New application of amino alkyl amide derivative

Abstract

The invention relates to a novel application of an aminoalkyl amide derivative. Specifically, the invention relates to the use of an aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for the treatment of skin pigmentation disorders characterized by the local accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin, the skin pigmented condition is selected from rosacea and / or contusion / ecchymosis (and other subcutaneous hematoma).

Description

Technical Field

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

[0002] As a striking example of human phenotypic diversity, the skin can display a variety of colors, ranging from pale or almost white skin to very dark tones (black), as well as various light brown and tan shades (Ortonne JP, Annales de Dermatologie et de Vénéréologie, 2012, vol. 139, pp. S73-S77). Regardless of intrinsic factors determined at birth (e.g., genetic factors) or even extrinsic factors (e.g., sun exposure), human skin has a natural color, i.e., pigmentation, that is imparted by a complex and sophisticated biochemical process. Therefore, ultimately, the so-called "normal" color of human skin is the result of the contribution and superposition / combination of four chromophore pigments: oxygenated or oxyhemoglobin (red) in the skin capillaries, deoxyhemoglobin or reduced hemoglobin (blue) in the dermal venules, carotene (yellow-orange) provided by dietary carotenoids, and finally melanin (brown to black) produced locally in melanocytes (specialized cells in the epidermis) (Casadio S., EMC Cosmetology and Aesthetic Dermatology, 2015 http: / / dx.doi.org / 10.1016 / S2211-0380(15)62942-8). Despite this diversity of pigments, the main factor determining skin color and therefore the differences and variations in skin color between individuals remains the dark pigment (melanin), in particular due to its size, intensity and dual types, namely eumelanin (brown to dark black) and the different pheomelanin (reddish yellow to light brown), but also depends on the activity level and distribution of melanosomes, which are intracellular organelles that synthesize and store melanin and subsequently transfer melanin to keratinocytes to ensure epidermal pigmentation and photoprotection against sunlight exposure (Delevoye C. et al, Med. Sci. (Paris), 2011 vol. 27 (2), pp. 153-162). As an illustration, darker skin pigmentation is associated with larger and more productive melanosomes, and the melanin they produce is retained in keratinocytes longer than in keratinocytes of light-skinned individuals (Deng L. et al., Heregitas, 2018, vol. 155 (1), pp. 1-12 and references cited therein). Eumelanin is logically found primarily in dark-skinned individuals, while pheomelanin accumulates more in light-skinned individuals (Barsh GS, PLoS Biology, 2003, vol. 1 (1), pp. 019-022).Finally, the Fitzpatrick Universal Classification, a reference tool for dermatologists, classifies skin phototypes (6 in total) according to the ability (strong or absent) of the integument to precisely form this dark to gray pigmentation when exposed to the sun (Sachdeva S., Indian J. Dermatol. Venereol. Leprol., 2009, vol. 75, pp. 93-96).

[0003] Broadly speaking and in a generalized manner, conditions / disorders affecting so-called "normal" skin color can be summarized as: an enlargement of the natural color of the skin, the clinical appearance of which is localized areas of uneven pigmentation, in particular darker and darker spots; or, conversely, a lightening or paling of the skin, the clinical appearance of which is localized brighter spots (Lipsker D. et al., Annales de Dermatologie et de Vénéréologie, 2019, vol. 146 (10), pp. 666-682). In addition to any harmful effects (melanoma, etc.), such "color defects" may also be perceived by the affected individual as unsightly or even undesirable, as they may interfere with the desired sense of skin color harmony. In order to correct / remove such defects that affect the appearance of the skin (and its aesthetic properties), the field of dermatology known as "aesthetics and cosmetics" has been developed (Wollina U., Dermatologic Therapy, 2008, vol. 21 (2), pp. 118-130). For example, in vocabulary terms, it is believed that the noun "skin discoloration (dyschromia)" describes any deposits of endogenous or exogenous, diffuse or multiple / unspecified pigments in the skin in a clear area, which causes changes in the normal color of the skin (Braun-Flaco O.et al., Dermatology, 1991, Chapter 27). Recently, some scholars have also adopted other general attributes to widely cover any form of illness related to skin discoloration, pigmentation and darkening (Nautiyal A.et al, Pigment Cell Melanoma Res, 2021, vol.00, pp.1-15). In fact, it is clear that the scope of such illnesses (they all have one or more uneven or abnormal skin pigmentation areas that darken or discolor the skin) becomes extensive due to its changes in color and shape. Therefore, such a scope may affect the skin pigmentation disorders / disorders of the following diseases:

[0004] a) Purely dermatological (involving diseased subjects (patients) who suffer from these pathological pigmentary disorders), such as solar lentigo, melasma, rosacea, solar erythema, vitiligo, and

[0005] b) Aesthetic / cosmetic (occurring especially in "healthy" subjects, separable from patients as described above), e.g. pigmented areas associated with sun exposure and / or age.

