NEW USES OF IMIDAZOLYL DERIVATIVES

Abstract

Non-therapeutic cosmetic or dermocosmetic use of at least one imidazolyl derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, cosmetic or dermocosmetic process involving the aforementioned at least one imidazolyl derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, to locally reduce the visibility of excessive and unsightly skin coloration characterized by a local accumulation of endogenous pigments.

Description

Title of the invention: NEW USES OF IMIDAZOLYL DERIVATIVES Field of invention

[0001] The present invention relates to new uses of imidazolyl derivatives to locally reduce the visibility of an unsightly skin manifestation associated with excessive and unsightly (and / or undesirable) skin coloration and characterized locally by an accumulation of endogenous pigments (chromophores). State of the art

[0002] A striking example of phenotypic diversity in humans, skin can display a wide variety of colors, ranging from pale or almost white to very dark shades (black), including various shades of light brown and chestnut brown (Ortonne JP, Annales de Dermatologie et de Vénéréologie, 2012, vol. 139, pp. S73-S77). Regardless of intrinsic factors determined at birth, such as genetic inheritance, or extrinsic factors such as sun exposure, human skin has a natural color conferred by a complex and subtle biochemical process: pigmentation.Thus, in the end, the color of so-called "normal" skin in humans results from the contribution and superposition / combination of four chromophore pigments, which are precisely oxyhemoglobin or oxygenated hemoglobin (red) from cutaneous capillaries, deoxygenated hemoglobin or reduced hemoglobin (blue) from dermal venules, carotene (yellow-orange) provided by dietary carotenoids, and finally melanin (brown to black) produced locally in melanocytes, specialized cells of the epidermis (Casadio S., EMC - Cosmetology and Aesthetic Dermatology, 2015 -http: / / dx.doi.org / 10.1016 / S2211-0380(15)62942-8).Despite this pigmentary plurality, the predominant factor in determining skin color, and consequently in the differences and variations in skin color between individuals, remains the dark pigment (melanin), due in particular to its size, intensity and typology, which is dual, with eumelanin (brown to dark black) distinct from pheomelanin (reddish yellow to light brown), but also due to the level of activity and distribution of melanosomes, intracellular organelles for the synthesis and storage of melanin pigments before their transfer to keratinocytes in order to ensure the pigmentation of the epidermis and its photoprotection against sun exposure (Delevoye C. et al., Med. Sci. (Paris), 2011 vol.27(2), pp. 153-162). As an illustration, it is noted that skin with dark pigmentation is associated with larger and more prolific melanosomes, and the melanin they produce is preserved longer in the keratinocytes. tinocytes are found in individuals with lighter skin than in those with lighter skin (Deng L. et al., Hereditas, 2018, vol. 155(1), pp.1-12 and references cited). Eumelanin is logically found in greater quantities in people with darker skin, while pheomelanin accumulates more in people with lighter skin (Barsh GS, PLoS Biology, 2003, vol. 1(1), pp.019-022). Finally, the universal Fitzpatrick classification, a reference tool for dermatologists, allows us to categorize skin phototypes (6 in total) according to the skin's ability, from strong to non-existent, to develop such dark to black pigmentation during sun exposure (Sachdeva S., Indian J. Dermatol. Venereol. Leprol., 2009, vol.75, pp.93-96).

[0003] In general terms, disorders affecting the color of so-called "normal" skin can be summarized as either an exaggeration of the natural skin color with the clinically localized appearance of uneven pigmented areas, particularly darker and darker patches, or, conversely, a reduction and pallor of the skin with the clinically localized appearance of lighter patches (Lipsker D. et al., Annales de Dermatologie et de Vénéréologie, 2019, vol. 146(10), pp. 666-682). Apart from any deleterious effects (melanoma, etc.), such "color defects" can also be perceived by the affected individual as unsightly and even undesirable because they are likely to disrupt the desired harmony of their complexion. In order to correct / reduce such defects affecting the appearance of the skin (and its aesthetic aspect) the field of so-called "aesthetic and cosmetic" dermatology has developed (Wollina U., Dermatology Therapy, 2008, vol.21(2), pp. 118-130). From a lexical standpoint, it is established, for example, that the noun "dyschromia" describes, whether endogenously or exogenously, diffusely or in well-defined areas, any deposit in the skin of various / any pigments that causes a change in the normal skin color (Braun-Flaco O. et al., Dermatology, 1991, chapter 27). More recently, some authors have also adopted other generic attributes to similarly broadly encompass any form of disorder related to discoloration, pigmentation, and darkening of the skin (Nautiyal A. et al., Pigment Cell Melanoma Res., 2021, vol. 00, pp. 1-15). In fact, it is clear that the range of such disorders, all sharing one or more areas of uneven and abnormal skin pigmentation, thus making the skin dark or discolored, is extensive because it varies in color and shape. Such a range is therefore likely to affect cutaneous pigmentary disorders of a:

[0004] a) purely dermatological (concerning sick subjects (patients) suffering from these pigmentary disorders of a pathological nature), such as solar lentigines, melasma, rosacea, solar erythema, vitiligo, but also

[0005] b) aesthetic / cosmetic (occurring in particular in "healthy" subjects, dissociable from the aforementioned sick subjects), such as infraorbital hyperchromia.

