Compounds useful for the treatment and / or care of the skin, hair, nails and / or mucous membranes

Abstract

The present invention relates to a compound of formula (I) R1-W m -X n -AA i -AA2-AA3-AA4-AA5-AA6-Y p -Z q -R a wherein AA1 is Asp, Gly, Asn, Gln, Ala, or no amino acid, AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, Trp, Lys, Arg, or His, AA4 is Lys, Arg, His, Pro, or Val, AA5 is Asn, Asp, Gln, or no amino acid, and AA6 is Thr, Ala, Ser, or no amino acid. The compounds are useful for treating and / or preventing symptoms of skin aging, in particular for treating and / or preventing skin wrinkles, treating and / or preventing the appearance of sagging skin, and / or reducing and / or preventing facial asymmetry.

Description

[Technical Field]

[0001] This invention relates to compounds useful for the treatment and / or care of skin, hair, nails and / or mucous membranes. In particular, the compounds are useful for preventing skin aging, especially for treating and / or preventing wrinkles, treating and / or preventing the appearance of sagging skin, and / or reducing and / or preventing facial asymmetry. This invention extends to compositions containing the compounds and treatment methods using the compounds. [Background technology]

[0002] The effects of aging play a major role in the appearance of the skin. The most prominent signs of facial aging are the appearance of wrinkles and sagging. With age, the epidermis and connective tissue of the skin weaken, the firmness of the facial muscles decreases, the epidermis loosens and begins to sag, the natural folds of skin in the cheeks, neck, and jaw area change, and facial fat is redistributed and reduced.

[0003] In particular, a decrease in facial muscle firmness is associated with muscle aging. Muscle aging is a well-known process that begins around the age of 40 and accelerates in later years. The resulting decrease in muscle mass (muscle tone) can give the face a loose, sagging appearance. The jawline may be lost, and the facial contours may become less defined.

[0004] Different methods have been proposed to improve the firmness of the facial muscles. One of the most common methods for reducing facial sagging is a facelift. Also known as wrinkle removal, a facelift is a cosmetic surgery procedure to reduce sagging or folds of skin along the cheek and jawline, as well as other changes in facial shape associated with aging. During a facelift, flap of skin on each side of the face is pulled back, and the tissue beneath the skin is surgically remodeled to restore the facial contour to a more youthful shape. Nevertheless, facelifts can be associated with different complications and risks. As with any other type of surgery, facelifts carry the risk of bleeding, infection, and side effects from anesthesia. Some other risks include, among others, hematoma, scarring, nerve damage, hair loss, and skin loss. Furthermore, the results of a facelift are not permanent. With age, the skin of the face may begin to sag again. Generally, a facelift can be expected to last for 10 years.

[0005] Naturally, there is growing interest in alternative non-invasive methods to reduce facial sagging. One of the most promising is electrical stimulation. Electromuscular stimulation (EMS) has been used as an alternative intervention in several biomedical fields to improve muscle recovery and enhance muscle structure and function. [Kern, H. et al. "Electrical stimulation counteracts muscle decline in seniors", (2014), Frontiers in Aging Neuroscience, Vol 6(189), pp.11-11]. There are four main types of treatment, differing in the type of current used: Galvani electrotherapy, neuromuscular electrical stimulation (NMES) (also known as Faradic treatment), microcurrent electroneuromuscular stimulation (MENS), and radiofrequency treatment.

[0006] MENS is distinguished by the use of extremely small currents (i.e., one millionth of an ampere, e.g., 300-500 μA) that are almost imperceptible but mimic the body's own bioelectricity. Therefore, MENS is not for medical use but is designed for cosmetic, non-therapeutic aesthetic treatments to improve skin rejuvenation as an effective, non-invasive, and inexpensive technique to combat the appearance of skin aging [Goldbert, A. et al. "Skin Rejuvenation with Non-Invasive Pulsed Electric Fields", (2015), Nature Scientific Reports, Vol 5(10187), pp.1-18; Seniee, F. et al. "Consider of Micro-Current's effect to variation of Facial Wrinkle trend, Randomized Clinical Trial Study", (2012), Life Science Journal Vol 9(3), pp.1184-1189]. By stimulating skin cells in a specific way, it is possible to reduce skin wrinkles and sagging.

[0007] At the cellular level, MENS is also known to stimulate the production of collagen and elastin. Collagen is the most abundant protein in the connective tissue of the skin, helping to support the growth of new cells while forming a mesh-like structure and providing the necessary flexibility. One of the well-known characteristics of aging is skin sagging. Increased collagen synthesis is thought to be beneficial in reducing the signs of aging. Collagen synthesis declines with age, leading to a decrease in skin firmness and contributing to the appearance of wrinkles in older adults [Varani, J. et al. "Decreased Collagen Production in Chronologically Aged Skin: Roles of Age-Dependent Alteration in Fibroblast Function and Defective Mechanical Stimulation", (2006), American Journal of Pathology, Vol.168(6), pp.1861-1868]. Therefore, MENS may improve the firmness and tone of facial skin.

[0008] Nevertheless, treatments using MENS have several drawbacks. For example, the intensity level of the current can depend on the individual's skin thickness. Generally, as health deteriorates or physical condition changes, the microcurrent flowing through the body weakens. Skin thickness is influenced by age or changes in external factors, resulting in significant intra-individual and inter-individual variability. In some cases, insufficient electrical contact between the electrodes and the surface being treated can cause discomfort and pain in the user, and in extreme cases, skin inflammation. Some MENS devices use electrodes and adhesive gels to improve conductivity, but these are expensive and inconvenient, for example, on the face, as there is no room to move the electrodes once they are in place. Furthermore, some devices may have difficulty precisely following the contours of the body surface being treated, which is problematic because the stimulation needs to address a precise area. For example, some devices require the use of a mirror to position the device's wand on the appropriate part of the face and to compress or stretch the skin. Finally, some potential users have negative preconceptions about MENS treatments, namely, prejudices against using electricity on the face as a daily cosmetic treatment, for example.

[0009] For example, there is a need to provide alternative methods to mitigate or prevent signs of skin aging, such as improving skin tone and firmness, and / or reducing the appearance of sagging skin. There is a need to provide methods to overcome the problems associated with known methods such as facelifts or MENS. There is a need to find novel active compounds that can mitigate or prevent signs of skin aging. In particular, there is a need to find novel active compounds that can prevent or reduce the appearance of wrinkles and / or facial sagging. The present invention aims to satisfy some or all of these needs and solve some or all of the problems identified above. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Kern, H. et al “Electrical stimulation counteracts muscle decline in seniors”, (2014), Frontiers in Aging Neuroscience, Vol 6(189), pp.11-11 [Non-Patent Document 2] Goldbert, A. et al. “Skin Rejuvenation with Non-Invasive Pulsed Electric Fields”, (2015), Nature Scientific Reports, Vol 5(10187), pp.1-18 [Non-Patent Document 3] Seniee, F. et al. "Consider of Micro-Current's effect to variation of Facial Wrinkle trend,Randomized Clinical Trial Study", (2012), Life Science Journal Vol 9(3), pp.1184-1189 [Non-Patent Document 4] Varani, J. et al. "Decreased Collagen Production in Chronologically Aged Skin: Roles of Age-Dependent Alteration in Fibroblast Function and Defective Mechanical Stimulation", (2006), American Journal of Pathology, Vol. 168(6), pp. 1861-1868 [Overview of the project] [Means for solving the problem]

[0011] In a first embodiment, the present invention relates to a compound represented by formula (I), R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Zq -R2(I) The stereoisomer and / or cosmetically acceptable salt thereof are provided, in the formula, AA1 is Asp, Glu, Asn, Gln, Ala, Gly, or an amino acid-free amino acid. AA2 is Val, Ile, Leu, or Ala. AA3 is Tyr, Phe, Trp, Lys, Arg, or His. AA4 stands for Lys, Arg, His, Pro, or Val. AA5 is Asn, Asp, Gln, or an amino acid-free compound. AA6 is either Thr, Ala, Ser, or an amino acid-free compound. W, X, Y, and Z are each independently any amino acid. m, n, p, and q are each independently either 0 or 1. m+n+p+q is less than or equal to 2, R1 is selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R5-CO-, and R5 is selected from the group consisting of H, acyclic aliphatic groups, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl. R2 is selected from the group consisting of -NR3R4, -OR3, and -SR3, and R3 and R4 are independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids.

[0012] In particular, the present invention provides a compound represented by formula (I), wherein AA5 is Asn, Asp, or Gln, AA1 is Ala, Gly, or no amino acid, AA2 is Val, Ile, or Leu, AA3 is Lys, Arg, or His, AA4 is Pro or Val, and AA6 is Thr, Ala, Ser, or no amino acid, provided that AA1 is different from AA6. Optionally, or further, the present invention provides a compound represented by formula (I), wherein AA5 is no amino acid, AA1 is Asp, Glu, Asn, or Gln, AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, or Trp, AA4 is Lys, Arg, or His, and AA6 is no amino acid.

[0013] The compounds of the present invention have been found to be effective in upregulating the expression of muscleblind-like 1 (MBNL1). MBNL1 is a highly conserved RNA-binding protein that plays a crucial role in the process of muscle differentiation and maintenance. An increase in MBNL1 protein in fibroblasts activates the process of differentiation into myofibroblasts, a cell type capable of releasing large amounts of extracellular matrix proteins such as collagen, elastin, and fibronectin. This increase in myofibroblasts leads to an increase in collagen in the skin, resulting in a skin firming effect. Therefore, the compounds of the present invention are useful in mitigating and / or preventing problems associated with the decrease in muscle mass (muscle tone) due to muscle aging, such as the appearance of facial sagging. Furthermore, the compounds of the present invention can be used in cosmetic treatments that exert a skin lifting effect through a chemical mechanism, similar to the effects of physical treatments such as electrical stimulation microcurrents, but without the inconvenience of the latter. In addition, the compounds of the present invention have been found to be effective in inhibiting norepinephrine release in the skin and increasing the amount of lipids in adipocytes. These further demonstrate their usefulness as anti-aging agents for the skin.

[0014] In another embodiment, the present invention provides a cosmetic composition comprising a compound of formula (I), its stereoisomers and / or cosmetically acceptable salts thereof, together with at least one cosmetically acceptable excipient or adjuvant.

[0015] In another embodiment, the present invention provides the use of a compound of formula (I), its stereoisomers and / or cosmetically acceptable salts, or a composition comprising a compound of formula (I), its stereoisomers and / or cosmetically acceptable salts, for the treatment and / or care of the skin, hair, nails and / or mucous membranes. The present invention provides the use of a compound of formula (I), its stereoisomers and / or cosmetically acceptable salts, or a cosmetic composition comprising a compound of formula (I), its stereoisomers and / or cosmetically acceptable salts, for the cosmetic non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes. Cosmetic non-therapeutic treatment and / or care may include the prevention or treatment of symptoms of skin aging, the treatment and / or prevention of skin wrinkles, the stimulation of collagen synthesis and / or the prevention of collagen loss, the improvement or maintenance of skin firmness, the treatment and / or prevention of the appearance of sagging skin, the treatment or prevention of facial asymmetry, the prevention and / or mitigation of the effects of increased and / or decreased adipose tissue volume.

[0016] In another embodiment, the present invention provides a method for treating and / or caring for the skin, hair, nails and / or mucous membranes of a subject, comprising administering to the subject an effective amount of a compound of formula (I), its stereoisomers and / or a cosmetically or pharmaceutically acceptable salt thereof, or a composition containing thereof. In particular, the present invention provides a method for cosmetic non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes of a subject, comprising administering to the subject a cosmetically effective amount of a compound of formula (I), its stereoisomers and / or a cosmetically acceptable salt thereof, or a cosmetic composition containing thereof. Typically, the compound is administered topically. Cosmetic non-therapeutic treatment and / or care may include the prevention or treatment of symptoms of skin aging, the treatment and / or prevention of skin wrinkles, the stimulation of collagen synthesis and / or the prevention of collagen loss, the improvement or maintenance of skin firmness, the treatment and / or prevention of the appearance of sagging skin, and / or the treatment or prevention of facial asymmetry, and the prevention and / or mitigation of the effects of increased and / or decreased adipose tissue volume.

[0017] In another embodiment, the present invention relates to a kit for use in cosmetic non-therapeutic treatments and / or care of the skin, (i) A composition containing botulinum toxin, (ii) optionally a composition containing Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 and (iii) A cosmetic composition comprising a compound of formula (I) is provided, and a kit comprising the above. [Brief explanation of the drawing]

[0018] [Figure 1] This shows the percentage of MBNL1 protein present in human skeletal muscle cells (based on the total protein content of human skeletal muscle cells), measured using a time-resolved fluorescence energy transfer assay. Measurements are performed on samples of human skeletal muscle cells treated with the compound of the present invention and control samples of human skeletal muscle cells not treated with the compound of the present invention (Example 7). Abbreviations: BC = Basic control. [Figure 2]This shows the levels of MBNL1 protein present in human dermal fibroblasts, measured using an immunofluorescence assay. Measurements are performed on samples of human dermal fibroblasts treated with the compound of the present invention and control samples of human dermal fibroblasts not treated with the compound of the present invention (Example 8). Abbreviations: BC = Basic control. [Figure 3] This shows the level of muscle mass reduction in human skeletal muscle cells, measured using an immunofluorescence assay. Measurements are performed on samples of human skeletal muscle cells treated with the compound of the present invention and control samples of human skeletal muscle cells not treated with the compound of the present invention (Example 9). Abbreviations: BC = Basic control. [Figure 4] This shows the percentage of muscle mass reduction in human skeletal muscle cells, measured using an immunofluorescence assay. Measurements are performed on samples of human skeletal muscle cells treated with tumor necrosis factor alpha (TNFα) and either (i) treated with the compound of the present invention, or (ii) not treated with the compound of the present invention. The results are also compared to human skeletal muscle cells that were neither treated with TNFα nor with the compound of the present invention (Example 10). Abbreviations: BC + TNF = 20 mg / ml TNFα for basic control, BC = basic control. [Figure 5] The levels of type I collagen on human dermal fibroblasts, determined by alpha-ELISA assay, are shown (Example 11). Measurements are performed on human dermal fibroblasts treated with the compound of the present invention and on a baseline control sample not treated with the compound of the present invention. Abbreviations: COL% = percentage of type I collagen, BC = baseline control. [Figure 6] This shows the norepinephrine release levels of human neuroblastoma cell line SS determined by immunofluorescence assay. Measurements are performed on human neuroblastoma cell lines treated with the compound of the present invention and on a base control sample not treated with the compound of the present invention (Example 12). Abbreviations: NA = norepinephrine, BC = base control. [Figure 7]This shows the level of lipid accumulation in human subcutaneous adipocytes, determined by fluorescence staining. Measurements were performed on co-culture samples of young and aged adipocytes, treated with or not treated with the compound of the present invention. The results are also compared with cultures of aged adipocytes. Abbreviations: LA% = Percentage of lipid accumulation, CC = Co-culture control, YC = Young control, OC = Old control. [Modes for carrying out the invention]

[0019] definition In the context of this invention, “skin” is understood to mean multiple layers that constitute it, from the outermost layer or stratum corneum to the bottom layer or subcutaneous tissue (including both the outermost layer or stratum corneum and the bottom layer or subcutaneous tissue). These layers are composed of different types of cells, among others, such as keratinizing cells, fibroblasts, melaninizing cells, mast cells, neurons and / or adipocytes. The term “skin” also includes the scalp. The term “skin” includes mammalian skin, including human skin. Similarly, the term “hair, nails, and mucous membranes” includes the hair, nails, and mucous membranes of mammals, e.g., humans.

[0020] As used herein, the term “treatment,” unless otherwise specified, “cosmetic non-therapeutic,” means a treatment method comprising a method toward administering a compound according to the present invention for the purpose of reducing or eliminating a disease or disorder, or for reducing or eliminating one or more symptoms associated with a disease or disorder. The term “treatment,” unless otherwise specified, also encompasses treatment methods aimed at reducing or eliminating the physiological consequences of a disease or disorder.

[0021] When the terms “treatment” and “care” are accompanied by the proviso “cosmetic non-therapeutic,” the treatment or care is intended to improve or maintain the aesthetic appearance of the skin, hair, nails, and / or mucous membranes. In particular, the treatment aims to improve the aesthetic properties of the skin, hair, nails, and / or mucous membranes, such as, but not limited to, the level of moisture, elasticity, firmness, luster, color, or texture, which affect the aesthetic appearance of the skin, hair, nails, and / or mucous membranes. In the context of this specification, the term “care” refers to the maintenance of the properties of the skin, hair, nails, and / or mucous membranes. These properties will be improved or maintained by cosmetic treatments and / or care of the skin, hair, nails, and / or mucous membranes in both healthy subjects and subjects exhibiting diseases and / or disorders of the skin, hair, nails, and / or mucous membranes.

[0022] As used in this invention, the term "prevention" refers to the ability of the compounds of the present invention to prevent, delay, or interfere with the onset or development of a disease or disorder, or to prevent, delay, or interfere with changes in the cosmetic properties of the skin, mucous membranes, and / or hair. As used in this invention, the term "prevention" is interchangeable with the term "inhibition," that is, to inhibit the onset or development of a disease or disorder, or to inhibit changes in the cosmetic properties of the compounds of the present invention.

[0023] In the context of the present invention, the term “aging” refers to changes experienced by the skin as a result of an intrinsic aging process (i.e., aging over time) or as a result of an extrinsic dermal aging process induced by environmental factors (i.e., environmental factors such as exposure to the sun (photoaging) or cigarette smoke, extreme climatic conditions such as cold winds, or wind, chemical pollutants or contaminants). In the context of the present invention, aging includes, for example, but not limited to, the progression of discontinuities on the skin such as wrinkles, fine lines, expression lines, stretch marks, deep wrinkles, unevenness, or roughness; increased pore size; decreased moisture; decreased elasticity; decreased firmness; decreased smoothness; decreased ability to recover from deformation; decreased resilience; sagging of the skin such as drooping cheeks; the appearance of dark circles or a double chin, in particular; changes in skin color such as age spots, redness, dark circles, or in particular the appearance of hyperpigmented areas such as senile lentigines or freckles; abnormal differentiation; hyperkeratosis; elastic fibrosis; keratosis; hair loss; orange peel skin; decreased collagen structure; and other histological changes in the stratum corneum, dermis, epidermis, vascular system (e.g., the appearance of spider veins or telangiectasias), or in particular, tissues close to the skin. The term "photoaging" encompasses a series of processes resulting from prolonged exposure of the skin to ultraviolet light, which causes premature aging. These processes exhibit, but are not limited to, the same physical characteristics as aging, such as sagging and loosening, as well as changes in color or irregular pigmentation, abnormality, and / or excessive keratinization. A combination of various environmental factors, such as exposure to cigarette smoke and pollution, as well as climatic conditions, such as cold and / or wind, also contribute to skin aging.

[0024] In this specification, abbreviations used for amino acids follow the rules of the IUPAC-IUB Biochemical Nomenclature Committee, as defined in Eur.J.Biochem.,(1984),138,9-37. Therefore, for example, Gly represents NH2-CH2-COOH, Gly- represents NH2-CH2-CO-, -Gly represents -NH-CH2-COOH, and -Gly- represents -NH-CH2-CO-. Thus, if the hyphen representing the peptide bond is located to the right of the symbol, the OH in the 1-carboxyl group of the amino acid (represented here in the conventional non-ionized form) is deleted, and if it is located to the left of the symbol, the H in the 2-amino group of the amino acid is deleted, and both modifications can be applied to the same symbol (see Table 1). [Table 1]

[0025] As used herein, the term “acyclic aliphatic group” includes linear (i.e., linear and unbranched) or branched, saturated or unsaturated hydrocarbyl groups such as alkyl, alkenyl, and alkynyl groups. Acyclic aliphatic groups may be substituted (mono or poly) or unsubstituted.

[0026] As used herein, the term “alkyl” includes both saturated linear and branched alkyl groups, the group may be substituted (mono or poly) or unsubstituted. The alkyl group is bonded to the rest of the molecule by a single bond. The alkyl group has 1 to 24 carbon atoms, preferably 1 to 16, more preferably 1 to 14, even more preferably 1 to 12, and even more preferably 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the term “alkyl” include methyl, ethyl, isopropyl, isobutyl, tert-butyl, 2-methylbutyl, heptyl, 5-methylhexyl, 2-ethylhexyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl, and amyl.

[0027] As used herein, the term “alkenyl” refers to a group comprising one or more carbon-carbon double bonds, which may be linear or branched, and which may be substituted (mono or poly) or unsubstituted. Preferably, an alkenyl has one, two, or three carbon-carbon double bonds. If two or more carbon-carbon double bonds are present, the double bonds may be conjugated or unconjugated. Preferably, an alkenyl group has 2 to 24 carbon atoms, preferably 2 to 16, more preferably 2 to 14, even more preferably 2 to 12, and even more preferably 2, 3, 4, 5, or 6 carbon atoms. The alkenyl group is bonded to the rest of the molecule by single bonds. The term “alkenyl” includes, for example, vinyl (-CH2=CH2), allyl (-CH2-CH=CH2), prenyl, oleyl, linoleyl groups, and similar groups.

[0028] The term "alkynyl" refers to a group containing one or more carbon-carbon triple bonds, which can be linear or branched, and which can be substituted (mono or poly) or unsubstituted. Preferably, the alkynyl group has one, two, or three carbon-carbon triple bonds. The double bonds may or may not be conjugated. The alkynyl group has 2 to 24 carbon atoms, preferably 2 to 16, more preferably 2 to 14, even more preferably 2 to 12, and even more preferably 2, 3, 4, 5, or 6 carbon atoms. The alkynyl group is bonded to the rest of the molecule by single bonds. The term "alkynyl" includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, and similar groups. Alkynyl groups can also contain one or more carbon-carbon double bonds, and include, but are not limited to, but buto-1-ene-3-inyl and pento-4-ene-1-inyl groups, as well as similar groups.

[0029] The term “alicyclyl” is used herein to encompass aliphatic cyclic (alicyclic) groups, such as, for example, cycloalkyl, cycloalkenyl, or cycloalkynyl groups, but is not limited to these. The term “alicyclyl” refers to a monoradical containing one or more carbon atom rings, which may be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl), but which are not aromatic. More specifically, an alicyclyl group contains three or more, 3 to 24, 3 to 12, or 6 to 12 ring carbon atoms. An alicyclyl group may be monocyclic, dicyclic, or tricyclic, and the rings may be condensed or linked by, for example, single bonds or linking groups such as methylene or other alkylene groups. An alicyclyl group may be substituted (mono or poly) or unsubstituted. In one embodiment, the alicyclyl group is a 6- to 12-membered ring system consisting of carbon atoms and optionally containing one or two double bonds.

