RU2847265C2 - Tetrapeptide derivative, cosmetic composition or pharmaceutical composition and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a peptide derivative of formula I: R₁-Pro-Lys-Glu-Lys-R₂, its cosmetic or pharmaceutical composition and use thereof. Peptide derivative is obtained by covalent bonding of niacin or tranexamic acid with the peptide; it has the effect of removing the inflammatory reaction of the skin and inhibiting the formation of melanin.

EFFECT: invention can be used in cosmetics or medicine for anti-inflammatory action, as well as bleaching and removal of freckles from the skin, especially for reducing post-inflammatory hyperpigmentation.

16 cl, 4 dwg, 3 tbl, 11 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[1] The present application relates to a peptide derivative, a cosmetic composition or a pharmaceutical composition comprising the peptide derivative, and their use in the treatment or care of skin and mucous membrane.

LEVEL OF TECHNOLOGY

[2] The skin is exposed to the external environment and is easily affected by various physical, chemical and pathogenic microorganisms, which leads to damage of skin tissue cells and initiates an inflammatory response. The inflammatory response not only increases the permeability of the skin, causing the release of collagenase and the breakdown of collagen and elastin, resulting in the skin being sagging and aging; moreover, the produced inflammatory factors such as interleukin IL-1α, IL-6 and tumor necrosis factor TNF-α stimulate the migration, proliferation and differentiation of melanocytes, induce the production of proopiomelanocortin (POMC) and α-melanocyte-stimulating hormone (α-MSH) by keratinocytes, and enhance tyrosinase activity, resulting in the skin producing more melanin, and the skin surface becomes darker or spots appear locally.

[3] Post-inflammatory hyperpigmentation (PIH) is one of the common consequences of the inflammatory response of the skin. Currently, the specific pathogenesis of PIH is not fully understood, however, as a secondary pigmentary abnormality, it is closely related to the degree of damage to the basement membranes, the level of inflammation and melanocytes. Bastonini E. found that melanocytes and the surrounding keratinocytes and fibroblasts play an important role in the development of PIH. At the same time, the migration, proliferation and differentiation of melanocytes, the synthesis and activation of tyrosinase and the transfer of melanosomes to keratinocytes can also influence the occurrence of PIH. Some inflammation-modulating factors, such as inflammatory mediators, inflammatory cytokines and α-melanocyte-stimulating hormone (α-MSH), also play a role in modulating the above-mentioned activities to varying degrees.

[4] The main treatment for PIH is to control the inflammatory response and inhibit melanin synthesis to reduce persistent pigmentation associated with the microinflammatory condition. Currently, glucocorticoids such as desonide and hydrocortisone are mainly used to control the inflammatory response. In addition, other compounds are used to inhibit melanin synthesis or deposition. For example, arbutin, kojic acid, and ascorbic acid can inhibit melanin synthesis by inhibiting tyrosinase activity. Niacin is converted to nicotinamide in vivo and inhibits the transport of melanin granules from melanocytes to keratinocytes. However, these compounds are usually cytotoxic, irritating to the skin, or chemically unstable, with one compound having only some anti-inflammatory effect or inhibiting melanin formation and needing to be used in combination. Thus, there is a need to develop a new compound that can not only treat the inflammatory response of the skin but also be used to inhibit melanin hyperpigmentation, which will overcome the existing shortcomings of the prior art.

ESSENCE OF THE INVENTION

[5] The present invention is directed to the creation of a polypeptide derivative with a whitening effect and anti-inflammatory activity. Such peptide derivatives and cosmetic compositions or pharmaceutical compositions including these peptide derivatives can produce whitening by reducing the expression of α-MSH or exhibit anti-inflammatory activity by suppressing the expression of IL-6 and TNF-α. They can be used in the field of cosmetics or medicine for an anti-inflammatory effect on the skin, as well as for whitening and removing freckles on the skin, in particular for improving pigmentation after inflammation.

[6] In this regard, the present invention provides a peptide derivative represented by Formula (I), or a stereoisomer or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof,

in Formula (I),

R1 is selected from substituent (i), substituent (ii) or substituent (iii), wherein substituent (i) is:

substituent (ii) is:

substituent (iii) is:

R2 is selected from -NR3R4 or -OR3, where each R3 and R4 is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;

alkyl refers to a saturated aliphatic straight or branched chain alkyl having 1-24 carbon atoms (optionally having 1-16 carbon atoms; optionally having 1-14 carbon atoms; optionally having 1-12 carbon atoms; or optionally having 1, 2, 3, 4, 5, or 6 carbon atoms); optionally selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 2-ethylhexyl, 2-methylbutyl, or 5-methylhexyl;

alkenyl refers to a straight or branched chain alkenyl having 2-24 carbon atoms (optionally having 2-16 carbon atoms; optionally having 2-14 carbon atoms; optionally having 2-12 carbon atoms; optionally having 2, 3, 4, 5, or 6 carbon atoms); the alkenyl has one or more carbon-carbon double bonds or optionally has 1, 2, or 3 conjugated or non-conjugated carbon-carbon double bonds; the alkenyl is bonded to the rest of the molecule through a single bond, optionally selected from vinyl, oleyl, or linoleyl;

optionally, the substituent in the "substituted alkyl" or "substituted alkenyl" is selected from C1-C4 alkyl; hydroxyl; C1-C4 alkoxy; amino; C1-C4 aminoalkyl; C1-C4 carbonyloxy; C1-C4 oxycarbonyl; halogen (such as fluorine, chlorine, bromine and iodine); cyano; nitro; azide; C1-C4 alkylsulfonyl; thiol; C1-C4 alkylthio; C6-C30 aryloxy, such as phenoxy; -NRb(C=NRb)NRbRc, where Rb and Rc are independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl, C6-C18 aryl, C7-C17 aralkyl, a heterocyclic group having 3-10 members, or an amino group protecting group.

[7] Optionally, each R3 and R4 is independently selected from H, methyl, ethyl, hexyl, dodecyl, or hexadecyl;

optionally, R3 is H, and R4 is selected from H, methyl, ethyl, hexyl, dodecyl or hexadecyl;

optionally, R2 is -OH or -NH ₂ .

[8] The peptide derivative represented by Formula (I), or a stereoisomer thereof or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is selected from the following peptide derivatives (1)-(6):

[9] The peptide derivative represented by Formula (I) of the present invention may be present as its stereoisomer or a mixture of its stereoisomers; for example, the amino acids included therein may have the L- or D-configuration, or each of them may independently be racemic. Thus, isomeric mixtures may be obtained, as well as racemic mixtures or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbon atoms and on which isomers or isomeric mixtures are present. Preferred structures of the peptide derivatives represented by Formula (I) of the present invention are pure isomers, i.e. enantiomers or diastereomers.

[10] For example, when -Lys- is indicated in the present invention, it is understood that -Lys- is selected from -L-Lys-, -D-Lys-, or a mixture thereof and is racemic or non-racemic. The production methods described in this document allow one skilled in the art to obtain each stereoisomer of the peptide derivatives of the present invention by selecting an amino acid having the correct configuration.