[0006] Although the skin aesthetic defects mentioned in b) above are completely separable from the skin pathologies mentioned in a) above, and as mentioned above usually involve different groups of individuals, both the cosmetic regimen (if for subjects with aesthetic / cosmetic disorders mentioned in b) above) and the existing treatment regimen (if for patients with one or more pure dermatological conditions mentioned in a) above) target uneven and abnormal skin coloring / pigmentation that affects the natural color of the skin. In this regard, based on a basic understanding of the skin pigmentation process and its complexity, the current state of the art shows technologies, products and targets that some people describe as "clinically proven" (Hakozaki T. et al., Textbook of Aging Skin, 2016, pp. 1017-1026). Admittedly, there is no such reference option, but only a collection of multiple options, which can range from non-invasive or minimally invasive interventions (such as simple application of cosmetic products (foundation), or more sophisticated local treatments to lighten the skin, or chemical peels, laser treatments, etc.) to surgical operations and other more invasive aesthetic medicine procedures (such as dermabrasion, microneedling, skin transplants and cell therapy) (Pijpe, A. et al., 2020, pp. 109-115). One of these options that has long been favored is the topical application of active ingredients to the skin with the support of topical preparations, which can interfere with its pigmentation level. In this regard, especially in the case of excessive melanin deposition, many ingredients of synthetic or natural origin have been developed after the war due to their ability to lighten the skin. Thus, the first ingredients historically found in whitening creams, milks, gels, lotions, serums and other cosmetic or medical skin care preparations were hydroquinone (a benzene derivative) and its derivatives, mercury compounds (mercuric oxide and mercuric chloride), retinoids (such as retinoic acid) and certain dermocorticoids diverted from their therapeutic use. However, due to their harmful effects and dangers to human health over the years (potential carcinogens, skin problems, etc.), some of these "first" whitening substances are now strictly regulated (mainly according to European and American regulations), even in the case of hydroquinone, which appears on the list of substances legally prohibited in cosmetics starting with Regulation (EC) No. 344 / 2013.As an alternative to these health restrictions and bans, ingredient manufacturers have turned to alternative products of natural origin, such as kojic acid (produced by several mushrooms), arbutin (phenolic isoglycosides found in the leaves and skins of many plants), niacinamide or ascorbic acid (a vitamin naturally present in some foods) or azelaic acid (produced by fermentation of cereal seeds or by lipid peroxidation of polyunsaturated fatty acids by yeasts present on the surface of the skin), or non-cytotoxic plant extracts with lightening properties, such as licorice extract, mulberry extract and bearberry extract (Fernandez X. et al, Techniques de l'Ingénieur, 2015, vol. J 2300, pp. 1-33 and references cited therein). Likewise, regulations in some countries (e.g., those in Switzerland) have subsequently restricted or banned the use of some of these naturally occurring substances (kojic acid, arbutin) because of evidence of undesirable and systemic side effects: toxicity, irritation, dryness and skin sensitization. Regarding the mechanism of biological action, many of the above active ingredients, as well as many other active ingredients, such as those summarized in a recent review article (Pillaiyar T. et al., J. Med. Chem, 2018, vol. 61 (17), pp. 7395-7418), logically show an inhibitory effect on tyrosinase (tyrosinase is a key metalloenzyme that converts tyrosine into melanin in melanocytes), which has a limiting effect on melanin production (the case of hydroquinone, azelaic acid and arbutin mentioned above) and a competitive interaction with the non-protease cofactor copper of tyrosinase (the case of kojic acid and ascorbic acid mentioned above). Other agents also aim to inhibit the transfer of melanosomes to keratinocytes (the case of niacinamide mentioned above), inhibit tyrosinase transcription (the case of retinoic acid derivatives mentioned above), block inflammation, scavenge free radicals (the case of glycyrrhetinic acid extracted from licorice and its roots mentioned above), and more simply increase epidermal turnover through peeling and thus eliminate excess melanin (α-hydroxy acids such as glycolic acid and lactic acid) (Resende DISP et al., Appl Sci, 2022, vol. 12 (775), pp. 1-15 and literature cited therein).

[0007] Peptides and so-called "related" compounds have also been described, in particular illustrated by peptides conjugated to carboxylic acids (ascorbic acid, kojic acid, etc.), all of which have the ability to artificially reduce skin melanin levels by inhibiting the enzymatic activity of tyrosinase (Boo YC, Biomedicines, 2020, vol. 8(9), pp. 1-26). It is also worth noting the synthesis of 2-substituted benzyl-4(7)-phenyl-1H-benzo[d]imidazoles, as their IC values ​​for inhibition of tyrosinase are 50 For some, it is close to the reference substance kojic acid ( I Set al., Arch. Pharm. Chem. Life Sci, 2016, vol. 349 (11), pp. 881-888), or patent applications FR2917087 and WO2008006824, which claim protection of compounds of the 4-phenyl-imidazole-2-thione and imidazole-2-thione type, respectively, for the prevention or medical treatment or cosmetic treatment of pigmentation disorders, in particular post-inflammatory or metabolic or pharmaceutical pigmentation disorders, although histamine and / or its imidazole metabolic byproducts are expected to have melanogenesis inducing behavior (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., Skin Pharmacol. Physiol, 2017, vol. 30 (3), pp. 139-145). al, J. Invest. Dermatol, 2000, vol. 114 (2), pp. 334-42). In addition, the above-mentioned peptides, related compounds carrying imidazole units and derivatives belonging to the prior art only specifically target the inhibitory effect on tyrosinase and / or melanin production, which may limit their efficacy. Summary of the invention

