New application of imidazolyl derivative

Abstract

The invention relates to a novel application of an imidazolyl derivative. The non-therapeutic cosmetic or dermatological use of at least one imidazolyl derivative of general formula (I) or a cosmetically or dermatologically acceptable salt thereof; relates to a cosmetic or dermatological process, to at least one imidazolyl derivative of general formula (I) as mentioned above or a cosmetically or dermatologically acceptable salt thereof, for locally reducing the visibility of excessive and unpleasant skin coloration characterized by local accumulation of endogenous pigments.

Description

Field of the Invention

[0001] The present invention relates to a novel use of imidazolyl derivatives for topically reducing the visibility of unaesthetic skin manifestations which are associated with excessive and unaesthetic (and / or undesirable) skin pigmentation and are characterized topically by the accumulation of endogenous pigments (chromophores).

[0002] Technology Status

[0003] As a striking example of phenotypic diversity in humans, skin can exhibit a variety of colors, ranging from gray or almost white skin, through various shades of light brown and chestnut brown, to very dark shades (black) (Ortonne J.P., Annales de Dermatologie et de Vénéréologie, 2012, Vol. 139, pp. S73-S77). Regardless of intrinsic factors such as genetic inheritance determined at birth, or even extrinsic factors such as sun exposure, human skin has a natural color, i.e., the natural color of pigmentation, imparted by a complex and subtle biochemical process. Ultimately, therefore, so-called “normal” human skin color is the result of the contribution and superposition / combination of four chromophore pigments, namely oxyhaemoglobin or oxygenated haemoglobin (red) in the skin capillaries, deoxyhaemoglobin or reduced haemoglobin (blue) in the dermal venules, carotene (yellow-orange) provided by dietary carotenoids and finally melanin (brown to black) produced locally in specialized cells in the epidermis, the melanocytes (Casadio S., Cosmétologie et Dermatologie Esthétique, 2015—http: / / dx.doi.org / 10.1016 / S2211-0380(15)62942-8). Despite this diversity of pigments, the main factor in determining skin color and therefore the differences and variations in skin color between individuals remains the dark pigment (melanin), in particular due to its size, intensity and dual typology, where eumelanin (brown to dark black) differs from pheomelanin (reddish-yellow to light brown), but also due to the activity level and distribution of melanosomes, which are intracellular organelles that synthesize and store melanin and then transfer it to keratinocytes to ensure pigmentation of the epidermis and photoprotection against sunlight (Delevoye C. et al., Med. Sci. (Paris), 2011 Vol. 27 No. 2, pp. 153-162). Thus, as an illustration, we can note that darker skin pigmentation is associated with larger and more productive melanosomes, and the melanin they produce is retained longer in keratinocytes than in keratinocytes of light-skinned individuals (Deng L. et al., Heregitas, 2018, Vol. 155, No. 1, pp. 1-12 and references cited therein).Logically, eumelanin is found primarily in individuals with dark skin, while pheomelanin accumulates more in individuals with light skin (Barsh GS, PLoS Biology, 2003, Vol. 1, No. 1, pp. 019-022). Finally, the Fitzpatrick universal classification, a reference tool for dermatologists, classifies skin phototypes (6 in total) according to the ability of the integument to accurately produce such dark to dark pigmentation when exposed to sunlight (from high to absent) (Sachdeva S., Indian J. Dermatol. Venereol. Leprol., 2009, Vol. 75, pp. 93-96).

[0004] In summary and simply put, the disorders affecting so-called "normal" skin color can be summarized as the expansion of natural skin color with local areas of uneven pigmentation and especially the clinical manifestations of darker and darker spots, or conversely, the reduction and pallor of skin with the clinical manifestations of local brighter spots (Lipsker D. et al., Annales de Dermatologie et de Vénéréologie, 2019, Vol. 146, No. 10, pp. 666-682). In addition to any harmful results (melanoma, etc.), such "color defects" may also be perceived by affected individuals as unsightly and even undesirable because they can destroy the desired skin color harmony. In order to correct / remove such defects that affect skin appearance (and its aesthetic aspects), the dermatology field known as "aesthetics and cosmetics" has been developed (Wollina U., Dermatologic Therapy, 2008, Vol. 21, No. 2, pp. 118-130). For example, in vocabulary terms, it is accepted that the noun "skin discoloration (dyschromia)" describes any deposition of multiple / unspecified pigments in the skin that causes the change of normal skin color endogenously or exogenously, widely or in a well-defined area (Braun-Flaco O. et al., Dermatology, 1991, Chapter 27). Recently, some authors have also adopted other universal attributes in the same way, to broadly cover any form of disorder related to skin discoloration, pigmentation and darkening (Nautiyal A. et al. Pigment Cell Melanoma Res, 2021, Vol. 00, pp. 1-15). In fact, it is obvious that the area with one or more uneven and abnormal skin pigmentation is darkened or discolored and the scope of such disorder becomes extensive due to the change of its color and shape. Therefore, such a scope can affect the following types of skin pigmentation disorders:

[0005] a) purely dermatological (involving subjects (patients) suffering from these pigmentary disorders in a pathological manner), such as solar lentigines, melasma, rosacea, solar erythema, vitiligo, and also

[0006] b) Aesthetic / cosmetic (particularly occurring in "healthy" subjects, separate from the aforementioned patients), such as infraorbital hyperchromia.