[0006] Although the aesthetic skin defects referred to in point b) above are entirely dissociable from the skin pathologies referred to in point a) above and generally concern distinct groups of individuals, as indicated previously, cosmetic solutions (if one is addressing a subject presenting the aesthetic / cosmetic disorders referred to in point b) above) and existing treatments (if one is addressing a sick subject (patient), suffering from one or more purely dermatological condition(s), such as presented in point a) above) target uneven and abnormal skin coloration / pigmentation affecting the natural skin color. In this regard, the state of the art displays, from a fundamental understanding of the skin pigmentation process and its complexity, technologies, products and targets described by some as "clinically proven" (Hakozaki T. et al., Textbook of Aging Skin, 2016, pp. 1017-1026).While there are no single best options per se, there is rather a range of solutions that can vary from minimally invasive or non-invasive interventions, such as the simple application of makeup (foundation) or more elaborate topical treatments to lighten the complexion, or even chemical peels, laser therapy, etc., to more invasive surgical procedures and other cosmetic medicine interventions such as dermabrasion, microneedling, skin grafting, and cell therapy (Pijpe, A. et al., 2020, pp. 109-115). One of these options, long favored, is the local application, using a topical preparation, of active ingredients to the skin capable of influencing its pigmentation level. In this respect, and particularly in the context of excessive melanin pigmentation, many ingredients, of synthetic or natural origin, were developed after the war for their ability to lighten the skin.Thus, the first ingredients historically found in creams, milks, gels, lotions, serums, and other cosmetic or dermo-cosmetic formulations intended for skin whitening were hydroquinone (a benzene derivative) and its derivatives, mercurial compounds (mercury oxide and chloride), retinoids such as retinoic acid, and certain dermocorticoids diverted from their therapeutic uses. However, due to their harmful effects and dangers observed over the years on human health (potentially carcinogenic, causing skin problems, etc.), some of these "early" skin-whitening substances are now subject to strict regulations, primarily European and American legislation, and, as with hydroquinone since Regulation (EC) No. 344 / 2013, even appear on a list of substances prohibited in cosmetic products.As an alternative to these health restrictions and bans, ingredient manufacturers have turned to substitute products, either of natural origin such as kojic acid (produced by several species of fungus), arbutin (phenolic heteroside contained in the leaves and bark of many plants), and so on. Niacinamide or ascorbic acid (vitamins naturally present in certain foods), or azelaic acid (derived from the fermentation of cereal grains or by lipoperoxidation of polyunsaturated fatty acids via a yeast present on the skin's surface), or non-cytotoxic plant extracts also possessing skin-lightening properties, such as extracts of licorice, mulberry, and bearberry (Fernandez X. et al., Techniques de l'Ingénieur, 2015, vol. J 2 300, pp. 1-33, and references cited). Here again, some national regulations, like those of Switzerland, have subsequently restricted or prohibited the use of some of these naturally derived substances (kojic acid, arbutin) in light of the evidence of undesirable and systemic side effects: toxicity, irritation, dryness, and skin sensitization.Regarding the biological mechanisms of action, many of the aforementioned active ingredients, as well as a multitude of others like those compiled in a recent review article (Pillaiyar T. et al., J. Med. Chem., 2018, vol.61(17), pp.7395-7418), logically display an inhibitory effect on tyrosinase, a key metalloenzyme in the conversion of tyrosine into melanin by melanocytes, with an effect shared between a limiting action on melanin production (case of hydroquinone, azelaic acid, and arbutin mentioned above) and that of a competitive interaction with the non-protein enzymatic cofactor of tyrosinase, copper (case of kojic and ascorbic acids mentioned above).Other agents have also sought, among other things, the inhibition of the transfer of melanosomes to keratinocytes (case of the aforementioned niacinamide), the inhibition of tyrosinase transcription (case of the aforementioned retinoic acid derivatives), the blocking of inflammation, the scavenging of free radicals (case of glycyrrhetinic acid extracted from the aforementioned licorice and its roots) but also more simply an increased renewal of the epidermis by a desquamating effect in order to eliminate excess melanin (case of alpha-hydroxy acids such as glycolic and lactic acids) (Resende DISP et al., Appl. Sci., 2022, vol.12(775), pp.1-15 and references cited).

[0007] Also described were peptides and so-called "related" compounds, illustrated in particular by peptides conjugated to carboxylic acids (ascorbic, kojic, etc.), all endowed with the ability to artificially reduce cutaneous melanin levels by inhibiting the enzymatic activity of tyrosinase (Boo YC, Bio-medicines, 2020, vol. 8(9), pp.1-26). Also noteworthy is the synthesis of 2-substituted benzy 1-4(7)-phenyl-1H-benzo[d]imidazole-type compounds, for their inhibitory action on tyrosinase at IC50 values ​​close, for some, to that of the reference substance, kojic acid (Dogan IS et al., Arch. Pharm. Chem. Life Sci., 2016, vol. 349(11), pp. 881-888), or the patent applications FR2917087 and WO2008006824, which respectively sought protection for 4-phenylimidazole-2-thiones type compounds and imidazole-2-thione, for the purposes of prevention, or pharmaceutical or cosmetic treatment, of pigmentary disorders, including post-inflammatory or metabolic or drug-induced disorders, despite the rather melanogenesis-inducing behavior expected for histamine and / or its imidazole metabolizing by-products (Tomita Y. et al., J. Dermatol. Sci., 1993, vol. 6(2), pp. 146-54; Liu J. et al., Skin Pharmacol. Physiol., 2017, vol.30(3), pp. 139-145; Yoshida M. et al., J. Invest. Dermatol., 2000, vol. 114(2), pp.334-42). Furthermore, the aforementioned peptides, related compounds and derivatives bearing an imidazole motif belonging to the prior art specifically target only an inhibitory action on the tyrosinase enzyme and / or on the production of melanin pigments, which is likely to limit their effectiveness.

[0008] In any event, and despite the availability of multiple and varied treatments / therapies intended to remedy / correct these pigmentation disorders that may affect the natural color of the skin, such a skin problem continues to be today, still and always, an interesting "challenge" for both the cosmetic and dermatological industries, as they are constantly searching for new safe and ever more effective ingredients.

[0009] The present invention is fully in line with this challenge of researching a better and more effective approach aimed at remedying, in a comprehensive and new / original way, an unsightly manifestation having as a common point one or more areas of excessive - generally uneven - and unsightly (and / or undesirable) skin coloration. Description of the invention

[0010] Also, based on all these observations and elements of literature, the inventor has focused on solving the following objective technical problem: to make available on the market cosmetic active ingredients interacting on the production of cutaneous pigments (chromophores), ingredients with improved behavior and assured safety, with the objective, decisive in his eyes, of being able to act simultaneously on several very distinct components of unsightly manifestations having in common one or more areas of excessive - generally uneven - and unsightly (and / or undesirable) skin coloration, namely to induce an effective action on the production of melanin coupled with that observed with regard to at least one other pigmentary component, and their intrinsic regulatory factors involved.

