NEW USES OF AMINOALKYLAMIDE DERIVATIVES

Abstract

An aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, for use in the treatment of 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, said cutaneous pigmentary disorder being selected from rosacea and / or contusions / ecchymoses (and other subcutaneous hematomas).

Description

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

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

[0002] A striking example of phenotypic diversity in humans, the skin can display a wide variety of colors, ranging from pale or almost white skin to very dark shades (black) through various shades of light brown and chestnut brown (Ortonne JP, Annales de Dermatologie et de Vénéréologie, 2012, vol. 139, pp.S73-S77). Independently of intrinsic factors determined at birth such as genetic heritage, or extrinsic factors such as exposure to the sun, human skin has a natural color conferred by a complex and subtle biochemical process, that of 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 the cutaneous capillaries, deoxygenated hemoglobin or reduced hemoglobin (blue) from the 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 the determinism of skin color, consequently in the differences and variations of skin color between individuals, remains the dark pigment (melanin), in particular by its size, its intensity and its typology, double, with eumelanin (brown to dark black) distinct from pheomelanin (reddish yellow to light brown), but also by 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 solar exposure (Delevoye C. et al., Med. Sci. (Paris), 2011 vol.27(2), pp. 153-162). As an illustration, we note that darkly pigmented skin is associated with larger and more melanosomes. prolific, and the melanin they produce is preserved longer in keratinocytes than in those of light-skinned individuals (Deng L. et al., Hereditas, 2018, vol.l55(l), pp.1-12 and references cited). Eumelanin is logically found in majority in dark-skinned people, while pheomelanin accumulates more in light-skinned people (Barsh GS, PLoS Biology, 2003, vol. 1(1), pp.019-022). Finally, the universal Fitzpatrick classification, a reference tool for dermatologists, makes it possible to categorize skin phototypes (6 in total) according to a strong to non-existent aptitude of the integument to develop such a dark to dark color pigmentation during sun exposure (Sachdeva S., Indian J. Dermatol. Venereol. Leprol., 2009, vol.75, pp.93-96).

[0003] Generally and briefly, disorders affecting the color of so-called "normal" skin can be summarized as either an exaggeration of the natural color of the skin with clinically the localized appearance of uneven pigmented areas and in particular darker and darker spots, or conversely a reduction and pallor of the skin with clinically the localized appearance of lighter spots (Lipsker D. et al., Annales de Dermatologie et de Vénéréologie, 2019, vol. 146(10), pp.666-682). Apart from any deleterious character (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 expected harmony of the complexion. In order to correct / reduce such defects affecting the appearance of the skin (and its aesthetic side), the field of so-called "aesthetic and cosmetic" dermatology has developed (Wollina U., Dermatology Therapy, 2008, vol.21(2), pp. 118-130). At the lexical level, it is accepted, for example, that the noun "dyschromia" qualifies, endogenously or exogenously, diffusely or in well-circumscribed areas, any deposit in the skin of various / any pigments causing a modification of the normal color of the skin (Braun-Flaco O. et al., Dermatology, 1991, chapter 27). More recently, some authors have also retained other generic attributes to, identically, broadly encompass any form of disorder linked 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 having as a common point one or more areas of uneven and abnormal pigmentation of the skin, thus making the latter dark or discolored, becomes wide because variable in color and shape.Such a range is thus likely to affect skin pigmentary disorders of the following nature: . a. purely dermatological (concerning sick subjects (patients), suffering from these pigmentary disorders of a pathological nature or skin lesions of traumatic origin), such as solar lentigines, melasma, rosacea, sunburn, vitiligo, bruises / ecchymoses (and other subcutaneous hematomas), but also b. aesthetic / cosmetic (occurring in particular in “healthy” subjects, dissociable from the aforementioned sick subjects), such as areas of discoloration linked to sun exposure and / or age.

