CN117642150A

CN117642150A - Cosmetic non-therapeutic use of peptides

Info

Publication number: CN117642150A
Application number: CN202280045438.4A
Authority: CN
Inventors: G·康苏埃洛; 曲向华
Original assignee: Lubrizol Advanced Materials Inc
Current assignee: Lubrizol Advanced Materials Inc
Priority date: 2021-07-02
Filing date: 2022-06-30
Publication date: 2024-03-01
Also published as: EP4362904A1; WO2023275811A1

Abstract

The present invention relates to cosmetic non-therapeutic treatment of the skin, and in particular to compounds (R ₁ ‑AA ₁ ‑AA ₂ ‑AA ₃ ‑AA ₄ ‑AA ₅ ‑AA ₆ ‑R ₂ ) For increasing energy metabolism and/or energy production in skin cells; improving and/or increasing skin luster; and/or reduceAnd/or preventing symptoms of skin aging.

Description

Cosmetic non-therapeutic use of peptides

Technical Field

The present invention relates to the cosmetic treatment and/or care of the skin. In particular, the present invention relates to the use of compounds effective in increasing the energy of skin cells and the use of such compounds for promoting skin luster and/or as anti-skin fatigue agents.

Background

Face play a key role in social cognition. Sleep deprivation, stress, illness, and physical or mental consumption can affect fatigue and facial expression, while the desire to appear less tired is one of the main motivations for cosmetic treatment.

Like all other cells of the body, skin cells are the locus of bioenergy metabolic processes. The energy necessary for all cellular functions (macromolecular synthesis, proliferation, defense, signalling, etc.) may originate from ATP (a typical intracellular energy source) or it may originate from an external source. The skin is highly energy demanding to support its metabolic demands, sustained tissue regeneration and repair, which is necessary for normal tissue maintenance. Other external factors that expose the skin to UV radiation and generate ROS (reactive oxidizing species) cause detrimental changes to (mitochondrial) DNA, cell membranes, catalysis, and structural proteins (e.g., collagen). Human skin cells that are directly exposed to environmental factors such as sunlight are highly dependent on a large amount of energy in order to combat cell imbalance and/or damage. The lack of skin energy capacity is closely related to significant changes in human skin structure. If the skin's repair mechanism is not stable, detrimental changes in the skin structure may occur, resulting in the skin appearing dull and unhealthy.

Mitochondria are batteries used to generate energy in cells and play a key role in the skin. While energy requirements may not be as great as other organs (such as skeletal muscle), energy remains indispensable for processes such as cell signaling, wound healing, pigmentation, and vascular homeostasis [ Stout, s. And Birch-machine, M ' Mitochondria's Role in Skin Ageing ', biology (Basel), 6 months 2019; 8 (2):29]. The data show that energy-balanced human skin cells are metabolically reactivating, thus significantly preventing structural changes in human skin [ Blatt T et al, ' Stimulation of skin's energy metabolism provides multiple benefits for mature human skin '. Biofactor.2005; 25 (1-4):179-85].

WO2019008452A1 discloses the use of specific peptides for energizing the skin and preventing symptoms of skin fatigue. However, alternative or improved ways to provide these cosmetic effects to the skin are needed. Other compounds active in this respect are needed. It is an object of the present invention to address some of the above problems or to meet some of the above needs.

Disclosure of Invention

According to a first aspect, the present invention provides a compound of formula (I)

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

Use of stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic non-therapeutic treatment and/or care of the skin, wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₁ selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclic groups, heterocyclic groups, heteroarylalkyl groups, aryl groups, aralkyl groups, and R ₅ -CO-, wherein R ₅ Selected from the group consisting of H, acyclic aliphatic, cycloaliphatic, aryl, aralkyl, heterocyclic, and heteroarylalkyl;

R ₂ selected from the group consisting of-NR ₃ R ₄ 、-OR ₃ 、-SR ₃ A group consisting of R ₃ And R is ₄ Independently selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclic groups, heterocyclic groups, heteroarylalkyl groups, aryl groups, and aralkyl groupsA group consisting of radicals; and is also provided with

R ₁ And R is ₂ Is not an amino acid, and is not an amino acid,

wherein the cosmetic non-therapeutic treatment and/or care is: increasing energy metabolism and/or energy production in skin cells; improving and/or increasing skin luster; and/or reducing and/or preventing skin fatigue.

The compounds of formula (I) have been found to be effective in energizing skin cells, improving skin luster and/or as anti-skin fatigue agents. Advantageously, the compound is relatively small (6 amino acids) and therefore can be prepared more efficiently than other cosmetic actives.

According to another aspect, the present invention provides a method of cosmetically non-therapeutically treating and/or caring for the skin of a subject, comprising administering to the subject a cosmetically effective amount of a compound of formula (I)

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

A stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₂ selected from the group consisting of-NR ₃ R ₄ 、-OR ₃ 、-SR ₃ A group consisting of R ₃ And R is ₄ Independently selected fromH. Polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclic groups, heterocyclic groups, heteroarylalkyl groups, aryl groups, and aralkyl groups; and is also provided with

R ₁ And R is ₂ Is not an amino acid, and is not an amino acid,

Detailed Description

Definition of the definition

In the context of the present invention, "skin" is understood to include the skin, layers from the uppermost or stratum corneum to the lowermost or hypodermis (including both). These layers are made up of different types of cells, such as keratinocytes, fibroblasts, melanocytes, mast cells, neurons and/or adipocytes, etc. The term "skin" also includes the scalp. The term "skin" includes mammalian skin and includes human 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), the collar, the neck, the chest, the arms, the hands, the legs, the feet, the thighs, the hips, the buttocks, the stomach, and the torso.

The terms "cosmetic non-therapeutic treatment" and "care" as used herein have the purpose of improving or maintaining the aesthetic appearance of skin. In particular, the treatment may have the purpose of improving the cosmetic properties of the skin. The term "care" in the context of this specification means maintaining the characteristics of the skin. The properties are improved or maintained by cosmetic treatment and/or care of the skin of both healthy subjects and subjects presenting with diseases and/or disorders of the skin.

In the present specification, abbreviations for amino acids follow the rules of the IUPAC-IUB Biochemical nomenclature Commission (IUPAC-IUB Commission of Biochemical Nomenclature) in European journal of biochemistry (Eur. J. Biochem.), (1984), 138, 9-37. Thus, gly represents NH, for example ₂ -CH ₂ -COOH, gly-TableShow NH ₂ -CH ₂ -CO-, -Gly represents-NH-CH ₂ -COOH, and-Gly-represents-NH-CH ₂ -CO-. Thus, the hyphen representing the peptide bond eliminates OH in the 1-carboxyl group of the amino acid (represented here in conventional non-ionized form) when located on the right side of the symbol and eliminates H in the 2-amino group of the amino acid when located on the left side of the symbol; both modifications can be applied to the same symbol (see table 1).

TABLE 1

As used herein, the term "acyclic aliphatic group" includes straight-chain (i.e., straight-chain and unbranched) or branched, saturated or unsaturated hydrocarbon groups, such as alkyl, alkenyl, and alkynyl groups. The acyclic aliphatic group may be substituted (mono or poly) or unsubstituted.

As used herein, the term "alkyl" includes saturated straight-chain and branched alkyl groups, which may be substituted (mono or poly) or unsubstituted. The alkyl group is bound to the rest of the molecule by a single bond. The alkyl group has 1 to 24, preferably 1 to 16, more preferably 1 to 14, even more preferably 1 to 12, yet more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. The term "alkyl" includes, for example, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 2-methylbutyl, heptyl, 5-methylhexyl, 2-ethylhexyl, octyl, decyl, dodecyl, lauryl, cetyl, stearyl and pentyl.

As used herein, the term "alkenyl" refers to a group that contains one or more carbon-carbon double bonds and may be linear or branched as well as substituted (mono or poly) or unsubstituted. Preferably, it has 1, 2 or 3 carbon-carbon double bonds. If more than one carbon-carbon double bond is present, the double bond may or may not be conjugated. Preferably, the alkenyl group has 2 to 24, preferably 2 to 16, more preferably 2 to 14, even more preferably 2 to 12, yet more preferably2, 3, 4, 5 or 6 carbon atoms. The alkenyl group is bound to the rest of the molecule by a single bond. The term "alkenyl" includes, for example, vinyl (-CH) ₂ ＝CH ₂ ) Allyl (-CH) ₂ -CH＝CH ₂ ) Groups such as prenyl, oleyl, linoleyl, and the like.

The term "alkynyl" refers to groups containing one or more carbon-carbon triple bonds and which may be linear or branched as well as substituted (mono-or poly) or unsubstituted. Preferably, the alkynyl group has 1, 2 or 3 carbon-carbon triple bonds. The triple bond may be conjugated or unconjugated. The alkynyl group has 2 to 24, preferably 2 to 16, more preferably 2 to 14, even more preferably 2 to 12, yet more preferably 2, 3, 4, 5 or 6 carbon atoms. The alkynyl group is bound to the remainder of the molecule by a single bond. The term "alkynyl" includes, for example and without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, such as 1-pentynyl and the like. The alkynyl group may also contain one or more carbon-carbon double bonds, and the alkynyl group includes, for example and without limitation, but-1-en-3-ynyl groups, pent-4-en-1-ynyl groups, and the like.

The term "cycloaliphatic" is used herein to encompass, for example and without limitation, aliphatic cyclic (alicyclic) groups such as cycloalkyl or cycloalkenyl or cycloalkynyl groups. The term "cycloaliphatic" refers to a monovalent group of one or more rings containing carbon atoms, which may be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl), provided that it is not aromatic. More specifically, the alicyclic group contains three or more, 3 to 24, 3 to 12, or 6 to 12 ring carbon atoms. The alicyclic group may be a monocyclic, bicyclic or tricyclic ring system, and the rings may be, for example, fused or may be joined by a single bond or a linking group such as methylene or other alkylene. The alicyclic group may be substituted (mono or poly) or unsubstituted. In one embodiment, the cycloaliphatic group is a 6-to 12-membered ring system consisting of carbon atoms and optionally containing one or two double bonds.

The term "cycloalkyl" refers to a saturated mono-or multicyclic alkyl group that may be substituted (mono-or multicyclic) or unsubstituted. Cycloalkyl groups have 3 to 24, preferably 3 to 16, more preferably 3 to 14, even more preferably 3 to 12, yet even more preferably 3, 4, 5 or 6 carbon atoms. Cycloalkyl groups are bound to the rest of the molecule by single bonds. Cycloalkyl groups include, for example and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahydroindene, decalin, dodecahydrophenalene, and the like.