[0007] Although the skin aesthetic imperfections mentioned in point b) above are completely separable from the skin pathologies mentioned in point a) above, and usually involve different groups of individuals, as indicated above, cosmetic solutions (if targeted at subjects presenting the aesthetic / cosmetic disorders mentioned in point b) above) and existing treatments (if targeted at subjects (patients) suffering from one or more pure dermatological conditions as presented in point a) above) target uneven and abnormal skin coloration / pigmentation that affects the natural skin color. In this regard, based on a basic understanding of the skin pigmentation process and its complexity, the prior art provides technologies, products and targets that are described by some as "clinically proven" (Hakozaki T. et al., Textbook of Aging Skin, 2016, pp. 1017-1026). Admittedly, there is no such reference option, but there is a library of solutions, which can range from non-invasive or minimally invasive surgery such as the simple application of cosmetic products (foundation), or more complex topical treatment solutions to whiten the skin, or chemical peels, laser therapy, etc., to surgical strategies and other more invasive cosmetic medicine operations, such as dermabrasion, microneedling, skin transplantation and cell therapy (Pijpe, A. et al., 2020, pp. 109-115). One of these options that has always been favored is to apply active ingredients that can interfere with its pigmentation level to the skin with the support of topical preparations. In this regard, and especially in the case of excessive melanin deposition, many ingredients of synthetic or natural origin were developed in the postwar period because of their ability to whiten the skin. Thus, the first ingredients found historically in whitening creams, emulsions, gels, lotions, serums and other cosmetic or dermocosmetic preparations were hydroquinone (a benzene derivative) and its derivatives, mercury compounds (mercuric oxide and mercuric chloride), retinoids such as retinoic acid and certain dermocorticoids diverted from their therapeutic uses. However, due to their harmful effects and dangers to human health over the years (potential carcinogens, skin problems, etc.), some of these "first" whitening substances are now strictly regulated, mainly under European and American regulations, and even appear on the list of substances banned by law in cosmetics, following the example of hydroquinone since Regulation (EC) No. 344 / 2013.As an alternative to these health restrictions and bans, ingredient manufacturers have turned to alternative products of natural origin, such as kojic acid (produced by several fungal species), arbutin (phenolic glucoside found in the leaves and skins of many plants), niacinamide or ascorbic acid (a vitamin naturally present in certain foods) or azelaic acid (produced by the fermentation of cereal seeds or by lipid peroxidation of polyunsaturated fatty acids by yeasts present on the skin surface), or non-cytotoxic plant extracts that also have whitening properties, such as extracts of licorice, mulberry and bearberry (Fernandez X. et al. Techniques de l'Ingénieur, 2015, Vol. J 2300, pp. 1-33, and references cited). Here again, certain national regulations, such as in Switzerland, have subsequently restricted or banned the use of some of these naturally occurring substances (kojic acid, arbutin) in view of the detection of systemic undesirable side effects: toxicity, irritation, dryness and skin sensitization. Regarding the mechanism of biological action, many of the active ingredients mentioned above, but also many others, such as those compiled in a recent review article (Pillaiyar T. et al., J. Med. Chem, 2018, Vol. 61 No. 17, pp. 7395-7418), quite logically exhibit an inhibitory effect on tyrosinase, the key metalloenzyme for the conversion of tyrosine into melanin by melanocytes, where the action is divided into a limiting effect on melanin production (in the case of hydroquinone, azelaic acid and arbutin mentioned above) and a competitive interaction with the non-protein enzyme cofactor of tyrosinase, namely copper (in the case of kojic acid and ascorbic acid mentioned above). Other agents also seek, among other things, to inhibit the transfer of melanosomes to keratinocytes (the case of niacinamide mentioned above), inhibit tyrosinase transcription (the case of the retinoic acid derivatives mentioned above), prevent inflammation, capture free radicals (the case of glycyrrhetinic acid extracted from licorice and its roots mentioned above), and, more simply, to increase the renewal of the epidermis through a desquamation effect to eliminate excess melanin (the case of α-hydroxy acids such as glycolic acid and lactic acid) (Resende DISP et al., Appl Sci, 2022, Vol. 12, No. 775, pp. 1-15 and cited references).

[0008] Peptides and so-called "related" compounds have also been described, particularly illustrated by peptides linked to carboxylic acids (ascorbic acid, kojic acid, etc.), all of which have the ability to artificially reduce skin melanin levels by inhibiting the enzymatic activity of tyrosinase (Boo YC, Biomedicines, 2020, Vol. 8, No. 9, pp. 1-26). The synthesis of compounds such as 2-substituted benzyl-4(7)-phenyl-1H-benzo[d]imidazoles can also be noted, as they are in some cases produced with IC values ​​similar to the reference substance kojic acid. 50 Inhibition of tyrosinase ( IS et al., Arch. Pharm. Chem. Life Sci, 2016, Vol. 349, No. 11, pp. 881-888), or patent applications FR2917087 and WO2008006824, which claim compounds such as 4-phenyl-imidazole-2-thione and imidazole-2-thione, respectively, for the purpose of preventing or medically or cosmetically treating pigmentation disorders, in particular post-inflammatory or metabolic or medicinal pigmentation disorders, although a comparable melanogenesis-inducing behavior is expected for histamine and / or its imidazole metabolic byproducts (Tomita Y. et al., J. Dermatol. Sci, 1993, Vol. 6, No. 2, pp. 146-154; Liu J. et al., Skin Pharmacol. Physiol, 2017, Vol. 30, No. 3, pp. 139-145; Yoshida M. et al., J. Invest. Dermatol, 2000, Vol. 114 No. 2, pp. 334-342). In addition, the aforementioned peptides with imidazole units, related compounds and derivatives belonging to the prior art specifically target only the inhibitory effect on tyrosinase and / or on the production of melanin, which may limit their effectiveness.

[0009] In any case, despite the fact that there are many and different treatments / therapies aimed at remedying / correcting these pigmentation disorders that can affect the natural skin color, this type of skin problem remains an attractive "challenge" for both the cosmetic and dermatological industries, which are constantly seeking new, safe and more effective ingredients.

[0010] Patent application WO2015 / 114176 reports a product called An imidazolyl derivative of the invention, in which the following benefits of the imidazolyl derivative on skin cells are described: increased expression of the circadian rhythm genes CLOCK and PER1, activated photoconversion of vitamin D; benefits that are different and clearly distinct from the benefits sought by the present invention.

[0011] The present invention is fully in line with the above-mentioned challenge of seeking better and more effective management, aiming to provide a comprehensive and new / original remedy for unaesthetic conditions that share one or more areas of excessive - often uneven - and unaesthetic (and / or undesirable) skin pigmentation.

[0012] Description of the invention

[0013] Based on all these observations and elements of the literature, the inventor set out to solve the following objective technical problem: to provide on the market of cosmetic active ingredients that interact with the production of skin pigments (chromophores) an ingredient with enhanced performance and guaranteed safety, the purpose of which, in his opinion decisive, is to be able to act simultaneously on several very different components that share in common the unaesthetic manifestation of one or more excessive - usually uneven - and unaesthetic (and / or undesirable) areas of skin pigmentation, namely to induce an effective effect on the production of melanin, together with the effective effect on the production of melanin observed with respect to at least one other pigment component and the intrinsic regulatory factors to which they are involved.