[0004] 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 above, the cosmetic solutions (if one is addressing a subject presenting the aesthetic / cosmetic disorders referred to in point b) above) and the existing treatments (if one is addressing a sick subject (patient), suffering from one or more purely dermatological condition(s), as presented in point a) above) target the uneven and abnormal coloring / pigmentation of the skin affecting the natural color of the skin. 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).Certainly, there are no reference options as such, but rather an arsenal of solutions that can range from non-invasive or minimally invasive interventions, such as the simple application of makeup products (foundation) or the more elaborate application of topical treatments to lighten the complexion, or even chemical peels, laser therapy, etc., to surgical maneuvers and other more invasive aesthetic medicine interventions such as dermabrasion, microneedling, skin grafting, cell therapy (Pijpe, A. et al., 2020, pp. 109-115). One of these options, which has been popular for a long time, is in fact the local application, with the support of a topical preparation, of active ingredients on the skin capable of interfering with its level of pigmentation. In this regard, and particularly in the context of excessive melanin pigmentation, numerous 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 for whitening purposes were hydroquinone (benzene derivative) and its derivatives, mercurial compounds (mercury oxide and chloride), retinoids such as retinoic acid, or even certain dermocorticoids diverted from their therapeutic uses. However, and due to their harmful effects and dangers observed over the years on human health (potentially carcinogenic, skin problems, etc.), some of these "first" whitening substances are now subject to strict regulation, mainly European and American legislation, or even, for example . hydroquinone since Regulation (EC) No. 344 / 2013, appear in a list of substances that are legally prohibited in cosmetic products. As an alternative to these health restrictions and prohibitions, ingredient manufacturers have turned to substitute products, either of natural origin such as kojic acid (produced by several species of fungus), arbutin (phenolic glycoside contained in the leaves and bark of many plants), 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 surface of the skin), or to non-cytotoxic plant extracts which also have lightening properties such as extracts of licorice, mulberry and other bearberry (Fernandez X. et al., Techniques de l'Ingénieur, 2015, vol.J 2 300, pp.1-33, and references cited). Here again, certain national regulations, like Switzerland, have subsequently restricted or prohibited the use of some of these substances of natural origin (kojic acid, arbutin) in view of the demonstration of undesirable and systemic side effects: toxicity, irritation, drying and skin sensitization. Regarding the mechanisms of biological action, many of the active ingredients mentioned above, but also a multitude of others like those compiled in a recent "review" type 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 the production of melanin (case of the aforementioned hydroquinone, azelaic acid, and arbutin) and that of a competitive interaction with the non-protein enzymatic cofactor of tyrosinase, copper (case of the aforementioned kojic and ascorbic acids).Other agents have also sought, among others, the inhibition of the transfer of melanosomes to keratinocytes (case of the aforementioned niacinamide), the inhibition of the transcription of tyrosinase (case of the aforementioned retinoic acid derivatives), a blockage of inflammation, a trapping of free radicals (case of the aforementioned glycyrrhetinic acid extracted from the aforementioned liquorice 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.l2(775), pp.1-15 and references cited).

[0005] Also described were so-called "related" peptides and compounds, illustrated in particular by peptides conjugated to carboxylic acids (ascorbic, kojic, etc.), all having the capacity to artificially reduce the levels of cutaneous melanin by inhibiting the enzymatic activity of tyrosinase (Boo YC, Biomedicines, 2020, vol. 8(9), pp.1-26). It may also be noted the synthesis of compounds of the benzyl-4(7)-phenyl-1H-benzo[d]imidazole 2-substituted type, for their inhibitory action on tyrosinase at IC50s close, for some, to the reference substance, kojic acid (Dogan IS et al., Arch. Pharm. Chem. Life Sci., 2016, vol.349(ll), pp.881-888), or the patent applications FR2917087 and WO2008006824 having respectively requested the protection of compounds of the 4-phenyl-imidazole-2-thiones and imidazole-2-thione type, for the purposes of prevention, or treatment, pharmaceutical or cosmetic, of pigmentary disorders, in particular post-inflammatory or of metabolic or drug origin, and this despite the rather melanogenesis-inducing behavior expected for Phistamine and / or its by-products. metabolizing imidazoles (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.H4(2), pp.334-42). Furthermore, the above-mentioned 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.

[0006] In any event, and despite this multiple and varied availability of treatments / therapies intended to remedy / correct these pigmentation disorders likely to 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, because they are in perpetual search for new safe and ever more effective ingredients.

[0007] The present invention is fully in line with this challenge of research into better and effective treatment aimed at remedying, in a comprehensive and new / original manner, an unsightly manifestation having as a common point one or more areas of excessive - generally uneven - and unsightly (and / or undesirable) coloring of the skin. Statement of the invention

[0008] Also, based on all these observations and elements of literature, the inventor set out to resolve the following objective technical problem: to make available on the market cosmetic active ingredients interacting with the production of skin pigments (chromophores), ingredients with improved behavior and assured safety, with the objective, determining in his eyes, of being able to act concomitantly on several very distinct components of unsightly manifestations having as a common point one or more zones of excessive coloring(ies) - generally uneven - and unsightly (and / or undesirable) of the skin, 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.