The term "cycloalkenyl" refers to a non-aromatic mono-or polycyclic alkenyl group that may be substituted (mono-or poly) or unsubstituted. Cycloalkenyl groups have 5 to 24, preferably 5 to 16, more preferably 5 to 14, even more preferably 5 to 12, yet more preferably 5 or 6 carbon atoms. Cycloalkenyl groups are bound to the rest of the molecule by single bonds. Preferably, cycloalkenyl groups contain 1, 2 or 3 carbon-carbon double bonds. If more than one carbon-carbon double bond is present, the double bond may or may not be conjugated. Cycloalkenyl groups include, for example and without limitation, cyclopent-1-en-1-yl and the like.

The term "cycloalkynyl" refers to a non-aromatic mono-or polycyclic alkynyl group that may be substituted (mono-or poly) or unsubstituted. The cycloalkynyl group has 8 to 24, preferably 8 to 16, more preferably 8 to 14, even more preferably 8 to 12, yet even more preferably 8 or 9 carbon atoms, and is bound to the rest of the molecule by a single bond. Preferably, the cycloalkynyl group contains 1, 2 or 3 carbon-carbon triple bonds, either conjugated or unconjugated. Cyclic alkynyl groups include, for example and without limitation, cyclooctyl-2-yn-1-yl and the like. The cycloalkynyl group may also contain one or more carbon-carbon double bonds, including, for example and without limitation, cyclooctyl-4-en-2-ynyl groups and the like.

As used herein, the term "heterocyclyl" or "heterocyclic" refers to a hydrocarbon ring system of 3 to 10 members in which one or more of the atoms in one or more rings is a heteroatom (i.e., not a carbon atom). Thus, "heterocyclyl" or "heterocyclic" refers to a cyclic group in which the ring atom consists of carbon and one or more heteroatoms. To satisfy the valence, a heteroatom may be bonded to H or a substituent. Preferably, 1, 2 or 3 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 O, N and S. The heterocyclic group may be substituted (mono or poly) or unsubstituted. The heterocyclic group may be a monocyclic, bicyclic or tricyclic ring system, and the rings may be, for example, fused or may be linked by a single bond or a linking group such as methylene or other alkylene. The nitrogen atom, carbon atom or sulfur atom present in the heterocyclic group may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heterocyclyl groups may be unsaturated or partially or fully saturated. The heterocyclyl group may be aliphatic or aromatic. In one embodiment, the heterocyclyl is aliphatic (also known as heteroalicyclic) and is a 3-to 10-membered ring system in which one or more ring atoms consist of carbon atoms and 1 to 4, or 1, 2, or 3 heteroatoms. In one embodiment, the heterocyclyl is a 6-to 10-membered ring system, wherein one or more ring atoms consist of carbon atoms and 1 to 4 heteroatoms, and wherein 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 carbon atoms and 1 to 4, or 1, 2 or 3 heteroatoms. Most preferably, the term heterocyclyl refers to a ring of 5 or 6 members. Examples of saturated heteroalicyclic groups are dioxane, piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine. Examples of aromatic heterocyclic groups are pyridine, pyrrole, furan, thiophene, benzofuran, imidazoline, quinoline (quinoline), pyridazine and naphthyridine.

The term "aryl group" refers to an aromatic group having from 6 to 30, preferably from 6 to 18, more preferably from 6 to 10, yet even more preferably 6 or 10 carbon atoms. The aryl group may include 1, 2, 3, or 4 aromatic rings that may be connected by a carbon-carbon bond or may be fused together and include, for example and without limitation, phenyl, naphthyl, diphenyl, indenyl, phenanthryl, anthracyl, or the like. The aryl groups may be substituted (mono or poly) or unsubstituted.

The term "aralkyl group" refers to an alkyl group substituted with an aromatic group having 7 to 24 carbon atoms and includes, for example and without limitation: - (CH) ₂ ) _1-6 -phenyl, - (CH) ₂ ) _1-6 - (1-naphthyl), - (CH) ₂ ) _1-6 - (2-naphthyl) - (CH) ₂ ) _1-6 -CH (phenyl) ₂ Etc.

The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl (also referred to as an aromatic heterocyclic group) as defined above, the alkyl group having from 1 to 6 carbon atoms, and the heteroaryl group having from 2 to 24 carbon atoms and from 1 to 3 heteroatoms. Heteroarylalkyl groups include, for example and without limitation, - (CH) ₂ ) _1-6 Imidazolyl, - (CH) ₂ ) _1-6 Triazolyl, - (CH) ₂ ) _1-6 Thienyl, - (CH) ₂ ) _1-6 Furyl, - (CH) ₂ ) _1-6 -a pyrrolidinyl group, etc.

The above groups may have a degree of substitution, as understood in the art. In particular, there may be substitution in any of the explicitly recited groups identified above. The above-mentioned substituted group (radical) is a group (or radical) substituted with one or more substituents in one or more positions available. Preferably, the substitution is in 1, 2 or 3 positions, more preferably in 1 or 2 positions, yet even more preferably in 1 position. Suitable substituents include, for example and without limitation: c (C) ₁ -C ₄ An alkyl group; a hydroxyl group; c (C) ₁ -C ₄ An alkoxy group; an amino group; amino-C ₁ -C ₄ An alkyl group; c (C) ₁ -C ₄ A carbonyloxy group; c (C) ₁ -C ₄ An oxycarbonyl group; halogen such as fluoride, chlorine, bromine, and iodine; cyano group; a nitro group; an azide; c (C) ₁ -C ₄ An alkylsulfonyl group; a mercaptan; c (C) ₁ -C ₄ Alkylthio; aryloxy groups such as phenoxy; -NR _b (C＝NR _b )NR _b R _c The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is _b And R is _c Independently selected from the group formed by: H. c (C) ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkenyl, alkynyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ -C ₁₈ Aryl, C ₇ -C ₁₇ Aralkyl, 3-10 membered heterocyclyl or amino protecting groups.

As used herein, the terms "comprises," comprising, "" including, "" is "or" includes "(which are inclusive or open-ended and do not exclude additional, non-enumerated elements or method steps) are intended to cover, in alternative embodiments, the phrases" consisting essentially of, and "consisting of," wherein "consisting of excludes any elements or steps not specified and" consisting essentially of, allows for the inclusion of additional, non-enumerated elements or steps that do not materially affect the nature or basic and novel characteristics of the composition or method under consideration.

Cosmetic use

The present invention is based on the discovery of surprising cosmetic non-therapeutic properties of compounds of formula (I). The compounds of formula (I), including all embodiments of formula (I) disclosed herein, are also referred to herein as compounds of the invention.

It has been found that the compounds of formula (I) are capable of increasing the energy of skin cells. In particular, it has been found that the compounds of formula (I) are capable of increasing the mitochondrial potential of human dermal fibroblast skin cells. Thus, it is believed that the compounds of formula (I) are capable of leading to higher energy production in skin cells. As used herein, the terms "increase in energy", "increase in energy metabolism" and/or "increase in energy production in skin cells" refer to an increase in energy supply to skin (i.e., skin) cells. The compounds of formula (I) are capable of increasing energy supply to cells by increasing mitochondrial membrane potential. An increase in energy metabolism of skin cells improves skin function. Thus, the compounds of formula (I) promote a healthy appearance of the skin. The present invention relates to the use of a compound of formula (I) for the cosmetic non-therapeutic treatment and/or care of the skin, wherein the cosmetic non-therapeutic treatment and/or care is to increase energy metabolism and/or energy production in skin cells.

It has also been found that the compounds of formula (I) are useful for improving and/or increasing skin luster. Skin luster is a vivid appearance associated with healthy, well resting skin. Skin luster is the ability of the skin to reflect light and is expressed in terms of the "glossiness" of the skin. Skin with high gloss reflects more light and therefore has better or stronger gloss than skin with low gloss. As used herein, improving and/or increasing skin luster means improving the physical appearance of skin by improving the natural luster of the skin. The present invention relates to the use of a compound of formula (I) for the cosmetic non-therapeutic treatment and/or care of the skin, wherein the cosmetic non-therapeutic treatment and/or care is an improvement and/or increase in skin shine.

Furthermore, it has been found that the compounds of formula (I) can be used as anti-skin fatigue agents. The compounds of formula (I) are useful for reducing and/or preventing skin fatigue. Skin fatigue is also known as "skin fatigue", which can be measured by measuring the "tiring effect" of the skin, for example by using a signal from Courage+ Khazaka electronic GmbHMPA 580 determines standard R9 parameters, where R9 represents the tiring effect of skin after repeated sucking. The smaller the R9 value, the smaller the tiring effect and thus the lower the skin fatigue. The compounds of formula (I) are useful for reducing and/or preventing the tiring effect of the skin. The present invention relates to the use of a compound of formula (I) for the cosmetic non-therapeutic treatment and/or care of the skin, wherein the cosmetic non-therapeutic treatment and/or care is to reduce and/or prevent skin fatigue.

A compound of formula (I)

The present invention relates to compounds of formula (I)

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

A stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₂ selected from the group consisting of-NR ₃ R ₄ 、-OR ₃ 、-SR ₃ A group consisting of R ₃ And R is ₄ Independently selected from the group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, an alicyclic group, a heterocyclic group, a heteroarylalkyl group, an aryl group, and an aralkyl group; and is also provided with

R ₁ And R is ₂ Not amino acids.

In the compounds of formula (I), R ₁ To the amino terminus (N-terminus) of the peptide, and R ₂ To the carboxyl terminus (C-terminus) of the peptide.

R ₁ May be selected from the group consisting of H, included polymers derived from polyethylene glycol having a molecular weight between 200 and 35000 daltons, and R ₅ -CO-, wherein R ₅ Selected from the group consisting of: c (C) ₁ -C ₂₄ Alkyl, C ₂ -C ₂₄ Alkenyl, C ₂ -C ₂₄ Alkynyl, C ₃ -C ₂₄ Cycloalkyl, C ₅ -C ₂₄ Cycloalkenyl, C ₈ -C ₂₄ Cycloalkynyl radicals, C ₆ -C ₃₀ Aryl, C ₇ -C ₂₄ Aralkyl, 3-to 10-membered heterocyclyl ring, and heteroarylalkyl containing 2 to 24 carbon atoms and 1 to 3 heteroatoms, wherein the alkyl group has 1 to 6 carbon atoms.