[0030] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, which may be substituted (mono or poly) or unsubstituted. Cycloalkyl groups have 3 to 24 carbon atoms, preferably 3 to 16, more preferably 3 to 14, even more preferably 3 to 12, and even more preferably 3, 4, 5, or 6 carbon atoms. Cycloalkyl groups are bonded to the rest of the molecule by single bonds. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrophenalene, and similar groups.

[0031] The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic alkenyl group that may be substituted (mono or poly) or unsubstituted. A cycloalkenyl group has 5 to 24 carbon atoms, preferably 5 to 16, more preferably 5 to 14, even more preferably 5 to 12, and even more preferably 5 or 6 carbon atoms. The cycloalkenyl group is bonded to the rest of the molecule by single bonds. Preferably, a cycloalkenyl group contains one, two, or three carbon-carbon double bonds. If two or more carbon-carbon double bonds are present, the double bonds may or may not be conjugated. Examples of cycloalkenyl groups include, but are not limited to, cyclopent-1-en-1-yl groups and similar groups.

[0032] The term "cycloalkynyl" refers to a non-aromatic monocyclic or polycyclic alkynyl group, which may be substituted (mono or poly) or unsubstituted. A cycloalkynyl group has 8 to 24 carbon atoms, preferably 8 to 16, more preferably 8 to 14, even more preferably 8 to 12, and even more preferably 8 or 9 carbon atoms, which are bonded to the rest of the molecule by single bonds. Preferably, a cycloalkynyl group contains one, two, or three carbon-carbon triple bonds, and may or may not be complexed. Cycloalkynyl groups include, for example, cycloocta-2-yn-1-yl groups and similar groups, and are not limited to those mentioned above. Cycloalkynyl groups also contain one or more carbon-carbon double bonds, including, for example, cycloocta-4-en-2-inyl groups and similar groups, and are not limited to those mentioned above.

[0033] As used herein, the term “heterocyclyl” or “heterocyclic” refers to a 3- to 10-membered hydrocarbon ring system in which one or more atoms of one or more rings are heteroatoms (i.e., not carbon atoms). Thus, “heterocyclyl” or “heterocyclic” refers to a cyclic group in which the ring atoms consist of carbon and one or more heteroatoms. To satisfy the valency, the heteroatoms may be bonded to H or substituents. Preferably, one, two, or three of the ring carbon atoms are heteroatoms. Each heteroatom may be independently selected from the group consisting of O, N, S, P, and B, or from the group consisting of O, N, and S. Heterocyclyl groups may be substituted (mono or poly) or unsubstituted. Heterocyclyl groups may be monocyclic, dicyclic, or tricyclic, and the rings may be condensed or linked by single bonds or linking groups such as methylene groups or other alkylene groups. The nitrogen, carbon, or sulfur atoms present in the heterocyclyl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heterocyclyl radical may be unsaturated, partially, or fully saturated. The heterocyclyl radical may be aliphatic or aromatic. In one embodiment, the heterocyclyl is aliphatic (also known as heteroaryl) and is a 3-10 membered ring system in which one or more ring atoms consist of a carbon atom and 1-4 or 1,2, or 3 heteroatoms. In one embodiment, the heterocyclyl group is a 6-10 membered ring system in which one or more ring atoms consist of a carbon atom and 1-4 heteroatoms, and the ring system optionally contains one or two double bonds. In one embodiment, the heterocyclyl is aromatic (also known as heteroaryl) and is a 6-10 membered ring system in which one or more ring atoms consist of a carbon atom and 1-4 or 1,2, or 3 heteroatoms. Regarding the term heterocyclyl, the primary meaning should be a five- or six-membered ring. Examples of saturated heterocyclyl groups include dioxane, piperidine, piperazine, pyrrolidine, morpholine, and thiomorpholine.Examples of aromatic heterocyclyl groups are pyridine, pyrrole, furan, thiophene, benzofuran, imidazoline, quinoline, quinoline, pyridazine, and naphthyridine.

[0034] The term "aryl group" refers to an aromatic group having 6 to 30, preferably 6 to 18, more preferably 6 to 10, and even more preferably 6 or 10 carbon atoms. The aryl group may be linked by carbon-carbon bonds and may include 1, 2, 3, or 4 aromatic rings that are fused together. Examples include, but are not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl, or anthranyl. The aryl group may be substituted (mono- or poly-) or unsubstituted.

[0035] The term "aralkyl group" refers to an alkyl group substituted by an aromatic group having 7 to 24 carbon atoms, for example, but not limited to, -(CH2) 1-6 -phenyl, -(CH2) 1-6 -(1-naphthyl), -(CH2) 1-6 -(2-naphthyl), -(CH2) 1-6 -CH(phenyl)2, and the like are included.

[0036] The term "heteroarylalkyl" refers to an alkyl group substituted by a heteroaryl group (also known as an aromatic heterocycle) as defined above. The alkyl group has 1 to 6 carbon atoms, and the heteroaryl group has 2 to 24 carbon atoms and 1 to 3 heteroatoms. Examples of heteroarylalkyl groups include, but are not limited to, -(CH2) 1-6 -imidazolyl, -(CH2) 1-6 -triazolyl, -(CH2) 1-6 -thienyl, -(CH2) 1-6 -furyl, -(CH2) 1-6 -pyrrolidinyl, and the like are included.

[0037] As is understood in the Art, the above-mentioned groups may be substituted to some extent. In particular, any of the groups identified above may be substituted, where explicitly indicated. The substituents (radicals) mentioned above are groups (or radicals) that are substituted by one or more substituents at one or more available positions. Preferably, the substitution is located at one, two, or three positions, more preferably at one or two positions, and even more preferably at one position. Suitable substituents include, but are not limited to, C1-C4 alkyl, hydroxyl, C1-C4 alkoxyl, amino, aminoC1-C4 alkyl, C1-C4 carbonyloxyl, C1-C4 oxycarbonyl, fluoride, halogens such as chlorine, bromine and iodine, cyano, nitro, azide, C1-C4 alkylsulfonyl, thiol, C1-C4 alkylthio, aryloxy such as phenoxyl, -NR b (C=NR b )NR b R c (In the formula, R b and R c These are independently H, C1-C4 alkyl, C2-C4 alkenyl, alkynyl, and C3-C 10 Cycloalkyl, C6-C 18 Aryl, C7-C 17 Examples include aralkyl groups (selected from the group formed by 3- to 10-membered heterocyclines or protecting groups of amino groups).

[0038] As should be understood, and as stated above, when R is described herein as being alkyl, alkenyl, alkynyl, alicyclyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclyl, heterocyclic, heteroarylalkyl, aryl, or aralkyl, it means that R is such a group. For example, when it is stated that R is alkyl, it means that R is alkyl. As used herein, the terms “contains” are inclusive or non-limiting and do not exclude additional non-enumerated elements or method steps, and are intended to encompass the phrases “essentially consist” and “consist of,” where “consist of” excludes any element or step not explicitly stated, and “essentially consist of” allows for the inclusion of additional non-enumerated elements or steps that are essential or basic to the composition or method under consideration and do not substantially affect the novel features.

[0039] The compound of the present invention A first aspect of the present invention relates to a compound of formula (I), R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Z q -R2(I) With respect to the stereoisomer and / or cosmetically acceptable salt, in the formula, AA1 is Asp, Glu, Asn, Gln, Ala, Gly, or an amino acid-free amino acid. AA2 is Val, Ile, Leu, or Ala. AA3 is Tyr, Phe, Trp, Lys, Arg, or His. AA4 stands for Lys, Arg, His, Pro, or Val. AA5 is Asn, Asp, Gln, or an amino acid-free compound. AA6 is Thr, Ala, Ser, or an amino acid-free amino acid. W, X, Y, and Z are each independently any amino acid. m, n, p, and q are each independently either 0 or 1. m+n+p+q is less than or equal to 2, R1 is selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R5-CO-, and R5 is selected from the group consisting of H, acyclic aliphatic groups, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl. R2 is selected from the group consisting of -NR3R4, -OR3, and -SR3, and R3 and R4 are independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids.

[0040] Conveniently, the compound of formula (I) was found to upregulate the MBNL1 protein in skin and dermal muscle cells.

[0041] The compound of formula (I) is a peptide containing 3, 4, 5, 6, 7, or 8 amino acids linked in a chain. R1 is attached to the amino terminus (N terminus) of the peptide, and R2 is attached to the carboxyl terminus (C terminus) of the peptide.

[0042] R1 is a polymer derived from polyethylene glycol having a molecular weight contained in H, 200 to 35,000 daltons, and R5-CO-(wherein R5 is C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkinyl, C3-C 24 Cycloalkyl, C5-C 24 Cycloalkenyl, C8-C 24 Cycloalkynyl, C6-C 30 Aryl, C7-C 24The group may be selected from aralkyl (selected from the group consisting of 3-10 membered heterocyclyl rings) and heteroarylalkyls comprising 2-24 carbon atoms and 1-3 heteroatoms, wherein the alkyl group has 1-6 carbon atoms.

[0043] R1 is H and R5-CO-(wherein R5 is C1-C 18 Alkyl, C2-C 24 Alkenil, C3-C 24 A group consisting of cycloalkyl groups, or C1-C 16 Alkyl, C2-C 18 The R5-CO- group may be selected from the group consisting of alkenyls and C3-C7 cycloalkyl groups. The R5-CO- group may be acetyl (CH3-CO-, abbreviated as "Ac-" herein) or myristoyl (CH3-(CH2), abbreviated as "Myr-" herein). 12 -CO-), and palmitoyl (abbreviated as "Palm-" herein, CH3-(CH2) 14 Contains alkanoyl groups such as -CO-).

[0044] R1 may be selected from H and the group consisting of acetyl, tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, and linoleoyl.

[0045] R1 is H and R5-CO-(wherein R5 is C1-C 16 Alkyl or C2-C 18 (Selected from the group consisting of alkenils)

[0046] R1 is H and R5-CO-(wherein R5 is C1-C 15 It can be selected from the group consisting of alkyl groups.

[0047] R1 can be selected from the group consisting of H, acetyl, and palmitoyl. In particular, R1 is either H or acetyl.

[0048] R2 is -NR3R4, -OR3, -SR3 (wherein R3 and R4 are independently H, a polymer derived from polyethylene glycol, C1-C) 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkinyl, C3-C 24 Cycloalkyl, C5-C 24 Cycloalkenyl, C8-C 24 Cycloalkynyl, C6-C 30 Aryl, C7-C 24 The group can be selected from the group consisting of aralkyl groups, 3-10 membered heterocyclyl rings, and groups formed from heteroarylalkyl groups containing 2-24 carbon atoms and 1-3 heteroatoms, where the alkyl group has 1-6 carbon atoms. Optionally, R3 and R4 may be linked by saturated or unsaturated carbon-carbon bonds to form a ring having a nitrogen atom.

[0049] R2 may be -NR3R4 or -OR3. R3 and R4 may be independently selected from the group consisting of H, polymers derived from polyethylene glycol having molecular weights ranging from 200 to 35,000 daltons, methyl, ethyl, hexyl, dodecyl, and hexadecyl. Alternatively, R3 and R4 may be independently H and C1-C 16 It can be selected from the group consisting of alkyl groups. In one embodiment, R2 is not OR3, where R3 is a methyl group, i.e., R2 is not OCH3. In one embodiment, R3 is H, R4 is H, and C1-C including methyl, ethyl, hexyl, dodecyl, and hexadecyl. 16 Selected from the group formed by alkyl groups.

[0050] R2 is -OH, -NH2, and -NHR4 (wherein R4 is C1-C) 16It may be selected from the group consisting of alkyl, or C1-C3 alkyl, or C1-C2 alkyl.

[0051] R2 can be -OH or -NH2. In particular, R2 is NH2.

[0052] R1 is H and R5-CO-(wherein R5 is C1-C 18 Alkyl, C2-C 24 Alkenil, C3-C 24 R2 may be selected from the group consisting of cycloalkyl groups, where R2 is -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0053] R1 may be selected from the group consisting of H, as well as acetyl, tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, and linoleoyl, and R2 may be -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0054] R1 is H and R5-CO-(wherein R5 is C1-C 16 Alkyl or C2-C 18R2 may be selected from the group consisting of alkenyls, and R2 may be -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0055] R1 may be selected from the group consisting of H, acetyl, myristoyl, or palmitoyl, and R2 may be -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C) 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0056] R1 is H and R5-CO-(wherein R5 is C1-C 15 R2 may be selected from the group consisting of alkyl groups, where R2 is -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0057] R1 may be selected from the group consisting of H, acetyl, and palmitoyl, and R2 may be -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C) 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0058] R1 may be selected from the group consisting of H and acetyl, and R2 may be -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C) 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 The group may be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 may be selected from the group consisting of -OH and -NH2.

[0059] R1 may be selected from the group consisting of H and acetyl, and R2 may be -NR3R4 (wherein R3 and R4 are independently H and C1-C 16 (Selected from the group consisting of alkyl groups). In this embodiment, R3 may be H, and R4 may be H, C1-C 16 It can be selected from the group formed by alkyl, C1-C3 alkyl, and C1-C2 alkyl. For example, R2 can be selected from the group consisting of -NH2 and -NHR4 (wherein R4 is a C1-C3 alkyl). R2 may be -NH2.

[0060] R1 can be H, and R2 can be -NH2.

[0061] R1 may be selected from the group consisting of substituted acyclic aliphatic groups, substituted alicyclyls, substituted heterocyclyls, substituted heteroarylalkyls, substituted aryls, substituted aralkyls, and R5-CO-, where R5 is selected from the group consisting of substituted acyclic aliphatic groups, substituted alicyclyls, substituted aryls, substituted aralkyls, substituted heterocyclyls, and substituted heteroarylalkyls, and / or R2 is -NR3R4, where at least one of R3 and R4 is selected from the group consisting of substituted acyclic aliphatic groups, substituted alicyclyls, substituted heterocyclyls, substituted heteroarylalkyls, substituted aryls, and substituted aralkyls, or R2 is -OR3 or -SR3, where R3 is selected from the group consisting of substituted acyclic aliphatic groups, substituted alicyclyls, substituted heterocyclyls, substituted heteroarylalkyls, substituted aryls, and substituted aralkyls.

[0062] According to another specific embodiment, the most preferred structure of a polymer derived from polyethylene glycol is the group (-CH2-CH2-O) r -H (wherein r is a number between 4 and 795), and base [ka] (In the formula, s is a number between 1 and 125.)

[0063] The present invention provides a compound of formula (I), wherein at least one of the R1 is not H and R2 is not OH. That is, the present invention provides a compound of formula (I), wherein R1 is not H and / or R2 is not OH.

[0064] In the compound of formula (I): AA1 is selected from the group consisting of Asp, Glu, Asn, Gln, Ala, Gly, and no amino acids; AA2 is selected from the group consisting of Val, Ile, Leu, or Ala; AA3 is selected from the group consisting of Tyr, Phe, Trp, Lys, Arg, and His; AA4 is selected from the group consisting of Lys, Arg, His, Pro, and Val; AA5 is selected from the group consisting of Asn, Asp, Gln, and no amino acids; and AA6 is selected from the group consisting of Thr, Ala, Ser, and no amino acids. If AA1 is, for example, no amino acid, it means that the amino acid AA1 is not present in this compound.

[0065] The present invention provides a compound of formula (I) having the condition that when an amino acid is present at the AA5 position, i.e., when AA5 is Asn, Asp, or Gln, AA1 is Ala, Gly, or no amino acid, AA2 is Val, Ile, or Leu, AA3 is Lys, Arg, or His, AA4 is Pro or Val, AA6 is Thr, Ala, Ser, or no amino acid, and AA1 is different from AA6.

[0066] The present invention provides a compound of formula (I) having the condition that, when there is no amino acid at the AA5 position, i.e., AA5 is amino acid-free, AA1 is Asp, Glu, Asn, or Gln, AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, or Trp, AA4 is Lys, Arg, or His, and AA6 is amino acid-free.

[0067] The present invention provides a compound of formula (I) such that, when AA5 is amino acid-free, AA1 is Asp, Glu, Asn, or Gln, AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, or Trp, AA4 is Lys, Arg, or His, and AA6 is amino acid-free. In this embodiment, AA1 is selected from the group consisting of ASP, Glu, Asn, and Gln, AA2 is selected from the group consisting of Val, Ile, Leu, and Ala, AA3 is selected from the group consisting of Tyr, Phe, and Trp, AA4 is selected from the group consisting of Lys, Arg, and His, AA5 is amino acid-free, and AA6 is amino acid-free. In other words, the present invention provides a compound of formula (II), R1-W m -X n -AA1-AA2-AA3-AA4-Y p -Z q -R2(II) The stereoisomer and / or cosmetically acceptable salt thereof are provided, in the formula, AA1 is Asp, Glu, Asn, or Gln. AA2 is Val, Ile, Leu, or Ala. AA3 is Tyr, Phe, or Trp. AA4 is Lys, Arg, or His. W, X, Y, and Z are each independently any amino acid. m, n, p, and q are each independently either 0 or 1. m+n+p+q is less than or equal to 2, R1 is selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R5-CO-, and R5 is selected from the group consisting of H, acyclic aliphatic groups, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl. R2 is selected from the group consisting of -NR3R4, -OR3, and -SR3, and R3 and R4 are independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids.

[0068] The compound of formula (II) is a peptide containing 4, 5, or 6 amino acids linked in a chain. R1 is attached to the amino terminus (N terminus) of the peptide, and R2 is attached to the carboxyl terminus (C terminus). R1 ​​and R2 are as defined above for the compound of formula (I).

[0069] The present invention provides a compound of formula (II), wherein AA1 is selected from the group consisting of Asp, Glu, and Asn; AA2 is selected from the group consisting of Val, Ile, Leu, and Ala; AA3 is selected from the group consisting of Tyr, Phe, and Trp; and AA4 is selected from the group consisting of Lys, Arg, and His. In this embodiment, AA1 may be selected from Asp and Glu.

[0070] The present invention provides a compound of formula (II), wherein AA1 is selected from the group consisting of Asp, Glu, Asn, and Gln; AA2 is selected from the group consisting of Val and Ile; AA3 is selected from the group consisting of Tyr, Phe, and Trp; and AA4 is selected from the group consisting of Lys, Arg, and His. In this embodiment, AA1 may be selected from ASP, Glu, and Asn, or from Asp and Glu.

[0071] The present invention provides a compound of formula (II), wherein AA1 is selected from the group consisting of Asp, Glu, Asn, and Gln; AA2 is selected from the group consisting of Val, Ile, Leu, and Ala, or from the group consisting of Val and Ile; AA3 is selected from the group consisting of Tyr and Phe; and AA4 is selected from the group consisting of Lys, Arg, and His. In this embodiment, AA1 may be selected from ASP, Glu, and Asn, or from Asp and Glu.

[0072] The present invention provides a compound of formula (II), wherein AA1 is selected from the group consisting of Asp, Glu, Asn, and Gln; AA2 is selected from the group consisting of Val, Ile, Leu, and Ala, or from the group consisting of Val and Ile; AA3 is selected from the group consisting of Tyr, Phe, and Trp, or from the group consisting of Tyr and Phe; and AA4 is selected from the group consisting of Lys and Arg. In this embodiment, AA1 may be selected from ASP, Glu, and Asn, or from Asp and Glu.

[0073] The present invention provides a compound of formula (II), where AA1 is Asp, AA2 is Val, AA3 is Tyr, and AA4 is Lys.

[0074] The present invention provides compounds of formula (I) such that when AA5 is Asn, Asp, or Gln, AA1 is Ala, Gly, or no amino acid, AA2 is Val, Ile, or Leu, AA3 is Lys, Arg, or His, AA4 is Pro or Val, and AA6 is Thr, Ala, Ser, or no amino acid, and AA1 is different from AA6. In this embodiment, AA1 is selected from the group consisting of Ala, Gly, and no amino acid, AA2 is selected from the group consisting of Val, Ile, and Leu, AA3 is selected from the group consisting of Lys, Arg, and His, AA4 is selected from the group consisting of Pro and Val, AA5 is selected from the group consisting of Asn, Asp, and Gln, AA6 is selected from the group consisting of Thr, Ala, Ser, and no amino acid, and AA1 is different from AA6. Therefore, when AA1 is Ala, AA6 is selected from the group consisting of Thr, Ser, and no amino acid. Furthermore, if AA1 is an amino acid-free molecule, that is, if amino acid AA1 does not exist, then amino acid AA6 must exist, meaning AA6 is selected from the group consisting of Thr, Ala, and Ser. Similarly, if AA6 is Ala, then AA1 is selected from the group consisting of Gly and no amino acid. Similarly, if AA6 is an amino acid-free molecule, that is, if amino acid AA6 does not exist, then AA1 is selected from the group consisting of Ala and Gly.

[0075] Therefore, the present invention relates to a compound of formula (III), R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Z q -R2(III) The stereoisomer and / or cosmetically acceptable salt thereof are provided, in the formula, AA1 is Ala, Gly, or an amino acid-free amino acid. AA2 is Val, Ile, or Leu. AA3 is Lys, Arg, or His. AA4 is either Pro or Val. AA5 is Asn, Asp, or Gln. AA6 is Thr, Ala, Ser, or an amino acid-free amino acid. Unlike AA6, AA1 is W, X, Y, and Z are each independently any amino acid. m, n, p, and q are each independently either 0 or 1. m+n+p+q is less than or equal to 2, R1 is selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R5-CO-, and R5 is selected from the group consisting of H, acyclic aliphatic groups, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl. R2 is selected from the group consisting of -NR3R4, -OR3, and -SR3, and R3 and R4 are independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids.

[0076] The compound of formula (III) is a peptide containing 5, 6, or 7 amino acids linked in a chain. R1 is attached to the amino terminus (N terminus) of the peptide, and R2 is attached to the carboxyl terminus (C terminus). R1 ​​and R2 are as defined above for the compound of formula (I).

[0077] The present invention provides compounds of formula (III), wherein AA1 is selected from the group consisting of Ala and Gly, AA2 is selected from the group consisting of Val, Ile, and Leu, AA3 is selected from the group consisting of Lys, Arg, and His, AA4 is selected from the group consisting of Pro and Val, AA5 is selected from the group consisting of Asn, Asp, and Gln, AA6 is selected from the group consisting of Thr, Ala, Ser, and amino acids, and AA1 is different from AA6.