[0014] To this end, the inventors have formulated the following description:

[0015] A) Although, as stated previously, the main factor determining skin color remains the dark pigment (brown / melanin), and although, as explained previously, such pigmentation is primarily related to the function of melanocytes and the enzyme responsible for melanogenesis (tyrosinase), without being bound by theory, the inventors aim to develop compounds / new substances that in parallel target other biological targets, i.e. cell populations other than individual peripheral melanocytes and keratinocytes, also capable of regulating other intrinsic aetiological factors of the constitutive pigmentation of the skin, such as the signal transduction pathways that produce the pigment system (Bastonini E. et al., Ann. Dermatol, 2016, Vol. 28 No. 3, pp. 279-289); this "multifactorial" approach:

[0016] making it possible to differentiate itself from topical monotherapies that are often specifically aimed at inhibiting tyrosinase and the resulting melanin production, or the transfer of melanin-laden melanosomes to keratinocytes; and

[0017] Proving particularly suitable in cosmetic (or dermocosmetic) cases such as infraorbital hyperpigmentation, involving and highlighting the duality of the pigments responsible, melanin and haemosiderotic pigmentation (Souza DM et al., Surg. Cosmet. Dermatol, 2011, Vol. 3, No. 3, pp. 233-239), or melasma and telangiectatic macules with a suspected link between pigmentation and microvascular formation in the regulation of physiological skin pigmentation (Regazzetti C. et al., Annales de Dermatologie et de Vénéréologie, 2015, Vol. 142, No. 12, p. S482 - Regazzetti C. et al., J. Invest. Dermatol, 2015, Vol. 135, No. 12, pp. 3096-3104);

[0018] B) These new compounds / substances primarily intended for incorporation into cosmetic products must be safe with regard to health and comply with the European cosmetic and chemical regulations (Regulation (EC) No 1223 / 2009 and Regulation (EC) No 1907 / 2006 of the European Parliament and of the Council, respectively) in order to guarantee consumer safety.

[0019] Thus, as stated above, the present invention was developed under conditions of ambitious research and specification. It was in this context, at the end of extensive research work carried out in particular with the aid of a variety of biological evaluation models, that the inventors subsequently discovered, surprisingly (in view of the teachings of the prior art to date), that a specific family of compounds developed was able to exhibit an advantageous general behavior, while meeting the requirements defined in points A) and B) above. The compounds in question are imidazolyl derivatives (or their cosmetically or dermatologically acceptable salts) having the following general formula (I):

[0020]

[0021] in:

[0022] R 1 and R 2 independently of one another represent a hydrogen atom or a methyl group;

[0023] R 3 yes:

[0024] i) a heterocycle selected from the group consisting of:

[0025]

[0026] ii) or a hydrocarbon chain having the following formula (IV):

[0027]

[0028] Where n=1 or 2.

[0029] The present invention therefore relates to the non-therapeutic cosmetic or dermocosmetic use of at least one imidazolyl derivative of the following general formula (I) or a cosmetically or dermocosmetically acceptable salt thereof:

[0030]

[0031] in:

[0032] R 1 and R 2 independently of one another represent a hydrogen atom or a methyl group;

[0033] R 3 yes:

[0034] i) a heterocycle selected from the group consisting of:

[0035]

[0036] ii) or a hydrocarbon chain having the following formula (IV)

[0037]

[0038] Where n = 1 or 2,

[0039] The use is for locally reducing the visibility of excessive and unaesthetic (and / or undesirable) skin pigmentation, which is characterized by the local accumulation of endogenous pigments, preferably endogenous pigments responsible for natural skin color.

[0040] According to a preferred embodiment of the invention, the local accumulation of endogenous pigments, characterizing said excessive and unaesthetic (and / or undesirable) skin coloration, is a local accumulation of at least two different types of endogenous pigments responsible for natural skin color, in particular a local accumulation of melanin and hemoglobin.

[0041] Therefore, another object of the present invention is the non-therapeutic cosmetic or dermocosmetic use of at least one imidazolyl derivative of the following general formula (I) or a cosmetically or dermocosmetically acceptable salt thereof:

[0042]

[0043] in:

[0044] R 1 and R 2 independently of one another represent a hydrogen atom or a methyl group;

[0045] R 3 yes:

[0046] i) a heterocycle selected from the group consisting of:

[0047]

[0048] ii) or a hydrocarbon chain having the following formula (IV):

[0049]

[0050] Where n = 1 or 2,

[0051] The use is for locally reducing the visibility of excessive and unaesthetic (and / or undesirable) skin pigmentation, which is characterized by the local accumulation of at least two different types of endogenous pigments responsible for the natural skin color.

[0052] More specifically, and without being bound by theory, the compounds according to the invention have in particular the following characteristics:

[0053] An entity having a peptidomimetic structure, in other words, capable of advantageously mimicking the biological behavior of active peptide compounds (oligopeptides, proteins) in three-dimensional space but with enhanced stability against proteolysis and enhanced local bioavailability;

[0054] The peptidomimetic structures all bear an imidazole heterocyclic aromatic ring due to the peptide coupling (forming an amide-type bond) involved between a selected amine functionality of a biogenic primary amine comprising such a nuclear unit and a selected carboxylic acid functionality of an α-amino acid (i.e. the amino group is at the α position), which α-amino acid is either aliphatic or heterocyclic.

[0055] Furthermore, these imidazolyl derivatives of general formula (I) are safe from a health point of view and comply with European cosmetic and chemical regulations (Regulation (EC) No. 1223 / 2009 and No. 1907 / 2006 of the European Parliament and of the Council, respectively) in order to guarantee consumer safety, as required.