[0011] To achieve this, the inventor established the following specifications:

[0012] A) although the predominant factor in determining skin color remains dark pigment (brown / melanin), as previously indicated, and such pigmentation is primarily linked to the functionality of melanocytes and the enzyme (tyrosinase) responsible for melanogenesis, as previously explained, and without However, while being linked by theory, the inventor aimed to develop compounds / new substances that simultaneously target other biological targets, namely a cell population other than just the surrounding melanocytes and keratinocytes, and other intrinsic etiological factors also likely to regulate the constitutive pigmentation of the skin, such as the signaling pathways producing the pigmentary system (Bastonini E. et al., Ann. Dermatol., 2016, vol. 28(3), pp. 279-289); this "multifactorial" approach:

[0013] - allowing it to stand out from topical monotherapies very often directed towards the exclusive inhibition of tyrosinase and the resulting production of melanin, or even that of the transfer of melanin-loaded melanosomes to keratinocytes; and

[0014] - proving particularly suitable, for example, in the cosmetic context (or dermocosmetics) of infraorbital hyperchromia with the implication and highlighting of a duality of responsible pigments, melanic and hemosiderotic (Souza DM et al., Surg. Cosmet. Dermatol., 2011, vol.3(3), pp.233-239) or that of melasma and telangiectatic macules with the suspected link between pigmentation and microvascularization in the regulation of physiological skin pigmentation (Regazzetti C. et al., Annales de Dermatologie et de Vénéréologie, 2015, vol. 142(12), pp.S482 - Regazzetti C. et al., J. Invest. Dermatol., 2015, vol. 135(12), pp.3096-3104);

[0015] B) these new compounds / substances intended mainly to be incorporated into cosmetic products must be safe from a health standpoint and comply with European cosmetic and chemical regulations (respectively Regulations (EC) No 1223 / 2009 and No 1907 / 2006 of the European Parliament and of the Council) in order to guarantee consumer safety.

[0016] The present invention was therefore developed within such an ambitious research context and specifications as indicated above. It was in this context that, following extensive research, conducted in particular using various biological evaluation models, the inventor discovered, to his surprise (in light of the prior art at that time), that a limited family of developed compounds was likely to exhibit generally advantageous behavior while meeting the requirements defined in points A) and B) above. Specifically, these are imidazolyl derivatives with the following general formula (I) (or one of their cosmetically or dermocosmetically acceptable salts):

[0017] in which:

[0018] - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group;

[0019] - R3 is:

[0020] i) let a heterocycle be chosen from: thread!)

[0021] ii) or an alkyl chain of the following formula (IV): H 0,0--(CHjïn OH | S (IV) NH2

[0022] in which n = 1 or 2.

[0023] The invention therefore relates to the cosmetic or non-therapeutic dermocosmetic use of at least one imidazolyl derivative of the following general formula (I), or one of its cosmetically or dermocosmetically acceptable salts:

[0024] in which:

[0025] - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group;

[0026] - R3 is:

[0027] i) Let a heterocycle be chosen from: H 00 (!!!)

[0028] ii) or an alkyl chain of the following formula (IV): HO^C----------CH : 5 | ? W) NH2

[0029] in which n = 1 or 2

[0030] to locally reduce the visibility of excessive and unsightly (and / or undesirable) skin coloration characterized by a local accumulation of endogenous pigments (preferably responsible for the natural skin color).

[0031] According to a preferred embodiment of the invention, the local accumulation of endogenous pigments (characterizing the aforementioned excessive and unsightly (and / or undesirable) skin coloration) is a local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin, in particular a local accumulation of melanin pigments and heme pigments.

[0032] The invention therefore also relates to the cosmetic or non-therapeutic dermo-cosmetic use of at least one imidazolyl derivative of the following general formula (I), or one of its cosmetically or dermo-cosmetically acceptable salts: r2 H an~—'

[0033] in which:

[0034] - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group;

[0035] - R3 is:

[0036] i) Let a heterocycle be chosen from: -?" ■ «A / A ■ H oo (k;)

[0037] ii) or an alkyl chain of the following formula (IV): HOjC (CH 2)rl Cri ? | S WJ NHa

[0038] in which n = 1 or 2

[0039] to locally reduce the visibility of excessive and unsightly (and / or undesirable) skin coloration characterized by a local accumulation of at least two different types of endogenous pigments responsible for the natural skin color.

[0040] More specifically, and without being bound by theory, the compounds according to the present invention possess in particular the following characteristics:

[0041] - possessing structures of a peptidomimetic nature, in other words an entity capable of favorably mimicking the biological behavior of active peptide compounds (oligopeptides, proteins) in three-dimensional space, but with in particular enhanced stability against proteolysis and increased bioavailability via topical application;

[0042] - said peptidomimetic structures all bearing an aromatic ring heterocyclic of the imidazole type, by virtue of the peptide coupling involved (with formation of an amide-type bond) between the amine function of a selection of biogenic primary amines containing such a nuclear motif and the carboxylic acid function of a selection of α-amino acids (i.e., amino acids in the alpha position), the latter being of an aliphatic or heterocyclic nature.

[0043] Furthermore, as sought, these imidazolyl derivatives of general formula (I) are safe from a health point of view and comply with European cosmetic and chemical regulations (respectively Regulations (EC) No 1223 / 2009 and No 1907 / 2006 of the European Parliament and of the Council) in order to guarantee consumer safety.

[0044] Moreover, the imidazolyl derivatives of general formula (I) usable according to the invention exhibit generally advantageous behavior, illustrated by a range of beneficial technical effects, including:

[0045] - a capacity firstly to trap and therefore specifically block the cofactor me Talc (copper) is essential for the enzymatic activity of tyrosinase (see example 1 below), consequently limiting its biological function, and this:

[0046] - at an active concentration, in this case in terms of effective concentration median required to chelate half of the copper(II) involved in the test of Example 1 (concentration designated "EC50"), surprisingly low, particularly for one of the preferred peptidomimetics usable according to the invention (67.4 pM, i.e., 0.0014% or 14 ppm by mass concentration), and moreover at the same level (65 pM, i.e. 18 ppm by mass concentration) than the so-called "reference" agent for the chelation of metal ions and the neutralization of their toxicity, namely EDTA or ethylenediaminetetraacetic acid (George T., Brady MF Ethylenediaminetetraacetic Acid (EDTA) [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-);

[0047] - to the aforementioned EC50 (14 ppm) estimated to be very different from that displayed by example by prior art peptide compounds (Yap PG et al., Foods, 2021, 10(675), pp. 1-17) presented as "anti-tyrosinase" due in particular to their performance in the same copper II chelation activity (experimental protocol identical to the present invention), with effectively EC50s in chelating peptide agent at a minimum (after extrapolation) of 0.5% by mass concentration (i.e. 5000 ppm) and de facto very far from the illustrations according to the present invention;