[0008] In any case, despite the many various treatments / therapies available to remedy / correct pigmentation conditions / disorders that can affect the natural color of the skin, this type of skin problem remains a high-profile "challenge" for the cosmetic and dermatological industries, which are constantly searching for new, safe and more effective ingredients.

[0009] The present invention is fully in line with the challenge of finding better and more effective treatments, and its purpose is to provide a comprehensive, novel / original remedy for unaesthetic conditions that have in common one or more areas of excessive (usually uneven) and unaesthetic (and / or undesirable) skin pigmentation.

[0010] Based on all these observations and elements of the literature, the inventors set out to solve the following objective technical problem: to make available, on the market of cosmetic active ingredients that interact with the production of skin pigments (chromophores), ingredients with improved behavior and ensured safety, the inventors believed that their purpose was to be able to act simultaneously on several very different components of unaesthetic manifestations, which have in common the presence of one or more areas of excessive (usually uneven) and unaesthetic (and / or undesirable) skin coloration, i.e. to induce an effective effect on melanin production while at the same time observing an effective effect on at least one other pigment component and its inherent regulatory factors involved. DETAILED DESCRIPTION

[0011] To this end, the inventors have established the following detailed description:

[0012] A) Although, as mentioned above, the main factor determining skin color is still dark pigment (brown / melanin), and although, as mentioned above, this pigmentation is mainly related to the function of melanocytes and the enzyme responsible for melanogenesis (tyrosinase), the inventors aim to develop compounds / new substances that target other parallel biological targets, i.e., cell populations other than just peripheral melanocytes and keratinocytes, which may also regulate other intrinsic etiological factors of the constitutive pigmentation of the skin, such as the signal transduction pathways of the pigment production system (Bastonini E. et al, Ann. Dermatol, 2016, vol. 28 (3), pp. 279-289); this "multifactorial" approach:

[0013] - allows a departure from topical monotherapies, which often aim only at inhibiting tyrosinase and the resulting melanin production, or the transport of melanin-laden melanosomes to keratinocytes; and

[0014] - has proven particularly suitable in the cosmetic (or dermocosmetic) context of, for example, infraorbital hyperchromia, which involves and highlights the responsible pigmentary duality, melanin and hemosiderin deposition (Souza DM et al., Surg. Cosmet. Dermatol, 2011, vol. 3(3), pp. 233-239), or in the cosmetic (or dermocosmetic) context of melasma and telangiectatic macules, given 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., Annales de Dermatologie et de Vénéréologie, 2015, vol. 142(12), pp. S482-Regazzetti C. et al. al.,J.Invest.Dermatol,2015,vol.135(12),pp.3096-3104);

[0015] B) These new compounds / substances, which are primarily intended for addition to cosmetics, must be health-safe and comply with European cosmetic and chemical legislation (Regulation (EC) No 1223 / 2009 and Regulation (EC) No 1907 / 2006 of the European Parliament and of the Council, respectively) to ensure consumer safety.

[0016] Thus, as mentioned above, the present invention was developed against the background of purposeful studies and various norms. In this context, at the end of extensive research work, in particular with the help of various biological evaluation models, the inventors found that, unexpectedly (based on the teachings of the prior art to date), the specific family of compounds developed was able to show an advantageous overall behavior while meeting the requirements defined in A) and B) above. The compounds in question are aminoalkylamide derivatives of the following general formula (I) (or one of their cosmetologically or dermatologically acceptable salts):

[0017]

[0018] Wherein, R1 and R2=H, that is, R1 and R2 each represent a hydrogen atom;

[0019] R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group;

[0020] R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3);

[0021] n=1 or 2.

[0022] The present invention therefore relates to the non-therapeutic cosmetic or dermo-cosmetic use of at least one aminoalkylamide derivative of the following general formula (I) or one of its cosmetically or dermo-cosmetically acceptable salts for topically reducing the visibility of excessive and unsightly (and / or undesirable) skin pigmentation characterized by the local accumulation of endogenous pigments, preferably those responsible for the natural color of the skin:

[0023]

[0024] Wherein, R1 and R2=H, that is, R1 and R2 each represent a hydrogen atom;

[0025] R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group;

[0026] R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3);

[0027] n=1 or 2.