[0078] The present invention provides compounds of formula (III), wherein AA1 is selected from the group consisting of Ala, Gly, and no amino acids, or from the group consisting of Ala and Gly; AA2 is selected from the group consisting of Ile and Leu; AA3 is selected from the group consisting of Lys, Arg, and His; AA4 is selected from the group consisting of Pro and Val; AA5 is selected from the group consisting of Asn, Asp, and Gln; AA6 is selected from the group consisting of Thr, Ala, Ser, and no amino acids, and AA1 is different from AA6.

[0079] The present invention provides compounds of formula (III), wherein AA1 is selected from the group consisting of Ala, Gly, and no amino acids, or from the group consisting of Ala and Gly; AA2 is selected from the group consisting of Val, Ile, and Leu; AA3 is selected from the group consisting of Lys and Arg; AA4 is selected from the group consisting of Pro and Val; AA5 is selected from the group consisting of Asn, Asp, and Gln; AA6 is selected from the group consisting of Thr, Ala, Ser, and no amino acids, and AA1 is different from AA6. In this embodiment, AA2 may be Leu or Ile.

[0080] The present invention provides compounds of formula (III), wherein AA1 is selected from the group consisting of Ala, Gly, and no amino acids, or from the group consisting of Ala and Gly; AA2 is selected from the group consisting of Val, Ile, and Leu; AA3 is selected from the group consisting of Lys, Arg, and His; AA4 is selected from the group consisting of Pro and Val; AA5 is selected from the group consisting of Asn and Asp; AA6 is selected from the group consisting of Thr, Ala, Ser, and no amino acids, and AA1 is different from AA6. In this embodiment, AA2 may be selected from the group consisting of Leu and Ile, and / or AA3 may be selected from the group consisting of Lys and Arg.

[0081] The present invention provides compounds of formula (III), wherein AA1 is selected from the group consisting of Ala, Gly, and no amino acids, or from the group consisting of Ala and Gly; AA2 is selected from the group consisting of Val, Ile, and Leu; AA3 is selected from the group consisting of Lys, Arg, and His; AA4 is selected from the group consisting of Pro and Val; AA5 is selected from the group consisting of Asn and Gln; AA6 is selected from the group consisting of Thr, Ala, Ser, and no amino acids, and AA1 is different from AA6. In this embodiment, AA2 may be selected from the group consisting of Leu and Ile, and / or AA3 may be selected from the group consisting of Lys and Arg.

[0082] The present invention provides compounds of formula (III), wherein AA1 is selected from the group consisting of Ala, Gly, and no amino acids, or from the group consisting of Ala and Gly; AA2 is selected from the group consisting of Val, Ile, and Leu; AA3 is selected from the group consisting of Lys, Arg, and His; AA4 is selected from the group consisting of Pro and Val; AA5 is selected from the group consisting of Asn, Asp, and Gln; AA6 is selected from the group consisting of Thr, Ala, and Ser, and AA1 is different from AA6. In this embodiment, AA2 may be selected from the group consisting of Leu and Ile, AA3 may be selected from the group consisting of Lys and Arg, and / or AA5 may be selected from the group consisting of Asn and Asp.

[0083] The present invention provides a compound of formula (III), where AA1 is Ala, AA2 is Leu, AA3 is Lys, AA4 is Pro, AA5 is Asn, and AA6 is Thr.

[0084] The compounds of the present invention can exclude Pro-Leu-Asp-Val-Tyr-Lys, that is, the present invention provides compounds of formula (I), (II), or (III) above, wherein the compound is not Pro-Leu-Asp-Val-Tyr-Lys.

[0085] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Tyr-Lys-Asp-Val-Tyr-Lys, or if m is 1, W is Tyr, n is 1, X is Lys, AA1 is Asp, AA2 is Val, AA3 is Tyr, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 0, q is 0, R1 is H, and R2 is OH.

[0086] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Arg-Lys-Asp-Val-Tyr-Lys, or if m is 1, W is Arg, n is 1, X is Lys, AA1 is Asp, AA2 is Val, AA3 is Tyr, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 0, q is 0, R1 is H, and R2 is OH.

[0087] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Arg-Asn-Asp-Val-Tyr-Lys, or if m is 1, W is Arg, n is 1, X is Asn, AA1 is Asp, AA2 is Val, AA3 is Tyr, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 0, q is 0, R1 is H, and R2 is OH.

[0088] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Arg-Asp-Val-Tyr-Lys-Gln-Asn, or if m is 0, n is 1, X is Arg, AA1 is Asp, AA2 is Val, AA3 is Tyr, AA4 is Lys, AA5 is Gln, AA6 is amino acid-free, p is 1, Y is Asn, q is 0, R1 is H, and R2 is OH.

[0089] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Asp-Ala-Tyr-Lys, or if m is 0, n is 0, AA1 is Asp, AA2 is Val, AA3 is Tyr, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 0, q is 0, R1 is H, and R2 is OH.

[0090] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Asp-Ala-Tyr-Lys, or if m is 0, n is 0, AA1 is Asp, AA2 is Val, AA3 is Tyr, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 0, q is 0, R1 is H, and R2 is OH 0.

[0091] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are Asp-Leu-Lys-Lys, or if m is 0, n is 0, AA1 is Asp, AA2 is Leu, AA3 is Lys, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 0, q is 0, R1 is H, and R2 is OH.

[0092] Embodiments of the present invention, i.e., compounds of formula (I), (II), or (III), can be excluded if they are His-Asp-Leu-Lys-Lys-Tyr, or if m is 0, n is 1, X is His, AA1 is Asp, AA2 is Leu, AA3 is Lys, AA4 is Lys, AA5 is amino acid-free, AA6 is amino acid-free, p is 1, Y is Tyr, q is 0, R1 is H, and R2 is OH.

[0093] The compounds of the present invention include compounds selected from the group of amino acid sequences listed in Table 2, in which the sequence identifiers of the amino acid sequences are described in detail, their stereoisomers, and / or cosmetically or pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2]

[0094] The compounds of the present invention comprise each of the sequences in Table 2, wherein one of the amino acids AA1 to AA6 is substituted by a substituted amino acid, the substituted amino acid being selected from the alternative amino acids listed for the amino acid substituted in formula (I), formula (II), or formula (III) above. The substituted amino acid is different from the amino acid being substituted. The substituted amino acid cannot be an amino acid-free amino acid. Accordingly, the present invention provides a compound of formula (II) corresponding to Sequence ID No. 1, wherein one of the amino acids AA1 to AA4 is substituted by an amino acid, where if Asp(AA1) is substituted, it is substituted by Gly, Asn, or Gln; if Val(AA2) is substituted, it is substituted by Ile, Leu, or Ala; if Tyr(AA3) is substituted, it is substituted by Phe or Trp; and if Lys(AA4) is substituted, it is substituted by Arg or Lys. Furthermore, the present invention provides a compound of formula (III) corresponding to Sequence ID No. 2, wherein one of the amino acids AA1 to AA6 is substituted with an amino acid, in which, if Ala (AA1) is substituted, it is substituted with Gly or no amino acid; if Leu (AA2) is substituted, it is substituted with Ile or Val; if Lys (AA3) is substituted, it is substituted with Arg or HIs; if Pro (AA4) is substituted, it is substituted with Val; if Asn (AA5) is substituted, it is substituted with Asp or Gln; and if Thr (AA6) is substituted, it is substituted with Ala, Ser, or no amino acid, provided that AA1 is not the same as AA6.

[0095] In the amino acid sequences of Table 2 according to formula (I), formula (II), or formula (III), R1 and R2 are H and OH, respectively. The compounds of the present invention include each of the sequences of Table 2, and their N-terminus and C-terminus are modified by other R1 and R2 groups, respectively, as defined herein for formula (I), formula (II), or formula (III). For example, the compounds of the present invention include each of the sequences of Table 2, with the N-terminal amino acid residue terminated by R1, as defined above for formula (I) (wherein R1 is not H), or, further, the C-terminal amino acid residue terminated by R2, as defined above for formula (I), formula (II), or formula (III) (wherein R2 is not OH).

[0096] Accordingly, the present invention provides compounds according to formula (I), (II), or (III), which are any of the amino acid sequences 1-39 or 40, their stereoisomers, and / or cosmetically acceptable salts thereof, wherein the sequence optionally has its N-terminal amino acid modified by R1 as defined above for formula (I), (II), or (III) (wherein R1 is not H), or further, the sequence has its C-terminal amino acid modified by R2 as defined above for formula (I) (wherein R2 is not OH). The amino acid sequence may be selected from sequence number 1 and sequence numbers 3-19. The amino acid sequence may be selected from sequence number 2 and sequence numbers 20-39, or from sequence number 2 and sequence numbers 20-40. The amino acid sequence may be sequence number 1 or sequence number 2.

[0097] The compounds of the present invention may exist as stereoisomers or mixtures of stereoisomers, for example, amino acids containing them may have configurations L-, D-, or may be racemic independently of each other. Therefore, depending on the number of chiral carbons and the presence of isomers or mixtures of isomers, it is possible to obtain a racemic mixture or a diastereomer mixture in addition to the isomer mixture, or to obtain a pure diastereomer or enantiomer. The preferred structures of the compounds of the present invention are the pure isomers, i.e., enantiomers or diastereomers. For example, where it is stated that AA2 may be Arg, it will be understood that, unless otherwise specified, AA2 is selected from L-Arg, D-Arg, or a mixture of both, racemic or non-racemic. By the preparation procedures described herein, those skilled in the art can obtain each of the stereoisomers of the compounds of the present invention by selecting amino acids with the correct stereoconfigurations.

[0098] In the context of the present invention, the term "amino acid" includes both genetically coded and non-coding amino acids, whether natural or not. Examples of non-coding amino acids include, in particular, citrulline, ornithine, sarcosine, desmosine, norvaline, 4-aminobutyric acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 6-aminohexanoic acid, 1-naphthylalanine, 2-naphthylalanine, 2-aminobenzoic acid, 4-aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline, alloisoleucine, allosreonine, isonipecotinic acid, isoserine, phenylglycine, statins, β-alanine, norleucine, N-methylamino acids, α-amino acids, and β-amino acids, as well as their derivatives. A list of unnatural amino acids can be found in the paper "Unusual amino acids in peptide synthesis" by D.C. Roberts and F. Vellaccio (The Peptides, Vol. 5 (1983), Chapter VI, Gross E. and Meienhofer J., Eds., Academic Press, New York, USA), or in commercial catalogs of companies specializing in this field.

[0099] In the context of the present invention, if W, X, Y, and / or Z are present, that is, if at least one of n, m, p, or q is not 0, then the properties of W, X, Y, and / or Z are understood to not interfere with the activity of the compound of the present invention, but rather to contribute to or not affect the activity. W, X, Y, and Z can each be independently selected from the group consisting of Ala, Gly, Val, and Ile. W, X, Y, and Z can each be independently selected from the group consisting of Ala, Gly, and Val. W, X, Y, and Z can each be independently Ala or Gly. W, X, Y, and Z can each be Ala.

[0100] Each of m, n, p, and q can be 0, that is, the compound of formula (I) consists of 3, 4, 5, or 6 amino acids linked in a chain (e.g., AA2-AA3-AA4, AA1-AA2-AA3-AA 4、 It is a peptide containing AA2-AA3-AA4-AA5-AA6 and AA1-AA2-AA3-AA4-AA5-AA6). Alternatively, the sum of m, n, p, and q may be 1, i.e., the compound of formula (I) is a peptide containing 4, 5, 6, or 7 amino acids linked in a chain. Alternatively, the sum of m, n, p, and q may be 2, i.e., the compound of formula (I) is a peptide containing 5, 6, 7, or 8 amino acids linked in a chain.

[0101] Each of m, n, p, and q can be 0, meaning the compound of formula (II) is a peptide containing four amino acids, AA1 to AA4, linked in a chain. Alternatively, the sum of m, n, p, and q can be 1, meaning the compound of formula (I) is a peptide containing five amino acids linked in a chain. Alternatively, the sum of m, n, p, and q can be 2, meaning the compound of formula (II) is a peptide containing six amino acids linked in a chain.

[0102] Each of m, n, p, and q can be 0, i.e., the compound of formula (III) is a peptide containing 5 or 6 amino acids linked in a chain, namely AA1-AA5, AA2-AA6, or AA1-AA6. Alternatively, the sum of m, n, p, and q can be 1, i.e., the compound of formula (III) is a peptide containing 6 or 7 amino acids linked in a chain. Alternatively, the sum of m, n, p, and q can be 2, i.e., the compound of formula (III) is a peptide containing 7 or 8 amino acids linked in a chain.

[0103] In particular, the compounds of the present invention may be selected from the group of compounds listed in Table 3, their stereoisomers, and / or cosmetically acceptable salts thereof. [Table 3-1] [Table 3-2]

[0104] The compounds of the present invention include each of the compounds in Table 3, wherein one of the amino acids AA1 to AA6 is substituted with a substituted amino acid, the substituted amino acid being selected from the alternative amino acids listed for the amino acid substituted in formula (I), formula (II), or formula (III) above. The substituted amino acid is different from the amino acid being substituted. The substituted amino acid cannot be an amino acid-free amino acid. Accordingly, the present invention provides a compound of formula (II) corresponding to Sequence ID No. 1, wherein one of the amino acids AA1 to AA4 is substituted with an amino acid, where if Asp(AA1) is substituted, it is substituted with Gly, Asn, or Gln; if Val(AA2) is substituted, it is substituted with Ile, Leu, or Ala; if Tyr(AA3) is substituted, it is substituted with Phe or Trp; and if Lys(AA4) is substituted, it is substituted with Arg or Lys. Furthermore, the present invention provides a compound of formula (III) corresponding to Sequence ID No. 2, wherein one of the amino acids AA1 to AA6 is substituted with an amino acid, in which, if Ala (AA1) is substituted, it is substituted with Gly or no amino acid; if Leu (AA2) is substituted, it is substituted with Ile or Val; if Lys (AA3) is substituted, it is substituted with Arg or HIs; if Pro (AA4) is substituted, it is substituted with Val; if Asn (AA5) is substituted, it is substituted with Asp or Gln; and if Thr (AA6) is substituted, it is substituted with Ala, Ser, or no amino acid, provided that AA1 is not the same as AA6.

[0105] The present invention provides a compound according to formula (I), which is selected from any of PEP1 to PEP49, or any of PEP1 to PEP50, their stereoisomers, and / or cosmetically or pharmaceutically acceptable salts thereof. The compound of the present invention may be selected from PEP1 and PEP3 to PEP24. The compound of the present invention may be selected from PEP2 and PEP25 to PEP49, or from PEP2 and PEP25 to PEP50. In particular, the compound may be selected from PEP1 and PEP2.

[0106] Cosmetically or pharmaceutically acceptable salts of the compounds provided by the present invention are also found within the scope of the present invention. The term “cosmetically or pharmaceutically acceptable salt” means a salt approved for use in animals, e.g., mammals, more specifically in humans, and includes base addition salts (where the salt is inorganic, e.g., lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc, or aluminum, but is not limited thereto, or where the salt is organic, e.g., ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, or piperazine, but is not limited thereto). The present invention includes salts used to form acid addition salts (the salt is organic and is, for example, not limited to, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate, or gluconate, or the salt is inorganic and is, for example, not limited to, chloride, sulfate, borate, or carbonate). The properties of the salt are not important, however, that it is cosmetically or pharmaceutically acceptable. Cosmetically or pharmaceutically acceptable salts of the compounds of the present invention can be obtained by conventional methods well known in the prior art [Berge SMet al., "Pharmaceutical Salts", (1977), J.Pharm.Sci., 66, 1-19].

[0107] The present invention also provides combinations of the compounds of the present invention in any of the embodiments described above, their stereoisomers, and / or cosmetically acceptable salts thereof with botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof.

[0108] Preparation procedure for the compound of the present invention The synthesis of the compounds of the present invention, their stereoisomers, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof can be carried out by solid-phase peptide synthesis [Stewart J.Mand and Young J.D., "Solid Phase Peptide Synthesis, 2nd edition", (1984), Pierce Chemical Company, Rockford, Illinois; Bodanzsky M. and Bodanzsky A., "The practice of Peptide Synthesis", (1994), Springer Verlag, Berlin; Lloyd-Williams P. et al., "Chemical Approaches to the Synthesis of Peptides and Proteins", (1997), CRC, Boca Raton, FL, USA], synthesis in solution, and enzymatic synthesis [Kullmann W. "Proteases as catalysts for enzymic syntheses of opioid The process may be carried out according to conventional methods known in the prior art, such as in "peptides" (1980), J. Biol. Chem., 255(17), 8234-8238, or any combination thereof. The compounds of the present invention may also be obtained by fermentation of genetically modified or unmodified bacterial strains for the purpose of producing the desired sequence, or by controlled hydrolysis of animal or plant-derived, preferably plant-derived, proteins that yield free peptide fragments containing the desired sequence.

[0109] For example, methods for obtaining compounds of formula (I), their stereoisomers, and mixtures thereof are: -Coupling an amino acid having a protected N-terminal end and a free C-terminal end with an amino acid having a free N-terminal end and a C-terminal end that is protected or bound to a solid support, -Removing the protecting group at the N-terminal end, - Repeat the coupling of sequences and removal of protecting groups at the N-terminal end until the desired peptide sequence is obtained. - This includes removing the protective group at the C-terminal end or cleaving the solid support.

[0110] Preferably, the C-terminal end is bound to a solid support, and this process is carried out in the solid phase and therefore comprises coupling an amino acid having a protected N-terminal end and a free C-terminal end with an amino acid having a free N-terminal end and a C-terminal end bound to a polymer support, removing the protecting group from the N-terminal end, and repeating this sequence of steps as many times as necessary to obtain a compound of the desired length, followed by finally cleaving the synthesized compound from the original polymer support.

[0111] The functional groups of the amino acid side chains are conveniently protected by temporary or permanent protecting groups throughout synthesis and can be deprotected simultaneously with or orthogonally to the peptide cleavage process from the polymer support.

[0112] Alternatively, solid-phase synthesis can be carried out using convergent strategies that couple a polymer support with a peptide, or a peptide or amino acid pre-conjugated to a polymer support with a peptide. Convergent synthesis strategies are widely known to those skilled in the art and are described in Lloyd-Williams P. et al., "Convergent Solid-Phase Peptide Synthesis", (1993), Tetrahedron, 49(48), 11065-11133.

[0113] The above process may include additional steps of deprotecting the N-terminal and C-terminal ends and / or cleaving the peptide from the polymer support in an indiscriminate order using standard procedures and conditions known in the prior art, after which the functional groups at these ends can be modified. Optional modification of the N-terminal and C-terminal ends can be performed using the peptide of formula (I) tethered to the polymer support, or after the peptide has been separated from the polymer support.

[0114] Optionally, R1 may be introduced by a nucleophilic substitution reaction between the N-terminal end of the compound of the present invention and the R1-X compound in the presence of a suitable base and solvent, and the fragment having a functional group not involved in NC bond formation is appropriately protected by a temporary or permanent protecting group. R1 is as defined above, and X is a leaving group, for example, but not limited to, a tosyl group, a mesyl group, and a halogen group.

[0115] Optionally and / or further, an R2 radical may be introduced by the reaction of compound HR2 with a complementary fragment corresponding to the peptide of formula (I) (wherein R2 is -OH) in the presence of a suitable solvent and a base such as N,N-diisopropylethylamine (DIEA) or triethylamine or an additive such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazole (HOAt), and a dehydrating agent such as carbodiimide, uronium salt, phosphonium salt or amidinium salt, in particular, or by prior formation of an acyl halogenate with thionyl chloride, for example, thereby obtaining the peptide of formula (I) according to the present invention, where the fragment having a functional group not involved in NC bond formation is appropriately protected by a transient or permanent protecting group. Alternatively, other R2 radicals may be introduced by simultaneous incorporation into the peptide cleavage process from a polymer carrier. R2 is -OR3, -NR3R4 or -SR3 (wherein R3 and R4 are as defined above).

[0116] Those skilled in the art will readily understand that the deprotection / cleavage steps at the C-terminus and N-terminus, and their subsequent derivatization, can be carried out in different sequences according to methods known in the prior art.

[0117] The term "protecting group" refers to a group that blocks an organic functional group and can be removed under controlled conditions. Protecting groups, their relative reactivity, and the conditions under which they remain inert are known to those skilled in the art.

[0118] Typical protecting groups for amino groups include amides such as acetic acid amide, benzoic acid amide, and pivalic acid amide, benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ), para-nitrobenzyloxycarbonyl (pNZ), tert-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc), or allyloxycarbonyl. Carbamates such as cyclocarbonyl (Alloc), trityl (Trt), methoxytrityl (Mtt), 2,4-dinitrophenyl (Dnp), N-[1-(4,4-dimethyl-2,6-dioxocyclohexa-1-ylidene)ethyl (Dde), 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl (ivDde), and 1-(1-adamantyl)-1-methylethoxycarbonyl (Adpoc), particularly preferably Boc or Fmoc.

[0119] Examples of typical protecting groups for carboxyl groups include, in particular, esters such as tert-butyl ester (tBu), allyl ester (All), triphenylmethyl ester (Trt ester), cyclohexyl ester (cHx), benzyl ester (Bzl), ortho-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzyl ester, trimethylsilylethyl ester, 2-phenylisopropyl ester, fluorenylmethyl ester (Fm), and 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl ester (Dmab). The preferred protecting groups of the present invention are All, tBu, cHex, Bzl, and Trt esters.

[0120] The side chains of trifunctional amino acids can be protected during the synthetic process by temporary or permanent protecting groups orthogonal to the N-terminal and C-terminal protecting groups.

[0121] The hydroxyl group of the tyrosine side chain can be protected with, in particular, 2-bromobenzyloxycarbonyl group (2-BrZ), tBu, All, Bzl, or 2,6-dichlorobenzyl (2,6-diClZ). In a preferred embodiment, the protecting group strategy used is one in which the amino group is protected by Boc, the carboxyl group is protected by an ester of Bzl, cHx, or All, and the tyrosine side chain is protected by 2-BrZ or Bzl. In another preferred embodiment, the protecting group strategy used is one in which the amino group is protected by Fmoc, the carboxyl group is protected by an ester of tBu, All, or Trt, and the tyrosine side chain is protected by tBu.