R ₁ Can be selected from H and R ₅ -CO-, wherein R ₅ Selected from C ₁ -C ₁₈ Alkyl, C ₂ -C ₂₄ Alkenyl, C ₃ -C ₂₄ Cycloalkyl or C ₁ -C ₁₆ Alkyl, C ₂ -C ₁₈ Alkenyl, C ₃ -C ₇ Cycloalkyl groups. R is R ₅ the-CO-group comprises an alkanoyl group, e.g. acetyl (CH ₃ -CO-, abbreviated herein as "Ac-", myristoyl (CH) ₃ -(CH ₂ ) ₁₂ -CO-, abbreviated herein as "Myr-") and palmitoyl (CH ₃ -(CH ₂ ) ₁₄ -CO-, which is abbreviated herein as "Palm-".

R ₁ May be selected from the group consisting of: h and acetyl, t-butyryl, isoprenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.

R ₁ Can be selected from H and R ₅ -CO-, wherein R ₅ Selected from C ₁ -C ₁₆ Alkyl or C ₂ -C ₁₈ Alkenyl groups.

R ₁ Can be selected from H and R ₅ -CO-, wherein R ₅ Is C ₁ -C ₁₅ An alkyl group.

R ₁ May be selected from the group consisting of H, acetyl and palmitoyl.

R ₂ Can be selected from the group consisting of-NR ₃ R ₄ 、-OR ₃ 、-SR ₃ A group consisting of R ₃ And R is ₄ Independently selected from the group formed by: H. polymers derived from polyethylene glycol, C ₁ -C ₂₄ Alkyl, C ₂ -C ₂₄ Alkenyl, C ₂ -C ₂₄ Alkynyl, C ₃ -C ₂₄ Cycloalkyl, C ₅ -C ₂₄ Cycloalkenyl, C ₈ -C ₂₄ Cycloalkynyl radicals, C ₆ -C ₃₀ Aryl, C ₇ -C ₂₄ Aralkyl, 3-to 10-membered heterocyclyl ring, and heteroarylalkyl containing 2 to 24 carbon atoms and 1 to 3 heteroatoms, wherein the alkyl group has 1 to 6 carbon atoms. Any oneOptionally R ₃ And R is ₄ The ring with nitrogen atoms may be formed by saturated or unsaturated carbon-carbon bond bonding.

R ₂ Can be-NR ₃ R ₄ OR-OR ₃ 。R ₃ And R is ₄ May be independently selected from the group consisting of: H. included are polymers of molecular weight between 200 and 35000 derived from polyethylene glycol, methyl, ethyl, hexyl, dodecyl, and hexadecyl groups. Alternatively, R ₃ And R is ₄ Can be independently selected from H and C ₁ -C ₁₆ Alkyl groups. In one embodiment, R ₂ Not being OR ₃ Wherein R is ₃ Is methyl, i.e. R ₂ Is not OCH ₃ . In one embodiment, R ₃ Is H, and R ₄ Selected from H and C ₁ -C ₁₆ Alkyl groups include methyl, ethyl, hexyl, dodecyl and hexadecyl groups.

R ₂ Can be selected from the group consisting of-OH, -NH ₂ and-NHR ₄ Wherein R is a group consisting of ₄ Is C ₁ -C ₁₆ Alkyl or C ₁ -C ₃ Alkyl or C ₁ -C ₂ An alkyl group.

R ₂ Can be-OH or-NH ₂ 。

R ₁ Can be selected from H and R ₅ -CO-, wherein R ₅ Selected from C ₁ -C ₁₈ Alkyl, C ₂ -C ₂₄ Alkenyl, C ₃ -C ₂₄ Cycloalkyl groups; and R is ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups. In this embodiment, R ₃ May be H, and R ₄ Can be selected from H, C ₁ -C ₁₆ Alkyl, C ₁ -C ₃ Alkyl and C ₁ -C ₂ A group of alkyl groups; for example, R ₂ Can be selected from the group consisting of-OH and-NH ₂ A group of groups.

R ₁ May be selected from the group consisting of: h and acetyl, t-butyryl, isoprenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl; and R is ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups. In this embodiment, R ₃ May be H, and R ₄ Can be selected from H, C ₁ -C ₁₆ Alkyl, C ₁ -C ₃ Alkyl and C ₁ -C ₂ A group of alkyl groups; for example, R ₂ Can be selected from the group consisting of-OH and-NH ₂ A group of groups.

R ₁ Can be selected from H and R ₅ -CO-, wherein R ₅ Selected from C ₁ -C ₁₆ Alkyl or C ₂ -C ₁₈ Alkenyl groups. And R is ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups. In this embodiment, R ₃ May be H, and R ₄ Can be selected from H, C ₁ -C ₁₆ Alkyl, C ₁ -C ₃ Alkyl and C ₁ -C ₂ A group of alkyl groups; for example, R ₂ Can be selected from the group consisting of-OH and-NH ₂ A group of groups.

R ₁ May be selected from the group consisting of H, acetyl, carob Kou Xianji and palmitoyl; and R is ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups. In this embodiment, R ₃ May be H, and R ₄ Can be selected from H, C ₁ -C ₁₆ Alkyl, C ₁ -C ₃ Alkyl and C ₁ -C ₂ A group of alkyl groups; for example, R ₂ Can be selected from the group consisting of-OH and-NH ₂ A group of groups.

R ₁ Can be selected from H and R ₅ -CO-, wherein R ₅ Is C ₁ -C ₁₅ Alkyl, and R ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups. In this embodiment, R ₃ May be H, and R ₄ Can be selected from H, C ₁ -C ₁₆ Alkyl, C ₁ -C ₃ Alkyl and C ₁ -C ₂ A group of alkyl groups; for example, R ₂ Can be selected from the group consisting of-OH and-NH ₂ A group of groups.

R ₁ May be selected from the group consisting of H, acetyl and palmitoyl, and R ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups. In this embodiment, R ₃ May be H, and R ₄ Can be selected from H, C ₁ -C ₁₆ Alkyl, C ₁ -C ₃ Alkyl and C ₁ -C ₂ A group of alkyl groups; for example, R ₂ Can be selected from the group consisting of-OH and-NH ₂ A group of groups.

R ₁ May be selected from the group consisting of substituted acyclic aliphatic groups, substituted cycloaliphatic groups, substituted heterocyclic groups, substituted heteroarylalkyl groups, substituted aryl groups, substituted aralkyl groups, and R ₅ -CO-, wherein R ₅ Selected from the group consisting of substituted acyclic aliphatic groups, substituted cycloaliphatic groups, substituted aryl groups, substituted aralkyl groups, substituted heterocyclic groups, and substituted heteroarylalkyl groups; and/or R ₂ is-NR ₃ R ₄ Wherein R is ₃ And R is ₄ At least one of which is selected from the group consisting of a substituted acyclic aliphatic group, a substituted cycloaliphatic group, a substituted heterocyclic group, a substituted heteroarylalkyl group, a substituted aryl group and a substituted aralkyl group, or R ₂ is-OR ₃ or-SR ₃ Wherein R is ₃ Selected from the group consisting of substituted acyclic aliphatic groups, substituted cycloaliphatic groups, substituted heterocyclic groups, substituted heteroarylalkyl groups, substituted aryl groups, and substituted aralkyl groups.

The most suitable polymer derived from polyethylene glycolThe preferable structure is as follows: group (-CH) ₂ -CH ₂ -O) _r -H, wherein r is a number between 4 and 795; and a group

Where s is a number comprised between 1 and 125.

The compound of formula (I) may be at least one of the following: r is R ₁ Is not H; and R is ₂ Not OH. That is, the compound of formula (I) may be such that: r is R ₁ Other than H and/or R ₂ Not OH.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of Arg and Lys; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Selected from the group consisting of gin and Asp; AA (AA) ₄ Selected from the group consisting of Met and Leu; AA (AA) ₅ Selected from the group consisting of Glu and Asp; and AA (AA) ₆ Selected from the group consisting of Glu and Gln. Preferably, AA ₁ Is Arg and/or AA ₂ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of Arg and Lys; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Is Gln; AA (AA) ₄ Met; AA (AA) ₅ Selected from the group consisting of Glu and Asp; and AA (AA) ₆ Selected from the group consisting of Glu and Gln. Preferably, AA ₁ Is Arg and/or AA ₂ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of Arg and Lys; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Selected from the group consisting of gin and Asp; AA (AA) ₄ Selected from the group consisting of Met and Leu; AA (AA) ₅ Selected from the group consisting of Glu, asp, and Gln; and AA (AA) ₆ Selected from the group consisting of Glu, gln and Asp; preferably, AA ₁ Is Arg and/or AA ₂ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting ofA group consisting of Arg and Lys; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Selected from the group consisting of Gln and Glu; AA (AA) ₄ Selected from the group consisting of Met and Leu; AA (AA) ₅ Selected from the group consisting of Glu, asp, and Gln; and AA (AA) ₆ Selected from the group consisting of Glu, gln and Asp; preferably, AA ₁ Is Arg and/or AA ₂ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of Arg and Lys; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Selected from the group consisting of Gln, glu, asn and Asp or from the group consisting of gin and Asp; AA (AA) ₄ Selected from the group consisting of Met and Leu; AA (AA) ₅ Selected from the group consisting of Glu and Gln; and AA (AA) ₆ Selected from the group consisting of Glu and Gln; preferably, AA ₁ Is Arg and/or AA ₂ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Arg; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Selected from the group consisting of gin and Asp; AA (AA) ₄ Selected from the group consisting of Met and Leu; AA (AA) ₅ Is Glu; and AA (AA) ₆ Is Glu. Preferably, AA ₂ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of Arg and Lys; AA (AA) ₂ Arg; AA (AA) ₃ Is Gln; AA (AA) ₄ Met; AA (AA) ₅ Selected from the group consisting of Glu and Asp; and AA (AA) ₆ Selected from the group consisting of Glu and Gln. Preferably, AA ₁ Arg.