[11] The term "cosmetically acceptable salt or pharmaceutically acceptable salt" refers to a salt approved for use in animals and in particular in humans, including a metal salt of a peptide derivative represented by Formula (I), wherein the metal includes, but is not limited to, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, etc.; a salt formed from a peptide derivative represented by Formula (I) and an organic base, wherein the organic base includes, but is not limited to, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine, etc.; a salt formed from a peptide derivative represented by Formula (I) and an inorganic acid or an organic acid, wherein the organic acid includes, but is not limited to, acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoic acid or gluconic acid, etc.; the inorganic acid includes, but is not limited to, hydrochloric acid, sulfuric acid, boric acid or carbonic acid.

[12] In another aspect of the present invention, there is provided a cosmetic or pharmaceutical composition comprising an effective amount of a peptide derivative represented by Formula (I), or a stereoisomer or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and at least one excipient and, optionally, a cosmetically or pharmaceutically acceptable adjuvant.

[13] Optionally, the adjuvant is selected from a collagen synthesis stimulator, an agent that modulates PGC-1α synthesis, an agent that modulates PPARγ activity, an agent that increases or decreases adipocyte triglyceride content, an agent that stimulates or delays adipocyte differentiation, a lipolytic agent or an agent that stimulates lipolysis, an lipid-depleting agent, an adipogenic agent, an acetylcholine receptor aggregation inhibitor, an agent that inhibits muscle contraction, an anticholinergic agent, an elastase inhibitor, a matrix metalloproteinase inhibitor, a melanin synthesis stimulator or inhibitor, a bleaching or bleaching agent, a pigmentation promoter, a self-tanning agent, an anti-aging agent, an NO synthase inhibitor, a 5α-reductase inhibitor, a lysyl hydroxylase and/or prolyl hydroxylase inhibitor, an antioxidant, free radical scavengers and/or air pollution control agents, reactive carbonyl scavengers, antiglycating agent, antihistamine, antiviral, antiparasitic, emulsifier, emollient, organic solvent, liquid propellant, skin conditioner, humectant, humectant, alpha hydroxy acid, beta hydroxy acid, humectant, epidermal hydrolase, vitamin, amino acid, protein, pigment or coloring agent, dye, biopolymer, gelling polymer, thickener, surfactant, softener, adhesive, preservative, anti-wrinkle agent, agent that can reduce or treat bags under the eyes, exfoliant, cuticle exfoliant, keratolytic, antimicrobial, antifungal, fungistatic, bactericidal, bacteriostatic, agent that stimulates synthesis of dermal or epidermal macromolecules and/or inhibits or prevents their degradation, an agent that stimulates the synthesis of elastin, an agent that stimulates the synthesis of decorin, an agent that stimulates the synthesis of laminin, an agent that stimulates the synthesis of defensin, an agent that stimulates the synthesis of a chaperone protein, an agent that stimulates the synthesis of cAMP, a heat shock protein, an agent that stimulates the synthesis of HSP70, an agent that stimulates the synthesis of heat shock protein, an agent that stimulates the synthesis of hyaluronic acid, an agent that stimulates the synthesis of fibronectin, an agent that stimulates the synthesis of deacetylase, an agent that stimulates the synthesis of a lipid and a component of the stratum corneum, ceramide, fatty acid, an agent that inhibits the degradation of collagen, an agent that inhibits the degradation of elastin, an agent that inhibits serine protease, an agent that stimulates the proliferation of fibroblasts, an agent that stimulates the proliferation of keratinocytes, an agent that stimulates adipocyte proliferation, an agent that stimulates melanocyte proliferation, an agent that stimulates keratinocyte differentiation, an agent that inhibits acetylcholinesterase, a skin relaxant, an agent that stimulates glycosaminoglycan synthesis, an anti-hyperkeratosis agent, a comedolytic agent, an anti-psoriatic agent, an anti-dermatitis agent, an anti-eczema agent, a DNA repair agent, a DNA protector, a stabilizer, an antipruritic agent, an agent for the treatment and/or care of sensitive skin, a tanning agent, a firming agent, a restructuring agent, an anti-stretch mark agent, an adhesive, an agent that regulates sebum production, an antiperspirant, an agent that stimulates healing, an agent that promotes healing, an agent that stimulates re-epithelialization, an agent that promotes re-epithelialization, a cytokine growth factor, a soothing agent, an anti-inflammatory an agent, an anesthetic agent, an agent acting on capillary blood circulation and/or microcirculation, an agent that stimulates angiogenesis, an agent that inhibits vascular permeability, a venotonic agent, an agent acting on cellular metabolism, an agent for improving the connection of the dermis and epidermis, an agent that causes hair growth, an agent that inhibits or slows down hair growth, a fragrance, a chelating agent, a plant extract, an essential oil, an extract of seaweed, agents obtained as a result of a biological fermentation process, an inorganic salt, a cellular extract, a sunscreen filter and an effective organic or inorganic photoprotector against UVA and/or UVB radiation or mixtures thereof.

[14] Optionally, the cosmetic or pharmaceutical composition preparation is selected from a cream, oil, milk, balm, foam, lotion, gel, liniment, serums, soap, shampoo, hair conditioner, whey, ointment, mousse, pomade, powder, bar, pencil, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, syrup, elixir, polysaccharide film, jelly or gelatin;

optionally, the capsule includes a soft capsule, a hard capsule, optionally a gelatin capsule;

optionally, the tablet includes a sugar-coated tablet.

[15] The peptide derivatives of the present invention have different solubility in water depending on the nature of their sequences or any potential modifications at the N-terminus and/or C-terminus. A peptide derivative of the present invention may thus be included in a composition as an aqueous solution, and those that are insoluble in water may be soluble in common, cosmetically or pharmaceutically acceptable solvents, including, but not limited to, ethanol, propanol, isopropanol, propylene glycol, glycerol, butylene glycol or polyethylene glycol, or any combination thereof.

[16] The cosmetically or pharmaceutically effective amounts of the peptide derivatives of the present invention to be administered, as well as the dosages thereof, will depend on many factors, including the age, condition of the patient, the severity of the disorder or disease, the route and frequency of administration, and the specific properties of the peptide derivatives used.

[17] "A cosmetically or pharmaceutically effective amount" refers to an amount of one or more peptide derivatives according to the present invention that does not cause toxic effects, but is sufficient to obtain the desired effects. The peptide derivative according to the present invention is used in the cosmetic or pharmaceutical composition according to the present invention at a cosmetically or pharmaceutically effective concentration to obtain the desired effects. In a preferred form, relative to the total weight of the composition, the concentration is from 0.00000001% (by weight) to 20% (by weight), preferably from 0.000001% (by weight) to 15% (by weight), more preferably from 0.0001% (by weight) to 10% (by weight), and even more preferably from 0.0001% (by weight) to 5% (by weight).

[18] In another aspect of the present invention, there is provided a cosmetically or pharmaceutically acceptable delivery system or a sustained release system for achieving better penetration of the active ingredient and/or improving its pharmacokinetic and pharmacodynamic properties, which comprises an effective amount of a peptide derivative represented by Formula (I), or a stereoisomer or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as defined above.

[19] The term "delivery system" refers to a diluent, adjuvant, excipient, or carrier administered with the peptide derivative of the present invention, selected from water, oil, or surfactants, including those derived from petroleum, animal, plant, or synthetic sources. Examples include, but are not limited to, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbate, sorbitan ester, ester sulfate, sulfate, betaine, glucoside, maltoside, fatty alcohol, nonoxynol, poloxamer, polyoxyethylene, macrogol, dextrose, glycerol, digitonin, and the like. Diluents that can be used in various delivery systems into which the peptide derivative of the present invention can be introduced are known to those skilled in the art.