[0009] To do this, the inventor established the following specifications:

[0010] A) although the predominant factor in determining skin color remains the dark pigment (brown / melanin), as previously indicated, and such pigmentation is mainly linked to the functionality of melanocytes and the enzyme (tyrosinase) responsible for melanogenesis, as previously explained, and without however being bound by theory, the inventor aimed to develop compounds / new substances targeting in parallel other biological targets, namely another cell population than just the surrounding melanocytes and keratinocytes, other intrinsic etiological factors also capable of regulating the constitutive pigmentation of the skin, such as the signaling pathways producing the pigment system (Bastonini E. et al., Ann. Dermatol., 2016, vol. 28(3), pp. 279-289); this "multifactorial" approach:

[0011] - allowing to stand out from topical monotherapies very often directed towards the exclusive inhibition of tyrosinase and resulting production of melanin, or that of the transfer of melanosomes loaded with melanin to keratinocytes; and

[0012] - proving particularly suitable, for example, in the cosmetic context (or dermocosmetics) 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 pigmentation of the skin (Regazzetti C. et al., Annales de Dermatologie et de Vénéréologie, 2015, vol.l42(12), pp.S482 - Regazzetti C. et al., J. Invest. Dermatol., 2015, vol.l35(12), pp.3096-3104);

[0013] B) these new compounds / substances intended primarily to be incorporated into cosmetic products must be healthily safe 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.

[0014] The present invention was therefore developed in such a research context and specifications - ambitious - as indicated above. It is in this context, that at the end of a large-scale research work, carried out in particular with the aid of different biological evaluation models, the inventor then discovered, to his astonishment (in view of the teaching of the state of the art to date), that a limited family of compounds developed was likely to display advantageous general behavior while respecting the requirements defined in points A) and B) above. In the species, these are the aminoalkylamide derivatives of general formula (I) following (or one of their cosmetically or dermocosmetically acceptable salts): {1}

[0015] in which: - Ri and R2 = H, namely that: - Ri and R2 each represent a hydrogen atom; - R3 = H, NH2, namely that: - R3 is a hydrogen atom or a primary amine group; - R4 = NH2, NH-CO-CH3, namely that: - R4 is a primary amine group (-NH2) or a secondary amine group carrying an N-acetyl group (-NH-CO-CH3); and - n = 1 or 2.

[0016] The subject of the invention is therefore the non-therapeutic cosmetic or dermocosmetic use of at least one aminoalkylamide derivative of the following general formula (I), or one of its cosmetically or dermocosmetically acceptable salts: n R. — (CH ...............IU | O R.., | r

[0017] in which: - Ri and R2 = H, namely that: - Ri and R2 each represent a hydrogen atom; - R3 = H, NH2, namely that: - R3 is a hydrogen atom or a primary amine group; - R4 = NH2, NH-CO-CH3, namely that: - Riest a primary amine group (-NH2) or a secondary amine group carrying an N-acetyl group (-NH-CO-CH3); and - n = 1 or 2,

[0018] to locally reduce the visibility of excessive and unsightly (and / or undesirable) coloration of the skin characterized by a local accumulation of endogenous pigments (preferably responsible for the natural color of the skin).

[0019] According to a preferred embodiment of the invention, the local accumulation of endogenous pigments (characterizing the above-mentioned excessive and unsightly (and / or undesirable) coloration of the skin) 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 hemin pigments.

[0020] The invention therefore also relates to the non-therapeutic cosmetic or dermocosmetic use of at least one aminoalkylamide derivative of the following general formula (I), or one of its cosmetically or dermocosmetically acceptable salts:

[0021] in which: - Ri and R2 = H, namely that: - Ri and R2 each represent a hydrogen atom; - R3 = H, NH2, namely that: - R3 is a hydrogen atom or a primary amine group; - R4 = NH2, NH-CO-CH3, namely that: - R4 is a primary amine group (-NH2) or a secondary amine group carrying an N-acetyl group (-NH-CO-CH3); and - n = 1 or 2,

[0022] to locally reduce the visibility of excessive and unsightly (and / or undesirable) coloration of the skin characterized by a local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin.