[0122] The amino group of the tryptophan side chain can be protected, for example, by a formyl group (For) or Boc. In one embodiment, when the amino group is protected by Fmoc, the tryptophan side chain is not protected, i.e., the amino acid is incorporated as Fmoc-Trp-OH; when protected by Boc, i.e., the amino acid is incorporated as Fmoc-Trp(Boc)-OH; or when protected by For, i.e., the amino acid is incorporated as Fmoc-Trp(For)-OH. In one embodiment, the amino group can be protected by Boc and the tryptophan side chain can be protected by For, i.e., the amino acid is incorporated as Boc-Trp(For)-OH.

[0123] Examples of the above-mentioned and other protecting groups, their introduction and removal, can be found in the literature [Atherton B. and Sheppard RC, "Solid Phase Peptide Synthesis: A practical approach", (1989), IRL Oxford University Press]. The term "protecting group" also includes polymer supports used in solid-phase synthesis.

[0124] When the synthesis is carried out entirely or partially in the solid phase, possible solid supports used in the process of the present invention include polystyrene supports, polyethylene glycol grafted onto polystyrene, and the like, for example, but not limited to, p-methylbenzhydrylamine resin (MBHA) [Matsueda GR et al., "A p-methylbenzhydrylamine resin for improved solid-phase synthesis of peptide amides", (1981), Peptides, 2, 45-50], 2-chlorotrityl resin [Barlos K. et al., "Darstellung geschutzter Peptid-Fragmente unter Einsatz substituierter Triphenylmethyl-Harze", (1989), Tetrahedron Lett., 30, 3943-3946, Barlos K. et al., "Veresterung von partiell geschutzten Peptid-Fragmenten mit Harzen. Einsatz von 2-Chlorotritylchlorid] This includes 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) [Albericio F. et al., "Preparation and application of the 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions", (1990), J. Org.], which is similar to 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) [Albericio F. et al., "Preparation and application of the 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions", (1990), J. Org.].The material may or may not contain unstable linkers such as 2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid (AM) [Rink H., "Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methylester resin", (1987), Tetrahedron Lett., 28, 3787-3790], [Wang SS, "p-Alkoxybenzyl Alcohol Resin and p-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis of Protected Peptide Fragments", (1973), J.Am.Chem.Soc., 95, 1328-1333] and similar materials, which allow for the simultaneous deprotection and cleavage of the compound from the polymer support.

[0125] Applicable This invention is based on the discovery that compounds of formula (I) (the compounds of the present invention) are useful for the treatment of the skin, hair, nails, and / or mucous membranes. In particular, the compounds of the present invention have been found to inhibit the upregulated expression of muscle bind-like 1 (MBNL-1) protein in skin / skeletal muscle, and are therefore useful for the prevention or treatment of symptoms of skin aging, including wrinkles, the appearance of sagging skin, and loss of firmness, as well as for the treatment or prevention of facial asymmetry. The compounds of the present invention have been found to inhibit norepinephrine release in the skin and increase collagen synthesis. The compounds of the present invention have been found to increase the lipid content of adipocytes, and therefore can cause an increase in the volume of adipose tissue. These effects further demonstrate the usefulness of the compounds of the present invention in the prevention or treatment of symptoms of skin aging. Therefore, compounds of formula (I) are useful in cosmetic non-therapeutic treatments of the skin, hair, nails, and / or mucous membranes.

[0126] MBNL1 is an RNA-binding protein involved in the differentiation and maintenance of splicing patterns necessary for healthy muscle function. Several observations have linked MBNL1 dysfunction to the loss of muscle mass during the natural muscle aging process in healthy humans [Malatesta, M. et al. "Muscleblind-like1 undergoes ectopic relocation in the nuclei of skeletal muscles in myotonic dystrophy and sarcopenia", (2013), European Journal of Histochemistry, vol.57(e15), pp.86-92; Malatesta, M. et al. "RNA transcription and maturation in skeletal muscle cells are similarly impaired in myotonic dystrophy and sarcopenia: the ultrastructural evidence", (2014), Frontiers in Aging Neuroscience, vol.6(196), pp.1-6]. It has also been demonstrated that an increase in MBNL1 protein in fibroblasts activates the differentiation process into myofibroblasts, a cell type capable of releasing large amounts of extracellular matrix proteins such as collagen, elastin, and fibronectin.In fact, electrical stimulation has been demonstrated to induce the appearance and function of myofibroblasts [Davis, J. et al. "MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response", (2015), Nature communications, vol.6(10084), pp.1-14; Jennings, JA, et al. "Regulation of gene expression in response to continuous low intensity direct current electrical fields", (2007), Doctoral Thesis, pp-1-208].

[0127] Increased MBNL1 protein in skin / facial muscles is thought to contribute to slowing and / or avoiding muscle mass loss resulting from the activation of atrophy processes caused by muscle aging. The compounds of the present invention are particularly effective in upregulating the expression of muscleblind-like 1 (MBNL-1) and are therefore useful in preventing or mitigating the effects on skin aesthetic properties associated with muscle mass loss due to muscle aging. Accordingly, the compounds of the present invention are particularly useful in maintaining or improving skin firmness, preventing the appearance of sagging skin, and / or reducing facial asymmetry.

[0128] Collagen is the most abundant protein in the connective tissue of the skin, forming a mesh-like structure and helping to support growing new cells while providing the necessary flexibility. Type I collagen (collagen I) is the major collagen in the skin and is involved in the strength and elasticity of this tissue. One of the well-known characteristics of aging is skin sagging. This is due to many factors, including a decrease in skin elasticity and firmness, the effects of gravity, a decrease in facial skeletal support, and a decrease in subcutaneous adipose tissue support in the face. Increased collagen synthesis, associated with an increase in MBLN1 protein, is thought to be beneficial in reducing the symptoms of skin aging described above.

[0129] Inhibition of norepinephrine release, like botulinum toxin, inhibits neuronal exocytosis. At the neuromuscular junction, muscle contraction occurs due to the release of neurotransmitters from peripheral neurons to skeletal muscles. Facial muscles also undergo these contractions. These contractions are more frequent around the eyes and mouth and on the forehead. With age, the continued release of neurotransmitters to the neuromuscular junction and the decrease in elasticity contribute to an increase in facial wrinkles and permanent expression lines. Therefore, inhibiting norepinephrine release is thought to be beneficial in reducing these signs of aging.

[0130] Adipose tissue, or body fat, is connective tissue that contains cells called adipocytes that store lipids. Advantageously, the compounds of the present invention have been found to be effective in increasing the lipid content of adipocytes and therefore useful in treatments that increase the volume of adipose tissue and prevent and / or mitigate the effects of adipose tissue loss.

[0131] In one embodiment, the present invention provides the use of the compounds of the present invention, their stereoisomers and / or cosmetically acceptable salts, or the use of cosmetic compositions comprising the compounds of the present invention, their stereoisomers and / or cosmetically acceptable salts, in cosmetic non-therapeutic treatments and / or care of the skin, hair, nails and / or mucous membranes. In particular, the cosmetic non-therapeutic treatments and / or care are of the skin. In the context of the present invention, skin includes the skin of the entire body, including the face (including the skin around the eyes), nape of the neck, neck, décolleté, arms, hands, legs, feet, thighs, buttocks, abdomen, and torso.

[0132] The compounds of the present invention are useful for non-therapeutic cosmetic treatments and / or care of the skin, including treating and / or preventing skin aging, treating and / or preventing skin wrinkles, maintaining and improving skin firmness, stimulating collagen synthesis and / or preventing collagen depletion, treating and / or preventing the appearance of sagging skin, reducing and / or preventing facial asymmetry, increasing the volume of adipose tissue, and / or preventing and / or mitigating the effects of adipose tissue depletion.

[0133] The compounds of the present invention are useful for non-therapeutic cosmetic treatments and / or care of the skin, including treating and / or preventing skin aging, treating and / or preventing skin wrinkles, maintaining and improving skin firmness, stimulating collagen synthesis and / or preventing collagen depletion, treating and / or preventing the appearance of sagging skin, reducing and / or preventing facial asymmetry, increasing adipose tissue volume, preventing and / or mitigating the effects of adipose tissue depletion, and / or reducing skin roughness and / or improving skin smoothness.

[0134] Non-therapeutic cosmetic treatments and / or care of the skin may include treating and / or preventing wrinkles, maintaining and improving skin firmness, stimulating collagen synthesis, and / or preventing collagen loss.

[0135] Cosmetic non-therapeutic treatments and / or care may be associated with stimulation of collagen synthesis and / or upregulation of MBNL-1 and / or inhibition of norepinephrine. Therefore, cosmetic non-therapeutic treatments and / or care of the skin, hair, nails and / or mucous membranes may be associated with increased collagen synthesis and / or upregulation of muscle-blind-like 1 (MBNL-1) expression and / or the presence of norepinephrine.

[0136] In one embodiment, the use of the compounds of the present invention, their stereoisomers and / or cosmetically acceptable salts, or the use of cosmetic compositions comprising the compounds of the present invention, their stereoisomers and / or cosmetically acceptable salts, is provided for the treatment and / or prevention of skin aging. Treatment and / or prevention of skin aging includes the mitigation and / or prevention of the symptoms of skin aging. Symptoms of skin aging include the appearance of wrinkles and a decrease in the biomechanical properties of the skin, such as firmness. A decrease in firmness may be due to a decrease in collagen production in the skin or a decrease in muscle tone (muscle mass) associated with aging. In particular, a decrease in muscle tone refers to the muscles of the skin, more specifically the facial muscles of the skin.

[0137] In one embodiment, the use of a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, or a cosmetic composition comprising a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, for the treatment and / or prevention of wrinkles of the skin, including facial wrinkles, also commonly known as expression lines.

[0138] In one embodiment, the use of a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, or a cosmetic composition comprising a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, for maintaining and / or improving skin firmness is provided.

[0139] In one embodiment, the use of a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, or a cosmetic composition comprising a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, for stimulating collagen synthesis and / or preventing collagen depletion is provided.

[0140] In one embodiment, the use of a compound of the present invention, its stereoisomer and / or cosmetically acceptable salt, or a cosmetic composition comprising a compound of the present invention, its stereoisomer and / or cosmetically acceptable salt, is provided for the treatment and / or prevention of the appearance of sagging skin. The appearance of sagging skin can be caused by muscle tone (muscle mass), in particular by muscle tone of the skin, more specifically by a decrease in facial muscles.

[0141] In one embodiment, the use of a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, or a cosmetic composition comprising a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, is provided for reducing and / or preventing facial asymmetry.

[0142] In one embodiment, the use of a cosmetic composition comprising the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, or the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, is provided for the prevention and / or reduction of an increase in the volume of adipose tissue and / or a decrease in adipose tissue. In particular, the adipose tissue is subcutaneous adipose tissue, more specifically, the subcutaneous adipose tissue of the face, hands, and lower neck. A cosmetic composition comprising the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, or the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, can reduce adquisis of the skin, hair, nails, and / or mucous membranes (SASP).

[0143] In one embodiment, the use of a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, or a cosmetic composition comprising a compound of the present invention, its stereoisomer and / or a cosmetically acceptable salt, is provided for reducing skin roughness and / or improving skin smoothness.

[0144] As described above regarding the application (use) of the compounds of the present invention, the present invention also extends to the use of the compounds of the present invention in combination with microcurrent electroneuromuscular stimulation (MENS) treatment in the treatment and / or care of the skin, hair, nails, and / or mucous membranes. MENS treatment is a cosmetic, non-therapeutic treatment of the skin, hair, nails, and / or mucous membranes. For example, MENS treatment typically uses a direct current (not alternating current) in the range of less than 1 mA, e.g., 300-500 μA, and this current may be optionally pulsed at a frequency of 0.1-680 Hz.

[0145] The present invention also extends to the use of the compounds of the present invention in combination with botulinum toxin and / or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 in the treatment and / or care of the skin, hair, nails, and / or mucous membranes, as described above regarding the application (use) of the compounds of the present invention. Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 is commercialized by Lipotec SAU (Lubrizol) as Argireline® peptide and is known to mimic the cosmetic effects of botulinum toxin on the skin by inhibiting nerve cell exocytosis.

[0146] In another embodiment, the present invention provides a method for treating and / or caring for the skin, hair, nails and / or mucous membranes of a subject, comprising administering to the subject a compound of the present invention, its stereoisomers and / or cosmetically or pharmaceutically acceptable salts, or a composition comprising the compound of the present invention, its stereoisomers and / or cosmetically or pharmaceutically acceptable salts. In particular, the present invention provides a method for a cosmetic non-therapeutic method for treating and / or caring for the skin, hair, nails and / or mucous membranes of a subject, comprising administering to the subject a cosmetically effective amount of the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, or a cosmetic composition comprising a cosmetically effective amount of the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts. The method may be for treating and / or caring for the skin, hair, nails and / or mucous membranes, as described above with respect to the application (use) of the compounds and compositions of the present invention. In particular, the cosmetic non-therapeutic method of treatment and / or care is for the skin. The administration may be topical or, for example, transdermal. In this embodiment of the present invention, the compounds of the present invention may be present in cosmetic compositions, such as the cosmetic compositions described herein. In one embodiment, the method includes administering the compound or administering the composition using microneedles.

[0147] The present invention relates to methods for treating and / or caring for target skin, hair, nails, and / or mucous membranes, and includes administering the compounds of the present invention, their stereoisomers, and / or combinations of cosmetically or pharmaceutically acceptable salts to the target, and performing cosmetic microcurrent electroneuromuscular stimulation (MENS) treatment to the target. The methods, with respect to the application (use) of the compounds of the present invention, may be for treating and / or caring for skin, hair, nails, and / or mucous membranes, as described above. MENS treatment is a cosmetic, non-therapeutic treatment of skin, hair, nails, and / or mucous membranes, and typically uses direct current (not alternating current) in the range of 300 to 500 μA. The current may be pulsed at a frequency of 0.1 to 680 Hz. Preferably, this treatment method is a skin anti-aging treatment. The compounds of the present invention may be administered simultaneously with (at the same time as) or consecutively with MENS treatment. The compounds of the present invention may be administered before or after MENS treatment. In non-limiting examples, the treatment method may include administering the compound at least once a day for a certain period, following a cosmetic treatment with MENS.

[0148] The present invention also extends to methods for treating and / or caring for the skin, hair, nails, and / or mucous membranes of a subject, and includes administering to the subject a combination of the compound of the present invention, its stereoisomers, and / or cosmetically or pharmaceutically acceptable salts, and botulinum toxin and / or Ac-Glu-Glu-Met-Gln-Arg-Arg-2. The methods, with respect to the application (use) of the compound of the present invention, may be for treating and / or caring for the skin, hair, nails, and / or mucous membranes, as described above. For example, a treatment method may include administering to the subject botulinum toxin and the compound of the present invention, its stereoisomers, and / or cosmetically or pharmaceutically acceptable salts. For example, a treatment method may include administering to the subject Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, and the compound of the present invention, its stereoisomers, and / or cosmetically or pharmaceutically acceptable salts. Preferably, this treatment method is a skin anti-aging treatment.

[0149] Botulinum toxin and / or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, and the compounds of the present invention, may be administered simultaneously (at the same time) or successively. When botulinum toxin and / or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, and the compounds or compositions of the present invention are administered at the same time, they may be administered as separate dosage forms or as part of a single composition. When the products are administered as separate dosage forms, the dosage forms may be in the same or different containers.

[0150] The methods of treatment described above include non-therapeutic cosmetic treatments and / or care of the skin, including treatment and / or prevention of skin aging, treatment and / or prevention of skin wrinkles, maintenance and improvement of skin firmness, stimulation of collagen synthesis and / or prevention of collagen depletion, treatment and / or prevention of the appearance of sagging skin, reduction and / or prevention of facial asymmetry, increase in adipose tissue volume, and / or prevention and / or reduction of adipose tissue. In one embodiment, the method of non-therapeutic cosmetic treatments and / or care of the skin is a treatment to prevent skin aging.

[0151] The methods of treatment described above include non-therapeutic cosmetic treatments and / or care of the skin, including treatment and / or prevention of skin aging, treatment and / or prevention of skin wrinkles, maintenance and improvement of skin firmness, stimulation of collagen synthesis and / or prevention of collagen loss, treatment and / or prevention of the appearance of sagging skin, reduction and / or prevention of facial asymmetry, increase of adipose tissue volume, prevention and / or reduction of adipose tissue loss, and / or reduction of skin roughness and / or improvement of skin smoothness. In one embodiment, the method of non-therapeutic cosmetic treatments and / or care of the skin is a treatment to prevent skin aging.

[0152] In another embodiment, the present invention provides a compound of formula (I), its stereoisomers and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing them, for use as a pharmacopoeia. In particular, the present invention provides a compound of formula (I), its stereoisomers and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing them, for use in the treatment or prevention of a disease or disorder. In another embodiment, the present invention provides the use of a compound of formula (I), its stereoisomers and / or pharmaceutically acceptable salts, for the production of a pharmacopoeia for the treatment or prevention of a disease or disorder. In another embodiment, the present invention provides a method for treating or preventing a disease or disorder of interest, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing the same to an interest subject.

[0153] The above-described method of the present invention may be performed by local or transdermal application, such as iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic gradient, occlusive therapy, microinjection, pressure-assisted needle injection, microelectropatch, face mask, or any combination thereof.

[0154] With respect to the methods of the present invention described above, the frequency of application or administration may vary considerably depending on the needs of each subject, but the recommended application is once a month to 10 times a day, preferably once a week to 4 times a day, more preferably three times a week to 2 times a day, and even more preferably once a day. For example, the frequency of administration by methods of treating and / or caring for the skin, hair, nails, and / or mucous membranes of a subject, which include administering the compound of the present invention, its stereoisomers and / or cosmetically or pharmaceutically acceptable salts to a subject in combination with botulinum toxin and / or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, may vary considerably depending on the needs of each subject. In one embodiment, the method of the present invention includes the administration of botulinum toxin followed by the administration of the compound or composition of the present invention. In a particular embodiment, after the administration of botulinum toxin, the compound or composition of the present invention is administered at least once a day for at least one week. More specifically, the compound or composition of the present invention is administered at least once a day until the next administration of botulinum toxin.

[0155] Composition of the present invention The compounds of the present invention may be administered for application in the form of a composition containing the compounds by any means that causes contact between the compound and the site of action of the target body, preferably a mammalian, preferably a human site.

[0156] In another embodiment, the present invention provides compositions comprising a compound according to formula (I), its stereoisomers and / or cosmetically or pharmaceutically acceptable salts.

[0157] In particular, the present invention provides cosmetic compositions comprising a compound according to formula (I), its stereoisomers and / or cosmetically acceptable salts, together with at least one cosmetically acceptable excipient or adjuvant. These compositions can be prepared by conventional means known to those skilled in the art ["Harry's Cosmeticology", Seventh edition, (1982), Wilkinson JB, Moore RJ, ed. Longman House, Essex, GB].

[0158] The compounds of the present invention have variable solubility in water, depending on their amino acid sequence or the nature of any possible modification at the N-terminus and / or C-terminus. Therefore, the compounds of the present invention can be incorporated into compositions by aqueous solutions, and the non-water-soluble compounds can be solubilized in conventional solvents that are cosmetically or pharmaceutically acceptable, including but not limited to ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol, or polyethylene glycol, or any combination thereof.

[0159] The cosmetically effective amount of the compound of the present invention to be administered, as well as the dosage of the compound, depends on a number of factors, including age, the patient's condition, the nature or severity of the condition, the disorder or disease being treated and / or cared for, the route and frequency of administration, and the specific properties of the compound used.

[0160] The terms “cosmetically effective amount” and “pharmaceutically effective amount” are understood to mean a non-toxic but sufficient amount of the compound(s) of the present invention to provide the desired effect. The terms “pharmaceutically effective” and “therapeutic effective” are used interchangeably herein. The compounds of the present invention are used in the cosmetic or pharmaceutical compositions of the present invention in concentrations that are cosmetically or pharmaceutically effective to achieve the desired effect, for example, in amounts of 0.00000001% to 20% (by weight), 0.000001% to 15% (by weight), 0.00001% to 10% (by weight), or 0.0001% to 5% (by weight) relative to the total weight of the composition.

[0161] Compounds of formula (I), their stereoisomers, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof may also be incorporated into cosmetic or pharmaceutical delivery systems and / or sustained-release systems.

[0162] The term “delivery system” refers to diluents, adjuvants, excipients, or carriers administered together with the compounds of the present invention. These cosmetic or pharmaceutical carriers are liquids such as water, oil, or surfactants, including those of petroleum, animal, plant, or synthetic origin, and include, but are not limited to, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltosides, fatty alcohols, nonoxynol, poloxamers, polyoxyethylene, polyethylene glycol, dextrose, glycerol, digitonin, and similar substances. Those skilled in the art will know of diluents, adjuvants, or excipients that can be used in various delivery systems that can administer the compounds of the present invention.

[0163] The term "sustained release" is used in its conventional sense to refer to a compound delivery system that brings about the gradual release of the compound at a relatively constant compound release level over a certain period, preferably but not necessarily.

[0164] Examples of delivery or sustained-release systems include, but are not limited to, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, milliparticles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, surfactant-phospholipid mixed micelles, millispheres, microspheres and nanospheres, lipospheres, millicapsules, microcapsules and nanocapsules, as well as microemulsions and nanoemulsions, which can be added to achieve better penetration of the active ingredient and / or improve its pharmacokinetic and pharmacodynamic properties. Preferred delivery or sustained-release systems are liposomes, surfactant-phospholipid mixed micelles, microemulsions, more preferably water-in-oil microemulsions having an inverse micelle internal structure and nanocapsules containing microemulsions.

[0165] In one embodiment, the present invention provides a cosmetic or pharmaceutical composition comprising a compound of formula (I) and a cosmetically or pharmaceutically acceptable carrier selected from the group consisting of creams, emulsions, gels, liposomes, nanoparticles, and ointments.

[0166] The sustained-release system can be prepared by methods known in the prior art, and the composition containing the system can be administered by topical or transdermal administration, including, for example, adhesive patches, non-adhesive patches, occlusive patches and microelectric patches, or by systemic administration (including, but not limited to, oral routes, or parenteral routes including nasal, rectal or subcutaneous implantation or injection, or direct implantation or injection into a specific body part), preferably releasing a relatively constant amount of the compound of the present invention. The amount of compound contained in the sustained-release system depends, for example, the site where the composition is administered, the dynamics and duration of release of the compound of the present invention, and the nature of the condition, disorder and / or disease being treated and / or cared for.