[20] The term "sustained release" is used in its generally accepted sense to refer to a delivery system that provides a gradual release of a compound over a period of time and, preferably, but not necessarily, a relatively constant level of the compound is released throughout the period of time.

[21] Examples of the delivery system or sustained release system include a liposome, an oleosome, a nonionic surfactant liposome vesicle, an ethosome, a millicapsule, a microcapsule, a nanocapsule, a nanostructured lipid carrier, a sponge, a cyclodextrin, a lipoid vesicle, a micelle, a millisphere, a microsphere, a nanosphere, a liposphere, a microemulsion, a nanoemulsion, a milliparticle, a microparticle, or a nanoparticle. A preferred delivery system or sustained release system is a liposome and a microemulsion, more preferably a water-in-oil type microemulsion having an internal structure of inverted micelles.

[22] The sustained release system can be prepared by methods known in the art and can be administered, for example, by topical or transdermal administration, including adhesive patches, non-adhesive patches, sealant patches and microelectronic patches; or by systemic administration, for example, but not limited to, by oral or parenteral routes, including nasal, rectal, subcutaneous implantation or injection, or direct implantation or injection into certain parts of the body. Preferably, a relatively constant amount of the peptide derivatives of the present invention should be released. The amount of the peptide derivative contained in the sustained release system will depend, for example, on the site to which the composition is to be administered, on the release kinetics and duration of action of the peptide derivative of the present invention, as well as on the nature of the condition, disorder and/or disease to be treated and/or cared for.

[23] In another aspect of the present invention, there is provided the use of a peptide derivative represented by Formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or a sustained release system as described above, in the manufacture of a cosmetic composition or a pharmaceutical composition for the treatment or care of skin or mucous membrane.

[24] In another aspect of the present invention, there is provided the use of a peptide derivative represented by Formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or a sustained release system as described above, in the manufacture of a cosmetic composition or a pharmaceutical composition for whitening.

[25] In another aspect of the present invention, there is provided the use of a peptide derivative represented by Formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or a sustained release system as described above, in the manufacture of a cosmetic composition or a pharmaceutical composition for the treatment of inflammation.

[26] In another aspect of the present invention, there is provided the use of a peptide derivative represented by Formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a cosmetically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a cosmetic or pharmaceutical composition as described above, or a cosmetically or pharmaceutically acceptable delivery system or a sustained release system as described above, in the manufacture of a cosmetic composition or a pharmaceutical composition for improving post-inflammatory hyperpigmentation.

[27] To facilitate understanding of the present invention, the meanings of some terms and expressions used in the present invention are explained as follows.

[28] In the present invention, the term "skin" should be understood as the layers that make it up, from the uppermost layer or stratum corneum to the lowermost layer or subcutaneous tissue, both inclusive. These layers are composed of various types of cells, such as keratinocytes, fibroblasts, melanocytes and/or adipocytes, among others. In the present invention, the term "skin" includes the scalp.

[29] The term "treatment" means the administration of a peptide derivative of the present invention to alleviate or eliminate a disease or disorder or to reduce or eliminate one or more symptoms associated with the disease or disorder. The term "treatment" also encompasses the ability to alleviate or eliminate the physiological consequences of the disease or disorder.

[30] The term "care" includes prevention of disease and/or disorder.

[31] In the present description, the abbreviations used for amino acids follow the rules established by the IUPAC-IUB Commission on Biochemical Nomenclature in the European Journal of Biochemistry (Eur. J. Biochem. 1984, 138:9-37).

[32] Thus, for example, Lys represents NH2-CH(CH2CH2CH2CH2NH2)-COOH, Lys- represents NH2-CH(CH2CH2CH2CH2NH2)-CO-, -Lys represents -NH-CH(CH2CH2CH2CH2NH2)-COOH, and -Lys- represents -NH-CH(CH2CH2CH2CH2NH2)-CO-. Thus, the hyphen denoting a peptide bond removes the OH on the 1-carboxyl of an amino acid (herein represented in its usual unionized form) when located to the right of the designation, and removes the H on the 2-amino group of an amino acid when located to the left of the designation; both modifications can be applied to the same designation (see Table 1).

Table 1. Structures of amino acid residues and their one-letter and three-letter abbreviations

[33] The advantageous effects that the present invention provides compared to the prior art include:

1. The peptide derivative according to the present invention is obtained by artificial design and simple synthesis.

2. The N-terminus of H-Pro-Lys-Glu-Lys-OH is covalently linked to niacin, tranexamic acid or kojic acid to obtain a compound of a new structure, which can reduce the expression of α-MSH, inhibit the formation of melanin, produce a whitening effect and have a higher whitening activity than one niacin, tranexamic acid or kojic acid and one H-Pro-Lys-Glu-Lys-OH polypeptide separately.

3. The N-terminus of H-Pro-Lys-Glu-Lys-OH was covalently linked with niacin, tranexamic acid or kojic acid to obtain a compound with a novel structure, which can reduce the expression of IL-6 and TNF-α and exhibits unexpected anti-inflammatory activity based on the whitening effect.

4. The peptide derivative according to the present invention has both a whitening effect and an anti-inflammatory activity, and can be used in the field of cosmetics or medicine for an anti-inflammatory effect, as well as whitening and removing freckles from the skin, especially for improving pigmentation after inflammation.

BRIEF DESCRIPTION OF DRAWINGS

[34]

FIG. 1 is a graph showing the effect of the peptide derivatives of the present invention on the viability of HaCaT cells (n=4).

FIG. 2 is a graph showing the results of the effect of 100 ppm of the peptide derivatives of the present invention on the expression of α-MSH. * indicates statistical difference between the drug group and the control group, p<0.05 (n=4). ** indicates significant difference between the drug group and the control group, p<0.01 (n=4). *** indicates strong difference between the drug group and the control group, p<0.001 (n=4).

FIG. 3 is a graph showing the results of the effect of 50 ppm of the peptide derivatives of the present invention on the expression of IL-6. ## indicates a significant difference between the UV group and the control group, p<0.01 (n=4). ** indicates a significant difference between the drug group and the UV group, p<0.01 (n=4). *** indicates a strong difference between the drug group and the UV group, p<0.001 (n=4).

FIG. 4 is a graph showing the results of the effect of 50 ppm of the peptide derivatives of the present invention on the expression of TNF-α. ## indicates a significant difference between the UV group and the control group, p<0.01 (n=4). * indicates a statistical difference between the drug group and the UV group, p<0.05 (n=4). ** indicates a significant difference between the drug group and the UV group, p<0.01 (n=4). *** indicates a strong difference between the drug group and the UV group, p<0.001 (n=4).

IMPLEMENTATION OPTIONS

[35] For a better understanding of the present invention, it will be described in detail below in conjunction with examples and drawings. However, it should be understood that these examples and drawings are used for illustrative purposes only and are not intended to limit the scope of the present invention.

[36] Abbreviations

[37] The abbreviations used for amino acids follow the rules established by the IUPAC-IUB Commission on Biochemical Nomenclature in Eur J. Biochem. (198 4) 138:9–37 and J. Chem. (1989) 264:633–673.