[0028] According to a preferred embodiment of the invention, the local accumulation of endogenous pigments, characterizing said excessive and unaesthetic (and / or undesirable) skin coloration, is a local accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin, in particular a local accumulation of melanin and heme pigments.

[0029] Therefore, the present invention also relates to the non-therapeutic cosmetic or dermatological use of at least one aminoalkylamide derivative of the following general formula (I) or one of its cosmetically or dermatologically acceptable salts for locally reducing the visibility of excessive and unsightly (and / or undesirable) skin pigmentation characterized by the local accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin:

[0030]

[0031] Wherein, R1 and R2=H, that is, R1 and R2 each represent a hydrogen atom;

[0032] R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group;

[0033] R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3);

[0034] n=1 or 2.

[0035] More specifically, and without being bound by theory, the compounds of the present invention have, inter alia, the following characteristics:

[0036] ● is a peptidomimetic structure, in other words, an entity that is able to advantageously mimic the biological behavior of an active peptide compound (oligopeptide, protein) in three-dimensional space, but with enhanced stability against proteolysis and improved local bioavailability;

[0037] ●The peptide mimetic structures all carry imidazole-type heterocyclic aromatic rings, because peptide coupling (forming amide-type bonds) occurs between the amine functional groups of a selected group of biogenic primary amines comprising the core unit and the carboxylic acid functional groups of a selected group of preferred β-amino acids (i.e., the amino group is in the β position, such as β-alanine, or 2,3-diaminopropionic acid; such amino acids are only aliphatic in nature).

[0038] Furthermore, as expected, these aminoalkylamide derivatives of general formula (I) are safe from a health point of view and comply with European cosmetic and chemical regulations (Regulation (EC) No. 1223 / 2009 and No. 1907 / 2006 of the European Parliament and of the Council, respectively) in order to ensure consumer safety.

[0039] Furthermore, the aminoalkylamide derivatives of the general formula (I) which can be used according to the invention exhibit an advantageous overall behavior, which is explained by a series of beneficial technical effects, in particular:

[0040] √ The first is the ability to inhibit the enzymatic activity of tyrosinase (see Example 1 below), and thus ultimately limit the specific production of the first type of pigment (chromophore) responsible for the natural color of the skin, namely melanin:

[0041] o At active concentrations, in this case the median inhibitory concentration (referred to as "IC 50 " concentration) to express:

[0042] ■ The latter is considered to be again different from the efficacy claimed by, for example, the commercially available oligopeptide "anti-melanin" agents of the prior art, due to its ability to interact with tyrosinase activity and more generally to slow down key enzymes in the pigmentation process (Lima TNet al., Cosmetics, 2018, 5(21), pp. 1-9), but the concentration seems to be much higher than the facts reported in the same article (at least 1% by mass) [as a signal peptide, it interacts well with cells when used at a concentration of 1.0%-2.5%];

[0043] √ Inhibit the ability of melanocytes (specialized cells in the epidermis) to produce melanin (see Example 2 below);

[0044] √ The ability to additionally act on subcutaneous microvascular characteristics (another major, single and unexpected aspect of the invention that is of interest in the context of A) above) by precisely:

[0045] o Inhibitory effect on the expression of vascular cell adhesion protein molecule type 1 (abbreviated as "VCAM-1") (see Example 3 below), in other words, VCAM-1 is a marker present on the surface of endothelial cells that are in direct contact with blood when endothelial cells line the interior of dermal capillaries:

[0046] ■The role of this marker is to regulate vascular adhesion and transendothelial blood cell diapedesis when they are associated with inflammatory phenomena (Kong DH et al., Int. J. Mol. Sciences, 2018, vol. 19, pp. 1-16);

[0047] o Thus, in the context of the present invention, it is ultimately the ability to slow down the extravasation of the second type of pigments (chromophores) responsible for the natural color of the skin, i.e. the chromophore hemoglobin and its related degraded pigments (hemosiderin, etc.), out of the skin's vasculature, which are also responsible for the visible changes in pigmentation in the skin and subcutaneous layers.

[0048] It should also be noted that the aminoalkylamide derivatives of general formula (I) that can be used according to the present invention are structurally significantly different from the peptides, related compounds with imidazole units and derivatives in the prior art mentioned at the end of the "Background Art" above. In addition, these prior art peptides, related compounds with imidazole units and derivatives only specifically target the inhibitory effect on tyrosinase and / or melanin production, which is different from the aminoalkylamide derivatives of general formula (I) that can be used according to the present invention. Finally, the results shown by the test of Example 1 of the present invention are even more unexpected, because the melanogenesis induction behavior exhibited by the biogenic amine histamine and / or its imidazole metabolic byproducts should also be highlighted (Tomita Y. et al., J. Dermatol. Sci, 1993, vol. 6 (2), pp. 146-54).

