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

Abstract

To provide compounds useful for the treatment and / or care of the skin, hair, nails and / or mucous membranes.SOLUTION: The invention relates to compounds of formula (I) defined by R1-Wm-Xn-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2, and stereoisomers and / or cosmetically acceptable salts thereof. In the formula: AA1 is Arg, Lys, or no amino acid; AA2 is Arg or Lys; AA3 is Gln, Glu, Asn, or Asp; AA4 is Met or Leu; AA5 is Glu, Asp, or Gin; AA6 is Glu, Asp, Gin, or no amino acid; and AA1 is different from AA6. The compounds are useful for the treatment and / or prevention of the symptoms of skin aging and, in particular, for the treatment and / or prevention of skin wrinkles, the treatment and / or prevention of a sagging appearance of the skin, and / or the reduction and / or prevention of facial asymmetry.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present 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 the prevention of skin aging, especially for the treatment and / or prevention of skin wrinkles, the treatment and / or prevention of the appearance of sagging skin, and / or the reduction and / or prevention of facial asymmetry. The present invention extends to compositions comprising 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 wrinkles and the appearance of facial sagging, which is associated with muscle aging. As we age, the epidermis and connective tissue of the skin weaken, facial muscle mass decreases, the epidermis loosens and begins to sag, the natural folds in the cheeks, neck, and chin areas change, and facial fat (adipose tissue) redistributes and decreases.

[0003] Muscle aging is a well-known process that begins around age 40 and accelerates in later years. The resulting decrease in muscle tone and thinning of the skin can give the face a loose, sagging appearance. The jawline becomes less defined, and the contours of the face become less pronounced.

[0004] The formation of facial wrinkles is directly related to the muscle tone of the epidermis, which pulls the skin inward. This muscle tone is a result of increased activity of the nerves that innervate the facial muscles. This increased nerve activity is characterized by the uncontrolled and excessive release of neurotransmitters that excite muscle fibers. Neuronal exocytosis is a highly regulated process that primarily involves the formation of a protein complex known as the SNARE complex. The nucleus of this fusion complex consists of SNAP-25 and syntaxin, proteins located on the presynaptic plasma membrane, and synaptobrevin (or VAMP), a protein located on the vesicle plasma membrane. The main function of the fusion complex is to bring vesicles carrying neurotransmitters (acetylcholine) closer to the presynaptic plasma membrane and into contact with it. In this way, in response to an increase in calcium concentration, the fusion of both plasma membranes is promoted, and thus the release of neurotransmitters occurs.

[0005] Since neurotransmitter release is associated with neuronal exocytosis, controlling neuronal exocytosis can contribute to muscle relaxation and wrinkle reduction. Cleaving any of the proteins that make up the SNARE complex disrupts its association, making this a key target method for controlling neuronal exocytosis. Botulinum toxin is a family of bacterial neurotoxins produced by Clostridium botulinum. Botulinum toxin is a protease that degrades neuroproteins involved in the exocytosis mechanism, which is activated by calcium ions. For example, botulinum toxin A, the most commonly used clinically and cosmetically, cleaves the neuroprotein SNAP-25. Therefore, botulinum toxin, particularly serotype A (BOTOX®, Allergan Inc, Dysport®, Ipsen Bipharm, Ltd, and Azzalure®, Galderma, SA), is widely used as an effective agent for reducing facial wrinkles and asymmetry. Indeed, the administration of botulinum toxin is the first effective non-surgical treatment used to eliminate signs of aging. However, in the field of cosmetic surgery, there is a growing conviction that long-term use of botulinum toxin may have cosmetically undesirable effects on facial muscles, which may lead to an increased appearance of sagging skin and, consequently, an increased appearance of facial aging (Durand, PD. "Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect", (2016), Aesthetic Surgery Journal, Vol 36(4), pp.482-487).

[0006] It is known in the art that certain peptides can mimic the effects of botulinum toxin by inhibiting neuronal exocytosis, such as the peptide derived from the amino terminus of the SNAP-25 protein disclosed in WO 2000 / 64932A1. One such peptide is acetyl hexapeptide-3, which is commercialized by Lipotec, SA under the trade name Argireline®. The use of the Argireline® peptide (Ac-Glu-Glu-Met-Gln-Arg-Arg) in skin whitening is disclosed in KR20120099550A. However, in the abstract of KR20120099550A, the peptide is incorrectly assigned the sequence Arg-Arg-Gln-Met-Glu-Glu-acetyl. This is a common practice for describing peptide sequences, and indeed, in the paragraph of KR20120099550A.

[0007] This sequence is consistent with the previous one and should be read as acetyl-Glu-Glu-Met-Gln-Arg-Arg. There is a need to find novel active compounds that can mitigate or prevent the 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. There is a need to find novel active compounds that can mimic the neuronal exocytosis inhibitory behavior of botulinum toxin. In fact, there is a need to provide novel active compounds that better mimic the neuronal exocytosis inhibitory behavior of botulinum toxin than known substitutes for botulinum toxin, such as Argireline® peptide. This invention aims to satisfy some or all of these needs and solve some or all of the problems identified above. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2000 / 064932 [Patent Document 2] Korean Published Patent Publication No. 20120099550 [Non-patent literature]

[0008] [Non-Patent Document 1] Durand, PD. “Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect”, (2016), Aesthetic Surgery Journal, Vol 36(4), pp.482-487) [Overview of the Initiative] [Means for solving the problem]

[0009] In a first embodiment, the present invention relates to formula (I) R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Z q -R2(I), We provide compounds represented by the formula, their stereoisomers and / or cosmetically acceptable salts thereof, wherein, AA1 is Arg, Lys, or amino acid-free. AA2 is Arg or Lys, AA3 is Gln, Glu, Asn, or Asp. AA4 is either Met or Leu, AA5 is Glu, Asp, or Gln. AA6 is Glu, Asp, Gln, 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-, where 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, where R3 and R4 are independently selected from the group consisting of H, polyethylene glycol-derived polymers, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids.

[0010] Compounds of formula (I) have been found to be effective in inhibiting norepinephrine release and increasing collagen synthesis in the skin. Furthermore, compounds of the present invention have been found to be effective in increasing the amount of lipids in adipocytes and therefore effective in increasing facial volume. Thus, the compounds are useful as anti-aging agents for the skin and can mimic the inhibition of neuronal exocytosis behavior of botulinum toxin, which is used to treat symptoms of skin aging. Moreover, unexpectedly, certain compounds of the present invention have been found to upregulate the expression of muscleblind-like 1 (MBNL-1), a highly conserved RNA-binding protein that plays a crucial role in the process of differentiation from fibroblasts to myofibroblasts. Naturally, these peptides are particularly useful for preventing or mitigating the cosmetic properties of the skin associated with decreased muscle tone due to muscle aging, and are indeed useful for mitigating the cosmetically undesirable side effects of anti-aging treatments, including botulinum toxin injections. Compounds of the present invention have been demonstrated to exhibit improved performance compared to known peptides that are alternatives to botulinum toxin Argireline®.

[0011] 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.

[0012] 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 and non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes. Cosmetic and non-therapeutic treatments 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. Cosmetic and non-therapeutic procedures and / or care may prevent and / or mitigate the effects of increased and / or decreased adipose tissue volume.

[0013] 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 stereoisomer and / or a cosmetically or pharmaceutically acceptable salt thereof, or a composition containing thereof. In particular, the present invention provides a method for cosmetic and non-therapeutic treatment and / or care of 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 stereoisomer and / or a cosmetically acceptable salt thereof, or a cosmetic composition containing thereof. Typically, the compound is administered topically. Cosmetic and non-therapeutic treatment and / or care may include the prevention or treatment of symptoms of skin aging, the treatment and / or prevention of 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. Cosmetic and non-therapeutic procedures and / or care may prevent and / or mitigate the effects of increased and / or decreased adipose tissue volume.

[0014] In another embodiment, the present invention relates to a kit for use in cosmetic non-therapeutic treatments and / or care of the skin, (i) Compositions containing botulinum toxin, (ii) optionally a composition comprising Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or a combination thereof, and (iii) A kit is provided that includes a cosmetic composition containing the compound of formula (I). [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows the average percentage of norepinephrine (NA) release relative to the basic conditions of SH-SY5Y for three assays (Example 6). [Figure 2]Figure 2 shows the average percentage of type I collagen relative to the basic conditions for five assays (Example 7). [Figure 3] Figure 3 shows the average percentage of MBNL1 relative to the basic conditions of hSkMc for the three assays (Example 8). [Figure 3a] Figure 3a shows the average percentage of MBNL1 relative to the baseline condition of hSkMc for three assays (Example 8). Abbreviations: BC = Basal control (no treatment) [Figure 4] Figure 4 shows the percentage of muscle mass loss in human skeletal muscle cells, measured using an immunofluorescence assay. Measurements were 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 with human skeletal muscle cells that were neither treated with TNFα nor the compound of the present invention (Example 17). Abbreviations: BC + TNF = 20 mg / ml TNFα basal control, BC = basal control. [Figure 5] Figure 5 shows the level of lipid accumulation in human subcutaneous adipocytes as determined by fluorescence staining (Example 19). 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 = aged control. [Modes for carrying out the invention]

[0016] definition In the context of this invention, “skin” is understood to mean the multiple layers that make up the skin, 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, such as humans.

[0017] As used herein, the term “treatment,” unless otherwise specified in the “cosmetic or non-therapeutic” proviso, 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 said disease or disorder. The term “treatment,” unless otherwise specified in the “cosmetic or non-therapeutic” proviso, also includes a treatment method toward the reduction or elimination of the physiological consequences of a disease or disorder.

[0018] When the terms “treatment” and “care” are accompanied by the proviso “cosmetic and non-therapeutic,” such treatment or care is intended to improve or maintain the aesthetic appearance of the skin, hair, nails, and / or mucous membranes. In particular, such treatment is intended to improve the aesthetic properties of the skin, hair, nails, and / or mucous membranes, such as, but not limited to, levels 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 are easily 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.

[0019] As used in the present 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 the present 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.

[0020] 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 and roughness, increased pore size, decreased moisture, decreased elasticity, decreased firmness, decreased smoothness, decreased ability to recover from deformation, decreased resilience, sagging skin such as drooping cheeks, in particular the appearance of dark circles under the eyes or a double chin, 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 of the stratum corneum, dermis, epidermis, vascular system (e.g., the appearance of spider veins or telangiectasia), or in particular other histological changes of 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.

[0021] 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]

[0022] 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.

[0023] As used herein, the term “alkyl” includes both saturated linear and branched alkyl groups, which 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.

[0024] 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.

[0025] The term "alkynyl" refers to a group containing one or more carbon-carbon triple bonds, which may be linear or branched, and may be substituted (mono or poly) or unsubstituted. Preferably, the alkynyl group has one, two, or three carbon-carbon triple bonds. The triple bonds may be conjugated or unconjugated. 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, groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, e.g., 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.

[0026] The term “alicyclyl” is used herein to encompass aliphatic cyclic (alicyclic) groups such as, for example, cycloalkyl, cycloalkenyl, or cycloalkynyl groups, for example, but not limited to these. The term “alicyclyl” refers to a monoradical comprising one or more carbon atom rings, which may be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl), provided that the rings are not aromatic. More specifically, an alicylic group comprises three or more, 3 to 24, 3 to 12, or 6 to 12 ring carbon atoms. Alicyclic groups are 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. Alicyclic groups may be substituted (mono or poly) or unsubstituted. In one embodiment, an alicyclyl group is a 6-12 membered ring system consisting of carbon atoms and optionally containing one or two double bonds.

[0027] 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.

[0028] 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 be conjugated or unconjugated. Examples of cycloalkenyl groups include, but are not limited to, cyclopent-1-en-1-yl groups and similar groups.

[0029] 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 1, 2, or 3 conjugated or unconjugated carbon-carbon triple bonds. Cycloalkynyl groups include, but are not limited to, cycloocto-2-in-1-yl and similar groups. Cycloalkynyl groups also contain one or more carbon-carbon double bonds, including, but are not limited to, cycloocto-4-en-2-inyl and similar groups.

[0030] 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, for example, 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- to 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- to 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- to 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. For the term heterocyclyl, the highest priority is to refer to a 5- or 6-membered ring. Examples of saturated heterocyclyl groups are dioxane, piperidine, piperazine, pyrrolidine, morpholine, and thiomorpholine. Examples of aromatic heterocyclyl groups are pyridine, pyrrole, furan, thiophene, benzofuran, imidazoline, quinolein, quinoline, pyridazine, and naphthyridine.

[0031] 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 contain 1, 2, 3 or 4 aromatic rings which may be linked by carbon-carbon bonds or may be fused together, and examples include, but are not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl, or anthryl. The aryl group may be substituted (mono- or poly-) or unsubstituted.

[0032] The term "aralkyl group" refers to an alkyl group substituted by an aromatic group having 7 to 24 carbon atoms, and examples include, but are not limited to, -(CH2) 1-6 -phenyl, -(CH2) 1-6 -(1-naphthyl), -(CH2) 1-6 -(2-naphthyl), -(CH2) 1-6 -CH(phenyl)2, and similar groups.

[0033] 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 having 1 to 6 carbon atoms and the heteroaryl group having 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, but are not limited thereto.

[0034] 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, amino--C1-C4 alkyl, C1-C4 carbonyloxyl, C1-C4 oxycarbonyl; halogens such as fluorides, 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 It includes, and 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 The group is selected from those formed by aralkyl groups, 3- to 10-membered heterocyclines, or protecting groups of amino groups.

[0035] As used herein, the term “including” is inclusive or non-exclusive and does not exclude additional non-enumerated elements or method steps, and is intended to include the phrases “essentially consisting of” and “consisting of,” where “consisting of” excludes any elements or steps not explicitly stated, and “essentially consisting 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.

[0036] 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 Arg, Lys, or amino acid-free. AA2 is Arg or Lys, AA3 is Gln, Glu, Asn, or Asp. AA4 is either Met or Leu, AA5 is Glu, Asp, or Gln. AA6 is Glu, Asp, Gln, 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-, where 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, where R3 and R4 are independently selected from the group consisting of H, polyethylene glycol-derived polymers, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids.

[0037] In particular, the compound of formula (I) was found to have a higher ability to inhibit norepinephrine release than Agireline®, and an equivalent or greater ability to stimulate collagen synthesis in the skin.

[0038] The compound of formula (I) is a peptide containing 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.