[0167] The compounds of the present invention can also be adsorbed onto solid organic polymers or solid inorganic supports, such as, but not limited to, talc, bentonite, silica, starch, or maltodextrin.

[0168] Compositions containing the compound of formula (I), its stereoisomers, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof can be incorporated into fabrics, nonwovens, and medical devices that come into direct contact with the skin, and thus release the compounds of the present invention by biodegradation of the binding system to the fabric, nonwoven, or medical device due to body moisture, skin pH, or body temperature, or by friction between them and the body. Furthermore, the compounds of the present invention can be incorporated into fabrics and nonwovens used in the manufacture of clothing that comes into direct contact with the body.

[0169] Examples of fabrics, nonwovens, clothing, medical devices, and means for immobilizing compounds thereon include the above-mentioned delivery and / or sustained-release systems, which can be found in the literature and are known in the prior art [Schaab CK (1986) HAPPI May 1986; Nelson G., "Application of microencapsulation in textiles", (2002), Int. J. Pharm., 242(1-2), 55-62; "Biofunctional Textiles and the Skin" (2006) Curr. Probl. Dermatol. v.33, Hipler UC and Elsner P., eds. S. Karger AG, Basel, Switzerland; Malcolm RK et al., "Controlled release of a model antibacterial drug from a novel self-lubricating silicone "biomaterial", (2004), J.Cont.Release, 97(2), 313-320. Preferred fabrics, nonwovens, clothing and medical devices include bandages, gauze, t-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectropatch and / or face masks.

[0170] Cosmetic or pharmaceutical compositions containing the compounds of the present invention, their stereoisomers, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof may be used in a variety of different types of compositions for topical or transdermal application, and the compositions may optionally contain cosmetically or pharmaceutically acceptable excipients necessary for formulation into desired dosage forms.

[0171] Compositions for topical or transdermal application can be any solid, liquid, or semi-solid formulations, such as creams; oil-in-water and / or silicone-in-water emulsions; water-in-oil and / or silicone-in-water emulsions; water / oil / water or water / silicone / water emulsions; and oil / water / oil or silicone / water / silicone emulsions; as well as multiple emulsions; anhydrous compositions; aqueous dispersions; oils; milks; balsams; foams; lotions; gels; cream gels; hydroalcoholic solutions; hydroglycolic solutions; hydrogels; liniments; serums; soaps; shampoos; conditioners; polysaccharide films; ointments; mousses; pomades; powders; bars; pencils; and sprays or aerosols (sprays), and include leave-on and rinse-off formulations. These topical or transdermal formulations can be incorporated using techniques known to those skilled in the art into a variety of solid equipment, such as bandages, gauze, T-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bed covers, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectrotherapy patches, or face masks, or, in particular, into a variety of makeup products such as liquid foundations and compact foundations, makeup remover lotions, makeup remover emulsions, dark circle concealers, eyeshadows, lipsticks, lip protectors, lip glosses, and powders.

[0172] The cosmetic or pharmaceutical composition of the present invention includes an agent that increases the transdermal absorption of the compounds of the present invention, and includes, but is not limited to, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecyl azacycloheptan-2-one), alcohol, urea, ethoxydiglycol, acetone, propylene glycol, or polyethylene glycol. Furthermore, the cosmetic or pharmaceutical composition of the present invention can be applied to the treated area by iontophoresis, sonophoresis, electroporation, microelectropatch, mechanical pressure, osmotic gradient, occlusive cure, microinjection, or pressure-assisted injection, or any combination thereof, to achieve better penetration of the peptides of the present invention. The application area is determined by the nature of the condition, disorder, and / or disease being treated and / or cared for.

[0173] Furthermore, compositions containing compounds of formula (I), their stereoisomers, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof may be used in various types of formulations for oral administration, preferably in the form of oral cosmetics or drugs, for example, but not limited to, capsules including gelatin capsules, soft capsules, hard capsules, tablets including sugar-coated tablets, tablets, pills, powders, granules, chewing gum, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, jellies or gelatin, and any other form known to those skilled in the art. In certain embodiments, the compounds of the present invention may be incorporated into any form of functional food or fortified food, such as, but not limited to, dietary bars or compact powders or non-compact powders. These powders may be dissolved in water, soda, dairy products, soy derivatives, or incorporated into dietary bars. The compounds of the present invention can be formulated with common excipients and adjuvants for oral compositions or nutritional supplements, which include, but are not limited to, fat components, aqueous components, water-retaining agents, preservatives, texture-improving agents, flavorings, fragrances, antioxidants, and colorings commonly used in the food industry.

[0174] Cosmetic or pharmaceutical compositions containing compounds of formula (I), their stereoisomers, mixtures thereof, and / or cosmetic or pharmaceutically acceptable salts thereof may be administered by any other suitable route, such as oral or parenteral routes, as well as by topical or transdermal routes, and so the compositions may contain pharmaceutically acceptable excipients necessary for formulation in the desired dosage form. In the context of the present invention, the term “parenteral” includes intravascular injections such as nasal, ear, eye, rectal, urethral, ​​vaginal, subcutaneous, intradermal, intravenous, intramuscular, intraocular, intravitreous, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intrameningeal, intraarticular, intrahepatic, intrathoracic, intratracheal, subarachnoid, and intraperitoneal injections, as well as any other similar injection or infusion techniques. Those skilled in the art will know of the various means by which cosmetic or pharmaceutical compositions containing the compounds of the present invention may be administered.

[0175] Among the cosmetically or pharmaceutically acceptable adjuvants contained in the cosmetic or pharmaceutical compositions described in the present invention are additional ingredients commonly used in cosmetic or pharmaceutical compositions, for example, but not limited to, anti-wrinkle agents, Botox-like agents, and / or anti-aging agents; (ii) firming agents, skin elasticity agents, and / or reconstructing agents; moisturizers; (iv) photoaging inhibitors and / or blue light protectants; DNA protectants, DNA repair agents, and / or stem cell protectants; free radical scavengers and / or anti-glycation agents; detoxifiers; antioxidants and / or anti-pollution agents; antiperspirants; melanin synthesis stimulants or inhibitors; whitening agents or decolorizing agents; pigmentants; self-tanning agents; lipolytic agents or agents that stimulate lipolysis; and lipogenic agents. Additional examples can be found in the CTFA International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).

[0176] In one embodiment, the present invention provides a cosmetic or pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically or cosmetically effective amount of an adjuvant selected from the group consisting of (i) an anti-wrinkle agent, a Botox-like agent, and / or an anti-aging agent, (ii) a firming agent, a skin elasticizing agent, and / or a reconstructing agent, (iii) a moisturizer, (iv) a photoaging inhibitor and / or a blue light protectant, (v) a DNA protector, a DNA repair agent, and / or a stem cell protectant, (vi) a free radical scavenger and / or an anti-glycation agent, an anti-detoxifier, an antioxidant, and / or a pollution inhibitor, and / or a combination thereof.

[0177] In certain embodiments, the anti-wrinkle agent, Botox-like agent, and / or anti-aging agent is Matrixyl® (INCI: palmitoyl pentapeptide-4), Matrixyl® 3000 (INCI: palmitoyl tetrapeptide-7, palmitoyl oligopeptide), Matrixyl® Synthe'6 (INCI: glycerin, water, hydroxypropyl cyclodextrin, palmitoyl tripeptide-38), Matrixyl® (Registered Trademark), sold by Sederma / Croda. Morphomics (trademark) (INCI: pentylene glycol, caprylyl glycol), Essenskin (trademark) (INCI: calcium hydroxymethionine), Renovage (INCI: teprenone), Dermaxyl (registered trademark) (INCI: palmitoyl oligopeptide), Calmosensine (INCI: butylene glycol, acetyl dipeptide-1 cetyl ester), Volulip (INCI: cetearyl ethyl hexanoate, sorbitan isostearate, Portulaca grandiflora) Pilosa extract, sucrose cocoate, palmitoyl tripeptide-38), Subliskin (INCI: alfalfa rhizobia (Sinorhizobium meliloti) ferment, cetyl hydroxyethylcellulose, lecithin), Biopeptide CL (INCI: palmitoyl oligopeptide), Biopeptide EL (INCI: palmitoyl oligopeptide), Rigin (INCI: palmitoyl tetrapeptide-3), Biobustyl (INCI: glyceryl polymethacrylate, Rahnella / soy protein ferment, palmitoyl oligopeptide), Dynalift (INCI: sodium polystyrene sulfonate, sorghum bicolor stem juice, glycerin), Idealift (INCI: acetyl dipeptide-1 cetyl ester), Siegesbeckia (INCI: SiegesbeckiaOrientales extract), Ovaliss (INCI: Coco-glucoside, Caprylyl glycol, Alcohol, Glaucine), Juvinity (Trademark) (INCI: Geranylgeraniisopropanol), Prolevis (INCI: Hydrolyzed vegetable protein), Idealift (Trademark) (INCI: Hydroxyethylcellulose, Acetyl dipeptide-1 cetyl ester), Beautifeye (Trademark) (INCI: Albizia julibrissin bark extract, Daltoside), Chromocare (Trademark) (INCI: Sigesbeckia Orientalis extract, Rabdosia rubescens extract), or Resistem (Trademark) (INCI: Globularia cordifolia) Cordifolia (fermented product), Vialox (registered trademark) (INCI: pentapeptide-3), Syn (registered trademark)-Ake (registered trademark) (INCI: dipeptide diaminobutyroyl benzylamide diacetate), Syn (registered trademark)-Coll (INCI: palmitoyl tripeptide-5), Phytaluronate (INCI: carob gum), Preregen (registered trademark) (INCI: soy protein, oxidoreductase), Pepha-Nutrix (INCI: natural nutritional factor), Pepha-Tight (INCI: algal extract, pullulan), Pentacare-NA (INCI: hydrolyzed wheat gluten, carob gum) Siliqua Gum, Syn(Registered Trademark)-TC (INCI: Glycerin, Palmitoyl Dipeptide-5 Diaminobutyroyl Hydroxythreonine, Palmitoyl Dipeptide-6 Diaminohydroxybutyrate), BeauActive MTP (INCI: Hydrolyzed Milk Protein), Syn(Registered Trademark)-TC (INCI: Tetradecyl Aminobutyroyl Valylaminobutyric Urea Trifluoroacetate)Trifluoroacetate), palmitoyl tripeptide-5, palmitoyl dipeptide-5 diaminobutyroyl hydroxythreonine), Syn(registered trademark)-Hycan(INCI: tetradecylaminobutyroyl valylaminobutyric acid urea trifluoroacetate), Syn(registered trademark)-Glycan(INCI: tetradecylaminobutyroyl valyl-aminobutyric acid urea trifluoroacetate), Regu-Age(INCI: hydrolyzed rice bran protein, oxidoreductase, Glycine soja protein), Pepha-Timp(INCI: human oligopeptide-20), Pepha-Age(INCI: Dunaliella salina extract), Colhibin(INCI: hydrolyzed rice protein), Elhibin(INCI: Glycine soja protein) Soja protein, disodium cocoamphodiacetate, or All-Q(trademark) Plus (INCI: ubiquinone, tocopheryl acetate), Myoxinol(trademark) (INCI: hydrolyzed okra (hibiscus esculentus)) extract, Myoxinol(trademark) LS 9736 (INCI: hydrolyzed okra (hibiscus esculentus)) extract, dextrin), sold by Laboratoires Serobiologiques / Cognis / BASF, Syniorage(trademark) (INCI: acetyl tetrapeptide-11), Dermican(trademark) (INCI: acetyl tetrapeptide-9), DN-AGE(registered trademark) LS (INCI: golden candle (Cassia alata) leaf extract), Hyalufix GL (INCI: galangal (Alpinia galanga) leaf extract), Neurobiox(INCI: yarrow (Achillea)) Millefolium extract, Deliner (INCI: Corn kernel extract), Lys'lastine V (INCI: Dill extract), Extracellium (INCI: Hydrolyzed potato protein), Proteasyl TP LS 8657 (INCI: Pea extract)Sativum extract), Flavagrum PEG (INCI: PEG-6 isostearate, hesperetin laurate), Micromerol (INCI: Apple (Pyrus Malus) fruit extract), Extracellium (INCI: Hydrolyzed potato protein), Marine Filling Spheres (INCI: Pentaerythrityl tetraisostearate, dimethylsilylated silica, sodium chondroitin sulfate, atelocollagen), Triactigen (INCI: Mannitol, cyclodextrin, yeast extract, disodium succinate), Eterniskin (INCI: Maitake mushroom (Grifola Frondosa) fruiting body extract, maltodextrin), Ascotide (INCI: Ascorbyl phosphate succinoyl pentapeptide-12), Hyalurosmooth (INCI: Senna (Cassia Angustifolia) seed polysaccharide), Indinyl CA (INCI: Senna (Cassia) Angustifolia (seed polysaccharides), Arganyl (INCI: Argania spinosa leaf extract), Sphingoceryl Veg (INCI: Phytoceramide), Vit-A-Like (INCI: Vigna Acontifolia seed extract), Peptiskin (INCI: Arginine / Lysine polypeptide), Prodejine (INCI: Mannitol, Cyclodextrin, Yeast extract, Disodium succinate), Aqu'activ (INCI: Behenyl alcohol, Glyceryl oleate, Cocamide MIPA, Calcium citrate), Elestan (INCI: Glycerin, Sapodilla (Manilkara) leaf extract), Hibiscin HP (INCI: Hibiscus esculentus seed extract), Collalift (registered trademark) 18 (INCI: Khaya Senegalensis (bark), Collrepair (trademark) DG (INCI: hexylene glycol, niacin), or Litchiderm (INCI: reishi (LitchiChinensis (fruit peel extract), Argireline® (INCI: acetyl hexapeptide-8), SNAP-7 (INCI: acetyl heptapeptide-4), SNAP-8 (INCI: acetyl octapeptide-3), Leuphasyl® (INCI: pentapeptide-18), Inyline® (INCI: acetyl hexapeptide-30), Aldenine® (INCI: hydrolyzed wheat protein, hydrolyzed soy protein, tripeptide-1) sold by Lipotec / Lubrizol. Preventhelia(registered trademark)(INCI: diaminopropionoyl tripeptide-33), Decorinyl(registered trademark)(INCI: tripeptide-10 citrulline), Decorinol(registered trademark)(INCI: tripeptide-9 citrulline), Trylagen(registered trademark)(INCI: Pseudoalteromonas fermented extract, hydrolyzed wheat protein, hydrolyzed soy protein, tripeptide-10 citrulline, tripeptide-1), Eyeseryl(registered trademark)(INCI: acetyl tetrapeptide-5), PeptideAC29 (INCI: Acetyl Tripeptide-30 Citrulline), Relistase (Registered Trademark) (INCI: Acetyl Arginyl Tryptophyllid Diphenylglycine), Thermostressine (Registered Trademark) (INCI: Acetyl Tetrapeptide-22), Lipochroman (Trademark) (INCI: Dimethyl Methoxychromanol), Chromabright (Registered Trademark) (INCI: Dimethyl Methoxychromanyl Palmitate), Antarcticine (Registered Trademark): Fermented Extract of Pseudoalteromonas ), dGlyage(registered trademark) (INCI: Lysine HCl, Lecithin, Tripeptide-9 Citrulline), Vilastene(trademark) (INCI: Lysine HCl, Lecithin, Tripeptide-10 Citrulline), Hyadisine(registered trademark) (INCI: Pseudoalteromonas fermented extract), Hyanify(trademark) (INCI: Saccharide isomerate), Diffuporine(registered trademark) (INCI: Acetyl hexapeptide-37), Silusyne(registered trademark) (INCI: Soybean (Glycine) Soybean oil, sorbitan sesquioleate, isohexadecane, sodium hyaluronate, lauryldimonium hydroxypropyl hydrolyzed soy protein, acetyl hexapeptide-39), Adifyline (registered trademark) (INCI: acetyl hexapeptide-38), Delisens (trademark) (INCI: acetyl hexapeptide-46), Telangyn (trademark) (INCI: acetyl tetrapeptide-40), Reproage (trademark) peptide (INCI: acetyl hexapeptide-8), Cellynkage (trademark) marine compound Min (INCI: Saccharide isomerate), Eyedeline (trademark) marine component (INCI: Plankton extract), uplevity (trademark) (INCI: Acetyl tetrapeptide-2), Seacode (trademark) marine component (INCI: Pseudoalteromonas ferment extract), or Serilesine (registered trademark) peptide solution (INCI: Hexapeptide-10), Sirtalice (trademark) (INCI: Bacillus ferment product) sold by Lipotrue, Epitensive (trademark) (INCI: Nicotiana benthamiana hexapeptide-40 SH-oligopeptide-1), Scelleye (trademark) (INCI: Nicotiana benthamiana Benthamiana SH-oligopeptide-2), Seadermium (INCI: Aqua, Glycerin, Bacillus ferment), Pauseile (INCI: Aqua, Glycerin, Bacillus ferment), or Neoclair pro (INCI: Aqua, Glycerin, Caprylyl Glycol, Acetyl Tetrapeptide-2), Collaxyl (Registered Trademark) IS (INCI: Hexapeptide-9) sold by Vincience / ISP / Ashland, Laminixyl IS (Trademark) (INCI: Heptapeptide), Orsirtine (Trademark) GL (INCI: Rice Extract), D'Orientine (Trademark) IS (INCI: Date Palm Seed Extract), Phytoquintescine (Trademark) (INCI: Triticum monococcum extract), Quintescine (trademark) IS (INCI: dipeptide-4), Peptide Vinci 01 (INCI: pentadecapeptide-1), Peptide Vinci 02 (trademark) (INCI: hexapeptide-3), Aquarize IS (trademark) (INCI: hydrolyzed rice extract), Lanablue (INCI: algae extract), Ederline (trademark) (INCI: apple (Pyrus)Malus (apple) seed extract, Dynachondrine (trademark) ISR (INCI: hydrolyzed soy protein), Prolixir S20 (trademark) (INCI: dimer tripeptide-43), Phytocohesine (trademark) PSP (INCI: sodium beta-sitosteryl sulfate, beta-sitosterol), Perenityl (trademark) IS (INCI: Pyrus Communis (European pear) seed extract), Caspaline 14 (trademark) (INCI: hexapeptide-42), Peptide Q10 (trademark) (INCI: pentapeptide-34 trifluoroacetate), Survixyl IS (trademark) (INCI: pentapeptide-31), ChroNOgen (trademark) (INCI: tetrapeptide-26), Elixiance (INCI: Schinus Molle extract), Harmoniance (INCI: Nelumbo nucifera flower extract), Serenityl (INCI: Marsdenia condurango bark extract), Natriance Wrinkle-less (INCI: hydrolyzed corn protein), Phytoneomatrix (INCI: hydrolyzed soy extract), Prolixir ICE (INCI: hydrolyzed rice protein), PhytoRNx Baobab (INCI: hydrolyzed African baobab (Adansonia digita) extract), Natriance Repair Extract (INCI: hydrolyzed flaxseed extract), Natriance Self-Hydration Extract (INCI: pea (Pisum sativum) extract), Actopontine YST (INCI: hydrolyzed yeast protein), or Telosense (INCI: hydrolyzed soy protein, hydrolyzed yeast protein), Infinitec BONT-L-peptide (INCI: palmitoyl hexapeptide-19), TIMP peptide (INCI: acetyl hexapeptide-20), and ECM are sold by Activos.Moduline (INCI: Palmitoyl Tripeptide-28), Renaissance (INCI: Hydrolyzed Wheat Protein, Palmitoyl Decapeptide-21, Decapeptide-22, Oligopeptide-78, Zinc Palmitoyl Nonapeptide-14), or X50 Anti-aging Agent (INCI: Lactic Acid / Glycolic Acid Copolymer, Polyvinyl Alcohol, Copper Palmitoyl Heptapeptide-14, Heptapeptide-15 Palmitate), EquiStat (INCI: Apple (Pyrus Malus) Fruit Extract, Glycine Soja (Glycine)) sold by Coletica / Engelhard / BASF Soybean (soybean) seed extract), Juvenesce (INCI: ethoxydiglycol and caprylic triglyceride, retinol, ursolic acid, phytonadione, iromat), Ursolisome (INCI: lecithin, ursolic acid, atelocollagen, xanthan gum, sodium chondroitin sulfate), Basaline (INCI: hydrolyzed malt extract), Phytokine (INCI: hydrolyzed soy protein), Ameliox (INCI: carnosine, tocopherol, milk thistle (Silybum marianum) fruit extract) or PhytoCellTec Malus domestica (INCI: apple (Malus domestica) fruit cell culture) sold by Mibelle Biochemistr, Lipobelle Soyaglicane (INCI: soy isoflavone), RoyalEpigen P5 (INCI: shea butter (Butyrospermum) Select from three groups consisting of Parkii butter, hydrogenated lecithin, maltodextrin, pentapeptide-48, phenethyl alcohol, ethylhexylglycerin, glycerin, aqua), or DermCom (INCI: golden crocus (Crocus Chrysanthus) bulb extract, gum arabic (Acacia Senegal) gum, aqua / water), ActiMatrix (INCI: peptide-based mushroom extract) sold by Active Organics / Arch, Peptamide 6 (INCI: hexapeptide-11), and combinations thereof.

[0178] In another embodiment, the tightening agent, skin elasticity agent and / or reconstructing agent is Argassential (INCI: C10-16 alkyl glucoside, dicaprylyl ether, glycerin) or Replexium BC (INCI: dimethyl isosorbide, polysorbate 20, aqua, acetyl tetrapeptide-11, acetyl tetrapeptide-9) sold by BASF, Prolevis (INCI: hydrolyzed vegetable protein) or Poretect (INCI: caprylic / capric triglyceride, sorbitan trioleate, celery (Apium Graveolens) seed extract, flax (Linum Usitatissimum) seed extract) sold by Sederma / Croda, Actifirm Ultra Advanced botanical ingredient (INCI: Centella Asiatica extract, rosemary (Rosmarinus Officinalis) leaf extract, dipropylene glycol, alcohol, echinacea) sold by Lipotec / Lubrizol Selected from the group consisting of Angustifolia leaf extract or Actifcol Advanced botanical ingredient (INCI: aqua, glycerin, sodium citrate, shiitake mushroom (Lentinus Edodes) extract, potassium sorbate, sodium benzoate, phytic acid), Densorphin (trademark) (INCI: Vitex Agnus Castus extract, aqua, maltodextrin) or PhytoCellTec (trademark) nunatak (registered trademark) (INCI: isomalt, aqua, Saponaria pumila callus culture extract, lecithin), and combinations thereof.

