkyl
group.
Preferably, according to the preceding scheme, ROH denotes ethanol and the R
radical of the compound of formula (IV) denotes the ethyl radical.
The reaction of resorcinol (Al) with itaconic acid (B) or its anhydride (B') or
one of its esters of formula (Bl) which are described above, in order to form the compound
C, is carried out in particular in the presence of an organic solvent which can be chosen
from toluene, tetrahydrofuran, heptane, isooctane, methyltetrahydrofuran, methyl ethyl
ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate, isododecane and
their mixtures, 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 by Pechmann reaction using Nafion resin/silica nanocomposites as
catalysts: Laufer MC, Hausmann H and Holderich WF, J . of Catalysis, 2003, 218, 315-
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 Aldrich).
The compounds (Bl) can 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 non-conjugated 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
esterification 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) can be obtained by
activation of the acid C according to the known methods for the activation of acids, in
particular described in Comprehensive Organic Transformations by R. Larock, Wiley VCH
Ed., in the chapter Interconversion of nitriles, carboxylic acids and derivatives.
Mention may be made, as acid activation method, of:
- the intermediate formation of acid chloride (for example by using thionyl or
oxalyl chloride, or l-chloro-N,N,2-trimethyl-l-propenamine),
- the intermediate formation of mixed anhydride (for example by using a C2-C
alkyl chloroformate, such as isobutyl chloroformate, in the presence of a base, such as, for
example, 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).
The compound C in the acid form can be subjected to a reduction using hydride
in order to result in the compound of formula (III) after acid treatment, according to the
following Scheme 2.
Scheme 2
C
This reduction can be carried out 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 the compound of formula (III) with a compound of formula YH
can be carried out according to the following Scheme 3.
Scheme 3
This reaction can optionally be carried out 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
diisopropy lethylamine;
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 (III) can be in equilibrium with the ethyl
ester form (III') in the presence of ethanol. The acyclic ester can then react with YH
compounds in order to result in the compounds (I).
The compounds of formula (I) for which R denotes an acetyl group can be
obtained by acetylation of compounds of formula (I) for which R = H.
The acetylation reaction can 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 can 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.
All of these stages can also resort to protection/deprotection strategies normally
used in organic chemistry and compiled in the work "Protecting Groups in Organic
Synthesis", Greene and Wuts, Wiley Interscience, as a function of the nature of the R', A
and R" radicals.
In addition, when the final compounds (I) exhibit a free carboxylic acid on the
A or R" radical, these compounds can be obtained by saponification using inorganic bases,
such as, for example, NaOH or LiOH, in the presence of protic or aprotic solvents, such as,
for example, ethanol or tetrahydrofuran or water, at temperatures varying between 0 and
100°C. The salts obtained are then re-acidified in the presence of conventional inorganic or
organic acids, such as, for example, 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 compatible with human keratinous substances, such as the skin of the body or of
the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and/or the hair.
The compound (I) can be present in the composition according to the
invention in an amount which can be between 0.01% and 10% by weight, preferably
between 0.1% and 5% by weight, in particular from 0.5% to 3% by weight, with respect 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 in particular be made of water, organic solvents, in particular C2-
C alcohols, oils, in particular hydrocarbon oils or silicone oils, waxes, pigments, fillers,
dyes, surfactants, emulsifiers, cosmetic active agents, UV screening agents, polymers,
thickeners, preservatives, fragrances, bactericides, ceramides, odour absorbers or
antioxidants.
These optional cosmetic adjuvants can be present in the composition in a
proportion of 0.00 1% to 80%> by weight, in particular of 0.1% to 40%> by weight, with
respect to the total weight of the composition. In any case, these adjuvants, and their
proportions, 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,
detrimentally 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;
soothing agents; organic or inorganic photoprotective agents; moisturizing agents;
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-relaxing agents and/or
dermo-decontracting agents; tightening agents; agents for combating pollution and/or free
radicals; agents which act on the microcirculation; agents which act on the energy
metabolism of cells; and their mixtures.
