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

文档序号：620843 发布日期：2021-05-07 浏览：10次中文

阅读说明：本技术 可用于对皮肤、毛发、指甲和/或粘膜进行处理和/或护理的化合物 (Compounds useful for the treatment and/or care of the skin, hair, nails and/or mucous membranes ) 是由 R·德尔加多 N·阿尔米尼亚纳 A·索莱 M·D·C·利多 C·罗德里格斯 G·莫拉 M 于 2019-08-09 设计创作，主要内容包括：本发明涉及一种式(I)化合物R-1-W-m-X-n-AA-1-AA-2-AA-3-AA-4-AA-5-AA-6-Y-p-Z-q-R-2、其立体异构体和/或化妆品上可接受的盐,其中：AA-1为Arg、Lys或无氨基酸；AA-2为Arg或Lys；AA-3为Gln、Glu、Asn或Asp；AA-4为Met或Leu；AA-5为Glu、Asp或Gln；AA-6为Glu、Asp、Gln或无氨基酸；并且AA-1与AA-6不同。所述化合物可用于治疗和/或预防皮肤衰老的症状,具体地,可用于治疗和/或预防皮肤皱纹、治疗和/或预防皮肤下垂出现和/或减少和/或预防面部不对称。(The invention relates to a compound R of formula (I) 1 ‑W m ‑X n ‑AA 1 ‑AA 2 ‑AA 3 ‑AA 4 ‑AA 5 ‑AA 6 ‑Y p ‑Z q ‑R 2 A stereoisomer and/or a cosmetically acceptable salt thereof, wherein: AA 1 Arg, Lys or no amino acid; AA 2 Is Arg or Lys; AA 3 Is Gln, Glu, Asn or Asp; AA 4 Is Met or Leu; AA 5 Glu, Asp or Gln; AA 6 Glu, Asp, Gln or no amino acid; and AA 1 And AA 6 Different. The compounds are useful for treating and/or preventing the symptoms of skin aging, in particular, for treating and/or preventing skin wrinkles, treating and/or preventing the appearance of skin sagging, and/or reducing and/or preventing facial asymmetry.)

1. A compound of formula (I):

R₁-W_m-X_n-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_p-Z_q-R₂(I)，

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

AA₁arg, Lys or no amino acid;

AA₂is Arg or Lys;

AA₃is Gln, Glu, Asn or Asp;

AA₄is Met or Leu;

AA₅glu, Asp or Gln;

AA₆glu, Asp, Gln or no amino acid;

AA₁and AA₆Different;

w, X, Y and Z are each independently any amino acid;

m, n, p and q are each independently 0 or 1;

m + n + p + q is less than or equal to 2;

R₁selected 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 R₅-CO-, wherein R₅Selected from the group consisting of: H. acyclic aliphatic groups, alicyclic groups, aryl groups, aralkyl groups, heterocyclic groups, and heteroarylalkyl groups;

R₂selected from the group consisting of-NR₃R₄、-OR₃、-SR₃Group of (I) wherein R₃And R₄Independently 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 groups; and is

R₁And R₂Is not an amino acid.

2. The compound of claim 1, wherein W, X, Y and Z are independently selected from the group consisting of Ala, Gly, Val, and Ile.

3. The compound of claim 1 or claim 2, wherein AA₃Gln or Asp.

4. The compound of any one of the preceding claims, wherein AA₅Selected from the group consisting of Glu and Asp; and AA₆Selected from the group consisting of Glu, Gln, or no amino acid.

5. The compound of any one of the preceding claims, wherein AA₁Selected from the group consisting of Arg and Lys; and AA₆Selected from the group consisting of Glu and Gln.

6. The compound of any one of the preceding claims, wherein AA₁Is Arg and/or AA₂Is Arg.

7. The compound of any one of the preceding claims, wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆1, 2 or 3 of (a) are D-amino acids, and AA₁To AA₆The remainder of (a) is an L-amino acid.

8. The compound of claim 7, wherein AA₃、AA₄And AA₅1, 2 or 3 of (a) are D amino acids.

9. The compound of claim 8, wherein AA₃、AA₄And AA₅1 or 2 of (a) is a D amino acid, and AA₁To AA₆Is an L-amino acid, and preferably AA₄Is a D-amino acid, and AA₁To AA₆The remainder of (a) is an L-amino acid.

10. The compound of claim 9, wherein the compound has the formula:

R₁-W_m-X_n-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(II)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(III)；

R₁-W_m-X_n-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(IV)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(V)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Met-L-Asp-L-Glu-Y_p-Z_q-R₂(VI)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Gln-Y_p-Z_q-R₂(VII)；

R₁-W_m-X_n-L-Arg-L-Lys-L-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(VIII)；

R₁-W_m-X_n-L-Lys-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(IX)；

R₁-W_m-L-Ala-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-L-Ala-Z_q-R₂(X)；

R₁-W_m-X_n-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(XI)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-Y_p-Z_q-R₂(XII); or

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Leu-L-Glu-L-Glu-Y_p-Z_q-R₂(XIII)。

11. A compound according to any one of the preceding claims, wherein R₁Selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₈Alkyl radical, C₂-C₂₄Alkenyl radical, C₃-C₂₄Cycloalkyl groupGroup (b); and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups.

12. The compound of claim 11, wherein R₁Selected from the group consisting of: H. acetyl, or palmitoyl, lauroyl, or myristoyl; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups.

13. The compound of claim 12, wherein R₁Selected from the group consisting of H, acetyl or palmitoyl; and R is₂is-NH₂or-OH, wherein R₃Is H, R₄Is H, and preferably R₁Is acetyl, R₂Is NH₂。

14. The compound of claim 1, wherein the compound is:

Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH₂(PEP-21)；

Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH₂(PEP-22)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-23)；

Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-24)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-OH(PEP-26)；

H-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-27)；

Ac-L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu-NH₂(PEP-41)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Asp-L-Glu-NH₂(PEP-30)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Gln-NH₂(PEP-31)；

Ac-L-Arg-L-Lys-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-35)；

Ac-L-Lys-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-36)；

Ac-L-Ala-L-Arg-L-Arg-Gln-D-Met-L-Glu-L-Glu-L-Ala-NH₂(PEP-42)；

Ac-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-43)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-NH₂(PEP-44); or

Ac-L-Arg-L-Arg-L-Gln-D-Leu-L-Glu-L-Glu-NH₂(PEP-37)。

15. A compound according to any one of claims 1 to 12, or a stereoisomer and/or a cosmetically acceptable salt thereof, and botulinum toxin and/or botulinum toxin having the sequence Ac-Glu-Met-Gln-Arg-NH₂A combination of peptides of (1).

16. A composition comprising a cosmetically effective amount of a compound of formula (I), its stereoisomers and/or cosmetically acceptable salts, according to any of claims 1 to 12, or a combination according to claim 13, and at least one cosmetically acceptable excipient or adjuvant.

17. Use of a compound according to any one of claims 1 to 12, stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes.

18. Use according to claim 15, wherein the cosmetic, non-therapeutic treatment and/or care is: treatment and/or prevention of skin aging; reducing and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; reducing and/or preventing facial asymmetry; increasing the volume of adipose tissue and/or preventing and/or mitigating the effects of adipose tissue loss.

19. A method of cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes of a subject, comprising applying to the subject a cosmetically effective amount of a compound according to any one of claims 1 to 12, a combination according to claim 13 or a composition according to claim 14.

20. A method of cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes of a subject according to claim 17, wherein cosmetic, non-therapeutic treatment and/or care is: treatment and/or prevention of skin aging; reducing and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; reducing and/or preventing facial asymmetry; increasing the volume of adipose tissue and/or preventing and/or mitigating the effects of adipose tissue loss.

Technical Field

The present invention relates to compounds useful for the treatment and/or care of skin, hair, nails and/or mucous membranes. In particular, the compounds are useful for preventing skin aging, in particular for treating and/or preventing skin wrinkles, treating and/or preventing the appearance of skin sagging and/or reducing and/or preventing facial asymmetry. The invention extends to compositions comprising the compounds and methods of treatment using the compounds.

Background

The effects of aging play a major role in the appearance of skin. The most obvious signs of facial aging are the appearance of facial wrinkles and sagging, which are associated with muscle aging. With age, the epidermis and connective tissue of the skin become fragile, facial muscle mass diminishes, the epidermis begins to relax and descend, the natural folds in the cheek, neck and chin regions change, and there is redistribution and loss of facial fat (adipose tissue).

Muscle aging is a well-known process that in humans may begin at about their age of 40 and accelerate in later years. The resulting loss of muscle tone and thinning of the skin can lead to facial laxity and sagging. The jaw bone loses its contour and the facial contour becomes less clear.

The formation of facial wrinkles is directly related to the tension of the epidermal muscles, which act to pull the skin inwards. This muscle tone is the result of overactivity of the nerves that innervate the facial muscles. Overactive nerves are characterized by uncontrolled and excessive release of neurotransmitters that stimulate muscle fibers. Neuronal exocytosis is a tightly regulated process in which the formation of a protein complex, called the SNARE complex, is primarily involved. The core of the fusion complex is made of the protein SNAP-25 and syntaxin located in the presynaptic plasma membrane and the protein synaptophysin (or VAMP) located in the vesicular plasma membrane. The main function of the fusion complex is to bring vesicles loaded with neurotransmitter (acetylcholine) closer to and into contact with the presynaptic plasma membrane. In this way, in response to an increase in calcium concentration, fusion of the two plasma membranes is encouraged, resulting in the release of neurotransmitters.

Since neurotransmitter release is associated with neuronal exocytosis, controlling neuronal exocytosis can contribute to relaxation of muscle toneAnd thus reduction of wrinkles. Cleavage of any of the proteins that make up the SNARE complex prevents its assembly, and thus this is a key target approach for controlling neuronal exocytosis. Botulinum toxins are a family of bacterial neurotoxins produced by clostridium botulinum. Botulinum toxin is a protease that degrades neuronal proteins involved in the exocytosis mechanism activated by calcium ions. For example, botulinum toxin A, which is the most commonly used clinically and cosmetically, cleaves the neuronal protein SNAP-25. Thus, botulinum toxin, particularly of serotype A (Allergan Inc)Dysport from lipen biopharmaceutical limited (Ipsen biphamer, Ltd.)^TMAnd of Gaodemei (Galderma, S.A)) Are widely used as effective agents for reducing facial wrinkles and asymmetry. Indeed, administration of botulinum toxin was the first effective non-surgical therapy for eliminating signs of aging. However, in the cosmetic field, it is increasingly believed that prolonged use of botulinum toxin may also cause cosmetically undesirable effects on facial muscles, which may lead to the appearance of skin sagging, and thus increased facial aging [ Durand, PD. "botulinum toxin and muscle atrophy: desired or undesired effects (Botulinum Toxin and Muscle Atrophy: A Wante or Un Wante Effect), (2016), "Journal of Aesthetic Surgery (Aesthitic Surgery Journal)," 36 (4), pages 482. 487-]。

It is known in the art that certain peptides may mimic the action of botulinum toxin because they inhibit neuronal exocytosis, for example, peptides derived from the amino terminus of the protein SNAP-25 as disclosed in WO2000/64932A 1. One such peptide is the peptide sold under the trade name Lipotec S.ACommercial acetyl hexapeptide-3.The use of a peptide (Ac-Glu-Glu-Met-Gln-Arg-Arg) for skin lightening is disclosed in KR 20120099550A. However, in the abstract of KR20120099550A, the peptide was erroneously assigned the sequence Arg-Arg-Gln-Met-Glu-Glu-acetyl. With the conventional practice for writing peptide sequences and indeed [0007 ] of KR20120099550A]In agreement, this sequence should be read as acetyl-Glu-Glu-Met-Gln-Arg-Arg.

There is a need to find new active compounds that can reduce or prevent the signs of skin aging. In particular, there is a need to find new active compounds that can prevent or reduce the appearance of skin wrinkles and/or facial sagging. There is a need to find new active compounds that can mimic the neuronal exocytosis inhibitory behavior of botulinum toxin. Indeed, there is a need to provide a neuronal exocytosis inhibitory behaviour that mimics botulinum toxin, rather than botulinum toxin, e.g.Novel active compounds of neuronal exocytosis inhibitory behaviour which are known alternatives to peptides.

The present invention addresses some or all of these needs and solves some or all of the problems identified above.

Disclosure of Invention

In a first aspect, the present invention provides a compound represented by formula (I):

R₁-W_m-X_n-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_p-Z_q-R₂(I)，

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

AA₁arg, Lys or no amino acid;

AA₂is Arg or Lys;

AA₃is Gln, Glu, Asn or Asp;

AA₄is Met or Leu;

AA₅glu, Asp or Gln;

AA₆glu, Asp, Gln or no amino acid;

AA₁and AA₆Different;

w, X, Y and Z are each independently any amino acid;

m, n, p and q are each independently 0 or 1;

m + n + p + q is less than or equal to 2;

R₁selected 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 R5-CO-wherein R₅Selected from the group consisting of: H. acyclic aliphatic groups, alicyclic groups, aryl groups, aralkyl groups, heterocyclic groups, and heteroarylalkyl groups;

R₁And R₂Is not an amino acid.

It has been found that the compounds of formula (I) are effective in inhibiting the release of norepinephrine and increasing collagen synthesis in the skin. Further, the compounds of the present invention have been found to be effective in increasing the amount of lipid in adipocytes, and thus in increasing facial volume. Thus, it is useful as an anti-skin aging agent and can mimic the inhibition of neuronal exocytosis behavior of botulinum toxin for the treatment of symptoms of skin aging. Furthermore, surprisingly, it has been found that certain compounds of the invention can upregulate expression of myoid 1(MBNL-1), a highly conserved RNA-binding protein that plays an important role in the lateral differentiation of fibroblasts into myofibroblasts. Thus, these peptides are particularly useful for preventing or alleviating the cosmetic properties of the skin associated with loss of muscle tone due to muscle aging, and indeed alleviating the concerns relating to botulinum toxin injectionThe cosmetic side effects of anti-aging treatment of (a). It has been demonstrated that the compounds of the present invention show advantages over botulinum toxinImproved performance of the known peptide substitutes of (a).

In another aspect, the present invention provides a cosmetic composition comprising a compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof, and at least one cosmetically acceptable excipient or adjuvant.

In a further aspect, the present invention provides the use of a compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof, or a composition comprising a compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof, for the treatment and/or care of the skin, hair, nails and/or mucous membranes. In particular, the present invention provides the use of a compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof, or a composition comprising a compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof, for the cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes. The cosmetic, non-therapeutic treatment and/or care may be: preventing or treating symptoms of skin aging; treating and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; and/or treating and/or preventing facial asymmetry. The cosmetic, non-therapeutic treatment and/or care may be increasing the volume of adipose tissue and/or preventing and/or reducing the effects of adipose tissue loss.

In another aspect, the present invention provides a method of treating and/or caring for skin, hair, nails and/or mucous membranes of a subject, the method comprising administering to the subject an effective amount of a compound of formula (I), a stereoisomer thereof and/or a cosmetically or pharmaceutically acceptable salt thereof, or a composition comprising the compound of formula (I), a stereoisomer thereof and/or a cosmetically or pharmaceutically acceptable salt thereof. In particular, the present invention provides a method of cosmetically, non-therapeutically treating and/or caring for the skin, hair, nails and/or mucous membranes of a subject, comprising applying to said subject a cosmetically effective amount of a compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof or of a composition comprising said compound of formula (I), a stereoisomer thereof and/or a cosmetically acceptable salt thereof. Typically, the compound will be administered topically. The cosmetic, non-therapeutic treatment and/or care may be: preventing or treating symptoms of skin aging; treating and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; and/or treating and/or preventing facial asymmetry. The cosmetic, non-therapeutic treatment and/or care may be increasing the volume of adipose tissue and/or preventing and/or reducing the effects of adipose tissue loss.

In another aspect, the present invention provides a kit for a cosmetic, non-therapeutic method of treating and/or caring for skin, the kit comprising:

(i) a composition comprising botulinum toxin;

(ii) optionally, comprising Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof; and

(iii) cosmetic compositions comprising a compound of formula (I).

Drawings

FIG. 1 shows the mean of the percentage of Norepinephrine (NA) release relative to basal conditions for 3 assays of SH-SY5Y (example 6).

Figure 2 shows the mean of the percentages of 5 determined types I collagen relative to the basal conditions (example 7).

Figure 3 shows the mean of the percentage of MBNL1 relative to the base condition in 3 assays of hSkMc (example 8).

Figure 3a shows the mean of the percentage of MBNL1 relative to the basal conditions in 3 assays of hSkMc (example 8). Abbreviations: BC ═ base control (untreated)

Figure 4 shows the percentage of muscle mass loss in human skeletal muscle cells measured using immunofluorescence assay. Measurements were performed on samples of human skeletal muscle cells treated with tumor necrosis factor α (TNF α) and either (i) treated with a compound of the invention or (ii) not treated with a compound of the invention. The results were also compared with human skeletal muscle cells not treated with TNF α and not treated with the compounds of the present invention (example 17). Abbreviations: BC + TNF ═ basal control with 20mg/ml TNF α; BC is the basal control.

Figure 5 shows the level of lipid accumulation in human subcutaneous preadipocytes as determined by fluorescent staining (example 19). Measurements were performed on samples of co-cultures of young and old preadipocytes that had been treated with or without the compounds of the invention. The results were also compared to cultures of old preadipocytes. Abbreviations: % LA is the percentage of lipid accumulation; CC ═ co-culture control; YC is young control; OC is an old control.

Detailed Description

Definition of

In the context of the present invention, "skin" is understood to be a layer comprising the skin, from the uppermost layer or stratum corneum to the lowermost layer or hypodermis (both inclusive). These layers are composed 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" encompasses mammalian skin and encompasses human skin. Likewise, the terms "hair, nail and mucosa" encompass mammalian (e.g., human) hair, nail and mucosa.

The term "treating" as used herein and when it is not accompanied by a defined condition "cosmetically, non-therapeutic" refers to a therapeutic method comprising a method involving administering a compound according to the present invention to reduce or eliminate a disease or disorder, or to reduce or eliminate one or more symptoms associated with the disease or disorder. The term "treating" when it is not accompanied by a limited qualitative condition "cosmetically, non-therapeutically" also encompasses therapeutic approaches involving reducing or eliminating the physiological consequences of a disease or disorder.

When the terms "treatment" and "care" are not accompanied by a limited qualitative condition "cosmetically, non-therapeutically", it means that the purpose of the treatment or care is to improve or maintain the aesthetic appearance of the skin, hair, nails and/or mucous membranes. In particular, the purpose of the treatment is to improve the cosmetic properties of the skin, hair, nails and/or mucous membranes, such as, and not limited to, hydration level, elasticity, firmness, luster, tension or texture, which properties affect the aesthetic appearance of the skin, hair, nails and/or mucous membranes. The term "care" in the context of the present specification refers to the maintenance of properties of the skin, hair, nails and/or mucous membranes. The properties are improved or maintained by cosmetically treating and/or caring for skin, hair, nails, and/or mucous membranes of both healthy subjects and subjects exhibiting diseases and/or conditions of the skin, hair, nails, and/or mucous membranes.