The compound of formula (I) may be such: AA (AA) ₁ Arg; AA (AA) ₂ Arg; AA (AA) ₃ Is Gln; AA (AA) ₄ Met; AA (AA) ₅ Is Glu; and AA (AA) ₆ Is Glu; and AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ With the proviso that 0, 1, 2, 3 or 4 of them are replaced, with the proviso that when AA ₁ When substituted, it is replaced by Lys; when AA is ₂ When substituted, it is replaced by Lys; when AA is ₃ When substituted, it is substituted with Glu, asn orAsp substitution; when AA is ₄ When substituted, it is substituted by Leu; when AA is ₅ When substituted, it is substituted with Asp or gin; and when AA ₆ When substituted, it is replaced by Asp or Gln. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced by 0, 1, 2 or 3. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ And 0 (none) of them is replaced. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced.

The compound of formula (I) may be such: AA (AA) ₁ Arg; AA (AA) ₂ Arg; AA (AA) ₃ Is Gln; AA (AA) ₄ Met; AA (AA) ₅ Is Glu; and AA (AA) ₆ Is Glu; and AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ With the proviso that 0, 1, 2, 3 or 4 of them are replaced, with the proviso that when AA ₁ When substituted, it is replaced by Lys; when AA is ₂ When substituted, it is replaced by Lys; when AA is ₃ When substituted, it is replaced with Glu; when AA is ₄ When substituted, it is substituted by Leu; when AA is ₅ When substituted, it is substituted with Asp; and when AA ₆ When substituted, it is replaced by Gln. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced by 0, 1, 2 or 3. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ And 0 (none) of them is replaced. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced. In one embodiment, AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is replaced.

The compounds of formula (I) may be as described above, wherein AA in formula (I) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Is an L-amino acid. This embodiment includes compounds of formula (I), wherein: AA (AA) ₁ Is L-Arg; AA (AA) ₂ Is L-Arg; AA (AA) ₃ Is L-Gln; AA (AA) ₄ Is L-Met; AA (AA) ₅ Is L-Glu; and AA (AA) ₆ Is L-Glu.

The compound of formula (I) may be such: AA in formula (I) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ At least one of which is a D-amino acid. This embodiment comprises a compound of formula (I), wherein AA in formula (I) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ 1, 2 or 3 of which are D amino acids, and AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ The remainder of which are L amino acids. For example, wherein AA ₃ 、AA ₄ And AA (alpha) ₅ 1, 2 or 3 of which are D amino acids, and the other amino acids, namely AA ₁ To AA ₆ The remainder of which are compounds of formula (I) of the L amino acid. This embodiment includes wherein AA ₃ 、AA ₄ And AA (alpha) ₅ 1 or 2 of them are D amino acids, and the other amino acids, namely AA ₁ To AA ₆ The remainder of which are L amino acids. This embodiment includes, for example, compounds of formula (I) wherein AA ₄ Is D amino acid and AA ₁ 、AA ₂ 、AA ₃ 、AA ₅ And AA (alpha) ₆ Each is an L-amino acid. These embodiments of the invention apply to all compounds of formula (I) described hereinEmbodiments, wherein amino acid AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ Neither is designated as a D-amino acid or an L-amino acid.

Thus, the compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of Arg and Lys; AA (AA) ₂ Selected from the group consisting of Arg and Lys; AA (AA) ₃ Selected from the group consisting of gin and Asp; AA (AA) ₄ Selected from the group consisting of Met and Leu; AA (AA) ₅ Selected from the group consisting of Glu and Asp; and AA (AA) ₆ Selected from the group consisting of Glu and Gln, and AA ₃ 、AA ₄ And AA (alpha) ₅ 1, 2 or 3 of which are D-amino acids, and the other amino acids, namely AA ₁ To AA ₆ The remainder of which are L amino acids. This embodiment includes wherein AA ₃ 、AA ₄ And AA (alpha) ₅ 1 or 2 of them are D-amino acids, and the other amino acids, namely AA ₁ To AA ₆ The rest of which are L-amino acids. This embodiment includes wherein AA ₄ Is a D-amino acid, and AA ₁ 、AA ₂ 、AA ₃ 、AA ₅ And AA (alpha) ₆ Each is an L-amino acid.

The compound of formula (I) may be such: AA (AA) ₁ Arg; AA (AA) ₂ Arg; AA (AA) ₃ Is Gln; AA (AA) ₄ Met; AA (AA) ₅ Is Glu; and AA (AA) ₆ Is Glu; and AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ With the proviso that 0, 1, 2, 3 or 4 of them are replaced, with the proviso that when AA ₁ When substituted, it is replaced by Lys; when AA is ₂ When substituted, it is replaced by Lys; when AA is ₃ When substituted, it is substituted with Glu, asn or Asp; when AA is ₄ When substituted, it is substituted by Leu; when AA is ₅ When substituted, it is substituted with Asp or gin; and when AA ₆ When substituted, it is substituted with Asp or Gln, and AA ₃ 、AA ₄ And AA (alpha) ₅ 1, 2 or 3 of which are D-amino acids, and the other amino acids, namely AA ₁ To AA ₆ The rest of which are L-amino acids. This embodiment includes whereinAA ₃ 、AA ₄ And AA (alpha) ₅ 1 or 2 of them are D amino acids, and the other amino acids, namely AA ₁ To AA ₆ The remainder of which are L amino acids. This embodiment includes wherein AA ₄ Is a D-amino acid, and AA ₁ 、AA ₂ 、AA ₃ 、AA ₅ And AA (alpha) ₆ Each is an L-amino acid. AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ May be substituted for 0, 1, 2 or 3 of the above. 0 (none) of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. One of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. Two of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ May be substituted.

The compound of formula (I) may be such: AA (AA) ₁ Arg; AA (AA) ₂ Arg; AA (AA) ₃ Is Gln; AA (AA) ₄ Met; AA (AA) ₅ Is Glu; and AA (AA) ₆ Is Glu; and AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ With the proviso that 0, 1, 2, 3 or 4 of them are replaced, with the proviso that when AA ₁ When substituted, it is replaced by Lys; when AA is ₂ When substituted, it is replaced by Lys; when AA is ₃ When substituted, it is replaced with Glu; when AA is ₄ When substituted, it is substituted by Leu; when AA is ₅ When substituted, it is substituted with Asp; and when AA ₆ When substituted, it is replaced by Gln, and AA ₃ 、AA ₄ And AA (alpha) ₅ 1, 2 or 3 of which are D amino acids, and the other amino acids, namely AA ₁ To AA ₆ The rest of which are L-amino acids. This embodiment includes wherein AA ₃ 、AA ₄ And AA (alpha) ₅ 1 or 2 of them are D amino acids, and the other amino acids, namely AA ₁ To AA ₆ The remainder of which are L amino acids. This embodiment includes wherein AA ₄ Is a D-amino acid, and AA ₁ 、AA ₂ 、AA ₃ 、AA ₅ And AA (alpha) ₆ Each isL-amino acid. AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ May be substituted for 0, 1, 2 or 3 of the above. 0 (none) of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. One of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. Two of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. AA (AA) ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ May be substituted.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₂ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₃ Selected from the group consisting of D-Gln, D-Glu, D-Asn and D-Asp or from the group consisting of D-Gln and D-Asp; AA (AA) ₄ Selected from the group consisting of L-Met and L-Leu; AA (AA) ₅ Selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA (AA) ₆ Selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, it is preferably AA ₁ Is L-Arg and AA ₂ Is L-Arg. This embodiment includes compounds of formula (I), wherein: AA (AA) ₁ Is L-Arg; AA (AA) ₂ Is L-Arg; AA (AA) ₃ Is D-Gln; AA (AA) ₄ Is L-Met; AA (AA) ₅ Is L-Glu; and AA (AA) ₆ Is L-Glu.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₂ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₃ Selected from the group consisting of L-Gln, L-Glu, L-Asn and L-Asp or from the group consisting of L-Gln and L-Asp; AA (AA) ₄ Selected from the group consisting of D-Met and D-Leu; AA (AA) ₅ Selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA (AA) ₆ Selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, it is preferably AA ₁ Is L-Arg and AA ₂ Is L-Arg. This embodiment includes compounds of formula (I), wherein: AA (AA) ₁ Is L-Arg; AA (AA) ₂ Is L-Arg; AA (AA) ₃ Is L-Gln; AA (AA) ₄ Is D-Met; AA (AA) ₅ Is L-Glu; and AA (AA) ₆ Is L-Glu.

Of formula (I)The compound may be such that: AA (AA) ₁ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₂ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₃ Selected from the group consisting of L-Gln, L-Glu, L-Asn and L-Asp or from the group consisting of L-Gln and L-Asp; AA (AA) ₄ Selected from the group consisting of L-Met and L-Leu; AA (AA) ₅ Selected from the group consisting of D-Glu, D-Asp and D-Gln; and AA (AA) ₆ Selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, it is preferably AA ₁ Is L-Arg and AA ₂ Is L-Arg. This embodiment includes compounds of formula (I), wherein: AA (AA) ₁ Is L-Arg; AA (AA) ₂ Is L-Arg; AA (AA) ₃ Is L-Gln; AA (AA) ₄ Is L-Met; AA (AA) ₅ Is D-Glu; and AA (AA) ₆ Is L-Glu.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₂ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₃ Selected from the group consisting of L-Gln, L-Glu, L-Asn and L-Asp or from the group consisting of L-Gln and L-Asp; AA (AA) ₄ Selected from the group consisting of D-Met and D-Leu; AA (AA) ₅ Selected from the group consisting of D-Glu, D-Asp and D-Gln; and AA (AA) ₆ Selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, it is preferably AA ₁ Is L-Arg and AA ₂ Is L-Arg. This embodiment includes compounds of formula (I), wherein: AA (AA) ₁ Is L-Arg; AA (AA) ₂ Is L-Arg; AA (AA) ₃ Is L-Gln; AA (AA) ₄ Is D-Met; AA (AA) ₅ Is D-Glu; and AA (AA) ₆ Is L-Glu.

The compound of formula (I) may be such: AA (AA) ₁ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₂ Selected from the group consisting of L-Arg and L-Lys; AA (AA) ₃ Selected from the group consisting of D-Gln, D-Glu, D-Asn and D-Asp or from the group consisting of D-Gln and D-Asp; AA (AA) ₄ Selected from the group consisting of D-Met and D-Leu; AA (AA) ₅ Selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA (AA) ₆ Selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, it is preferably AA ₁ Is L-Arg and AA ₂ Is L-Arg. This embodiment packageA compound comprising formula (I), wherein: AA (AA) ₁ Is L-Arg; AA (AA) ₂ Is L-Arg; AA (AA) ₃ Is D-Gln; AA (AA) ₄ Is D-Met; AA (AA) ₅ Is L-Glu; and AA (AA) ₆ Is L-Glu.