Examples of such additional compounds are: retinol and its derivatives, such as
retinyl palmitate; ascorbic acid and its derivatives, such as magnesium ascorbyl phosphate
and ascorbyl glucoside; tocopherol and its derivatives, such as tocopheryl acetate; nicotinic
acid and its precursors, such as nicotinamide; ubiquinone; glutathione and its precursors,
such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and in particular plant
proteins and their hydrolysates, and also phytohormones; marine extracts, such as algal
extracts; bacterial extracts; sapogenins, such as diosgenin, and wild yam extracts
comprising same; ceramides; hydroxy acids, such as salicylic acid and 5-(noctanoyl)
salicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acylated
derivatives; manganese salts and magnesium salts, in particular gluconates; and their
mixtures.
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-(n-octanoyl)salicylic
acid); a-hydroxy acids, such as glycolic, citric, lactic, tartaric, malic or mandelic acid;
urea; gentisic acid; oligofucoses; cinnamic acid; Saphorajaponica 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 inorganic salts: EDTA; N-acyl-N,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, preferably ranging
from 0.1% to 10% by weight, with respect to the total weight of the composition.
Mention may be made, as soothing agents which can be used in the
composition according to the invention, 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 Codif, a
Laminaria saccharina extract, canola oil, bisabolol, camomile extracts, allantoin, Sepivital
EPC (phosphoric diester of vitamins E and C) from Seppic, W-3 unsaturated oils, such as
musk rose oil, blackcurrant oil, echium oil or fish oil, plankton extracts, capryloyl 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, Cola nitida extracts, piperonal,
a clove extract, an Epilobium angustifolium extract, aloe vera, a Bacopa moniera extract,
phytosterols, cortisone, hydrocortisone, indomethacin and betamethasone.
The soothing agents are generally present in the composition according to the
invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from
0.1% > to 10% by weight, with respect 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 517 104, 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 Applications
US 5 237 071, US 5 166 355, GB 2 303 549, DE19726184 and EP 893 119; screening
polymers and screening silicones, such as those described in particular in Application WO-
93/04665; dimers derived from a-alkylstyrene, such as those described in Patent
Application DE19855649; and merocyanine derivatives, such as those described in
Applications WO 201 1/1 13719 and FR 2 957 251.
The inorganic photoprotective agents can 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), such as, for
example, titanium oxide (amorphous or crystallized in rutile and/or anatase form), iron
oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments, which are all wellknown
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 518 772 and EP 518 773.
The photoprotective agents are generally present in the composition according
to the invention in proportions ranging from 0.1% to 20% by weight, preferably ranging
from 0.2% to 15% by weight, with respect to the total weight of the composition.
The composition according to the invention can be provided in all the
formulation forms normally used in the cosmetics field and in particular in the form of an
aqueous or aqueous/alcoholic solution, which is optionally gelled, of a dispersion of the
lotion type, optionally comprising two phases, of an oil-in-water or water-in-oil or multiple
(W/O/W or 0 /W/O, for example) emulsion, of an aqueous gel, of 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 non-ionic type, or of 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 antisun
creams); a fluid foundation; a make-up-removing 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.
Example 1: attainment of intermediates
1.1. Attainment of the lactone C in the acid form C1
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: 174-175°C. The 1H NMR and mass spectra are in accordance
with the structure of the expected product.
1.2. Synthesis of 4-(2,4-dihydroxybenzyl)dihydrofuran-2(3H)-one of formula
C1
6.8 g of sodium borohydride (2 eq.) are added to a solution of 20 g of the
intermediate CI in 100 ml of tetrahydrofuran. The mixture is stirred at ambient
temperature for 5 days. Water is added and the organic phase is extracted by 3 times with
ethyl acetate. After concentrating under vacuum, the crude reaction product is placed in a
heated desiccator overnight. The next day, the crude product is triturated with 50 ml of
dichloromethane. A pink precipitate is formed which, after filtration on a sintered glass
filter, gives the compound of formula (III) with a yield of 77%.
The 1H NMR and mass spectra are in accordance with the structure of the
expected product (III).
The compound of formula (III) is subsequently reacted according to Scheme 3
described above with the YH compound, used as reactant and solvent when YH is liquid,
for example when YH is an amine (3 equivalents), and then the reaction medium is brought
to 60°C for 2h.
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 0.1N 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.
The examples below illustrate these subsequent stages.