[0048] - to the aforementioned EC50, which is surprisingly low for one of the preferred peptidomimetics usable according to the invention (14 ppm), consequently an active concentration observed from the dissolution of very small quantities of solute, whereas on the contrary the two substrates [which are precisely, in IUP AC systematic nomenclature, (2S)-pyrrolidine-2-carboxylic acid or, trivially, L-proline on the one hand, amine 2-(1H-imidazol-5-yl)ethanamine or, trivially, histamine on the other hand] at the origin of the chemically obtained said preferred compound usable according to the invention [the (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide in IUP AC systematic nomenclature], exhibit a chelating behavior with respect to the same quantity of copper II much below that observed for the aforementioned preferred peptidomimetic, or even non-existent for one of the two substrates;

[0049] - a capacity to then inhibit the enzymatic activity of tyrosinase (see example 2 (see below), consequently ultimately to limit the specific production of a first type of pigment (chromophores) responsible for the natural color of the skin, namely melanin pigments, and this:

[0050] - at an active concentration, in this case in terms of inhibitory concentration median required to achieve 50% inhibition of the tyrosinase enzyme involved in the test of example 2 (concentration designated "ZC50"):

[0051] - the latter being considered to be again differentiating from the efficiency claimed by example by an oligopeptide of the prior art commercially exploited as an "anti-melasma" agent for its ability to interact on the activity of tyrosinase and more broadly to slow down the key enzymes of the pigmentation process (Lima TN et al., Cosmetics, 2018, 5(21), pp. 1-9), but at concentrations which appear to be much higher (at least 1% by mass concentration) in view of the fact reported in the same article "A sa signal peptide, it interacts well with cells when used at concentrations of 1.0-2.5%";

[0052] - finally, a capacity, and this is another major, unique and unexpected aspect of the This invention, which is also capable of acting on a subcutaneous microvascular component precisely through, and of interest in the context of point A) mentioned above:

[0053] - an inhibitory effect on the expression of cell adhesion protein molecules vascular type 1 (abbreviation "VCAM-1") (see example 3 below), in other words markers present on the surface of endothelial cells in direct contact with blood because they line the inside of dermal capillaries:

[0054] - markers whose role is to regulate vascular adhesion and trans diapedesis endothelial when they are associated with an inflammatory phenomenon (Kong DH et al., Int. J. Mol. Sciences, 2018, vol.19, pp. 1-16);

[0055] - consequently, in the end, within the framework of the present invention, a capacity to brake extravasation outside the cutaneous vascularization of a second type of pigment (chromophores) responsible for the natural color of the skin, that of the chromophore hemoglobin and its related degradation pigments (hemosiderin, etc.), which also cause visible changes in pigmentation in the cutaneous and subcutaneous layers.

[0056] It is also important to emphasize the unexpected nature of the results of the test which is the subject of Example 3, in particular the inhibitory effect observed on the expression of VCAM-1 in view of the contrary behavior of a dipeptide substance structurally analogous to the imidazolyl derivative of general formula (I) tested, commercially available, namely, in IUP AC systematic nomenclature, (25)-3-(1 / / -imidazol-5-yl)-2-[[(25)-pyrrolidine-2-carbonyl]amino]propanoic acid (trivially referred to as NL-prolyl-L-histidine).

[0057] It should also be emphasized that the imidazolyl derivatives of general formula (I) usable according to the invention are structurally distinct from the peptides, related compounds, and derivatives bearing an imidazole motif belonging to the prior art and mentioned above, at the end of the section entitled "Prior Art". Furthermore, these same peptides, related compounds, and derivatives bearing an imidazole motif belonging to the prior art specifically target only an inhibitory action on the tyrosinase enzyme and / or on the production of melanin pigments, unlike the imidazolyl derivatives of general formula (I) above usable according to the invention. Finally, the results shown by the test of example 2 of the present invention are all the more unexpected given that the rather melanogenesis-inducing behavior shown for the biogenic amine histamine and / or its imidazole metabolizing by-products should also be highlighted (Tomita Y. et al., J.Dermatol. Sci., 1993, vol. 6(2), pp. 146-54). .

[0058] Preferably, with regard to use according to the invention, said at least one

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066] an imidazolyl derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, is: (a) such that Ri and R2 each represent a hydrogen atom, R3 is a heterocycle chosen from: preferably R3 being: (b) such that Ri and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2; preferably said at least one imidazolyl derivative of general formula (I) being (in IUP systematic nomenclature AC): - the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide [namely, in the general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is of formula (II)], advantageously its enantiomer with absolute configuration S with precisely the compound (2S)-N-[2-(lH-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or - the acid compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid [namely, in the general formula (I) above, Ri and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2], advantageously its enantiomer of absolute configuration S with precisely the acid compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid. The salts of said imidazolyl derivatives according to the invention, in particular of the aforementioned preferred compounds, can be obtained by reaction of said derivatives and compounds with an inorganic acid, preferably hydrochloric acid, or an organic acid, in particular said cosmetically or dermocosmetically acceptable salt according to the invention is a hydrochloride. According to one embodiment of the invention, said excessive skin pigmentation, characterized by the local accumulation of endogenous pigments, is located in a cutaneous area exhibiting infraorbital hyperpigmentation. In this case, said at least one imidazolyl derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, used for the purposes of the present The invention is preferably:

[0067] (a) such that Ri and R2 each represent a hydrogen atom, R3 is a heterocycle chosen from:

[0068] preferably R3 being: / ----A , and / or vile}

[0069] (b) such that Ri and R2 each represent a hydrogen atom, R3 is a chain alkyl of formula (II) in which n is equal to 2.

[0070] In this embodiment, preferably, said at least one imidazolyl derivative of general formula (I) is (in IUP AC systematic nomenclature):

[0071] - the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide [namely, in the general formula (I) above, Ri and R2 each represent a hydrogen atom, R3 is of formula (II)], advantageously its enantiomer of absolute configuration S with precisely the compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or

[0072] - the acidic compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic [namely, in the general formula (I) above, Ri and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2], advantageously its enantiomer of absolute configuration S with precisely the acidic compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid.

[0073] Another object of the invention also relates to the above-mentioned use, said imidazolyl derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, being included in a cosmetic or dermocosmetic composition, preferably in a concentration of approximately 0.1 to 2% by weight (for example, between 0.2 and 1.5% by weight) relative to the total weight of said composition, further comprising at least one cosmetically or dermocosmetically acceptable excipient, preferably said composition being in a form suitable for topical administration and said at least one excipient being physiologically acceptable to the skin. Indeed, said imidazolyl derivative of general formula (I) usable according to the invention, or one of its cosmetically or dermocosmetically acceptable salts usable according to the invention, can also be implemented, as a cosmetic or dermocosmetic active ingredient, in a cosmetic or dermocosmetic composition further comprising at least one cosmetically or dermocosmetically acceptable excipient, as indicated above. According to one embodiment, in such a cosmetic or dermocosmetic composition context, said imidazolyl derivative of general formula (I) is the peptidomimetic compound (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide in IUP AC systematic nomenclature [namely, in the general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is of formula (II)].