[0023] More precisely, and without however being bound by theory, the compounds according to the present invention possess in particular the following characteristics: - possess structures of a peptidomimetic nature, in other words an entity capable of favorably mimicking the biological behavior of active peptide compounds (oligopeptides, proteins) in space three-dimensional, but with notably reinforced stability against proteolysis and increased bioavailability by topical route; - said peptidomimetic structures all bearing a heterocyclic aromatic nucleus of imidazole type, due to the peptide coupling engaged (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 preferentially b-amino acids (i.e. amino acids in the beta position - like b-alanine or 2,3-diaminopropionic acid) or y-amino acids (i.e. amino acids in the gamma position - like 2,4-diaminobutanoic acid), such amino acids being exclusively aliphatic in nature.

[0024] Furthermore, as sought, these aminoalkylamide 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.

[0025] In addition, the aminoalkylamide derivatives of general formula (I) which can be used according to the invention exhibit advantageous general behavior, illustrated by a range of beneficial technical effects, which are in particular: - a capacity first of all to inhibit the enzymatic activity of tyrosinase (see example 1 below), consequently ultimately to limit the specific production of a first typology of pigments (chromophores) responsible for the natural color of the skin, namely melanin pigments, and this: - at an active concentration, in this case in terms of the median inhibitory concentration required to achieve 50% inhibition of the tyrosinase enzyme involved in the test of Example 1 (concentration referred to as "IC - the latter considered to be different from the efficacy claimed for example by an oligopeptide of the prior art commercially exploited as an "anti-melasma" agent for its capacity 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 largely higher (at least 1% in mass concentration) with regard to the fact reported in this same article “A sa signal peptide, it interacts well with cells when used at concentrations of 1.0-2.5%”; - a capacity to inhibit the production of melanin pigments by the specialized cells of the epidermis, the melanocytes (see example 2 below); - finally, and this is another major, unique and unexpected aspect of the present invention, a capacity to be able to act furthermore on a subcutaneous microvascular component through precisely, and of interest in the context of point A) mentioned above: - an inhibitory effect on the expression of type 1 vascular cell adhesion protein molecules (abbreviation "VCAM-1") (see example 3 below), in other words markers present on the surface of endothelial cells in direct contact with the blood because they line the inside of dermal capillaries: - markers whose role is to regulate vascular adhesion and trans-endothelial diapedesis when they are associated with an inflammatory phenomenon (Kong DH et al., Int. J. Mol. Sciences, 2018, vol.19, pp.1-16); - consequently ultimately, within the framework of the present invention, a capacity to slow the extravasation outside the cutaneous vascularization of a second type of pigments (chromophores) responsible for the natural color of the skin, that of the chromophore hemoglobin and its related degradation pigments (hemosiderin, etc.), also at the origin of visible changes in pigmentation in the cutaneous and subcutaneous layers.

[0026] It should also be emphasized that the aminoalkylamide derivatives of general formula (I) which can be used according to the invention are structurally distant from the peptides, related compounds and derivatives carrying an imidazole unit belonging to the prior art and mentioned above, at the end of the section entitled "State of the art". On the other hand, these same peptides, related compounds and derivatives carrying an imidazole unit 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 aminoalkylamide derivatives of general formula (I) above which can be used according to the invention. Finally, the results displayed by the test of example 1 or 2 of the present invention are all the more unexpected as it is also necessary to highlight the rather melanogenesis-inducing behavior exhibited for the biogenic amine histamine and / or its imidazole by-products of metabolism (Tomita Y.et al., J. Dermatol. Sci., 1993, vol. 6(2), pp. 146-54). .

[0027] Preferably, with regard to the use according to the invention, said at least one aminoalkylamide derivative of general formula (I), or one of its cosmetically acceptable salts or dermocosmetically acceptable, is as follows (in systematic nomenclature IUP AC): - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n is equal to 1], and / or - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R4 is a secondary amine group carrying an N-acetyl group, and n is equal to 1], and / or - of the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a primary amine group, R4 is a primary amine group, and n is equal to 1],

[0028] even more preferably, said at least one aminoalkylamide derivative of general formula (I) is (in systematic nomenclature IUP AC) the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide.

[0029] The salts of said aminoalkylamide derivatives according to the invention, in particular of the above-mentioned 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.