[38] 2-Cl-Trt resin: 2-chlorotrityl resin, a precursor resin for polypeptide synthesis (degree of crosslinking 1%, degree of substitution 1.24 mmol/g); Trt: trityl; DMF: N,N-dimethylformamide; DCM: dichloromethane; DIPEA: diisopropylethylamine; DIC: diisopropylcarbodiimide; piperidine: piperidine; HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid; TIS: triisopropylsilane; Pro: proline; Lys: lysine; Glu: glutamate; Fmoc: 9-fluorenylmethoxycarbonyl; Boc: tert-butoxycarbonyl; OtBu: tert-butoxyl; CDI: N,N'-carbonyldiimidazole; Py: pyridine;

[39] In accordance with the amino acid structure of the C-terminus of the polypeptide sequence, an appropriate resin was selected as a carrier for solid-phase synthesis.

[40] The resin is added for swelling and washed with solvent. Activated amino acids are added. Under the influence of the coupling system, the resin binds to amino acids in the order from C-terminus to N-terminus in the coupling solvent according to the peptide sequence, and the resin is washed to obtain a peptidyl resin.

[41] Specifically, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Pro-OH are added for reaction until all amino acids are bound. The reaction product is washed with dichloromethane and then dried to obtain Fmoc-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc) resin, which is divided into three portions.

[42] One portion of the above peptidyl resin is used to couple with NA to obtain NA-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-resin, which is subjected to cleavage, concentration, precipitation, centrifugation and vacuum drying to obtain a crude peptide; the crude peptide is purified by reverse-phase high-performance liquid chromatography and freeze-dried to obtain NA-Pro-Lys-Glu-Lys-OH or NA-Pro-Lys-Glu-Lys-NH2.

[43] One portion of the above peptidyl resin is used to couple with Fmoc-TXC-OH to obtain Fmoc-TXC-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-resin, which is subjected to cleavage, concentration, precipitation, centrifugation and vacuum drying to obtain a crude peptide; the crude peptide is purified by reverse-phase high-performance liquid chromatography and freeze-dried to obtain TXC-Pro-Lys-Glu-Lys-OH or TXC-Pro-Lys-Glu-Lys-NH2.

[44] CA cannot directly form an amide bond with the N-terminus of the polypeptide, so in the presence of Ru and DMF, CA is reacted with CDI to form a CA-CO-imidazole intermediate, and then covalently linked to the N-terminus of the polypeptide via the intermediate.

[45] One portion of the above peptidyl resin is used to couple with the intermediate KA-CO-imidazole to give KA-CO-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-resin, which is cleaved, concentrated, precipitated, centrifuged and vacuum dried to give the crude peptide; the crude peptide is purified by reverse-phase high-performance liquid chromatography and freeze-dried to give KA-CO-Pro-Lys-Glu-Lys-OH or KA-CO-Pro-Lys-Glu-Lys-NH2.

[46] EXAMPLE 1 Preparation of Fmoc-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin

[47] 1.1 Resin swelling

200 mL of DMF was sprayed onto the column wall and left to drain for 3 minutes, 200 mL of DMF was sprayed onto the column wall again and left to drain for 5 minutes. 20 g of 2-Cl-Trt resin having a substitution degree of 1.42 mmol/g was added to the solid-phase column, 200 mL of DMF was added to completely immerse the resin, then nitrogen was passed through and stirred at 100 rpm for 5 minutes, and then the solvent was drained off for 5 minutes, 200 mL of DMF was added again to completely immerse the resin, then nitrogen was passed through and stirred at 100 rpm for 30 minutes, and then the solvent was drained off. Another 200 ml of DMF was added to completely immerse the resin, then nitrogen was passed through and stirred at 100 rpm, and then the solvent was drained off over 5 min to complete swelling.

[48] 1.2 Removal of Fmoc protection

200 mL of 20% piperidine/DMF was added under nitrogen, stirred, reacted for 5 min, and drained within 3 min. Another 200 mL of 20% piperidine/DMF was added under nitrogen, stirred for 8 min, and drained within 3 min. Then 200 mL of DMF was added under nitrogen, stirred for 1-2 min, and drained within 3 min. The resin was washed again 7-8 times.

[49] 1.3 Feed reaction

17.4 g of Fmoc-Lys(Boc)-OH was dissolved in 100 mL of DMF containing 4.3 mL of DIPEA (1.5 equiv.) and added to the solid phase reactor to react with 2-Cl-Trt resin for 14 h. After filtration and washing, the reaction product was treated with methanol for 1 h to block the remaining chloride groups.

The degree of substitution was determined to be 0.55 mmol/g, and the scale of synthesis was determined to be 16.7 mmol. Based on this, the amounts of the remaining starting amino acids and reagents were calculated as shown in Table 2 below.

The N-terminal Fmoc group was removed, and 17.8 g of activated Fmoc-Glu(OtBu)-OH was coupled to peptidyl resins in the presence of 6.8 g of HOBt and 7 g of DIC using DMF as the solvent. The reaction was continued for 2.5 h. The resins were then washed and reprocessed to remove the Fmoc group to allow the addition of the next amino acid.

In each coupling, in the presence of 6.8 g HOBt and 7 g DIC and DMF as solvent, the resin was sequentially coupled with 19.5 g Fmoc-Lys(Boc)-OH and 14.1 g Fmoc-Pro-OH.

[50] 1.4 Washing the resin after completion of the reaction

After synthesis, the resin was washed with DMF, 100 ml each time. The resin and solvent were mixed uniformly and then stirred for 2 min. The solvent was decanted. The resin was washed repeatedly with DMF until the filtered solvent was clear and transparent. After shrinkage and drying, the resin Fmoc-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt was obtained.

[51] EXAMPLE 2 Preparation of NA-Pro-Lys-Glu-Lys-OH

[52] 2.1 Preparation of NA-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin 10 g of Fmoc-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin was weighed and added to a 100 mL solid phase column, and then washed three times with DMF after swelling in DMF. Fmoc was stripped using 20% piperidine/DMF solution and then washed, and the K-test (Kaiser test, 5% ethanol ninhydrin solution) showed a dark blue color.

In the presence of 2.65 g DIC and 2.27 g HOBt, 1.71 g NA was reacted with the above Fmoc-deprotected peptidyl resin for 2 h, and the K-test showed that the resin was colorless and transparent. The resin was washed three times with 30 mL DMF and twice with 30 mL DCM. The resin was shrinked and dried with 30 mL methanol to obtain NA-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin.

[53] 2.2 Obtaining NA-Pro-Lys-Glu-Lys-OH

[54] 2.2.1 Preparation of lysis buffer

24.75 ml TFA, 1.5 ml TIS and 1.5 ml water were measured out, mixed and stirred, and then placed in a freezer at -18°C for later use.

[55] 2.2.2 Cleavage

Ten grams of NA-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin were weighed and added to a 100-mL round-bottomed flask. The reaction was then stirred for two hours with 30 mL of frozen lysis buffer. After the reaction product was filtered and concentrated to 10 mL, isopropyl ether was added, precipitating a white solid, which was washed six times with isopropyl ether to pH 3-4 and dried under vacuum. This yielded 6 g of crude peptide (85% purity).