[0074] The invention also relates to a non-therapeutic cosmetic or dermocosmetic composition comprising at least one imidazolyl derivative of the following general formula (I), or one of its cosmetically or dermocosmetically acceptable salts:

[0075] in which:

[0076] - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group;

[0077] - R3 is:

[0078] i) Let a heterocycle be chosen from:

[0079] ii) or an alkyl chain of the following formula (IV): S HO-jC-----(CHjJn-----CH > | S (IV) NHj

[0080] in which n = 1 or 2

[0081] to locally reduce the visibility of excessive and unsightly (and / or undesirable) skin coloration characterized by a local accumulation of endogenous pigments (preferably responsible for the natural skin color).

[0082] Still on the "cosmetic" (or dermocosmetic) level, the invention also relates to a non-therapeutic cosmetic or dermocosmetic process for reducing locally the visibility of excessive and unsightly (and / or undesirable) skin coloration characterized by a local accumulation of at least two different types of endogenous pigments responsible for the natural skin color,

[0083] said process comprising:

[0084] (a) identify, in a subject, an area of ​​skin exhibiting said excessive coloration and unsightly (and / or undesirable) skin; and

[0085] (b) administer to said subject, topically or orally, advantageously by Apply topically to the said area of ​​skin, an effective amount:

[0086] - of at least one imidazolyl derivative of general formula (I), or one of its cosmetic salts tically or dermocosmetically acceptable, as defined above, or

[0087] - of a cosmetic or dermocosmetic composition as defined above previously.

[0088] As indicated in the preamble to this patent application, another aspect of the invention, distinct from the "cosmetic" aspect, concerns the "dermatological" aspect. In this respect, the invention also relates to an imidazolyl derivative of the following general formula (I), or one of its dermatologically acceptable salts:

[0089] in which:

[0090] - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group;

[0091] - R3 is:

[0092] i) let a heterocycle be chosen from: ('|J (!!!)

[0093] ii) or an alkyl chain of the following formula (IV): HAS nh2

[0094] in which n = 1 or 2

[0095] to treat a skin pigmentary disorder.

[0096] The invention also relates to an imidazolyl derivative of the following general formula (I), or one of its dermatologically acceptable salts: (!)

[0097] in which:

[0098] - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group;

[0099] - R3 is:

[0100] i) let a heterocycle be chosen from: dH)

[0101] ii) or an alkyl chain of the following formula (IV): HO2C---- (IV)

[0102] in which n = 1 or 2

[0103] to treat a cutaneous pigmentary disorder characterized by the local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin.

[0104] According to a preferred embodiment, the above at least one imidazolyl derivative of general formula (I) is:

[0105] (a) such that Ri and R2 each represent a hydrogen atom, R3 is a heterocycle chosen from:

[0106] preferably R3 being:

[0107]

[0108]

[0109]

[0110] [YES]

[0112] / ----A , and / or ITS H (f!) (b) such that Ri and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2; preferably said at least one imidazolyl derivative of general formula (I) being (in IUP systematic nomenclature AC): - the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide [namely, in the general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is of formula (II)], advantageously its enantiomer with absolute configuration S with precisely the compound (2S)-N-[2-(lH-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, and / or - the acid compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid [namely, in the general formula (I) above, Ri and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2], advantageously its enantiomer of absolute configuration S with precisely the acid compound (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid. Preferably, the cutaneous pigmentary disorder characterized by the local accumulation of at least two different types of endogenous pigments consists of a local accumulation of melanin pigments and heme pigments. According to one embodiment of the invention, said cutaneous pigmentary disorder being selected from: solar lentigines, melasma, rosacea, and / or solar erythema. Preferably, solar lentigines and / or rosacea are selected. In such a context, for the aforementioned solar lentigines and / or rosacea, an imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, is preferably selected, in which Ri and R2 each represent a hydrogen atom, and R3 is a heterocycle selected from:

[0113]

[0114] Still in this same context for the aforementioned solar lentigines and / or couperose, the following peptidomimetic compound (in systematic nomenclature IUP AC) is cited in particular as a non-limiting example of an imidazolyl derivative of general formula (I). (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide. Furthermore, the aforementioned imidazolyl derivative of general formula (I), or one of its salts dermatologically acceptable, for its dermatological use, may be included in a dermatological preparation, preferably at a concentration of approximately 0.1 to 2% by weight (for example, between 0.2 and 1.5% by weight) relative to the total weight of said preparation, further comprising at least one dermatologically acceptable excipient, preferably said preparation being in a form suitable for topical administration and said at least one excipient being physiologically acceptable to the skin. Indeed, said imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, usable according to the invention, may also be used, as a dermatological active ingredient, in a dermatological preparation, the latter further comprising at least one dermatologically acceptable excipient, as indicated above.According to one embodiment, in such a dermatological preparation context, said imidazolyl derivative of general formula (I) is the peptidomimetic compound (in systematic nomenclature IUP AC): (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide. .

[0115] The salts of said imidazolyl derivatives according to the invention, in particular of the aforementioned preferred compounds, can be obtained by reaction of said derivatives and compounds with an inorganic acid, preferably hydrochloric acid, or an organic acid, in particular said dermatologically acceptable salt according to the invention is a hydrochloride.