[0030] According to one embodiment of the invention, said excessive coloration of the skin characterized by the local accumulation of endogenous pigments is expressed through areas of coloration linked to sun exposure and / or age. In this case, said at least one aminoalkylamide derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, used for the purposes of the present invention is, preferably (in systematic nomenclature IUP AC): - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R1 is a primary amine group, and n is equal to 1], and / or - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R4 is a secondary amine group carrying an N-acetyl group, and n is equal to 1], and / or - the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a primary amine group, R4 is a primary amine group, and n is equal to 1].

[0031] In this embodiment, preferably, said at least one aminoalkylamide derivative of general formula (I) is (in systematic nomenclature IUP AC): - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide.

[0032] Another subject of the invention also relates to the above-mentioned use, said aminoalkylamide derivative of general formula (I), or one of its cosmetically or dermocosmetically acceptable salts, being included in a cosmetic or dermocosmetic composition, or in a nutricosmetic formulation, preferably in a content of the order of 0.1 to 2% by weight (for example between 0.2 and 1.5% by weight) relative to the total weight of said composition or formulation, further comprising at least one cosmetically or dermocosmetically acceptable excipient, said composition or formulation being in a form suitable for topical or oral administration, preferably topically, and said at least one excipient also being physiologically acceptable with the skin.Indeed, said aminoalkylamide 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 used, as a cosmetic or dermocosmetic active ingredient, in a cosmetic or dermocosmetic composition, or in a nutricosmetic formulation, further comprising at least one cosmetically or dermocosmetically acceptable excipient, as indicated above. According to one embodiment, in such a context of cosmetic or dermocosmetic composition or nutricosmetic formulation, said aminoalkylamide derivative of general formula (I) is the peptidomimetic compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n is equal to 1]. .

[0033] The invention also relates to a non-therapeutic cosmetic or dermocosmetic composition comprising at least one aminoalkylamide derivative, or one of its cosmetically or dermocosmetically acceptable salts:

[0034] in which: - Ri and R2 = H, namely that: - Ri and R2 each represent a hydrogen atom; - R3 = H, NH2, namely that: - R3 is a hydrogen atom or a primary amine group; - R4 = NH2, NH-CO-CH3, namely that: - R4 is a primary amine group (-NH2) or a secondary amine group carrying an N-acetyl group (-NH-CO-CH3); and - n = 1 or 2,

[0035] to locally reduce the visibility of excessive and unsightly (and / or undesirable) coloration of the skin characterized by a local accumulation of endogenous pigments (preferably responsible for the natural color of the skin).

[0036] Still on the "cosmetic" (or dermocosmetic) level, the invention also relates to a non-therapeutic cosmetic or dermocosmetic process for locally reducing the visibility of excessive and unsightly (and / or undesirable) coloration of the skin characterized by a local accumulation of at least two different types of endogenous pigments, responsible for the natural color of the skin,

[0037] said method comprising:

[0038] (a) identifying, in a subject, an area of ​​skin exhibiting said excessive coloration and unsightly (and / or undesirable) skin; and

[0039] (b) administering to said subject, topically or orally, advantageously by topically on said area of ​​skin, an effective amount:

[0040] - at least one aminoalkylamide derivative of general formula (I), or one of its salts cosmetically or dermocosmetically acceptable, as defined above, or

[0041] - of a cosmetic or dermocosmetic composition or of a formulation nutricosmetics, as defined above.

[0042] As indicated in the preamble to the present 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 aminoalkylamide derivative of the following general formula (I), or one of its dermatologically acceptable salts:

[0043]

[0044]

[0045] in which: - Ri and R2 = H, namely that: - Ri and R2 each represent a hydrogen atom; - R3 = H, NH2, namely that: - R3 is a hydrogen atom or a primary amine group; - R4 = NH2, NH-CO-CH3, namely that: - R4 is a primary amine group (-NH2) or a secondary amine group carrying an N-acetyl group (-NH-CO-CH3); and - n = 1 or 2, to treat a skin pigmentation disorder. The invention also relates to an aminoalkylamide derivative of general formula (I) following, or one of its dermatologically acceptable salts: K:

[0046] we in which: - Ri and R2 = H, namely that: - Ri and R2 each represent a hydrogen atom; - R3 = H, NH2, namely that: - R3 is a hydrogen atom or a primary amine group; - R4 = NH2, NH-CO-CH3, namely that: - R4 is a primary amine group (-NH2) or a secondary amine group carrying an N-acetyl group (-NH-CO-CH3); and - n = 1 or 2,

[0047] for treating 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.