The term "preventing" as used herein refers to the ability of a compound of the present invention to prevent, delay or retard the appearance or development of a disease or disorder, or to prevent, delay or retard changes in the cosmetic properties of the skin, mucous membranes and/or hair. The term "prevention" as used herein, is interchangeable with the term "inhibition", that is, it refers to the ability of a compound of the invention to inhibit the appearance or development of a disease or condition, or to inhibit a change in the cosmetic properties of the skin, hair, nails, and/or mucous membranes.

In the context of the present invention, the term "aging" refers to the changes that the skin undergoes as a result of the intrinsic aging process (i.e., chronic aging) or the extrinsic aging process of the skin induced by environmental factors (i.e., exposure to the sun (photoaging) or environmental agents (such as tobacco smoke), extreme climatic conditions of severe cold or high winds, chemical pollutants or pollutants). In the context of the present invention, aging encompasses all externally visible and/or tactile perceptible changes, such as and not limited to: development of discontinuities in the skin, such as wrinkles, fine lines, expression lines, stretch marks, furrows, irregularities or roughness; increased pore size, loss of hydration, loss of elasticity, loss of firmness, loss of smoothness, loss of ability to recover from deformation, loss of resiliency; sagging skin, such as cheek sagging, eye bags under the eyes or double chin, etc.; skin color changes such as streaking, redness, under-eye puffiness, or the appearance of hyperpigmented areas such as age spots or freckles; abnormal differentiation, hyperkeratosis, elastosis, keratosis, hair loss, cellulite skin, loss of collagen structure, and other histological changes of the stratum corneum, dermis, epidermis, vascular system (e.g., spider veins or telangiectasias present), or those tissues near the skin, among others. The term "photoaging" is grouped with a group of methods that result from prolonged exposure of the skin to ultraviolet radiation that causes permanent aging of the skin, and which exhibit the same physical characteristics as aging, such as, and without limitation, weakness, sagging, color changes or pigmentation irregularities, abnormalities and/or hyperkeratosis. The sum of various environmental factors, such as exposure to tobacco smoke, exposure to pollution, and climatic conditions (e.g., severe cold and/or high winds), also contribute to skin aging.

In this description, the abbreviations used for amino acids follow the rules specified in the IUPAC-IUB Commission on Biochemical Nomenclature (IUPAC-IUB Commission of Biochemical Nomenclature) in the European journal of biochemistry (Eur.J.biochem.), (1984),138, 9-37. Thus, for example, Gly represents NH₂-CH₂-COOH, Gly-represents NH₂-CH₂-CO-, -Gly represents-NH-CH₂-COOH and-Gly-represent-NH-CH₂-CO-. Thus, the hyphen representing a peptide bond, when located to the right of the symbol, eliminates the OH in the 1-carboxy group of the amino acid (represented herein in the conventional non-ionized form), and, when located to the left of the symbol, eliminates the H in the 2-amino group of the amino acid; both modifications can be applied to the same symbol (see table 1).

TABLE 1

As used herein, the term "acyclic aliphatic group" encompasses 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" encompasses saturated straight-chain and branched-chain alkyl groups, which may be substituted (mono-or poly-) or unsubstituted. The alkyl group is bonded to the rest of the molecule by a single bond. The alkyl group has 1 to 24, 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 that may be straight or branched chain and 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 alkenyl 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 alkenyl group is bonded to the rest of the molecule by a single bond. The term "alkenyl" embraces, for example, vinyl (-CH)₂＝CH₂) Allyl (-CH)₂-CH＝CH₂) Isoprenyl, oleyl, linoleyl, and the like.

The term "alkynyl" refers to a group that contains one or more carbon-carbon triple bonds and that may be straight or branched chain and 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. Alkynyl groups have from 2 to 24, preferably from 2 to 16, more preferably from 2 to 14, even more preferably from 2 to 12, yet more preferably 2,3, 4, 5 or 6 carbon atoms. The alkynyl group is bonded to the rest 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. Alkynyl groups can also contain one or more carbon-carbon double bonds, and alkynyl groups include, for example and without limitation, but-1-en-3-ynyl, pent-4-en-1-ynyl, and the like.

The term "alicyclic" is used herein to encompass, for example and without limitation, aliphatic cyclic (alicyclic) groups such as cycloalkyl or cycloalkenyl or cycloalkynyl. The term "alicyclic group" refers to a monovalent group containing one or more rings of carbon atoms, which rings may be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl), provided that it is not aromatic. More specifically, alicyclic groups contain three or more, 3 to 24, 3 to 12, or 6 to 12 ring carbon atoms. An alicyclic group may be a monocyclic, bicyclic or tricyclic ring system, and the rings may be, for example, fused or may be connected by a single bond or a linking group such as methylene or other alkylene. The cycloaliphatic group may be substituted (mono-or poly-) or unsubstituted. In one embodiment, the alicyclic 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 monocyclic or polycyclic alkyl group which may be substituted (mono or poly) or unsubstituted. Cycloalkyl groups have from 3 to 24, preferably from 3 to 16, more preferably from 3 to 14, even more preferably from 3 to 12, yet even more preferably 3, 4, 5 or 6 carbon atoms. The cycloalkyl group is bound to the rest of the molecule by a single bond. Cycloalkyl groups include, for example and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrophenalene, and the like.

The term "cycloalkenyl" refers to a non-aromatic mono-or multicyclic alkenyl group that may be substituted (mono or poly) or unsubstituted. Cycloalkenyl groups have from 5 to 24, preferably from 5 to 16, more preferably from 5 to 14, even more preferably from 5 to 12, still more preferably 5 or 6 carbon atoms. The cycloalkenyl group is bonded to the rest of the molecule by a single bond. 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 monocyclic or polycyclic alkynyl group that may be substituted (mono-or poly-) or unsubstituted. Cycloalkynyl has from 8 to 24, preferably from 8 to 16, more preferably from 8 to 14, even more preferably from 8 to 12, yet even more preferably 8 or 9 carbon atoms and is bonded to the remainder of the molecule by a single bond. Preferably, cycloalkynyl contains 1, 2 or 3 carbon-carbon triple bonds, which may or may not be conjugated. Cycloalkynyl includes, for example and without limitation, cyclooctyl-2-yn-1-yl and the like. Cycloalkynyl groups may also contain one or more carbon-carbon double bonds including, for example and without limitation, cyclooctyl-4-en-2-ynyl and the like.

As used herein, the term "heterocyclyl" or "heterocyclic" refers to a3 to 10 member hydrocarbon ring system in which one or more of the atoms in one or more rings is a heteroatom (i.e., is not a carbon atom). Thus, "heterocyclyl" or "heterocyclic" refers to a cyclic group in which the ring atoms consist of carbon and one or more heteroatoms. To satisfy valency, 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 the group consisting of O, N and S. Heterocyclyl groups may be substituted (mono or poly) or unsubstituted. The heterocyclyl group may be a monocyclic, bicyclic or tricyclic ring system, and the rings may be, for example, fused or may be connected by a single bond or a linker such as methylene or other alkylene. The nitrogen, carbon or sulfur atoms present in the heterocyclic group may optionally be oxidized, and the nitrogen may optionally be quaternized. The heterocyclyl group may be unsaturated or partially or fully saturated. The heterocyclic group may be aliphatic or aromatic. In one embodiment, heterocyclyl is aliphatic (also referred to as heteroalicyclyl) 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, 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, heterocyclyl is aromatic (also referred to as heteroaryl) and is a 6-to 10-membered ring system, wherein 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 a5 or 6 member ring. 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 (quinolein), quinoline (quinoline), pyridazine and naphthyridine.

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

The term "aralkyl" refers to an alkyl group substituted with an aromatic group, having from 7 to 24 carbon atoms and containing, 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)₂And the like.

The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group (also referred to as an aromatic heterocyclyl 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 includes, 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)_1-6Pyrrolidinyl and the like.

As understood in the art, the above groups may have some degree of substitution. In particular, there may be substitution in any of the explicitly stated groups identified above. The above-mentioned substituted group (radical) is a group (or radical) substituted with one or more substituents in an available position or positions. 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: c₁-C₄An alkyl group; a hydroxyl group; c₁-C₄An alkoxy group; an amino group; amino-C₁-C₄An alkyl group; c₁-C₄A carbonyloxy group; c₁-C₄An oxycarbonyl group; halogen such as fluorine, chlorine, bromine and iodine; a cyano group; a nitro group; an azide; c₁-C₄An alkylsulfonyl group; a sulfur radical; c₁-C₄An alkylthio group; aryloxy groups such as phenoxy; -NR_b(C＝NR_b)NR_bR_c(ii) a Wherein R is_bAnd R_cIndependently selected from the group formed by: H. c₁-C₄Alkyl radical, C₂-C₄Alkenyl, alkynyl, C₃-C₁₀Cycloalkyl radical, C₆-C₁₈Aryl radical, C₇-C₁₇Aralkyl, heterocyclic group of 3 to 10 members, or a protecting group of amino group.

As used herein, the term "comprising" inclusive or open-ended and not excluding additional unrecited elements or method steps is intended to encompass the phrases "consisting essentially of … …" and "consisting of … …" as alternative embodiments, wherein "consisting of … …" excludes any unspecified elements or steps, and "consisting essentially of … …" permits the inclusion of additional unrecited elements or steps that do not materially affect the nature or the essential and novel characteristics of the contemplated composition or method.

Compounds of the invention

A first aspect of the present invention relates to a compound of formula (I)

R₁-W_m-X_n-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_p-Z_q-R₂ (I)，

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

AA₁arg, Lys or no amino acid;

AA₂is Arg or Lys;

AA₃is Gln, Glu, Asn or Asp;

AA₄is Met or Leu;

AA₅glu, Asp or Gln;

AA₆glu, Asp, Gln or no amino acid;

AA₁and AA₆Different;

w, X, Y and Z are each independently any amino acid;

m, n, p and q are each independently 0 or 1;

m + n + p + q is less than or equal to 2;

R₁selected 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 R5-CO-wherein R₅Selected from the group consisting of: H. acyclic aliphatic groups, alicyclic groups, aryl groups, aralkyl groups, heterocyclic groups, and heteroarylalkyl groups;

R₁And R₂Is not an amino acid.

In particular, it has been found that compounds of the formula (I) andcompared to having a greater ability to inhibit the release of norepinephrine and a similar or greater ability to stimulate collagen synthesis in the skin.

The compounds of formula (I) are peptides comprising 5, 6,7 or 8 amino acids linked in a chain. R₁Is bound to the amino terminus (N-terminus) of the peptide, and R₂To the carboxy terminus (C-terminus) of the peptide.

R₁Can be selected from the group consisting of H, polymers derived from polyethylene glycol comprising molecular weights between 200 daltons and 35000 daltons, and R₅-CO-wherein R is₅Selected from the group consisting of: c₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₄Cycloalkyl radical, C₅-C₂₄Cycloalkenyl radical, C₈-C₂₄Cycloalkynyl group, C₆-C₃₀Aryl radical, C₇-C₂₄Aralkyl, 3-to 10-membered heterocyclyl rings, and heteroarylalkyl groups containing 2 to 24 carbon atoms and 1 to 3 heteroatoms, wherein the alkyl groups have 1 to 6 carbon atoms.

R₁Can be selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₈Alkyl radical, C₂-C₂₄Alkenyl radical, C₃-C₂₄Cycloalkyl radicals or radicals consisting of C₁-C₁₆Alkyl radical, C₂-C₁₈Alkenyl radical, C₃-C₇Cycloalkyl groups. R₅the-CO-group comprising alkanoyl, e.g. acetyl (CH)₃-CO-, which is abbreviated herein as "Ac-"), myristyl (CH)₃-(CH₂)₁₂-CO-, which is abbreviated herein as "Myr-") and palmitoyl (CH)₃-(CH₂)₁₄-CO-, which is abbreviated herein as "Palm-").

R₁Can be selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₆Alkyl or C₂-C₁₈Alkenyl groups.

R₁May be selected from H and R₅-CO-wherein R is₅Is C₁-C₁₅An alkyl group.

R₁May be selected from the group consisting of H, acyl, and palmitoyl.

R₂Can be selected from the group consisting of-NR₃R₄、-OR₃、-SR₃Group of (I) wherein R₃And R₄Independently selected from the group formed by: H. polymers derived from polyethylene glycol, C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₄Cycloalkyl radical, C₅-C₂₄Cycloalkenyl radical, C₈-C₂₄Cycloalkynyl group, C₆-C₃₀Aryl radical, C₇-C₂₄Aralkyl, 3-to 10-membered heterocyclyl rings, and heteroarylalkyl groups containing 2 to 24 carbon atoms and 1 to 3 heteroatoms, wherein the alkyl groups have 1 to 6 carbon atoms. Optionally, R₃And R₄The ring having a nitrogen atom may be formed by a saturated or unsaturated carbon-carbon bond combination.

R₂May be-NR₃R₄OR-OR₃。R₃And R₄May be independently selected from the group consisting of: H. included polymers derived from polyethylene glycol have molecular weights between 200 and 35000, methyl, ethyl, hexyl, dodecyl and hexadecyl. Alternatively, R₃And R₄Can be independently selected from H and C₁-C₁₆Alkyl groups. In one embodiment, R₂Is not OR₃Wherein R is₃Not being methyl, i.e. R₂Is not OCH₃. In one embodiment, R₃Is H, and R₄Selected from H and C₁-C₁₆The group formed by alkyl groups, including methyl, ethyl, hexyl, dodecyl and hexadecyl.

R₂Can be selected from the group consisting of-OH and-NH₂and-NHR₄Group of (I) wherein R₄Is C₁-C₁₆Alkyl or C₁-C₃Alkyl or C₁-C₂An alkyl group.

R₂Can be-OH or-NH₂。

R₁Can be selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₈Alkyl radical, C₂-C₂₄Alkenyl radical, C₃-C₂₄Cycloalkyl groups; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups. In this embodiment, R₃May be H, and R₄Can be selected from H, C₁-C₁₆Alkyl radical, C₁-C₃Alkyl and C₁-C₂Alkyl groups; for example, R₂Can be selected from the group consisting of-OH and-NH₂Group (d) of (a).

R₁May be selected from the group consisting of: h and acetyl, tert-butyryl, isoprenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups. In this embodiment, R₃May be H, and R₄Can be selected from H, C₁-C₁₆Alkyl radical, C₁-C₃Alkyl and C₁-C₂Alkyl groups; for example, R₂Can be selected from the group consisting of-OH and-NH₂Group (d) of (a).

R₁Can be selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₆Alkyl or C₂-C₁₈Alkenyl groups; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups. In this embodiment, R₃May be H, and R₄Can be selected from H, C₁-C₁₆Alkyl radical, C₁-C₃Alkyl and C₁-C₂Alkyl groups; for example, R₂Can be selected from the group consisting of-OH and-NH₂Group (d) of (a).

R₁May be selected from the group consisting of: H. acetyl, myristyl or palmitoyl; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups. In this embodiment, R₃May be H, and R₄Can be selected from H, C₁-C₁₆Alkyl radical, C₁-C₃Alkyl and C₁-C₂Alkyl groups; for example, R₂Can be selected from the group consisting of-OH and-NH₂Group (d) of (a).

R₁Can be selected from the group consisting of H and R₅-CO-wherein R is₅Is C₁-C₁₅Alkyl, and R₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups. In this embodiment, R₃May be H, and R₄Can be selected from H, C₁-C₁₆Alkyl radical, C₁-C₃Alkyl and C₁-C₂Alkyl groups; for example, R₂Can be selected from the group consisting of-OH and-NH₂Group (d) of (a).

R₁May be selected from the group consisting of H, acetyl and palmitoyl, and R₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups. In this embodiment, R₃Can be HAnd R is₄Can be selected from H, C₁-C₁₆Alkyl radical, C₁-C₃Alkyl and C₁-C₂Alkyl groups; for example, R₂Can be selected from the group consisting of-OH and-NH₂Group (d) of (a).

R₁May be selected from the group consisting of: substituted acyclic aliphatic group, substituted alicyclic group, substituted heterocyclic group, substituted heteroarylalkyl group, substituted aryl group, substituted aralkyl group, and R₅-CO-, wherein R₅Selected from the group consisting of: a substituted acyclic aliphatic group, a substituted alicyclic group, a substituted aryl group, a substituted aralkyl group, a substituted heterocyclic group, and a substituted heteroarylalkyl group; and/or R₂is-NR₃R₄Wherein R is₃And R₄At least one of which is selected from the group consisting of: a substituted acyclic aliphatic group, a substituted alicyclic group, a substituted heterocyclic group, a substituted heteroarylalkyl group, a substituted aryl group, and a substituted aralkyl group, or R₂is-OR₃or-SR₃Wherein R is₃Selected from the group consisting of: substituted acyclic aliphatic groups, substituted alicyclic groups, substituted heterocyclic groups, substituted heteroarylalkyl groups, substituted aryl groups, and substituted aralkyl groups.

According to another particular embodiment, the most preferred structure of the polymer derived from polyethylene glycol is a group (-CH) wherein r is a number comprised between 4 and 795₂-CH₂-O)_r-H and

where s is a radical of a number comprised between 1 and 125.

The present invention provides a compound of formula (I), wherein at least one of the following is present: r₁Is not H; and R is₂Is not OH. That is, the present invention provides a compound wherein R₁Not H and/or R₂Compounds of formula (I) which are not OH.

In the compounds of formula (I): AA₁Selected from the group consisting of Arg, Lys, or no amino acid; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln, Glu, Asn and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu, Asp, and Gln; and AA₆Selected from the group consisting of Glu, Gln and Asp or no amino acid. The requirement is AA₁And AA₆Different. Therefore, when AA₁In the absence of amino acids, i.e. when the amino acid AA₁In the absence, amino acid AA₆Must be present, i.e. AA₆Selected from the group consisting of Glu, Asp and Gln. Further, when AA₆In the absence of amino acids, i.e. amino acid AA₆In the absence, amino acid AA₁Must be present, i.e. AA₁Selected from the group consisting of Arg and Lys. In one embodiment of the compound of formula (I): AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg, Lys, or no amino acid; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu and Asp; and AA₆Selected from the group consisting of Glu, Gln, or no amino acid. In one embodiment of the compound of formula (I): AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu and Asp; and AA₆Selected from the group consisting of Glu and Gln. In one embodiment of the compound of formula (I): AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg, LysOr no amino acid; AA₂Selected from the group consisting of Arg and Lys; AA₃Is Gln; AA₄Is Met; AA₅Glu and Asp; and AA₆Selected from the group consisting of Glu, Gln, or no amino acid. In one embodiment of the compound of formula (I): AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln, Glu, Asn and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu, Asp, and Gln; and AA₆Selected from the group consisting of Glu, Gln and Asp. In this embodiment, preferably AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu, Asp, and Gln; and AA₆Selected from the group consisting of Glu, Gln and Asp. In this embodiment, preferably AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Glu; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu, Asp, and Gln; and AA₆Selected from the group consisting of Glu, Gln and Asp. In this embodiment, preferably AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln, Glu, Asn and Asp or the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu and Gln; and AA₆Selected from the group consisting of Glu and Gln.