[0179] In another embodiment, the humectant is qua Shuttle (INCI: sorbitol, oweed (Laminaria digita) extract, diatomaceous earth) sold by Infinitec, Aqua-Osmoline (trademark) (INCI: carob (Ceratonia siliqua) seed extract) sold by Vincience / ISP / Ashland, Hydralphatine (trademark) Asia (INCI: hydrogenated starch hydrolysate, panthenol, bamboo shoot extract, lotus (Nelumbo nucifera) flower extract, water lily (Nymphaea alba) root extract) sold by Lucas Meyer Cosmetics / Unipex, or Hydraporine (trademark) (INCI: betaine, hydrogenated lecithin, honey, pectin), L.PatcH2O(trademark) (INCI: trehalose, urea, serine, glyceryl polyacrylate, algin, sodium hyaluronate, pullulan), Aqu'activ(trademark) (INCI: behenyl alcohol, glyceryl oleate, cocamide MIPA), Irwinol(registered trademark) (INCI: octyldodecanol, African mango (Irvingia Gabonensis) kernel butter, hydrogenated cocoglycerides), Lipodermol(registered trademark) (INCI: octyldodecanol, arachidyl propionate, tocopheryl acetate, retinyl palmitate, ethyl linoleate, ethyl linolenate), or Seanamin(registered trademark)SU (INCI: sorbitol, algal extract, Chrondrus Crispus (carrageenan), Fucus vesiculosus) sold by Serobiologiques / Cognis / BASF. Vesiculosus extract, algin, ice algae powder (INCI: Coenochloris Signiensis extract) sold by Mibelle, Hyasol BT (INCI: sodium hyaluronate) sold by Pentapharm / DSM, Syn-Up (trademark) (INCI: benzyl sulfonyl D-ceryl homophenylalanine amidinobenzamide acetate), or Pentavitin (registered trademark) (INCI: saccharide isomerate). Aqualance (trademark) (INCI: erythritol, fomarin HCl), Hydraprotectol (trademark) (INCI: glyceryl polymethacrylate, alloyl phosphate, yeast extract (Faex), glycoprotein), Moist 24 (trademark) (INCI: Imperata Cylindrica root extract), sold by Sederma / Croda, Optim Hyal (trademark) (INCI: hydrolyzed yeast extract, cetyl hydroxyethylcellulose, polyglucuronic acid), Osmocide (registered trademark) 4 (INCI: glycerin, acrylate / C10-30 alkyl acrylate crosspolymer), or Revidrate (trademark) (INCI: ethylhexyl palmitate, sorbitan oleate, sorbitan laurate, myristylmalate phosphonic acid), Xpertmoist (registered trademark) molecular film sold by Lipotec / Lubrizol (INCI: glycerin, Pseudoalteromonas ferment extract, xanthan gum, proline, alanine, serine, ethylhexylglycerin, caprylyl glycol), or Actizyme GL advanced plant extract (INCI: glycerin, Mucor myehai). Selected from the group consisting of miehei extract, aqua, sodium citrate, potassium sorbate, sodium benzoate, phytic acid, and combinations thereof.

[0180] In another embodiment, photoaging inhibitors and / or blue light protectants include Algaktiv Genofix CPD (INCI: Plankton Extract, Aqua, Lecithin) sold by Greenaltech, Blumilight® Biofunctional (INCI: Water / Aqua (and) Butylene Glycol (and) Cocoa Tree (Theobroma cacao) (Cocoa) Seed Extract) sold by Ashland, Lys'Sun (INCI: Hamamelis Virginiana Leaf Extract, Aqua, Pentylene Glycol, Caprylyl Glycol, Xanthan Gum) sold by BASF, Vitachelox (INCI: Vitis Vinifera Seed Extract, Camellia Sinensis Leaf Extract, Quercus Robur Wood Extract) sold by Indena, and Freshine L-VCG (INCI: Ascorbyl Glucoside) sold by Bio-technology, Lumicease Blue Ingredient (INCI: Glycerin, Aqua, Hydrolyzed Pea Protein, Glucose, Sodium Chloride) sold by Lipotec / Lubrizol, Lightwaves Defense (JS+M) (INCI: Jasminum Sambac Leaf Cell Extract) sold by Naolys, Blue Oleoactif (INCI: Glycine Soja Oil, Polyglyceryl-3 Diisostearate, Oryza Sativa Germ Extract, Oryza Sativa Extract) sold by Oleos-Hallstar, Majestem (INCI: Glycerin, Leontopodium Alpinum Callus Culture Extract, Xanthan Gum) or Senestem (INCI: Glycerin, Plantago Major) sold by Sederma Blueshield (INCI: Glycerin, Capsicum lanceolata leaf extract, xanthan gum), sold by SolabiaSelected from the group consisting of Annuum fruit extract, xanthan gum, and combinations thereof.

[0181] In another embodiment, the DNA protectant, DNA repair agent, and / or stem cell protectant is GP4G SP (INCI: Aqua, Glycerin, Aretomia Extract), Heliostatine (INCI: Aqua, Glycerin, Pisum Sativum Extract), Orsirtine (INCI: Aqua, Glycerin, Oryza Sativa Extract), Chronogen (INCI: Aqua, Butylene Glycol, Tetrapeptide (presented INCI)), Survixyl IS (INCI: Water, Butylene Glycol, Pentapeptide-31), and Chrondricare (INCI: Aqua, Butylene Glycol Pentapeptide-28), sold by Vincience / ISP / Ashland, and Lanacityn® (INCI: Glycerin, Aqua, Alteromonas Ferment Extract, Chrysanthellum Indicum), sold by Atrium Innovations / Lucas Meyer Cosmetics. Indicum (extract) or Melinoil (INCI: Isopropyl palmitate, lecithin, aqua, acetyl hexapeptide-1), Repair complex sold by CLR (INCI: Bifida fermentation lysate), Phycojuvenine sold by Codif (INCI: Oweed (Laminaria digita)), Unirepair T-43 sold by Induchem (INCI: Butylene glycol, acetyl tyrosine, proline, hydrolyzed vegetable protein, adenosine triphosphate), Dragosine sold by Symrise (INCI: Carnosine), DN-Age sold by Laboratories Serobiologiques / Cognis / BASF (INCI: Golden candle (Cassia alata) leaf extract), Helioguard sold by Mibelle Biochemistry (INCI: Porphyra ambilicarius (Porphyra ambilicarius) encapsulated in liposomes) Umbilicalis)) PhytoCellTec Malus DomesticaDomestica) (INCI: PhytoCellTec malus domestica), or PhytoCellTec Argan (INCI: Argania spinosa sprout cell extract, isomalt, lecithin, sodium benzoate, aqua), Pepha-Protect (INCI: watermelon extract) sold by Pentapharm / DSM, Celligent (INCI: Helianthus annuus seed oil, ethyl ferulate, polyglyceryl-5 trioleate, Rosmarinus officinalis leaf extract, aqua, disodium uridine phosphate) sold by Rahn, or Defensil (INCI: octyldodecanol, Echium plantagineum seed oil, Cardiospermum halicacabum extract, Helianthus annuus) Annuus (seed oil unsaponifiables), Venuceane (INCI: Thermus Thermophilus ferment, glycerin) sold by Sederma / Croda, UV-Soft (INCI: yeast extract), Renovage (INCI: caprylic / capric triglyceride, teprenone), Juvinity (INCI: caprylic / capric triglyceride, geranylgeranylpropanol (presented)), Phytessence Holyherb (INCI: butylene glycol, Eriodictyon Californicum (holy herb) flower / leaf / stem extract), or Resistem (INCI: glycerin, Globularia Cordifolia ferment), Infraguard (INCI: Caesalpinia tara) sold by Mibelle Spinosa fruit pod extract, propylene glycol, aqua, sunflower (Helianthus)Selected from the group consisting of Annuus (sprout extract, sodium benzoate, phenoxyethanol), Heliomoduline (INCI: low molecular weight peptide from cottonseed) or Stem-C-Guard (hydrolyzed pea), sold by Silab, or combinations thereof.

[0182] In another embodiment, reactive carbonyl species scavengers, free radical scavengers and / or anti-glycation agents, detoxifiers, antioxidants and / or anti-pollution agents include, for example, but are not limited to, carnosine and its derivatives, GHK (INCI: tripeptide-1) sold by Vincience / ISP / Ashland, its salts and / or derivatives or Quintescine IS (INCI: dipeptide-4), Preregen (INCI: Glycine soja (soybean) protein, oxidoreductase) sold by Pentapharm / DSM, Edelweiss GC (INCI: Leontopodium alpinum extract), Lipogard (INCI: squalane, ubiquinone), Nectapure (INCI: Buddleja davidiana extract, Thymus vulgaris extract) Vulgaris extract), Alpaflor Nectapure (INCI: Buddleja Davidii extract, Thymus Vulgaris extract, glycerin, water), or Dismutin-BT (INCI: Saccharomyces budding yeast) Highly purified SOD from natural yeast strain of Cerevisiae, Preventhelia® (INCI: Diaminopropionoyl Tripeptide-33), Aldenine® (INCI: Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, Tripeptide-1), Lipochroman® (INCI: Dimethylmethoxychromanol), Thermostressine® (INCI: Acetyl Tetrapeptide-22), Pollushield® (INCI: Diisopropyl Adipate, Lecithin, Acrylates / Acrylamide Methylpropanesulfonic Acid Copolymer, Dimethylmethoxychromanol, Xanthan Gum), or Bodyfensine® (INCI: Acetyl Dipeptide-3 Aminohexanoate), LaboratoiresUnactyl (INCI: Mannitol, Pisum Sativum extract, Histidine HCl, Arginine, Cyclodextrin, Dextrin, Yeast extract, Acetyltrisoin (Trysoine), Pyridoxine HCl, Khaya Senegalensis bark extract, Nicotinamide, Adenine dinucleotide, Disodium succinate, Aspartic acid), Imidinyl (INCI: Tamarindus indica seed polysaccharide), Phystrogene (INCI: Butylene glycol, Malva Sylvestris (Mallow) extract, Xanthan gum), or Purisoft (INCI: Moringa Pterogysperma seed extract), sold by Serobiologiques / Cognis / BASF, and AquaCacteen (INCI: Glycerin, Opuntia cactus), sold by Mibelle Biochemistry. Ficus Indica (stem extract, phenoxyethanol, aqua), Trimoist (KMF) (INCI: sodium stearoyl lactylate, cetyl alcohol, orthocarpus vegetable oil, tocopheryl acetate, glycerin, Glycine soja (bean) sterol, sodium lactate, barboxymethyl beta-glucan sodium, carnosine, lactic acid), MelanoBronze (INCI: Vitex Agnus Castus (chrysanthemum) extract (Vitex Agnus berries extract (phytoendorphin)), acetyltyrosine), CM-Glucan (INCI: carobxymethyl beta-glucan sodium, phenoxyethanol), SunActin (INCI: Helianthus Annuus (sunflower) sprout extract, tocopherol, glycerin, lecithin, phenoxyethanol, aqua), GSP-T skin (INCI: glycerin, alcohol, aqua, PEG-40 hydrogenated castor oil, European grape (Vitis Vinifera) (grape) seed extract), or Detoxophane (INCI: LepidiumSativum (sprout extract, lecithin, phenoxyethanol, glycerin, water), Bacocalmine (INCI: PEG-8, Bacopa monniera extract, water (aqua), hydroxyethylcellulose) sold by Sederma / Croda, Kombuchka (INCI: Saccharomyces / Xylinum black tea ferment, glycerin, hydroxyethylcellulose), Citystem (INCI: glycerin, Marrubium vulgare extract), or Prodizia (INCI: Albizia julibrissin extract, glycerin), Extramel C (INCI: hydroxypropyltrimonium maltodextrin crosspolymer, cucumber fruit extract) sold by Seppic, Defensine (INCI: Triticum) sold by Silab Selected from Vulgare (germ extract), Apolluskin (registered trademark) (INCI: Taraxacum officinale (dandelion) extract), Detoxyl (registered trademark) (INCI: water, butylene glycol, shea butter tree (Butyrospermum parkii) seed cake extract), or Antiglyskin (INCI: aqua, sunflower (Helianthus Annuus) seed extract), and combinations thereof.

[0183] The compositions of the present invention may be used in any of the applications or uses discussed above under the heading "Applications".

[0184] In another embodiment, the present invention is a kit for use in cosmetic non-therapeutic treatment methods of skin treatment and / or care, (i) A composition containing botulinum toxin, (ii) optionally a composition containing Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, (iii) A kit is provided comprising a cosmetic composition containing a compound of formula (I), (II), or (III).

[0185] (i) a composition containing botulinum toxin, (ii) a composition containing Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 (if present), and (iii) a composition containing the compound of the present invention according to the first embodiment may be present in the same or separate containers. In one embodiment, the kit may further include means for applying the composition to the skin. For example, the kit may include means such as a syringe or microneedle.

[0186] The present invention is illustrated by the following non-limiting embodiments. [Examples]

[0187] General method Abbreviation The abbreviations used for amino acids follow the recommendations of the 1983 Joint Committee on Biochemical Nomenclature, outlined in Eur.J.Biochem.(1984)138:9-37.

[0188] (R), resin; 2-ClTrt-(R), 2-chlorotrityl resin; Ac, acetyl; AcOH, acetic acid; Ala, alanine; AM, 2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid; Arg, arginine; Asn, asparagine; Asp, aspartic acid; Boc, tert-butyloxycarbonyl; DCM, dichloromethane; DIEA, N,N'-diisopropylethylamine; DIPCDI, N,N'-diisopropylcarbodiimide; DMF, N,N-dimethylformamide; ESI-MS, electrospray ionization mass spectrometry; Fmoc, 9-fluorenylmethyloxycarbonyl; Gln, glutamine; Glu Glutamic acid; Gly, glycine; His, histidine; HOBt, 1-hydroxybenzotriazole; HPLC, high-performance liquid chromatography; Ile, isoleucine; KOH, potassium hydroxide; Leu, leucine; Lys, lysine; MBHA, p-methylbenzhydrylamine; MeCN, acetonitrile; MeOH, methanol; Met, methionine; Myr, myristoyl; Palm, palmitoyl; Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Pro, proline; Ser, serine; tBu, tert-butyl; TFA, trifluoroacetic acid; Thr, threonine; Trt, trityl; Val, valine.

[0189] chemical synthesis All synthesis processes are carried out in a polypropylene syringe fitted with a porous polyethylene disc. The coupling procedure is carried out according to a standard procedure based on references, and the solvent and soluble reagents are removed by aspirate. The Fmoc group is removed using piperidine-DMF (2:8, v / v) (1 × 1 min, 1 × 5 min, 5 mL / g resin) [Lloyd-Williams P. et al. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton (FL, USA)]. Washing between the deprotection, coupling, and re-deprotection steps is performed with DMF (3 × 1 min) using 10 mL solvent / g resin each time. The coupling reaction is carried out using 3 mL solvent / g resin. Coupling is controlled by either a ninhydrin test (Kaiser E. et al., Anal. Biochem. (1970), 34:595-598) or a chloranil test (Christensen T., Acta Chem. Scand., (1979), 33B, 763-766). The coupling reaction is repeated while synthesizing the desired peptide. All synthesis reactions and washings are performed at 25°C.

[0190] Those skilled in the art know that some amino acids are used with their side-chain functional groups protected. For example, a non-limiting example of a protecting group is: • In the case of the amino acid Glu, tBu, tert-butyl, and • In the case of the amino acid Arg, Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl, and • In the case of the amino acid Gln, it is Trt, or trityl.

[0191] HPLC chromatography analysis is performed on a Shimadzu device (Kyoto, Japan) using a reversed-phase column (50×4.6 mm, Kromasil C18, 3.5 μm, Akzo Nobel, Sweden) thermostated at 30 °C. Elution is carried out at a flow rate of 1.6 mL / min using a gradient of water (+0.1% TFA) containing acetonitrile (+0.07% TFA), and detection is performed at 220 nm. Electrospray ionization mass spectrometry is carried out on a WATERS Alliance ZQ 2000 detector at a flow rate of 0.3 mL / min using a 4:1 MeCN:H2O (+0.1% TFA) mixture as the mobile phase.

[0192] Example 1 Fmoc-W m -X n -AA1-AA2-AA 3- AA4-Y p -Z q -AM-MBHA-(R) (where AA1 is L-Asp, AA2 is L-Val, AA3 is L-Tyr, AA4 is L-Lys, and n, m, p, and q are each 0) is obtained. The weight is normalized. To remove the Fmoc group, the Fmoc-AM-pMBHA resin is treated with piperidine:DMF according to the described general protocol. 5 equivalents of Fmoc-L-Lys(Boc)-OH are incorporated into the deprotected resin for 1 hour in the presence of 5.5 equivalents of DIPCDI and 5 equivalents of HOBt using DMF as the solvent.

[0193] Then, the resin is washed in the general manner described and the Fmoc group deprotection process is repeated to couple the next amino acid. 5 equivalents of Fmoc-L-Tyr(tBu)-OH, and then 5 equivalents of Fmoc-L-Val-OH, 5 equivalents of Fmoc-L-Asp(tBu)-OH) are sequentially coupled in each coupling step in the presence of 5 equivalents of HOBt and 5.5 equivalents of DIPCDI.

[0194] After synthesis, the peptidyl resin is washed with DCM (3×1 min).

[0195] By following the described method, it is possible to obtain different sequences that modify the desired amino acids to be coupled.

[0196] Example 2 Fmoc-W m -X n -AA1-AA2-AA 3- AA4-AA5-AA 6- -Y p -Z q -AM-MBHA-(R) (where AA1 is L-Ala, AA2 is L-Leu, AA3 is L-Lys, AA4 is L-Pro, AA5 is L-Asn, AA6 is L-Thr, and n, m, p, and q are each 0) is obtained. The weight was normalized. To remove the Fmoc group, the Fmoc-AM-pMBHA resin was treated with piperidine:DMF according to the described general protocol. 5 equivalents of Fmoc-L-Thr(tBu)-OH were incorporated into the deprotected resin for 1 hour using DMF as the solvent in the presence of 5.5 equivalents of DIPCDI and 5 equivalents of HOBt.

[0197] Then, the resin was washed in the general manner described and the deprotection of the Fmoc group was repeated to couple the next amino acid. 5 equivalents of Fmoc-L-Asn(Trt)-OH, and then 5 equivalents of Fmoc-L-Pro-OH, 5 equivalents of Fmoc-L-Lys(Boc)-OH, 5 equivalents of Fmoc-L-Leu-OH, and finally 5 equivalents of Fmoc-L-Ala-OH were sequentially coupled in each coupling step in the presence of 5 equivalents of HOBt and 5.5 equivalents of DIPCDI.

[0198] After synthesis, the peptidyl resin was washed with DCM (3×1 min).

[0199] By following the described method, it is possible to obtain different sequences that modify the desired amino acids to be coupled.

[0200] Example 3 General method for removing the Fmoc N-terminal protecting group. Deprotect the N-terminal Fmoc group of the peptidyl resin obtained in Example 1 or 2 as described in the general method (20% piperidine in DMF, 1×1 min + 1×5 min). Wash the peptidyl resin with DMF (5×1 min), DCM (3×1 min), diethyl ether (3×1 min), and dry it under vacuum.

[0201] Example 4 Method for introducing the R1 palmitoyl group into the peptidyl resin obtained in Example 3. Add 5 equivalents of palmitic acid previously dissolved in DMF (1 ml) to each of the peptidyl resins obtained in Example 3 in the presence of HOBt and DIPCDI. React the mixture for 3 hours, then wash the resin with DMF (3×1 min), DCM (3×1 min), diethyl ether (3×1 min), and dry it under vacuum.

[0202] Example 5 Method for introducing the R1 acetyl group into the peptidyl resin obtained in Example 3. Treat each of the peptidyl resins obtained in Example 3 with acetic anhydride in the presence of DIEA using DMF as the solvent. React the mixture for 30 minutes, then wash the resin with DMF (3×1 min), DCM (3×1 min), diethyl ether (3×1 min), and dry it under vacuum.

[0203] Example 6 Method for cleavage of the peptidyl resins obtained in Examples 3, 4, and 5 from the polymer support. Treat each of the dry peptidyl resins obtained in Examples 3, 4, and 5 with 3 ml of TFA:H2O (95:5, v / v) at room temperature for 2 hours with stirring. Then filter them through a polypropylene syringe fitted with a porous polyethylene disk. Collect the filtrate onto cold diethyl ether and wash it 5 times with diethyl ether. Dry the final precipitate under vacuum.

[0204] General formula R1-W m -X n -AA1-AA2-AA3- AA4-Y p -Z q -OH, R1-W m -X n -AA1-AA2-AA 3- AA4-NH 2、 R1-W m -X n -AA1-AA2-AA 3- AA4-AA5-AA6-Y p -Z q -OH, or R1-W m -X n -AA1-AA2-AA 3- AA4-AA5-AA6-Y p -Z q A peptide of -NH2 (wherein R1 is H, acetyl, or palmitoyl) is obtained according to this method.

[0205] HPLC analysis of peptides obtained using a gradient of H2O (+0.1% TFA) containing MeCN (+0.07% TFA) shows a purity exceeding 80% in all cases. The uniqueness of the obtained peptides is confirmed by ESI-MS.

[0206] Example 7 In vitro quantification of muscle bind-like protein 1 (MBNL1) in human skeletal muscle cells by time-resolved fluorescence resonance energy transfer. Aging is associated with a decrease in muscle mass. A decline in the function of muscle bind-like protein 1 (MBNL1) is linked to the decrease in muscle mass associated with the aging process of facial muscles.

[0207] MBNL1 induction by the peptides of this invention is evaluated by a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The objective of this study is to investigate the ability of candidate peptides to increase MBNL1 in human skeletal muscle cells (hSkMc).

[0208] hSkMc(Innoprot) was incubated in skeletal muscle cell growth medium (Promocell) at a rate of 1.5 x 10⁻¹⁰ 4Seed cells in a 12-well plate at a cell / well density. After 72 hours of incubation, remove the medium and replace it with skeletal muscle cell differentiation medium (Promocell). 48 hours after the start of cell differentiation, add fresh differentiation medium containing 0.5 mg / ml of the test item. Treatment is continued for 48 hours, with untreated cells used as a baseline control. After 48 hours of treatment, remove the cell medium and add cell lysis buffer to the wells. Immediately, maintain the plate at -80°C to improve protein extraction during the thawing process. After 72 hours, lyse the cells by shaking the plate in an orbital rotor at room temperature for 45 minutes. Then, collect the nuclear lysates and subject them to assays to quantify MBNL1 protein levels and total protein concentration.