[0039] R1 is selected from the group consisting of H, polymers derived from polyethylene glycol having a molecular weight of 200 to 35,000 Daltons, and R5-CO-, where 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 24 The group is selected from aralkyl, 3-10 membered heterocyclyl rings, and heteroarylalkyls containing 2-24 carbon atoms and 1-3 heteroatoms, where the alkyl group has 1-6 carbon atoms.

[0040] R1 is selected from the group consisting of H and R5-CO-, where 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 group is selected from alkenyls and C3-C7 cycloalkyls. The R5-CO- group can be acetyl (CH3-CO-, abbreviated as "Ac-" herein), myristoyl (CH3-(CH2) 12 -CO- (abbreviated as "Myr-" in this specification) and palmitoyl (CH3-(CH2) 14 It contains alkanoyl groups such as -CO- (abbreviated as "Palm-" in this specification).

[0041] R1 may be selected from the group consisting of H and acetyl, tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, and linoleyl.

[0042] R1 is selected from the group consisting of H and R5-CO-, where R5 is C1-C 16 Alkyl or C2-C 18 Selected from the group consisting of alkenyls.

[0043] R1 can be selected from the group consisting of H and R5-CO-, where R5 is C1-C 15 It is alkyl.

[0044] R1 can be selected from the group consisting of H, acetyl, and palmitoyl.

[0045] R2 is selected from the group consisting of -NR3R4, OR3, and -SR3, where R3 and R4 are independently H, a polymer derived from polyethylene glycol, and 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 is selected from aralkyls, 3-10 membered heterocyclyl rings, and heteroarylalkyls 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 containing a nitrogen atom.

[0046] R2 may be -NR3R4 or -OR3. R3 and R4 can be independently selected from the group consisting of H, polymers derived from polyethylene glycol having a molecular weight of 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, and R4 is H, as well as C1-C including methyl, ethyl, hexyl, dodecyl and hexadecyl. 16 The group is selected from those formed by alkyl groups.

[0047] R2 can be selected from the group consisting of -OH, -NH2, and -NHR4, where R4 is C1-C 16 It is alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0048] R2 can be -OH or -NH2.

[0049] R1 is selected from the group consisting of H and R5-CO-, where R5 is C1-C 18 Alkyl, C2-C 24 Alkenil, C3-C 24 Selected from the group consisting of cycloalkyls, R2 is -NR3R4 or -OR3, where R3 and R4 are independently H and C1-C 16 Selected from the group consisting of alkyl groups. In this embodiment, R3 is H, and R4 is H, C1-C 16 The group can be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 can be selected from the group consisting of -OH and -NH2.

[0050] R1 is 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 is -NR3R4 or -OR3, where R3 and R4 are independently H and C1-C 16 Selected from the group consisting of alkyl groups. In this embodiment, R3 is H, and R4 is H, C1-C 16 The group can be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 can be selected from the group consisting of -OH and -NH2.

[0051] R1 can be selected from the group consisting of H and R5-CO-, where R5 is C1-C 16 Alkyl or C2-C 18 Selected from the group consisting of alkenyls, R2 is -NR3R4 or -OR3, where R3 and R4 are independently H and C1-C 16 Selected from the group consisting of alkyl groups. In this embodiment, R3 is H, and R4 is H, C1-C 16 The group can be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 can be selected from the group consisting of -OH and -NH2.

[0052] R1 can be selected from the group consisting of H, acetyl, myristoyl, or palmitoyl, and R2 is -NR3R4 or -OR3, where R3 and R4 are independently H and C1-C 16 Selected from the group consisting of alkyl groups. In this embodiment, R3 is H, and R4 is H, C1-C 16 The group can be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 can be selected from the group consisting of -OH and -NH2.

[0053] R1 can be selected from the group consisting of H and R5-CO-, where R5 is C1-C 15 It is an alkyl group, where R2 is -NR3R4 or -OR3, and in the formula, R3 and R4 are independently H and C1-C 16 Selected from the group consisting of alkyl groups. In this embodiment, R3 is H, and R4 is H, C1-C 16 The group can be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 can be selected from the group consisting of -OH and -NH2.

[0054] R1 can be selected from the group consisting of H, acetyl, or palmitoyl, and R2 is -NR3R4 or -OR3, where R3 and R4 are independently H and C1-C 16 Selected from the group consisting of alkyl groups. In this embodiment, R3 is H, and R4 is H, C1-C 16 The group can be selected from alkyl, C1-C3 alkyl, and C1-C2 alkyl groups. For example, R2 can be selected from the group consisting of -OH and -NH2.

[0055] R1 can be selected from the group consisting of substituted acyclic aliphatic groups, substituted alicyclyls, substituted heterocyclyls, substituted heteroarylalkyls, substituted aryls, substituted aralkyls, and R5-CO-, 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.

[0056] 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.)

[0057] 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.

[0058] In the compound of formula (I), AA1 is selected from the group consisting of Arg, Lys, and no amino acids; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gln, Glu, Asn, and Asp; AA4 is selected from the group consisting of Met and Leu; AA5 is selected from the group consisting of Glu, Asp, and Gln; and AA6 is selected from the group consisting of Glu, Gln, Asp, and no amino acids. It is a requirement that AA1 is different from AA6. Therefore, if AA1 is no amino acid, i.e., if amino acid AA1 is absent, then amino acid AA6 must be present, i.e., AA6 is selected from the group consisting of Glu, Asp, and Gln. Furthermore, if amino acid AA6 is no amino acid, i.e., if amino acid AA6 is absent, then amino acid AA1 must be present, i.e., AA1 is selected from the group consisting of Arg and Lys. In one embodiment of the compound of formula (I), AA1 is Arg and / or AA2 is Arg.

[0059] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of Arg, Lys, and amino acids; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gln and Asp; AA4 is selected from the group consisting of Met and Leu; AA5 is selected from the group consisting of Glu and Asp; and AA6 is selected from the group consisting of Glu, Gln, and amino acids. In one embodiment of the compound of formula (I), AA1 is Arg and / or AA2 is Arg.

[0060] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu and Asp, and AA6 is selected from the group consisting of Glu and Gln. In one embodiment of the compound of formula (I), AA1 is Arg and / or AA2 is Arg.

[0061] The present invention provides compounds of formula (I), wherein AA1 is selected from Arg, Lys, and amino acids; AA2 is selected from the group consisting of Arg and Lys; AA3 is Gln; AA4 is Met; AA5 is Glu and Asp; and AA6 is selected from the group consisting of Glu, Gln, and amino acids. In one embodiment of the compound of formula (I), AA1 is Arg and / or AA2 is Arg.

[0062] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln, Glu, Asn and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu, Asp and Gln, and AA6 is selected from the group consisting of Glu, Gln and Asp. In this embodiment, preferably AA1 is Arg and / or AA2 is Arg.

[0063] The present invention provides a compound of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu, Asp and Gln, and AA6 is selected from the group consisting of Glu, Gln and Asp. In this embodiment, preferably AA1 is Arg and / or AA2 is Arg.

[0064] The present invention provides a compound of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln and Glu, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu, Asp and Gln, and AA6 is selected from the group consisting of Glu, Gln and Asp. In this embodiment, preferably AA1 is Arg and / or AA2 is Arg.

[0065] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln, Glu, Asn and Asp or the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu and Gln, and AA6 is selected from the group consisting of Glu and Gln.

[0066] The present invention provides a compound of formula (I), wherein AA1 is Arg, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is Glu, and AA6 is Glu.

[0067] The present invention provides a compound of formula (I), wherein AA1 is selected from Arg, Lys, and amino acids; AA2 is Arg; AA3 is Gln; AA4 is Met; AA5 is selected from the group consisting of Glu and Asp; and AA6 is selected from the group consisting of Glu, Gln, and amino acids.

[0068] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln, Glu, Asn and Asp or the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu, Asp and Gln, and AA6 is amino acid-free. In this embodiment, preferably AA1 is Arg and / or AA2 is Arg.

[0069] The present invention provides compounds of formula (I), wherein AA1 is amino acid-free, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln, Glu, Asn and Asp or the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu, Asp and Gln, and AA6 is selected from the group consisting of Glu, Gln and Asp.

[0070] The present invention provides a compound of formula (I), where AA1 is Arg, AA2 is Arg, AA3 is Gln, AA4 is Met, AA5 is Glu, and AA6 is Glu, and 0, 1, 2, 3, or 4 of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted under the following conditions: If AA1 is substituted, it is either substituted with Lys or not substituted with an amino acid; if AA2 is substituted, it is substituted with Lys; if AA3 is substituted, it is substituted with Glu, Asn, or Asp; if AA4 is substituted, it is substituted with Leu; if AA5 is substituted, it is substituted with Asp or Gln; and if AA6 is substituted, it is substituted with Asp, Gln, or not substituted with an amino acid. In one embodiment, 0, 1, 2, or 3 of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted. In one embodiment, zero (none) of AA1, AA2, AA3, AA4, AA5, and AA6 are replaced. In one embodiment, one of AA1, AA2, AA3, AA4, AA5, and AA6 is replaced. In one embodiment, two of AA1, AA2, AA3, AA4, AA5, and AA6 are replaced. In one embodiment, three of AA1, AA2, AA3, AA4, AA5, and AA6 are replaced.

[0071] The present invention provides compounds of formula (I), where AA1 is Arg, AA2 is Arg, AA3 is Gln, AA4 is Met, AA5 is Glu, and AA6 is Glu, and 0, 1, 2, 3, or 4 of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted under the following conditions: If AA1 is substituted, it is substituted with Lys; if AA2 is substituted, it is substituted with Lys; if AA3 is substituted, it is substituted with Glu; if AA4 is substituted, it is substituted with Leu; if AA5 is substituted, it is substituted with Asp; and if AA6 is substituted, it is substituted with Gln. In one embodiment, 0, 1, 2, or 3 of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted. In one embodiment, 0 (none) of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted. In one embodiment, one of AA1, AA2, AA3, AA4, AA5, and AA6 is replaced. In one embodiment, two of AA1, AA2, AA3, AA4, AA5, and AA6 are replaced. In one embodiment, three of AA1, AA2, AA3, AA4, AA5, and AA6 are replaced.

[0072] In each of the embodiments described herein, the present invention provides a compound of formula (I), wherein AA1 is amino acid-free, and W, X, Y, and Z are each independently selected from the group consisting of Ala, Gly, Val, and Ile.

[0073] The present invention provides a compound of formula (I) in each of the embodiments described herein, wherein m, n, p, and q are each 0 when AA1 is amino acid-free.

[0074] The compounds of the present invention can exclude Arg-Arg-Glu-Leu-Glu-Glu-Leu, that is, the present invention provides a compound of formula (I) above, which is not Arg-Arg-Glu-Leu-Glu-Glu-Leu. The compounds of the present invention can exclude Lys-Lys-Glu-Leu-Glu-Glu-Leu, that is, the present invention provides a compound of formula (I) above, which is not Lys-Lys-Glu-Leu-Glu-Glu-Leu.

[0075] The present invention provides a compound of formula (I) above, wherein each of AA1, AA2, AA3, AA4, AA5, and AA6 in formula (I) is an L-amino acid. The compounds of this embodiment have been found to be particularly effective in inhibiting norepinephrine release and stimulating collagen synthesis in the skin. This embodiment comprises the compound described in formula (I), wherein AA1 is L-Arg, AA2 is L-Arg, AA3 is L-Gln, AA4 is L-Met, AA5 is L-Glu, and AA6 is L-Glu.

[0076] The present invention provides a compound of formula (I), wherein at least one of AA1, AA2, AA3, AA4, AA5, and AA6 in formula (I) is a D-amino acid. The compound of this embodiment of the compound of formula (I) is particularly effective in upregulating the expression of muscle-blind-like 1 (MBNL-1), and is therefore useful in preventing or mitigating the cosmetic properties of the skin associated with decreased muscle tone due to muscle aging, and is indeed useful in mitigating the cosmetically undesirable side effects of anti-aging treatments, including botulinum toxin injections. This embodiment comprises a compound of formula (I), wherein one, two, or three of AA1, AA2, AA3, AA4, AA5, and AA6 in formula (I) are D-amino acids, and the remainder of AA1, AA2, AA3, AA4, AA5, and AA6 are L-amino acids. For example, a compound of formula (I) in which one, two, or three of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., AA1 to AA6, are L-amino acids. This embodiment includes the case in which one or two of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., AA1 to AA6, are L-amino acids. These embodiments of the present invention apply to all embodiments of the compound of formula (I) described herein in which none of the amino acids AA1, AA2, AA3, AA4, AA5, and AA6 are assigned as D-amino acids or L-amino acids.

[0077] Accordingly, the present invention provides a compound of formula (I), wherein AA1 is selected from the group consisting of Arg, Lys, and no amino acids; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gln and Asp; AA4 is selected from the group consisting of Met and Leu; AA5 is selected from the group consisting of Glu and Asp; and AA6 is selected from the group consisting of Glu, Gln, and no amino acids, wherein one, two, or three of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., the remainder of AA1 to AA6, are L-amino acids. This embodiment includes the case where one or two of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., the remainder of AA1 to AA6, are L-amino acids.

[0078] Accordingly, the present invention provides a compound of formula (I), wherein AA1 is selected from the group consisting of Arg and Lys, AA2 is selected from the group consisting of Arg and Lys, AA3 is selected from the group consisting of Gln and Asp, AA4 is selected from the group consisting of Met and Leu, AA5 is selected from the group consisting of Glu and Asp, and AA6 is selected from the group consisting of Glu and Gln, wherein one, two, or three of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., the remainder of AA1 to AA6, are L-amino acids. This embodiment includes the case where one or two of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., the remainder of AA1 to AA6, are L-amino acids.