The present invention provides a compound of formula (I) wherein: AA₁Is Arg; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Is Glu; and AA₆Is Glu.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg, Lys, or no amino acid; AA₂Is Arg; AA₃Is Gln; AA₄Is Met; AA₅Selected from the group consisting of Glu and Asp; and AA₆Selected from the group consisting of Glu, Gln, or no amino acid.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln, Glu, Asn and Asp or the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu, Asp, and Gln; and AA₆No amino acid. In this embodiment, preferably AA₁Is Arg and/or AA₂Is Arg.

The present invention provides a compound of formula (I) wherein: AA₁No amino acid; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln, Glu, Asn and Asp or the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu, Asp, and Gln; and AA₆Selected from the group consisting of Glu, Gln and Asp.

The present invention provides a compound of formula (I) wherein: AA₁Is Arg; AA₂Is Arg; AA₃Is Gln; AA₄Is Met; AA₅Is Glu; and AA₆Is Glu; and AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2,3 or 4 of which are substituted if: when AA₁When being replacedSubstituted with Lys or without an amino acid; when AA₂When substituted, it is substituted with Lys; when AA₃When substituted, it is substituted with Glu, Asn or Asp; when AA₄When substituted, it is substituted by Leu; when AA₅When substituted, it is substituted with Asp or Gln; and when AA₆When substituted, it is substituted with Asp, Gln or no amino acid. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2 or 3 of these are replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0 (none) of them are replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆One of which is replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Two of which are replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Three of which are replaced.

The present invention provides a compound of formula (I) wherein: AA₁Is Arg; AA₂Is Arg; AA₃Is Gln; AA₄Is Met; AA₅Is Glu; and AA₆Is Glu; and AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2,3 or 4 of which are substituted if: when AA₁When substituted, it is substituted with Lys; when AA₂When substituted, it is substituted with Lys; when AA₃When substituted, it is substituted with Glu; when AA₄When substituted, it is substituted by Leu; when AA₅When substituted, it is substituted with Asp; and when AA₆When substituted, it is replaced by Gln. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2 or 3 of these are replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0 (none) of them are replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆One of which is replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Two of which are replaced. In one embodiment, AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Three of which are replaced.

The present invention provides, in each of the examples described herein, a compound of formula (I) wherein AA is substituted with a substituted or unsubstituted alkyl group₁In the absence of an amino acid, W, X, Y and Z are each independently selected from the group consisting of Ala, Gly, Val, and Ile.

The compounds of the invention may exclude Arg-Arg-Glu-Leu-Glu-Glu-Leu, i.e. the invention provides a compound of formula (I) as described above wherein the compound is not Arg-Arg-Glu-Leu-Glu-Glu-Leu. The compounds of the invention may exclude Lys-Lys-Glu-Leu-Glu-Glu-Leu, i.e. the invention provides a compound of formula (I) as described above wherein the compound is not Lys-Lys-Glu-Leu-Glu-Glu-Leu.

The present invention provides a compound of formula (I) as described above wherein AA in formula (I)₁、AA₂、AA₃、AA₄、AA₅And AA₆Are each an L amino acid. The compounds of this example have been found to be particularly effective in inhibiting the release of norepinephrine and stimulating collagen synthesis in the skin. This embodiment encompasses compounds of formula (I) wherein: AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is L-Gln; AA₄Is L-Met; AA₅Is L-Glu; and AA₆Is L-Glu.

The invention provides a compound of formula (I), wherein AA in formula (I)₁、AA₂、AA₃、AA₄、AA₅And AA₆Is a D amino acid. It has been found that the compounds of this embodiment of the compounds of formula (I) are particularly useful in upregulating blind myoid 1(MBNL-1) and are therefore useful in preventing or alleviating the cosmetic properties of the skin associated with loss of muscle tone due to muscle senescence and indeed alleviating the cosmetically undesirable side effects of anti-aging treatments involving botulinum toxin injection. This example includes compounds of formula (I), wherein AA in formula (I)₁、AA₂、AA₃、AA₄、AA₅And AA₆1, 2 or 3 of (a) are D amino acids, and AA₁、AA₂、AA₃、AA₄、AA₅And AA₆The remainder of (a) is L amino acid. For example, wherein AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The rest of (A) is L amino acid. This example includes AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. These embodiments of the invention apply to all embodiments of the compounds of formula (I) described herein, in which the amino acid AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Neither is designated as a D amino acid or an L amino acid.

The present invention therefore provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg, Lys, or no amino acid; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu and Asp; and AA₆Selected from the group consisting of Glu, Gln or no amino acid, and wherein AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. This embodiment includesAA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid.

The present invention therefore provides a compound of formula (I) wherein: AA₁Selected from the group consisting of Arg and Lys; AA₂Selected from the group consisting of Arg and Lys; AA₃Selected from the group consisting of Gln and Asp; AA₄Selected from the group consisting of Met and Leu; AA₅Selected from the group consisting of Glu and Asp; and AA₆Selected from the group consisting of Glu and Gln, and wherein AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. This example includes AA₃、AA₄And AA₅1 or 2 of (a) are D amino acids and the remaining amino acids, i.e. AA1 to AA6, are L amino acids.

The present invention therefore provides a compound of formula (I) wherein: AA₁Is Arg; AA₂Is Arg; AA₃Is Gln; AA₄Is Met; AA₅Is Glu; and AA₆Is Glu; and AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2,3 or 4 of which are substituted if: when AA₁When substituted, it is substituted with Lys or without an amino acid substitution; when AA₂When substituted, it is substituted with Lys; when AA₃When substituted, it is substituted with Glu, Asn or Asp; when AA₄When substituted, it is substituted by Leu; when AA₅When substituted, it is substituted with Asp or Gln; and when AA₆When substituted, it is substituted by Asp, Gln or by no amino acid, and wherein AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. This example includes AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2 or 3 of these may be substituted. AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0 (none) of (a) may be substituted. AA₁、AA₂、AA₃、AA₄、AA₅And AA₆May be substituted. AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Two of which may be substituted. AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Three of which may be substituted.

The present invention therefore provides a compound of formula (I) wherein: AA₁Is Arg; AA₂Is Arg; AA₃Is Gln; AA₄Is Met; AA₅Is Glu; and AA₆Is Glu; and AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2,3 or 4 of which are substituted if: when AA₁When substituted, it is substituted with Lys; when AA₂When substituted, it is substituted with Lys; when AA₃When substituted, it is substituted with Glu; when AA₄When substituted, it is substituted by Leu; when AA₅When substituted, it is substituted with Asp; and when AA₆When substituted, it is substituted with Gln, and wherein AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. This example includes AA₃、AA₄And AA₅Is a D amino acid, and the other amino acid, i.e., AA₁To AA₆The remainder of (a) is L amino acid. AA₁、AA₂、AA₃、AA₄、AA₅And AA₆0, 1, 2 or 3 of these may be substituted. 0 (none) of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. AA1, AA2, AA3, AA4, AA5 and AA6May be substituted. Two of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted. Three of AA1, AA2, AA3, AA4, AA5 and AA6 may be substituted.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of L-Arg, L-Lys, or no amino acid; AA₂Selected from the group consisting of L-Arg and L-Lys; AA₃Selected 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; AA₄Selected from the group consisting of L-Met and L-Leu; AA₅Selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA₆Selected from the group consisting of L-Glu, L-Gln and L-Asp or no amino acid. In this embodiment, preferably AA₁Is L-Arg, and AA₂Is L-Arg. This embodiment encompasses compounds of formula (I) wherein: AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is D-Gln; AA₄Is L-Met; AA₅Is L-Glu; and AA₆Is L-Glu.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of L-Arg, L-Lys, or no amino acid; AA₂Selected from the group consisting of L-Arg and L-Lys; AA₃Selected 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; AA₄Selected from the group consisting of D-Met and D-Leu; AA₅Selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA₆Selected from the group consisting of L-Glu, L-Gln and L-Asp or no amino acid. The compounds of this example have been found to be particularly effective in inhibiting the release of norepinephrine and stimulating collagen synthesis in the skin. In this embodiment, preferably AA₁Is L-Arg, and AA₂Is L-Arg. This embodiment encompasses compounds of formula (I) wherein: AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is L-Gln; AA₄Is D-Met; AA₅Is L-Glu; and AA₆Is L-Glu.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of L-Arg, L-Lys, or no amino acid; AA₂Selected from the group consisting of L-Arg and L-Lys;AA₃selected 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; AA₄Selected from the group consisting of L-Met and L-Leu; AA₅Selected from the group consisting of D-Glu, D-Asp and D-Gln; and AA₆Selected from the group consisting of L-Glu, L-Gln and L-Asp or no amino acid. In this embodiment, preferably AA₁Is L-Arg, and AA₂Is L-Arg. This embodiment encompasses compounds of formula (I) wherein: AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is L-Gln; AA₄Is L-Met; AA₅Is D-Glu; and AA₆Is L-Glu.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of L-Arg, L-Lys, or no amino acid; AA₂Selected from the group consisting of L-Arg and L-Lys; AA₃Selected 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; AA₄Selected from the group consisting of D-Met and D-Leu; AA₅Selected from the group consisting of D-Glu, D-Asp and D-Gln; and AA₆Selected from the group consisting of L-Glu, L-Gln and L-Asp or no amino acid. In this embodiment, preferably AA₁Is L-Arg, and AA₂Is L-Arg. This embodiment encompasses compounds of formula (I) wherein: AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is L-Gln; AA₄Is D-Met; AA₅Is D-Glu; and AA₆Is L-Glu.

The present invention provides a compound of formula (I) wherein: AA₁Selected from the group consisting of L-Arg, L-Lys, or no amino acid; AA₂Selected from the group consisting of L-Arg and L-Lys; AA₃Selected 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; AA₄Selected from the group consisting of D-Met and D-Leu; AA₅Selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA₆Selected from the group consisting of L-Glu, L-Gln and L-Asp or no amino acid. In this embodiment, preferably AA₁Is L-Arg, and AA₂Is L-Arg. This embodiment encompasses compounds of formula (I) wherein: AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is D-Gln; AA₄Is D-Met; AA₅Is L-Glu; and AA₆Is L-Glu.

The compounds of the invention comprise those selected from the group of amino acid sequences listed in tables 2 and 2a, wherein their sequence identifiers, their stereoisomers and/or their cosmetically or pharmaceutically acceptable salts are detailed.

TABLE 2

TABLE 2a

The compounds of the invention comprise each of the sequences in tables 2 and 2a, wherein the amino acid AA₁To AA₆One of which is substituted with a replacement amino acid, wherein the replacement amino acid is selected from the list of replacement amino acids substituted in formula (I) above. The substituted amino acid is different from the substituted amino acid. The invention therefore provides each of the sequences in tables 2 and 2a, wherein the amino acid AA₁To AA₆One of which is substituted with an amino acid, wherein: AA in one of the sequences in tables 2 and 2a₁When an amino acid is substituted, it is replaced by Arg or Lys, provided that if AA is substituted₁If the amino acid is Arg, it is replaced by Lys, and if AA₁Amino acid Lys, it is replaced by Arg; AA in one of the sequences in tables 2 and 2a₂When an amino acid is substituted, it is replaced by Arg or Lys, provided that if AA is substituted₂If the amino acid is Arg, it is replaced by Lys, and if AA₂Amino acid Lys, it is replaced by Arg; AA in one of the sequences in tables 2 and 2a₃When an amino acid is substituted, it is substituted with Gln, Glu, Asn or Asp, with the proviso that if AA is present₃If the amino acid is Gln, it is replaced by Glu, Asn or Asp, if AA₃If the amino acid is Glu, it is replaced by Gln, Asn or Asp, if AA₃Amino acid is Asn, thenIt is replaced by Glu, Gln or Asp, and if AA₃Amino acid Asp, then it is replaced by Glu, Gln or Asn; AA in one of the sequences in tables 2 and 2a₄When an amino acid is substituted, it is substituted by Met or Leu, with the proviso that if AA is substituted₄The amino acid is Met, it is replaced by Leu, and if AA₄If the amino acid is Leu, then it is replaced by Met; AA in one of the sequences in tables 2 and 2a₅When an amino acid is substituted, it is substituted with Glu, Asp or Gln, provided that if AA is present₅If the amino acid is Gln, it is replaced by Glu or Asp, if AA₅If the amino acid is Glu, it is replaced by Gln or Asp, and if AA is₅Amino acid Asp, then it is replaced by Glu or Gln; and AA in one of the sequences in tables 2 and 2a₆When an amino acid is substituted, it is substituted with Glu, Asp or Gln, provided that if AA is present₆If the amino acid is Gln, it is replaced by Glu or Asp, if AA₆If the amino acid is Glu, it is replaced by Gln or Asp, and if AA is₆If the amino acid is Asp, it is replaced by Glu or Gln.

In the amino acid sequences according to formula (1) of tables 2 and 2a, R₁And R₂H and OH, respectively. The compounds of the invention comprise each of the sequences in tables 2 and 2a, wherein the N-and C-termini thereof are respectively substituted by other R of formula (1) as defined herein₁And R₂And (4) modifying groups. For example, the compounds of the invention comprise each of the sequences in table 2 wherein the N-terminal amino acid residue terminates in R of formula (1) as defined above₁Wherein R is₁Is not H, and alternatively or additionally wherein the C-terminal amino acid residue optionally terminates in R of formula (1) as defined above₂Wherein R is₂Is not OH.

Thus, in particular, the present invention provides a compound according to formula (i) as well as stereoisomers thereof and/or cosmetically or pharmaceutically acceptable salts thereof, wherein the compound is an amino acid sequence selected from the group consisting of: SEQ ID No.1, 2, 15, 18, 21, 22, 23, 24, 25, 29, 30, 32, 33, 34, 35, 36 and 38 or SEQ ID No.1, 2, 15, 18, 21, 22, 35 and 38, wherein optionally the sequence has its N-terminal amino acid defined as aboveR of the general formula (1)₁Modification of wherein R₁Is not H, and alternatively or additionally, the sequence has its C-terminal amino acid substituted by R of formula (1) as defined above₂Modification of wherein R₂Is not OH. The amino acid sequence may be SEQ ID No.21, 22, 23, 24, 25, 29, 30, 32, 33, 34, 35, 36, 38. The amino acid sequence may be SEQ ID NO.21, 22, 35 or 38. The amino acid sequence may be SEQ ID NO. 21. The amino acid sequence may be SEQ ID NO. 22. The amino acid sequence may be SEQ ID NO. 35. The amino acid sequence may be SEQ ID NO. 38.

The compounds of the present invention may exist as stereoisomers or mixtures of stereoisomers; for example, amino acids comprising the compounds may have the configuration L-, D-, or be racemic independently of each other. Thus, it is possible to obtain mixtures of isomers as well as racemic or diastereomeric mixtures or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and which isomers or mixtures of isomers are present. Preferred structures of the compounds of the invention are pure isomers, i.e. enantiomers or diastereomers. For example, when AA is indicated₂When Arg is possible, it is understood that AA, unless otherwise indicated₂Selected from L-Arg, D-Arg or a mixture of both (racemic or non-racemic). The preparation procedures described in this document enable one skilled in the art to obtain each of the stereoisomers of the compounds of the present invention by selecting amino acids with the correct configuration.

In the context of the present invention, the term "amino acid" encompasses 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 not limited to: citrulline, ornithine, sarcosine, desmosine, norvaline, 4-aminobutyric acid, 2-aminoisobutyric acid, 6-aminocaproic acid, 1-naphthylalanine, 2-aminobenzoic acid, 4-chlorophenylalanine, 2, 3-diaminopropionic acid, 2, 4-diaminobutyric acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline, alloisoleucine, allothreonine, isoperidine, isoserine, phenylglycine, statin, β -alanine, norleucine, N-methyl amino acids, α -amino acids, β -amino acids, and the like, as well as derivatives thereof. A list of unnatural amino acids can be found in articles D.C. Roberts and F.Vellaccio, Peptides (Peptides), Vol.5 (1983), Chapter VI, Gross E. and Meienhofer J. eds., Academic Press, New York, USA, "Unusual amino acids in peptide synthesis" or in the commercial catalogues of companies specializing in this field.

In the context of the present invention, when W, X, Y and/or Z are present, i.e. at least one of n, m, p or q is not 0, it is understood that the nature of W, X, Y and/or Z does not hinder the activity of the compounds of the present invention, but rather promotes or does not contribute thereto. W, X, Y and Z may be independently selected from the group consisting of Ala, Gly, Val and Ile. W, X, Y and Z may be independently selected from the group consisting of Ala, Gly, and Val. W, X, Y and Z can each be Ala.

Each of m, n, p and q may be 0, i.e. the compound of formula (I) is AA included in the chain₁And AA₅、AA₂And AA₆Or AA₁And AA₆Linked 5 or 6 amino acid peptides. Alternatively, the total number of m, n, p and q may be 1, i.e. the compound of formula (I) is a peptide comprising 6 or 7 amino acids linked in a chain. Alternatively, the total number of m, n, p and q may be 2, i.e. the compound of formula (I) is a peptide comprising 7 or 8 amino acids linked in a chain.

In particular, the compounds of the present invention may be selected from the group of the compounds listed in tables 3 and 3a, stereoisomers thereof and/or cosmetically acceptable salts thereof.