[56] 2.2.3 Cleaning

Six grams of crude peptide were weighed and dissolved in 85 ml of pure water, yielding a light-yellow liquid. The liquid was filtered through a microporous filter membrane with 0.22 µm pores, yielding a clear, light-yellow solution. The solution was purified using reversed-phase HPLC. The purification gradient was as follows:

The filtered sample was injected and purified. Fractions were collected, concentrated, and lyophilized to yield the peptide (1) NA-Pro-Lys-Glu-Lys-OH, which had a purity of 97.97%.

[57] EXAMPLE 3 Preparation of TXC-Pro-Lys-Glu-Lys-OH

[58] 3.1 Preparation of TXC-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin

Ten grams of Fmoc-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin were weighed, added to a 100 mL solid-phase column, and washed three times with DMF after swelling in DMF. Fmoc protection was removed using a 20% piperidine/DMF solution followed by washing, and the K-test (5% ethanol ninhydrin solution) showed a dark blue color.

In the presence of 2.65 g DIC and 2.27 g HOBt, 5.31 g Fmoc-TXC-OH was reacted for 2 h with the above-mentioned Fmoc-deprotected peptidyl resin, and the K-test showed that the resin was colorless and transparent. Fmoc-deprotection was performed using 20% piperidine/DMF solution. The resin was washed three times with 30 mL DMF and twice with 30 mL DCM. The resin was shrinked and dried with 30 mL methanol to obtain TXC-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin.

[59] 3.2 Obtaining TXC-Pro-Lys-Glu-Lys-OH,

[60] 3.2.1 Preparation of lysis buffer

24.75 ml TFA, 1.5 ml TIS and 1.5 ml water were measured out, mixed and stirred, and then placed in a freezer at -18°C for later use.

[61] 3.2.2 Cleavage

10 g of TXC-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin were weighed and added to a 100 ml round-bottomed flask, and 30 ml of frozen lysis buffer was added for a 2-h stirring reaction. After the reaction product was filtered and concentrated to 10 ml, isopropyl ether was added to precipitate a white solid, which was washed six times with isopropyl ether to obtain a pH of 3-4 and dried under vacuum. 5.7 g of crude peptide (87% purity) was obtained.

[62] 3.2.3 Cleaning

5.7 g of crude peptide were weighed and dissolved in 85 ml of pure water to yield a light yellow liquid. The solution was filtered through a 0.22 μm microporous membrane filter to yield a clear, light yellow solution. The solution was subjected to reversed-phase HPLC purification. The purification gradient was as follows:

The filtered sample was injected and purified. Fractions were collected, concentrated, and lyophilized to yield the peptide (3) TXC-Pro-Lys-Glu-Lys-OH, which had a purity of 96.50%.

[63] EXAMPLE 4 Preparation of KA-CO-Pro-Lys-Glu-Lys-OH

[64] 4.1 Synthesis of the intermediate CA-CO-imidazole

CA (50 g, 35.2 mmol) was added to a 250 ml three-necked flask and dissolved in 150 ml DMF; Py (pyridine, 8 g, 100 mmol) was added; the temperature was lowered to 0°C; CDI (6.6 g, 40 mmol) was added and the reaction was carried out for 4 h. TLC analysis showed that the reaction was complete (developing reagent: MeOH:DCM = 1:20, Rf value 0.67).

The reaction solution was poured into ice water, forming a large amount of white precipitate. After filtration, the solid phase was washed with ice water until the odor disappeared and dried under vacuum, yielding 74 g of product with a yield of 89.05%.

[65] 4.2 Preparation of KA-CO-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin

Ten grams of Fmoc-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin were weighed and added to a 100 mL solid-phase column, washed three times with DMF after swelling in DMF. Fmoc protection was removed using a 20% piperidine/DMF solution, washed, and subjected to a K-test (5% ninhydrin in ethanol), which revealed a dark blue color.

In the presence of 3.62 g of DIPEA, 3.31 g of the intermediate KA-CO-imidazole was reacted with the above peptidyl resin after Fmoc deprotection for 2 h, and the K-test showed that the resin was colorless and transparent. The resin was washed three times with 30 ml of DMF and twice with 30 ml of DCM. The resin was shrinked and dried with 30 ml of methanol to obtain KA-CO-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin.

[66] 4.3 Preparation of KA-CO-Pro-Lys-Glu-Lys-OH

[67] 4.3.1 Preparation of lysis buffer

24.75 ml TFA, 1.5 ml thioanisole, 1.5 ml phenol, 1.5 ml water and 0.75 ml EDT were measured out, mixed and stirred, and then placed in a refrigerator at -18°C for later use.

[68] 4.3.2 Cleavage

10 g of KA-CO-Pro-Lys(Boc)-Glu(OtBu)-Lys(Boc)-2-Cl-Trt resin was weighed and added to a 100 ml round-bottomed flask, and 30 ml of frozen lysis buffer was added to carry out the reaction with stirring for 2 h. After the reaction product was filtered and concentrated to 10 ml, isopropyl ether was added to precipitate a white solid, which was washed six times with isopropyl ether to obtain a pH of 3-4 and dried under vacuum. 5.7 g of crude peptide (purity 83.5%) was obtained.

[69] 4.3.3 Cleaning

5.7 g of crude peptide was weighed and dissolved in 65 ml of pure water to yield a light-yellow liquid. The liquid was filtered through a microporous filter membrane with 0.22 μm pores to yield a clear, light-yellow solution. The solution was purified using reversed-phase HPLC. The purification gradient was as follows:

The filtered sample was injected and purified. Fractions were collected, concentrated, and lyophilized to yield the peptide (5) KA-CO-Pro-Lys-Glu-Lys-OH, which had a purity of 97.34%.

[70] EXAMPLE 5

Other compounds of Formula (I) of the present invention can be prepared by similar processes.

The molecular weight of the obtained peptide derivatives was determined using ESI-MS. The results of the analysis of some compounds are shown in Table 3 below.

[71] EXAMPLE 6 Analysis of cell viability

[72] 6.1 Reagents and materials

Phosphate-buffered saline (PBS) (Gibco), thiazolyl blue (MTT) (Sigma), dimethyl sulfoxide (DMSO) (Sigma), high glucose medium (DMEM) (Gibco), and fetal bovine serum (Gibco).

[73] 6.2 Devices

Microplate spectrophotometer (MD, USA), _CO2 incubator (Shanghai Yiheng) and ultra-clean workbench (Suzhou Purification).

[74] 6.3 Cell lines

Human keratinocytes (HaCaT) were purchased from the Kunyming Cell Bank of China Type Culture Collection Center, Chinese Academy of Sciences.

[75] 6.4 Samples for testing

Groups of drugs:

peptide H-Pro-Lys-Glu-Lys-OH (hereinafter referred to as the reference peptide) at a test concentration of 1 ppm, 10 ppm, 100 ppm and 200 ppm, respectively;

peptide (1) at the tested concentration of 1 ppm, 10 ppm, 100 ppm and 200 ppm, respectively;

peptide (3) at the tested concentration of 1 ppm, 10 ppm, 100 ppm and 200 ppm, respectively;

peptide (5) at the tested concentrations of 1 ppm, 10 ppm, 100 ppm and 200 ppm, respectively.

Control group:

Blank PBS control.