[0049] Preferably, for the use according to the invention, the at least one aminoalkylamide derivative of the general formula (I) or one of its cosmetically or dermatologically acceptable salts is (IUPAC systematic nomenclature):

[0050] - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n=1), and / or

[0051] - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a secondary amine group with an N-acetyl group, and n=1), and / or

[0052] - the compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide (that is, in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a primary amine group, R4 is a primary amine group, and n=1),

[0053] More preferably, the at least one aminoalkylamide derivative of the general formula (I) is the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide.

[0054] The salts of the aminoalkylamide derivatives of the present invention, especially the salts of the above-mentioned preferred compounds, can be obtained by reacting the derivatives and compounds with an inorganic acid (preferably hydrochloric acid) or an organic acid. In particular, the cosmetically or dermatologically acceptable salt of the present invention is a hydrochloride.

[0055] According to one embodiment of the invention, the skin hyperpigmentation characterized by local accumulation of endogenous pigments is expressed by pigmented areas associated with sun exposure and / or age. In this case, at least one aminoalkylamide derivative of general formula (I) or one of its cosmetically or dermatologically acceptable salts for the purposes of the present invention is preferably (IUPAC systematic nomenclature):

[0056] - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n=1), and / or

[0057] - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a secondary amine group with an N-acetyl group, and n=1), and / or

[0058] - Compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide (ie, in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a primary amine group, R4 is a primary amine group, and n=1).

[0059] In a preferred embodiment, the at least one aminoalkylamide derivative of the general formula (I) is the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (IUPAC nomenclature).

[0060] Another object of the present invention also relates to the above-mentioned use, wherein the aminoalkylamide derivative of general formula (I) or one of its cosmetically or dermatologically acceptable salts is contained in a cosmetic or dermatological composition or even in a nutricosmetic preparation, preferably in an amount of about 0.1-2% by weight (e.g. 0.2-1.5% by weight) of the total weight of the composition, the composition further comprising at least one cosmetically or dermatologically acceptable excipient, the composition preferably being in a form suitable for topical or oral administration, and the at least one excipient being also physiologically acceptable to the skin. In fact, in a cosmetic or dermatological composition, the aminoalkylamide derivative of general formula (I) or one of its cosmetically or dermatologically acceptable salts that can be used according to the present invention can also be used as a cosmetic or dermatologically acceptable active ingredient, or even in a nutricosmetic preparation, the cosmetic or dermatological composition further comprising at least one cosmetically or dermatologically acceptable excipient, as described above. According to one embodiment, in the context of such a cosmetic or medical skin care composition or nutritional cosmetic preparation, the aminoalkylamide derivative is a peptide mimetic compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n=1).

[0061] The present invention also relates to a non-therapeutic cosmetic or dermatological composition comprising at least one aminoalkylamide derivative of general formula (I) or one of its cosmetically or dermatologically acceptable salts for topically reducing the visibility of excessive and unsightly (and / or undesirable) skin pigmentation characterized by a local accumulation of endogenous pigments, preferably endogenous pigments responsible for the natural color of the skin:

[0062]

[0063] Wherein, R1 and R2=H, that is, R1 and R2 each represent a hydrogen atom;

[0064] R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group;

[0065] R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3);

[0066] n=1 or 2.

[0067] Still in the field of "cosmetics" (or medical skincare), the present invention also relates to a non-therapeutic cosmetic or medical skincare method for locally reducing the visibility of excessive and unaesthetic (and / or undesirable) skin pigmentation, characterized by the local accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin, the method comprising:

[0068] (a) identifying areas of skin in a subject having excessive and unaesthetic (and / or undesirable) skin pigmentation; and

[0069] (b) topically or orally administering to said subject (advantageously topically on said skin area) an effective amount of:

[0070] - at least one aminoalkylamide derivative of the general formula (I) as defined above or one of its cosmetically or dermatologically acceptable salts, or

[0071] - A cosmetic or dermo-medical composition or a nutricosmetic preparation as defined above.

[0072] As indicated in the preamble to this patent application, another aspect of the invention, different from the "cosmetic" aspect, relates to the "dermatological" aspect. To this end, the present invention also relates to the following aminoalkylamide derivatives of the general formula (I) or one of their dermatologically acceptable salts for use in the treatment of skin pigment disorders:

[0073]

[0074] Wherein, R1 and R2=H, that is, R1 and R2 each represent a hydrogen atom;

[0075] R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group;

[0076] R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3);

[0077] n=1 or 2.

[0078] The present invention also relates to aminoalkylamide derivatives of the general formula (I) or one of their dermatologically acceptable salts for use in the treatment of skin pigment disorders:

[0079]

[0080] Wherein, R1 and R2=H, that is, R1 and R2 each represent a hydrogen atom;

[0081] R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group;

[0082] R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3);

[0083] n = 1 or 2;

[0084] Therein the skin pigment disorder is characterized by the localized accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin.