Compound (I)	Identifier
		Ac-Arg-Arg-Gln-Met-Glu-Glu-NH₂	PEP1
Ac-Arg-Arg-D-Gln-Met-Glu-Glu-NH₂	PEP2
		Ac-Arg-Arg-Gln-D-Met-Glu-Glu-NH₂	PEP3
Ac-Arg-Arg-D-Gln-D-Met-Glu-Glu-NH₂	PEP4
		Palm-Arg-Arg-Gln-D-Met-Glu-Glu-NH₂	PEP5
Ac-Arg-Arg-Gln-D-Met-Glu-Glu-OH	PEP6
		H-Arg-Arg-Gln-D-Met-Glu-Glu-NH₂	PEP7
Palm-Arg-Arg-Gln-D-Met-Glu-Glu-OH	PEP8
		Ac-Arg-Arg-Asp-D-Met-Glu-Glu-OH	PEP9
Ac-Arg-Arg-Gln-D-Met-Asp-Glu-NH₂	PEP10
		Ac-Arg-Arg-Gln-D-Met-Glu-Gln-NH₂	PEP11
Ac-Arg-Arg-Gln-Leu-Glu-Glu-NH₂	PEP12
		Ac-Arg-Arg-Gln-D-Met-Gln-Glu-NH₂	PEP13
Ac-Arg-Arg-Gln-D-Met-Glu-Asp-NH₂	PEP14
		Ac-Arg-Lys-Gln-D-Met-Glu-Glu-NH₂	PEP15
Ac-Lys-Arg-Gln-D-Met-Glu-Glu-NH₂	PEP16
		Ac-Arg-Arg-Gln-D-Leu-Glu-Glu-NH₂	PEP17
Ac-Arg-Arg-Gln-D-Met-D-Glu-Glu-NH₂	PEP18
		Ac-Arg-Arg-Asp-D-Met-Asp-Gln-NH₂	PEP19
Ac-Arg-Arg-Asp-D-Leu-Asp-Gln-NH₂	PEP20

TABLE 3

Compound (I)	Identifier
		Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH₂	PEP21
Ac-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH₂	PEP22
		Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP23
Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP24
		Palm-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP25
Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-OH	PEP26
		H-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP27
Palm-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-OH	PEP28
		Ac-L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu-OH	PEP29
Ac-L-Arg-L-Arg-L-Gln-D-Met L-Asp-L-Glu-NH₂	PEP30
		Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Gln-NH₂	PEP31
Ac-L-Arg-L-Arg-L-Gln-L-Leu-L-Glu L-Glu-NH₂	PEP32
		Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Gln-L-Glu-NH₂	PEP33
Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Asp-NH₂	PEP34
		Ac-L-Arg-L-Lys-L-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP35
Ac-L-Lys-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP36
		Ac-L-Arg-L-Arg-L-Gln-D-Leu-L-Glu-L-Glu-NH₂	PEP37
Ac-L-Arg-L-Arg-L-Gln-D-Met-D-Glu-L-Glu-NH₂	PEP38
		Ac-L-Arg-L-Arg-L-Asp-D-Met-L-Asp-L-Gln-NH₂	PEP39
Ac-L-Arg-L-Arg-L-Asp-D-Leu-L-Asp-L-Gln-NH₂	PEP40

TABLE 3a

Compound (I)	Identifier
		Ac-L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu-NH₂	PEP41
Ac-L-Ala-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-L-Ala-NH₂	PEP42
		Ac-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂	PEP43
Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-NH₂	PEP44

TABLE 3b

The compounds of the present invention comprise each of the compounds in tables 3, 3a and 3b, wherein the amino acid AA₁To AA₆One of which is replaced by a substituted amino acidAnd (b) wherein the substituted amino acid is selected from the list of substituted amino acids substituted in formula (I) above. The substituted amino acid is different from the substituted amino acid. The invention therefore provides each of the compounds in tables 3, 3a and 3b, wherein the amino acid AA₁To AA₆One of which is substituted with an amino acid, wherein: AA in one of the sequences in tables 3, 3a and 3b₁When an amino acid is substituted, it is replaced by Arg or Lys, provided that if AA is substituted₁If the amino acid is Arg, it is replaced by Lys, and if AA₁Amino acid Lys, it is replaced by Arg; AA in one of the sequences in tables 3, 3a and 3b₂When an amino acid is substituted, it is replaced by Arg or Lys, provided that if AA is substituted₂If the amino acid is Arg, it is replaced by Lys, and if AA₂Amino acid Lys, it is replaced by Arg; AA in one of the sequences in tables 3, 3a and 3b₃When an amino acid is substituted, it is substituted with Gln, Glu, Asn or Asp, with the proviso that if AA is present₃If the amino acid is Gln, it is replaced by Glu, Asn or Asp, if AA₃If the amino acid is Glu, it is replaced by Gln, Asn or Asp, if AA₃The amino acid is Asn, it is replaced by Glu, Gln or Asp, and if AA is₃Amino acid Asp, then it is replaced by Glu, Gln or Asn; AA in one of the sequences in tables 3, 3a and 3b₄When an amino acid is substituted, it is substituted by Met or Leu, with the proviso that if AA is substituted₄The amino acid is Met, it is replaced by Leu, and if AA₄If the amino acid is Leu, then it is replaced by Met; AA in one of the sequences in tables 3, 3a and 3b₅When an amino acid is substituted, it is substituted with Glu, Asp or Gln, provided that if AA is present₅If the amino acid is Gln, it is replaced by Glu or Asp, if AA₅If the amino acid is Glu, it is replaced by Gln or Asp, and if AA is₅Amino acid Asp, then it is replaced by Glu or Gln; and AA in one of the sequences in tables 3, 3a and 3b₆When an amino acid is substituted, it is substituted with Glu, Asp or Gln, provided that if AA is present₆If the amino acid is Gln, it is replaced by Glu or Asp, if AA₆If the amino acid is Glu, it is replaced by Gln or Asp, and if AA is₆If the amino acid is Asp, it is replaced by Glu or Gln.

The present invention provides a compound according to formula (i) as well as stereoisomers thereof and/or cosmetically or pharmaceutically acceptable salts thereof, wherein the compound is selected from those in tables 3, 3a and 3b, in particular, may be selected from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37, PEP41, PEP42, PEP43 and PEP44 or PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23 and PEP 24. The compound may be PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37, PEP41, PEP42, PEP43, or PEP 44. The compound may be PEP21, PEP22, PEP23 or PEP 24. The compound may be PEP 21. The compound may be PEP 22. The compound may be PEP 23. The compound may be PEP 24.

Cosmetically or pharmaceutically acceptable salts of the compounds provided herein are also found within the scope of the invention. The term "cosmetically or pharmaceutically acceptable salt" means a salt that is approved for use in animals (e.g., mammals), more specifically, in humans, and comprises: salts for forming: base addition salts which are inorganic, such as and not limited to lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc, or aluminum, and the like, or organic, such as and not limited to ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, piperazine, and the like; or acid addition salts which are organic such as, for example and without limitation, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate, gluconate, or the like, or inorganic such as, for example and without limitation, chloride, sulfate, borate, or carbonate, or the like. 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 can be obtained by conventional methods well known in the art [ Berge s.m. et al, "Pharmaceutical Salts" (1977), in the journal of Pharmaceutical sciences (j.pharm.sci.), 66,1-19 ].

The present invention also provides a combination of a compound of the invention, a stereoisomer thereof, and/or a cosmetically acceptable salt thereof, in any of the above-described embodiments, having: botulinum toxin; Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂(ii) a Or H-Tyr-D-Ala-Gly-Phe-Leu-OH; or a combination thereof.

Preparation procedure of the Compound of the present invention

The Synthesis of the compounds of the invention, 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 the Solid Phase Peptide Synthesis methods [ Stewart j.m. and Young j.d., "Solid Phase Peptide Synthesis (Solid Phase Peptide Synthesis) 2 nd edition", (1984), Pierce Chemical Company, Rockford il (Rockford, Illinois); bodanzsky m, and Bodanzsky a., "practice of Peptide Synthesis" (The practice of Peptide Synthesis), (1994), Berlin schringeg (Springer Verlag, Berlin); Lloyd-Williams P. et al, "Chemical methods of peptide and protein Synthesis (Chemical applications to the Synthesis of Peptides and Proteins)", (1997), CRC Co., Bocardon, Florida (Boca Raton, FL, USA) ], Synthesis in solution, enzyme Synthesis [ Kullmann W. "protease as a catalyst for enzyme Synthesis of opioid Peptides (Proteases as catalysts for enzymatic Synthesis 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 unmodified 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 results in free peptide fragments containing the desired sequence.

For example, the process for obtaining the compounds of formula (I), stereoisomers thereof and mixtures thereof comprises the steps of:

-coupling an amino acid having a protected N-terminus and a free C-terminus with an amino acid having a free N-terminus and a protected or solid support bound C-terminus;

-elimination of the protecting group at the N-terminus;

-repeating the coupling sequence and eliminating the protecting group at the N-terminus until the desired peptide sequence is obtained;

-elimination of the protecting group at the C-terminus or cleavage of the solid support.

Preferably, the C-terminus is bound to a solid support and the method is performed in a solid phase and thus comprises coupling an amino acid having a protected N-terminus and a free C-terminus to an amino acid having a free N-terminus and a C-terminus bound to a polymer support; elimination of the protecting group at the N-terminus; and repeating this sequence as many times as is necessary to thereby obtain a compound of the desired length, followed finally by cleaving the synthesized compound from the original polymer support.

The functional groups of the side chains of amino acids remain sufficiently protected throughout the synthesis with temporary or permanent protecting groups and may be deprotected simultaneously or orthogonally to the process of cleaving the peptide from the polymer support.

Alternatively, solid phase synthesis can be performed using a convergent strategy (convergent strategy) of coupling a peptide with a polymer support to a peptide or amino acid previously bound to the polymer support. Convergent Synthesis strategies are widely known to those skilled in the art and are described in Lloyd-Williams P. et al, "Convergent Solid-Phase Peptide Synthesis" (1993), "Tetrahedron" (Tetrahedron), 49(48), 11065-11133.

The method may include additional steps of deprotecting the N-and C-termini and/or cleaving the peptide from the polymer support in an indiscriminate order using standard methods and conditions known in the art, after which the functional groups of these termini may be modified. The optional modification of the N-and C-termini may be performed using a peptide of formula (I) anchored to the polymeric support, or when the peptide has been separated from the polymeric support.

Optionally, R₁Can be assisted by chargingReacting the N-terminus of the compound of the present invention with R by nucleophilic substitution in the presence of a base and a solution₁-the compound X is introduced by reaction, wherein the fragments having functional groups not involved in the formation of N-C bonds are suitably protected with temporary or permanent protecting groups. R₁As defined above, and X is a leaving group such as, for example and without limitation, tosyl, mesyl, and halogen groups, and the like.

Optionally and/or additionally, R₂Groups may be introduced by: the compound HR is reacted with a base such as N, N-Diisopropylethylamine (DIEA) or trimethylamine, or in the presence of an additive such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazol (HOAt) and a dehydrating agent such as carbodiimide, urea salt, phosphonium salt or amidine salt₂And corresponds to wherein R₂The peptide of formula (I) being-OH is reacted or by pre-forming an acid halide with e.g. thionyl chloride and thereby obtaining the invention according to formula (I) wherein the fragment having a functional group not involving N-C bond formation is suitably protected with a temporary or permanent protecting group. Alternatively, other R₂Groups may be introduced by simultaneous incorporation into the peptide cleavage process from a polymeric carrier. R₂is-OR₃、-NR₃R₄or-SR₃Wherein R is₃And R₄As defined above.

The person skilled in the art will readily understand that the deprotection/cleavage steps of the C-and N-termini and their subsequent derivatisation can be performed in different orders according to methods known in the art.

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

Examples of representative protecting groups for amino groups are amides, such as acetic acid amide, benzoic acid amide, pivalic acid amide; carbamates such as benzyloxycarbonyl (Cbz or Z), 2-Chlorobenzyl (CIZ), p-nitrobenzyloxycarbonyl (pNZ), tert-butoxycarbonyl (Boc), 2,2, 2-trichloroethoxycarbonyl (Troc), 2- (trimethylsilyl) ethoxycarbonyl (Teoc), 9-fluorenylmethoxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), trityl (Trt), methoxytrityl (Mtt), 2, 4-dinitrophenyl (Dnp), N- [1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene) ethyl (Dde), 1- (4, 4-dimethyl-2, 6-dioxo-cyclohexylidene) -3-methylbutyl (ivDde), 1- (1-adamantyl) -1-methylethoxycarbonyl (Adpoc), etc., preferably Boc or Fmoc.

Examples of representative protecting groups for carboxyl groups are esters such as tert-butyl ester (tBu), allyl ester (All), triphenylmethyl ester (Trt ester), cyclohexyl ester (cHx), benzyl ester (Bzl), o-nitrobenzyl ester, p-methoxybenzyl ester, trimethylsilylethyl ester, 2-phenylisopropyl ester, fluorenylmethyl ester (Fm), 4- (N- [1- (4, 4-dimethyl-2, 6-dioxocyclohexylidene) -3-methylbutyl ] amino) benzyl ester (Dmab), and the like; preferred protecting groups according to the invention are All, tBu, cHex, Bzl and Trt esters.

The side chains of trifunctional amino acids may be protected during the synthetic process with temporary or permanent protecting groups orthogonal to the protecting groups at the N-and C-terminus.

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

The amino group of the tryptophan side chain may be protected, For example, by a formyl group (For) or a Boc group. In one example, when the amino acid is Fmoc protected, the tryptophan side chain may be: unprotected, i.e. the amino acid is incorporated as Fmoc-Trp-OH; boc protection, i.e.incorporation of the amino acid as Fmoc-Trp (Boc) -OH; or For protection, i.e. the amino acid is incorporated in the form Fmoc-Trp (For) -OH. In one example, the amino group is Boc protected and the tryptophan side chain can be For protected, i.e., the amino acid is incorporated as Boc-Trp (For) -OH.

Examples of these and other protecting groups, their introduction and removal, can be found in the literature [ Atherton b. and Sheppard r.c., "solid phase peptide synthesis: practical methods (Solid Phase Peptide Synthesis: A practical approach), (1989), IRL Oxford University Press). The term "protecting group" also encompasses polymeric supports used in solid phase synthesis.

Possible solid supports for use in the method of the invention when the synthesis takes place wholly or partly in the solid phase relate to polystyrene supports, polyethylene glycols grafted to polystyrene, and the like, such as, and without limitation: p-methylbenzhydrylamine resin (MBHA) [ Matsueda G.R. et al, "A p-methylbenzhydrylamine resin for improved solid phase synthesis of peptide amides" (1981), "peptides", 2,45-50 ]; 2-chlorotrityl resin [ Barlos K. et al, "Darstellung getextra Peptid-fragment unit Einstez subsisturizer Triphenylmethyl-Harze", (1989), "Tetrahedron Lett.), (30), 3943-; barlos K. et al, "Veresterung von Partiell gesch ü tzten Peptid-Fragmenten mit Harzen. Einstatz von 2-Chlorotrityl chloride orid zur Synthese von Leu1-Gastrin I", (1989), "tetrahedron communication", 30, 3947-; TentaGel resin (Rapp Polymer GmbH); ChemMatrix resins (Matrix Innovation, Inc.), etc., which may or may not contain labile linkers, such as 5- (4-aminomethyl-3, 5-dimethoxyphenoxy) Pentanoic Acid (PAL) [ Albericio F. et al, "Preparation and application of the solid phase synthesis of the 5- (4- (9-fluorenylmethyloxycarbonyl) aminomethyl-3,5-dimethoxy-phenoxy) Pentanoic Acid (PAL) and the use of the solid phase synthesis of the C-terminal peptide amide under mild conditions (Preparation and application of the 5- (4- (9-fluorenylmethyloxy) amide-3, 5-methoxy-phenoxy) value acid (PAL) handle for the solid phase synthesis of C-terminal peptide amide derivatives, chemistry, journal J. 1990. J. et al, 55,3730-3743 ]; 2- [ 4-aminomethyl- (2, 4-dimethoxyphenyl) ] phenoxyacetic Acid (AM) [ Rink H., "Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methyl ester resin (Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methyl ester resin)", (1987), "tetrahedron communication, 28, 3787-containing 3790], wang S.S. "para-Alkoxybenzyl Alcohol Resin and para-alkoxybenzyloxycarbonyl hydrazide Resin for Solid Phase Synthesis of Protected Peptide Fragments (p-alkoxyybenzyl Alcohol Resin and p-alkoxyoxybenzylcarbonyl hydrazide Resin)", (1973), "J.Am.chem.Soc.), (95, 1328) -1333 et al which enable deprotection and cleavage of compounds from the polymer support at the same time.

Applications of

The present invention is based on the following findings: the compounds of formula (I) (compounds of the invention) are useful for the treatment of skin, hair, nails and/or mucous membranes. In particular, it has been found that the compounds of the present invention can inhibit norepinephrine release and increase collagen synthesis in the skin, and thus are useful for preventing or treating the symptoms of skin aging, including the appearance of skin wrinkles, sagging skin, and loss of firmness, and for treating or preventing facial asymmetry. Further, it has been found that the compounds of the invention can increase the lipid content of adipocytes and thus can cause an increase in the volume of adipose tissue. Thus, the compounds of the invention may be used to increase the volume of the additive face, for example in the region of the cheek. These effects further indicate the usefulness of the compounds in preventing or treating the symptoms of skin aging. Thus, the compounds of formula (I) are useful for the cosmetic, non-therapeutic treatment of the skin, hair, nails and/or mucous membranes.

Inhibition of norepinephrine release is indicative of inhibition of neuronal exocytosis, similar to that of botulinum toxin. In the neuromuscular junction, release of neurotransmitters from peripheral neurons to skeletal muscles allows muscle contraction. Facial muscles also undergo these contractions. These contractions are more frequent around the eyes, mouth and forehead. With age, the sustained release of neurotransmitters to the neuromuscular junction and the decrease in elasticity contribute to the increase in facial wrinkles and permanent expression lines. Thus, inhibition of norepinephrine release is considered beneficial in reducing these aging symptoms. Increasing collagen synthesis helps to counteract the effects of a decrease in collagen synthesis in the skin that accompanies the aging process.

Collagen is the most abundant protein in the connective tissue of the skin; which, while providing the required flexibility, form a network that helps support new cells as they grow. Type I collagen (collagen I) is the major collagen of the skin and is responsible for the strength and elasticity of this tissue. One of the well-recognized characteristics of aging is skin sagging. This is due to a number of factors, including loss of skin elasticity and firmness, the effects of gravity, loss of skeletal support of the face, and loss of subcutaneous adipose tissue support in the face. An increase in collagen synthesis is considered to be beneficial in reducing these symptoms of aging.

Adipose tissue or body fat is connective tissue that includes cells called adipocytes, which accumulate lipids. Advantageously, the compounds of the invention have been found to be effective in increasing the lipid content of adipocytes and therefore useful in treatments that increase the volume of adipose tissue and prevent and/or mitigate the effects of adipose tissue loss. The compounds of the invention may be used to increase facial volume, for example, in the cheek region.

Further, in some embodiments, the compounds of the invention have been found to upregulate expression of blind myoid 1 (MBNL-1). Without being bound by theory, it is believed that the increase in MBNL1 protein helps to reduce and/or avoid loss of muscle mass due to activation of the atrophy process, which may be due to muscle aging. Botulinum toxin treatment also exacerbates muscle aging. Thus, in these embodiments, the compounds of the present invention are particularly useful for maintaining or improving skin firmness, preventing the appearance of skin sagging, and/or reducing facial asymmetry.