[0209] MBNL1 protein levels will be measured using the Human MBNL1 Assay Kit (Cisbio) according to the manufacturer's protocol. Briefly, the kit is used to perform TR-FRET for MBNL1 quantification. The protein is detected with the antibody included in the kit and quantified by fluorescence measurement. Quantification will be performed using a microplate reader (ClarioStar, BMG) set to 665 nm and 620 nm.

[0210] The total protein concentration of cell lysates is determined using the Pierce BCA Protein Assay Kit (Thermo Scientific) according to the manufacturer's protocol. Briefly, after adding Working Reagent to the sample and standard, the sample is incubated. Then, the color change at 562 nm is measured using an absorbance microplate reader (Clariostar, BMG). The total protein amount is used to normalize the MBNL1 protein concentration level obtained by the TR-FRET test of the sample.

[0211] The results demonstrate that the peptides PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) and PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) of the present invention increase MBNL1 levels compared to a baseline control (Figure 1). Enhancement of the MBNL1 protein is thought to slow the decline in muscle mass during aging and thus avoid the appearance of sagging facial skin in older adults.

[0212] Example 8 In vitro quantification of muscle bind-like protein 1 (MBNL1) in human dermal fibroblasts using immunofluorescence. Increased collagen synthesis is thought to be beneficial in reducing signs of aging. Muscle bind-like protein 1 (MBNL1) in fibroblasts activates the conversion of cells into myofibroblasts. These cells can release large amounts of extracellular matrix proteins such as collagen, elastin, or fibronectin, which can prevent the appearance of wrinkles.

[0213] The induction of MBNL1 by the peptide of this invention will be evaluated by immunofluorescence assay. The objective of this study is to investigate the ability of candidate peptides to increase MBNL1 in human dermal fibroblasts (HDFs).

[0214] HDF (Cascade) in fibroblast growth medium (Promocell) in 8x10 3Cells are seeded in a 96-well plate at a cell / well density. After 48 hours of incubation, the medium is removed and fresh medium containing 1, 0.5, and 0.01 mg / ml of the test items is added. The treatment is continued for 24 hours, and untreated cells are used as a basic control. After 24 hours of treatment, immunofluorescence is performed. Cells are fixed with 4% paraformaldehyde (Sigma) for 15 minutes, perfumed with 1% Triton X-100 (Sigma) for 15 minutes, and then blocked with 5% bovine serum albumin (Sigma). Next, the primary antibody anti-MBNL1 rabbit (Sigma) is added and incubated for 2 hours. Then, the secondary antibody Alexa Fluor 488 goat anti-rabbit IgG (Life Technologies) is added and incubated for 1 hour. To stain the nuclei, Hoechst (Life Technologies) is added and incubated for 10 minutes. Finally, the fluorescence intensity and number of MBNL1 cell nuclei are measured using Operetta (Perkin Elmer). Fluorescence was normalized by the cell nucleus, and the results were presented relative to a cobasic control. The results are shown in Figure 2.

[0215] The results demonstrate that the peptides PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) and PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) of the present invention increase MBNL1 levels compared to the baseline control.

[0216] Example 9 In vitro prevention of muscle mass loss induced in human skeletal muscle cells using immunofluorescence. Muscle mass loss is associated with facial muscle aging. Decreased function of muscle bind-like protein 1 (MBNL1) in muscle cells has been suggested to be associated with age-related muscle mass loss. The literature describes a myotubular diameter of less than 20 μm in muscle cells as an indicator of muscle mass loss.

[0217] Myosin heavy chain (MHyC) is used as a morphological marker for differentiated myotubes, allowing for the measurement of diameter and thus the determination of the degree of mass loss. Tumor necrosis factor α (TNF-α) has been described in the literature as a factor that induces muscle mass loss.

[0218] The prevention of muscle mass loss by the peptide of the present invention will be evaluated by immunofluorescence assay. The purpose of this study is to investigate the ability of candidate peptides to prevent muscle mass loss in human musculoskeletal cells (hSKMCs) in the presence of TNF-α.

[0219] hSkMc (Tebu-Bio) in skeletal muscle cell growth medium (Promocell) at 1.5x10 4 Cells are seeded in 96-well plates at a cell / well density. After 24 hours of incubation, the medium is replaced with skeletal muscle cell differentiation medium (Promocell), and the cells are differentiated for 6 days. After this, fresh differentiation medium containing 0.5 mg / ml of the test substance and 20 ng / ml of TNFα (Sigma) is added. The treatment is continued for 48 hours, with untreated cells used as the basic control and 20 ng / ml TNFα-treated cells used as a control for muscle mass reduction. Immunofluorescence is performed 48 hours after treatment. Cells are fixed with 4% paraformaldehyde (Sigma) for 15 minutes, perfumed with 1% Triton X-100 (Sigma) for 15 minutes, and then blocked with 5% bovine serum albumin (Sigma). Next, primary antibody anti-MHyC mice (1:100, in vitro) are added and incubated for 2 hours. Subsequently, the secondary antibody Alexa Fluor 488 goat anti-mouse IgG (1:250, Life Technologies) was added, and the samples were incubated for 1 hour. Finally, the diameter of the myotubes was determined by imaging with MHyC staining using Operetta (Perkin Elmer). The percentage of mass loss was automatically calculated using Harmony (Perkin Elmer) software by classifying the myotubes by diameter using a 20 μm atrophy threshold. The results are shown in Figure 4 and normalized to TNF-α.

[0220] The results demonstrate that the peptides PEP1 and PEP2 of the present invention prevent mass loss when compared to TNF-α treatment.

[0221] Example 10 In vitro reduction of the effect of muscle mass loss induced in human skeletal muscle cells by immunofluorescence method. The correction of muscle mass loss by the peptides of the present invention is evaluated by immunofluorescence assay. The purpose of this study is to investigate the ability of peptide candidates to correct the decrease in muscle mass after treatment with TNF-α in human muscle skeletal cells (hSKMC). Myosin heavy chain (MHyC) is used as a morphological marker of differentiated myotubes, which allows the measurement of the diameter and thus the degree of mass loss to be known. Tumor necrosis factor α (TNF-α) has been described in the literature as a muscle mass loss inducer.

[0222] hSkMc (Tebu-Bio) was cultured in skeletal muscle cell growth medium (Promocell) at 1.5x10 4Cells are seeded in a 96-well plate at a cell / well density. After 24 hours of incubation, the culture medium is replaced with skeletal muscle cell differentiation medium (Promocell), and the cells are differentiated for 6 days. After this, a reduction in muscle cell mass is induced by adding fresh differentiation medium containing 20 ng / ml TNFα (Sigma). Cells not treated with TNFα are used as the basal mass reduction control (BC). 24 hours after the induction of mass reduction, the culture medium is replaced with fresh differentiation medium containing 0.01 mg / ml of the peptide of the present invention. Cells treated with TNFα are used as the mass reduction control (BCN+TNF), and cells not treated with either the peptide of the present invention or TNFα are used as the basal mass reduction control (BC). The treatment is renewed after 24 hours. Immunofluorescence is measured 24 hours after the second treatment. Cells were fixed with 4% paraformaldehyde (Sigma) for 15 minutes, permeated with 1% Triton X-100 (Sigma) for 15 minutes, and then blocked with 5% bovine serum albumin (Sigma). Next, the primary antibody anti-MHyC mouse (1:100, in vitro) was added and incubated overnight at 4°C. Then, the secondary antibody Alexa Fluor 488 goat anti-mouse IgG (1:250, Life Technologies) was added and incubated for 1 hour. Finally, the diameter of the myotubes was determined by imaging with MHyC staining using Operetta (Perkin Elmer). The percentage of mass loss was automatically calculated using Harmony (Perkin Elmer) software by classifying the myotubes by diameter using a mass loss threshold of 20 μm. The results shown in Figure 4 were normalized to the mass loss control.

[0223] The results demonstrate that the peptides PEP1 and PEP2 of the present invention correct (i.e., reduce) the mass loss compared to a basic control treated with TNF-α.

[0224] Example 11 In vitro study of type I collagen synthesis in human dermal fibroblasts using AlphaLISA. The collagen induction by the peptide of this invention will be evaluated using the AlphaLISA assay. The objective of this study is to investigate the ability of the product to induce type I collagen synthesis in human dermal fibroblasts (HDFa) isolated from adult skin.

[0225] HDFa (Promocell) was added to fibroblast growth medium supplemented with C-39016 (Promocell) in a 1x10 5 Seeds were seeded in 48-well plates at a density of [density]. After 24 hours of incubation, fresh medium 106 supplemented with a low serum growth supplement (Gibco) containing 0.5 μg / ml of the test item was added. Treatment was continued for 48 hours, with untreated cells used as a basic control. After 48 hours of treatment, the cell supernatant was collected. A protease inhibitor cocktail (Sigma) was added to each supernatant, and the cells were then stored at -80°C until analysis with AlphaLISA using an AlphaLISA COL1A1 detection kit (PerkinElmer) according to the manufacturer's instructions. In short, the donor and acceptor beads in the presence of type I collagen were close enough to produce a luminescence signal that was directly proportional to the amount of type I collagen present under each condition tested. The color produced by this reaction was measured with a microtiter plate reader, and the concentration of type I collagen was determined using linear regression of a standard curve. The results for collagen synthesis versus untreated cells are shown in Figure 5.

[0226] The results demonstrate that the peptide of the present invention enhances the production of type I collagen under basic conditions in HDFa at the test concentration.

[0227] Example 12 Inhibition of norepinephrine release from human neuroblastoma cells. The purpose of this study is to evaluate the efficacy of the peptide of the present invention in inhibiting neuronal exocytosis by measuring the level of norepinephrine (NA) release in human neuroblastoma cell lines (SH-SY5Y cells) using enzyme-linked immunosorbent assay (ELISA).

[0228] SH-SY5Y(ECACC) cells, 1 × 10 6 Cells are seeded in a 12-well plate at a cell / well density. After 6 days of culture, the medium is removed from the wells, and the cells are treated for 60 minutes with the peptide of the present invention dissolved in Hanks equilibrium salt solution (HBSS, Life Technologies) at 0.01 and 0.5 mg / ml. Cells treated with HBSS alone are used as a baseline control. To recruit NA vesicles, the supernatant is removed, and 100 nM tetradecanoyl phorbol-13-acetate (TPA, Sigma) is dissolved in the presence of HBSS containing the test item, or in HBSS alone for the baseline control. Subsequently, the solution containing TPA is removed, and 100 nM TPA is dissolved in the presence of HBSS containing the test item, or in HBSS alone for the baseline control, and NA release is induced by the addition of 10 μM ionomycin (Epica). The medium from the wells containing the released NA is then collected and centrifuged. The obtained supernatant is used for quantification of NA by ELISA using a norepinephrine ELISA kit (IBL International) according to the manufacturer's instructions. In short, direct sandwich ELISA is performed using plates pre-coated with anti-NA antibody. The color obtained after substrate addition is directly proportional to the amount of NA present under each test condition. The absorbance at 405 nm is read using a microplate absorbance reader (Clariostar, BMG). The percentage of NA release for each condition is calculated relative to the base control. The results of the percentage of NA release relative to untreated cells (base control) are shown in Figure 6.

[0229] The results demonstrate that the peptide of the present invention inhibits NA release in SH-SY5Y under baseline conditions at test concentrations. Increased exocytotic release at the neuromuscular junction is associated with aging and the increase in facial wrinkles and expression lines. The peptide of the present invention reduces exocytotic levels by reducing NA release in SH-SY5Y.

[0230] Example 13 In vitro lipid accumulation in human subcutaneous preadipocytes. The objective of this study is to investigate the ability of candidate peptides to induce lipid accumulation in human subcutaneous adipocytes and, consequently, prevent adipocyte aging. Measuring lipid accumulation in co-cultures of young and aged adipocytes indirectly assesses the inhibition of the senescence-associated secretory phenotype (SASP). The pool of aged adipocytes contains more senescent cells. When co-cultured with young cells, the observed lipid accumulation is below theoretically expected levels, attributable to the senescence-inducing effect of SASP on young adipocytes.

[0231] The induction of lipid accumulation by the peptide of the present invention is evaluated by the Adipored® assay reagent and lipid fluorescence staining. Human subcutaneous preadipocytes (26-year-old and 60-year-old donors, Cell applications) were placed in 96-well plates, with each age group measured in 4x10⁶ cells. 3 Co-culture cells at a cell / well density in human adipocyte growth medium (Sigma). Single cultures for each age group are prepared at 8 × 10⁶. 3 Cells are seeded at a cell / well density as an age-related lipid accumulation control. After 24 hours of incubation, differentiation of preadipocytes into adipocytes is induced by replacing the medium with fresh human preadipocyte differentiation medium (Promocell). At the same time, co-cultured cells are treated with a test item at 0.01 mg / ml. Untreated co-cultured cells are used as a base control, and monocultured young and senescent cells are used as age-related lipid accumulation controls. Twelve days after treatment and differentiation, cells are stained with Adipored® assay reagent (Lonza) according to the manufacturer's instructions. Briefly, plates are washed with phosphate-buffered saline (Sigma), then Adipored® reagent and Hoechst 33342 (Life Technologies) are added, and incubated at 37°C for 15 minutes. Finally, fluorescence intensity and nucleus count are measured by Operetta (Perkin Elmer). Fluorescence is normalized by cell nuclei, and results are expressed relative to the co-cultured base control. Figure 7 shows the percentage of lipid content compared to untreated cells (basic control).

[0232] The results demonstrate that the peptides PEP1 and PEP2 of the present invention increase lipid accumulation in adipocytes compared to baseline and aged controls.

[0233] Example 14 Preparation of a cream containing peptide PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) solution Dissolve the components of Phase A in a suitable container: water (INCI: water (aqua)), Zemea (trademark) (INCI: propanediol), Hydrolite (registered trademark) 5 (INCI: pentylene glycol), Phenoxetol (trademark) (INCI: phenoxyethanol), and Dissolvine (registered trademark) NA2 (INCI: disodium EDTA).

[0234] Add the A1 phase component, Carbopol® Ultrez 10 Polymer (INCI: carbomer), to the mixture. Once dispersed, introduce the A2 phase, Cola® Fax CPE-K (INCI: potassium cetyl phosphate). Then, heat the mixture to a maximum of 70-75°C.

[0235] In a separate container, the components of Phase B—Schercemol® DIS ester (INCI: diisopropyl sebacate), Phytocream® 2000 (INCI: glyceryl stearate, cetearyl alcohol, potassium palmitoyl hydrolyzed wheat protein), Massocare® EC (INCI: ethylhexyl cocoate), Astro-sil 2C 350 (INCI: dimethicone), and tocopheryl acetate (INCI: tocopheryl acetate)—are mixed, and the resulting mixture is heated to 70-75°C.

[0236] The emulsion is produced by slowly adding phase A to phase B under conditions of high-speed stirring by a turbine.

[0237] Once the mixture has cooled to 40°C, the components of phase C, Novemer® EC-1 polymer (INCI: mineral oil (paraphinum lycidia), water (aqua), acrylate / acrylamide crosspolymer, polysorbate 85), are added to the mixture while stirring and mixed until dispersed.

[0238] Phase D: Add the peptide PEP1 solution (INCI: glycerin, water (aqua), peptide PEP1) to the mixture above.

[0239] Phase E: Fragrance (INCI: Fragrance (Parfum)) is added.

[0240] The pH is adjusted to 6.0-6.5 using the F phase component: 20% w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 4]

[0241] Preparation of a cream containing peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) solution Dissolve the components of Phase A in a suitable container: water (INCI: water (aqua)), Zemea (trademark) (INCI: propanediol), Hydrolite (registered trademark) 5 (INCI: pentylene glycol), Phenoxetol (trademark) (INCI: phenoxyethanol), and Dissolvine (registered trademark) NA2 (INCI: disodium EDTA).

[0242] Add the A1 phase component, Carbopol® Ultrez 10 Polymer (INCI: carbomer), to the mixture. Once dispersed, introduce the A2 phase, Cola® Fax CPE-K (INCI: potassium cetyl phosphate). Then, heat the mixture to a maximum of 70-75°C.

[0243] In a separate container, the components of Phase B—Schercemol® DIS ester (INCI: diisopropyl sebacate), Phytocream® 2000 (INCI: glyceryl stearate, cetearyl alcohol, potassium palmitoyl hydrolyzed wheat protein), Massocare® EC (INCI: ethylhexyl cocoate), Astro-sil 2C 350 (INCI: dimethicone), and tocopheryl acetate (INCI: tocopheryl acetate)—are mixed, and the resulting mixture is heated to 70-75°C.

[0244] The emulsion is produced by slowly adding phase A to phase B under conditions of high-speed stirring by a turbine.

[0245] Once the mixture has cooled to 40°C, the components of phase C, Novemer® EC-1 polymer (INCI: mineral oil (paraphinum lycidia), water (aqua), acrylate / acrylamide crosspolymer, polysorbate 85), are added to the mixture while stirring and mixed until dispersed.

[0246] Phase D: Add the peptide PEP2 solution (INCI: glycerin, water (aqua), peptide PEP2) to the mixture above.

[0247] Phase E: Fragrance (INCI: Fragrance (Parfum)) is added.

[0248] Adjust the pH to 6.0-6.5 using the components of phase F: 20% w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 5]

[0249] Example 15 Preparation of a cream containing peptide PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) solution. Disperse the components of Phase A: water (INCI: water (aqua)), Zemea (trademark) (INCI: propanediol), Phenoxetol (registered trademark) (INCI: phenoxyethanol), Dissolvine (registered trademark) NA2 (INCI: disodium EDTA), and potassium sorbate granules (potassium sorbate) in a suitable container.

[0250] Add the component of Phase A1, Carbopol® Ultrez 21 Polymer (INCI: acrylate / C10 / 30 alkyl acrylate crosspolymer), to the mixture while stirring. Once dispersed, add Phase A2, xanthan gum (INCI: xanthan gum), to the mixture and stir until completely dispersed.

[0251] In a separate container, weigh out the component of phase B: Schercemol (trademark) 1818 Ester (INCI: isostearyl isostearate).

[0252] The emulsion is produced by slowly adding phase A to phase B under conditions of high-speed stirring by a turbine.

[0253] Phase C: Add the peptide PEP1 solution (INCI: water (aqua), caprylyl glycol, peptide PEP1) to the mixture mentioned above.

[0254] The pH is adjusted to 6.0-6.5 using the components of phase D: 20% w / w sodium hydroxide [INCI: water (AQUA), sodium hydroxide]. [Table 6]

[0255] In this example, by substituting PEP1 with PEP2, a gel cream containing peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) can be obtained.

[0256] Example 16 Preparation of a gel containing a 2% peptide PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) solution. Dissolve the components of Phase A: water (INCI: water (aqua)), Zemea (trademark) (INCI: propanediol), Glucam (trademark) E-20 Humectant (INCI: methyl gluceth-20), Dissolvine (registered trademark) NA2 (INCI: disodium EDTA), and Phenoxetol (registered trademark) (INCI: phenoxyethanol) in a suitable container.

[0257] Phase A1: Add Carbopol® ultraz 10 polymer (INCI: carbomer) to the mixture above and mix until completely dispersed.

[0258] Phase B: Add the peptide PEP-23 solution (INCI: water (aqua), caprylyl glycol, PEP-23) to the mixture above and mix.

[0259] Phase C: EUMULGIN (registered trademark) CO40 (INCI: PEG-40 hydrogenated castor oil), fragrance (INCI: fragrance (parfum)) are added to the above mixture and mixed.

[0260] Phase D components: The pH is adjusted to 6.0-6.5 using 20% ​​w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 7]

[0261] In this example, by substituting PEP1 with PEP2, a gel containing peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) can be obtained.

[0262] Example 17 Preparation of a lotion containing a 2% peptide PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) solution. Dissolve the components of Phase A1: water (INCI: aqua), Zemea (INCI: propanediol), glycerin (INCI: glycerin), potassium sorbate (INCI: potassium sorbate), and Dissolvine (registered trademark) NA2 (INCI: disodium EDTA) in a suitable container.

[0263] Phase A2 component: Add Carbopol® Ultrez 30 Polymer (INCI: carbomer) to the mixture. After dispersion, Phase A3: Xanthan gum (INCI: xanthan gum) is introduced. Then, the mixture is heated to 70-75°C.

[0264] In a separate container, the components of Phase B—Fancor® Meadowfoam Seed Oil (INCI: Limnanthes Alba (Meadowfoam) Seed Oil), Kodasil 600 IDD Gel (INCI: Isododecane, Vinyl Dimethicone / Lauryl Dimethicone Crosspolymer, Dimethicone, Lauryl Dimethicone), Astro-sil 2C 350 (INCI: Dimethicone), Schercemol® CATC Ester (INCI: Cocoyl Adipic Acid / Trimethylolpropane Copolymer, Trimethylolpropane), Schercemol® DIS Ester (INCI: Diisopropyl Sebacate), Tocopheryl Acetate (INCI: Tocopheryl Acetate), and Phenoxetol® (INCI: Phenoxyethanol)—are mixed, and the resulting mixture is heated to 70-75°C.

[0265] The emulsion is produced by slowly adding phase A to phase B under conditions of high-speed stirring by a turbine.

[0266] After the mixture has cooled to 40°C, the components of phase C—Novemer™ EC-2 polymer (INCI: water (aqua), sodium acrylate / beheneth-25 methacrylate crosspolymer, hydrogenated polydecene, lauryl glucoside), SA-SB-300 (7%) (INCI: silica, dimethicone), fragrance (INCI: fragrance (parfum)), and peptide PEP1 solution (INCI: water (aqua), caprylyl glycol, peptide PEP1)—are added to the mixture.

[0267] The pH is adjusted to 6.0-6.5 using the D phase component: 20% w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 8]

[0268] In this example, by substituting PEP1 with PEP2, a lotion containing peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) can be obtained.

[0269] Example 18 Preparation of a fluid emulsion containing a 2% peptide PEP1 (Ac-Asp-Val-Tyr-Lys-NH2) solution. Dissolve the components of Phase A1: water (INCI: aqua), Zemea (INCI: propanediol), glycerin (INCI: glycerin), Genencare (INCI) OSMS BA (INCI: betaine), Dissolvine (registered trademark) NA2 (INCI: disodium EDTA), and potassium sorbate (INCI: potassium sorbate) in a suitable container.