[0085] According to a preferred embodiment, the at least one aminoalkylamide derivative of general formula (I) is (IUPAC systematic nomenclature):

[0086] - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group, and n=1), and / or

[0087] - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propionamide (i.e., in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a secondary amine group with an N-acetyl group, and n=1), and / or

[0088] - Compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide (ie, in the general formula (I), R1 and R2 are each a hydrogen atom, R3 is a primary amine group, R4 is a primary amine group, and n=1).

[0089] Preferably, said skin pigment disorder characterized by the localized accumulation of at least two different types of endogenous pigments consists of a localized accumulation of melanin and a haem pigment.

[0090] According to one embodiment of the present invention, the skin pigment disorder is selected from rosacea and / or contusions / ecchymoses (and other subcutaneous hematomas). Preferably, it is rosacea. In the context of the above-mentioned rosacea and / or contusions / ecchymoses (and other subcutaneous hematomas), it is preferred to select an aminoalkylamide derivative of the general formula (I) or one of its dermatologically acceptable salts, wherein R1 and R2 are each a hydrogen atom, R3 is a hydrogen atom, R4 is a primary amine group or a secondary amine group with an N-acetyl group, and n=1.

[0091] Still in the same context of rosacea and / or contusions / ecchymoses (and other subcutaneous hematomas) as described above, the following peptide mimetic compounds (IUPAC systematic nomenclature) are specifically mentioned as non-limiting examples of aminoalkylamide derivatives of general formula (I): 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide.

[0092] Furthermore, the above-mentioned aminoalkylamide derivatives of the general formula (I) for dermatological use or one of their dermatologically acceptable salts may be included in a dermatological preparation, preferably in an amount of about 0.1 to 2% by weight (e.g. 0.2 to 1.5% by weight) relative to the total weight of the preparation, the preparation also comprising at least one dermatologically acceptable excipient, preferably the preparation is in a form suitable for topical or oral administration, and the at least one excipient is also physiologically acceptable to the skin. In fact, the aminoalkylamide derivatives of the general formula (I) that can be used according to the invention or one of their dermatologically acceptable salts may also be used as dermatologically active ingredients in dermatological preparations, the preparation also comprising at least one dermatologically acceptable excipient, as described above. According to one embodiment, in the context of dermatological preparations, the aminoalkylamide derivatives of the general formula (I) are peptidomimetic compounds (IUPAC systematic nomenclature): 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide.

[0093] The salts of the aminoalkylamide derivatives of the present invention, especially the salts of the above-mentioned preferred compounds, can be obtained by reacting the derivatives and compounds with an inorganic acid (preferably hydrochloric acid) or an organic acid. In particular, the dermatologically acceptable salt of the present invention is a hydrochloride.

[0094] Advantageously, these dermatological preparations and the abovementioned cosmetic or dermo-medical compositions are in a form suitable for topical or oral administration, advantageously by topical administration, and in all forms usually used for such administration.

[0095] By way of example and without limitation, they may be in the form of aqueous or hydroalcoholic solutions (which may be gelled), dispersions of the lotion type (which may be two-phase), oil-in-water or water-in-oil emulsions, suspensions, lotions, creams, aqueous or hydroalcoholic gels, or in the form of (micronized) powders, foams, slurries, pastes, suspensions, dispersions or multiple emulsions (which may be microemulsions or nanoemulsions). As far as adjuvants present in the above-mentioned compositions, formulations and other supplements are concerned and are physiologically compatible with the skin, mention may be made of compounds chosen from the group consisting of oils, waxes, silicone elastomers, surfactants, cosurfactants, thickeners and / or gelling agents, humectants, emollients, organic or inorganic sunscreens, photostabilizers, preservatives other than aldehyde-donating preservatives, colorants, abrasive fillers, pearlescent agents, matting agents, tonicity agents, chelating agents, fragrances, etc., and mixtures thereof. As an example and not a limitation, the content of such adjuvants acceptable in the fields of application covered by the present invention in the formulation is about 0.01% to 20% by weight of the total weight of the above-mentioned composition, preparation or other supplement, in particular as cited in the "International Cosmetic Ingredient Dictionary and Handbook" published by the "Personal Care Products Committee (PCPC)" of the American Cosmetic Association. Finally, the above-mentioned compositions, preparations and other supplements may advantageously contain at least one additional active ingredient, however, the person skilled in the art should note that these possible additional active ingredients and their proportions are selected in such a way that the advantageous properties recognized for the above-mentioned compositions, preparations and other supplements are not or are not substantially altered by the considered addition. Such additional active ingredients may be selected from, but are not limited to, depigmenting agents, photoprotective agents, agents stimulating barrier function, hydrating or moisturizing agents, desquamating agents, soothing agents, and exfoliating agents, agents stimulating cell proliferation (e.g., fibroblasts and keratinocytes), degumming agents, agents stimulating the synthesis of collagen or elastin or preventing its degradation, agents stimulating the synthesis of glycosaminoglycans or proteoglycans or preventing its degradation, antioxidant or anti-free radical or anti-pollution agents, lipolysis stimulating agents, excretion or detoxification agents, anti-inflammatory agents, penetration enhancers, desquamating agents, soothing agents and / or anti-irritants, astringents, exfoliating agents, agents acting on microcirculation, etc., and mixtures thereof, and such additional active ingredients are present in the formulation in an amount of 0.0001 to 20% by weight, preferably 0.01 to 5% by weight, relative to the total weight of the above-mentioned compositions, preparations and other supplements.