Example 2: synthesis of compound 2 :
15 g of the compound of formula (III) are introduced, with 3.5 equivalents of
ethyl leucinate (49 g in the hydrochloride form before neutralization), into a roundbottomed
flask. The reaction medium is heated at 145°C for 5 hours. After cooling, the
reaction medium is diluted in ethyl acetate and the organic phase is washed with a IN
hydrochloric acid solution and then with a saturated sodium chloride solution. After drying
the organic phase over sodium sulfate and concentrating under vacuum, an orangecoloured
wax is obtained (18 g). The latter is purified on a silica column (eluent
dichloromethane:methanol 9:1). After collecting the fractions of interest and concentrating,
12.8 g of a pale yellow solid are obtained, corresponding to compound 2 in the form of a
mixture of 2 diastereoisomers in a 53/47 ratio determined by 1H NMR. (48%).
The 1H NMR and mass spectra are in accordance with the structure of the
expected mixture of diastereoisomers.
Example 3: synthesis of compound 6:
1.6 g of the compound of formula (IV) are introduced, with 9.6 g of ethyl
tyrosinate, into a round-bottomed flask. The reaction medium is heated at 130°C for 4
hours. After cooling, the reaction medium is diluted in 100 ml of methanol and filtered.
The filtrate is concentrated under vacuum to result, after purification on a silica column
(eluent dichloromethane/methanol 30/1), in 1.5 g of a white solid, corresponding to
compound 6 (yield 47%) in the form of a mixture of 2 diastereoisomers in a 55/45 ratio
determined by 1H NMR. (48%)
The 1H NMR and mass spectra are in accordance with the structure of the
expected mixture of diastereoisomers.
Example 4: synthesis of compound 5 (saponification of compound 6)
1 g of compound 6 is placed in 5 ml of ethanol in the presence of 480 mg of
lithium hydroxide. After stirring for 14 hours, the solvent is concentrated under vacuum
and the reaction medium is acidified to pH 2 using IN hydrochloric acid in the presence of
ethyl acetate. After extracting the aqueous phase twice with ethyl acetate and then drying
over magnesium sulfate, the combined organic phases are concentrated under vacuum. The
crude product obtained is purified on a silica column (eluent dichloromethane/methanol
20/1) to result in 260 mg of a yellow solid (27% yield) corresponding to compound 5.

CLAIMS
1. Compound of formula (I)
in which:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR5,
ii) -SR5,
iii) -NR6R7,
iv) -C(0)NHR6,
v) -C(0)NR6R7,
vi) -C(0)OR6,
vii) -NHC(0)NHR6,
viii) -C(0)(Ci-C 4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group;
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from
· H, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group,
R6 and R7, which are identical or different, being chosen from
· H,
• an acetyl radical, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group,
a branched (C3-Cio)alkyl group or a (C3-C8 )cycloalkyl group; and a phenyl(Ci-C 4)alkyl
group, such as a benzyl group, or a pyridyl(Ci-C 4)alkyl group,
it being possible for R6 and R7 to form, with the nitrogen which carries them, a
saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle
to be optionally substituted by a (Ci-Cio)alkyl group;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
v) -C(0)NR16R17,
vi) -C(0)OR16,
vii) -NHC(0)NHR16,
viii) -C(0)(Ci-C 4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group,
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; and
xi) -NH-C=NH(NH2) (guanidine group);
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
d) -NR12R13;
e) -OR14;
f) -C(0)NHR14;
g) -C(0)(Ci-Cio)alkyl;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different -OR 15 groups, and
• an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group and a (Ci-Cs)alkoxy group,
it being possible for R12 and R13 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl
optionally being substituted by one to three groups chosen from a hydroxyl group and a
(Ci -C4)alkoxy group;
R14 denoting a radical chosen from:
· -H,
• a saturated linear (Ci-Cio )alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally substituted by one to three identical or different groups chosen
from:
vi) - C(0)OR16, and
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group, and
• an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio )alkyl group, an
unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl
group;
R16 and R17, which are identical or different, being chosen from H; an acetyl
radical; a saturated linear (Ci-Cio )alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-C8 )cycloalkyl group; and a phenyl(Ci -C4)alkyl
group, such as a benzyl group, or a pyridyl(Ci -C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio )alkyl group;
R" denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C 2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR25,
ii) -SR25,
iii) -NR26R27,
iv) -C(0)NHR26,
v) -C(0)NR26R27,
vi) -C(0)OR26,
vii) -NHC(0)NHR26,
viii) -C(0)(Ci-C 4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; and
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R25 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an
unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl
group;
R26 and R27, which are identical or different, being chosen from H, a
saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C -
Cio)alkyl group or a (C -C8)cycloalkyl group; a phenyl(Ci-C 4)alkyl group, such as a benzyl
group, or a pyridyl(Ci-C 4)alkyl group;
it being possible for R26 and R27 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
it being understood that A and R" can form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a group chosen from (Ci-Cio)alkyl, hydroxy(Ci-
Cio)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-Cio)alkyl
group and a branched (C3-Cio)alkyl group;
and their salts, their solvates and their optical isomers, their racemates, alone or
as mixtures.