[0079] Accordingly, the present invention provides a compound of formula (I), where AA1 is Arg, AA2 is Arg, AA3 is Gln, AA4 is Met, AA5 is Glu, and AA6 is Glu, and 0, 1, 2, 3, or 4 of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted under the following conditions: If AA1 is substituted, it is substituted with Lys or no amino acid; if AA2 is substituted, it is substituted with Lys; if AA3 is substituted, it is substituted with Glu, Asn, or Asp; if AA4 is substituted, it is substituted with Leu; if AA5 is substituted, it is substituted with Asp or Gln; if AA6 is substituted, it is substituted with Asp, Gln, or no amino acid; and 1, 2, or 3 of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., AA1 to AA6, are L-amino acids. This embodiment includes the case where one or two of AA3, AA4, and AA5 are D-amino acids, and the remaining amino acids, i.e., AA1 to AA6, are L-amino acids. 0, 1, 2, or 3 of AA1, AA2, AA3, AA4, AA5, and AA6 can be substituted. 0 (none) of AA1, AA2, AA3, AA4, AA5, and AA6 can be substituted. 1 of AA1, AA2, AA3, AA4, AA5, and AA6 can be substituted. 2 of AA1, AA2, AA3, AA4, AA5, and AA6 can be substituted. 3 of AA1, AA2, AA3, AA4, AA5, and AA6 can be substituted.

[0080] Accordingly, the present invention provides a compound of formula (I), where AA1 is Arg, AA2 is Arg, AA3 is Gln, AA4 is Met, AA5 is Glu, and AA6 is Glu, and 0, 1, 2, 3, or 4 of AA1, AA2, AA3, AA4, AA5, and AA6 are substituted under the following conditions: If AA1 is substituted, it is substituted with Lys; if AA2 is substituted, it is substituted with Lys; if AA3 is substituted, it is substituted with Glu; if AA4 is substituted, it is substituted with Leu; if AA5 is substituted, it is substituted with Asp; if AA6 is substituted, it is substituted with Gln; and 1, 2, or 3 of AA3, AA4, and AA5 are D-amino acids, and the remaining other amino acids, i.e., the remainder of AA1 to AA6, are L-amino acids. This embodiment includes the case where 1 or 2 of AA3, AA4, and AA5 are D-amino acids, and the remaining other amino acids, i.e., the remainder of AA1 to AA6, are L-amino acids. AA1, AA2, AA3, AA4, AA5, and AA6 can be replaced by 0, 1, 2, or 3. AA1, AA2, AA3, AA4, AA5, and AA6 can be replaced by 0 (none). AA1, AA2, AA3, AA4, AA5, and AA6 can be replaced by 1. AA1, AA2, AA3, AA4, AA5, and AA6 can be replaced by 2. AA1, AA2, AA3, AA4, AA5, and AA6 can be replaced by 3.

[0081] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of L-Arg, L-Lys, and amino acids; AA2 is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of D-Gln, D-Glu, D-Asn, and D-Asp or the group consisting of D-Gln and D-Asp; AA4 is selected from the group consisting of L-Met and L-Leu; AA5 is selected from the group consisting of L-Glu, L-Asp, and L-Gln; and AA6 is selected from the group consisting of L-Glu, L-Gln, L-Asp, and amino acids. In this embodiment, preferably, AA1 is L-Arg and AA2 is L-Arg. This embodiment includes the compound described in formula (I), where AA1 is L-Arg, AA2 is L-Arg, AA3 is L-Gln, AA4 is L-Met, AA5 is L-Glu, and AA6 is L-Glu.

[0082] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of L-Arg, L-Lys, and amino acids; AA2 is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of L-Gln, L-Glu, L-Asn, and L-Asp or the group consisting of L-Gln and L-Asp; AA4 is selected from the group consisting of D-Met and D-Leu; AA5 is selected from the group consisting of L-Glu, L-Asp, and L-Gln; and AA6 is selected from the group consisting of L-Glu, L-Gln, L-Asp, and amino acids. The compounds of this embodiment have been found to be particularly effective in inhibiting norepinephrine release and stimulating collagen synthesis in the skin. In this embodiment, preferably, AA1 is L-Arg and AA2 is L-Arg. This embodiment includes the compound described in formula (I), where AA1 is L-Arg, AA2 is L-Arg, AA3 is L-Gln, AA4 is D-Met, AA5 is L-Glu, and AA6 is L-Glu.

[0083] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of L-Arg, L-Lys, and amino acids; AA2 is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of L-Gln, L-Glu, L-Asn, and L-Asp or the group consisting of L-Gln and L-Asp; AA4 is selected from the group consisting of L-Met and L-Leu; AA5 is selected from the group consisting of D-Glu, D-Asp, and D-Gln; and AA6 is selected from the group consisting of L-Glu, L-Gln, L-Asp, and amino acids. In this embodiment, preferably, AA1 is L-Arg and AA2 is L-Arg. This embodiment includes the compound described in formula (I), where AA1 is L-Arg, AA2 is L-Arg, AA3 is L-Gln, AA4 is L-Met, AA5 is L-Glu, and AA6 is L-Glu.

[0084] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of L-Arg, L-Lys, and amino acids; AA2 is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of L-Gln, L-Glu, L-Asn, and L-Asp or the group consisting of L-Gln and L-Asp; AA4 is selected from the group consisting of D-Met and D-Leu; AA5 is selected from the group consisting of D-Glu, D-Asp, and D-Gln; and AA6 is selected from the group consisting of L-Glu, L-Gln, L-Asp, and amino acids. In this embodiment, preferably, AA1 is L-Arg and AA2 is L-Arg. This embodiment includes the compound described in formula (I), where AA1 is L-Arg, AA2 is L-Arg, AA3 is L-Gln, AA4 is D-Met, AA5 is D-Glu, and AA6 is L-Glu.

[0085] The present invention provides compounds of formula (I), wherein AA1 is selected from the group consisting of L-Arg, L-Lys, and amino acids; AA2 is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of D-Gln, D-Glu, D-Asn, and D-Asp or the group consisting of D-Gln and D-Asp; AA4 is selected from the group consisting of D-Met and D-Leu; AA5 is selected from the group consisting of L-Glu, L-Asp, and L-Gln; and AA6 is selected from the group consisting of L-Glu, L-Gln, L-Asp, and amino acids. In this embodiment, preferably, AA1 is L-Arg and AA2 is L-Arg. This embodiment includes the compound described in formula (I), where AA1 is L-Arg, AA2 is L-Arg, AA3 is D-Gln, AA4 is D-Met, AA5 is L-Glu, and AA6 is L-Glu.

[0086] The compounds of the present invention include those selected from the group of amino acid sequences, stereoisomers thereof, and / or cosmetically or pharmaceutically acceptable salts thereof, as listed in Tables 2 and 2a, where their sequence identifiers are detailed. [Table 2]

[0087] The compounds of the present invention each comprise the sequences of Tables 2 and 2a, in which one of the amino acids AA1 to AA6 is replaced by a substituted amino acid, the substituted amino acid being selected from the list of alternative amino acids enumerated for the amino acid substituted by formula (I) above. The substituted amino acid is different from the amino acid that is substituted.Accordingly, the present invention provides sequences in Tables 2 and 2a in which one of the amino acids AA1 to AA6 is substituted with one amino acid, wherein when the AA1 amino acid in one of the sequences in Tables 2 and 2a is substituted, if the AA1 amino acid is Arg, it is substituted with Lys, and if the AA1 amino acid is Lys, it is substituted with Arg or Lys; when the AA2 amino acid in one of the sequences in Tables 2 and 2a is substituted, if the AA2 amino acid is Arg, it is substituted with Lys, and if the AA2 amino acid is Lys, it is substituted with Arg or Lys; when the AA3 amino acid in one of the sequences in Tables 2 and 2a is substituted, if the AA3 amino acid is Gln, it is substituted with Glu, Asn or Asp, if the AA3 amino acid is Glu, it is substituted with Gln, Asn or Asp, if the AA3 amino acid is Asn, it is substituted with Glu, Gln or Asp, and if the AA3 amino acid is Asp, it is substituted with Glu, Gln or Asn. Under the condition that the amino acid is replaced with Gln, Glu, Asn, or Asp, if the AA4 amino acid in one of the sequences in Table 2 and 2a is replaced, if the AA4 amino acid is Met, it is replaced with Leu, and if the AA4 amino acid is Leu, it is replaced with Met or Leu, if the AA5 amino acid in one of the sequences in Table 2 and 2a is replaced, if the AA5 amino acid is Gln, it is replaced with Glu or Asp, if the AA5 amino acid is Glu, it is replaced with Gln or Asp, and if the AA5 amino acid is Asp, it is replaced with Glu, Asp, or Gln, if the AA6 amino acid in one of the sequences in Table 2 and 2a is replaced, if the AA6 amino acid is Gln, it is replaced with Glu or Asp, if the AA6 amino acid is Glu, it is replaced with Gln or Asp, and if the AA6 amino acid is Asp, it is replaced with Glu, Asp, or Gln.

[0088] In the amino acid sequences of Tables 2 and 2a, which conform to formula (I), R1 and R2 are H and OH, respectively. The compounds of the present invention include the sequences of Tables 2 and 2a having N-terminuses and C-terminuses modified by other R1 and R2 groups as defined herein for formula (1). For example, the compounds of the present invention include the sequences of Table 2, where, if the N-terminal amino acid residue terminates with R1 as defined above for formula (1), R1 is not H; and alternatively or additionally, if the C-terminal amino acid residue terminates with R2 as defined above for formula (1), R2 is not H.

[0089] Accordingly, the present invention provides a compound according to formula (i), which is an amino acid sequence selected from SEQ ID NOs: 1, 2, 15, 18, 21, 22, 23, 24, 25, 29, 30, 32, 33, 34, 35, 36, and 38, or the stereoisomer thereof, and / or a cosmetically or pharmaceutically acceptable salt thereof, wherein the sequence optionally has an N-terminal amino acid modified by R1 as defined above for formula (1), in which case R1 is not H, and alternatively or additionally, the sequence has a C-terminal amino acid modified by R2 as defined above for formula (1), in which case R2 is not H. The amino acid sequence may be SEQ ID NOs: 21, 22, 23, 24, 25, 29, 30, 32, 33, 34, 35, 36, and 38. The amino acid sequence may be SEQ ID NO: 21, 22, 35, or 38. The amino acid sequence may be SEQ ID NO: 21. The amino acid sequence may be SEQ ID NO: 22. The amino acid sequence may be SEQ ID NO: 35. The amino acid sequence may be SEQ ID NO: 38.

[0090] The compounds of the present invention exist as stereoisomers or mixtures of stereoisomers, and for example, the amino acids containing them may have configurations L-, D-, or 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 pure isomers, i.e., enantiomers or diastereomers. For example, where it is stated that AA2 may be Arg, unless otherwise specified, it will be understood that AA2 is selected from L-Arg, D-Arg, or a mixture of both Arg, 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.

[0091] 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, but are not limited to, 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, allo-isoleucine, allo-threonine, isonipecotinic acid, isoserine, phenylglycine, statins, β-alanine, norleucine, N-methylamino acids, α-amino acids and β-amino acids, and 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.

[0092] 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, the properties of W, X, Y, and / or Z are understood not to 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 Ala.

[0093] m, n, p, and q can each be 0, i.e., the compound of formula (I) 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 (I) 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 (I) is a peptide containing 7 or 8 amino acids linked in a chain.

[0094] In particular, the compounds of the present invention can be selected from the group of compounds listed in Tables 3 and 3a, their stereoisomers, and / or their cosmetically acceptable salts. [Table 3]

[0095] The compounds of the present invention include the compounds in Tables 3, 3a, and 3b, in which one of the amino acids AA1 to AA6 is replaced by a substituted amino acid, the substituted amino acid being selected from the alternative amino acids listed for the amino acid substituted by formula (I) above. The substituted amino acid is different from the amino acid that is substituted.Therefore, the present invention provides compounds of Tables 3, 3a, and 3b in which one of the amino acids AA1 to AA6 is substituted with one amino acid, wherein when the AA1 amino acid in one of the sequences of Tables 3, 3a, and 3b is substituted, if the AA1 amino acid is Arg it is substituted with Lys, and if the AA1 amino acid is Lys it is substituted with Arg, then it is substituted with Arg, and when the AA2 amino acid in one of the sequences of Tables 3, 3a, and 3b is substituted, if the AA2 amino acid is Arg If the AA2 amino acid is Lys, it is substituted with Arg. If the AA3 amino acid is substituted with Arg or Lys, and one of the sequences in Tables 3, 3a, and 3b is substituted, if the AA3 amino acid is Gln, it is substituted with Glu, Asn, or Asp. If the AA3 amino acid is Glu, it is substituted with Gln, Asn, or Asp. If the AA3 amino acid is Asn, it is substituted with Glu, Gln, or Asp. If the AA3 amino acid is Asp, it is substituted with Glu, Gln, or Asn. Under the condition that substitution occurs, the AA4 amino acid is substituted with Gln, Glu, Asn, or Asp, and if the AA4 amino acid in one of the sequences in Tables 3, 3a, and 3b is substituted, then if the AA4 amino acid is Met, it is substituted with Leu, and if the AA4 amino acid is Leu, it is substituted with Met, and if the AA5 amino acid in one of the sequences in Tables 3, 3a, and 3b is substituted, then if the AA5 amino acid is Gln, it is substituted with Glu or Asp, and if the AA5 amino acid is Glu It is substituted with Gln or Asp, and if the AA5 amino acid is Asp, it is substituted with Glu or Gln, and if the AA6 amino acid in one of the sequences in Table 3, 3a, and 3b is substituted, if the AA6 amino acid is Gln, it is substituted with Glu or Asp, if the AA6 amino acid is Glu, it is substituted with Gln or Asp, and if the AA6 amino acid is Asp, it is substituted with Glu or Gln,

[0096] The present invention provides compounds according to formula (i), wherein the compounds are selected from those in Tables 3, 3a and 3b, and in particular can be selected from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37, PEP41, PEP42, PEP43, and PEP44, or can be selected from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23, and PEP24, their stereoisomers, and / or cosmetically or pharmaceutically acceptable salts thereof. The compound may be PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37, PEP41, PEP42, PEP43, or PEP44. The compound may be PEP21, PEP22, PEP23, or PEP24. The compound may be PEP21. The compound may be PEP22. The compound may be PEP23. The compound may be PEP24.

[0097] 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 (which are organic, for example, in particular acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate, or gluconate; or which are inorganic, for example, in particular chloride, sulfate, borate, or carbonate). The properties of the salt are not important, except 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).

[0098] 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.

[0099] 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 performed using 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 compounds of the present invention may also be carried out according to conventional methods known in the prior art, such as "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.

[0100] For example, methods for obtaining compounds of formula (I), their stereoisomers, and mixtures thereof are: - A step of coupling an amino acid having a protected N-terminus and a free C-terminus with an amino acid having a free N-terminus and a protected or solid support-bound C-terminus. -Step of removing the protecting group at the N-terminus, - Repeat the coupling procedure until the desired peptide sequence is obtained, and remove the protecting group at the N-terminus. -Includes the step of removing the C-terminal protecting group or cleaving the solid support.