[0116] Advantageously, both these dermatological preparations and the aforementioned cosmetic or dermocosmetic compositions are in a form suitable for topical (cutaneous) administration, presented in all the forms normally used for such administration. By way of example and not limitation, they may be in the form of an aqueous or hydroalcoholic solution, possibly gelled, a lotion-type dispersion, possibly biphasic, an oil-in-water or water-in-oil emulsion, a suspension, a lotion, a cream, an aqueous or hydroalcoholic gel, or even in the form of a (micronized) powder, a foam, a serum, a paste, a suspension, a dispersion, or multiple emulsions, which may optionally be microemulsions or nanoemulsions.In terms of adjuvants present in the aforementioned compositions, preparations, and other supplements and physiologically compatible with the skin, one can cite a compound chosen from among oils, waxes, silicone elastomers, surfactants, co-surfactants, thickeners and / or gelling agents, humectants, emollients, organic or inorganic sunscreens, photostabilizers, preservatives (with the exception of aldehyde-donating preservatives), colorants, abrasive fillers, pearlescent pigments, mattifying agents, tightening agents, sequestering agents, perfumes, etc., and mixtures thereof. This list is for illustrative purposes only and is not exhaustive. Limitingly, such an adjuvant, acceptable in the fields of application covered by the present invention, present in the formula at a concentration of approximately 0.01 to 20% by weight relative to the total weight of the aforementioned composition, preparation, and other supplement, is notably cited in the "International Cosmetic Ingredient Dictionary and Handbook" published by the "Personal Care Product Council (PCPC)" of the American Cosmetic Association. Finally, these same aforementioned compositions, preparations, and other supplements may advantageously comprise at least one additional active ingredient, provided that those skilled in the art ensure that any additional active ingredients, as well as their proportions, are chosen in such a way that the advantageous properties attributed to these aforementioned compositions, preparations, and other supplements are not, or are substantially not,altered by the proposed addition. Such additional active ingredients may be chosen, without limitation, from among depigmenting agents, photoprotective agents, barrier function stimulants, moisturizing or humectant agents, desquamating agents, soothing agents, exfoliating agents, agents that stimulate cell proliferation such as fibroblasts and keratinocytes, deglycating agents, agents that stimulate collagen or elastin synthesis or prevent their degradation, agents that stimulate glycosaminoglycan or proteoglycan synthesis or prevent their degradation, antioxidant, free radical scavenging, or anti-pollution agents, lipolysis stimulants, draining or detoxifying agents, anti-inflammatory agents, penetration accelerators, desquamating agents, soothing and / or anti-irritant agents, astringent agents, exfoliating agents,agents acting on microcirculation, etc., and their mixtures, such an additional active ingredient being present in the formula in a content of approximately 0.0001 to 20% by weight, preferably 0.01 to 5% by weight, relative to the total weight of the aforementioned composition, preparation and other supplement.

[0117] Definitions

[0118] General definitions

[0119] By "an ability to restrain extravasation out of the cutaneous vascularization", it is necessary to understand an effect limiting an abnormal diffusion / outflow, in the extracellular matrix of the skin, of pigments of heme nature under the action of an inflammation with a vascular component.

[0120] By "in systematic nomenclature IUPAC", it is necessary to understand a designation according to a standardized system of chemical compounds based on the application of the strictest recommendations established by the International Union of Pure and Applied Chemistry ("IUPAC" in French, or "IUPAC" in English for "International Union of Pure and Applied Chemistry"), recommendations which aim to ensure that a name corresponds to one and only one molecular structure.

[0121] By "absolute configuration enantiomer" is meant an enantiomer established according to the universal nomenclature system allowing the absolute configuration of two enantiomers to be described (system referred to as "Cahn-Ingold-Prelog Sequential Rules").

[0122] By "absolute configuration enantiomer S", one must understand the configuration enantiomer in which the priority substituents "rotate" and correspond to an anticlockwise rotation.

[0123] Definitions inherent to the cosmetic and dermocosmetic (non-therapeutic) field

[0124] By "infraorbital hyperchromia" is meant an aesthetic / cosmetic disorder presenting one or more areas of uneven and abnormal skin pigmentation, more prosaically called "colored circles," also found under the designations "periorbital hyperchromia" (Souza DM et al., Surg. Cosmet. Dermatol., 2011, vol.3(3), pp.233-239), or "infraorbital discoloration" (Sarkar R. et al., J. Clin. Aesthet. Dermatol., 2016, vol.9(1), pp.49-55), in other words, the expression of an excess of coloration in the area around the eye, which constitutes another localized color difference existing between the thin, transparent palpebral skin and the rest of the facial skin (Souza DM and al., Surg. Cosmetic. Dermatol., 2011, vol.3(3), pp. 233-9).Furthermore, it should be emphasized that the pigmented / dark circle, also called "colored," etiologically distinct from hollow circles whose origin is a disappearance with age of the periocular subcutaneous fat, results mainly from a tissue accumulation, around the eyes, of pigments of melanin and heme nature, the latter accumulated by the extravasation of the chromophore hemoglobin and its related degradation pigments (hemosiderin, etc.) outside the cutaneous vascularization (Chavan M. et al., J. Cosmet. Sci., 2014, vol.65(2), pp. 103-113; Vrcek I. et al., J. Cutan. Aesthet. Surg., 2016, vol.9(2), pp.65-72).Thus, depending on such pigment overlap / concentration coupled with the intensity of this capillary permeability / leakage, the color of said colored circle will likely oscillate between a yellowish or brown coloration to black or even bluish-purple and thus contribute to the dark and aged appearance of this area, which is highly unsightly (and, consequently, undesirable).

[0125] Definitions inherent to the dermatological field

[0126] By “solar lentigines”, one must understand a skin condition expressed by dark-colored macular lesion plaques.

[0127] The term "melasma" should also be understood to mean a skin condition observed mainly in women, particularly during pregnancy with the use of hormonal treatments, and which is characterized by the appearance of irregular patches of light to dark brown or grey-brown lesions on parts of the skin exposed to the sun, in particular particularly the face (Nautiyal A. et al., Pigment Cell Melanoma Res., 2021, vol.OO, pp.1-15 and references cited).

[0128] By "couperose" or "telangiectasia" according to the medical term, we must understand a condition of the color of the skin when it is associated with the vascular development of very fine small vessels, red and sometimes even purplish, visible just below the surface of the skin. Detailed description

[0129] The detailed description below is intended to set out the invention in a sufficiently clear and complete manner, in particular by means of examples, but shall in no case be regarded as limiting the scope of protection to the particular embodiments and examples presented below. Examples

[0130] Example 1: Test demonstrating the ability of imidazolyl derivatives usable according to the invention to specifically trap and block the metal cofactor essential to the enzymatic activity of tyrosinase

[0131] Experimentally, the test was performed under the following conditions, based on the publication: Seung-hwa Baek et al., "Proton pump inhibitors decrease melanogenesis in melanocytes" Biomedical Reports, 726-730, 2015).

[0132] In each well of a 96-well microplate, 100 pL of the imidazolyl derivative to be tested according to the invention, 50 pL of 200 mM acetate buffer pH 6.0, and 50 pL of 800 pM CuSO4 solution are placed. After 10 minutes, 50 pL of 800 pM pyrocatechol violet (PV) is added. After 20 minutes, the absorbance is measured at 632 nm. Ethylenediaminetetraacetic acid (EDTA, Sigma lot no. MKBQ7974V) is used as the reference agent (positive control).