[76] 6.5 Purpose of the experiment

The aim of this experiment is to evaluate the viability of cells 72 hours after administration and to determine the effect of the peptide derivatives of the present invention on cell viability using HaCaT cells as the experimental subject.

[77] 6.6 Experimental protocol

Frozen HaCaT cells were cultured and passaged at a 1:2 ratio until approximately the 5th generation, and cells with the best growth performance were selected as experimental subjects.

Cells were inoculated into a 9-well plate at 2000 cells/well. After cell attachment, samples of the drug and control groups were added using the serial dilution method. Culture medium was added to 200 µl, and the cells were cultured in an incubator with 5% _CO2 at 37°C for 72 hours.

Then, 20 μl of 5 mg/ml MTT were added to each well and incubation was continued in an incubator with 5% _CO2 at 37°C for 4 h. The stock solution was removed and DMSO was added at 150 μl/well. After 5 min, a microplate spectrophotometer was used to read the control OD values at wavelengths of 490 nm and 630 nm.

[78] 6.7 Results

The MTT assay is a method for determining cell viability and growth. The measured OD values are directly proportional to cell viability.

FIG. 1 shows the results of the HaCaT cell viability study. The results showed that, compared with the control group, peptide (1), peptide (3), and peptide (5) did not have a significant effect on the viability of HaCaT cells, indicating that the peptide derivatives of the present invention do not have a toxic effect on HaCaT cells in an amount within 0-200 ppm.

[79] Example 7 Cell-based assay for inhibition of α-MSH formation

[80] 7.1 Reagents and materials

Fetal bovine serum, DMEM, penicillin, streptomycin and α-MSH ELISA kit.

[81] 7.2 Devices

Microplate spectrophotometer, _CO2 incubator and constant temperature shaker.

[82] 7.3 Cell lines

Human keratinocytes (HaCaT) were purchased from the Kunyming Cell Bank of China Type Culture Collection Center, Chinese Academy of Sciences.

[83] 7.4 Samples for testing

Groups of drugs:

100 ppm reference peptide, 100 ppm peptide (1), 100 ppm peptide (3), 100 ppm peptide (5), 100 ppm NA, 100 ppm TCS and 100 ppm CA.

Control group:

Blank PBS control.

[84] 7.5 Experimental protocol

Frozen HaCaT cells were cultured and passaged at a 1:2 ratio until approximately the 5th generation, and cells with the best growth rates were selected as experimental subjects.

At approximately 80% cell confluence, samples were added to each group. In the control group, PBS was added, and culture medium was added to 1000 µl. In the drug groups, the diluted active substance and culture medium were added to 1000 µl, and the groups were further incubated in an incubator with 5% _CO2 at 37°C for 48 h. After completion of culturing, the solutions were centrifuged at 3000 rpm for 10 min, after which the cell supernatants were collected to obtain a liquid sample. The procedures were performed according to the instructions for the α-MSH kit.

[85] 7.6 Results

α-MSH can induce melanin formation by activating tyrosinase. Therefore, reducing α-MSH expression may reduce melanin production and produce a whitening effect.

The results of the effect of 100 ppm of the peptide derivatives according to the present invention on the expression of α-MSH are shown in FIG. 2. The results showed that, compared with the control group, the reference peptide, NA, TCS, and CA inhibited the expression of α-MSH to some extent. However, except for TCS, the reference peptide, NA, and CA at 100 ppm did not show a statistical difference in the inhibition of α-MSH compared with the control group.

In contrast, the compounds with new structures, peptide (1), peptide (3) and peptide (5), obtained by covalently linking the N-terminus of the reference peptide to NA, TCS and CA, respectively, significantly reduced the expression of α-MSH and had a higher activity compared to NA, TCS or CA alone or the reference peptide alone, producing unexpected technical effects, where peptide (1) demonstrated the strongest inhibitory effect on α-MSH. Thus, it was shown that the peptide derivatives according to the present invention significantly reduced the expression of α-MSH, thereby inhibiting melanin production, and demonstrated a better whitening effect compared to NA, TCS or CA alone or the reference peptide alone.

[86] EXAMPLE 8 Anti-inflammatory cell assay

[87] 8.1 Reagents and materials

Fetal bovine serum, DMEM, penicillin, streptomycin, IL-6 ELISA kit and TNF-α ELISA kit.

[88] 8.2 Devices

Microplate spectrophotometer, constant temperature _CO2 incubator and constant temperature shaker.

[89] 8.3 Cell lines

Human keratinocytes (HaCaT) were purchased from the Kunyming Cell Bank of China Type Culture Collection Center, Chinese Academy of Sciences.

[90] 8.4 Samples for testing

Groups of drugs:

50 ppm reference peptide, 50 ppm peptide (1), 50 ppm peptide (3), and 50 ppm peptide (5). Control group: Blank PBS control.

[91] 8.5 Experimental protocol

Frozen HaCaT cells were cultured and passaged at a 1:2 ratio until approximately the 5th generation, and cells with the best growth performance were selected as experimental subjects.

At approximately 80% cell confluence, a UV-induced inflammation model was established. In the control group, PBS and culture medium were added to 1000 μL without UV irradiation; the UV group and drug groups were exposed to UV irradiation at an intensity of 80 J/ ^cm3 . After irradiation, PBS and culture medium were added to 1000 μL in the UV group, and the diluted active substance and culture medium to 1000 μL in the drug groups. The control group, UV group, and drug groups were then incubated in a 5% _CO2 incubator at 37°C for 48 h. After completion of the culture, the solutions were centrifuged at 3000 rpm for 10 min, and the cell supernatants were collected to obtain a liquid sample. The operations were performed in accordance with the instructions for the IL-6 and TNF-α kits.

[92] 8.6 Results

Ultraviolet radiation can stimulate the skin's inflammatory response, leading to increased secretion of TNF-α and IL-6. Therefore, inhibiting the secretion of inflammatory factors such as IL-6 and TNF-α may have an anti-inflammatory effect.

The results of the effect of 50 ppm of the peptide derivatives according to the present invention on the expression of inflammatory factors such as IL-6 and TNF-α are shown in FIGS. 3 and 4, respectively. The results in FIG. 3 showed that, compared with the control group, IL-6 was significantly increased in the UV group after ultraviolet irradiation. After administration, the reference peptide, peptide (1), peptide (3), and peptide (5) significantly reduced the expression of IL-6, and the drug groups of peptide (1), peptide (3), and peptide (5) were significantly different from the UV group and demonstrated higher anti-inflammatory activity than the reference peptide.

The results in FIG. 4 showed that, compared with the control group, TNF-α was significantly increased in the UV group after ultraviolet irradiation. After administration, the reference peptide inhibited the expression of TNF-α to some extent, but the inhibitory effect was not obvious; peptide (1), peptide (3), and peptide (5) significantly reduced the expression of TNF-α and had higher anti-inflammatory activity than the reference peptide.

In summary, the compounds with new structures, peptide (1), peptide (3), and peptide (5), obtained by covalently linking the N-terminus of the reference peptide to NA, TCS, and CA, respectively, significantly reduced the expression of IL-6 and TNF-α and demonstrated superior activity compared to the reference peptide alone, demonstrating unexpected anti-inflammatory activity based on the whitening effect. Thus, it was shown that the peptide derivatives according to the present invention have both a whitening effect and anti-inflammatory activity and can be used in the field of cosmetics or medicine as anti-inflammatory agents, as well as for whitening and removing freckles from the skin, in particular for improving post-inflammatory hyperpigmentation.