[0101] Preferably, the C-terminus 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-terminus and a free C-terminus with an amino acid having a free N-terminus and a C-terminus bound to a polymer support, removing the N-terminal protecting group, repeating this procedure the number of times required to obtain a compound of the desired length, and finally cleaving the synthetic compound from the original polymer support.

[0102] 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.

[0103] 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-bound to a polymer support with a peptide. Convergent synthetic 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.

[0104] The above process may include additional steps of deprotecting the N-terminus and C-terminus and / or cleaving the peptide from the polymer support in a non-discriminatory order using standard procedures and conditions known in the prior art, after which the functional groups of these terminals can be modified. Any modification of the N-terminus and C-terminus can be performed using the peptide of formula (I) immobilized on the polymer support, or after the peptide has been separated from the polymer support.

[0105] Optionally, R1 is introduced by a nucleophilic substitution reaction between the N-terminus 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, such as, but not limited to, a tosyl group, a mesyl group, and a halogen group.

[0106] Optionally and / or additionally, 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 base such as N,N-diisopropylethylamine (DIEA) or trimethylamine, or an additive such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazole (HOAt), and in particular a dehydrating agent such as carbodiimide, uronium salt, phosphonium salt, or amidinium salt, 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 support, wherein R2 is -OR3, -NR3R4, or -SR3, and R3 and R4 are as defined above.

[0107] Those skilled in the art will readily understand that the deprotection / cleavage steps of the C-terminus and N-terminus, as well as their subsequent derivatization, can be carried out in different sequences according to methods known in the prior art.

[0108] 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.

[0109] 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 (ClZ), para-nitrobenzyloxycarbonyl (pNZ), tert-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc), or allyloxycarbonyl. Carbamates such as xycarbonyl (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-methylbutyl (ivDde), and 1-(1-adamantyl)-1-methylethoxycarbonyl (Adpoc), with Boc or Fmoc being particularly preferred.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Examples of these 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.

[0115] When the synthesis is carried out entirely or partially in solid phase, possible solid supports used in the process of the present invention include polystyrene supports, polyethylene glycol grafted onto polystyrene, and similar supports, 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 zur Synthese von Leu1-Gastrin I'', (1989), Tetrahedron 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. Chem., 55, 3730-3743), and 2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid (AM) (Rink H., "Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methylester The resin may or may not contain unstable linkers such as (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 ones, the linkers enabling the simultaneous deprotection and cleavage of the compound from the polymer support.

[0116] Applicable This invention is based on the discovery that compounds of formula (I) (compounds of the present invention) are useful for the treatment of skin, hair, nails, and / or mucous membranes. In particular, compounds of the present invention have been found to inhibit norepinephrine release and increase collagen synthesis in the skin, and are therefore useful for the prevention or treatment of symptoms of skin aging, including wrinkles, sagging skin appearance, and loss of firmness, and for the treatment or prevention of facial asymmetry. Furthermore, compounds of the present invention have been found to increase the lipid content of adipocytes, and are therefore capable of causing an increase in the volume of adipose tissue. Therefore, compounds of the present invention can be used to increase facial volume, for example, in the cheek area. These effects further demonstrate the usefulness of compounds in the prevention or treatment of symptoms of skin aging. Therefore, compounds of formula (I) are useful in cosmetic and non-therapeutic treatments of skin, hair, nails, and / or mucous membranes.

[0117] 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 mitigating these signs of aging. Increased collagen synthesis helps counteract the effects of decreased collagen synthesis in the skin associated with the aging process.

[0118] 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 sagging skin. 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. Increasing collagen synthesis is thought to be beneficial in reducing these symptoms of aging.

[0119] Adipose tissue, or body fat, is connective tissue that contains cells called adipocytes, which store lipids. Advantageously, the compounds of the present invention have been found to be effective in increasing the lipid content of adipocytes and are therefore useful in treatments to increase the volume of adipose tissue and in treatments to prevent and / or mitigate the effects of adipose tissue loss. The compounds of the present invention can be used, for example, to increase facial volume in the cheek area.

[0120] Furthermore, in several embodiments, the compounds of the present invention have been found to upregulate the expression of muscle-blind-like 1 (MBNL-1). Without being constrained by theory, it is thought that an increase in MBNL1 protein contributes to slowing and / or avoiding muscle mass loss due to activation of atrophic processes that may be caused by muscle aging. Muscle aging can also be exacerbated by botulinum toxin treatment. Therefore, in these embodiments, 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 symmetry.

[0121] 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 and non-therapeutic treatments and / or care of the skin, hair, nails and / or mucous membranes. In particular, the cosmetic and 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 skin of the face (including the skin around the eyes), nape of the neck, neck, décolletage, arms, hands, legs, feet, thighs, waist, buttocks, abdomen, and torso.

[0122] The compounds of the present invention are useful in cosmetic and non-therapeutic treatments and / or care of the skin, which include 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, and / or reducing and / or preventing facial asymmetry, increasing adipose tissue volume, and / or preventing and / or mitigating the effects of adipose tissue depletion.

[0123] The compounds of the present invention are useful for cosmetic and non-therapeutic treatments and / or care of the skin, including the treatment and / or prevention of skin aging, the treatment and / or prevention of skin wrinkles, the maintenance and improvement of skin firmness, the stimulation of collagen synthesis and / or the prevention of collagen depletion, the treatment and / or prevention of the appearance of sagging skin, and / or the reduction and / or prevention of facial asymmetry.

[0124] Cosmetic and non-therapeutic 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.

[0125] Cosmetic and non-therapeutic treatments and / or care may involve inhibition of norepinephrine, stimulation of collagen synthesis, and / or upregulation of MBNL-1. Therefore, cosmetic and non-therapeutic treatments and / or care of the skin, hair, nails, and / or mucous membranes may be associated with inhibition of norepinephrine release, increased collagen synthesis, and / or upregulation of muscle-blind-like 1 (MBNL-1) expression.

[0126] 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 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. Symptoms of skin aging include a decrease in volume due to a decrease in adipose tissue.

[0127] 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 wrinkles of the skin. Wrinkles of the skin include facial wrinkles, also commonly known as expression lines.

[0128] In one embodiment, the use of the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, or the use of a cosmetic composition containing the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, is provided for maintaining and / or improving skin firmness.

[0129] In one embodiment, the use of the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, or the use of a cosmetic composition containing the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, is provided for stimulating collagen synthesis and / or preventing collagen depletion.

[0130] 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 containing the compounds of the present invention, their stereoisomers and / or cosmetically acceptable salts, is provided for the prevention and / or mitigation of the effects of increased and / or decreased adipose tissue volume. Adipose tissue is subcutaneous adipose tissue and may be subcutaneous adipose tissue of the face, hands and / or neck (particularly the neck portion). Increasing the amount of adipose tissue in the skin increases the amount of skin. In particular, the decrease in adipose tissue is due to aging.

[0131] 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 the appearance of sagging skin. Sagging skin can be caused by a decrease in muscle tone, particularly the muscle tone of the skin, more specifically, a decrease in the muscles of the face.

[0132] In one embodiment, the use of the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, or the use of a cosmetic composition comprising the compound of the present invention, its stereoisomers and / or cosmetically acceptable salts, is provided for the treatment and / or prevention of facial asymmetry.

[0133] The present invention also extends to the use of the compounds of the present invention in combination with botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof in the treatment and / or care of the skin, hair, nails and / or mucous membranes, as described above with respect to the application (use) of the compounds of the present invention.

[0134] 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 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 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.

[0135] The present invention also extends to methods for treating and / or caring for the skin, hair, nails and / or mucous membranes of a subject, the method comprising 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 Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or -Tyr-D-Ala-Gly-Phe-Leu-OH or a combination thereof. 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 compound of the present invention. For example, a therapeutic 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, the treatment method may include administering to the subject Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH, or a combination thereof, and the compounds of the present invention, their stereoisomers and / or cosmetically or pharmaceutically acceptable salts. Preferably, this treatment method is a skin anti-aging treatment.

[0136] Botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof, and the compounds of the present invention may be administered simultaneously (at the same time) or successively. When botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof, and the compounds or compositions of the present invention are administered simultaneously, 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.

[0137] The above treatment methods include cosmetic non-therapeutic treatments and / or care of the skin, which include 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, and / or prevention and / or mitigation of the effects of adipose tissue loss. The above treatment methods include cosmetic non-therapeutic treatments and / or care of the skin, which include 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, and / or reduction and / or prevention of facial asymmetry. In one embodiment, the method of cosmetic non-therapeutic treatment and / or care of the skin is a skin anti-aging treatment.

[0138] 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 manufacture 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 to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing the same.

[0139] 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.

[0140] Regarding the above-described method of the present invention, 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 involves administering the compound of the present invention, its stereoisomers and / or cosmetically or pharmaceutically acceptable salts to the subject in combination with botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 or H-Tyr-D-Ala-Gly-Phe-Leu-OH or a combination thereof, may vary considerably depending on the needs of each subject. In one embodiment, the method of the present invention comprises 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 dose of botulinum toxin.

[0141] In another embodiment, the present invention provides a method for selecting compounds useful for preventing or treating symptoms of skin aging, improving or maintaining skin firmness, treating and / or preventing the appearance of sagging skin, and / or treating or preventing facial asymmetry, and includes determining the ability of compounds to upregulate MLBN-1 in human skeletal muscle cells.

[0142] 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 in mammals, preferably in humans.

[0143] In another embodiment, the present invention provides compositions comprising a compound according to formula (I), its stereoisomers and / or cosmetically or pharmaceutically acceptable salts.

[0144] 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).

[0145] The solubility of the compounds of the present invention in water varies depending on the properties of their amino acid sequence or any possible modifications at the N-terminus and / or C-terminus. Therefore, the compounds of the present invention can be incorporated into compositions by aqueous solutions, and 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.

[0146] 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.

[0147] 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 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) with respect to the total weight of the composition.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] Examples of fabrics, nonwovens, clothing, medical devices, and means for immobilizing compounds thereon, among others, are 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”). 1616973217211_4 Probl. Dermatol.v.33, Hipler UCand Elsner P., eds. S. Karger AG, Basel, Switzerland, Malcolm RKet 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.

[0157] Cosmetic compositions or pharmaceutical compositions containing the compounds of the present invention, their stereoisomers, mixtures thereof, and / or cosmetically or pharmaceutically acceptable salts thereof can be used in different types of compositions for topical or transdermal application, and the compositions optionally contain cosmetically or pharmaceutically acceptable excipients necessary for formulation into desired dosage forms.

[0158] 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.

[0159] The cosmetic or pharmaceutical composition of the present invention contains an agent that increases the transdermal absorption of the compound 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 local area to be treated by iontophoresis, sonophoresis, electroporation, microelectropatch, mechanical pressure, osmotic gradient, occlusive cure, needle-free injection by pressure such as microinjection or oxygen pressure injection, or any combination thereof, to achieve better penetration of the peptide of the present invention. The area of ​​application is determined by the nature of the condition, disorder, and / or disease being treated and / or cared for.

[0160] 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.

[0161] 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.

[0162] The cosmetically or pharmaceutically acceptable adjuvants contained in the cosmetic or pharmaceutical compositions described in the present invention include, but are not limited to, additional ingredients commonly used in cosmetic or pharmaceutical compositions, such as (ii) 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, lipogenic agents, etc. Additional examples can be found in the CTFA International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).

[0163] 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) anti-wrinkle agents, Botox-like agents and / or anti-aging agents; (ii) firming agents, skin elasticity agents and / or reconstructing agents; (iii) moisturizing agents; (iv) photoaging inhibitors and / or blue light protectants; (v) DNA protectants, DNA repair agents and / or stem cell protectants; (vi) free radical scavengers and / or anti-glycation agents, detoxifiers, antioxidants and / or anti-pollution agents; and / or combinations thereof.