[0133] The results are gathered in Table 1 below, hereinafter referred to as [Table 1], in particular expressed in median effective concentration or "EC50", namely an effective chelating concentration of half of the copper ions (Cu2+) involved [EC 50 determined experimentally in mM then converted into % mass using the molecular molar mass of the imidazolyl derivative usable according to the invention].

[0134] The imidazolyl derivatives usable according to the invention were the following compounds:

[0135] . (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, namely the enantiomer with absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, the latter being the subject of the general formula (I) above in which Ri = R2 = H ; R3 = formula (II)

[0136] . (4S)-4-amino-5-[2-(l / / -imidazol-5-yl)ethylamino]-5-oxopentanoic acid, to to know the enantiomer with absolute configuration S of the compound 4-amino-5-[2-(l / / -imidazol-5-yl)ethylamino]-5-oxopentanoic acid, the latter being the object of the general formula (I) above in which Ri = R2 = H; R3 = formula (IV) and n = 2

[0137] [Tables 1] Compound (in IUPAC systematic nomenclature) ECS0(pM) ECSo(ppm) EDTA (reference agent) 65 18 (0.0018% expressed as % by mass) (2S)-N-[2-(lH-imidazol-5-yl)ethyl]pyrrolidin e-2-carboxamide [according to the invention; lot no. 0098.15] 67.4 14 (0.0014% expressed as % by mass) (4S)-4-amino-5-[2-(l / / -imidazol-5-yl)ethyl lamino]-5-oxopentanoic acid [according to the invention; lot no. 5057.22] 73 17 (0.0017% expressed as % by mass) (2S)-pyrrolidine-2-carboxylic acid [substrate; ref. Sigma lot no. SLBR2808V] 1400 161 (0.016% expressed as % by mass) 2-(1H-imidazol-5-yl)ethanamine [substrate; ref. Sigma lot no. XWB00664V] > 10000 > 1110 (> 0.111% expressed as % by mass)

[0138] The results highlight, for the derivatives usable according to the invention, an ability to inhibit the metallic cofactor essential to the enzymatic activity of tyrosinase, moreover at a surprisingly low active concentration on the order of that of the reference agent.

[0139] Example 2: Test demonstrating the ability of imidazolyl derivatives usable according to the invention to limit / inhibit the enzymatic activity of tyrosinase

[0140] The evaluation of the inhibition or induction of tyrosinase activity by an imidazolyl derivative usable according to the invention is carried out by adding the tyrosinase enzyme and its substrate, dopamine, under optimal conditions (pH 6.5 and room temperature, approximately 25 °C) to a range of concentrations of the derivative to be tested. The test mixture is incubated at room temperature for 15 minutes. During incubation, the amount of L-DOPA-quinone produced in the reaction mixture is determined by spectrophotometry of dopachrome formation at 475 nm in a microplate reader. Kojic acid (ref. Sigma K3125 lot no. BCCB7130) is used as a reference agent (positive control). The results were repeated three times for each imidazolyl derivative usable according to the invention.

[0141] The results are summarized in Table 2 below, hereinafter referred to as [Table 2], in particular expressed as median inhibitory concentration or "IC50", namely a concentration required to achieve 50% inhibition of the activity of the amount of tyrosinase involved in the test [IC50 determined experimentally in mM then converted into % mass using the molecular molar mass of the imidazolyl derivative usable according to the invention].

[0142] The imidazolyl derivatives usable according to the invention were the following compounds:

[0143] . (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, namely the enantiomer with absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, the latter being the subject of the general formula (I) above in which Ri = R2 = H ; R3 = formula (II)

[0144] . (4S)-4-amino-5-[2-(l / / -imidazol-5-yl)ethylamino]-5-oxopentanoic acid, to to know the enantiomer with absolute configuration S of the compound 4-amino-5-[2-(l / / -imidazol-5-yl)ethylamino]-5-oxopentanoic acid, the latter being the subject of the general formula (I) above in which Ri = R2 = H; R3 = formula (IV) and n = 2

[0145] [Tables2] Compound (in IUPAC systematic nomenclature) ICS0(mM) ICS0(wt%) kojic acid (reference agent) 0.093 0.0013 (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidin e-2-carboxamide [according to the invention; lot no. 0098.15] 1.4 0.029 (4S)-4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid [according to the invention; lot no. 5057.22] 2.3 0.055

[0146] The results highlight, for the derivatives usable according to the invention, an ability to inhibit the activity of tyrosinase.

[0147] Example 3: Test demonstrating the ability of imidazolyl derivatives usable according to the invention to inhibit the expression of type 1 vascular cell adhesion protein molecules

[0148] Human dermal microvascular endothelial cells (HDMECs) were obtained from Promocell (lot 449Z005.3, cells isolated from breast tissue - 43-year-old patient).

[0149] The cells were cultured at 37°C and 5% CO2 in the growth medium of MV2 endothelial cells + supplement Mix (Promocell). 24 hours after seeding, the HDMEC cells were pretreated with imidazolyl derivatives usable according to the invention for 2 hours before the application of 5 ng / ml of TNF-alpha (stress). The cells were then incubated for 22 hours.

[0150] After 24 h of treatment, the cells were washed with PBS and a CELISA assay was performed to quantify the expression of VCAM-1 adhesion molecules. Absorbances were measured at 450 nm using a spectrophotometer (Micro-Quant, BioTek Instruments). Deferoxamine (ref. D9533 Sigma lot no. BCCB3792) was used as the reference agent (positive control).

[0151] The results are gathered in Table 3 below, hereinafter referred to as [Table 3], in particular expressed as a percentage of inhibition on the expression of VCAM-1 adhesion molecules.