[0048] According to a preferred embodiment, the above-mentioned at least one aminoalkylamide derivative of general formula (I) is (in systematic nomenclature IUP AC): - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, R1 and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n is equal to 1], and / or - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [namely, in general formula (I) above, Ri and R2 each represent a hydrogen atom, R3 is a hydrogen atom, R4 is a secondary amine group carrying an N-acetyl group, and n is equal to 1], and / or - the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanamide [namely, in general formula (I) above, Ri and R2 each represent a hydrogen atom, R3 is a primary amine group, R4 is a primary amine group, and n is equal to 1].

[0049] 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 hemin pigments.

[0050] According to one embodiment of the invention, said cutaneous pigmentary disorder being selected from couperose and / or contusions / ecchymoses (and other subcutaneous hematomas). Preferably, it is couperose. In such a context for the above-mentioned couperose and / or contusions / ecchymoses (and other subcutaneous hematomas), an aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, is preferably retained, in which R 1 and R 2 each represent a hydrogen atom, R 3 is a hydrogen atom, IC is a primary amine group or a secondary amine group carrying an N-acetyl group.Still in this same context for the aforementioned couperose and / or contusions / ecchymoses (and other subcutaneous hematomas), the following peptidomimetic compound (in systematic nomenclature IUP AC) is particularly cited as a non-limiting example of an aminoalkylamide derivative of general formula (I): 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide.

[0051] Furthermore, the above-mentioned aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, for its dermatological use, may be included in a dermatological preparation, preferably in a content of the order of 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 or oral administration and said at least one excipient also being physiologically acceptable with the skin. Indeed, said aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, usable according to the invention, can 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 context of dermatological preparation, said aminoalkylamide derivative of general formula (I) is the peptidomimetic compound (in systematic nomenclature IUP AC): 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide.

[0052] The salts of said aminoalkylamide derivatives according to the invention, in particular of the above-mentioned 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.

[0053] Advantageously, both these dermatological preparations and the aforementioned cosmetic or dermocosmetic compositions are in a form suitable for topical (cutaneous) or oral administration, advantageously topical, presented in all the forms normally used for such administration. For informational and non-limiting purposes, they may be in the form of an aqueous or hydroalcoholic solution, possibly gelled, a dispersion of the lotion type, 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 mousse, a serum, a paste, a suspension, a dispersion or multiple emulsions which may possibly be microemulsions or nanoemulsions.In terms of adjuvants present in the compositions, preparations and other formulations mentioned above and physiologically compatible with the skin, mention may be made of a compound chosen from 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 agents, matting agents, tensing agents, sequestering agents, perfumes, etc., and mixtures thereof. By way of indication and not limitation, such an adjuvant acceptable in the fields of application targeted by the present invention, present in the formula. in a content of the order of 0.01 to 20% by weight relative to the total weight of the composition, preparation and other formulation referred to above, is notably cited in the dictionary "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 formulations referred to above may advantageously comprise at least one additional active ingredient, the person skilled in the art ensuring, however, that these possible additional active ingredients, as well as their proportions, are chosen in such a way that the advantageous properties recognized for these compositions, preparations and other formulations referred to above are not, or not substantially, altered by the envisaged addition. Such additional active ingredients may be chosen, without this list being limiting, 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, lipolysis stimulating agents, draining or detoxifying agents, anti-inflammatory agents, penetration accelerator agents, desquamating agents, soothing and / or anti-irritant agents, astringent agents, exfoliating agents, agents acting on microcirculation, etc., and mixtures thereof, such an additional active ingredient being present in the formula in a content of the order of 0.0001 to 20% by weight, preferably 0.01 to 5% by weight, relative to the total weight of the composition, preparation and other formulation mentioned above.

[0054] Definitions

[0055] General definitions

[0056] By "a capacity to slow down extravasation outside the cutaneous vascularization", we mean an effect limiting an abnormal diffusion / exit, in the extracellular matrix of the skin, of pigments of a heminic nature under the action of an inflammation with a vascular component.

[0057] By "in 1UPAC systematic nomenclature" is meant a name 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.