2. Compound according to the preceding claim, in which:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different -OR5 groups; and
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from H and a saturated linear (Ci-C4)alkyl group;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a
branched (C3-C2o)alkyl group or a (C3 -Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three heteroatoms or groups chosen from N,
O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be
optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0 )NHR16,
vi) -C(0 )OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci -C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3 -Cs)cycloalkyl or
heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl
group, a (Ci -C8)alkoxy group and a (Ci -C4)alkyl group;
c) an aryl or heteroaryl group, optionally substituted by one to three groups
chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
d) -NR12R13; and
e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H;
• a saturated linear (Ci -C4)alkyl group; and
• a phenyl group, optionally substituted by one to three groups chosen from a
hydroxyl group and a (Ci -C8)alkoxy group; and
it being possible for R12 and R13 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl
optionally being substituted by one to three groups chosen from a hydroxyl group and a
(Ci -C4)alkoxy group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-Cio)alkyl group which can optionally be substituted by
one to three identical or different groups chosen from a saturated linear (Ci-Cio)alkyl
group, optionally substituted by one or more phenyl radicals, it being possible for the said
phenyl radicals to be optionally substituted by one to three identical or different groups
chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an
unsaturated (C2 -Cio)alkyl group, a branched (C3-Cio)alkyl group and a (C3-Cs)cycloalkyl
group;
R16 and R17, which are identical or different, being chosen from
· H;
• an acetyl radical; and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group,
a branched (C3-Cio)alkyl group or a (C3-C8 )cycloalkyl group; and a phenyl(Ci -C4)alkyl
group, such as a benzyl group, or a pyridyl(Ci -C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-C2o)alkyl group, it
being possible for the said groups to be optionally substituted by one to three identical or
different -OR25 groups;
R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group;
it being understood that A and R" can form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a group chosen from (Ci -C4)alkyl, hydroxy(Ci-
C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci -C6 )alkyl
group and a branched (C3-C )alkyl group;
and their salts, their solvates and their optical isomers, their racemates, alone or
as mixtures.
3. Compound according to either one of the preceding claims, in which:
R denotes a hydrogen atom;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three oxygen atoms, it being possible for the
said groups to be optionally substituted by one to three identical or different groups chosen
from hydroxyl, methoxy and ethoxy;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a
branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said
groups to be optionally interrupted by one to three oxygen atoms, it being possible for the
said groups to be optionally substituted by one or more identical or different groups chosen
from:
i) -OR15,
ii) -SR15, preferably SMe,
iii) -NR16R17,
vi) -C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three
groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, preferably an imidazole
or indole radical or a phenyl radical optionally substituted by one to three groups chosen
from a hydroxyl group and a (Ci -C8)alkoxy group, particularly preferably an imidazolyl,
indolyl or phenyl group, and
x) a saturated or unsaturated nonaromatic, preferably saturated, (C3-
C )cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen
from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci -C4)alkyl group;
c) a phenyl group optionally substituted by one to three groups chosen from
hydroxyl, methoxy and ethoxy;
d) -NR12R13; and
e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H,
• a saturated linear (Ci -C4)alkyl group, and
• a phenyl group, optionally substituted by one to three groups chosen from a
hydroxyl group and a (Ci -C8)alkoxy group;
R12 and R13 preferably denoting a hydrogen atom or a (Ci -C4)alkyl group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-C4)alkyl group, optionally substituted by a phenyl
radical, such as the benzyl group;
R15 being chosen from H, a saturated linear (Ci -C4)alkyl group and a branched
(C -C4)alkyl group;
R16 and R17, which are identical or different, being chosen from H; an acetyl
radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2 -Cio)alkyl group, a
branched (C -Cio)alkyl group or a (C -C8)cycloalkyl group; and a phenyl(Ci -C4)alkyl
group, such as a benzyl group, or a pyridyl(Ci -C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle comprising one to three
heteroatoms or groups chosen from N, O and -C(O)-, it being possible for the said
heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-Cio)alkyl group or a
(C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted
by one to three identical or different -OR25 groups;
R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group;
it being understood that A and R" can form, with the nitrogen which carries
them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said
heterocycle to be optionally substituted by a group chosen from (Ci-C4)alkyl, hydroxy(Ci-
C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-C6)alkyl
group and a branched (C -Ce)alkyl group, the said heterocycle preferably being a
piperidinyl or morpholinyl group;
and their salts, their solvates and their optical isomers, their racemates, alone or
as mixtures.