[0152] The imidazolyl derivatives usable according to the invention were the following compounds:

[0153] . (2S)-N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, namely the enantiomer with absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]pyrrolidine-2-carboxamide, the latter being the subject of the general formula (I) above in which Ri = R2 = H ; R3 = formula (II)

[0154] . (4S)-4-amino-5-[2-(l / / -imidazol-5-yl)ethylamino]-5-oxopentanoic acid, to to know the enantiomer with absolute configuration S of the compound 4-amino-5-[2-(l / / -imidazol-5-yl)ethylamino]-5-oxopentanoic acid, the latter being the subject of the general formula (I) above in which Ri = R2 = H; R3 = formula (IV) and n = 2

[0155] . the (2S)-N-[2-(1H-imidazol-5-yl)ethyl]-5-oxopyrrolidine-2-carboxamide, namely the enantiomer with absolute configuration S of the compound N-[2-(1H-imidazol-5-yl)ethyl]-5-oxopyrrolidine-2-carboxamide, the latter being the subject of the general formula (I) above in which Ri = R2 = H ; R3 = formula (III)

[0156] [Tables3] Compound (in IUPAC systematic nomenclature) (concentration) % VCAM-1 expression % decrease in VCAM-1 expression TNF-alpha [control] (5 ng / mL) 100 - deferoxamine [reference agent] (50 pM) 9 91 (2S)-N-[2-(lH-imidazol-5-yl)ethyl]pyrrolidin e-2-carboxamide [according to the invention; lot no. 343.19] (7.5 mM) 63 37 (4S)-4-amino-5-[2-(l / / - imidazol- 5 - yl)ethyl lamino] - 5 -oxopentanoic acid [according to the invention; batch no. 5057.22] (7.5 mM) 73 27 (2S)-N-[2-(lH-imidazol-5-yl)ethyl]-5-oxopyrrolidine-2-carboxamide [according to the invention; batch no. 35476] (7.5 mM) 64 36 (25)-3-(1 / / -imidazol-5 -y 1) -2- [[(25)-pyrrolidine-2-carbonyl]amino]propanoic acid [ref. BOC Sciences; batch no. B22BS12012] (7.5 mM) 99 1

[0157] The results highlight, for the derivatives usable according to the invention, unlike, for one of them, its peptide structural analogue, an ability to limit the expression of type 1 vascular cell adhesion protein molecules, i.e. an ability to curb the extravasation out of the cutaneous vascularization of hemoglobin pigments (chromophores) and related degradation pigments.

Claims

Claims

1. Non-therapeutic cosmetic or dermocosmetic use of at least one imidazolyl derivative of the following general formula (I), or one of its cosmetically or dermocosmetically acceptable salts: HX / \ -X (j ■ o N--- in which: - R1 and R2 represent, independently of each other, a hydrogen atom or a methyl group; - R3 is: i) either a heterocycle chosen from: / \ y...........\ ' oA > HN ii) or an alkyl chain of the following formula (IV): HO.C (CH?!,, CH ? | 5 (iV) nh2 in which n = 1 or 2 for locally reducing the visibility of excessive and unsightly coloration of the skin in a healthy subject, said excessive and unsightly coloration of the skin being characterized by a local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin.

2. Use according to claim 1, characterized in that the local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin, is a local accumulation of melanin pigments and hemin pigments.

3. Use according to claim 1 or 2, characterized in that said at least one imidazolyl derivative of general formula (I) is: (a) such that R 1 and R 2 each represent a hydrogen atom, R 3 is a heterocycle chosen from: preferably R3 being: W)

4.

5.

6.

7. and / or (b) such that R1 and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2; preferably said at least one imidazolyl derivative of general formula (I) being: - 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. Use according to one of the preceding claims, characterized in that said excessive and unsightly coloration of the skin is located in a skin area exhibiting infraorbital hyperchromia. Use according to one of claims 1 to 4, said imidazolyl derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, being included in a cosmetic or dermocosmetic composition further comprising at least one cosmetically or dermocosmetically acceptable excipient, preferably said composition being in a form suitable for topical administration and said at least one excipient further being physiologically acceptable with the skin. Use according to one of claims 1 to 5, said cosmetically or dermocosmetically acceptable salt of said imidazolyl derivative of general formula (I) being a hydrochloride. Imidazolyl derivative of the following general formula (I), or one of its dermatologically acceptable salts: R? H t rj 0 N-----1 in which: - Ri and R2 represent, independently of each other, a hydrogen atom or a methyl group; - R3 is: i) either a heterocycle chosen from: O / ■ H ii) or an alkyl chain of the following formula (IV): HO?C------CH I | S fiV) NHj in which n = 1 or 2 to treat a cutaneous pigmentary disorder characterized by the local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin.

8. Imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, according to claim 7, for its use according to claim 7, in which the local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin, is a local accumulation of melanin pigments and hemin pigments.

9. Imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, according to claim 7 or 8, for its use according to claim 7 or 8, said cutaneous pigmentary disorder being selected from solar lentigines, melasma, rosacea and / or solar erythema.

10. Imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 7 to 9, for its use according to one of claims 7 to 9, characterized in that that said at least one imidazolyl derivative of general formula (I) is: (a) such that R1 and R2 each represent a hydrogen atom, R3 is a heterocycle chosen from: (bed) preferably R3 being: (he) and / or (b) such that R1 and R2 each represent a hydrogen atom, R3 is an alkyl chain of formula (IV) in which n is equal to 2; preferably said at least one imidazolyl derivative of general formula (I) being: - 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 acidic compound 4-amino-5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, advantageously the acid compound (4S)-4-amino-5-[2-(lH-imidazol-5-yl)ethylamino]-5-oxopenta noic.

11. Imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 7 to 10, for its use according to one of claims 7 to 10, said imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, being included in a dermatological preparation further comprising at least one dermatologically acceptable excipient, preferably said preparation being in a form suitable for topical administration and said at least one excipient being furthermore physiologically acceptable with the skin.

12. Imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 7 to 11, for its use according to one of claims 7 to 11, said dermatologically acceptable salt of said imidazolyl derivative of general formula (I) being a hydrochloride.

13. Use according to claim 5, or imidazolyl derivative of general formula (I), or one of its dermatologically acceptable salts, according to claim 11, for its use according to claim 11, said cosmetic or dermocosmetic composition as defined in claim 5 or said dermatological preparation as defined in claim 11 further comprising at least one additional active ingredient chosen from depigmenting agents, photoprotective agents, barrier function stimulating agents, moisturizing or humectant agents, desquamating agents, soothing agents, exfoliating agents, agents stimulating cell proliferation such as fibroblasts and keratinocytes, deglycating agents, agents stimulating the synthesis of collagen or elastin or preventing their degradation,agents stimulating the synthesis of glycosaminoglycans or proteoglycans or preventing their degradation, antioxidant or anti-radical or anti-pollution agents, agents stimulating lipolysis, draining or detoxifying agents, anti-inflammatory agents, penetration accelerator and / or anti-irritant agents, astringent agents, agents acting on microcirculation, and mixtures thereof.,