[0164] 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), all marketed 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) fermentation, 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 fermentation, 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) Vialox® (INCI: Pentapeptide-3), Syn®-Ake® (INCI: Dipeptide Diaminobutyroyl Benzylamide Diacetate), Syn®-Coll (INCI: Palmitoyl Tripeptide-5), Phytaluronate (INCI: Carob Gum), Preregen® (INCI: Glycine Soja Protein, Oxidoreductase), Pepha-Nutrix (INCI: Natural Nutrients), Pepha-Tight (INCI: Algae Extract, Pullulan), Pentacare-NA (INCI: Hydrolyzed Wheat Gluten, Carob Gum) Siliqua Gum, Syn(Registered Trademark)-Tack (INCI: Glycerin, Palmitoyl Dipeptide-5 Diaminobutyroyl Hydroxythreonine, Palmitoyl Dipeptide-6 Diaminohydroxybutyrate), BeauActiveMTP (INCI: Hydrolyzed Milk Protein), Syn(registered trademark)-TC (INCI: Tetradecylaminobutyroylvalylaminobutyric acid urea trifluoroacetate, palmitoyl tripeptide-5, palmitoyl dipeptide-5 diaminobutyroyl hydroxythreonine), Syn(registered trademark)-Hycan (INCI: Tetradecylaminobutyroylvalylaminobutyric acid urea trifluoroacetate), Syn(registered trademark)-Glycan (INCI: Tetradecylaminobutyroylvalyl-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, 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), 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: Alpinia galanga leaf extract), Neurobiox (INCI: Achillea millefolium extract), Deliner (INCI: Zea May kernel extract), Lys'lastine V (INCI: PeucedanumGraveolens (dill) extract), Extracellium (INCI: hydrolyzed potato protein), Proteasyl TP LS 8657 (INCI: pea (Pisum 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, sodium 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 polysaccharide), Arganyl (INCI: Argania spinosa leaf extract), Sphingoceryl Veg (INCI: Phytoceramide), Vit-A-Like (INCI: Moss bean (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: Okra (Hibiscus) (Esculentus) seed extract, Collalift (registered trademark) 18 (INCI: Kaya (Khaya Senegalensis) bark), Collrepair (trademark) DG (INCI: Hexylene glycol, niacin) or Litchiderm (INCI: Reishi (LitchiChinensis (fruit peel extract); sold by Lipotec / Lubrizol: 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), Preve nthelia(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 soybean 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 component (INCI: saccharide isomerate), Eyedeline (trademark) marine component (INCI: plankton extract), uplevity (trademark) (INCI: acetyl tetrapeptide-2), Seacode (trademark) (Trademark) Marine component (INCI: Pseudoalteromonas fermented extract) or Serilesine® peptide solution (INCI: Hexapeptide-10); Sirtalice® (Trademark) (INCI: Bacillus fermented), Epitensive® (Trademark) (INCI: Nicotiana benthamiana hexapeptide-40 SH-oligopeptide-1), Scelleye® (Trademark) (INCI: Nicotiana benthamiana SH-oligopeptide-2), Seadermium (INCI: Aqua, glycerin, Bacillus fermented), Pauseile (INCI: Aqua, glycerin, Bacillus fermented), or Neoclair pro(INCI: Aqua, Glycerin, Caprylyl Glycol, Acetyl Tetrapeptide-2); Sold by Vincience / ISP / Ashland: Collaxyl(Registered Trademark) IS(INCI: Hexapeptide-9), Laminixyl IS(Trademark)(INCI: Heptapeptide), Orsirtine(Trademark) GL(INCI: Rice Extract (Oryza sativa)), D'Orientine(Trademark) IS(INCI: Date Palm Seed Extract (Phoenix dactylifera)), Phytoquintescine(Trademark)(INCI: Echinopodium alkekengi) Extract (Triticum monococcum), 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), ProlixirS20 (trademark) (INCI: Dimer Tripeptide-43), Phytocohesine (trademark) PSP (INCI: Beta-Sitosteryl Sulfate Sodium, 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 (trademark) (INCI: Nelumbo Nucifera Flower Extract), Serenityl (INCI: Marsdenia) Condurango bark extract), Natriance Wrinkle-less (INCI: hydrolyzed corn protein), Phytoneomatrix (INCI: hydrolyzed soybean extract), Prolixir ICE (INCI: hydrolyzed rice protein), PhytoRNx Baobab(TM) (INCI: hydrolyzed African baobab (Adansonia) Digitata extract), Natriance Renovate extract (INCI: hydrolyzed flaxseed extract), Natriance Self-Hydrate Extract (INCI: pea (Pisum Sativum) extract), Actontine YST (INCI: hydrolyzed yeast protein) or Telosense (trademark) (INCI: hydrolyzed soy protein, hydrolyzed yeast protein); BONT-L-Peptide (INCI: palmitoyl hexapeptide-19), TIMP Peptide (INCI: acetyl hexapeptide-20), ECM Moduline (INCI: palmitoyl tripeptide-28), Renaissance (INCI: hydrolyzed wheat protein, palmitoyl decapeptide-21, decapeptide-22, oligopeptide-78, zinc palmitoyl nonapeptide-14) or X50 sold by InfinitecActivos Antiaging (INCI: Lactic acid / glycolic acid copolymer, polyvinyl alcohol, copper palmitoyl heptapeptide-14, heptapeptide-15 palmitate); EquiStat (INCI: Apple (Pyrus Malus) fruit extract, Soybean (Glycine soja) seed extract), sold by Coletica / Engelhard / BASF; Juvenesce (INCI: Ethoxydiglycol and caprylic triglyceride, retinol, ursolic acid, phytonadione, ilostat); 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: Malus domestica Fruit Cell Culture), Lipobelle Soyaglicane (INCI: Soy Isoflavones), RoyalEpigen P5 (INCI: Butyrospermum 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), sold by Mibelle Biochemistr; ActiMatrix (INCI: Peptide-based Mushroom Extract), Peptamide, sold by Active Organics / Arch. Selected from three groups consisting of 6 (INCI: hexapeptide-11) and combinations thereof.

[0165] 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) sold by Mibelle; and combinations thereof.

[0166] In another embodiment, the humectants include: qua Shuttle (INCI: sorbitol, oweed (Laminaria digita) extract, diatomaceous earth) sold by Infinitec; Aqua-Osmoline (INCI: carob (Ceratonia siliqua) seed extract) sold by Vincience / ISP / Ashland; and Hydroalphatine (INCI: hydrogenated starch hydrolysate, panthenol, bamboo shoot extract, lotus (Nelumbo nucifera) flower extract, water lily (Nymphaea) sold by Lucas Meyer Cosmetics / Unipex. Alba (root extract) or Hydraporine (trademark) (INCI: betaine, hydrogenated lecithin, honey, pectin); PatcH2O (trademark) (INCI: trehalose, urea, serine, glyceryl polyacrylate, algin, sodium hyaluronate, pullulan), sold by L.Serobiologiques / Cognis / BASF; Aqu'activ (trademark) (INCI: behenyl alcohol, glyceryl oleate, cocamide MIPA); Irwinol (registered trademark) (INCI: octyldodecanol, African mango (Irvingia) Gabonensis kernel butter, hydrogenated cocoglycerides, Lipodermol (INCI: octyldodecanol, arachidyl propionate, tocopheryl acetate, retinyl palmitate, ethyl linoleate, ethyl linolenate), or Seanamin (INCI: sorbitol, algae extract, Chrondrus Crispus (carrageenan), Fucus Vesiculosus extract, algin); Ice algae powder sold by Mibelle (INCI: Coenochloris signiensis extract);Hyasol BT (INCI: Sodium Hyaluronate), Syn-Up (Trademark) (INCI: Benzylsulfonyl D-Ceryl Homophenylalanine Amidinobenzamide Acetate), or Pentavitin (Registered Trademark) (INCI: Saccharide Isomerate), sold by Pentapharm / DSM; Aqualance (Trademark) (INCI: Erythritol, Fomarin HCl), Hydraprotectol (Trademark) (INCI: Glyceryl Polymethacrylate, Alloylitol Acid, Yeast Extract (Faex), Glycoprotein), Moist 24 (Trademark) (INCI: Imperata Cylindrica Root Extract), Optim Selected from the group consisting of 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 (INCI: glycerin, Pseudoalteromonas ferment extract, xanthan gum, proline, alanine, serine, ethylhexylglycerin, caprylyl glycol) or Actizyme GL advanced plant components (INCI: glycerin, Mucor miehei extract, aqua, sodium citrate, potassium sorbate, sodium benzoate, phytic acid); and combinations thereof.

[0167] In another embodiment, photoaging inhibitors and / or blue light protectants include Algaktiv Genofix CPD (INCI: Plankton Extract, Aqua, Lecithin) sold by Greenaltech; Blumilight (Trademark) Biofunctional (INCI: Water / Aqua (and) Butylene Glycol (and) 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; L-VCG (INCI: Ascorbyl Glucoside) sold by Freshine Bio-technology; and Lumicease Blue sold by Lipotec / Lubrizol. Ingredients (INCI: Glycerin, Aqua, Hydrolyzed Pea Protein, Glucose, Sodium Chloride); 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 Lanceolata Leaf Extract, Xanthan Gum) sold by Sederma;Selected from Blueshield (INCI: glycerin, Capsicum annuum fruit extract, xanthan gum) sold by Solabia, and combinations thereof.

[0168] In another embodiment, DNA protectants, DNA repair agents, and / or stem cell protectants include 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 AtriumInnovations / LucasMeyerCosmetics. Indicum (extract) or Melinoil (INCI: isopropyl palmitate, lecithin, aqua, acetyl hexapeptide-1); Repair Complex (INCI: Bifida fermentation lysate) sold by CLR; Phycojuvenine (INCI: Oweed (Laminaria digita)) sold by Codif; Unirepair T-43 (INCI: butylene glycol, acetyl tyrosine, proline, hydrolyzed vegetable protein, adenosine triphosphate) sold by Induchem; Dragosine (INCI: carnosine) sold by Symrise; DN-Age (INCI: golden candle (Cassia alata) leaf extract) sold by Laboratories Serobiologiques / Cognis / BASF;Helioguard (INCI: Porphyra Umbilicalis encapsulated in liposomes), PhytoCellTec Malus Domestica (INCI: PhytoCellTec Malus domestica), or PhytoCellTec Argan (INCI: Argania spinosa sprout cell extract, isomalt, lecithin, sodium benzoate, aqua), sold by Mibelle Biochemistry; Pepha-Protect (INCI: Watermelon extract), sold by Pentapharm / DSM; Celligent (INCI: Helianthus annuus seed oil, ethyl ferrate, polyglyceryl-5 trioleate, Rosmarinus), sold by Rahn (Officinalis) leaf extract, aqua, uridine phosphate disodium) or Defensil (INCI: octyldodecanol, Echium plantagineum seed oil, Cardiospermum halicacabum extract, Helianthus (sunflower) Annuus) Seed Oil Unsaponifiables); Venuceane (INCI: Thermus Thermophilus Ferment, Glycerin), UV-Soft (INCI: Yeast Extract), Renovage (INCI: Caprylic / Capric Triglyceride, Teprenone), Juvinity (INCI: Caprylic / Capric Triglyceride, Geranylgeranylpropanol (Suggested)), Phytessence Holyherb (INCI: Butylene Glycol, Eriodictyon Californicum (Holy Herb) Flower / Leaf / Stem Extract) or Resistem (INCI: Glycerin, Globularia Cordifolia Ferment Filtrate); Infraguard (INCI: Caesalpinia Tara), sold by Mibelle Selected from the group consisting of: Spinosa fruit pod extract, propylene glycol, aqua, sunflower (Helianthus annuus) sprout extract, sodium benzoate, phenoxyethanol; Heliomoduline (INCI: low molecular weight peptide from cottonseed) or Stem-C-Guard (hydrolyzed pea), sold by Silab; and combinations thereof.

[0169] 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, carnosine and its derivatives; GHK (INCI: tripeptide-1) and its salts and / or derivatives sold by Vincience / ISP / Ashland or Quintescine IS (INCI: dipeptide-4); Preregen (INCI: soybean protein, oxidoreductase) sold by Pentapharm / DSM; Edelweiss GC (INCI: Leontopodium Alpinum extract); Lipogard (INCI: squalane, ubiquinone); Nectapure (INCI: Buddleja Davidii extract, Thymus Vulgaris extract); Alpaflor Nectapure (INCI: Buddleja davidi extract, Thymus vulgaris extract, glycerin, water) or Dismutin-BT (INCI: Saccharomyces fuciformis extract) Highly purified SOD from natural yeast strain of Ceresiae); 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), sold by Lipotec / Lubrizol.unactyl (INCI: mannitol, pea (Pisum Sativum) extract, histidine HCl, arginine, cyclodextrin, dextrin, yeast extract, acetyltrisoin (Trysoine), pyridoxine HCl, khaya (Khaya Senegalensis) bark extract, nicotinamide, adenine dinucleotide, disodium succinate, aspartic acid), imidinyl (INCI: tamarind (Tamarindus indica) seed polysaccharide), phystrogene (INCI: butylene glycol, mallow (Malva Sylvestris) extract, xanthan gum), or Purisoft (INCI: moringa (Moringa Pterogysperma) seed extract) sold by Laboratoires Serobiologiques / Cognis / BASF;AquaCacteen (INCI: Glycerin, Opuntia Ficus Indica stem extract, Phenoxyethanol, Aqua), Trimoist (KMF) (INCI: Sodium stearoyl lactylate, Cetyl alcohol, Orthovenium vegetable oil, Tocopheryl acetate, Glycerin, Glycine soja sterol, Sodium lactate, Barboxymethyl-beta-glucan sodium, Carnosine, Lactic acid), MelanoBronze (INCI: Vitex Agnus Castus extract (Vitex Agnus berry extract (phytoendorphins)), Acetyltyrosine), CM-Glucan (INCI: Carobxymethyl-beta-glucan sodium, Phenoxyethanol), SunActin (INCI: Helianthus annuus extract) Annuus (Sunflower) sprout extract, tocopherol, glycerin, lecithin, phenoxyethanol, aqua), GSP-T skin (INCI: glycerin, alcohol, aqua, PEG-40 hydrogenated castor oil, Vitis Vinifera (grape) seed extract) or Detoxophane (INCI: Lepidium Sativum) 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; Selected from, but not limited to, the group formed by: Vulgare extract) or Prodizia (INCI: Albizia julibrissin extract, glycerin); Extramel C (INCI: Hydroxypropyltrimonium maltodextrin crosspolymer, Cucumis melo (melon) fruit extract) sold by Seppic; Defensine (INCI: Triticum vulgare germ extract) sold by Silab; Apolluskin (registered trademark) (INCI: Taraxacum officinale (dandelion) extract); Detoxyl (registered trademark) (INCI: Water, butylene glycol, Butyrospermum parkii (shea butter) seed cake extract) or Antiglyskin (INCI: Aqua, Helianthus annuus seed extract); and combinations thereof.

[0170] The compositions of the present invention may be used in any of the applications or uses discussed above under the heading "Applications".

[0171] In another embodiment, the present invention is a kit for use in cosmetic and non-therapeutic treatment methods of skin treatment and / or care, (i) Compositions containing botulinum toxin, (ii) optionally a composition comprising Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or a combination thereof, and (iii) A kit is provided that includes a cosmetic composition containing the compound of formula (I).

[0172] (i) a composition containing botulinum toxin, (ii) a composition containing Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or a combination thereof (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 a microneedle.

[0173] The present invention is illustrated by the following non-limiting embodiments. [Examples]

[0174] 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.

[0175] (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.

[0176] chemical synthesis All synthesis processes are carried out using a polypropylene syringe fitted with a porous polyethylene disc. The coupling procedure is performed 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 the ninhydrin test (Kaiser E. et al., Anal. Biochem. (1970), 34:595-598) or the chloranil test (Christensen T., Acta The reaction is carried out by following the procedure in Chem.Scand., (1979), 33B, 763-766). The coupling reaction is repeated while synthesizing the target peptide. All synthesis reactions and washings are performed at 25°C.

[0177] 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.

[0178] HPLC chromatography analysis is performed using a Shimadzu instrument (Kyoto, Japan) with a reversed-phase column (50 × 4.6 mm, Kromasil C18, 3.5 μm, Akzo Nobel, Sweden) that is automatically temperature-controlled to 30°C. Elution is performed at a flow rate of 1.6 mL / min using a water (+0.1% TFA) gradient containing acetonitrile (+0.07% TFA), and detection is performed at 220 nm. Electrospray ionization mass spectrometry is performed using a WATERS Alliance ZQ 2000 detector at a flow rate of 0.3 mL / min with a 4:1 MeCN:H2O (+0.1% TFA) mixture as the mobile phase.