[0056] Furthermore, the imidazolyl derivatives of the general formula (I) which can be used according to the invention exhibit an advantageous general behavior, which is explained by a series of beneficial technical effects, which are in particular:

[0057] The first is the ability to capture and thus specifically block the metal cofactor (copper) essential for the enzymatic activity of tyrosinase (see Example 1 below), and thus ultimately limit the biological function of said metal cofactor, wherein:

[0058] The active concentration, in this case, is the median effective concentration (referred to as the "EC 50 ” concentration), which is surprisingly low, especially for one of the preferred peptoids that can be used according to the present invention (67.4 μM, i.e. a mass concentration of 0.0014% or 14 ppm), and in addition, at the same level (65 μM, i.e. a mass concentration of 18 ppm) as a so-called “reference” agent for chelating metal ions and neutralizing their toxicity, namely EDTA or ethylenediaminetetraacetic acid (George T., Brady M. F. Ethylenediaminetetraacetic Acid (EDTA) [updated on June 27, 2022]. In: Stat Pearls [Internet]. Treasure Island (FL): Stat Pearls Publishing; January 2022);

[0059] In the above mentioned EC 50 (14 ppm), which is estimated to be comparable to the EC exhibited, for example, by peptide compounds in the prior art presented as “anti-tyrosinase” (Yap PG et al., Foods, 2021, 10(675), pp. 1-17). 50 very different, especially since they behave in the same copper II chelating activity (same experimental protocol as the present invention) and in fact have the smallest EC at a mass concentration of at least (after extrapolation) 0.5% (i.e. 5000 ppm) of the peptide chelator 50 , and therefore deviate greatly from the embodiments according to the invention;

[0060] In the above mentioned EC 50, which is surprisingly low for the active concentration observed for one of the preferred peptoids that can be used according to the invention (14 ppm), and therefore for very small amounts of solute dissolved, whereas, on the other hand, the two substrates [i.e., (2S)-pyrrolidine-2-carboxylic acid, on the other hand generally known as L-proline in the IUPAC nomenclature, and the amine 2-(1H-imidazol-5-yl)ethylamine, on the other hand generally known as histamine] used to obtain by chemical means the preferred compound that can be used according to the invention [(2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide in the IUPAC nomenclature], show a chelation behavior towards the same amount of copper II that is much less than that observed for the preferred peptoids mentioned above, or even no chelation behavior towards one of the two substrates;

[0061] Then there is the ability to inhibit the enzymatic activity of tyrosinase (see Example 2 below) and thus finally the ability to limit the specific production of the first type of pigment (chromophore) responsible for the natural skin color, namely melanin, wherein:

[0062] The active concentration, in this case, is the median inhibitory concentration (referred to as the "IC 50 " concentration):

[0063] Tyrosinase is again estimated to differ from the efficacy claimed for example for prior art oligopeptides, which are commercially used as “anti-melasma agents” due to their ability to interact with tyrosinase enzymatic activity and more generally slow down key enzymes in the pigmentation process (Lima TN et al., Cosmetics, 2018, 5(21), pp. 1-9), although at what appears to be much higher concentrations (at least 1% mass concentration) given the fact reported in the same article that “As a signal peptide, it interacts well with cells when used at concentrations of 1.0-2.5%”;

[0064] Finally, the ability to precisely act on the subcutaneous microvascular component and in the context of point A) mentioned above is of interest, and is another major, unique and unexpected aspect of the present invention:

[0065] Inhibitory effect on the expression of vascular cell adhesion protein molecule type 1 (abbreviated as "VCAM-1") (see Example 3 below), in other words, a marker present on the surface of endothelial cells that are in direct contact with the blood, since endothelial cells line the interior of dermal capillaries:

[0066] When the marker is associated with inflammatory phenomena, it acts as a marker regulating vascular adhesion and trans-endothelial diapedesis (Kong DH et al., Int. J. Mol. Sciences, 2018, Vol. 19, pp. 1-16);

[0067] As a final result, in the case of the present invention, the ability of the second type of pigment (chromophore) responsible for natural skin color, namely the chromophore hemoglobin and its related broken down pigments (hemosiderin, etc.) to extravasate outside the skin vasculature is slowed, and this second type of pigment is also responsible for the visible changes in pigmentation in the dermal and subcutaneous layers.

[0068] It is also important to emphasize the unexpected nature of the test results in Example 3, in particular the inhibition observed on VCAM-1 expression, in view of the opposite behavior of a commercially available dipeptide substance that is structurally similar to the imidazolyl derivative of general formula (I) tested, namely, (2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-pyrrolidine-2-carbonyl]amino]propionic acid (commonly known as NL-prolyl-L-histidine) in the IUPAC systematic nomenclature.

[0069] It should also be noted that the imidazolyl derivatives of the general formula (I) that can be used according to the present invention are structurally different from the peptides, related compounds and derivatives with imidazole units that belong to the prior art and are mentioned at the end of the section entitled "State of the Art" above. In addition, unlike the imidazolyl derivatives of the general formula (I) that can be used according to the present invention above, the same peptides, related compounds and derivatives with imidazole units that belong to the prior art only specifically target the inhibitory effect on tyrosinase and / or the inhibitory effect on the production of melanin. Finally, the results shown by the tests in Example 2 of the present invention are all more unexpected, because it should also be emphasized that the rather melanogenesis-inducing behavior (rather melanogenesis-inducing behavior) shown by the biological amine histamine and / or its imidazole metabolic byproducts (Tomita Y. et al., J. Dermatol. Sci, 1993, Vol. 6 No. 2, pp. 146-154).

[0070] Preferably, for the use according to the invention, the at least one imidazolyl derivative of the general formula (I) or a cosmetically or dermatologically acceptable salt thereof is:

[0071] (a) Make R 1 and R 2 Each represents a hydrogen atom, R 3 is a heterocyclic ring selected from:

[0072]

[0073] Preferably, R 3 yes:

[0074]

[0075] (b) Make R 1 and R 2 Each represents a hydrogen atom, R 3 is a hydrocarbyl chain of formula (IV) wherein n is equal to 2;

[0076] Preferably, the at least one imidazolyl derivative of the general formula (I) is (in IUPAC nomenclature):

[0077] Compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide [that is, in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 having formula (II)], advantageously, the enantiomer of its absolute configuration S, and specifically, the compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or

[0078] Compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid [that is, in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 is a hydrocarbon chain of formula (IV) wherein n is equal to 2], advantageously, an enantiomer of its absolute configuration S, and specifically, the compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid.