In one aspect, the present invention provides the use of a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, or a cosmetic composition comprising a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, for the cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes. In particular, the cosmetic, non-therapeutic treatment and/or care is the cosmetic, non-therapeutic treatment and/or care of the skin. In the context of the present invention, skin includes skin of the whole body, including skin of the face (including skin around the eyes), neck, chest, arms, hands, legs, feet, thighs, hips, buttocks, stomach, and torso.

The compounds of the invention are useful for the cosmetic, non-therapeutic treatment and/or care of the skin comprising: treating and/or preventing skin aging, treating and/or preventing skin wrinkles; maintaining and improving skin firmness; stimulating collagen synthesis and/or preventing collagen loss; treating and/or preventing the appearance of skin sagging; and/or reducing and/or preventing facial asymmetry; increasing the volume of adipose tissue; and/or preventing and/or reducing the effects of adipose tissue loss.

Cosmetic, non-therapeutic treatment and/or care of the skin may: treating and/or preventing skin wrinkles; maintaining and improving skin firmness; stimulating collagen synthesis and/or preventing collagen loss.

Cosmetic, non-therapeutic treatment and/or care may involve inhibition of norepinephrine, stimulation of collagen synthesis and/or upregulation of MBNL-1. Thus, cosmetic, non-therapeutic treatment and/or care of skin, hair, nails and/or mucous membranes may be associated with inhibiting norepinephrine release, increasing collagen synthesis and/or upregulating expression of Blind muscle-like 1 (MBNL-1).

In one embodiment, there is provided the use of a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, or a cosmetic composition comprising a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, for the treatment and/or prevention of skin aging. Treatment and/or prevention of skin aging comprises reducing and/or preventing the symptoms of skin aging. Symptoms of skin aging include the appearance of wrinkles and the loss of skin biomechanical properties (e.g., firmness). Loss of firmness may be due to a decrease in collagen production in the skin or a loss of muscle tone with age. Specifically, loss of muscle tone refers to the cutaneous muscles, more specifically, the cutaneous facial muscles. Symptoms of skin aging include loss of volume due to loss of adipose tissue.

In one embodiment, there is provided a use of a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, or a cosmetic composition comprising a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, for treating and/or preventing skin wrinkles. Skin wrinkles include expression wrinkles, also commonly referred to as expression lines.

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

In one embodiment, there is provided the use of a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, or a cosmetic composition comprising a compound of the present invention, a stereoisomer and/or a cosmetically acceptable salt thereof, for increasing the volume of adipose tissue and/or preventing and/or reducing the effects of adipose tissue loss. The adipose tissue may be subcutaneous adipose tissue and may be subcutaneous adipose tissue of the face, hands and/or neck (particularly a portion of the neck). Increasing the volume of adipose tissue in the skin will result in an increase in skin volume. In particular, adipose tissue loss is due to aging.

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

The invention also extends to the combination of a compound of the invention and botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH, or a combination thereof, for the treatment and/or care of the skin, hair, nails and/or mucous membranes, as described above in connection with the use of the compounds of the invention.

In another aspect, the present invention provides a method of treating and/or caring for the skin, hair, nails and/or mucous membranes of a subject, comprising administering a compound of the invention, a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof, or a composition comprising a compound of the invention, a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof. In particular, the present invention provides a cosmetic, non-therapeutic method of treating and/or caring for the skin, hair, nails and/or mucous membranes of a subject, comprising applying to said subject a cosmetically effective amount of a compound of the invention, a stereoisomer and/or a cosmetically acceptable salt thereof, or a cosmetic composition comprising a cosmetically effective amount of a compound of the invention, a stereoisomer and/or a cosmetically acceptable salt thereof. The method may be used for the treatment and/or care of skin, hair, nails and/or mucous membranes as described above in relation to the use of the compounds and compositions of the invention. In particular, the cosmetic, non-therapeutic method of treatment and/or care is the treatment and/or care of the skin. Administration may be topical or, for example, transdermal. In this aspect of the invention, the compounds of the invention may be present in a cosmetic composition, such as the cosmetic compositions described herein. In one embodiment, the method involves administering the compound or administering the composition using microneedles.

The invention also extends to a method of treating and/or caring for the skin, hair, nails and/or mucous membranes of a subject, which comprises administering to said subject a compound of the invention, its stereoisomers and/or cosmetically or pharmaceutically acceptable salts, and the botulinum toxin Ac-Glu-Met-Gln-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof. The method may be used for the treatment and/or care of the skin, hair, nails and/or mucous membranes as described above in relation to the application (use) of the compounds of the invention. For example, the method of treatment can comprise administering to the subject a botulinum toxin and a compound of the invention, a stereoisomer, and/or a cosmetically or pharmaceutically acceptable salt thereof. For example, the method of treatment may comprise administering to the subject: Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof; and the compounds of the present invention, stereoisomers and/or cosmetically or pharmaceutically acceptable salts thereof. Preferably, the method of treatment is anti-aging treatment of the skin.

Botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof and the compounds of the invention may be administered simultaneously (simultaneously) or one after the other. When botulinum toxin Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof and the compounds and compositions of the invention are administered simultaneouslyWhen used, they may be administered in separate dosage forms or as part of a single composition. When the products are administered in separate dosage forms, the dosage forms may be in the same or different containers.

The method of the above treatment comprises the cosmetic, non-therapeutic treatment and/or care of the skin, comprising: treating and/or preventing skin aging, treating and/or preventing skin wrinkles; maintaining and improving skin firmness; stimulating collagen synthesis and/or preventing collagen loss; treating and/or preventing the appearance of skin sagging; reducing and/or preventing facial asymmetry; increasing the volume of adipose tissue; and/or preventing and/or reducing the effects of adipose tissue loss. The method of the above treatment comprises the cosmetic, non-therapeutic treatment and/or care of the skin, comprising: treating and/or preventing skin aging, treating and/or preventing skin wrinkles; maintaining and improving skin firmness; stimulating collagen synthesis and/or preventing collagen loss; treating and/or preventing the appearance of skin sagging; and/or reduce and/or prevent facial asymmetry. In one embodiment, the cosmetically, non-therapeutic method of treating and/or caring for skin is an anti-aging treatment of skin.

In another aspect, the present invention provides a compound of formula (I), a stereoisomer and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), a stereoisomer and/or a pharmaceutically acceptable salt thereof, for use as a medicament. In particular, the present invention provides a compound of formula (I), stereoisomers and/or pharmaceutically acceptable salts thereof or a pharmaceutical composition comprising a compound of formula (I), stereoisomers and/or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of a disease or disorder. In another aspect, the present invention provides the use of a compound of formula (I), a stereoisomer and/or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition. In another aspect, the present invention provides a method of treating or preventing a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising the compound.

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

For the methods of the invention described above, the frequency of application or administration may vary widely depending on the needs of each subject, with application recommendations ranging from 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 method of treatment and/or care of the skin, hair, nails and/or mucous membranes of a subject, depending on the needs of each subject, comprising administering to said subject a compound of the invention, its stereoisomers and/or cosmetically or pharmaceutically acceptable salts thereof, with botulinum toxin Ac-Glu-Met-Gln-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof. In one embodiment, the methods of the present invention comprise administering a botulinum toxin followed by administration of a compound or composition of the present invention. In a particular embodiment, the compound or composition of the present invention is administered at least once daily for at least one week after the botulinum toxin is administered. More specifically, the compound or composition of the present invention is applied at least once daily until the next botulinum toxin application.

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

Compositions of the invention

The compounds of the invention may be administered for their use by causing contact between the compound and the site of action of a subject's body, preferably a mammalian body, preferably a human body, and in the form of a composition containing the compound.

In another aspect, the present invention provides a composition comprising a compound according to formula (I), a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof.

In particular, the present invention provides a cosmetic composition comprising a compound according to formula (I), stereoisomers and/or cosmetically acceptable salts thereof, and at least one cosmetically acceptable excipient or adjuvant. These compositions may be prepared in a conventional manner known to those skilled in the art [ "Harry's cosmetic method (Harry's cosmetics)," seventh edition, (1982), Wilkinson j.b., Moore r.j. editors (Longman House), eisex (Essex, GB) in the uk.

The compounds of the invention have variable solubility in water depending on the nature of their amino acid sequence, or any possible modification in the N-terminus and/or C-terminus. Thus, the compounds of the present invention may be incorporated into the composition by aqueous solution, and those that are not soluble in water may be dissolved in conventional cosmetically or pharmaceutically acceptable solvents 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 a compound of this invention that should be administered, as well as the dosage thereof, will depend on a number 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 specific nature of the compound to be used.

The terms "cosmetically effective amount" and "pharmaceutically effective amount" are understood to mean a non-toxic but sufficient amount of one or more compounds of the invention 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 at cosmetically or pharmaceutically effective concentrations to achieve the desired effect; for example, the following are used in amounts relative to the total weight of the composition: 0.00000001% (by weight) to 20% (by weight); 0.000001% (by weight) to 15% (by weight), 0.00001% (by weight) to 10% (by weight); or 0.0001% (by weight) 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 sustained release systems.

The term "delivery system" relates to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. These cosmetic or pharmaceutical carriers can be liquids, such as water, oils, or surfactants, including those of petroleum, animal, vegetable, or synthetic origin, such as, for example and without limitation, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters, ether sulfates, betaines, glucosides, maltosides, fatty alcohols, nonoxynol ethers, poloxamers, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, digitonin, and the like. Diluents, adjuvants or excipients which can be used in different delivery systems to which the compounds of the invention can be administered are known to those skilled in the art.

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

Examples of delivery or sustained release systems include, but are not limited to, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, millimeter particles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, surfactant-phospholipid mixed micelles, nanospheres, microspheres and nanospheres, lipid globules, nanocapsules, microcapsules and nanocapsules, and microemulsions and nanoemulsions, which can be added to achieve greater permeability of the active ingredient and/or to improve its pharmacokinetic and pharmacodynamic properties. Preferred delivery or sustained release systems are liposomes, surfactant-phospholipid mixed micelles, microemulsions, more preferably water-in-oil microemulsions having reverse micellar internal structures and nanocapsules containing microemulsions.

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

Sustained release systems can be prepared by methods known in the art, and compositions containing the sustained release systems can be administered, for example, by: by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches, and microelectronic patches; or by systemic administration, such as, but not limited to, oral or parenteral routes, including nasal, rectal or subcutaneous implantation or injection, or direct implantation or injection into a specific body site, and preferably should release relatively constant amounts of the compounds of the invention. The amount of compound contained in the sustained release system will depend on, for example, where the composition will be administered, the kinetics and duration of release of the compounds of the invention, and the nature of the condition, disorder and/or disease to be treated and/or cared for.

The compounds of the invention may also be adsorbed on solid organic polymers or solid mineral supports such as, without limitation, talc, bentonite, silica, starch or maltodextrin, and the like.

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, nonwovens and medical devices that are in direct contact with the skin, so that the compounds of the invention are released by biodegradation of the binding system into the fabric, nonwoven or medical device, 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 non-woven fabrics used in the manufacture of garments for direct contact with the body.

Examples of fabrics, non-woven fabrics, garments, medical devices and devices for immobilizing compounds thereto (which are the delivery systems and/or sustained release systems described above) and the like can be found in the literature and are known in the prior art [ Schaab C.K (1986) HAPPI, 5 months 1986; nelson g., "Application of microencapsulation in textiles", (2002), "journal of international pharmacy (int.j.pharm.)," 242(1-2), 55-62; "Biofunctional Textiles and Skin (Biofunctional Textiles and the Skin)" (2006) "current Skin problems (current. probl. dermotol.) volume 33, Hipler u.c. and Elsner p. editors, carger (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-. Preferred fabrics, nonwoven garments, garments and medical devices are bandages, gauzes, t-shirts, socks, tights, undergarments, waistbands, gloves, diapers, sanitary napkins, dressings, bed covers, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectronic patches and/or facial masks.

The cosmetic or pharmaceutical compositions containing the compounds of the invention, their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, can be used in different types of compositions for topical or transdermal application, optionally comprising cosmetically or pharmaceutically acceptable excipients required for the formulation of the desired application form.

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, and not limited to, oil-in-water and/or silicone 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, milks, balms, foams, emulsions, gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions, hydrogels, liniments, slurries, soaps, shampoos, conditioners, sera, 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 excipients, such as, and without limitation, bandages, gauzes, t-shirts, socks, tights, undergarments, belts, gloves, diapers, sanitary napkins, dressings, bed covers, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectronic patches, or masks, using techniques known to those skilled in the art, or they may be incorporated into different cosmetic products, such as cosmetic foundations (e.g., foundation solutions and cakes), make-up removers, eye concealers, eye shadows, lipsticks, lip glosses, and lip powders, among others.

The cosmetic or pharmaceutical composition of the present invention may comprise an agent that increases transdermal absorption of the compound of the present invention, such as, without limitation, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylazacycloheptan-2-one), alcohols, urea, ethoxydiglycol, acetone, propylene glycol, or polyethylene glycol, and the like. Furthermore, the cosmetic or pharmaceutical composition of the invention may be applied to the local area to be treated by iontophoresis, sonophoresis, electroporation, microelectronic patches, mechanical pressure, osmotic pressure gradient, bandaging care, microinjection or needleless injection by means of pressure (such as injection by oxygen pressure) or any combination thereof, in order to achieve greater penetration of the peptide 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 cared for.

Furthermore, the compositions containing the compounds of formula (I), their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts may be used in different types of formulations for oral administration, preferably in the form of oral cosmetic or pharmaceutical products, such as and not limited to: capsules, including gelatin capsules, soft capsules, hard capsules; tablets, including sugar-coated tablets, troches, pills, powders, granules, chewing gums; a solution; a suspension; an emulsion; a syrup; elixirs; a polysaccharide film; a jelly or gelatin; and any other form known to those skilled in the art. In particular embodiments, the compounds of the present invention may be incorporated into any form of functional or fortified food, such as, but not limited to, a dietary bar or a compressed or non-compressed powder. These powders may be dissolved in water, soda, dairy products, soy derivatives or may be incorporated into a dietary bar. The compounds of the present invention may be formulated with common excipients and adjuvants for oral compositions or food supplements such as, but not limited to, fatty components, aqueous components, humectants, preservatives, thickeners, flavoring agents, antioxidants, and coloring agents common in the food industry.

Cosmetic or pharmaceutical compositions containing a compound of formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, may be administered by any other suitable route, besides topical or transdermal routes, such as oral or parenteral routes, for which these compositions will comprise the pharmaceutically acceptable excipients necessary for formulating the desired form of administration. In the context of the present invention, the term "parenteral" encompasses nasal, otic, ocular, rectal, urethral, vaginal, subcutaneous, intradermal routes, intravascular injections, such as intravenous, intramuscular, intraocular, intravitreal, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intraarticular, intrahepatic, intrathoracic, intratracheal, intrathecal, and intraperitoneal, as well as any other similar injection or infusion technique. Different devices are known to the person skilled in the art with which cosmetic or pharmaceutical compositions containing the compounds of the invention can be applied.

Among the cosmetically or pharmaceutically acceptable adjuvants contained in the pharmaceutical compositions described in this invention are additional ingredients commonly used in cosmetic or pharmaceutical compositions, such as, and not limited to, anti-wrinkle agents, botulinum-like agents, and/or anti-aging agents; (ii) tightening, skin elasticity and/or restructuring agents; a humectant; (iv) anti-photoaging agents and/or blue light protectants; DNA protective, DNA repair and/or stem cell protective agents; free radical scavengers and/or anti-glycosylation agents, antidotes, antioxidants and/or anti-fouling agents; an antiperspirant; a melanin synthesis stimulator or inhibitor; whitening or depigmenting agents; a pigmentation-promoting agent; a self-tanning agent; lipolytic agent, agent for stimulating lipolysis, fat-producing agent, etc. Additional examples can be found in the CTFA International Cosmetic Ingredient Dictionary and Handbook (CTFA International Cosmetic Ingredient Dictionary & Handbook), 12 th edition (2008).

In one embodiment, the present invention provides a cosmetic or pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically or cosmetically effective amount of an adjuvant selected from the group consisting of: (i) anti-wrinkle, botulinus-like and/or anti-aging agents; (ii) tightening, skin elasticity and/or restructuring agents; (iii) a humectant; (iv) anti-photoaging agents and/or blue light protectants; (v) DNA protective, DNA repair and/or stem cell protective agents; (vi) free radical scavengers and/or anti-glycosylation agents, antidotes, antioxidants and/or anti-fouling agents; and/or combinations thereof.