[93] EXAMPLE 9 Preparation of a skin tonic containing a peptide (1)

Allantoin and glycerin were dissolved in water and heated to 85°C, and kept at this temperature for 30 minutes; PEG-7 glyceryl cocoate and peptide (1) were dissolved in water; the above solutions were mixed after cooling and stirred uniformly to obtain a mixed solution; propylene glycol, preservative and perfume composition were added to the above mixed solution one by one, and water was added with stirring into a homogeneous mixture to obtain a skin tonic.

[94] EXAMPLE 10 Preparation of a cleansing gel containing a peptide (3)

The peptide (3) was dissolved in water and mixed uniformly to obtain a polypeptide solution; carbomer and EDTA were dissolved in water and heated to 85°C; the temperature was maintained for 30 minutes; after cooling, triethanolamine was added and mixed uniformly to obtain a mixed solution; the above mixed solution, the polypeptide solution, the preservative and the perfume composition were added to water one by one and mixed until completely swollen to obtain a cleansing gel.

[95] EXAMPLE 11 An emulsion composition comprising a peptide (5)

0.01 g of peptide (5) was prepared as an aqueous solution of 0.02 mg/ml; cetearyl alcohol (and) cetearyl glucoside, jojoba oil, mineral oil and isopropyl palmitate were heated to 85°C and mixed uniformly to obtain phase A; glycerin, allantoin, polyacrylamide (and) C13-14 isoparaffin (and) laureth-7 were dissolved in water and heated to 85°C to obtain phase B; phase A was quickly added to phase B, homogenized at a constant temperature for 3-5 minutes and cooled; while cooling the above mixture to a temperature below 60°C, a preservative was added and mixed uniformly; while cooling the above mixture to a temperature below 45°C, the polypeptide solution and the perfume composition were added to obtain an emulsion.

[96] The above is a more detailed description of the present invention in conjunction with specific preferred embodiments, but it is not indicated that the specific embodiments of the present invention are limited thereto. For a person of ordinary skill in the art to which the present invention pertains, without departing from the concept of the present invention, some simple conclusions or substitutions that need to be made should be considered as falling within the scope of legal protection of the present invention.

Claims (35)