[0079] The salts of the imidazolyl derivatives according to the present invention, in particular the preferred compounds mentioned above, can be obtained by reacting the derivatives and compounds with an inorganic acid (preferably hydrochloric acid) or an organic acid. In particular, the cosmetically or dermatologically acceptable salt according to the present invention is a hydrochloride.

[0080] According to one embodiment of the invention, the excessive skin pigmentation characterized by local accumulation of endogenous pigments is located in the skin area showing infraorbital hyperpigmentation. In this case, the at least one imidazolyl derivative of general formula (I) or its cosmetically or dermatologically acceptable salt for the purposes of the present invention is preferably:

[0081] (a) Make R 1 and R 2 Each represents a hydrogen atom, R 3 is a heterocyclic ring selected from:

[0082]

[0083] Preferably, R 3 yes:

[0084]

[0085] (b) Make R 1 and R 2 Each represents a hydrogen atom, R 3 is a hydrocarbyl chain of formula (II) wherein n is equal to 2.

[0086] In this embodiment, preferably, the at least one imidazolyl derivative of the general formula (I) is (in IUPAC systematic nomenclature):

[0087] Compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide [that is, in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 having formula (II)], advantageously, the enantiomer of its absolute configuration S, and specifically, the compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or

[0088] Compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid [that is, in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 is a hydrocarbon chain of formula (IV) wherein n is equal to 2], advantageously, an enantiomer of its absolute configuration S, and specifically, the compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid.

[0089] Another object of the present invention also relates to the use mentioned above, wherein the imidazolyl derivative of general formula (I) or its cosmetically or dermatologically acceptable salt is contained in a cosmetic or dermatological composition, preferably with a content of about 0.1% to 2% by weight (for example, between 0.2% and 1.5% by weight) relative to the total weight of the composition, the composition also comprising at least one cosmetically or dermatologically acceptable excipient, the composition is preferably in a form suitable for topical application, and the at least one excipient is also physiologically acceptable to the skin. In fact, the imidazolyl derivative of general formula (I) that can be used according to the invention or its cosmetically or dermatologically acceptable salt that can be used according to the invention can also be used as a cosmetic active ingredient or dermatologically active ingredient (for example, as the only cosmetic active ingredient or dermatologically active ingredient) in a cosmetic or dermatological composition, the cosmetic or dermatological composition also comprising at least one cosmetically or dermatologically acceptable excipient, as stated above. According to one embodiment, in the case of such a cosmetic composition or a dermatological composition, the imidazolyl derivative of the general formula (I) is a peptidomimetic compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide in the IUPAC systematic nomenclature [i.e., in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 Having formula (II)].

[0090] The present invention also relates to a non-therapeutic cosmetic composition or dermatological composition, which comprises (or is mainly composed of) at least one imidazolyl derivative having the following general formula (I) or a cosmetically or dermatologically acceptable salt thereof:

[0091]

[0092] in:

[0093] R 1 and R 2 independently of one another represent a hydrogen atom or a methyl group;

[0094] R 3 yes:

[0095] i) a heterocycle selected from the group consisting of:

[0096]

[0097] ii) or a hydrocarbon chain having the following formula (IV):

[0098]

[0099] Where n = 1 or 2,

[0100] The non-therapeutic cosmetic or dermocosmetic composition is used to locally reduce the visibility of excessive and unaesthetic (and / or undesirable) skin pigmentation, which is characterized by the local accumulation of endogenous pigments, preferably endogenous pigments responsible for natural skin color.

[0101] Still in the field of "cosmetics" (or dermocosmetics), the present invention also relates to a non-therapeutic cosmetic or dermocosmetic method for locally reducing the visibility of excessive and unaesthetic (and / or undesirable) skin pigmentation characterized by the local accumulation of at least two different types of endogenous pigments responsible for the natural skin color, the method comprising:

[0102] (a) identifying areas of skin having said excessive and unaesthetic (and / or undesirable) skin pigmentation in a subject; and

[0103] (b) administering topically or orally to said subject, advantageously topically to said skin area, an effective amount of:

[0104] at least one imidazolyl derivative of the general formula (I) as defined above or a cosmetically or dermatologically acceptable salt thereof, or

[0105] A cosmetic or dermocosmetic composition as defined above.

[0106] According to one embodiment, the non-therapeutic cosmetic or dermocosmetic method comprises:

[0107] (a) identifying an area of ​​(healthy) skin in a subject that exhibits said excessive and unaesthetic (and / or undesirable) skin pigmentation (e.g. located in an area of ​​skin that exhibits infraorbital hyperpigmentation); and

[0108] (b) administering topically or orally to said subject, advantageously topically to said skin area, an effective amount of:

[0109] at least one imidazolyl derivative of the general formula (I) as defined above or a cosmetically or dermatologically acceptable salt thereof, or

[0110] A cosmetic or dermocosmetic composition as defined above.

[0111] As indicated in the preface of this patent application, another aspect of the invention, different from the "cosmetic" aspect, relates to the "dermatological" aspect. For this purpose, the invention also covers imidazolyl derivatives or dermatologically acceptable salts thereof having the following general formula (I):

[0112]

[0113] in:

[0114] R 1 and R 2 independently of one another represent a hydrogen atom or a methyl group;

[0115] R 3 yes:

[0116] i) a heterocycle selected from the group consisting of:

[0117]

[0118] ii) or a hydrocarbon chain having the following formula (IV):

[0119]

[0120] Where n = 1 or 2,

[0121] The imidazolyl derivatives of the general formula (I) or dermatologically acceptable salts thereof are used for treating skin pigmentation disorders.

[0122] The present invention also relates to imidazolyl derivatives having the following general formula (I) or dermatologically acceptable salts thereof:

[0123]

[0124] in:

[0125] R 1 and R 2 independently of one another represent a hydrogen atom or a methyl group;

[0126] R 3 yes:

[0127] i) a heterocycle selected from the group consisting of:

[0128]

[0129] ii) or a hydrocarbon chain having the following formula (IV):

[0130]

[0131] Where n = 1 or 2,

[0132] The imidazolyl derivatives of the general formula (I) or dermatologically acceptable salts thereof are useful for treating skin pigment disorders characterized by the local accumulation of at least two different types of endogenous pigments responsible for the natural skin color.