In particular embodiments, the anti-wrinkling agent, botulinum-like agent and/or anti-aging agent is selected from the group consisting of:[ INCI: palmitoyl pentapeptide-4]、[ INCI: palmitoyl tetrapeptide-7, palmitoyl oligopeptide]、Synthe'6[ INCI: glycerol, water, hydroxypropyl cyclodextrin, palmitoyl triglycerin-38]、Morphomics^TM[ INCI: pentanediol, octanediol]、Essenskin^TM[ INCI: hydroxy methionine calcium]Renovage [ INCI: teprenone (Teprenone)]、[ INCI: palmitoyl oligoPeptides]Calmosense [ INCI: butanediol, acetyl dipeptide-1 cetyl ester]Volulip [ INCI: cetearyl ethyl hexanoate, sorbitan isostearate, Portulaca oleracea extract, sucrose-cocoate, palmitoyl tripeptide-38]Subliskin [ INCI: sinorhizobium meliloti fermented product, cetyl hydroxyethyl cellulose, and lecithin]Biological peptide CL [ INCI: palmitoyl oligopeptides]And a biological peptide EL [ INCI: palmitoyl oligopeptides]-lijing peptide (Rigin) [ INCI: palmitoyl tetrapeptide-3]And Biobustyl [ INCI: glycerol polymethacrylate, Rahnella/soy protein fermentation product, palmitoyl oligopeptide]Dynalift [ INCI: sodium polystyrene sulfonate, sorghum stem juice and glycerin]Ideal [ INCI: acetyl dipeptide-1 cetyl ester]And siegesbeckia orientalis [ INCI: siegesbeckiae herba extract]Ovaliss [ INCI: coco glucoside, octyl glycol, alcohol, glaucine]、Juvinity^TM[ INCI: geranylgeraniol isopropanol]Prolevis [ INCI: hydrolyzed vegetable proteins]、Idealift^TM[ INCI: hydroxyethyl cellulose, acetyl dipeptide-1 cetyl ester]、Beautifeye^TM[ INCI: albizzia julibrissin bark extract and siegesbeckia orientalis glycoside]、Chromocare^TM[ INCI: siegesbeckiae herba extract and Rabdosia rubescens extract]Or Resistem^TM[ proposed by INCI: heart leaf globularia fermented product]Sold by Sederma/David (Sederma/Croda);[ INCI: pentapeptide-3]、[ INCI: dipeptide Diaminobutyrylbenzylamide diacetate]、[ INCI: palmitoyl tripeptide-5]And phytauronate [ INCI: carob (locust bean tree) gum]、[ INCI: wild soybean protein, oxido-reductase]pepa-Nutrix [ INCI: natural nutrient factors]And pepa-light [ INCI: seaweed extract and pullulan]、Pentacare-NA[INCI: hydrolyzed wheat gluten and carob bean dreg chewing gum]、[ INCI: glycerol, palmitoyl dipeptide-5 diaminobutyrylhydroxythreonine, palmitoyl dipeptide-6 diaminohydroxybutyrate]Beauactive MTP [ INCI: hydrolyzed milk protein]、[ INCI: tetradecylaminobutylamidobutyryl urea butyrate trifluoroacetate, palmitoyl tripeptide-5, palmitoyl dipeptide-5 diaminobutyryl hydroxythreonine]、[ INCI: tetradecylaminobutylamidobutanoic acid urea trifluoroacetate]、[ INCI: tetradecylaminobutylamidobutanoic acid urea trifluoroacetate]Regu-Age [ INCI: hydrolyzed rice bran protein, oxidoreductase, and wild soybean protein]And pepa-Timp [ INCI: human oligopeptide-20]And pepa-Age [ INCI: dunaliella salina extract]Colhibin [ INCI: hydrolyzed rice protein]Elhibin [ INCI: wild soybean protein, cocoyl amphodiacetate disodium]Or All-Q^TMPlus [ INCI: ubiquinone, tocopheryl acetate]Sold by Pentapharm/DSM corporation; myoxinol^TM[ INCI: hydrolyzed okra extract]、Myoxinol^TMLS 9736[ INCI: hydrolyzed okra extract and dextrin]、Syniorage^TM[ INCI: acetyl tetrapeptide-11]、Dermican^TM[ INCI: acetyl tetrapeptide-9]、LS [ INCI: cassia alata leaf extract]Hyalufix GL [ INCI: alpinia officinarum leaf extract]Neurobix [ INCI: achillea millefolium extract]Deliner [ INCI: corn kernel extract]Lys' last V [ INCI: radix Peucedani (dill) extract]Excellium [ INCI: hydrolyzed potato protein]Proteosyl TP LS 8657[ INCI: pea shapeBean extract]Flavagrum PEG [ INCI: PEG-6 isostearate, hesperetin laurate]Ursolic acid [ INCI: malus fruit extract]Excellium [ INCI: hydrolyzed potato protein]Marine packed Spheres [ INCI: pentaerythritol tetraisostearate, silica dimethyl silylate, sodium chondroitin sulfate, atelocollagen]Tricigen [ INCI: mannitol, cyclodextrin, yeast extract, and disodium succinate]Eterniskin [ INCI: grifola frondosa fruiting body extract and maltodextrin]Ascotide [ INCI: ascorbic acid phosphate succinyl pentapeptide-12]Hyalurosmooth [ INCI: cassia angustifolia Vahl polysaccharide]And Indinyl CA [ INCI: cassia angustifolia Vahl polysaccharide]Arganyl [ INCI: acacia spinosa leaf extract]Sphingoceryl Veg [ INCI: plant ceramides]Vit-a-Like [ INCI: cowpea seed extract]Peptiskin [ INCI: arginine/lysine polypeptides]Prodejine [ INCI: mannitol, cyclodextrin, yeast extract, disodium succinate, Aqu' activ [ INCI: behenyl alcohol, glyceryl oleate, cocamide MIPA, and calcium citrate]Elestan [ INCI: glycerol, Tie-Lin cotyledon extract]Hibiscin HP [ INCI: coffea arabica seed extract]、[ INCI: melia africana bark extract]、Collrepair^TMDG [ INCI: hexanediol and nicotinic acid]Or Litchiderm [ INCI: litchi pericarp extract]Sold by the laboratory Serobiologiciques/Corning/Basff (Laboratoriales Serobiologiciques/Cognis/BASF);[ INCI: acetyl hexapeptide-8]SNAP-7[ INCI: acetyl heptapeptide-4]SNAP-8[ INCI: acetyl octapeptide-3]、[ INCI: pentapeptide-18]、[ INCI: acetyl hexapeptide-30]、[ INCI: hydrolyzed wheat protein, hydrolyzed soybean protein, tripeptide-1]、[ INCI: diaminopropionyl tripeptide-33]、[ INCI: tripeptide-10 citrulline]、[ INCI: tripeptide-9 citrulline]、[ INCI: pseudoalteromonas ferment extract, hydrolyzed wheat protein, hydrolyzed soybean protein, tripeptide-10 citrulline and tripeptide-1]、[ INCI: acetyl tetrapeptide-5]Peptide AC29[ INCI: acetyl tripeptide-30 citrulline]、[ INCI: acetyl arginyl tryptophyl diphenylglycine]、[ INCI: acetyl tetrapeptide-22]、Lipochroman^TM[ INCI: dimethyl methoxy chromans]、[ INCI: dimethyl methoxy chroman-yl palmitate]、[ INCI: pseudoalteromonas ferment extract]、[ INCI: lysine HCl, lecithin, tripeptide-9 citrullineAcid(s)]、Vilastene^TM[ INCI: lysine HCl, lecithin, tripeptide-10 citrulline]、[ INCI: pseudoalteromonas ferment extract]、Hyanify^TM[ INCI: saccharide isomerate]、[ INCI: acetyl hexapeptide-37]、[ INCI: soybean oil, sorbitan sesquioleate, isohexadecane, hyaluronic acid, lauryl dimethyl ammonium hydroxypropyl hydrolyzed soybean protein, acetyl hexapeptide-39]、[ INCI: acetyl hexapeptide-38]、Delisens^TM[ INCI: acetyl hexapeptide-46]、Telangyn^TM[ INCI: acetyl tetrapeptide-40]、Reproage^TMPeptide [ INCI: acetyl hexapeptide-8]、Cellynkage^TMMarine composition [ INCI: saccharide isomerate]、Eyedeline^TMMarine composition [ INCI: plankton extracts]、uplevity^TM[ INCI: acetyl tetrapeptide-2]、Seacode^TMMarine composition [ INCI: pseudoalteromonas ferment extract]OrPeptide solution [ INCI: hexapeptide-10]Sold by the company Riptotai/Lubrizol (Lipotec/Lubrizol); sirtaice^TM[ INCI: bacillus fermentation product]、Epitensive^TM[ INCI: nicotiana benthamiana hexapeptide-40 SH-oligopeptide-1]、Scelleye^TM[ INCI: nicotiana benthamiana SH-oligopeptide-2]Seaderium [ INCI: water, glycerol, Bacillus fermentation product]Pauseile [ INCI: water, glycerol, Bacillus fermentation product]Or Neoclair pro [ INCI: water, glycerin, caprylyl glycol, acetyl tetrapeptide-2]Sold by Lipotrue corporation;IS [ INCI: hexapeptide-9]、Laminixyl IS^TM[ INCI: heptapeptides]、Orsirtine^TMGL [ INCI: rice (rice) extract]、D'Orientine^TMIS [ INCI: date seed extract]、Phytoquintescine^TM[ INCI: einkorn (Triticum aestivum) extract]、Quintescine^TMIS [ INCI: dipeptide-4]Peptide Vinci 01[ INCI: penta-decapeptide-1]Peptide Vinci 02^TM[ INCI: hexapeptide-3]、Aquarize IS^TM[ INCI: hydrolyzed rice extract]Lanablue [ INCI: seaweed extract]、Ederline^TM[ INCI: malus (apple) seed extract]、Dynachondrine^TMISR [ INCI: hydrolyzed soy protein]、Prolixir S20^TM[ INCI: dimer tripeptide-43]、Phytocohesine^TMPSP [ INCI: beta-sitosterol sodium sulfate, beta-sitosterol]、Perenityl^TMIS [ INCI: chinese pear (pear) seed extract]、Caspaline 14^TM[ INCI: hexapeptide-42]Peptide Q10^TM[ INCI: pentapeptide-34 trifluoroacetate salt]、Survixyl IS^TM[ INCI: pentapeptide-31]、ChroNOgen^TM[ INCI: tetrapeptide-26]Elixiance [ INCI: extract of olibanum of the genus Elaeagnus]、Harmoniance^TM[ INCI: lotus flower extract]Serenityl [ INCI: extract of south American milk vine]Natriance wrinkle reduction [ INCI: hydrolyzed corn protein]Phytonemomatrix [ INCI: hydrolyzed soybean extract]Prolixir ICE [ INCI: hydrolyzed rice protein]、PhytoRNx Baobab^TM[ INCI: hydrolyzed Palmaria championii extract]Natriance innovative extract [ INCI: hydrolyzed flaxseed extract]Natriance self-hydrating extract [ INCI: pea extract]Actopontine YST [ INCI: hydrolyzed yeast protein]Or Telosense^TM[ proposed INCI: hydrolyzed soybean protein and hydrolyzed yeast protein]Sold by Vincience/International specialty/Ashland (Vincience/ISP/Ashland); BONT-L-peptide [ INCI: palmitoyl hexapeptide-19]TIMP peptide [ INCI: acetyl hexapeptide-20]ECM Moduline [ INCI: palmitoyl tripeptide-28]Renaissance [ INCI: hydrolyzed wheat protein, palmitoyl decapeptide-21, decapeptide-22, oligopeptide-78, and zinc palmitoyl decapeptide-14]Or X50 anti-aging [ INCI: lactic acid/glycolic acid copolymer, polyvinyl alcohol, copper palmitoyl heptapeptide-14, heptapeptide-15 palmitate]From InfiSold by nitec Activos, Inc.; EquiStat [ INCI: extract of fruit of Malus genus/extract of Glycine max seed]Juvenesce [ INCI: ethoxy diglycol and caprylic triglyceride, ursolic acid, plant menadione, Ilomastat (Ilomastat)]And Ursolisome [ INCI: lecithin, ursolic acid, atelocollagen, xanthan gum and sodium chondroitin sulfate]And Basaline [ INCI: hydrolyzed malt extract]And phytokinin [ INCI: hydrolyzed soy protein]Sold by Coletica/Engelhard/Pasteur (Coletica/Engelhard/BASF); ameliox [ INCI: carnosine, tocopherol, and Silybum marianum fruit extract]Or PhytoCellTec Malus Domestica [ INCI: apple fruit cell culture]Lipobelle Soyaglicane [ INCI: soy isoflavone]Royal Epigen P5[ INCI: butyrospermum parkii fruit oil, hydrogenated lecithin, maltodextrin, pentapeptide-48, phenethyl alcohol, ethylhexyl glycerol, glycerol and water]Or DermCom [ INCI: calendula officinalis corm extract, gum arabic, Water/Water (Aqua/Water)]Sold by mibeLe Biochemical company (Mibelle biochemistry); ActiMatrix [ INCI: peptide-based mushroom extract]Peptamide 6[ INCI: hexapeptide-11]Sold by Active Organics/Arch corporation; and combinations thereof.

In another aspect, the firming agent, skin elasticity agent and/or restructuring agent is selected from the group consisting of: argassential [ INCI: c10-16 alkyl glucoside, dioctyl ether, and glycerol]Or Relexium BC [ INCI: dimethyl isosorbide, polysorbate 20, water, acetyl tetrapeptide-11 and acetyl tetrapeptide-9]Sold by basf corporation; prolevis [ INCI: hydrolyzed vegetable proteins]Or Poretect [ INCI: caprylic/capric triglyceride, sorbitan trioleate, celery extract, linseed extract]Sold by Sederma/procrastina; actifirm high-grade plant components [ INCI: centella asiatica extract, rosemary leaf extract, dipropylene glycol, alcohol, Echinacea angustifolia leaf extract]Or Actifcol high-grade plant components [ INCI: water, glycerin, sodium citrate, Lentinus Edodes extract, potassium sorbate, sodium benzoate, and phytic acid]Sold by the company Riptat/Luborun; densorphin^TM[ INCI: vitex agnus-castus extract, water and maltodextrin]Or PhytoCellTec^TM [ INCI: isomalt, water, Aoshu callus culture, lecithin]Sold by milbeLe corporation; and combinations thereof.

In another embodiment, the humectant is selected from the group consisting of: qua Shuttle [ INCI: sorbitol, Laminaria digitata extract, and diatomaceous earth]Sold by Infinitec corporation; Aqua-Osmoline^TM[ INCI: extract of carob seed]Sold by Vincience/International specialties/Ashland; hydralphatine^TMAsia [ INCI: hydrogenated starch hydrolysate, panthenol, extract of bamboo shoot, extract of flos Nelumbinis, and extract of radix Nymphaeae]Or Hydraporine^TM[ INCI: betaine, hydrogenated lecithin, honey, and pectin]Sold by Lucas Meyer Cosmetics/Unipex; patch2O^TM[ INCI: trehalose, urea, serine, glycerol polyacrylate, algin, hyaluronic acid, and pullulan]、Aqu'activ^TM[ INCI: behenyl alcohol, glyceryl oleate, cocamide MIPA]、[ INCI: octyl dodecanol, miscanthus oil, hydro-glyceride cocoate]、) [ INCI: octyl dodecanol, arachidyl alcohol propionate, tocopherol acetate, retinol palmitate, ethyl linoleate and ethyl linolenate]OrSU [ INCI: sorbitol, seaweed extract, carrageenan, Fucus vesiculosus extract, and algin]Sold by the laboratory serobioliques/cotinine/basf; masterland snow algae powder [ INCI: snow algae extract]Sold by milbeLe corporation; hyasol BT [ INCI: hyaluronic acid]、Syn-Up^TM[ INCI: benzylsulfonyl D-seryl homophenylalanine amidinobenzamide acetate]Or[ INCI: saccharide isomerate]Sold by Pentapharm/DSM corporation; aqualance^TM[ INCI: erythritol and lobster sarcosine HCl]、Hydraprotectol^TM[ INCI: glycerol polymethacrylate, elaeostearic acid, yeast extract (yeast extract), glycoprotein]、Moist 24^TM[ INCI: lalang grass rhizome extract]、Optim Hyal^TM[ INCI: hydrolyzed yeast extract, cetyl hydroxyethyl cellulose, and poly-polysaccharide acid]、[ INCI: glycerol, acrylate/C10-30 alkanol acrylate crosspolymer]Or Revidrate^TM[ INCI: ethylhexyl palmitate, sorbitan oleate, sorbitan laurate, myristyl phosphate malate]Sold by Sederma/procrastina;molecular membranes [ INCI: glycerol, pseudoalteromonas ferment extract, xanthan gum, proline, alanine, serine, ethylhexyl glycerol, and caprylyl glycol]Or Actizyme GL advanced plant components [ INCI: glycerol, Mucor miehei extract, water, sodium citrate, potassium sorbate, sodium benzoate, and phytic acid]Sold by the company Riptat/Luborun; and combinations thereof.

In another embodiment, the anti-photoaging agent and/or the blue light protectant is selected from the group consisting of: algaktiv Genofix CPD [ INCI: plankton extract, water, lecithin]Sold by Greenaltech corporation; blumilight^TMBiological function [ INCI proposal: Water/Water (and) butylene glycol (and) Theobroma (cacao) seed extract]Sold by the company Ashland; lys' Sun [ INCI: hamamelis virginiana leaf extract, water, pentanediol, caprylyl glycol, and xanthan gum]Sold by basf; vitechelox [ INCI: grape seed extract, tea leaf extract, and Quercus robur extract]Sold by Indena corporation; L-VCG [ INCI: ascorbic acid glucoside]Marketed by Freshine Biotechnology, Inc. (Freshine Bio-technology); lumimease blue component [ INCI: glycerol, water, hydrolyzed pea protein, glucose, and sodium chloride]By the company Riptat/LuborunSelling; lightwaves Defense [ JS + M ]][ INCI: jasmine leaf cell extract]Sold by Naolys corporation; blue Oleoactif [ INCI: wild soybean oil, polyglycerol-3 diisostearate, rice germ extract and rice extract]Sold by Oleos-Hallstar corporation; majesteem [ INCI: glycerol, extract of callus culture of Leontopodium alpinum, and xanthan gum]Or Senestem [ INCI: glycerin, extract of leaf of Carpesium Merrill, and xanthan gum]Sold by Sederma corporation; blueshield [ INCI: glycerin, capsicum fruit extract, xanthan gum]Sold by Solabia corporation; and combinations thereof.

In another embodiment, the DNA protective agent, DNA repair agent and/or stem cell protective agent is selected from the group consisting of: GP4G SP [ INCI: water, glycerin, artemia salina extract]Heliostatin [ INCI: water, glycerol, and pea extract]Orsirtine [ INCI: water, glycerin, rice extract]Chronogen [ INCI: water, butanediol, tetrapeptide (INCI proposal)]Survivyl IS [ INCI: water, butanediol, pentapeptide-31]And Chrondricare [ INCI: water, butanediol pentapeptide-28]Sold by Vincience/International specialties/Ashland;[ INCI: glycerol, water, alteromonas ferment extract, and flos Chrysanthemi Indici extract]Or Melinoil [ INCI: isopropyl palmitate, lecithin, water, acetyl hexapeptide-1]Marketed by Atrium Innovations/Lucas Meyer Cosmetics; repair complex [ INCI: displit yeast fermentation lysate]Sold by CLR corporation; brown algae [ INCI: palm-shaped kelp]Sold by Codif; unirepair T-43[ INCI: butanediol, acetyltyrosine, proline, hydrolyzed vegetable protein, adenosine triphosphate]Sold by Induchem; dragosine [ INCI: carnosine]Sold by Symrise, Inc.; DN-Age [ INCI: cassia alata leaf extract]Sold by the laboratory srobiologiques/koning/basf; helioguard [ INCI: porphyra umbilicalis encapsulated in liposomes]PhytoCellTec apples [ INCI: PhytobellTec apples]Or PhytoCellTec ayania tree [ INCI: acacia spinosa bud cell extract, isomalt, lecithin, benzoic acidSodium and water]Sold by milbema biochemical corporation; pepa-Protect [ INCI: watermelon extract]Sold by Pentapharm/DSM; celligent [ INCI: sunflower seed oil, ferulic acid ethyl ester, polyglycerol-5 trioleate, rosemary leaf extract, water and uridylic acid disodium]Or Defensil [ INCI: octyl dodecanol, echeveria oil, extract of fructus seu radix camptothecae acuminatae, and unsaponifiable sunflower oil]Marketed by Rahn; venuceane [ INCI: thermus thermophilus fermentation product and glycerol]UV-Soft [ INCI: yeast extract]Renovage [ INCI: caprylic/capric triglyceride, teprenone]Juvinity [ INCI: caprylic/capric triglyceride, geranylgeranyl propanol (proposed)]And, science Holyherb [ INCI: extract of flower/leaf/stem of Butylene glycol, California herba Desmodii Styracifolii (eriodictyon sempervirens)]Or Resistem [ INCI: glycerol, heart leaf ball flower fermentation product]Sold by Sederma/proctosigma; infragard [ INCI: fructus Caesalpiniae cristae pod extract, propylene glycol, water, sunflower bud extract, sodium benzoate, and phenoxyethanol]Sold by milbeLe corporation; heliomoduline [ INCI: low molecular weight peptides from cottonseed]Or Stem-C-Guard [ hydrolyzed peas ]]Sold by silicon laboratories corporation; and combinations thereof.