4. Compound according to any one of the preceding claims, in which R = H.
5. Compound according to any one of the preceding claims, in which the
compound has the following meaning:
a) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, optionally substituted by a
i) hydroxyl;
b) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, interrupted by an oxygen atom and
optionally substituted by a
i) hydroxyl;
c) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by
vi) one or two identical COOR16 groups,
and optionally substituted by a group chosen from
ii) -SR15,
ix) phenyl, optionally being substituted by a hydroxyl, and
ix) a heteroaryl having from 5 to 12 ring members, comprising one or two
heteroatoms chosen from O, N or S,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl hydrocarbon group
and a branched (C3-Cio)alkyl group, and
R15 being a saturated linear (Ci-Cio)alkyl group;
d) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by a group chosen from
iii) -NR16R17,
ix) phenyl, optionally being substituted by a hydroxyl and/or a (Ci-Cs)alkoxy
radical,
ix) a heteroaryl having from 5 to 12 ring members, comprising an oxygen
atom,
x) a saturated heterocycle having from 5 to 8 ring members, comprising one or
two oxygen atoms, optionally substituted by one or two (Ci-C4)alkyl radicals,
xii) a (C3-Cs)cycloalkyl,
R16 and R17, which are identical or different, being chosen from H, a saturated
linear (Ci-Cio)alkyl group and an acetyl;
e) R = H, Y = -NAR", R" = H,
A = branched (C3-Cio)alkyl, optionally substituted by a group chosen from
i) hydroxyl,
vi) a COOR16 group,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl group and a
branched (C3 -Cio)alkyl group;
f) R = H, Y = -NAR", R" = H, and
A = cyclic (C -C )alkyl or
A = phenyl optionally substituted by a hydroxyl;
g) R = H, Y = -NAR", and
A and R' ' form, with the nitrogen atom which carries them, a saturated 5- to 8-
membered heterocycle, optionally comprising an oxygen atom and optionally
being substituted by a C(0)OT group, T denoting a saturated linear (Ci-
Cio)alkyl group;
h) R = H, Y = -NAR", and
A denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one
or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR16,
R16 being a saturated linear (Ci-Cio)alkyl group; and
R" denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by
one or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR26,
R26 being a saturated linear (Ci-Cio)alkyl group;
j) R = acetyl, Y = -NAR' ' , R" = H,
A = saturated linear (Ci-Cio)alkyl;
k) R = H, Y = -NAR", R" = H, and
A = -NR12R13 or
A = -OR14,
R12 and R13, which are identical, denoting a radical chosen from:
a) - H and
b) a saturated linear (Ci-Cio)alkyl group;
R14 denoting a radical chosen from:
a) -H,
b) a saturated linear (Ci-Cio)alkyl group substituted by a phenyl;
1) R = H, Y = -ORR' = saturated linear (Ci-Cio)alkyl or a branched (C3 -Cio)alkyl group,
optionally interrupted by an oxygen atom and optionally substituted by one or
two
i) hydroxy Is.