[0270] Phase A2: Add Carbopol® ultraz 10 polymer (INCI: carbomer) to the mixture. Once dispersed, add Phase A3: Cola® Fax CPE-K (INCI: potassium cetyl phosphate). Heat the resulting mixture at 70-75°C.

[0271] In a separate container, the components of Phase B—Massocare® HD (INCI: isohexadecane), Lincoln BAS (INCI: C12-15 alkyl benzoate), Gandak C (INCI: cetyl alcohol), Sorbital T 20 P (INCI: polysorbate 20), 2-phenoxyethanol (INCI: phenoxyethanol), and vegetable stearic acid 50 / 50 (INCI: stearic acid, palmitic acid)—are mixed and heated to 70-75°C. Phase B is slowly introduced into Phase A under conditions of vigorous stirring with a turbine.

[0272] The mixture is cooled to 40°C, and phase C is added: BRB CM 56-S (INCI: cyclomethicone), peptide PEP1 solution (INCI: water (aqua), caprylyl glycol, peptide PEP1), and fragrance (INCI: fragrance (parfum)). Phase D is added: sodium hydroxide 20% w / w (INCI: water (aqua), sodium hydroxide) to adjust the pH to 6.0-6.5. [Table 9]

[0273] In this example, by substituting PEP1 with PEP2, a fluid emulsion containing the peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH2) can be obtained.

[0274] Example 19 In vitro quantification of muscle bind-like protein 1 (MBNL1) in human skeletal muscle cells by time-resolved fluorescence resonance energy transfer. Different peptides of the present invention were tested at 0.5 mg / mL, as disclosed in Example 7. The results are shown in Table 10, demonstrating that all peptides increased MBNL1 levels compared to the baseline control. [Table 10]

[0275] Example 20 In vitro quantification of muscle bind-like protein 1 (MBNL1) in human skeletal muscle cells by time-resolved fluorescence resonance energy transfer. The assay is carried out as disclosed in Example 7, except that hSkMc from TEBU-BIO (Barcelona, ​​Spain) is used. Different peptides of the present invention are tested at a concentration of 0.5 mg / ml.

[0276] The results are shown in Table 11, demonstrating that all peptides increase MBNL1 levels compared to the baseline control. [Table 11]

[0277] Example 21 An in vivo study using a composition containing PEP1 to evaluate the long-term anti-wrinkle and smoothing efficacy of a PEP1-containing composition in female volunteers with Caucasian skin type. The study will be conducted over 28 days. It will include 42(42) Caucasian female volunteers aged 35–58 years who exhibit skin wrinkles in the area of ​​fine lines around the eyes. Participants will have either a cream containing PEP1 (active cream) or a placebo cream with the same composition but without PEP1 applied to one side of their face (left or right). Both creams will be applied twice daily (morning and evening) for 28 days. Participants will serve as the baseline, and the results obtained on day 28 will be compared to the results obtained at the initial stage and during treatment (active vs. placebo).

[0278] The anti-wrinkle effectiveness of the cream in the area of ​​crow's feet was evaluated by determining the maximum depth of the largest wrinkle, and images of the crow's feet area of ​​volunteers were measured using a 3D microtopography imaging system. Volunteers were instructed to maintain a smile, and the maximum depth of the largest wrinkle was taken at initial time and 28 days after application of the product. The results of wrinkle reduction after treatment are shown in Table 12. [Table 12]

[0279] The results show that 28 days after application of the cream, the maximum depth of the largest wrinkles is reduced compared to the initial state. This reduction is much greater with the active cream than with the placebo cream.

[0280] The effectiveness of the cream's smoothing effect is evaluated by determining the arithmetic roughness (Sa). Images of volunteer cheeks are taken using a 3D microtopography imaging system. Arithmetic roughness (Sa) is measured initially and 28 days after cream application. The results of roughness reduction after treatment are shown in Table 13. [Table 13]

[0281] The results show a reduction in arithmetic roughness (Sa) after treatment with the active cream, while this effect is negligible with the placebo cream. A reduction in roughness means that the skin is smoother.

[0282] Various aspects and embodiments of the present invention are defined by the following numbered clauses.

[0283] 1. Compound of formula (I), R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Z q -R2(I) The stereoisomer and / or cosmetically acceptable salt thereof, in the formula, AA1 is Asp, Glu, Asn, Gln, Ala, Gly, or no amino acid. AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, Trp, Lys, Arg, or His. AA4 is Lys, Arg, His, Pro, or Val. AA5 is Asn, Asp, Gln, or an amino acid-free amino acid. AA6 is Thr, Ala, Ser, or no amino acid. W, X, Y, and Z are each independently any amino acid. m, n, p, and q are each independently either 0 or 1. m+n+p+q is less than or equal to 2, R1 is selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R5-CO-, and R5 is selected from the group consisting of H, acyclic aliphatic groups, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl. R2 is selected from the group consisting of -NR3R4, -OR3, and -SR3, and R3 and R4 are independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are compounds that are not amino acids, their stereoisomers, and / or cosmetically acceptable salts.

[0284] 2. The compound described in Clause 1, where AA5 is amino acid-free, AA1 is Asp, Glu, Asn, or Gln, AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, or Trp, AA4 is Lys, Arg, or His, and AA6 is amino acid-free.

[0285] 3. The compound described in Clause 2, wherein AA1 is Asp, Glu, Asn, or Gln, AA2 is Val, Ile, Leu, or Ala, AA3 is Tyr, Phe, or Trp, AA4 is Lys, Arg, or His, AA5 is amino acid-free, and AA6 is amino acid-free.

[0286] 4. (I) The compound described in Clause 3, wherein AA1 is Asp, Glu, or Asn, or (II) AA1 is Asp or Glu.

[0287] 5. The compound according to Clause 3 or Clause 4, wherein AA2 is Val or Ile.

[0288] 6. A compound according to any one of clauses 3 to 5, wherein AA3 is Tyr or Phe.

[0289] 7. A compound according to any one of clauses 3 to 6, wherein AA4 is Lys or Arg.

[0290] 8. A compound according to any one of clauses 3 to 7, wherein AA1 is Asp, AA2 is Val, AA3 is Tyr, and AA4 is Lys.

[0291] 9. R1 is H and R5-CO-(wherein R5 is C1-C 18 Alkyl, C2-C 24 Alkenil, C3-C 24 Selected from the group consisting of cycloalkyls, where R2 is -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C 16 A compound as described in any one of clauses 1 to 8, which is selected from the group consisting of alkyl groups.

[0292] 10. The compound, Ac-W m -X n -Asp-Val-Tyr-Lys-Y p -Z q -NH2(IV), HW m -X n -Ala-Leu-Lys-Pro-Asn-Thr-Y p -Z q -NH2(V), Ac-Asp-Val-Tyr-Lys-NH2(PEP1), or The compound described in Clause 1, which is H-Ala-Leu-Lys-Pro-Asn-Thr-NH2(PEP2).

[0293] 11. A combination of any one of the compounds described in paragraphs 1 to 10 or their stereoisomers and / or cosmetically acceptable salts, and botulinum toxin and / or the peptide of the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2.

[0294] 12. A composition comprising a cosmetically effective amount of a compound of formula (I) described in any one of clauses 1 to 11, its stereoisomer and / or a cosmetically acceptable salt, or a combination described in clause 10, and at least one cosmetically acceptable excipient or auxiliary agent.

[0295] 13. Use of any one of the compounds described in paragraphs 1 to 10, their stereoisomers and / or cosmetically acceptable salts for cosmetic non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes.

[0296] 14. Use as described in Clause 13, where the cosmetic non-therapeutic treatment and / or care is the treatment and / or prevention of skin aging, the reduction and / or prevention of skin wrinkles, the stimulation of collagen synthesis and / or the prevention of collagen loss, the improvement or maintenance of skin firmness, the treatment and / or prevention of the appearance of sagging skin, the reduction and / or prevention of facial asymmetry, the increase in adipose tissue volume, and / or the prevention and / or reduction of adipose tissue volume.

[0297] 15. A method for cosmetic non-therapeutic treatment and / or care of the skin, hair, nails, and / or mucous membranes of a subject, comprising administering to the subject a cosmetically effective amount of any one of the compounds described in Clauses 1 to 10, the combination described in Clause 11, or the composition described in Clause 13.

[0298] 16. The method according to Clause 15, wherein non-therapeutic cosmetic procedures and / or care include treating and / or preventing skin aging, reducing and / or preventing skin wrinkles, stimulating collagen synthesis and / or preventing collagen loss, improving or maintaining skin firmness, treating and / or preventing the appearance of sagging skin, reducing and / or preventing facial asymmetry, and / or increasing the volume of adipose tissue and / or preventing and / or reducing adipose tissue.

[0299] 17. If AA5 is Asn, Asp, or Gln, AA1 is Ala, Gly, or no amino acid, AA2 is Val, Ile, or Leu, AA3 is Lys, Arg, or His, AA4 is Pro or Val, AA6 is Thr, Ala, Ser, or no amino acid, and AA1 is different from AA6, the compound as described in Clause 1.

[0300] 18. The compound described in Clause 17, wherein AA1 is Ala, Gly, or no amino acid, AA2 is Val, Ile, or Leu, AA3 is Lys, Arg, or His, AA4 is Pro or Val, AA5 is Asn, Asp, or Gln, AA6 is Thr, Ala, Ser, or no amino acid, and AA1 is different from AA6.

[0301] 19. The compound described in Clause 18, wherein AA1 is Ala or Gly.

[0302] 20. The compound described in Clause 18 or Clause 19, wherein AA2 is Leu or Ile.

[0303] 21. A compound according to any one of the clauses 18-20, wherein AA3 is Lys or Arg.

[0304] 22. A compound according to any one of the clauses 18 to 21, wherein AA5 is Asn or Asp.

[0305] 23. A compound according to any one of the clauses 18 to 22, wherein (i) AA6 is Thr, Ala, or Ser, or (ii) AA6 is Thr or Ala.

[0306] 24. A compound according to any one of the clauses 18 to 23, wherein AA1 is Ala, AA2 is Leu, AA3 is Lys, AA4 is Pro, AA5 is Asn, and AA6 is Thr.

[0307] 25. R1 is H and R5-CO-(wherein R5 is C1-C 18 Alkyl, C2-C 24 Alkenil, C3-C 24 Selected from the group consisting of cycloalkyls, where R2 is -NR3R4 or -OR3 (wherein R3 and R4 are independently H and C1-C 16 A compound as described in any one of clauses 17 to 23, which is selected from the group consisting of alkyl groups.

[0308] 26. A combination of any one of the compounds described in paragraphs 17 to 25 or their stereoisomers and / or cosmetically acceptable salts, and botulinum toxin and / or the peptide of the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2.

[0309] 27. A composition comprising a cosmetically effective amount of a compound of formula (I) as described in any one of clauses 17 to 25, its stereoisomer and / or a cosmetically acceptable salt, or a combination as described in clause 26, and at least one cosmetically acceptable excipient or auxiliary agent.

[0310] 28. Use of any one of the compounds described in any of clauses 17-25, their stereoisomers and / or cosmetically acceptable salts for cosmetic non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes.

[0311] 29. Use as described in Clause 28, where the cosmetic non-therapeutic treatment and / or care is the treatment and / or prevention of skin aging, the reduction and / or prevention of skin wrinkles, the stimulation of collagen synthesis and / or the prevention of collagen loss, the improvement or maintenance of skin firmness, the treatment and / or prevention of the appearance of sagging skin, the reduction and / or prevention of facial asymmetry, the increase in adipose tissue volume, and / or the prevention and / or reduction of adipose tissue volume.

[0312] 30. A method for cosmetic non-therapeutic treatment and / or care of the skin, hair, nails, and / or mucous membranes of a subject, comprising administering to the subject a cosmetically effective amount of any one of the compounds described in any one of Clauses 17 to 23, the combination described in Clause 26, or the composition described in Clause 27.

[0313] 31. Use as described in Clause 30, where non-therapeutic cosmetic procedures and / or care are the treatment and / or prevention of skin aging, reduction and / or prevention of skin wrinkles, stimulation of collagen synthesis and / or prevention of collagen loss, improvement or maintenance of skin firmness, treatment and / or prevention of the appearance of sagging skin, reduction and / or prevention of facial asymmetry, and / or the increase and / or prevention and / or reduction of adipose tissue volume.

Claims

1. A compound of formula (I), R １ -W ｍ -X ｎ -AA １ -AA ２ -AA ３ -AA ４ -AA ５ -AA ６ -Y ｐ -Z ｑ -R ２ (I) Stereoisomers and / or cosmetically acceptable salts thereof, wherein: A.A. １ is Asp, Glu, Asn, Gln, Ala, Gly, or no amino acid; A.A. ２ is Val, Ile, Leu, or Ala; A.A. ３ is Tyr, Phe, Trp, Lys, Arg, or His; A.A. ４ is Lys, Arg, His, Pro, or Val; A.A. ５ is Asn, Asp, Gln, or no amino acid; A.A. ６ is Thr, Ala, Ser, or no amino acid; W, X, Y, and Z are each independently any amino acid; m, n, p, and q each independently represent 0 or 1; m+n+p+q is equal to or less than 2; R １ is H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R ５ -CO-, and R ５ is selected from the group consisting of H, an acyclic aliphatic group, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl; R ２ But, -NR ３ R ４ , -OR ３ , -SR ３ and R ３ and R ４ is independently selected from the group consisting of H, a polymer derived from polyethylene glycol, an acyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl; R １ and R ２ but is not an amino acid, its stereoisomers and / or cosmetically acceptable salts.

2. A.A. ５ is an amino acid-free １ is Asp, Glu, Asn, or Gln, and AA ２ is Val, Ile, Leu, or Ala, and AA ３ is Tyr, Phe, or Trp, and AA ４ is Lys, Arg, or His, and AA ６ is amino acid-free, and / or A.A. ５ is Asn, Asp, or Gln, then AA １ is Ala, Gly, or no amino acid, and AA ２ is Val, Ile, or Leu, and AA ３ is Lys, Arg, or His, and AA ４ is Pro or Val, and AA ６ is Thr, Ala, Ser, or no amino acid, and AA １ is AA ６ The compound of claim 1 which is different from

3. A.A. １ is Asp, Glu, Asn, or Gln, and AA ２ is Val, Ile, Leu, or Ala, and AA ３ is Tyr, Phe, or Trp, and AA ４ is Lys, Arg, or His, and AA ５ is free of amino acids, and AA ６ The compound of claim 2, wherein is free of amino acids.

4. (i) AA １ is Asp, Glu, or Asn, or (ii) AA １ The compound of claim 3, wherein is Asp or Glu.

5. A.A. ２ 5. The compound of claim 3 or claim 4, wherein is Val or He.

6. A.A. ３ The compound according to any one of claims 3 to 5, wherein is Tyr or Phe.

7. A.A. ４ The compound according to any one of claims 3 to 6, wherein is Lys or Arg.

8. A.A. １ is Asp, and AA ２ is Val and AA ３ is Tyr, and AA ４ The compound according to any one of claims 3 to 7, wherein is Lys.

9. A.A. １ is Ala, Gly, or no amino acid, and AA ２ is Val, Ile, or Leu, and AA ３ is Lys, Arg, or His, and AA ４ is Pro or Val, and AA ５ is Asn, Asp, or Gln, and AA ６ is Thr, Ala, Ser, or no amino acid, and AA １ AA ６ The compound of claim 2, which is different from

10. A.A. １ The compound of claim 9, wherein is Ala or Gly.

11. A.A. ２ 11. The compound of claim 9 or claim 10, wherein is Leu or He.

12. A.A. ３ The compound according to any one of claims 9 to 11, wherein is Lys or Arg.

13. A.A. ５ The compound according to any one of claims 9 to 12, wherein is Asn or Asp.

14. (i) AA ６ is Thr, Ala, or Ser, or (ii) AA ６ The compound according to any one of claims 9 to 13, wherein is Thr or Ala.

15. A.A. １ is Ala, and AA ２ is Leu, and AA ３ is Lys, and AA ４ is Pro and AA ５ is Asn, and AA ６ The compound according to any one of claims 9 to 14, wherein is Thr.

16. The compound according to any one of claims 1 to 15, wherein m+n+p+q is 0 or 1.

17. The compound according to any one of claims 2 to 15, wherein m+n+p+q is 0 or 1.

18. The compound is R １ -Asp-Val-Tyr-Lys-R ２ 、 R １ -Glu-Val-Tyr-Lys-R ２ 、 R １ -A-E,%-T92-L93-R ２ 、 R １ -Asp-Ile-Phe-Lys-R ２ 、 R １ -Asp-Val-Tyr-Arr-R ２ 、 R １ -A-V!,-T92-L93-R ２ 、 R １ -Asp-Leu-Tyr-Lys-R ２ 、 R １ -Ala-Asp-Val-Tyr-Lys-R ２ 、 R １ -Asp-Val-Tyr-Lys-Ala-R ２ 、 R １ -Glu-Ile-Tyr-Lys-R ２ 、 R １ -Glu-Ile-Tyr-Arg-R ２ 、 R １ -Glu-Ile-Phe-Arg-R ２ 、 R １ -Alpha -Black -Argon -Purple -Agnus -Thunder -Rhine ２ 、 R １ -Ala-Leu-Lys-Val-Asn-Thr-R ２ 、 R １ -Leu-Lys-Pro-Asn-Thr-R ２ 、 R １ -Ala-Leu-Lys-Pro-Asn-R ２ 、 R １ -Gly-Ile-Lys-Pro-Asn-Thr-R ２ 、 R １ -Ala-Ile-Arg-Pro-Asn-Thr-R ２ 、 R １ -Gly-Val-Arg-Pro-Asn-Thr-R ２ ,or R １ -Ala-Leu-Lys-Pro-Gln-Thr-R ２ 2. The compound of claim 1, wherein:

19. R １ H and R ５ -CO- (wherein, R ５ But C １ -C １８ Alkyl, C ２ -C ２４ Alkenyl, C ３ -C ２４ cycloalkyl), and R ２ But, -NR ３ R ４ or -OR ３ (In the formula, R ３ and R ４ independently H and C １ -C １６ 19. The compound of any one of claims 1 to 18, wherein the aryl group is selected from the group consisting of alkyl.

20. The compound is 1.c ｍ ︹ ｎ ______________________________________ ｐ  ｑ H ２ (=()、 H-W ｍ -X ｎ -Ala-Leu-Lys-Pro-Asn-Thr-Y ｐ -Z ｑ -NH ２ (V)、 Ac-Asp-Val-Tyr-Lys-NH ２ (PEP1), or H-Ala-Leu-Lys-Pro-Asn-Thr-NH ２ 2. The compound of claim 1, wherein the compound is (PEP2).

21. The compound is Palm-Asp-Val-Tyr-Lys-NH ２ (PEP3)、 Ac-Asp-Val-Tyr-Lys-OH (PEP4), H-Asp-Val-Tyr-Lys-NH ２ (PEP5)、 Ac-Glu-Val-Tyr-Lys-NH ２ (PEP7)、 ____________________________________________________ ２ (#..#)、 Ac-Asp-Val-Phe-Lys-NH ２ (PEP9)、 _______________________________________ ２ (?.|)、 Ac-Asn-Val-Tyr-Lys-NH ２ (PEP11)、 Ac-Asp-Leu-Tyr-Lys-NH ２ (PEP12)、 Palm-Glu-Val-Tyr-Lys-NH ２ (PEP13)、 _______________________________________ ２ (!!.)、 Ac-Asp-Val-Tyr-Lys-Ala-NH ２ (PEP15)、 Ac-Glu-Ile-Tyr-Lys-NH ２ (PEP20), Ac-Glu-Ile-Tyr-Arg-NH ２ (PEP23), ________________________________________ ２ (!!.).、 Ac-Ala-Leu-Lys-Pro-Asn-Thr-OH (PEP27), H-Ala-Leu-Arg-Pro-Asn-Thr-NH ２ (PEP30)、 H-Ala-Leu-Lys-Val-Asn-Thr-NH ２ (PEP31)、 H-Leu-Lys-Pro-Asn-Thr-NH ２ (PEP40)、 H-Ala-Leu-Lys-Pro-Asn-NH ２ (PEP41)、 H-Gly-Ile-Lys-Pro-Asn-Thr-NH ２ (PEP42)、 H-Ala-Ile-Arg-Pro-Asn-Thr-NH ２ (PEP44)、 H-Gly-Val-Arg-Pro-Asn-Thr-NH ２ (PEP46), or H-Ala-Leu-Lys-Pro-Gln-Thr-NH ２ 2. The compound of claim 1, wherein the compound is (PEP50).

22. A compound according to any one of claims 1 to 21, or a stereoisomer and / or a cosmetically acceptable salt thereof, in combination with a botulinum toxin and / or a compound having the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH ２ in combination with peptides.

23. A composition comprising a cosmetically effective amount of a compound of formula (I) according to any one of claims 1 to 21, a stereoisomer and / or a cosmetically acceptable salt thereof, or a combination according to claim 22, and at least one cosmetically acceptable excipient or adjuvant.

24. Use of a compound, its stereoisomer and / or cosmetically acceptable salt according to any one of claims 1 to 21 for the cosmetic non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes.

25. 25. Use according to claim 24, wherein the cosmetic non-therapeutic treatment and / or care is the treatment and / or prevention of skin aging, reduction and / or prevention of skin wrinkles, stimulation of collagen synthesis and / or prevention of collagen loss, improvement or maintenance of skin firmness, treatment and / or prevention of the appearance of sagging skin, reduction and / or prevention of facial asymmetry, increase in adipose tissue volume, prevention and / or reduction of adipose tissue loss, and / or reduction of skin roughness and / or improvement of skin smoothness.

26. 24. A method for the cosmetic non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes of a subject, comprising administering to said subject a cosmetically effective amount of a compound according to any one of claims 1 to 21, a combination according to claim 22, or a composition according to claim 23.

27. 27. The method according to claim 26, wherein the non-therapeutic cosmetic treatment and / or care is the treatment and / or prevention of skin aging, reduction and / or prevention of skin wrinkles, stimulation of collagen synthesis and / or prevention of collagen loss, improvement or maintenance of skin firmness, treatment and / or prevention of the appearance of sagging skin, reduction and / or prevention of facial asymmetry, and / or increase in adipose tissue volume, prevention and / or reduction of adipose tissue loss, and / or reduction of skin roughness and / or improvement of skin smoothness.

Images