[0058] Definitions inherent in the cosmetic and dermocosmetic field (non-therapeutic)

[0059] By "areas of coloration linked to sun exposure and / or age", we mean a skin condition expressed by areas of uneven and abnormal pigmentation of the skin, of a dark, aged and highly unsightly color, said areas resulting from a tissue accumulation of pigments of a melanin nature but also of a hemin nature (the latter by the extravasation - capillary permeability / leakage - of the hemoglobin chromophore and its related degradation pigments (hemosiderin, etc.) outside the cutaneous vascularization).

[0060] Definitions inherent in the dermatological field

[0061] By "rosacea" or "telangiectasia" according to the medical term, we mean a skin color disorder when it is associated with the vascular development of small, very fine, red and sometimes even purplish vessels, visible just under the surface of the skin.

[0062] By "contusions / ecchymoses (and other subcutaneous hematomas)" is meant pigmented areas of skin, more or less stained with blood and which, in a manner distinct from the aforementioned couperose, will first present a reddish color then successively acquire a blue, green and yellow color. Detailed description

[0063] The detailed description below is intended to set out the invention in a sufficiently clear and complete manner, in particular with the aid of examples, but should in no case be regarded as limiting the scope of the protection to the particular embodiments and examples presented below. Examples

[0064] Example 1: Test for demonstrating the ability of the aminoalkylamide derivatives that can be used according to the invention to limit / inhibit the enzymatic activity of tyrosinase

[0065] The evaluation of the inhibition or induction of tyrosinase activity by an aminoalkylamide derivative that can be used 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 the incubation, the amount of L-DOPA-quinone production in the reaction mixture is determined by spectrophotometry of the formation of dopachrome at 475 nm in a microplate reader. Kojic acid (ref. Sigma K3125 lot no. BCCB7130) is used as a reference agent (positive control / control).The results were repeated three times for each aminoalkylamide derivative usable according to the invention.

[0066] The results are collated in Table 1 below, referred to as [Table 1] hereinafter, in particular expressed as median inhibitory concentration or "IC50", namely a concentration required to achieve 50% inhibition of the activity of the quantity of tyrosinase used in the test [IC50 determined experimentally in mM then converted into % by mass using the molecular molar mass of the aminoalkylamide derivative that can be used according to the invention].

[0067] The aminoalkylamide derivatives which can be used according to the invention were the following compounds:

[0068] . the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide object of the formula general (I) above in which Ri = R2 = R3 = H; R4 = NH2, and n = 1, and

[0069] . the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanamide subject of the general formula (I) above in which Ri = R2 = H; R3 = NH2; R4 = NH2, and n = 1.

[0070] [Tables 1] Compound (in IUPAC systematic nomenclature) IC so (mM) IC 50 (% by mass) kojic acid [reference agent] 0.037 0.00052 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanami de [according to the invention; lot no. 5008.15] 49 1.24 N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropan amide [according to the invention; lot no. 36150] 21 0.64

[0071] The results highlight, for the derivatives usable according to the invention, a capacity to inhibit the activity of tyrosinase.

[0072] Example 2: test to demonstrate the capacity of the aminoalkylamide derivatives usable according to the invention to limit / inhibit in vitro the production of melanic pigments by melanocytes

[0073] Experimentally, the test was carried out on B16F10 melanocytes. The B16F10 melanocytes were thus cultured in an atmosphere at 37°C and 5% CO2 in a complete culture medium called "DMEM". 24 hours after seeding, the cells were then treated in the same complete DMEM medium, without phenol red, and containing an aminoalkylamide derivative usable according to the invention. After 48 hours (treatment), the culture medium was removed and the cells were then harvested by trypsinization.

[0074] The cells thus harvested were then centrifuged and the growth medium was removed. The pelleted cells were lysed by adding NaOH and heating at 60°C for 15 minutes. Absorbances were measured at 405 nm using the Micro-Quant spectrophotometer (BioTek Instruments).

[0075] The aminoalkylamide derivative usable according to the invention was the following compound:

[0076] . the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide object of the formula general (I) above in which Ri = R2 = H; R3 = H; R4 = NH2, and n = 1.

[0077] The results are collated in Table 2 below, referred to as [Table 2] hereinafter. They are expressed as % inhibition of the production of melanin produced in B16F10 cells, compared to an untreated control (control). Arbutin (ref. A4256 Sigma lot no. BCBN6022V) is used as a reference agent (positive control).