[0133] According to a preferred embodiment, at least one imidazolyl derivative of the general formula (I) mentioned above:

[0134] (a) Make R 1 and R 2 Each represents a hydrogen atom, R 3 is a heterocyclic ring selected from:

[0135]

[0136] R 3 Preferably:

[0137]

[0138] (b) Make R 1 and R 2 Each represents a hydrogen atom, R 3 is a hydrocarbyl chain of formula (IV) wherein n is equal to 2;

[0139] Preferably, the at least one imidazolyl derivative of the general formula (I) is (in IUPAC nomenclature):

[0140] Compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide [that is, in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 having formula (II)], advantageously, the enantiomer of its absolute configuration S, and specifically, the compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or

[0141] Compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid [that is, in the general formula (I) above, R 1 and R 2 Each represents a hydrogen atom, R 3 is a hydrocarbon chain of formula (IV) wherein n is equal to 2], advantageously, an enantiomer of its absolute configuration S, and specifically, the compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid.

[0142] Preferably, the skin pigmentation disorder characterized by the localized accumulation of at least two different types of endogenous pigments consists of localized accumulation of melanin and hemoglobin.

[0143] According to one embodiment of the present invention, the skin pigment disorder is selected from: solar lentigo, chloasma, rosacea and / or solar erythema. Preferably, solar lentigo and / or rosacea are selected. In the case of solar lentigo and / or rosacea mentioned above, an imidazolyl derivative of the general formula (I) or a dermatologically acceptable salt thereof is selected, wherein R 1 and R 2 Each represents a hydrogen atom, R 3 is a heterocyclic ring selected from:

[0144]

[0145] Still in the same case of solar lentigo and / or rosacea mentioned above, specifically mentioning as non-limiting examples of imidazolyl derivatives of general formula (I), the following peptidomimetic compounds (in IUPAC systematic nomenclature) can be prepared from:

[0146] (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide.

[0147] Furthermore, for their dermatological use, the above-mentioned imidazolyl derivatives of general formula (I) or their dermatologically acceptable salts may be included in a dermatological preparation, preferably in a content of about 0.1% to 2% by weight (e.g. between 0.2% and 1.5% by weight) relative to the total weight of the preparation, the dermatological preparation also comprising at least one dermatologically acceptable excipient, preferably the preparation is in a form suitable for topical application and the at least one excipient is also physiologically acceptable to the skin. In fact, the imidazolyl derivatives of general formula (I) or their dermatologically acceptable salts that can be used according to the invention can also be used as dermatologically active ingredients (e.g. as the only dermatologically active ingredient) in dermatological preparations, the dermatological preparations also comprising at least one dermatologically acceptable excipient, as indicated above. According to one embodiment, in such case of dermatological preparations, the imidazolyl derivative of general formula (I) is a peptidomimetic compound (in IUPAC systematic nomenclature): (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide.

[0148] The salts of the imidazolyl derivatives according to the invention, in particular the preferred compounds mentioned above, can be obtained by reacting the derivatives and compounds with an inorganic acid (preferably hydrochloric acid) or an organic acid. In particular, the dermatologically acceptable salt according to the invention is a hydrochloride.

[0149] Advantageously, both these dermatological preparations and the cosmetic or dermocosmetic compositions mentioned above are in a form suitable for topical (skin) administration, which is presented in all forms usually used for such administration. As an example and not a limitation, they may be in the form of aqueous or hydroalcoholic solutions that may be gelled, lotion-type dispersions that may be two-phase, emulsions of oil-in-water or water-in-oil, suspensions, lotions, creams, hydrogels or hydroalcoholic gels, or in the form of (micronized) powders, foams, slurries, pastes, suspensions, dispersions that may be microemulsions or nanoemulsions, or multiple emulsions. As far as adjuvants present in the compositions, preparations and other supplements mentioned above and physiologically compatible with the skin are concerned, mention may be made of compounds chosen from oils, waxes, silicone elastomers, surfactants, cosurfactants, thickeners and / or gelling agents, moisturizers, emollients, organic or inorganic sunscreens, light stabilizers, preservatives other than aldehyde-donating preservatives, colorants, abrasives, pearlescent agents, mattifying agents, tensing agents, chelating agents, fragrances, etc., and mixtures thereof. By way of example and not limitation, such adjuvants acceptable in the fields of application encompassed by the present invention are present in the formulation in a content of about 0.01% to 20% by weight relative to the total weight of the compositions, preparations or other supplements mentioned above, in particular, the adjuvants mentioned in the "International Cosmetic Ingredient Dictionary and Handbook", published by the "Personal Care Product Council" (PCPC) of the American Cosmetic Association. Finally, these same compositions, preparations and other supplements mentioned above may advantageously contain at least one additional active ingredient, however, the skilled person will ensure that these possible additional active ingredients and their proportions are selected in such a way that the recognized advantageous properties for these compositions, preparations and other supplements mentioned above are not or are not substantially altered by the addition under consideration.Such additional active ingredients may be chosen from, but are not limited to, depigmenting agents, photoprotective agents, agents stimulating barrier function, moisturizing agents or humectants, peeling agents, soothing agents and exfoliating agents, agents stimulating cell proliferation such as fibroblasts and keratinocytes, deglycating agents, agents stimulating the synthesis of collagen or elastin or preventing its breakdown, agents stimulating the synthesis of glycosaminoglycans or proteoglycans or preventing its breakdown, antioxidants or anti-free radical agents or anti-pollution agents, lipolysis stimulants, draining agents or detoxifying agents, anti-inflammatory agents, penetration accelerators, peeling agents, soothing agents and / or anti-irritants, astringents, exfoliating agents, agents acting on microcirculation, etc., and mixtures thereof, such additional active ingredients are present in the formulation in a content of 0.0001% to 20% by weight, preferably 0.01% to 5% by weight, relative to the total weight of the above-mentioned compositions, preparations and other supplements.