The compounds of formula (I) include those selected from the group of amino acid sequences listed in table 2, wherein the sequence identifiers thereof, stereoisomers thereof and/or cosmetically or pharmaceutically acceptable salts thereof are detailed.

TABLE 2

The compound of formula (I) comprises each of the sequences in Table 2, wherein amino acid AA ₁ To AA ₆ One of which is replaced with a replacement amino acid, wherein the replacement amino acid is selected from the listed replacement amino acids of the amino acids replaced in formula (I) above. The substituted amino acid is different from the amino acid to be substituted. Thus the invention provides each of the sequences in Table 2, wherein amino acid AA ₁ To AA ₆ One of which is replaced by an amino acid, wherein: when AA in one of the sequences in Table 2 ₁ When an amino acid is substituted, it is substituted by Arg or Lys, provided that if AA ₁ Amino acid Arg, then it is replaced by Lys, and if AA ₁ Amino acid Lys, then it is replaced by Arg; when AA in one of the sequences in Table 2 ₂ When an amino acid is substituted, it is substituted by Arg or Lys, provided that if AA ₂ Amino acid Arg, then it is replaced by Lys, and if AA ₂ Amino acid Lys, then it is replaced by Arg; if AA in one of the sequences in Table 2 ₃ Amino acid is substituted, then it is substituted by Gln, glu, asn or Asp, provided that if AA ₃ Amino acid is Gln, which is replaced by Glu, asn or Asp, if AA ₃ The amino acid is Glu, then it is Gln, asnOr Asp instead, if AA ₃ Amino acid is Asn, which is replaced by Glu, gln or Asp, and if AA ₃ Amino acid is Asp, then it is replaced by Glu, gin or Asn; when AA in one of the sequences in Table 2 ₄ When an amino acid is substituted, it is substituted with Met or Leu, provided that if AA ₄ Amino acid is Met, it is replaced by Leu, and if AA ₄ Amino acid is Leu, then it is replaced by Met; when AA in one of the sequences in Table 2 ₅ When an amino acid is replaced, it is replaced by Glu, asp or Gln, provided that if AA ₅ Amino acid is Gln, which is replaced by Glu or Asp, if AA ₅ Amino acid is Glu, it is replaced by Gln or Asp, and if AA ₅ Amino acid is Asp, then it is replaced by Glu or gin; and when AA in one of the sequences of Table 2 ₆ Amino acid is replaced by Glu, asp or Gln, provided that if AA ₆ Amino acid is Gln, which is replaced by Glu or Asp, if AA ₆ Amino acid is Glu, it is replaced by Gln or Asp, and if AA ₆ Amino acid is Asp, then it is replaced by Glu or Gln.

In the amino acid sequence according to formula (1) of Table 2, R ₁ And R is ₂ H and OH, respectively. The compound of formula (1) comprises each of the sequences of Table 2, wherein the N-and C-termini thereof are each independently defined by other R of formula (1) as defined herein ₁ And R is ₂ And (3) group modification. For example, the compound of formula (I) comprises each of the sequences in Table 2 wherein the N-terminal amino acid residue terminates in R of formula (1) as defined above ₁ Wherein R is ₁ Is other than H, and alternatively or additionally wherein the C-terminal amino acid residue optionally terminates in R of formula (1) as defined above ₂ Wherein R is ₂ Not OH.

Thus, in particular, the compound according to formula (I) may be an amino acid sequence selected from: SEQ ID NO.1, 2, 11, 13, 17, 18, 19, 20, 21, 25, 26, 27, 28, 29 and 30 or SEQ ID NO.1, 2, 11, 13, 17, 18, 27 and 30, stereoisomers thereof and/or cosmetically or pharmaceutically acceptable salts thereof, wherein optionally the sequence is such that the N-terminal amino acid thereof is of formula as defined above(1) R of (2) ₁ Modification, wherein R ₁ Is other than H, and alternatively or additionally, the sequence is such that its C-terminal amino acid is substituted by R of formula (1) as defined above ₂ Modification, wherein R ₂ Not OH. The amino acid sequences may be SEQ ID NO.17, 18, 19, 20, 21, 25, 26, 27, 28, 29 and 30. The amino acid sequences may be SEQ ID NO.17, 18, 27 and 30. The amino acid sequence may be SEQ ID NO.17. The amino acid sequence may be SEQ ID NO.27. The amino acid sequence may be SEQ ID NO.18. The amino acid sequence may be SEQ ID NO.30.

The compounds of formula (I) may exist as stereoisomers or as mixtures of stereoisomers; for example, the amino acids comprising them may have the configuration L-, the configuration D-, or be racemic independently of each other. Thus, it is possible to obtain mixtures of isomers as well as racemic mixtures or diastereomeric mixtures or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and which isomers or mixtures of isomers are present. The preferred structure of the compounds of formula (I) is the pure isomer, i.e. enantiomer or diastereomer. For example, when AA is indicated ₂ Where Arg is present, it is to be understood that AA, unless otherwise indicated ₂ Selected from L-Arg, D-Arg or a mixture of both (racemic or non-racemic). The preparation procedure described in this document enables one skilled in the art to obtain each of the stereoisomers of the compound by selecting the amino acid with the correct configuration.

In the context of the present invention, the term "amino acid" includes amino acids encoded by the genetic code as well as non-encoded amino acids, whether natural or non-natural. Examples of uncoded amino acids are, but are not limited to: citrulline, ornithine, sarcosine, desmin, norvaline, 4-aminobutyric acid, 2-aminoisobutyric acid, 6-aminocaproic acid, 1-naphthylalanine, 2-aminobenzoic acid, 4-chlorophenyl alanine, 2, 3-diaminopropionic acid, 2, 4-diaminobutyric acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline, alloisoleucine, allothreonine, isopiperidinic acid, isoserine, phenylglycine, statin, beta-alanine, norleucine, N-methylaminoacid, alpha-amino acid, beta-amino acid, and the like, and derivatives thereof. A list of unnatural amino acids can be found in D.C. Roberts and F.Vellaccio, in Peptides, volume 5 (1983), chapter VI, gross E. And Meienhofer J, academic Press (Academic Press), unusual amino acids in peptide synthesis (Unusual amino acids in peptide synthesis) in New York, USA) or in commercial catalogues of companies specializing in this area.

In particular, the compounds of formula (I) may be selected from the group of compounds listed in table 3, stereoisomers thereof and/or cosmetically acceptable salts thereof.

TABLE 3 Table 3

The compound of formula (I) includes each of the compounds in Table 3, wherein amino acid AA ₁ To AA ₆ One of which is replaced with a replacement amino acid, wherein the replacement amino acid is selected from the group of replacement amino acids listed for the amino acids replaced in formula (I) above. The substituted amino acid is different from the amino acid to be substituted. Thus the compounds of formula (I) include those of Table 3 wherein amino acid AA ₁ To AA ₆ One of which is replaced by an amino acid, wherein: when AA in one of the sequences of Table 3 ₁ When an amino acid is substituted, it is substituted by Arg or Lys, provided that if AA ₁ Amino acid Arg, then it is replaced by Lys, and if AA ₁ Amino acid Lys, then it is replaced by Arg; when AA in one of the sequences in Table 3 ₂ When an amino acid is substituted, it is substituted by Arg or Lys, provided that if AA ₂ Amino acid Arg, then it is replaced by Lys, and if AA ₂ The amino acid is Lys, then it is Arg is substituted; if AA in one of the sequences in Table 3 ₃ Amino acid is substituted, then it is substituted by Gln, glu, asn or Asp, provided that if AA ₃ Amino acid is Gln, which is replaced by Glu, asn or Asp, if AA ₃ The amino acid being Glu, being replaced by Gln, asn or Asp, if AA ₃ Amino acid is Asn, which is replaced by Glu, gln or Asp, and if AA ₃ Amino acid is Asp, then it is replaced by Glu, gin or Asn; when AA in one of the sequences in Table 3 ₄ When an amino acid is substituted, it is substituted with Met or Leu, provided that if AA ₄ Amino acid is Met, it is replaced by Leu, and if AA ₄ Amino acid is Leu, then it is replaced by Met; when AA in one of the sequences in Table 3 ₅ When an amino acid is replaced, it is replaced by Glu, asp or Gln, provided that if AA ₅ Amino acid is Gln, which is replaced by Glu or Asp, if AA ₅ Amino acid is Glu, it is replaced by Gln or Asp, and if AA ₅ Amino acid is Asp, then it is replaced by Glu or gin; and when AA in one of the sequences of Table 3 ₆ Amino acid is replaced by Glu, asp or Gln, provided that if AA ₆ Amino acid is Gln, which is replaced by Glu or Asp, if AA ₆ Amino acid is Glu, it is replaced by Gln or Asp, and if AA ₆ Amino acid is Asp, then it is replaced by Glu or Gln.

The compounds according to formula (I) may be those selected from table 3, and in particular may be selected from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37 and PEP41, or from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23 and PEP24, and stereoisomers and/or cosmetically or pharmaceutically acceptable salts thereof. The compound may be PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37 and PEP41. 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.

Cosmetically or pharmaceutically acceptable salts of the compounds of formula (I) are also found in the field of the invention. The term "cosmetically or pharmaceutically acceptable salt" refers to salts that are approved for use in animals (e.g., mammals), more specifically, humans, and include: for forming the following salts: a base addition salt that is inorganic, such as, but not limited to, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc, or aluminum, etc., or organic, such as, but not limited to, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, or piperazine, etc.; or acid addition salts, which are organic, such as, but not limited to, acetates, citrates, lactates, malonates, maleates, tartrates, fumarates, benzoates, aspartate, glutamate, succinates, oleates, trifluoroacetates, oxalates, pamoate or gluconate, etc., or inorganic, such as, but not limited to, chlorides, sulfates, borates or carbonates, etc. The nature of the salt is not critical, provided that it is cosmetically or pharmaceutically acceptable. Cosmetically or pharmaceutically acceptable salts of the compounds of the invention may be obtained by conventional methods well known in the art [ Berge s.m. et al, "pharmaceutical salts (Pharmaceutical Salts)", (1977), "journal of pharmaceutical science (j.pharm.sci.), 66,1-19].