In another embodiment, the reactive carbonyl species scavenger, radical scavenger and/or anti-glycosylation agent, antidote, antioxidant and/or anti-fouling agent is selected from, for example and without limitation, the group formed by: carnosine and derivatives thereof; GHK [ INCI: tripeptide-1]And salts and/or derivatives thereof or quintesine IS [ INCI: dipeptide-4]Sold by Vincience/International specialties/Ashland; preregen [ INCI: wild soybean protein, oxido-reductase]Edelweiss GC [ INCI: extract of Leontopodium alpinum]Lipogard [ INCI: squalane, ubiquinone]Nectalure [ INCI: herba Buddlejae Davidii extract and herba Thymi extract]Alpaflor Nectaure [ INCI: flos Iridis Tectori extract, herba Thymi extract, glycerol, and water]Or Dismutin-BT [ INCI: highly purified SOD from native yeast strains of Saccharomyces cerevisiae]Sold by Pentapharm/DSM corporation;[ INCI: diaminopropionyl tripeptide-33]、[ INCI: hydrolyzed wheat protein, hydrolyzed soybean protein, tripeptide 1]、Lipochroman^TM[ INCI: dimethyl methoxy chromans]、[ INCI: acetyl tetrapeptide-22]、Pollushield^TMFunctional components [ INCI: diisopropyl adipate, lecithin, acrylic acid/acrylamide methyl propane sulfonic acid copolymer, dimethyl methoxy chromanol, xanthan gum]Or[ INCI: acetyl dipeptide-3-amino caproic acid tert-butyl ester]Sold by the company Riptat/Luborun; unicyl [ INCI: mannitol, pea extract, histidine HCl, arginine, cyclodextrin, dextrin, yeast extract, acetyl tyrosine, pyridoxine HCl, African strain extract, nicotinamide, adenine dinucleotide, disodium succinate, aspartic acid]And, Imidinyl [ INCI: sour bean seed polysaccharide]Phystrogen [ INCI: butanediol, mallow (Malva) extract, xanthan gum]Or puripot [ INCI: moringa oleifera seed extract]Sold by the laboratory srobiologiques/koning/basf; AquaCacteen [ INCI: glycerin, cactus stem extract, phenoxyethanol and water]Trimoist (kmf) [ INCI: sodium stearoyl lactylate, cetyl alcohol, Olus vegetable oil, tocopheryl acetate, glycerol, glycine soja sterol, sodium lactate, sodium carboxymethyl beta-glucan, carnosine, lactic acid]MelanoBronze [ INCI: vitex agnus-castus extract (and cranberry fruit (Monk's pepper berries) extract (phytoendorphin)), acetyl-tyrosine]CM-Glucan [ INCI: sodium carboxymethyl β glucan, phenoxyethanol, SunActin [ INCI: extract of sunflower (sunflower) bud, tocopherol, glycerol, lecithin, phenoxyethanol, and water]GSP-T skin [ INCI: glycerol, alcohol, water, PEG-40 hydrogenated castor oil, grape (Vitis Vinifera) seed extract]Or Detoxophane [ INCI: cortex Phellodendri extract, lecithin, phenoxyethanol, glycerol, and water]Sold by milbema biochemical corporation;baccalamine [ INCI: PEG-8, herba Bacopae Monnieri extract, and water (water) hydroxyethyl cellulose]Kombuchka [ INCI: yeast of Saccharomyces/greater tea, glycerol, and hydroxyethyl cellulose]Citystem [ INCI: glycerol and marrubium vulgare extract]Or Prodizia [ INCI: albizzia julibrissin bark extract and glycerin]Sold by Sederma/procrastina; extramel C [ INCI: hydroxypropyl trimethyl ammonium chloride malt burned essence crosslinked polymer, and melon (muskmelon) fruit extract]Sold by the company Seppic (Seppic); defensine [ INCI: wheat germ extract]、[ INCI: taraxacum officinale (dandelion) extract]、[ INCI: water, butanediol, Butyrospermum parkii (Shea butter) seed cake extract]Or Antiglysky [ INCI: water, sunflower seed extract]Sold by Silab; and combinations thereof.

The compositions of the present invention may be used in an application or any of the uses discussed above under the heading "applications".

In another aspect, the present invention provides a kit for a cosmetic, non-therapeutic method of treating and/or caring for skin, the kit comprising:

(i) a composition comprising botulinum toxin;

(ii) optionally, Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof; and

(iii) cosmetic compositions comprising a compound of formula (I).

(i) A composition comprising botulinum toxin (ii) a composition comprising Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂Or H-Tyr-D-Ala-Gly-Phe-Leu-OH or combinations thereof, if present, and (iii) compositions comprising a compound of the invention according to the first aspect, may be in the same or separate containers. In one embodiment, the kit may further comprise a means for applying the composition to the skin. For example, the kit may include, for example, a syringeOr microneedles.

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

Examples of the invention

General procedure

Abbreviations

Abbreviations for amino acids follow the recommendations of the 1983IUPAC-IUB Joint Commission on Biochemical nomenclature, outlined in the journal of European biochemistry (Eur.J.biochem.) (1984)138: 9-37.

(R), a resin; 2-ClTrt- (R), 2-chlorotrityl resin; ac, acetyl; AcOH, acetic acid; ala, alanine; AM, 2- [ 4-aminomethyl- (2, 4-dimethoxyphenyl) ] phenoxyacetic acid; arg, arginine; asn, asparagine; asp, aspartic acid; boc, tert-butoxycarbonyl; DCM, dichloromethane; DIEA, N' -diisopropylethylamine; DIPCDI, N' -diisopropylcarbodiimide; DMF, N-dimethylformamide; ESI-MS, electrospray ionization mass spectrometry; fmoc, 9-fluorenylmethoxycarbonyl; gln, glutamine; glu, glutamic acid; gly, glycine; his, histidine; HOBt, 1-hydroxybenzotriazole; HPLC, high performance liquid chromatography; ile, isoleucine; KOH, potassium hydroxide; leu, leucine; lys, lysine; MBHA, p-methyl benzhydrylamine; MeCN, acetonitrile; MeOH, methanol; met, methionine; myr, myristyl; palm, palmitoyl; pbf, 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl; pro, proline; ser, serine; tBu, tert-butyl; TFA, trifluoroacetic acid; thr, threonine; trt, trityl; val, valine.

Chemical synthesis

All synthetic methods were performed in polypropylene syringes equipped with porous polyethylene discs. The coupling protocol was performed according to the standard protocol established in the bibliography and the solvent and soluble reagents were removed by aspiration. piperidine-DMF (2:8, v/v) (1X 1 min, 1X 5 min, 5ml/g resin) was used to remove the Fmoc group [ Lloyd-Williams P. et al, (1997) chemistry of peptide and protein Synthesis (Chemical intermediates to the Synthesis of Peptides and Proteins) CRC, Bocardon (Boca Raton)) U.S. Freyda (FL, USA) ]. Washes (3 × 1 min) between deprotection, coupling and deprotection stages were performed with DMF using 10ml of solvent per gram of resin each time. The coupling reaction was performed with 3ml of solvent per gram of resin. The control of the coupling is performed by performing: ninhydrin test [ Kaiser E et al, "analytical chemistry (anal. biochem.) (1970),34:595 & 598] or chloranil test [ Christensen T.," Scandinavian Chemicals (Acta chem. Scand.) (1979),33B,763 & 766 ]. The coupling reaction is repeated when the desired peptide is synthesized. All synthesis reactions and washes were performed at 25 ℃.

It is known to those skilled in the art that some amino acids are used with their protected functional groups in the side chains. For example, non-limiting examples of protecting groups are:

tBu, tert-butyl of the amino acid Glu; and

pbf, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl of the amino acid Arg; and

trt, trioctyl of amino acid Gln.

HPLC chromatography was performed using a Shimadzu apparatus (Kyoto, Japan) using a reverse phase column thermostated at 30 ℃ (50X 4.6mm, Kromasil C18, 3.5 μm, Akzo Nobel, Sweden). Elution was performed using a gradient of water (+ 0.1% TFA) containing acetonitrile (+ 0.07% TFA) at a flow rate of 1.6 ml/min and detection was performed at 220 nm. Using MeCN H in mobile phase₂Mixture of O4: 1(+ 0.1% TFA) and flow rate of 0.3 ml/min electrospray ionization mass spectrometry was performed in a Waters Alliance (Waters Alliance) ZQ 2000 detector.

Example 1

Obtaining Fmoc-W_m-X_n-AA₁-AA₂-AA_3-AA₄-AA₅-AA_6--Y_p-Z_q-AM-MBHA- (R), wherein AA₁Is L-Arg; AA₂Is L-Arg; AA₃Is L-Gln or D-Gln; AA₄Is L-Met or D-Met; AA₅Is L-Glu; AA₆Is L-Glu; and n, m, p and q are each 0 or 1.

The weights were normalized. Fmoc-AM-pMBH was paired with piperidine, DMF according to the general protocolResin a was treated to remove the Fmoc group. 5 equivalents of Fmoc-L-Glu (tBu) -OH (Fmoc-AA) in the presence of 5.5 equivalents of DIPCDI and 5 equivalents of HOBt using DMF as solvent₆OH) was incorporated onto the deprotected resin for 1 hour.

The resin was then washed as described in the general method and the deprotection treatment of the Fmoc group was repeated to couple the next amino acid: 5 equivalents of Fmoc-Glu (tBu) -OH (Fmoc-AA)₅-OH); and subsequently 5 equivalents of Fmoc-D-Met-OH (Fmoc-AA)₄-OH); 5 equivalents of Fmoc-L-Gln (Trt) -OH (Fmoc-AA)₃-OH); 5 equivalents of Fmoc-L-Arg (Pbf) -OH (Fmoc-AA)₂-OH); and finally 5 equivalents of Fmoc-L-Arg (Pbf) -OH (Fmoc-AA)₁-OH) in the presence of 5 equivalents of HOBt and 5.5 equivalents of DIPCDI, in a sequential coupling step with each other.

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

Non-limiting examples of peptides synthesized by this method are shown in table 4:

TABLE 4

By following the described method it is possible to obtain different sequences that alter the desired amino acid to be coupled.

Example 2

General procedure for Fmoc N-terminal protecting group removal.

Deprotection of the N-terminal Fmoc group of the peptidyl resin obtained in example 1 was performed as described in the general method (DMF with 20% piperidine, 1 × 1 min +1 × 5 min). Peptidyl resins were detoxified with DMF (5X 1 min), DCM (3X 1 min), diethyl ether (3X 1 min) and dried under vacuum.

Example 3

For mixing R₁Method of introducing palmitoyl group onto the peptidyl resin obtained in example 1.

To each of the peptidyl resins obtained in example 2 was added 5 equivalents of palmitic acid (1ml) pre-dissolved in DMF in the presence of HOBt and DIPCDI, respectively. The mixture was allowed to react for 3 hours, then the resin was washed with DMF (3 × 1 min), DCM (3 × 1 min), diethyl ether (3 × 1 min) and dried under vacuum.

Example 4

For mixing R₁Method of introducing acetyl group to the peptidyl resin obtained in example 1.

Each of the peptidyl resins obtained in example 2 was treated with acetic anhydride in the presence of DIEA using DMF as solvent. The mixture was allowed to react for 30 min, then the resin was washed with DMF (3 × 1 min), DCM (3 × 1 min), diethyl ether (3 × 1 min) and dried under vacuum.

Example 5

Cleavage method from the polymer support of the peptidyl resin obtained in examples 2,3 and 4.

With 3ml of TFA H₂O (95:5, v/v) each of the dried peptidyl resins obtained in examples 2,3 and 4 was treated for 2 hours at room temperature under agitation. It was then filtered through a polypropylene syringe fitted with a porous polyethylene disc. The filtrate was collected on cold diethyl ether and washed 5 times with diethyl ether. The final precipitate was dried under vacuum.

Wherein R is obtained after the process₁Is H, acetyl or palmitoyl₁-W_m-X_n-AA₁-AA₂-AA_3-AA₄-AA₅-AA₆-Y_p-Z_q-OH or R₁-W_m-X_n-AA₁-AA₂-AA_3-AA₄-AA₅-AA₆-Y_p-Z_q-NH₂The peptide of (1).

For a gradient of MeCN (+ 0.07% TFA) in H₂HPLC analysis of the obtained peptide in O (+ 0.1% TFA) showed more than 80% purity in all cases. The identity of the obtained peptide was confirmed by ESI-MS.

Example 6

Inhibition of norepinephrine release from human neuroblastoma cells.

Release of neurotransmitters from peripheral neurons to skeletal muscle by exocytosis in the neuromuscular junction may allow muscle contraction. Facial muscles undergo the contraction and facial muscles around the eyes, mouth and forehead contract more frequently than elsewhere on the face. With age, the sustained release of neurotransmitters to the neuromuscular junction and the decrease in elasticity contribute to the increase in facial wrinkles and permanent expression lines. Compounds capable of blocking or reducing exocytosis at the neuromuscular junction site are therefore good candidates for cosmetic treatment of unsightly wrinkles. The in vitro induction of the release of the neurotransmitter Norepinephrine (NA) in the human neuroblastoma cell line (SH-SY5Y) was considered to be a direct and reliable method for exocytosis measurements. The aim of this study was to evaluate the efficacy of the peptides of the invention for the inhibition of neuronal exocytosis by measuring the level of NA release in SH-SY5Y cells by enzyme linked immunosorbent assay (ELISA).

SH-SY5Y (ECACC) cells at 1X 10⁶The density of individual cells/well was seeded in 12-well plates. After 6 days of culture, the medium was removed from the wells and the cells were treated with the peptides of the invention dissolved in hanks (Hank's) balanced salt solution (HBSS, Life technology), at 1 and 2.5mg/ml for 60 minutes. Cells treated with HBSS alone were used as basal controls. To mobilize NA vesicles, the supernatant was removed and 100nM of tetradecanoyl-13-acetate (TPA, Sigma (Sigma)) was dissolved in HBSS in the presence of test items or HBSS alone in the case of basal controls. After this, the solution with TPA was removed and NA release was induced by adding 10 μ M ionomycin (Epica) with 100nM TPA dissolved in HBSS in the presence of test items, or dissolved in HBSS alone in the case of basal controls. After that, the medium containing the released NA in the wells was collected and centrifuged. The obtained supernatant was used for quantification of NA by ELISA using a noradrenaline ELISA kit (IBL International). Briefly, theDirect sandwich ELISA was performed using plates pre-coated with anti-NA antibodies. The color obtained after substrate addition is directly proportional to the amount of NA present under each condition tested. The absorbance read in a microplate absorbance reader (Clariostar from BMG) was 405 nm. The percentage of NA released was calculated for each condition relative to the basal control. The results of the percentage of NA release relative to untreated cells (basal control) are shown in fig. 1 and provided in the table below.

TABLE 4a

The results demonstrate that the peptides of the invention inhibit NA release in SH-SY5Y at one or more of the concentrations tested relative to the basal conditions. It also demonstrates that the peptides of the invention can be reduced to even greater than the utilityNA release of the achieved low value.

Increased exocytosis release in the neuromuscular junction is associated with aging and increased facial wrinkles and expression lines. The peptides of the invention reduce exocytosis levels because they reduce NA release in SH-SY 5Y. Furthermore, the peptides of the invention are even more specificThe release can be further reduced.

Example 7

In vitro study of type I collagen synthesis on human skin fibroblasts by enzyme linked immunosorbent assay.

Collagen type I is the major collagen of the skin. This molecule is produced primarily by fibroblasts and is responsible for the strength and elasticity of this tissue. Thus, in vitro quantification of collagen induction by cosmetic products on human skin fibroblasts provides information on its potential anti-aging effect on skin. Collagen induction by the peptides of the present invention was evaluated using enzyme-linked immunosorbent assay (ELISA). The objective of this study was to investigate the ability of the product to induce collagen type I synthesis in primary human skin fibroblasts (HDFn) isolated from neonatal skin.

At 5X 10⁴HDFn (cascade) were seeded in 48-well plates. After 24 hours incubation, fresh medium with test items in scalar dilution of 0.5 μ g/ml was added. Untreated cells were used as basal controls. Cells were treated for 48 hours. Then, the culture medium of the wells was collected and transferred to a 96-well plate. A standard calibration curve prepared with calf skin type I collagen (sigma) was also transferred to the plate. The plate was left overnight to coat type I collagen onto its surface. Thereafter, collagen I was detected with an anti-collagen type I antibody (sigma). Then, the primary antibody was recognized by a secondary antibody IgG-HRP (molecular probe). 3,3,5, 5-tetramethylbenzidine liquid substrate (TMB, Sigma) was added to measure the amount of attached secondary antibody. The color produced by this reaction was measured in a microtiter plate reader (Clariostar of BMG) and the type I collagen concentration was determined using linear regression of a standard curve. The results of collagen synthesis relative to untreated cells are shown in figure 2 and are also provided in the table below.

TABLE 4b

The results demonstrate that the peptides of the invention promote type I collagen production in HDFn at the concentrations tested, relative to basal conditions. It also demonstrates the peptides of the invention relative toWith similar or increased collagen type I production.

During the aging process of the skin, type I collagen is reduced. The peptides of the invention increase the collagen type I produced by HDFn. In particular, the peptides PEP-21 and PEP-23 were found to be more effective in increasing collagen type IPeptides are even higher.

Example 8

In vitro quantification of blind myoid protein 1 in human skeletal muscle cells by time-resolved fluorescence resonance energy transfer.

Aging is associated with a decrease in muscle mass due to activation of muscle atrophy-related events. In processes associated with muscle atrophy, loss of function of blinded myoid 1(MBNL1) is associated with loss of muscle mass involved in the aging process of facial muscles. Thus, compounds capable of potentiating MBNL1 can be used as a good method for cosmetic treatment of the appearance of sagging face due to loss of muscle mass.

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

In skeletal muscle cell growth medium (Promocell Co., Ltd.), at a rate of 1.5X 10⁴Density of individual cells/well hSkMc (Innoprot) was seeded in 12-well plates. After 72 hours incubation, the medium was removed and replaced with skeletal muscle cell differentiation medium (Promocell). 48 hours after the start of cell differentiation, fresh differentiation medium with 0.5mg/ml test item was added. Treatment was continued for 48 hours and untreated cells were used as basal controls. After 48 hours of treatment, the cell culture medium was removed and cell lysis buffer was added to the wells. The plates were immediately kept at-80 ℃ to improve protein extraction during the defrost process. After 72 hours, cells were lysed by shaking the plate in an orbital rotor for 45 minutes at room temperature. Next, cell lysates were collected and assayed to quantify the levels of MBNL-1 protein and total protein concentration.