[0150] definition

[0151] General Definition

[0152] "Capacity to slow down extravasation outside the cutaneous vasculature" must be considered to mean the effect of limiting the abnormal diffusion / release of hemoglobin into the extracellular matrix of the skin under the effect of inflammation with a vascular component.

[0153] "In IUPAC systematic nomenclature" must be understood to mean the naming of chemical compounds according to a standardized system based on the most stringent recommendations established by the International Union of Pure and Applied Chemistry (IUPAC). These recommendations are intended to ensure that a name corresponds to one and only one molecular structure.

[0154] "Enantiomers of absolute configuration" must be understood to mean the enantiomers determined according to the common nomenclature system for describing the absolute configuration of two enantiomers (the system known as the "Cahn-Ingold-Prelog order rules").

[0155] An "enantiomer of absolute configuration S" must be understood to mean the enantiomer of the configuration in which the preferred substituents are "rotated" and which corresponds to a counterclockwise rotation.

[0156] Definition of cosmetics and dermatological (non-therapeutic)

[0157] "Infraorbital hyperpigmentation" must be considered to mean an aesthetic / cosmetic disorder with one or more areas of uneven and abnormal skin pigmentation, more colloquially known as "pigmented dark circles", also known as "periorbital hyperpigmentation" (Souza DM et al., Surg. Cosmet. Dermatol, 2011, Vol. 3, No. 3, pp. 233-239), or "infraorbital discoloration" (Sarkar R. et al., J. Clin. Aesthet. Dermatol, 2016, Vol. 9, No. 1, pp. 49-55), in other words, a manifestation of excessive pigmentation in the area around the eyes and constituting another local color difference that exists between the thin and transparent eyelid skin and the rest of the facial skin (Souza DM et al., Surg. Cosmet. Dermatol, 2011, Vol. 3, No. 3, pp. 233-239). It should also be noted that pigmented / dark circles, also known as "pigmented" circles, are etiologically different from hollow circles, which originate from the loss of periocular subcutaneous fat with age, which is mainly caused by the accumulation of melanin and hemoglobin in the tissues around the eyes, which accumulates through the extravasation of the chromophore hemoglobin and its related decomposed pigments (hemosiderin, etc.) outside the skin vascular system (Chavan M. et al., J. Cosmet. Sci. 2014, Vol. 65, No. 2, pp. 103-113; Vrcek I. et al., J. Cutan. Aesthet. Surg, 2016, Vol. 9, No. 2, pp. 65-72). Thus, depending on such pigment superposition / concentration combined with the intensity of such capillary permeability / leakage, the colour of the pigmented dark circles may vary between light yellow or brown to black or bluish purple, and thus result in a dark and aged appearance of the area, which is highly unaesthetic (and therefore undesirable).

[0158] Dermatological Definition

[0159] "Solar lentigo" must be understood to mean a skin disease characterized by patches of dark macular lesions.

[0160] “Melasma” must be considered to mean a skin disease that occurs primarily in women, especially during pregnancy and when taking hormonal therapy, and is characterized by the appearance of irregular patches of light to dark brown or gray-brown lesions on areas of the skin exposed to the sun, especially on the face (Nautiyal A. et al., Pigment Cell Melanoma Res, 2021, Vol. 00, pp. 1-15 and cited references).

[0161] According to medical terminology, "rosacea" or "telangiectasia" must be considered to mean a skin color disorder associated with the vascular development of small, very thin, red and sometimes even purplish blood vessels visible just under the surface of the skin. Detailed Description

[0163] The following detailed description is intended to illustrate the present invention in a sufficiently clear and complete manner, particularly using examples, but should in no way be construed as limiting the scope of protection to the specific embodiments and examples presented below. Example

[0164] Example 1: Test for demonstrating the ability of the imidazolyl derivatives according to the invention to specifically capture and block the metal cofactors necessary for the enzymatic activity of tyrosinase

[0165] Experimentally, testing was performed under the following conditions based on the publication: Seung-hwa Baek et al., "Protonpump inhibitors decrease melanogenesis in melanocytes" Biomedical Reports, 726-730, 2015.

[0166] In each well of a 96-well microplate, 100 μL of the imidazole derivative to be tested according to the present invention, 50 μL of 200 mM acetate buffer pH 6.0 and 50 μL of 800 μM CuSO 4 Solution. After 10 minutes, 50 μL of 800 μM purple pyrocatechol (PV) was added. After 20 minutes, the absorbance at 632 nm was measured. Ethylenediaminetetraacetic acid (EDTA, Sigma reference batch number MKBQ7974V) was used as a reference agent (control / positive control).

[0167] The results are summarized in Table 1 below and are specifically presented as median effective concentration or "EC 50 "The divalent copper ion (Cu 2+ ) is expressed as half of the effective chelating concentration [EC 50It is determined experimentally in mM and then converted to % by weight using the molecular molar mass of the imidazolyl derivatives which can be used according to the invention].

[0168] The imidazolyl derivatives according to the present invention are the following compounds:

[0169] (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, i.e., the enantiomer of the absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 = Formula (II)

[0170] (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, i.e., the enantiomer of the absolute configuration S of the compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 =Formula (IV) and n=2.

[0171] Table 1

[0172]

[0173] For the derivatives according to the invention, the results highlight the ability to inhibit the metal cofactors necessary for the enzymatic activity of tyrosinase, and at surprisingly low active concentrations, approximately that of the reference agent.

[0174] Example 2: Test for demonstrating the ability of the imidazolyl derivatives according to the invention to limit / inhibit the enzymatic activity of tyrosinase

[0175] The inhibition or induction of tyrosinase activity according to the imidazole derivatives of the present invention is assessed by adding tyrosinase and its substrate dopamine to a series of concentrations to be tested under optimal conditions (pH 6.5 and room temperature, about 25°C). The test mixture is incubated at room temperature for 15 minutes. During the incubation period, the amount of L-dopaquinone produced in the reaction mixture is determined by the spectrophotometry of dopachrome formation at 475nm in a microplate reader. Kojic acid (Sigma reference K3125 batch number BCCB7130) is used as a reference agent (control / positive control). For each imidazole derivative according to the present invention, the result is repeated three times.