The synthesis of the compounds of formula (I), stereoisomers thereof, mixtures thereof and/or cosmetically or pharmaceutically acceptable salts thereof may be carried out according to conventional methods known in the art, such as solid phase peptide synthesis methods [ Stewart j.m. and Young j.d. "Solid Phase Peptide Synthesis, 2 nd 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 ], solution synthesis, enzymatic synthesis [ Kullmann W. "Proteases as catalysts for enzymic syntheses of opioid peptides" (1980), J.biol. Chem.,255 (17), 8234-8238] or any combination thereof. The compounds may also be obtained by fermentation of bacterial strains, modified or not modified by genetic engineering to produce the desired sequence, or controlled by hydrolysis of proteins of animal or plant origin, preferably of plant origin, which hydrolysis produces free peptide fragments containing the desired sequence.

For example, compounds of formula (I), stereoisomers thereof and mixtures thereof may be obtained as described in WO2020031146 A1. WO2020031146A1 discloses the use of a peptide as defined therein for treating and/or preventing skin ageing and reducing wrinkles. WO2020031146A1 does not mention the use of these peptides for supplying energy to the skin or for preventing skin fatigue.

The invention also extends to the use of a compound of formula (I) in combination with: botulinum toxin, ac-Glu-Glu-Met-Gln-Arg-Arg-NH ₂ Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ Or a combination thereof. In one embodiment, the invention extends to compounds of formula (I) and H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ Use of the combination.

Treatment method

In another aspect, the invention provides a method of cosmetically non-therapeutically treating and/or caring for the skin of a subject, comprising administering to the subject an effective amount of a compound of formula (I), a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof, or a composition comprising a cosmetically effective amount of a compound of formula (I), a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof, wherein the cosmetically non-therapeutic treatment and/or caring is: increasing energy metabolism and/or energy production in skin cells; improving or increasing skin luster; and/or reducing or preventing skin fatigue.

The invention also extends to a method of treatment and/or care of the above-mentioned skin, wherein the compound of formula (I) is applied in combination with: botulinum toxin, ac-Glu-Glu-Met-Gln-Arg-Arg-NH ₂ H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ Or a combination thereof.

Botulinum toxin, ac-Glu-Glu-Met-Gln-Arg-Arg-NH ₂ Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ Or a combination thereof, may be administered simultaneously (simultaneously) or one after the other with the compound of formula (I). When botulinum toxin, ac-Glu-Glu-Met-Gln-Arg-Arg-NH ₂ Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ Or combinations thereof, with compounds and compositions comprising an effective amount of a compound of formula (I), which may be administered in separate dosage forms or as part of a single composition. When the product is administered in separate dosage forms, the dosage forms may be in the same or different containers.

The methods of treatment and/or care of the skin described herein may comprise topically applying a compound of formula (I) or a composition comprising a compound of formula (I).

For the methods of the invention described above, topical or transdermal administration may be performed by iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic gradients, bandaging care, microinjection, needleless injection by pressure, by microelectronic patches, masks, or any combination thereof.

For the methods of the invention described above, the application or frequency of administration may vary widely depending on the needs of each subject, with application advice being once a month to ten times a day, preferably once a week to four times a day, more preferably three times a week to two times a day, even more preferably once a day. For example, the frequency of administration may vary widely depending on the needs of each subject, according to the method of treating and/or caring for the skin of the subject, which comprises administering to the subject a compound of formula (I), a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof in combination with: botulinum toxin, ac-Glu-Glu-Met-Gln-Arg-Arg-NH ₂ Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ Or a combination thereof. In one embodiment, the methods of the invention comprise administering a botulinum toxin and then administering a compound of formula (I) or a composition comprising a compound of formula (I). In particular embodimentsIn a variant, the compound of formula (I) or the composition comprising the compound of formula (I) is administered at least once daily for at least one week after administration of the botulinum toxin. More specifically, the compound of formula (I) or a composition comprising the compound of formula (I) is administered at least once per day prior to the next administration of the botulinum toxin.

Cosmetic compositions comprising a compound according to formula (I), stereoisomers and/or cosmetically acceptable salts thereof, together with at least one cosmetically acceptable excipient or adjuvant, may be prepared by conventional means known to the person skilled in the art [ "Harry's cosmetic chemistry", seventh edition, (1982), wilkinson j.b., moore r.j. Edit, longman House, essex, GB ].

The compounds of formula (I) have a variable solubility in water, depending on the nature of their amino acid sequence or any possible modification of the N-and/or C-terminus. Thus, the compounds of formula (I) may be incorporated into the composition by aqueous solutions, and those that are insoluble in water may be dissolved in conventional solvents that are cosmetically or pharmaceutically acceptable, such as, but not limited to, ethanol, propanol, isopropanol, propylene glycol, glycerol, butylene glycol or polyethylene glycol, or any combination thereof.

The cosmetically effective amount of the compound of formula (I) to be administered, as well as the dosage thereof, will depend on a variety of factors including the age, the state of the patient, the nature or severity of the condition, disorder or disease to be treated and/or cared for, the route and frequency of administration, and the particular nature of the compound to be used.

The terms "cosmetically effective amount" and "pharmaceutically effective amount" are understood to mean an amount of one or more compounds of the present invention that is non-toxic but sufficient to provide the desired effect. The terms "pharmaceutically effective" and "therapeutically effective" are used interchangeably herein. The compounds of the present invention are used in the cosmetic or pharmaceutical compositions of the present invention in cosmetically or pharmaceutically effective concentrations to achieve the desired effect; for example, the amounts used are, relative to the total weight of the composition: 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;

the compounds of formula (I), stereoisomers thereof, mixtures thereof and/or cosmetically or pharmaceutically acceptable salts thereof may also be incorporated into cosmetic or drug delivery systems and/or slow release systems.

The term "delivery system" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered. These cosmetic or pharmaceutical carriers may be liquids, such as water, oils, or surfactants, including petroleum, animal, vegetable, or synthetic sources, such as, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbate, sorbitan esters, ether sulfates, betaines, glucosides, maltosides, fatty alcohols, nonoxynol, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin, and the like. Diluents, adjuvants or excipients that may be used in different delivery systems in which the compounds of the invention may be administered are known to those skilled in the art.

The term "sustained release" is used in its conventional sense for a delivery system of a compound that provides gradual release of such compound over a period of time, and preferably, but not necessarily, has a relatively constant level of release of the compound over a period of time.

Examples of delivery or sustained release systems include, but are not limited to, liposomes, hybrid liposomes, oleosomes, liposomes, ethosomes, millimeter particles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed micelles of surfactant-phospholipids, millimeter spheres, microspheres and nanospheres, lipid spheres, millimeter capsules, microcapsules and nanocapsules, and microemulsions and nanoemulsions, which may be added to achieve greater permeability 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 with reverse micelle internal structures and nanocapsules containing microemulsions.

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

The slow release system can be prepared by methods known in the art and the composition containing the slow release system can be applied, for example, by: by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches, and microelectronic patches; or by systemic administration, for example and without limitation, oral or parenteral routes, including nasal, rectal or subcutaneous implantation or injection, or direct implantation or injection into a specific body part, and preferably a relatively constant amount of the compound of formula (I) should be released. The amount of compound contained in the sustained release system will depend, for example, on where the composition is to be administered, the kinetics and duration of release of the compound of formula (I), and the nature of the condition, disorder and/or disease to be treated and/or cared for.

The compounds of formula (I) may also be adsorbed on solid organic polymers or solid mineral supports such as, but not limited to, talc, bentonite, silica, starch or maltodextrin and the like.

The compositions containing the compounds of formula (I), stereoisomers thereof, mixtures thereof and/or cosmetically or pharmaceutically acceptable salts thereof may also be incorporated into fabrics, nonwoven fabrics and medical devices which are in direct contact with the skin, whereby the compounds of the invention are released by biodegradation of the incorporated systems into the fabrics, nonwoven fabrics and medical devices, or by friction between them and the body, due to body moisture, pH of the skin or body temperature. Furthermore, the compounds of the present invention may be incorporated into fabrics and nonwoven fabrics used in the manufacture of garments for direct physical contact.

Examples of fabrics, nonwoven fabrics, garments, medical devices and devices for securing compounds thereto (which are delivery systems and/or sustained release systems described above) and the like can be found in the literature and are known in the art [ Schaab c.k. (1986) HAPPI, month 5 1986; nelson g., "Application of microencapsulation in textiles" (2002), int.j.pharm.,242 (1-2), 55-62; "Biofunctional Textiles and the Skin" (2006) curr.probl. Dermatol. 33 volume, hipler U.C. and Elsner P. Edit, S.Karger AG, basel, switzerland; malcolm R.K. et al, "Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial", (2004), J.Cont.Release,97 (2), 313-320]. Preferred fabrics, nonwoven fabrics, garments and medical devices are bandages, gauzes, T-shirts, socks, tights, undergarments, waistband, gloves, diapers, sanitary napkins, dressings, bedsheets, wipes, adhesive patches, non-adhesive patches, occlusive patches, micro-electric patches and/or face masks.

Cosmetic compositions containing the compounds of formula (I), stereoisomers thereof, mixtures thereof and/or cosmetically acceptable salts thereof may be used in different types of compositions for topical or transdermal application, optionally containing cosmetically or pharmaceutically acceptable excipients necessary to formulate the desired form of application.

Compositions for topical or transdermal application may be prepared in any solid, liquid or semi-solid formulation such as, but not limited to, creams, multiple emulsions (such as, but not limited to, oil-in-water and/or silicone-in-water emulsions, water-in-oil and/or silicone emulsions, water/oil/water or water/silicone/water emulsions, and oil/water/oil/or silicone/water/silicone emulsions), anhydrous compositions, aqueous dispersions, oils, creams, balms, foams, emulsions, gels, cream gels, hydroalcoholic solutions, hydroglycol solutions, hydrogels, liniments, soaps, shampoos, conditioners, essences, polysaccharide films, ointments, mousses, pomades, powders, sticks, pens, and sprays or aerosols (sprays), including leave-on and rinse-off formulations. These topical or transdermal application formulations may be incorporated into different types of solid adjuvants using techniques known to those skilled in the art, such as, but not limited to, bandages, gauze, t-shirts, socks, tights, undergarments, waistbands, gloves, diapers, sanitary napkins, dressings, bed covers, wipes, adhesive patches, non-adhesive patches, occlusive patches, micro-electric patches or masks, or they may be incorporated into different cosmetic products, such as make-up foundations (such as liquid foundations and foundation pads), make-up removers, eye concealers, eye shadows, lipsticks, lip balms, lip colors, lip powders, and the like.