[0179] Example 1 Fmoc-W m -X n -AA1-AA2-AA 3- AA4-AA5-AA 6- -Y p -Z q The formula -AM-MBHA-(R) is obtained, where AA1 is L-Arg, AA2 is L-Arg, AA3 is L-Gln or D-Gln, AA4 is L-Met or D-Met, AA5 is L-Glu, AA6 is L-Glu, and n, m, p, and q are 0 or 1, respectively.

[0180] The weights were normalized. The Fmoc-AM-pMBHA resin was treated with piperidine:DMF according to the general procedure described to remove the Fmoc group. Five equivalents of Fmoc-L-Glu(tBu)-OH(Fmoc-AA6-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.

[0181] Next, the resin is washed as described in general procedures, and the deprotection treatment of the Fmoc group is repeated to couple the following amino acids: 5 equivalents of Fmoc-Glu(tBu)-OH (Fmoc-AA5-OH), followed by 5 equivalents of Fmoc-D-Met-OH (Fmoc-AA4-OH), 5 equivalents of Fmoc-L-Gln(Trt)-OH (Fmoc-AA3-OH), 5 equivalents of Fmoc-L-Arg(Pbf)-OH (Fmoc-AA2-OH), and finally, 5 equivalents of Fmoc-L-Arg(Pbf)-OH (Fmoc-AA1-OH), in the presence of 5 equivalents of HOBt and 5.5 equivalents of DIPCDI in each coupling step.

[0182] After synthesis, the peptidyl resin is washed with DCM (3 x 1 min). Table 4 shows non-restrictive examples of peptides synthesized using this method. [Table 4]

[0183] By following the described method, it is possible to obtain different sequences by changing the desired amino acids that are coupled.

[0184] Example 2 A general method for removing the Fmoc N-terminal protecting group. The N-terminal Fmoc group of the peptidyl resin obtained in Example 1 is deprotected as described by general methods (20% piperidine in DMF, 1 × 1 min + 1 × 5 min). The peptidyl resin is washed with DMF (5 × 1 min), DCM (3 × 1 min), and diethyl ether (3 × 1 min), and then vacuum dried.

[0185] Example 3 A method for introducing an R1 palmitoyl group into the peptidyl resin obtained in Example 1. 5 equivalents of palmitic acid previously dissolved in DMF (1 ml) are each added to each of the peptidyl resins obtained in Example 2 in the presence of HOBt and DIPCDI. The mixture is reacted for 3 hours, and then the resin is washed with DMF (3×1 min), DCM (3×1 min), and diethyl ether (3×1 min), and dried under vacuum.

[0186] Example 4 A method for introducing an R1 acetyl group into the peptidyl resin obtained in Example 1. Each of the peptidyl resins obtained in Example 2 is treated with acetic anhydride in the presence of DIEA using DMF as a solvent. The mixture is reacted for 30 minutes, and then the resin is washed with DMF (3×1 min), DCM (3×1 min), and diethyl ether (3×1 min), and dried under vacuum.

[0187] Example 5 A method for cleaving the peptidyl resins obtained in Examples 2, 3, and 4 from the polymer support. Each of the dried peptidyl resins obtained in Examples 2, 3, and 4 is treated with 3 mL of TFA:H2O (95:5, v / v) at room temperature for 2 hours with stirring. Then it is filtered through a polypropylene syringe fitted with a porous polyethylene disk. The filtrate is collected on cold diethyl ether and washed 5 times with diethyl ether. The final precipitate is dried under vacuum. General formula 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 Peptides of -NH2 are obtained according to this method, wherein R1 is H, acetyl or palmitoyl. HPLC analysis of peptides obtained using a gradient of H2O (+0.1% TFA) containing MeCN (+0.07% TFA) shows a purity of over 80% in all cases. The uniqueness of the obtained peptides is confirmed by ESI-MS.

[0188] Example 6 Inhibition of norepinephrine release from human neuroblastoma cells. The release of neurotransmitters via exocytosis at the neuromuscular junction from peripheral neurons to skeletal muscle enables muscle contraction. Facial muscles are affected by this contraction, and it occurs more frequently around the eyes, mouth, and forehead than elsewhere on the face. With age, the continued release of neurotransmitters to the neuromuscular junction and the decrease in elasticity contribute to the increase of facial wrinkles and permanent expression lines. Therefore, compounds that can block or reduce exocytosis at the neuromuscular junction are excellent candidates for cosmetic treatments of non-aesthetic wrinkles. In vitro induction of the neurotransmitter norepinephrine (NA) release in human neuroblastoma cell lines (SH-SY5Y) is considered a direct and reliable method for measuring exocytosis. The objective of this study is to evaluate the efficacy of the peptide of the present invention in inhibiting neuronal exocytosis by measuring the level of NA release in SH-SY5Y cells by enzyme-linked immunosorbent assay (ELISA).

[0189] SH-SY5Y(ECACC) cells, 1 × 10 6Seed in a 12-well plate at a cell / well density. After culturing for 6 days, remove the medium from the wells and treat the cells with the peptide of the present invention dissolved in Hank's balanced salt solution (HBSS, Life Technologies) at 1 and 2.5 mg / ml for 60 minutes. Cells treated with HBSS alone are used as a basic control. To mobilize NA vesicles, remove the supernatant and dissolve 100 nM tetradecanoyl phorbol-13-acetate (TPA, Sigma) in the presence of HBSS containing the test item or in HBSS alone in the case of the basic control. Thereafter, remove the solution containing TPA and dissolve 100 nM TPA in the presence of HBSS containing the test item or in HBSS alone in the case of the basic control, and induce NA release by the addition of 10 μM ionomycin (Epica). Then, collect the medium in the wells containing the released NA and centrifuge. The resulting supernatant is used for the quantification of NA by ELISA using a noradrenaline ELISA kit (IBL International) according to the manufacturer's instructions. Briefly, the direct sandwich ELISA is performed using a plate pre-coated with an anti-NA antibody. The color obtained after the addition of the substrate is directly proportional to the amount of NA present under each condition of the test. Read the absorbance at 405 nm with a microplate absorbance reader (Clariostar, BMG). The percentage of NA release for each condition is calculated based on the basic control. The results of the percentage of NA release relative to untreated cells (basic control) are shown in FIG. 1 and also in the following table.

Table 5

[0190] The results demonstrate that the peptide of the present invention inhibits NA release against the basic conditions in SH-SY5Y at the test concentrations. It is also demonstrated that the peptide of the present invention can reduce NA release to a value even lower than that achieved by Argireline®.

[0191] Increased exocytotic release at the neuromuscular junction is associated with aging as well as the increase in facial wrinkles and expression lines. The peptide of the present invention decreases exocytosis levels in order to decrease NA release in SH-SY5Y. Furthermore, the peptide of the present invention decreases such release even more than Argireline (registered trademark).

[0192] Example 7 In vitro study of type I collagen synthesis in human dermal fibroblasts by enzyme-linked immunosorbent assay. Type I collagen is the main collagen in the skin. This molecule, mainly produced by fibroblasts, is involved in the strength and elasticity of this tissue. Therefore, in vitro quantification of collagen induction by cosmetics on human dermal fibroblasts provides information on the potential anti-aging effect on the skin. Collagen induction by the peptide of the present invention is evaluated by enzyme-linked immunosorbent assay (ELISA). The purpose of this study is to investigate the ability of products to induce type I collagen synthesis in primary human dermal fibroblasts (HDFn) isolated from neonatal skin.

[0193] HDFn (cascade) was plated in a 48-well plate at 5×10 4Seeds are seeded at the specified density. After 24 hours of incubation, fresh medium containing a scalar dilution of the test item at 0.5 μg / ml is added. Untreated cells are used as a basic control. Cells are treated for 48 hours. Next, the medium from the wells is collected and transferred to a 96-well plate. A standard calibration curve prepared with calf skin type I collagen (Sigma) is also transferred to the plate. The plate is left overnight to coat its surface with type I collagen. Collagen I is then detected with anti-collagen type I antibody (Sigma). The primary antibody is then recognized by the secondary antibody IgG-HRP (molecular probe). 3,3,5,5-tetramethylbenzidine liquid substrate (TMB, Sigma) is added to measure the amount of attached secondary antibody. The color produced by this reaction is measured with a microtiter plate reader (Clariostar, BMG), and the concentration of type I collagen is determined using linear regression of the standard curve. The results of collagen synthesis versus untreated cells are shown in Figure 2 and also in the table below. [Table 6]

[0194] The results demonstrate that the peptide of the present invention promotes type I collagen production under the baseline conditions of HDFn at the test concentration. Furthermore, the results demonstrate that the peptide of the present invention produces similar or increased type I collagen compared to Argireline®.

[0195] During the aging process of the skin, type I collagen decreases. The peptides of the present invention increase type I collagen produced by HDFn. In particular, the efficacy of peptides PEP-21 and PEP-23 in increasing type I collagen is even greater than that observed with Argireline® peptides.

[0196] Example 8 In vitro quantification of muscleblind-like protein 1 in human skeletal muscle cells by time-resolved fluorescence resonance energy transfer. Aging is associated with a decrease in muscle mass due to the activation of muscle atrophy-related events. Among the processes associated with muscle atrophy, a decrease in the function of muscle blind-like protein 1 (MBNL1) is linked to the decrease in muscle mass associated with the aging process of facial muscles. Therefore, compounds that can enhance MBNL1 can be used as an excellent approach to cosmetic treatment for the appearance of sagging faces caused by muscle loss.

[0197] MBNL1 induction by the peptides of this invention is evaluated by time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The objective of this study is to investigate the ability of candidate peptides to increase MBNL-1 in human skeletal muscle cells (hSkMc).

[0198] hSkMc(Innoprot) was incubated in skeletal muscle cell growth medium (Promocell) at a rate of 1.5 x 10⁻¹⁰ 4 Cells are seeded in a 12-well plate at a cell / well density. After 72 hours of incubation, the medium is removed and replaced with skeletal muscle cell differentiation medium (Promocell). 48 hours after the start of cell differentiation, fresh differentiation medium containing 0.5 mg / ml of the test item is added. Treatment is continued for 48 hours, and untreated cells are used as a basic control. After 48 hours of treatment, the cell medium is removed and cell lysis buffer is added to the wells. Immediately, the plate is kept at -80°C to improve protein extraction during the thawing process. After 72 hours, the cells are lysed by shaking the plate in an orbital rotor at room temperature for 45 minutes. The cell lysates are then collected and assayed to quantify the MBNL-1 protein level and total protein concentration.

[0199] Measurement of MBNL-1 protein levels is performed using the Human MBNL1 Assay Kit (Cisbio) according to the manufacturer's instructions. 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 assay. Quantification is performed using a microplate reader (ClarioStar, BMG) set to 665 nm and 620 nm.

[0200] 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 the 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 level of MBNL1 protein concentration obtained by the TR-FRET test of the sample. The results of induced %MBNL1 protein relative to the base control are shown in Figures 3 and 3a, and also in the table below. [Table 7]

[0201] The results demonstrate that the peptides PEP-22, PEP-23, PEP-24, PEP-26, PEP-27, PEP-41, PEP-30, PEP-31, PEP-35, PEP-36, PEP-42, PEP-43, PEP-44, and PEP-37 of the present invention increase MBNL1 levels compared to a baseline control and Argireline®. In fact, the results show that Argireline® does not affect MBNL1 even at twice the concentration (1 mg / mL) of the peptides of the present invention (0-5 mg / mL). Enhancement of 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.

[0202] Example 9 Preparation of a cream containing a solution of the peptide PEP-21, specifically the Ac-L-Arg-L-Arg-L-Gln-L-Glu-L-Glu-NH2 peptide. Dissolve the components of Phase A: 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) in a suitable container. 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). Next, heat the mixture to 70-75°C.

[0203] In a separate container, the components of Phase B—Schercemol® DIS Ester (INCI: diisopropyl sebacate), Phytocream® 2000 (INCI: glyceryl stearate, cetearyl alcohol, palmitoyl hydrolyzed wheat protein K), 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. The emulsion is produced by slowly adding phase A to phase B under conditions of high-speed stirring by a turbine.

[0204] Once the mixture has cooled to 40°C, the C-phase component: Novemer® EC-1 polymer (INCI: mineral oil (PARAFFINUM LIQUIDUM), water (Aqua), acrylate / acrylamide crosspolymer, polysorbate 85) is added to the mixture while stirring and mixed until dispersed. Phase D: Add the peptide PEP-21 solution (INCI: glycerin, water (aqua), peptide PEP-21) to the mixture above. Phase E: Fragrance (INCI: Fragrance (Parfum)) is added. Adjust the pH to 6.0 - 6.5 with the components of Phase F: 20% w / w sodium hydroxide (INCI: Aqua, Sodium Hydroxide). [Table 8]

[0205] Example 10 Preparation of a gel cream containing the peptide PEP - 23 (Ac - L - Arg - L - Arg - L - Gln - D - Met - L - Glu - L - Glu). In a suitable container, disperse the components of Phase A: water (INCI: Aqua), Zemea (trademark) (INCI: Propanediol), Phenoxetol (registered trademark) (INCI: Phenoxyethanol), Dissolvine (registered trademark) NA2 (INCI: Disodium EDTA), and potassium sorbate granules (potassium sorbate). Add the components of Phase A1: Carbopol (registered trademark) Ultrez 21 Polymer (INCI: (Acrylate / C10 / 30 Alkyl Acrylate) Crosspolymer) to the previous mixture while stirring. After dispersion, introduce Phase A2: xanthan gum (INCI: Xanthan Gum) into the previous mixture and stir until completely dispersed.

[0206] In a separate container, weigh the components of Phase B: Schercemol (trademark) 1818 Ester (INCI: Isostearyl Isostearate). The emulsion is made by slowly adding Phase B to Phase A under the condition of high - speed stirring with a turbine. Add Phase C: peptide PEP - 23 solution (INCI: Aqua, Caprylyl Glycol, Peptide PEP - 23) to the previous mixture. Adjust the pH to 6.0 - 6.5 with the components of Phase D: 20% w / w sodium hydroxide (INCI: Aqua, Sodium Hydroxide). [Table 9]

[0207] Example 11 Preparation of a gel containing a 2% peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-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. Phase A1: Add Carbopol® ultraz10 polymer (INCI: carbomer) to the above mixture and mix until completely dispersed. Phase B: Add the peptide PEP-23 solution (INCI: water (aqua), caprylyl glycol, PEP-23) to the mixture above and mix. Phase C: EUMULGIN (registered trademark) CO40 (INCI: PEG-40 hydrogenated castor oil), Fragrance (INCI: perfume) are added to the above mixture and mixed. Phase D components: The pH is adjusted to 6.0-6.5 using 20% ​​w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 10]

[0208] Example 12 Preparation of a lotion containing a 2% peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-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. 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.