6. Compound according to any one of Claims 1 to 3, chosen from the following
compounds:
N-butyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]leucinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]valinate,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]valine,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]tyrosine,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]tyrosinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glycinate,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(1-hydroxy-3-methylbutan-2-yl)butanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(1-hydroxy-4-methylpentan-2-yl)butanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-propylbutanamide,
N-cyclopentyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(2-hydroxyethyl)butanamide,
3-(2,4-dihydroxybenzyl)-N-ethyl-4-hydroxybutanamide,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]leucine,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glycine,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]phenylalaninate,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-octylbutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(6-methylheptyl)butanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-pentylbutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-nonylbutanamide,
N-(cyclohexylmethyl)-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]-D-tryptophanate,
3-(2,4-dihydroxybenzyl)-N-(2-ethylhexyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-hexyl-4-hydroxybutanamide,
N-(2-cyclohexylethyl)-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-heptyl-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-(2,3-dihydroxypropyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-4-
hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy- 1-(morpholin-4-yl)butan- 1-one,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N,N-bis(2-hydroxyethyl)butanamide,
3-(2,4-dihydroxybenzyl)-N,N-diethyl-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy- 1-(piperidin- 1-yl)butan- 1-one,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]-N-methylglycinate,
N-benzyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-[2-(4-hydroxy-3-
methoxyphenyl)ethyl]butanamide,
N-phenyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(4-hydroxyphenyl)butanamide,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glutamate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]prolinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]histidinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]methioninate,
propan-2-ylN-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glycinate,
4- {2-[(acetyloxy)methyl]-4-(butylamino)-4-oxobutyl}benzene-l,3-diyl diacetate,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(3-methoxypropyl)butanamide,
3-(2,4-dihydroxybenzyl)-N-(2-ethoxyethyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-[2-(2-hydroxyethoxy)ethyl]butanamide,
ethyl 4- {[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl] amino}butanoate,
3-(2,4-dihydroxybenzyl)-N-[2-(dimethylamino)ethyl]-4-hydroxybutanamide,
N-[2-(acetylamino)ethyl]-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N,N-bis(2-methoxyethyl)butanamide,
3-(2,4-dihydroxybenzyl)-N-(furan-2-ylmethyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N,4-dihydroxybutanamide,
N-(benzyloxy)-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxybutanohydrazide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N',N'-dimethylbutanohydrazide,
ethyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
isopropyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
butyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
hexyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
2,3-dihydroxypropyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
2-methoxypropyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
and their salts, their solvates, their optical isomers, their racemates, taken alone
or as mixtures.
7. Composition comprising, in a physiologically acceptable medium, a
compound of formula (I) according to any one of the preceding claims.
8. Composition according to the preceding claim, characterized in that the
compound of formula (I) is present in a content of between 0.01% and 10% by weight,
preferably between 0.1% and 5% by weight, in particular from 0.5%> to 3% by weight, with
respect 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 chosen from the group formed by: water, organic solvents,
hydrocarbon oils, silicone oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers,
cosmetic active agents, UV screening agents, polymers, thickeners, preservatives,
fragrances, bactericides, ceramides, odour absorbers and antioxidants.
10. Composition according to any one of Claims 7 to 9, characterized in that it
comprises at least one active agent chosen from: desquamating agents; soothing agents;
organic or inorganic photoprotective agents; moisturizing agents; 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-relaxing agents and/or dermo-decontracting
agents; tightening agents; agents for combating pollution and/or free radicals; agents which
act on the microcirculation; agents which act on the energy metabolism of cells; and their
mixtures.
11. Non-therapeutic cosmetic method for depigmenting, lightening and/or
whitening keratinous substances, in particular the skin, comprising the application of a
composition according to any one 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
according to any one of Claims 1 to 6 as whitening, lightening and/or depigmenting agent
for keratinous substances, in particular the skin.
14. Process for the preparation of the compounds of formula (I) according to
one of Claims 1 to 6, comprising the following stages:
a) reaction of resorcinol (Al) with itaconic acid (B) or its anhydride (B') or one
of its esters of formula (Bl)
B1
in which Ri denotes H or a linear (Ci -C6 )alkyl group or a branched (C3-
C )alkyl group, in order to form a compound C of formula
b) reduction of this compound C, in order to result in the intermediate (III) then
c) reaction of the intermediate (III) with a derivative YH, in which Y is as
defined according to any one of Claims 1 to 5, in order to access the
compounds (I).
15. Intermediate compounds of formulae (III) and (IV)
in which R denotes H or a linear (Ci-C )alkyl group or a branched (C -C6 )al l
group.