Cosmetic compositions may contain agents that increase the percutaneous absorption of the compounds of the present invention, such as, but not limited to, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azones (1-dodecylazepan-2-one), alcohols, urea, ethoxydiglycol, acetone, propylene glycol or polyethylene glycols, and the like. Furthermore, the cosmetic composition may be suitable for local areas treated by iontophoresis, sonophoresis, electroporation, microelectronics, mechanical pressure, osmotic pressure gradients, occlusion healing, microinjection or needleless injection by pressure (such as injection by oxygen pressure) or any combination thereof, to achieve greater penetration of the peptides of the invention. The area of application will be determined by the nature of the condition, disorder and/or disease to be treated and/or treated.

Among the cosmetically acceptable adjuvants contained in the cosmetic compositions described herein are additional ingredients commonly used in cosmetic or pharmaceutical compositions, such as, but not limited to, anti-wrinkle agents, botulinum-like agents, and/or anti-aging agents; (ii) a tightening agent, a skin elastant and/or a reconstruction agent; a humectant; (iv) an anti-photoaging agent and/or a blue light protectant; DNA protectants, DNA repair agents, and/or stem cell protectants; radical scavengers and/or anti-glycation agents, antidotes, antioxidants and/or anti-pollution agents; antiperspirant agents; melanin synthesis-stimulating or inhibiting agents; whitening or decolorizing agents; a pigment-promoting agent; imitation tanning agent; lipolytic agents or agents that stimulate lipolysis, adipogenic agents, and the like. Additional examples can be found in CTFA International Cosmetic Ingredient Dictionary & Handbook, 12 th edition (2008).

The cosmetic compositions described herein may comprise a compound of formula (I) and a cosmetically effective amount of an adjuvant selected from the group consisting of: (i) Anti-wrinkle agents, botulinum-like agents and/or anti-aging agents; (ii) a tightening agent, a skin elastant and/or a reconstruction agent; (iii) a humectant; (iv) an anti-photoaging agent and/or a blue light protectant; (v) DNA protectants, DNA repair agents, and/or stem cell protectants; (vi) Radical scavengers and/or anti-glycation agents, antidotes, antioxidants and/or anti-pollution agents; and/or combinations thereof. Such adjuvants are known in the art and examples are given for example in WO2019008452 A1.

The invention is illustrated by the following non-limiting examples.

Examples

Example 1

Cosmetic enhancement of mitochondrial membrane potential in human skin fibroblasts (HDFa) using immunofluorescence assay In vitro study of the ability of (2)。

Mitochondria are intracellular organelles that play an important role in cellular metabolism, including heme, fatty acid and steroid synthesis; oxidative phosphorylation; ca2+ steady state; apoptosis. Mitochondria are encapsulated in the outer and inner membranes. The intima is more structurally complex and contains an Electron Transfer Chain (ETC) complex and a complex for ATP synthesis by oxidative phosphorylation. The process consists of a series of redox reactions in which electrons are transferred from an electron donor to an electron acceptor. The energy released by the electrons flowing through the ETC transports protons across the inner membrane, creating an electrochemical gradient. The electrochemical gradient consists of two parts (potential and proton gradient). This electrochemical gradient drives ATP synthesis. Mitochondrial membrane potential (MMP, Δψm) is generated by the potential across the intragranular membrane. Measurement of MMPs can be used to assess mitochondrial function as it is a direct biomarker of Adenosine Triphosphate (ATP) synthesis, a major source of energy in cells. Thus, products with increased MMP capacity can increase energy in cells and improve skin function.

The main objective of this experiment was to evaluate the ability of peptides to increase mitochondrial membrane potential in human skin fibroblasts.

Human skin fibroblasts (HDFa, life Technologies) from adults were seeded in 96-well plates at a density of 6,000 cells/well (3 wells per treatment)Is a kind of medium. During 24 hours, at 37℃at 5% CO ₂ Cells were inoculated in M106 medium with low serum growth supplements (Life Technologies). The medium was then removed and, during 16 hours, at 37 ℃ at 5% co ₂ Cells were treated with the above peptide or peptide composition dissolved in Dulbecco's Modified Eagle Medium) (Life Technologies) modified eagle's medium supplemented with 10% (v/v) fetal bovine serum (FBS, cultek). Untreated cells incubated in medium alone were used as basal conditions. FCCP (carbonyl cyanide 4- (trifluoromethoxy) phenylhydrazone), which is an ionophore uncoupler that inhibits oxidative phosphorylation of Δψm, was used as a negative control.

After 16 hours of treatment, cells were used to quantify mitochondrial membrane potential by using JC-1 mitochondrial membrane potential assay kit (Abcam) according to the manufacturer's protocol. Briefly, in the presence of treatment with peptide (each treatment always present during the assay), at 37℃at 5% CO ₂ Cells were incubated for 30 minutes with JC-1 working solution prepared with supplemental dilution buffer. JC-1 dye emits red or green fluorescence when it aggregates in healthy mitochondria with high membrane potential (hyperpolarization; charged cells) or exists as a monomer in mitochondria with reduced membrane potential (depolarization; uncharged cells), respectively.

Imaging cells and usingThe mitochondrial membrane potential was measured by a high content imaging system (PerkinElmer, inc). In charged cells, when excited at 520nm-550nm, red aggregates appear and dyes emit at 560nm-630 nm. In depolarized cells, the dye emits at 500nm-550nm when excited at 460nm-490 nm. The cell number was quantified by using Hoechst33342 (ThermoFisher Scientific) staining, a cell permeable nuclear counterstain that fluoresces blue at 460nm and excites at 350nm when bound to dsDNA. For each image, the intensity from the charged and depolarized cellsFluorescence was quantified and normalized to the number of nuclei.

The average of the percentage mitochondrial membrane potential relative to basal conditions after treatment of cells with the peptide or peptide combination is summarized in table 4. These values represent at least three independently determined values.

TABLE 4 Table 4

PEP23 was able to increase the mitochondrial potential of HDFa cells, demonstrating the ability of this peptide to increase cellular energy metabolism. Advantageously, with H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH ₂ PEP23 is relatively small (6 amino acids) compared to (9 amino acids) and can therefore be prepared more efficiently.

Example 2

Cosmetic composition for in vivo testing

The cosmetic composition is prepared by the following method:

dissolving phase A in a suitable container and addingUltrez 21 polymer (from Lubrizol Corporation) (phase A1).

Completely dispersing.

Mix phase A2 until completely dispersed.

Mix phase B in a separate vessel and then add to phase a while mixing with a turbine.

Add phase C while mixing with an overhead stirrer with dispersing blades.

Phase D is added to adjust the pH to 6-6.5.

TABLE 5

Example 3

Gloss and anti-fatigue effect

Forty (40) healthy female volunteers were recruited from the healthy subject panel under the supervision of committee-certified dermatologists according to the following inclusion and non-inclusion criteria.

Inclusion criteria:

-between the ages of 30 and 60 years, with clinical symptoms of skin ageing, such as fine lines or light/medium wrinkles in the area of the fish tail.

Subjects who have not recently (at least 3 weeks) participated in any other similar study and/or used any similar product.

A subject product having a similar effect as one of the products to be tested is not willing to be used during all study phases.

Willing not to change daily life.

-subjects who have informed the test procedure and signed an informed consent form.

Exclusion criteria:

-a subject not meeting the inclusion criteria.

-a subject showing allergy to cosmetics, toiletries, sunscreens and/or topical drugs.

-a subject having a skin condition in a test area.

Subjects under medication (local or systemic) that may interfere with the test execution.

Positive past history of atopy (if this situation interferes with test performance).

The study lasted 28 days. The subjects applied the composition described in example 2 (active cream) on one side of the face (left or right) and a placebo cream with the same composition except for the peptide of the invention on the other side of the face. The active and placebo creams were applied for 28 days twice daily (morning and evening).

Skin luster (or skin brightness) is the ability of the skin to reflect light, and it is measured using a glossiness parameter (obtained using a spectrophotometer/colorimeter CM-700D (Konica-Minolta)). The gloss value is used to control the brightness of the color.

From the following componentsMPA 580 (Courage + Khazaka electronic GmbH) determines the fatigue effect (or tiredness effect) by determining the R9 value, where smaller values represent smaller fatigue effects.

TABLE 6

The results show that the active cream significantly increases skin luster compared to placebo cream. The active cream significantly reduces skin fatigue, which may be associated with a reduction in skin fatigue.

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<223> SEQ ID NO.5

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 5

Arg Arg Gln Xaa Glu Gln

1 5

<210> 6

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.6

<400> 6

Arg Arg Gln Leu Glu Glu

1 5

<210> 7

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.7

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 7

Arg Arg Gln Xaa Gln Glu

1 5

<210> 8

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.8

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 8

Arg Arg Gln Xaa Glu Asp

1 5

<210> 9

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.9

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 9

Arg Lys Gln Xaa Glu Glu

1 5

<210> 10

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.10

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 10

Lys Arg Gln Xaa Glu Glu

1 5

<210> 11

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.11

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<400> 11

Arg Arg Xaa Met Glu Glu

1 5

<210> 12

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.12

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 12

Arg Arg Gln Xaa Glu Glu

1 5

<210> 13

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.13

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> X is D-Glu

<400> 13

Arg Arg Gln Xaa Xaa Glu

1 5

<210> 14

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.14

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 14

Arg Arg Xaa Xaa Glu Glu

1 5

<210> 15

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.15

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 15

Arg Arg Asp Xaa Asp Gln

1 5

<210> 16

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.16

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 16

Arg Arg Asp Xaa Asp Gln

1 5

<210> 17

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.17

<400> 17

Arg Arg Gln Met Glu Glu

1 5

<210> 18

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.18

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 18

Arg Arg Gln Xaa Glu Glu

1 5

<210> 19

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.19

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 19

Arg Arg Asp Xaa Glu Glu

1 5

<210> 20

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.20

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 20

Arg Arg Gln Xaa Asp Glu

1 5

<210> 21

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.21

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 21

Arg Arg Gln Xaa Glu Gln

1 5

<210> 22

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.22

<400> 22

Arg Arg Gln Leu Glu Glu

1 5

<210> 23

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.23

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 23

Arg Arg Gln Xaa Gln Glu

1 5

<210> 24

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.24

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 24

Arg Arg Gln Xaa Glu Asp

1 5

<210> 25

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.25

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 25

Arg Lys Gln Xaa Glu Glu

1 5

<210> 26

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.26

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 26

Lys Arg Gln Xaa Glu Glu

1 5

<210> 27

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.27

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<400> 27

Arg Arg Xaa Met Glu Glu

1 5

<210> 28

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.28

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 28

Arg Arg Gln Xaa Glu Glu

1 5

<210> 29

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.29

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> X is D-Glu

<400> 29

Arg Arg Gln Xaa Xaa Glu

1 5

<210> 30

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.30

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 30

Arg Arg Xaa Xaa Glu Glu

1 5

<210> 31

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.31

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 31

Arg Arg Asp Xaa Asp Gln

1 5

<210> 32

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> SEQ ID NO.32

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 32

Arg Arg Asp Xaa Asp Gln

1 5

<210> 33

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP1

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<400> 33

Arg Arg Gln Met Glu Glu

1 5

<210> 34

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP2

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<400> 34

Arg Arg Xaa Met Glu Glu

1 5

<210> 35

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP3

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 35

Arg Arg Gln Xaa Glu Glu

1 5

<210> 36

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP4

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 36

Arg Arg Xaa Xaa Glu Glu

1 5

<210> 37

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP5

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> palmitoyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 37