[0209] In a separate container, the ingredients of Phase B are: 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 (trademark) (INCI: phenoxyethanol) are mixed, and the resulting mixture is heated to 70-75°C. The emulsion is produced by slowly adding phase A to phase B under conditions of high-speed stirring by a turbine.

[0210] 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 PEP-23 solution (INCI: water (aqua), caprylyl glycol, Peptide PEP-23) are added to the mixture. Phase D components: The pH is adjusted to 6.0-6.5 using 20% ​​w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 11]

[0211] Example 13 Preparation of a liquid emulsion containing a 2% peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-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. 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.

[0212] 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. The mixture is cooled to 40°C, and the following components are added: Phase C: BRB CM 56-S (INCI: cyclomethicone), peptide PEP-23 solution (INCI: water (aqua), caprylyl glycol, peptide PEP-23), and Fragrance (INCI: fragrance (parfum)). The pH is adjusted to 6.0-6.5 with the component of Phase D: sodium hydroxide 20% w / w (INCI: water (aqua), sodium hydroxide). [Table 12]

[0213] Example 14 An in vivo study to evaluate the anti-wrinkle effect of the peptide of the present invention after long-term application to female volunteers with Caucasian skin type. The study will be conducted over 28 days. It will include 30 Caucasian female volunteers aged 35 to 50 years with facial wrinkles. The subjects will apply the composition described in Example 10 (active cream) to one side of their face (left or right), and a placebo cream having the same composition except for the peptide of the present invention. The active cream and placebo cream will be applied twice a day (morning and evening) for 28 days. The subjects will serve as their own baseline, and the results obtained at 14 and 28 days will be compared to the results obtained at the initial stage. Furthermore, the results obtained with the active cream will be compared to the results obtained with the placebo cream.

[0214] The anti-wrinkle effect of the composition on the faces of volunteers is evaluated as follows. - Wrinkle depth: Images of the crow's feet wrinkle area of ​​volunteers were taken using a 3D microtopography imaging system. Wrinkle depth was measured at the first day of product application, 14 days later, and 28 days later. The results are shown in Table 10. [Table 13] The results demonstrate a statistically significant reduction in wrinkle depth 14 and 28 days after application of the composition of the present invention, compared to the initial measurement. Furthermore, the reduction in wrinkle depth is greater with the active cream than with the placebo cream. - Wrinkle amount: Images of the crow's feet wrinkle area of ​​volunteers were taken using a 3D microtopography imaging system. Wrinkle amount was measured at the first day, 14 days, and 28 days after product application. The results are shown in Table 11. [Table 14] The results demonstrate a statistically significant reduction in the amount of wrinkles 14 and 28 days after product application compared to the initial assessment. Furthermore, the reduction in wrinkles was greater with the active cream than with the placebo. - Wrinkle length: Images of the crow's feet wrinkle area of ​​volunteers were taken using a 3D microtopography imaging system. Wrinkle length was measured first, 14 days, and 28 days after product application. The results are shown in Table 12. [Table 15] The results demonstrate a statistically significant reduction in wrinkle length 14 and 28 days after product application compared to the initial assessment. Furthermore, the reduction in wrinkle length was greater with the active cream than with the placebo. - Clinical evaluation of skin wrinkles: Skin wrinkles were evaluated by a dermatologist using a clinical scale at the first day, 14 days, and 28 days after product application. The results are shown in Table 13. [Table 16] The results demonstrate that 28 days after product application of the active cream composition, a higher percentage of subjects showed improvement in skin wrinkles compared to the placebo cream. - Self-assessment: After 28 days, volunteers receiving the active cream and placebo completed a self-assessment to evaluate the effectiveness of both products. The results are shown in Table 14. [Table 17] The results, according to volunteer responses, demonstrate that after 28 days, the active cream showed greater improvement than the placebo.

[0215] Example 15 Preparation of a gel cream containing peptide PEP-22 (Ac-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu). 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. 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.

[0216] In a separate container, weigh out the component of phase B: Schercemol (trademark) 1818 Ester (INCI: isostearyl isostearate). The emulsion is prepared by slowly adding phase B to phase A while rapidly stirring it with a turbine. Phase C: Add the peptide PEP-22 peptide solution (INCI: water (aqua), caprylyl glycol, peptide PEP-22) to the mixture above. Phase D components: The pH is adjusted to 6.0-6.5 using 20% ​​w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 18]

[0217] Example 16 Preparation of a lotion containing 2% PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2) and 2% ARGIRELINE® peptide 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. 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.

[0218] In a separate container, the ingredients of Phase B are: 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 (trademark) (INCI: phenoxyethanol) are mixed, and the resulting mixture is heated to 70-75°C. The emulsion is produced by slowly adding phase B to phase A under conditions of rapid stirring by a turbine.

[0219] Once the mixture has cooled to 40°C, add the following to the mixture: 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)), ARGIRELINE® peptide (INCI: water (aqua), acetyl hexapeptide-8, caprylyl glycol), and PEP-23 peptide solution (INCI: water (aqua), caprylyl glycol, PEP-23 peptide)). Phase D components: The pH is adjusted to 6.0-6.5 using 20% ​​w / w sodium hydroxide (INCI: water (aqua), sodium hydroxide). [Table 19]

[0220] Example 17 In vitro reduction of muscle mass reduction effect induced in human skeletal muscle cells by immunofluorescence. The correction of muscle mass loss by the peptides of this invention is evaluated by immunofluorescence assay. The objective of this study is to investigate the ability of candidate peptides to mitigate muscle mass loss after TNF-α treatment in human musculoskeletal cells (hSKMCs), i.e., to reverse the adverse effects induced by TNF-α (a model of muscle aging). Myosin heavy chain (MHyC) is used as a morphological marker of differentiated myotubes, allowing for the measurement of diameter, which can be used to confirm the degree of mass loss. Tumor necrosis factor α (TNF-α) has been documented in the literature as a muscle mass loss inducer.

[0221] hSKMC (Tebu-Bio) in skeletal muscle cell growth medium (Promocell) in 1.5 × 10⁶ units. 4Cells 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, 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 a basic control (BC). 24 hours after the induction of mass reduction, the culture medium is replaced in several well plates with fresh differentiation medium containing 0.01 mg / ml of the peptide of the present invention. TNFα-treated cells not treated with the peptide are used as a mass reduction control (BC+TNF), and cells not treated with either the peptide of the present invention or TNFα are used as a basic mass reduction control (BC). 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, Vitro) was added, and the cells were incubated overnight at 4°C. Subsequently, the secondary antibody Alexa Fluor 488 goat anti-mouse IgG (1:250, Life Technologies) was added, and the cells 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 mass loss threshold of 20 μm. The results of % muscle mass loss compared to untreated cells of the base control are shown in Figure 4 and Table 17. The results are normalized against the mass loss control (BC+TNF). [Table 20] These results demonstrate that the peptides PEP-22 and PEP-23 of the present invention reduce mass loss compared to a basic control treated with TNF-α.

[0222] Example 18 In vitro effects of PEP-22 and PEP-23 on lipid accumulation in human subcutaneous preadipocytes. As we age, the skin experiences a decrease in adipose tissue, leading to an aesthetically distorted reduction in facial volume. This decrease in adipose tissue is primarily caused by the aging of adipocytes, that is, when adipocytes become unable to differentiate and therefore normal lipid storage decreases. Furthermore, aging adipocytes express aging-associated secretory phenotypes (SASPs), which induce aging in younger adipocytes.

[0223] Measuring lipid accumulation in co-cultures of young and aged adipocytes indirectly assesses the inhibition of SASP. A pool of aged adipocytes contains more senescent cells. When co-cultured with young cells, the observed lipid accumulation is below theoretically expected levels due to the aging-inducing effect of SASP from aged adipocytes to young adipocytes. Therefore, compounds that can increase lipid accumulation can be used as an excellent approach to prevent facial volume loss caused by adipocyte aging.

[0224] The induction of lipid accumulation by the peptides of the present invention is evaluated using the Adipored® assay reagent and lipid fluorescence staining. The purpose of this study is to investigate the ability of candidate peptides to induce lipid accumulation in human subcutaneous adipocytes and, consequently, to prevent adipocyte aging.

[0225] Human subcutaneous preadipocytes (from 26-year-old and 60-year-old donors, Cell applications) were stored 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. 3Cells 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). Simultaneously, co-cultured cells are treated with 0.01 mg / ml of the peptide of this invention. Untreated co-cultured cells are used as a basic 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 basic control. Figure 5 and Table 18 show the percentage of lipid content compared to untreated cells (basic control). Abbreviations: %LA = percentage of lipid accumulation, CC = co-culture control, YC = young control, OC = old control [Table 21] The results demonstrate that the peptides PEP-22 and PEP-23 of the present invention increase lipid accumulation in adipocytes compared to a basic control (co-culture, CC) that was not treated with the peptides. The percentage of lipid accumulation in cells treated with PEP-22 and PEP-23 is similar to that in young cells. During the aging process, lipid accumulation in adipocytes decreases with age. The peptide of the present invention increases lipid accumulation in co-cultured HPAd cells, thereby preventing the aging of adipocytes.

[0226] Example 19 An in vivo study to evaluate the anti-wrinkle effect of the peptide PEP-23 of the present invention after long-term application to female volunteers with Caucasian skin type. The study will be conducted over 28 days. Forty-one Caucasian female volunteers aged 35 to 60 years with facial wrinkles will be included in the study. Each subject will apply the composition described in Example 10 (active cream) to one side of their face (left or right) and a placebo cream having the same composition except for the peptide of the present invention to the opposite side of their face. The active cream and placebo cream will be applied twice daily (morning and evening) for 28 days. Each subject will serve as their own baseline, and the results obtained after 5, 14, and 28 days will be compared to the results obtained at the initial stage. Furthermore, the results obtained with the active cream will be compared to the results obtained with the placebo cream.

[0227] Skin isotropy is assessed by analyzing images of crow's feet wrinkles from volunteers, taken with a PRIMOS 3D microtopography imaging system. Isotropy determines how the collagen fibers in the skin are structured and oriented. High levels of isotropy correspond to collagen fibers uniformly oriented in various directions and are characteristic of young skin. Low levels of isotropy (i.e., anisotropy) are characteristic of aged skin. Therefore, it is desirable to increase the level of skin isotropy to provide a youthful appearance.

[0228] Images taken with the PRIMOS 3D microtopography imaging system 5, 14, and 28 days after product application were analyzed to measure skin isotropy. The results are shown in Table 19. [Table 22] Skin isotropy increases 5, 14, and 28 days after product application. The results demonstrate an increase in skin isotropy 5, 14, and 28 days after application of the active cream, compared to the initial state (i.e., the baseline on day 1). Furthermore, the increase in skin isotropy was greater with both the active cream and the placebo cream.

[0229] Example 20 An in vivo study to evaluate the effect of the PEP-23 peptide on the facial volume of female volunteers with white skin type after long-term application. In the process of aging, there is a natural process in which the facial volume decreases and the appearance of skin sagging increases. To evaluate the effect of PEP-23 on facial volume, a 28-day study was conducted, and the effectiveness of the product was evaluated in 19 white female volunteers aged 35 to 45 years. The subjects applied the composition described in Example 10 (active cream) to one side of the face (left or right), and a placebo cream having the same composition except for the peptide of the present invention was applied to the remaining half of the face. The active cream and the placebo cream are applied twice a day (in the morning and evening) for 28 days. The subjects serve as their own reference, and the results obtained after 14 days and 28 days are compared with the results obtained at the first time (at the start of the first day). Further, the results obtained with the active cream are compared with the results obtained with the placebo cream.

[0230] The increase in volume of the volunteer's face is evaluated after obtaining the facial topography of the entire face with a 3D device. The volume of the cheek area was analyzed using dedicated software. The measurement results on the 5th, 14th day and 28 days after product application are analyzed to obtain the facial volume of the cheek area. The results are shown in Table 20.