[0096] definition

[0097] General Definition

[0098] The "ability to slow down extravasation outside the cutaneous vasculature" must be considered to refer to the effect of limiting the abnormal diffusion / release of heme pigments into the extracellular matrix of the skin under the influence of inflammation with vascular characteristics.

[0099] "IUPAC systematic nomenclature" must be understood to mean a standardized system for naming chemical compounds based on the most stringent recommendations established by the International Union of Pure and Applied Chemistry (IUPAC). These recommendations are intended to ensure that a name corresponds to one and only one molecular structure.

[0100] Dermatological Definition

[0101] “Pigmented areas associated with sun exposure and / or age” must be understood as meaning a skin condition represented by areas of uneven and abnormal pigmentation of the skin (of a dark and aged color and very unsightly) caused by the tissue accumulation of pigments of a melanin nature as well as of a heme nature (the heme nature being caused by the extravasation of the chromophore hemoglobin and its associated degraded pigments (hemosiderin, etc.) outside the cutaneous vasculature - capillary permeation / leakage).

[0102] The medical term "rosacea" or "telangiectasia" must be considered to refer to a skin color disorder associated with the vascular development of small, very thin, red and sometimes even purple blood vessels visible just under the surface of the skin.

[0103] "Contusions / ecchymoses (and other subcutaneous hematomas)" must be understood as meaning pigmented areas of the skin, more or less stained with blood, which, distinct from the above-mentioned rosacea, will initially appear reddish and then successively acquire blue, green and yellow.

[0104] The following detailed description is intended to explain the present invention in a sufficiently clear and complete manner, particularly using examples, but should in no way be considered to limit the scope of protection to the specific embodiments and examples presented below.

[0105] Example 1: Demonstration of the ability of the aminoalkylamide derivatives of the present invention to limit / inhibit the enzymatic activity of tyrosinase Force Test

[0106] The inhibitory or inducing effect of the aminoalkylamide derivatives of the present invention on tyrosinase activity was evaluated by adding tyrosinase and its substrate dopamine to the derivatives to be tested at different concentrations under optimal conditions (pH 6.5 and room temperature, about 25°C). The test mixture was incubated at room temperature for 15 minutes. During the incubation, the formation of dopachrome was spectrophotometrically determined at 475nm in a microplate reader, thereby determining the amount of L-DOPA-quinone produced in the reaction mixture. Kojic acid (Sigma K3125 batch number BCCB7130) was used as a reference reagent (control / positive control). For each aminoalkylamide derivative of the present invention, the results were repeated three times.

[0107] The results are summarized in Table 1 below and are presented as median inhibitory concentration or “IC 50 ” means the concentration required to achieve 50% inhibition of tyrosinase activity in the amount used in the assay [IC 50 is measured in mM and then converted to weight % using the molecular molar mass of the aminoalkylamide derivative of the present invention].

[0108] The aminoalkylamide derivatives of the present invention are the following compounds:

[0109] -Compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide, general formula (I) wherein R1=R2=R3=H, R4=NH2, n=1,

[0110] -Compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide, in the general formula (I), R1=R2=H, R3=NH2, R4=NH2, and n=1.

[0111] [Table 1]

[0112]

[0113] The above results highlight the ability of the derivatives of the present invention to inhibit tyrosinase activity.

[0114] Example 2: Demonstration of the restriction / inhibition of melanin production by the aminoalkylamide derivatives of the present invention Ability Test

[0115] The experiments were performed with B16F10 melanocytes. B16F10 melanocytes were cultured in "DMEM" complete medium at 37°C and 5% CO2. 24 hours after inoculation, the cells were treated with the same complete DMEM medium without phenol red but containing the aminoalkylamide derivatives of the present invention. After 48 hours of treatment, the medium was removed and the cells were harvested by trypsinization. The harvested cells were then centrifuged and the growth medium removed. Aggregated cells were lysed by adding NaOH and heating at 60°C for 15 minutes. The absorbance was measured at 405nm using a Micro-Quant spectrophotometer (BioTek Instruments).

[0116] The aminoalkylamide derivatives of the present invention are the following compounds:

[0117] -Compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide, with the general formula (I) wherein R1=R2=R3=H, R4=NH2, and n=1.

[0118] The results are shown in Table 2 below. The results are expressed as the percentage of melanin production in B16F10 cells compared to the untreated control group. Arbutin (A4256 Sigma batch number BCBN6022V) was used as a reference reagent (positive control).