Arg Arg Gln Xaa Glu Glu

1 5

<210> 38

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP6

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 38

Arg Arg Gln Xaa Glu Glu

1 5

<210> 39

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP7

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 39

Arg Arg Gln Xaa Glu Glu

1 5

<210> 40

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP8

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> palmitoyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 40

Arg Arg Gln Xaa Glu Glu

1 5

<210> 41

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP9

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 41

Arg Arg Asp Xaa Glu Glu

1 5

<210> 42

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP10

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 42

Arg Arg Gln Xaa Asp Glu

1 5

<210> 43

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP11

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 43

Arg Arg Gln Xaa Glu Gln

1 5

<210> 44

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP12

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<400> 44

Arg Arg Gln Leu Glu Glu

1 5

<210> 45

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP13

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 45

Arg Arg Gln Xaa Gln Glu

1 5

<210> 46

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP14

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 46

Arg Arg Gln Xaa Glu Asp

1 5

<210> 47

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP15

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 47

Arg Lys Gln Xaa Glu Glu

1 5

<210> 48

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP16

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 48

Lys Arg Gln Xaa Glu Glu

1 5

<210> 49

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP17

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 49

Arg Arg Gln Xaa Glu Glu

1 5

<210> 50

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP18

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> X is D-Glu

<400> 50

Arg Arg Gln Xaa Xaa Glu

1 5

<210> 51

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP19

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 51

Arg Arg Asp Xaa Asp Gln

1 5

<210> 52

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP20

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 52

Arg Arg Asp Xaa Asp Gln

1 5

<210> 53

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP21

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<400> 53

Arg Arg Gln Met Glu Glu

1 5

<210> 54

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP22

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<400> 54

Arg Arg Xaa Met Glu Glu

1 5

<210> 55

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP23

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 55

Arg Arg Gln Xaa Glu Glu

1 5

<210> 56

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP24

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> X is D-Gln

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 56

Arg Arg Xaa Xaa Glu Glu

1 5

<210> 57

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP25

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> palmitoyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 57

Arg Arg Gln Xaa Glu Glu

1 5

<210> 58

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP26

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 58

Arg Arg Gln Xaa Glu Glu

1 5

<210> 59

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP27

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 59

Arg Arg Gln Xaa Glu Glu

1 5

<210> 60

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP28

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> palmitoyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 60

Arg Arg Gln Xaa Glu Glu

1 5

<210> 61

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP29

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 61

Arg Arg Asp Xaa Glu Glu

1 5

<210> 62

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP30

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 62

Arg Arg Gln Xaa Asp Glu

1 5

<210> 63

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP31

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 63

Arg Arg Gln Xaa Glu Gln

1 5

<210> 64

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP32

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<400> 64

Arg Arg Gln Leu Glu Glu

1 5

<210> 65

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP33

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 65

Arg Arg Gln Xaa Gln Glu

1 5

<210> 66

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP34

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 66

Arg Arg Gln Xaa Glu Asp

1 5

<210> 67

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP35

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 67

Arg Lys Gln Xaa Glu Glu

1 5

<210> 68

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP36

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 68

Lys Arg Gln Xaa Glu Glu

1 5

<210> 69

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP37

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 69

Arg Arg Gln Xaa Glu Glu

1 5

<210> 70

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP38

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> X is D-Glu

<400> 70

Arg Arg Gln Xaa Xaa Glu

1 5

<210> 71

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP39

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 71

Arg Arg Asp Xaa Asp Gln

1 5

<210> 72

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP40

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Leu

<400> 72

Arg Arg Asp Xaa Asp Gln

1 5

<210> 73

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> PEP41

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> acetyl group

<220>

<221> MISC_FEATURE

<222> (4)..(4)

<223> X is D-Met

<400> 73

Arg Arg Asp Xaa Glu Glu

1 5

Claims

1. The use of compounds of formula (I), stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic non-therapeutic treatment and/or care of the skin,

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₁ And R is ₂ Is not an amino acid, and is not an amino acid,

wherein the cosmetic non-therapeutic treatment and/or care is to increase energy metabolism and/or energy production in skin cells.

2. The use of compounds of formula (I), stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic non-therapeutic treatment and/or care of the skin,

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₁ selected from the group consisting of H, polymers derived from polyethylene glycol, acyclic aliphatic groups, alicyclic groups, heterocyclic groups, heteroarylalkyl groups, aryl groups, aralkyl groups, and R ₅ -CO-, wherein R ₅ Selected from H, notA cycloaliphatic group, an alicyclic group, an aryl group, an aralkyl group, a heterocyclic group, and a heteroarylalkyl group;

R ₁ And R is ₂ Is not an amino acid, and is not an amino acid,

wherein the cosmetic non-therapeutic treatment and/or care improves and/or increases skin shine.

3. The use of compounds of formula (I), stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic non-therapeutic treatment and/or care of the skin,

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₂ selected from the group consisting of-NR ₃ R ₄ 、-OR ₃ 、-SR ₃ A group consisting of R ₃ And R is ₄ Independently selected from H, polymers derived from polyethylene glycol, acyclic aliphatic groupsAlicyclic, heterocyclic, heteroarylalkyl, aryl, and aralkyl groups; and is also provided with

R ₁ And R is ₂ Is not an amino acid, and is not an amino acid,

wherein the cosmetic non-therapeutic treatment and/or care is to reduce and/or prevent skin fatigue.

4. A method of cosmetically non-therapeutically treating and/or caring for the skin of a subject comprising administering to the subject a cosmetically effective amount of a compound of formula (I)

R ₁ -AA ₁ -AA ₂ -AA ₃ -AA ₄ -AA ₅ -AA ₆ -R ₂ (I)，

A stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AA ₁ arg or Lys;

AA ₂ arg or Lys;

AA ₃ gln, glu, asn or Asp;

AA ₄ met or Leu;

AA ₅ is Glu, asp or Gln;

AA ₆ is Glu, asp or Gln;

R ₁ And R is ₂ Is not an amino acid, and is not an amino acid,

wherein the cosmetic non-therapeutic treatment and/or care is to increase energy metabolism and/or energy production in skin cells; improving and/or increasing skin luster; and/or reducing or preventing skin fatigue.

5. The use according to any one of claims 1 to 3, or the method according to claim 4, wherein AA ₃ Is Gln or Asp.

6. The use according to any one of claims 1 to 3 or 5, or the method according to claim 4 or 5, wherein AA ₅ Selected from the group consisting of Glu and Asp; and AA (AA) ₆ Selected from the group consisting of Glu or Gln.

7. The use according to any one of claims 1 to 3, 5 or 6, or the method according to any one of claims 4 to 6, wherein AA ₁ Is Arg and/or AA ₂ Arg.

8. The use according to any one of claims 1 to 3, 5 or 7, or the method according to any one of claims 4 to 7, wherein AA ₃ Is Gln, AA ₄ Met, AA ₅ Is Glu and/or AA ₆ Is Glu.

9. The use according to any one of claims 1 to 3 or 5 to 8, or the method according to any one of claims 4 to 8, wherein AA ₁ 、AA ₂ 、AA ₃ 、AA ₄ 、AA ₅ And AA (alpha) ₆ At least one of which is a D-amino acid.

10. The use according to any one of claims 1 to 3 or 5 to 9, or the method according to any one of claims 4 to 9, wherein AA ₃ 、AA ₄ And AA (alpha) ₅ 1, 2 or 3 of which are D-amino acids, and AA ₁ To AA (AA) ₆ The rest of which are L-amino acids.

11. The use of claim 10, or the method of claim 10, wherein the compound has the formula:

R ₁ -L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-R ₂ (II)；

R ₁ -L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-R ₂ (III)；

R ₁ -L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-R ₂ (IV)。

12. the use according to any one of claims 1 to 3 or 5 to 11, or the method according to any one of claims 4 to 11, wherein R ₁ Selected from H and R ₅ -CO-, wherein R ₅ Selected from C ₁ -C ₁₈ Alkyl, C ₂ -C ₂₄ Alkenyl, C ₃ -C ₂₄ Cycloalkyl groups; and R is ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups.

13. The use according to claim 12, or the method according to claim 12, wherein R ₁ Selected from the group consisting of H, acetyl or palmitoyl, lauroyl or myristoyl; and R is ₂ is-NR ₃ R ₄ OR-OR ₃ Wherein R is ₃ And R is ₄ Independently selected from H and C ₁ -C ₁₆ Alkyl groups.

14. The use according to claim 13, or the method according to claim 13, wherein R ₁ Selected from the group consisting of H, acetyl or palmitoyl; and R is ₂ is-NH ₂ or-OH, wherein R ₃ Is H and R ₄ Is H, and preferably R ₁ Is acetyl and R ₂ Is NH ₂ 。

15. The use according to any one of claims 1 to 3 or 5 to 14, or the method according to any one of claims 4 to 14, wherein the compound is

Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH ₂ (PEP22)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH ₂ (PEP23)；

Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH ₂ (PEP24)。