1. A peptide derivative represented by Formula (I) or a cosmetically acceptable salt thereof or a pharmaceutically acceptable salt thereof, R ₁ -Pro-Lys-Glu-Lys-R ₂ (I) in Formula (I), R ₁ is selected from substituent (i) or substituent (ii), where substituent (i) is substituent (ii) is R ₂ is selected from –OH or –NH ₂ . 2. A peptide derivative represented by Formula (I) according to claim 1, or a cosmetically acceptable salt thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following peptide derivatives (1)-(4): . 3. A peptide derivative represented by Formula (I) according to claim 1, or a cosmetically acceptable salt thereof or a pharmaceutically acceptable salt thereof, characterized in that: the cosmetically acceptable salt or the pharmaceutically acceptable salt includes a metal salt of the peptide derivative represented by Formula (I), wherein the metal includes lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum; optionally, the cosmetically acceptable salt or the pharmaceutically acceptable salt includes a salt formed from a derivative of the peptide represented by Formula (I), and an organic base, wherein the organic base comprises ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine; optionally, the cosmetically acceptable salt or the pharmaceutically acceptable salt includes a salt formed from a derivative of the peptide represented by Formula (I), and an inorganic acid or an organic acid, wherein the organic acid comprises acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoic acid or gluconic acid; optionally, the inorganic acid comprises hydrochloric acid, sulfuric acid, boric acid or carbonic acid. 4. A cosmetic composition for whitening or relieving inflammation, characterized in that it includes an effective amount of a peptide derivative represented by Formula (I), according to any one of claims 1 to 3, or a cosmetically acceptable salt thereof, and at least one auxiliary substance and, optionally, a cosmetically acceptable adjuvant; optionally, the adjuvant is selected from a collagen synthesis stimulator, an agent that modulates the synthesis of PGC-1α, an agent that modulates the activity of PPARγ, an agent that increases or decreases the content of triglycerides in adipocytes, an agent that stimulates or delays the differentiation of adipocytes, a lipolytic agent or an agent that stimulates lipolysis, an lipid-depleting agent, an adipogenic agent, an acetylcholine receptor aggregation inhibitor, an agent that inhibits muscle contraction, an anticholinergic, an elastase inhibitor, a matrix metalloproteinase inhibitor, a melanin synthesis stimulator or inhibitor, a whitening or bleaching agent, a pigmentation promoter, a self-tanning agent, an anti-aging agent, an NO synthase inhibitor, a 5α-reductase inhibitor, a lysyl hydroxylase and/or prolyl hydroxylase inhibitor, an antioxidant, a free radical scavenger and/or an air pollution control agent, a reactive carbonyl scavenger, an antiglycating agent, an antihistamine, an antiviral, an antiparasitic, an emulsifier, an emollient, an organic solvent, a liquid propellant, a skin conditioner, a humectant, a humectant, an alpha hydroxy acid, a beta hydroxy acid, humectant, epidermal hydrolase, vitamin, amino acid, protein, pigment or coloring agent, dye, biopolymer, gelling polymer, thickener, surfactant, emollient, adhesive, preservative, anti-wrinkle agent, agent that can reduce or treat bags under the eyes, exfoliant, cuticle exfoliant, keratolytic agent, antimicrobial, antifungal, fungistatic, bactericidal, bacteriostatic agent, agent that stimulates the synthesis of dermal or epidermal macromolecules and/or inhibits or prevents their degradation, agent that stimulates the synthesis of elastin, agent that stimulates the synthesis of decorin, agent that stimulates the synthesis of laminin, agent that stimulates the synthesis of defensin, agent that stimulates the synthesis of chaperone protein, agent that stimulates the synthesis of cAMP, heat shock protein, agent that stimulates the synthesis of HSP70, agent that stimulates the synthesis of heat shock protein, agent that stimulates the synthesis of hyaluronic acid, an agent that stimulates the synthesis of fibronectin, an agent that stimulates the synthesis of deacetylase, an agent that stimulates the synthesis of lipid and a component of the stratum corneum, ceramide, fatty acid, an agent that inhibits the degradation of collagen, an agent that inhibits the degradation of elastin, an agent that inhibits serine protease, an agent that stimulates the proliferation of fibroblasts, an agent that stimulates the proliferation of keratinocytes, an agent that stimulates the proliferation of adipocytes, an agent that stimulates the proliferation of melanocytes, an agent that stimulates the differentiation of keratinocytes, an agent that inhibits acetylcholinesterase, a skin relaxant, an agent that stimulates the synthesis of glycosaminoglycans, an anti-hyperkeratosis agent, a comedolytic agent, an anti-psoriatic agent, anti-dermatitis agent, anti-eczema agent, DNA repair agent, DNA protector, stabilizer, antipruritic agent, agent for the treatment and/or care of sensitive skin, tanning agent, firming agent, restructuring agent, anti-stretch mark agent, adhesive, agent that regulates sebum production, antiperspirant, agent that stimulates healing, agent that promotes healing, agent that stimulates re-epithelialization, agent that promotes re-epithelialization, cytokine growth factor, soothing agent, anti-inflammatory agent, anesthetic agent, agent acting on capillary blood circulation and/or microcirculation, agent that stimulates angiogenesis, agent that inhibits vascular permeability, venotonic agent, agent acting on cellular metabolism, agent for improving the connection of the dermis and epidermis, agent that induces hair growth, agent that inhibits or slows down hair growth, fragrance, chelating agent plant extract, essential oil, seaweed extract, products obtained through a biological fermentation process, inorganic salt, cell extract, sunscreen filter and an effective organic or inorganic photoprotector against UVA and/or UVB radiation or mixtures thereof. 5. The cosmetic composition according to claim 4, characterized in that the preparation of the cosmetic composition is selected from a cream, oil, milk, balm, foam, lotion, gel, liniment, serum, soap, shampoo, hair conditioner, serum, ointment, mousse, lipstick, powder, bar, pencil, spray, aerosol, granule, solution, suspension, emulsion or jelly. 6. A pharmaceutical composition for whitening or relieving inflammation, characterized in that it includes an effective amount of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and at least one auxiliary substance and, optionally, a pharmaceutically acceptable adjuvant; optionally, the adjuvant is selected from a collagen synthesis stimulator, an agent that modulates the synthesis of PGC-1α, an agent that modulates the activity of PPARγ, an agent that increases or decreases the content of triglycerides in adipocytes, an agent that stimulates or delays the differentiation of adipocytes, a lipolytic agent or an agent that stimulates lipolysis, an lipid-removing agent, an adipogenic agent, an acetylcholine receptor aggregation inhibitor, an agent that inhibits muscle contraction, an anticholinergic agent, an elastase inhibitor, an inhibitor of matrix metalloproteinases, a stimulator or inhibitor of melanin synthesis, a bleaching or bleaching agent, a pigmentation promoter, a self-tanning agent, an anti-aging agent, an NO synthase inhibitor, a 5α-reductase inhibitor, a lysyl hydroxylase and/or prolyl hydroxylase inhibitor, an antioxidant, a free radical scavenger and/or air pollution control agent, reactive carbonyl scavenger, antiglycating agent, antihistamine, antiviral, antiparasitic, emulsifier, emollient, organic solvent, liquid propellant, skin conditioner, humectant, humectant, alpha hydroxy acid, beta hydroxy acid, humectant, epidermal hydrolase, vitamin, amino acid, protein, pigment or coloring matter, dye, biopolymer, gelling polymer, thickener, surfactant, softener, adhesive, preservative, anti-wrinkle agent, agent that can reduce or treat bags under the eyes, exfoliant, cuticle exfoliant, keratolytic, antimicrobial, antifungal, fungistatic, bactericidal, bacteriostatic, agent that stimulates the synthesis of dermal or epidermal macromolecules and/or inhibits or prevents their degradation, an agent that stimulates the synthesis of elastin, an agent that stimulates the synthesis of decorin, an agent that stimulates the synthesis of laminin, an agent that stimulates the synthesis of defensin, an agent that stimulates the synthesis of chaperone protein, an agent that stimulates the synthesis of cAMP, heat shock protein, an agent that stimulates the synthesis of HSP70, an agent that stimulates the synthesis of heat shock protein, an agent that stimulates the synthesis of hyaluronic acid, an agent that stimulates the synthesis of fibronectin, an agent that stimulates the synthesis of deacetylase, an agent that stimulates the synthesis of lipid and a component of the stratum corneum, ceramide, fatty acid, an agent that inhibits the degradation of collagen, an agent that inhibits the degradation of elastin, an agent that inhibits serine protease, an agent that stimulates the proliferation of fibroblasts, an agent that stimulates the proliferation of keratinocytes, an agent that stimulates adipocyte proliferation, an agent that stimulates melanocyte proliferation, an agent that stimulates keratinocyte differentiation, an agent that inhibits acetylcholinesterase, a skin relaxant, an agent that stimulates glycosaminoglycan synthesis, an anti-hyperkeratosis agent, a comedolytic agent, an anti-psoriatic agent, an anti-dermatitis agent, an anti-eczema agent, a DNA repair agent, a DNA protecting agent, a stabilizer, an antipruritic agent, an agent for the treatment and/or care of sensitive skin, a tanning agent, a firming agent, a restructuring agent, an anti-stretch mark agent, an adhesive, an agent that regulates sebum production, an antiperspirant, an agent that stimulates healing, an agent that promotes healing, an agent that stimulates re-epithelialization, an agent that promotes re-epithelialization, a cytokine growth factor, a sedative, an anti-inflammatory agent, an anesthetic, an agent acting on capillary blood circulation and/or microcirculation, an agent that stimulates angiogenesis, an agent that inhibits vascular permeability, a venotonic agent, an agent acting on cellular metabolism, an agent for improving the connection of the dermis and epidermis, an agent that causes hair growth, an agent that inhibits or slows down hair growth, a fragrance, a chelating agent, a plant extract, an essential oil, an extract of seaweed, agents obtained as a result of a biological fermentation process, an inorganic salt, a cellular extract, a sunscreen filter and an effective organic or inorganic photoprotector against UVA and/or UVB radiation or mixtures thereof. 7. The pharmaceutical composition according to claim 6, characterized in that the preparation of the pharmaceutical composition is selected from a cream, oil, milk, balm, foam, lotion, gel, liniment, serum, soap, shampoo, hair conditioner, serum, ointment, mousse, lipstick, powder, bar, pencil, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, syrup, elixir, polysaccharide film, jelly or gelatin; optionally, the capsule includes a soft capsule, a hard capsule, optionally a gelatin capsule; optionally, the tablet includes a sugar-coated tablet. 8. A cosmetically acceptable delivery system for whitening or for relieving inflammation, characterized in that it includes an effective amount of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3 or a cosmetically acceptable salt thereof; the cosmetically acceptable delivery system is selected from a microemulsion or a nanoemulsion; or, optionally, a microemulsion; or, optionally, a water-fat microemulsion having an internal reverse micelle structure. 9. The use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a cosmetically acceptable salt thereof, or a cosmetic composition according to claim 4, or a cosmetically acceptable delivery system according to claim 8, in the production of a cosmetic composition for relieving skin inflammation, as well as whitening and removing freckles, especially for improving post-inflammatory pigmentation. 10. The use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a pharmaceutical composition for relieving skin inflammation, as well as whitening and removing freckles, especially for improving post-inflammatory pigmentation. 11. The use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a cosmetically acceptable salt thereof, or a cosmetic composition according to claim 4, or a cosmetically acceptable delivery system according to claim 8, in the production of a cosmetic whitening composition. 12. Use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the production of a pharmaceutical composition for whitening. 13. The use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a cosmetically acceptable salt thereof, or a cosmetic composition according to claim 4, or a cosmetically acceptable delivery system according to claim 8, in the production of a cosmetic composition for relieving inflammation. 14. Use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a pharmaceutical composition for relieving inflammation. 15. Use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a cosmetically acceptable salt thereof, or a cosmetic composition according to claim 4, or a cosmetically acceptable delivery system according to claim 8, in the production of a cosmetic composition for improving post-inflammatory hyperpigmentation. 16. Use of a peptide derivative represented by Formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a pharmaceutical composition for improving post-inflammatory hyperpigmentation.