[0119] [Table 2]

[0120]

[0121] The above results highlight that the aminoalkylamide derivatives of the present invention are capable of limiting / inhibiting the production of melanin by melanin-producing cells.

[0122] Example 3: Demonstration of the inhibitory effect of the aminoalkylamide derivatives of the present invention on the activity of type 1 vascular cell adhesion protein molecules Test of expressive ability

[0123] Human dermal microvascular endothelial cells (HDMEC) were obtained from Promocell (lot number 449Z005.3, cells isolated from breast tissue of a 43-year-old female patient).

[0124] Cells were cultured in MV2 endothelial cell growth medium + supplement mixture (Promocell) at 37°C and 5% CO2. 24 hours after seeding, HDMEC cells were pretreated with the aminoalkylamide derivatives of the invention for 2 hours and then 5 ng / ml TNF-α was applied (stress). Cells were then incubated for 22 hours.

[0125] After 24 hours of treatment, cells were washed with PBS and subjected to CELISA to quantify the expression of VCAM-1 adhesion molecule. Absorbance was measured at 450 nm using a spectrophotometer (Micro-Quant, Biotek Instruments). Deferoxamine (D9533 Sigma batch number BCCB3792) was used as a reference reagent (positive control).

[0126] The results are summarized in Table 3 below and are expressed as percentage inhibition of the expression of the VCAM-1 adhesion molecule.

[0127] The aminoalkylamide derivatives of the present invention are the following compounds:

[0128] -Compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide, general formula (I) wherein R1=R2=R3=H, R4=NH2, n=1,

[0129] -Compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide, in the general formula (I), R1=R2=H, R3=NH2, R4=NH2, and n=1.

[0130] [Table 3]

[0131]

[0132] The above results highlight the ability of the derivatives of the invention to limit the expression of vascular cell adhesion protein type 1 molecules, ie to slow down the extravasation of hemoglobin and related degradation pigments (chromophores) out of the skin vasculature.

Claims

1. An aminoalkylamide derivative of the following general formula (I) or a dermatologically acceptable salt thereof for use in treating skin pigmentation disorders: in, R1 and R2=H, i.e. R1 and R2 each represent a hydrogen atom; R3=H or NH2, that is, R3 is a hydrogen atom or a primary amine group; R4=NH2 or NH-CO-CH3, i.e., R4 is a primary amine group (-NH2) or a secondary amine group with an N-acetyl group (-NH-CO-CH3); n = 1 or 2; Therein, the skin pigment disorder is characterized by a localized accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin, the skin pigment disorder being selected from rosacea and / or bruises / ecchymoses and other subcutaneous hematomas.

2. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to claim 1, wherein: The localized accumulation of at least two different types of endogenous pigments responsible for the natural color of the skin is a localized accumulation of melanin and heme pigments.

3. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to claim 1 or 2, wherein: The aminoalkylamide derivative of the general formula (I) is: - the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide, and / or - the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propionamide, and / or - Compound N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide.

4. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to any one of claims 1 to 3, wherein: The aminoalkylamide derivative of the general formula (I) is the compound 3-amino-N-[2-(1H-imidazol-5-yl)ethyl]propionamide.

5. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to any one of claims 1 to 3, wherein: The aminoalkylamide derivative of the general formula (I) is the compound 3-acetamido-N-[2-(1H-imidazol-5-yl)ethyl]propionamide.

6. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to any one of claims 1 to 3, wherein: The aminoalkylamide derivative of the general formula (I) is N-(2-(1H-imidazol-5-yl)ethyl)-2,3-diaminopropionamide.

7. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to any one of claims 1 to 6, wherein: The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof is contained in a dermatological preparation, which further comprises at least one dermatologically acceptable excipient, and the preparation is preferably in a form suitable for topical or oral administration, and the at least one excipient is also physiologically acceptable to the skin.

8. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to any one of claims 1 to 7, wherein: The dermatologically acceptable salt of the aminoalkylamide derivative is the hydrochloride salt.

9. The aminoalkylamide derivative of general formula (I) or a dermatologically acceptable salt thereof for use according to claim 7, wherein: The dermatological preparation also contains at least one additional active ingredient, which is selected from the group consisting of: depigmenting agents, photoprotective agents, agents that stimulate barrier function, hydrating or moisturizing agents, desquamating agents, soothing agents, exfoliating agents, agents that stimulate cell proliferation (such as proliferation of fibroblasts and keratinocytes), degumming agents, agents that stimulate the synthesis of collagen or elastin or prevent their degradation, agents that stimulate the synthesis of glycosaminoglycans or proteoglycans or prevent their degradation, antioxidant or anti-free radical or anti-pollution agents, lipolysis stimulants, excretion or detoxification agents, anti-inflammatory agents, penetration enhancers and / or anti-irritants, astringents, agents acting on microcirculation, etc., and mixtures thereof.

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