Table 23

[0231] Various aspects and embodiments of the present invention are defined by the following appended items. 1. A compound of formula (I), R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Z q-R2(I), During the ceremony, AA1 is Arg, Lys, or amino acid-free. AA2 is Arg or Lys, AA3 is Gln, Glu, Asn, or Asp. AA4 is either Met or Leu, AA5 is Glu, Asp, or Gln. AA6 is Glu, Asp, Gln, 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-, where 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, where R3 and R4 are independently selected from the group consisting of H, polyethylene glycol-derived polymers, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids. Compounds, their stereoisomers, and / or cosmetically acceptable salts. 2. The compound described in item 1, wherein the compound is not Arg-Arg-Glu-Leu-Glu-Glu-Leu. 3. The compound described in item 1 or 2, wherein each of AA1, AA2, AA3, AA4, AA5, and AA6 is an L-amino acid. 4. A compound according to any one of items 1 to 3, wherein at least one of AA1, AA2, AA3, AA4, AA5, and AA6 is a D-amino acid. 5. The compound described in item 4, wherein one, two, or three of AA1, AA2, AA3, AA4, AA5, and AA6 are D-amino acids, and the remaining ones from AA1 to AA6 are L-amino acids. 6. The compound described in section 5, wherein one, two, or three of AA3, AA4, and AA5 are D-amino acids. 7. The compound according to item 6, wherein one or two of AA3, AA4, and AA5 are D-amino acids, and the remainder of AA1 to AA6 are L-amino acids, preferably AA4 is a D-amino acid and the remainder of AA1 to AA6 are L-amino acids. 8. The compound is, R1-W m -X n -L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-Y p -Z q -R2(II), R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(III), or R1-W m -X n -L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-Y p -Z q A compound described in item 7, having the formula -R2(IV). 9. R1 is selected from the group consisting of H and R5-CO-, and in the formula, R5 is C1~ 18 Alkyl, C2~C 24 Alkenil, C3~C 24 Selected from the group consisting of cycloalkyls, where R2 is -NR3R4 or -OR3, and in the formula, R3 and R4 are independently H and C1-C 16 A compound selected from the group consisting of alkyl groups, as described in any one of items 1 to 8. 10. The compound is Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH2(PEP-21), Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH2(PEP-22), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-23), or The compound described in item 1, which is Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-24). 11. Combinations of any one of the compounds described in paragraphs 1 to 10 or their stereoisomers and / or cosmetically acceptable salts, with botulinum toxin and / or peptides of the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2. 12. A composition comprising a cosmetically effective amount of a compound of formula (I) described in any one of items 1 to 10, a stereoisomer thereof and / or a cosmetically acceptable salt, or a combination described in item 11, and at least one cosmetically acceptable excipient or auxiliary agent. 13. Use of any one of the compounds described in paragraphs 1 to 10, their stereoisomers and / or cosmetically acceptable salts for cosmetic and non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes. 14. Use as described in paragraph 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, and / or the reduction and / or prevention of facial asymmetry. 15. Methods for cosmetic and 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 the items 1 to 10, the combination described in item 11, or the composition described in item 12. 16. The compound described in Section 1 or 2, wherein AA1 is Arg and / or AA2 is Arg. 17. A compound according to any one of the following paragraphs, 1, 2, or 16, wherein AA3 is Gln or Asp. 18. A compound according to any one of items 1, 2, 16, or 17, wherein each of AA1, AA2, AA3, AA4, AA5, and AA6 is an L-amino acid. 19. A compound according to any one of items 1, 2, 16, or 17, wherein at least one of AA1, AA2, AA3, AA4, AA5, and AA6 is a D-amino acid. 20. The compound described in item 19, wherein one, two, or three of AA1, AA2, AA3, AA4, AA5, and AA6 are D-amino acids, and the remaining AA1-AA6 are L-amino acids. 21. The compound described in section 20, wherein one, two, or three of AA3, AA4, and AA5 are D-amino acids. 22. The compound according to claim 21, wherein one or two of AA3, AA4, and AA5 are D-amino acids, and the remainder of AA1 to AA6 are L-amino acids, preferably AA4 is a D-amino acid and the remainder of AA1 to AA6 are L-amino acids. 23. The compound, R1-W m -X n -L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-Y p -Z q -R2(II), R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(III), or R1-W m -X n -L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-Y p -Z q A compound described in item 22, having the formula -R2(IV). 24. R1 is selected from the group consisting of H and R5-CO-, and in the formula, R5 is C1~C 18 Alkyl, C2~C 24 Alkenil, C3~C 24Selected from the group consisting of cycloalkyls, where R2 is -NR3R4 or -OR3, and in the formula, R3 and R4 are independently H and C1~C 16 A compound selected from the group consisting of alkyl groups, as described in item 1, item 2, or any one of items 16 to 23. 25. R1 is selected from the group consisting of H, acetyl or palmitol, lauroyl or myristyl, and R2 is -NR3R4 or -OR3, where R3 and R4 are H and C1-C 16 A compound independently selected from the group consisting of alkyl groups, as described in item 24. 26. The compound according to item 25, wherein R1 is selected from the group consisting of H, acetyl, or palmitol, R2 is -NH2 or -OH, R3 is H, R4 is H, preferably R1 is acetyl and R2 is NH2. 27. The compound is, Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH2(PEP-21), Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH2(PEP-22), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-23), or The compound described in item 1, which is Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-24). 28. Combinations of a compound or its stereoisomer and / or cosmetically acceptable salt described in any one of paragraphs 1, 2, or 16-27, with botulinum toxin and / or the peptide of sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2. 29. A composition comprising a cosmetically effective amount of a compound of formula (I) as described in any one of the items 1, 2, or 16-27, a stereoisomer thereof and / or a cosmetically acceptable salt, or a combination as described in item 28, and at least one cosmetically acceptable excipient or auxiliary agent. 30. Use of the compounds described in any one of the paragraphs 1, 2 or 16-27, their stereoisomers and / or cosmetically acceptable salts for cosmetic and non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes. 31. The use described in paragraph 30, wherein 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, and / or the reduction and / or prevention of facial asymmetry. 32. 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 the compound described in any one of paragraphs 1, 2 or 16-27, the combination described in paragraph 28 or the composition described in paragraph 29. 33. The method according to paragraph 15 or 32, wherein the non-therapeutic cosmetic 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, and / or the reduction and / or prevention of facial asymmetry. The present invention provides, for example, the following items: (Item 1) A compound of formula (I), R1-W m -X n -AA1-AA2-AA3-AA4-AA5-AA6-Y p -Z q -R2(I) During the ceremony, AA1 is Arg, Lys, or amino acid-free. AA2 is Arg or Lys, AA3 is Gln, Glu, Asn, or Asp. AA4 is either Met or Leu, AA5 is Glu, Asp, or Gln. AA6 is Glu, Asp, Gln, 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-, where 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, where R3 and R4 are independently selected from the group consisting of H, polyethylene glycol-derived polymers, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R1 and R2 are not amino acids. Compounds, their stereoisomers, and / or cosmetically acceptable salts. (Item 2) The compound described in item 1, wherein W, X, Y, and Z are each independently selected from the group consisting of Ala, Gly, Val, and Ile. (Item 3) A compound as described in item 1 or item 2, wherein AA3 is Gln or Asp. (Item 4) A compound according to any one of items 1 to 3, wherein AA5 is selected from the group consisting of Glu and Asp, and AA6 is selected from the group consisting of Glu, Gln, or no amino acids. (Item 5) A compound according to any one of items 1 to 4, wherein AA1 is selected from the group consisting of Arg and Lys, and AA6 is selected from the group consisting of Glu and Gln. (Item 6) A compound as described in any of items 1-5, wherein AA1 is Arg and / or AA2 is Arg. (Item 7) A compound described in any one of items 1 to 6, wherein one, two, or three of AA1, AA2, AA3, AA4, AA5, and AA6 are D-amino acids, and the remaining AA1 to AA6 are L-amino acids. (Item 8) A compound as described in item 7, wherein one, two, or three of AA3, AA4, and AA5 are D-amino acids. (Item 9) The compound according to item 8, wherein one or two of AA3, AA4, and AA5 are D-amino acids, and the remainder of AA1 to AA6 are L-amino acids, preferably AA4 is a D-amino acid and the remainder of AA1 to AA6 are L-amino acids. (Item 10) The aforementioned compound, R1-W m -X n -L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-Y p -Z q -R2(II), R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(III), R1-W m -X n -L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(IV), R1-W m -X n -L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu-Y p -Z q -R2(V), R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Met-L-Asp-L-Glu-Yp -Z q -R2(VI), R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Gln-Y p -Z q -R2(VII), R1-W m -X n -L-Arg-L-Lys-L-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(VIII), R1-W m -X n -L-Lys-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(IX), R1-W m -L-Ala-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-L-Ala-Z q -R2(X), R1-W m -X n -L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y p -Z q -R2(XI), R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Met-L-Glu-Y p -Z q -R2(XII), or R1-W m -X n -L-Arg-L-Arg-L-Gln-D-Leu-L-Glu-L-Glu-Y p -Z q A compound described in item 9 having the formula -R2(XIII). (Item 11) R1 is selected from the group consisting of H and R5-CO-, and in the formula, R5 is C1~C 18 Alkyl, C2~C 24 Alkenil, C3~C 24Selected from the group consisting of cycloalkyls, where R2 is -NR3R4 or -OR3, and in the formula, R3 and R4 are independently H and C1-C 16 A compound selected from the group consisting of alkyl groups, as described in any one of items 1 to 10. (Item 12) R1 is selected from the group consisting of H, acetyl or palmitol, lauroyl or myristyl, R2 is -NR3R4 or -OR3, where R3 and R4 are H and C1-C 16 A compound independently selected from the group consisting of alkyl groups, as described in item 11. (Item 13) The compound according to item 12, wherein R1 is selected from the group consisting of H, acetyl, or palmitol, R2 is -NH2 or -OH, R3 is H, R4 is H, preferably R1 is acetyl and R2 is NH2. (Item 14) The aforementioned compound, Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH2(PEP-21), Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH2(PEP-22), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-23), Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-24), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-OH(PEP-26), HL-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-27), Ac-L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu-NH2(PEP-41), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Asp-L-Glu-NH2(PEP-30), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Gln-NH2(PEP-31), Ac-L-Arg-L-Lys-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-35), Ac-L-Lys-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-36), Ac-L-Ala-L-Arg-L-Arg-Gln-D-Met-L-Glu-L-Glu-L-Ala-NH2(PEP-42), Ac-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH2(PEP-43), Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-NH2(PEP-44), or The compound described in item 1, which is Ac-L-Arg-L-Arg-L-Gln-D-Leu-L-Glu-L-Glu-NH2(PEP-37). (Item 13) A combination of any one of the compounds described in items 1-12 or their stereoisomers and / or cosmetically acceptable salts with botulinum toxin and / or the peptide of the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2. (Item 14) A composition comprising a cosmetically effective amount of a compound of formula (I) described in any one of items 1 to 12, its stereoisomer and / or a cosmetically acceptable salt, or a combination described in item 13, and at least one cosmetically acceptable excipient or auxiliary agent. (Item 15) Use of any one of the compounds described in items 1 to 12, their stereoisomers and / or cosmetically acceptable salts for cosmetic and non-therapeutic treatment and / or care of the skin, hair, nails and / or mucous membranes. (Item 16) The use described in item 15, wherein 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, and the prevention and / or reduction of the effects of increased and / or decreased adipose tissue volume. (Item 17) A method for cosmetic and 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 described in any one of items 1 to 12, a combination described in item 13, or a composition described in item 14. (Item 18) Methods for cosmetic non-therapeutic treatment and / or care of the subject skin, hair, nails and / or mucous membranes as described in item 17, wherein 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, and the prevention and / or reduction of the effects of increased and / or decreased adipose tissue volume.

Claims

1. Equation (I) R １ -AA １ -AA ２ -AA ３ -AA ４ -AA ５ -AA ６ -R ２ (I) Compounds thereof, their stereoisomers and / or cosmetically acceptable salts, During the ceremony, AA １ is Arg or Lys, AA ２ is Arg or Lys, AA ３ is GLN, AA ４ It is Met, AA ５ This is either Glu or Asp, AA ６ Glu is, R １ H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl, and R ５ Selected from the group consisting of -CO-, in the formula, R ５ This is selected from the group consisting of H, an acyclic aliphatic group, alicyclyl, aryl, aralkyl, heterocyclyl, and heteroarylalkyl. R ２ -NR ３ R ４ , -OR ３ ,-SR ３ Selected from the group consisting of, in the formula, R ３ and R ４ These are independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, and aralkyl. R １ and R ２ It is not an amino acid, AA ３ and AA ４ However, it is an L-amino acid, The polymer derived from polyethylene glycol is (-CH2-CH2-O)r-H (wherein r is a number from 4 to 795), and 【Chemistry 1】 Selected from the group consisting of (wherein s is a number from 1 to 125), Compounds, their stereoisomers, and / or cosmetically acceptable salts.

2. AA １ However, Arg and / or AA ２ The compound according to claim 1, its stereoisomers and / or cosmetically acceptable salts, wherein the compound is Arg.

3. AA １ AA ２ AA ３ AA ４ AA ５ and AA ６ The compound according to claim 1, its stereoisomers and / or cosmetically acceptable salts, each of which is an L-amino acid.

4. AA １ L-Arg and AA ２ L-Arg and AA ３ L-Gln and AA ４ L-Met and AA ５ L-Glu is AA ６ The compound according to claim 1, its stereoisomers and / or cosmetically acceptable salts, wherein L-Glu is the compound.

5. R １ However, H and R ５ Selected from the group consisting of -CO-, in the formula, R ５ However, C １ ~C １８ Alkyl, C ２ ~C ２４ Alkenil, C ３ ~C ２４ Selected from the group consisting of cycloalkyls, R ２ ga-NR ３ R ４ OR ３ And in the formula, R ３ and R ４ However, independently, H and C １ ~C １６ A compound according to claim 1, a stereoisomer thereof, and / or a cosmetically acceptable salt, selected from the group consisting of alkyl groups.

6. R １ However, R is selected from the group consisting of H, acetyl or palmitol, lauroyl or myristyl, ２ However, -NR ３ R ４ OR ３ And in the formula, R ３ and R ４ However, H and C １ ~C １６ A compound according to claim 5, a stereoisomer thereof, and / or a cosmetically acceptable salt, independently selected from the group consisting of alkyl groups.

7. R １ However, it is selected from the group consisting of H, acetyl, or palmitol, and R ２ However, -NH ２ Or -OH, R ３ However, H is R ４ The compound according to claim 6, its stereoisomers and / or cosmetically acceptable salts, wherein H is present.

8. The compound according to claim 7, its stereoisomer and / or cosmetically acceptable salt, wherein R1 is acetyl and R2 is NH2.

9. The aforementioned compound, Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH ２ (PEP-21) The compound according to claim 1, its stereoisomers and / or cosmetically acceptable salts.

10. A compound according to any one of claims 1 to 9, or a stereoisomer thereof and / or a cosmetically acceptable salt, and botulinum toxin and / or sequence Ac-Glu-Glu-Met-Glun-Arg-Arg-NH ２ A combination of peptides.

11. A composition comprising a cosmetically effective amount of a compound of formula (I) according to any one of claims 1 to 9, a stereoisomer thereof and / or a cosmetically acceptable salt, or a combination according to claim 10, and at least one cosmetically acceptable excipient or auxiliary agent.

12. A composition comprising a compound according to any one of claims 1 to 9, a stereoisomer thereof, and / or a cosmetically acceptable salt, or a combination according to claim 10, or a composition according to claim 11, for the cosmetic and non-therapeutic treatment and / or care of the target skin, hair, nails, and / or mucous membranes.

13. A composition or combination for cosmetic non-therapeutic treatment and / or care of the target skin, hair, nails and / or mucous membranes as described in claim 12, wherein the cosmetic non-therapeutic treatment and / or care is the treatment and / or prevention of skin aging.

14. A composition or combination for cosmetic non-therapeutic treatment and / or care of the target skin, hair, nails and / or mucous membranes as described in claim 12, wherein the cosmetic non-therapeutic treatment and / or care is the reduction and / or prevention of wrinkles of the skin.

15. A composition or combination for cosmetic non-therapeutic treatment and / or care of the target skin, hair, nails and / or mucous membranes as described in claim 12, wherein the cosmetic non-therapeutic treatment and / or care is stimulation of collagen synthesis and / or prevention of collagen reduction.

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