[0176] The results are summarized in Table 2 below and are presented as median inhibitory concentration or “IC 50 The concentration required to achieve 50% inhibition of the activity of the amount of tyrosinase involved in the test is expressed as [IC 50 It is experimentally determined in mM and then converted to weight % using the molecular molar mass of the imidazolyl derivative according to the invention].

[0177] The imidazolyl derivatives according to the present invention are the following compounds:

[0178] (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, i.e., the enantiomer of the absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 = Formula (II)

[0179] (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, i.e., the enantiomer of the absolute configuration S of the compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 =Formula (IV) and n=2.

[0180] Table 2

[0181]

[0182] For the derivatives according to the invention, the results emphasize the ability to inhibit tyrosinase activity.

[0183] Example 3: Test for demonstrating the ability of the imidazole derivatives according to the present invention to inhibit the expression of type 1 vascular cell adhesion protein molecules

[0184] Human dermal microvascular endothelial cells (HDMEC) were obtained from Promocell (Batch 449Z005.3, cells isolated from breast tissue—43-year-old female patient).

[0185] The cells were cultured in MV2 endothelial cell growth medium + mixed supplement (Promocell) at 37°C and 5% CO. 2 Cultivation was performed. 24 hours after seeding, HDMEC cells were pretreated with the imidazolyl derivatives according to the invention for 2 h before the administration of 5 ng / ml of TNF-α (stress). The cells were then incubated for 22 hours.

[0186] After 24h treatment, cells were washed with PBS and subjected to CELISA to quantify the expression of VCAM-1 adhesion molecule. Absorbance was measured at 450nm using a spectrophotometer (Micro-Quant, BioTek Instruments). Deferoxamine (reference D9533 Sigma batch number BCCB3792) was used as a reference agent (positive control).

[0187] The results are collated in Table 3 below and are expressed as a percentage of inhibition of the expression of the VCAM-1 adhesion molecule.

[0188] The imidazolyl derivatives according to the present invention are the following compounds:

[0189] (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, i.e., the enantiomer of the absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 = Formula (II)

[0190] (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, i.e., the enantiomer of the absolute configuration S of the compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 =Formula (IV) and n=2.

[0191] (2S)-N-[2-(1H-imidazol-5-yl)ethyl]-5-oxopyrrolidine-2-carboxamide, i.e., the enantiomer of the absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]-5-oxopyrrolidine-2-carboxamide, which is the subject of the above general formula (I), wherein R 1 =R 2 =H; R 3 =Formula (III).

[0192] Table 3

[0193]

[0194] For the derivatives according to the invention, for one of them, unlike its peptide structural analogue, the results highlight the ability to limit the expression of vascular cell adhesion protein type 1 molecules, i.e. to slow down the extravasation of hemoglobin and related decomposed pigments (chromophores) outside the cutaneous vascular system.

Claims

1. Non-therapeutic cosmetic or dermatological use of at least one of the following imidazolyl derivatives of the following general formula (I) or a cosmetically or dermatologically acceptable salt thereof: in: R1 and R2 independently represent a hydrogen atom or a methyl group; R3 is: i) a heterocycle selected from the group consisting of: ii) or a hydrocarbon chain having the following formula (IV): Where n = 1 or 2 The use is for locally reducing the visibility of excessive and unsightly skin pigmentation in healthy subjects, characterized by localized accumulation of at least two different types of endogenous pigments responsible for natural skin color, in areas of the skin exhibiting infraorbital hyperpigmentation.

2. The use according to claim 1, characterized in that Said localized accumulation of at least two different types of endogenous pigments responsible for natural skin color is that of melanin and hemoglobin.

3. The use according to claim 1 or 2, characterized in that The at least one imidazolyl derivative of the general formula (I): (a) such that R1 and R2 each represent a hydrogen atom, and R3 is a heterocycle selected from the group consisting of: R3 is preferably: and / or (b) such that R1 and R2 each represent a hydrogen atom and R3 is a hydrocarbyl chain of formula (IV) wherein n is equal to 2; Preferably, the at least one imidazolyl derivative of general formula (I) is: The compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, advantageously the compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or The compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, advantageously the compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid.

4. The use according to any one of claims 1 to 3, wherein the imidazolyl derivative of general formula (I) or a cosmetically or dermatologically acceptable salt thereof is contained in a cosmetic composition or a dermatologically acceptable composition, and the cosmetic composition or the dermatologically acceptable composition further comprises at least one cosmetically or dermatologically acceptable excipient, and the composition is preferably in a form suitable for topical administration, and the at least one excipient is also physiologically acceptable to the skin.

5. The use according to any one of claims 1 to 4, wherein the cosmetically or dermatologically acceptable salt of the imidazolyl derivative of the general formula (I) is a hydrochloride.

6. The use according to claim 4, wherein the cosmetic composition or dermocosmetic composition as defined in claim 4 further comprises at least one additional active ingredient, the at least one additional active ingredient being selected from depigmenting agents, photoprotective agents, barrier function stimulants, moisturizing agents or humectants, peeling agents, soothing agents, exfoliating agents, agents that stimulate cell proliferation such as fibroblasts and keratinocytes, deglycation agents, agents that stimulate the synthesis of collagen or elastin or prevent their degradation, agents that stimulate the synthesis of glycosaminoglycans or proteoglycans or prevent their degradation, antioxidants or anti-free radical agents or anti-pollution agents, lipolysis stimulants, drainage agents or detoxifying agents, anti-inflammatory agents, penetration accelerators and / or anti-irritants, astringents, agents that act on microcirculation, and mixtures thereof.

7. A non-therapeutic cosmetic or dermocosmetic method for locally reducing the visibility of excessive and unaesthetic skin pigmentation characterized by localized accumulation of at least two different types of endogenous pigments responsible for natural skin color, said excessive and unaesthetic skin pigmentation being located in an area of ​​the skin exhibiting infraorbital hyperpigmentation, said method comprising: (a) identifying skin areas that exhibit said excessive and unattractive skin pigmentation in healthy subjects; as well as (b) administering topically or orally to said subject, advantageously topically to said skin area, an effective amount of: at least one imidazolyl derivative of the general formula (I) as defined in claim 1 or 3 or a cosmetically or dermatologically acceptable salt thereof, or A cosmetic composition or skin care composition as defined in claim 4.

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