[0078] [Tables2] Compound (in IUPAC systematic nomenclature) % ​​of melanin VS. control % of inhibition of 1 a production of melanin VS. control control 100 0 arbutin [reference agent] (0.5 mM) 66 -34 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [according to the invention; lot no. 5008.15] (10 mM) 80 -20 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [according to the invention; lot no. 5008.15] (25 mM) 46 -54

[0079] The results highlight, for the aminoalkylamide derivative according to the invention, a capacity to limit / inhibit the production of melanin pigments by its producing cells.

[0080] Example 3: test to demonstrate the capacity of aminoalkylamide derivatives usable according to the invention to inhibit the expression of type 1 vascular cell adhesion protein molecules

[0081] Human dermal microvascular endothelial cells (HDMEC) were obtained from Promocell (lot 449Z005.3, cells isolated from breast tissue - 43-year-old patient).

[0082] The cells were cultured at 37°C and 5% CO2 in MV2 endothelial cell growth medium + Mix supplement (Promocell). 24 hours after seeding, the HDMEC cells were pretreated with aminoalkylamide derivatives usable according to the invention for 2 h before the application of 5 ng / ml of TNF-alpha (stress). The cells were then incubated for 22 hours.

[0083] 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) is used as a reference agent (control / positive control).

[0084] The results are gathered in Table 3 below, referred to as [Table 3] hereinafter, notably expressed as a percentage of inhibition on the expression of VCAM-1 adhesion molecules.

[0085] The aminoalkylamide derivatives which can be used according to the invention were the following compounds:

[0086] . the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide object of the formula general (I) above in which Ri = R2 = H; R3 = H; R4 = NH2, and n = 1

[0087] . the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanamide object of the general formula (I) above in which Ri = R2 = H; R3 = NH2; R4 = NH2, and n = 1.

[0088] [Tables3] Compound (in IUPAC systematic nomenclature) (concentration) % VC AM-1 expression % decrease VCAM-1 expression TNF-alpha [control] (5 ng / mL) 100 - deferoxamine [reference agent] (50 pM) 9 91 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide [according to the invention; lot no. 5008.15] 89 11 N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropan amide [according to the invention; lot no. 34885 / 34887] 87 13

[0089] The results highlight, for the derivatives usable according to the invention, a capacity to limit the expression of type 1 vascular cell adhesion protein molecules, i.e. a capacity to slow down the extravasation outside the cutaneous vascularization of hemoglobin pigments (chromophores) and related degradation pigments.

Claims

Claims

1. Aminoalkylamide derivative of the following general formula (I), or one of its dermatologically acceptable salts: / ■"....... / R., ---------. çg ---------pjj ............. çg-----------) % in which: - Ri and R2 = H; R3 = H or -NH2; R4 =-NH2 or -NH-CO-CH3; and - n = 1 or 2, for its use in the treatment of 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, said cutaneous pigmentary disorder being selected from rosacea and / or contusions, ecchymoses and other subcutaneous hematomas.

2. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to claim 1, for its use according to claim 1, 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.

3. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to claim 1 or 2, for its use according to claim 1 or 2, characterized in that said aminoalkylamide derivative of general formula (I) is: - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide, and / or - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propanam ide, and / or - the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanam ide.

4. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 1 to 3, for its use according to one of claims 1 to 3, characterized in that said aminoalkylamide derivative of general formula (I) is the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propanamide.

5. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 1 to 3, for its use according to one of claims 1 to 3, characterized in that said aminoalkylamide derivative of general formula (I) is the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propanamide.

6. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 1 to 3, for its use according to one of claims 1 to 3, characterized in that said aminoalkylamide derivative of general formula (I) is the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropanamide.

7. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 1 to 6, for its use according to one of claims 1 to 6, said aminoalkylamide 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 or oral administration and said at least one excipient being further physiologically acceptable with the skin.

8. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to one of claims 1 to 7, for its use according to one of claims 1 to 7, said dermatologically acceptable salt of said aminoalkylamide derivative being a hydrochloride.

9. Aminoalkylamide derivative of general formula (I), or one of its dermatologically acceptable salts, according to claim 7, for its use according to claim 7, said dermatological preparation as defined in claim 7 further comprising at least one additional active ingredient chosen from the agents 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, lipolysis stimulating agents, draining or detoxifying agents, anti-inflammatory agents, penetration accelerator and / or anti-irritant agents, astringent agents, agents acting on microcirculation, and mixtures thereof.