MBNL-1 protein level measurements were performed using the human MBNL1 assay kit (Cisbio) according to the manufacturer's protocol. Briefly, the kit is used to perform TR-FRET quantification against MBNL 1. The protein is detected with the antibodies provided in the kit and quantified by fluorescence measurement. Quantification was performed by using microplate readers (ClarioStar of BMG) set at 665nm and 620 nm.

The total protein concentration of the cell lysate was determined by using Pierce BCA protein assay kit (Thermo Scientific) according to the manufacturer's protocol. Briefly, after the working reagents are added to the sample and standard solution, the sample is incubated. Thereafter, the color change was measured at 562nm with an absorbance microplate reader (Clariostar from BMG). The total protein mass was used to normalize the concentration levels of MBNL1 protein in the sample obtained by the TR-FRET assay. The results for% induced MBNL1 protein relative to the basal control are shown in fig. 3 and fig. 3a, and are provided in the table below.

TABLE 4c

The results demonstrate, in comparison with the basic sumIn contrast, the peptides PEP-22, PEP-23, PEP-24, PEP-26, PEP-27, PEP-41, PEP-30, PEP-31, PEP-35, PEP-36, PEP-42, PEP-43, PEP-44 and PEP-37 of the present invention increased the MBNL1 level. In fact, the results show that, even in the case of twice (1mg/mL) the peptide of the present invention (0-5mg/mL),there was also no effect on MBNL 1. It is believed that the enhancement of the MBNL1 protein slows the loss of muscle mass during aging, thereby avoiding the appearance of sagging facial skin in older people.

Example 9

Contains the peptide PEP-21Ac-L-Arg-L-Arg-L-Gln-L-Glu-L-Glu-NH₂Preparation of cream of peptide solution

In a suitable vessel, the ingredients of phase a are: water [ INCI: water (Water)]、Zemea^TM[ INCI: propylene glycol]、[ INCI: pentanediol]、Phenoxetol^TM[ INCI: phenoxyethanol]And[ INCI: EDTA disodium salt]And (4) dissolving.

Phase a1 composition:ultrez 10 polymer [ INCI: CARBOMER (CARBOMER)]Added to the previous mixture. Once dispersed, phase a 2:CPE-K [ INCI: cetyl phosphate potassium]And (4) introducing. The mixture was then heated to 70-75 ℃.

In a separate vessel, phase B ingredients: schercemel^TMDIS ester [ INCI: sebacic acid diisopropyl ester]、2000[ INCI: glyceryl stearate, cetostearyl alcohol, palmitoyl hydrolyzed wheat protein potassium]、EC [ INCI: ethyl hexyl cocoate]Astro-sil 2C 350[ INCI: dimethicone]And tocopherol acetate [ INCI: tocopherol acetate]Mixing, and heating the mixture at 70-75 deg.C.

The emulsion was prepared by slowly adding phase B to phase a under rapid agitation with a turbine.

Once the mixture was cooled to 40 ℃, the components of phase C: novemer^TMEC-1 polymer [ INCI: mineral oil (liquid paraffin); water (water); acrylate/acrylamide cross-linked polymers; polysorbate 85]Added to the previous mixture under agitation and mixed until dispersed.

Phase D: peptide PEP-21 solution [ INCI: glycerol; water (water); peptide PEP-21) was added to the previous mixture.

Addition of phase E: perfume [ INCI: flavor (essence) ].

The pH was adjusted to 6.0-6.5 with the lower phase F ingredient: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide).

TABLE 5

Example 10

Preparation of gel-cream comprising the peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu).

In a suitable vessel, the ingredients of phase a are: water [ INCI: water (Water)]、Zemea^TM[ INCI: propylene glycol]、[ INCI: phenoxyethanol]、NA2[ INCI: EDTA disodium salt]And potassium sorbate granule [ potassium sorbate ]]And (4) dispersing.

Phase a1 composition:ultrez 21 polymer [ INCI: acrylate/C10/30 alkanol acrylate crosspolymer]Added to the previous mixture under agitation. Once dispersed, phase a 2: xanthan gum [ INCI: xanthan gum]Introduced into the previous mixture and agitated until completely dispersed.

In a separate vessel, phase B ingredients: schercemel^TM1818 esters [ INCI: ISOSTE aryl isostearate]And (5) weighing.

The emulsion was prepared by slowly adding phase B to phase a under rapid agitation with a turbine.

Phase C: peptide PEP-23 solution [ INCI: water (water); caprylyl glycol; peptide PEP-23] was added to the previous mixture.

The pH was adjusted to 6.0-6.5 using the lower phase D ingredient: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide).

TABLE 6

Example 11

Comprises 2% of the peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH)₂) Preparation of gels of solutions

In a suitable vessel, the ingredients of phase a are: water [ INCI: water (Water)]、Zemea^TM[ INCI: propylene glycol]、Glucam^TME-20 moisturizer [ INCI: methyl glucitol polyether-20]、NA2[ INCI: EDTA disodium salt]、[ INCI: phenoxyethanol]And (4) dissolving.

Phase a 1:ultrez 10 polymer [ INCI: carbomer]Added to the previous mixture and mixed until completely dispersed.

Phase B: peptide PEP-23 solution [ INCI: water (water); caprylyl glycol; PEP-23] was added to the previous mixture and mixed.

Phase C:CO 40[ INCI: PEG-40 hydrogenated Castor oil]Perfume [ INCI: spice (essence)]Added to the previous mixture and mixed.

The pH was adjusted to 6.0-6.5 using the ingredients of phase D: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide ].

TABLE 7

Example 12

Comprises 2% of the peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH)₂) Preparation of emulsions of solutions

In a suitable vessel, the ingredients of phase a 1: water [ INCI: water (Water)]、Zemea^TM[ INCI: propylene glycol]Glycerol [ INCI: glycerol]Potassium sorbate [ INCI: potassium sorbate]AndNA2[ INCI: EDTA disodium salt]And (4) dissolving.

Phase a2 composition:ultrez 30 polymer [ INCI: carbomer]Added to the previous mixture. Once dispersed, phase a 3: xanthan gum [ INCI: xanthan gum]And (4) introducing. The mixture is then heated at 70-75 ℃.

In a separate vessel, phase B ingredients:meadowfoam seed oil [ INCI: seed oil of Potentilla chinensis (Miscanthus sinensis (Burm.) F.Chen)]Kodasil 600IDD gel [ INCI: isododecane; vinyl/lauryl dimethicone crosspolymer; a dimethicone; lauryl dimethyl polysiloxane]Astro-sil 2C 350[ INCI: dimethicone]、Schercemol^TMThe CATC ester [ INCI: cocoyl adipic acid/trimethylolpropane copolymers; trimethylolpropane]、Schercemol^TMDIS ester [ INCI: sebacic acid diisopropyl ester]Tocopherol acetate [ INCI: tocopherol acetate]And Phenoxetol^TM[ INCI: phenoxyethanol]Mixing and heating the resulting mixture at 70-75 ℃.

The emulsion was prepared by slowly adding phase B to phase a under rapid agitation with a turbine.

Once the mixture was cooled to 40 ℃, the components of phase C: novemer^TMEC-2 polymer [ INCI: water (water); sodium acrylate/behenyl polyether-25 methylAn acrylate cross-linked polymer; hydrogenated polydecene and lauryl glucoside]SA-SB-300 (7%) [ INCI: silicon dioxide; dimethicone]Perfume [ INCI: spice (essence)]And peptide PEP-23 solution [ INCI: water (water); caprylyl glycol; peptide PEP-23) was added to the previous mixture.

The pH was adjusted to 6.0-6.5 with the lower phase D ingredients: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide).

TABLE 8

Example 13

Comprises 2% of the peptide PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH)₂) Preparation of liquid emulsions of solutions

In a suitable vessel, the ingredients of phase a 1: water [ INCI: water (Water)]、Zemea^TM[ INCI: propylene glycol]Glycerol [ INCI: glycerol]、Genencare^TMOSMS BA [ INCI: betaine]、NA2[ INCI: EDTA disodium salt]Potassium sorbate [ INCI: potassium sorbate]And (4) dissolving.

Phase a 2:ultrez 10 polymer [ INCI: carbomer]Added to the previous mixture. Once dispersed, phase a 3:CPE-K [ INCI: cetyl phosphate potassium]And (4) adding. The resulting mixture is heated at 70-75 ℃.

In another vessel, the components of phase B:HD [ INCI: isohexadecane]Lincol BAS [ INCI: c12-15 alkyl benzoates]Gandak C [ INCI: cetyl alcohol]Sorbitol T20P [ INCI:polysorbate 20]2-phenoxyethanol [ INCI: phenoxyethanol]Vegetable stearic acid 50/50[ INCI: stearic acid; palmitic acid]Mixing and heating at 70-75 deg.C. Phase B was slowly introduced over phase a with close turbine agitation.

The mixture was cooled at 40 ℃, and phase C: BRB CM 56-S [ INCI: cyclomethicone ], peptide PEP-23 solution [ INCI: water (water); caprylyl glycol; peptide PEP-23), perfume [ INCI: adding spices (essence). The pH was adjusted to 6.0-6.5 using the ingredients of phase D: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide ].

TABLE 9

Example 14

In vivo studies directed to the evaluation of anti-wrinkle effects of the peptides of the invention after long-term application to caucasian skin type female volunteers.

The study was performed for 28 days. Thirty (30) caucasian female volunteers aged between 35 and 50 years with facial skin wrinkles were included. The subject applied the composition described in example 10 (active cream) on one side of the face (left or right), as well as a placebo cream with the same composition except for the peptide of the invention. The active cream and placebo cream were applied for 28 days, twice daily (morning and evening). The subject served as its own reference and the results obtained at times 14 and 28 days were compared to the results obtained at the initial time. Furthermore, the results obtained with the active cream were compared with the results obtained with the placebo cream.

The anti-wrinkle efficacy of the composition on the face of volunteers was evaluated by:

-wrinkle depth: images of the fishtail region of the volunteers were obtained using a 3D microtopography imaging system. Wrinkle depth measurements were taken at the initial time, 14 days of product application and 28 days later. The results are shown in table 10.

Table 10. wrinkle depth decreased after 14 and 28 days of product application. Statistical significance relative to initial time: p <0.05 using paired sparton (Student's) t test and initial time.

The results demonstrate that there was a statistically significant reduction in wrinkle depth compared to the initial time after 14 days and 28 days of application of the composition of the invention. Furthermore, the reduction in wrinkle depth was higher with the active cream than with the placebo cream.

-wrinkle volume: images of the fishtail region of the volunteers were obtained using a 3D microtopography imaging system. Wrinkle volume measurements were taken at the initial time, 14 days of product application and 28 days later. The results are shown in table 11.

Table 11. wrinkle volume decreased after 14 and 28 days of product application. Statistical significance relative to initial time: p <0.05 using paired sparton t test and initial time.

The results demonstrate that there was a statistically significant increase in wrinkle volume after 14 and 28 days of product application compared to the initial time. Furthermore, the reduction in wrinkle volume with the active cream was higher than that of the placebo.

-wrinkle length: images of the fishtail region of the volunteers were obtained using a 3D microtopography imaging system. Wrinkle length measurements were taken at the initial time, 14 days of product application and 28 days later. The results are shown in table 12.

Table 12. wrinkle length decreased after 14 and 28 days of product application. Statistical significance relative to initial time: p <0.05 using paired sparton t test and initial time.

The results demonstrate that there was a statistically significant increase in wrinkle length after 14 and 28 days of product application compared to the initial time. Furthermore, the reduction in wrinkle length was higher with the active cream than with placebo.

Clinical evaluation of skin wrinkles: on a clinical scale, dermatologists evaluated skin wrinkles after the initial time, 14 and 28 days of product application. The results are shown in table 13.

Table 13% of subjects showing improvement in clinical evaluation after 14 and 28 days of product application.

The results demonstrate that the percentage of subjects showing improvement of skin wrinkles is higher after 28 days of product application of the composition of the active cream compared to the placebo cream.

-self questionnaire: after 28 days of active cream and placebo, volunteers answered a self questionnaire to evaluate the efficacy of both products. The results are shown in table 14.

Table 14 percentage of positive response to wrinkle-related problems after 28 days of product application.

According to the responses of the volunteers, the results demonstrate that the active cream shows a higher improvement after 28 days compared to placebo.

Example 15

Preparation of a gel cream comprising the peptide PEP-22 (Ac-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu).

In a separate vessel, phase B ingredients: schercemel^TM1818 esters [ INCI: ISOSTE aryl isostearate]And (5) weighing.

The emulsion was prepared by slowly adding phase B to phase a under rapid agitation with a turbine.

Phase C: peptide PEP-22 peptide solution [ INCI: water (water); caprylyl glycol; peptide PEP-22] was added to the previous mixture.

The pH was adjusted to 6.0-6.5 using the lower phase D ingredient: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide).

Watch 15

Example 16

Comprises 2 percent PEP-23 (Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH)₂) And 2%Preparation of emulsions of peptide solutions

In a suitable vessel, the ingredients of phase a 1: water [ INCI: water (Water)],Zemea^TM[INCI：PROPANEDIOL]Glycerol [ INCI: glycerol]Potassium sorbate [ INCI: potassium sorbate]AndNA2[ INCI: EDTA disodium salt]And (4) dissolving.

The emulsion was prepared by slowly adding phase B to phase a under rapid agitation with a turbine.

Once the mixture was cooled to 40 ℃, phase C: novemer^TMEC-2 polymer [ INCI: water (water); sodium acrylate/behenyl polyether-25 methacrylate crosspolymer; hydrogenated polydecene and lauryl glucoside]SA-SB-300 (7%) [ INCI: silicon dioxide; dimethicone]Perfume [ INCI: spice (essence)]、Peptide [ INCI: water (water); acetyl hexapeptide-8; octylene glycol]And PEP-23 peptide solution [ INCI: water (water); caprylyl glycol; PEP-23 peptides]) Added to the previous mixture.

The pH was adjusted to 6.0-6.5 with the lower phase D ingredients: sodium hydroxide 20% w/w [ INCI: water (water); sodium hydroxide).

TABLE 16

Example 17

In vitro reduction of the effects of muscle mass loss induced in human skeletal muscle cells by immunofluorescence.

Muscle mass loss correction by the peptides of the invention was evaluated by immunofluorescence assay. The objective of this study was to investigate the ability of peptide candidates to alleviate muscle mass loss, i.e., to reverse TNF- α -induced adverse effects, after treatment with TNF- α in human musculoskeletal cells (hSKMC) (a model of muscle senescence). Myosin heavy chain (MHyC) is used as a morphological marker of differentiated myotubes that allows measurement of their diameter and this can be used to determine the extent of mass loss. Tumor necrosis factor alpha (TNF- α) has been described in the literature as an inducer of muscle mass loss.

In skeletal muscle cell growth medium (Promocell Co., Ltd.), at a rate of 1.5X 10⁴Density of individual cells/well hSKMC (Tebu-Bio) was seeded in a 96-well plate. After 24 hours of incubation, the medium was replaced with skeletal muscle cell differentiation medium (Promocell corporation), and the cells were differentiated for 6 days. After this, muscle cell mass loss was induced by adding fresh differentiation medium with 20ng/ml TNF α (sigma). Cells not treated with TNF α were used as Basal Controls (BC). After 24 hours of mass loss induction, the medium was replaced in some of the plates with fresh differentiation medium comprising 0.01mg/ml of the peptide of the invention. TNF α -treated cells without peptide treatment were used as mass loss control (BC + TNF), and cells without peptide or TNF α treatment of the invention were both used as basal mass loss control (BC). The treatment was resumed after 24 hours. Immunofluorescence was determined after 24 hours after the second treatment. Cells were fixed with 4% paraformaldehyde (sigma) for 15 minutes, permeabilized with 1% Triton X-100 (sigma) for 15 minutes, and then with 5% bovine serum albumin (sigma)) And (4) blocking. Next, primary antibody anti-MHyC mice (1:100, in vitro) were added and incubated overnight at 4 ℃. After this time, the secondary antibody Alexa Fluor 488 goat anti-mouse IgG (1:250, Life technologies) was added and incubated for 1 hour. Finally, the myotube diameter was determined by imaging MHyC staining by Operetta (Perkin Elmer). The percentage of mass loss was automatically calculated using the Harmony (perkin elmer) software by classifying the myotubes according to their diameter using a mass loss threshold of 20 μm. Results for muscle mass loss versus% untreated cells of the basal control are shown in figure 4 and table 17. Results were normalized to the mass loss control (BC + TNF).

	Loss%
		Basal Control (BC) + TNF-alpha	100.0
Basic Control (BC)	68.3
		PEP-22	76.2
PEP-23	71.9

TABLE 17

The results demonstrate that peptides PEP-22 and PEP-23 of the invention reduce mass loss compared to TNF-alpha treated basal controls.

Example 18

In vitro effects of PEP-22 and PEP-23 on lipid accumulation in human subcutaneous preadipocytes.

The skin may experience loss of adipose tissue, resulting in non-aesthetic reduction of facial volume and aging. This loss of adipose tissue is mainly caused by adipocyte senescence, i.e., when the cells of the adipocytes are no longer able to differentiate, resulting in a reduction in normal lipid accumulation. In addition, old aging adipocytes express an aging-associated secretory phenotype (SASP) that induces senescence of young adipocytes.

Measurement of lipid accumulation in co-cultures of young and old adipocytes indirectly assessed inhibition of SASP. A pool of old adipocytes has a greater number of senescent cells. When co-cultured with young cells, lipid accumulation was observed to be below the theoretically expected level due to senescence-inducing effects of SASP from old to young adipocytes. Therefore, compounds capable of increasing lipid accumulation can be used as good methods for preventing loss of facial volume caused by aging of adipocytes.

Induction of lipid accumulation by the peptides of the present inventionThe evaluation was carried out by measuring fluorescent staining of lipids by the reagent. The objective of this study was to investigate the ability of peptide candidates to induce lipid accumulation in human subcutaneous adipocytes, and thus to prevent adipocyte senescence.

Cells of human subcutaneous preadipocytes (26 and 60 year old donors, cell application) were grown in human preadipocyte growth medium (Sigma) at 4X 10 for each age³The density of individual cells/well was co-cultured in 96-well plates. At 8X 10³The density of individual cells/well was inoculated for a single culture at each age as age lipid accumulation control. After 24 hours of incubation, differentiation of preadipocytes into adipocytes was induced by changing the medium to fresh human preadipocyte differentiation medium (Promocell corporation). At the same time, the co-cultured cells were treated with 0.01mg/ml of the peptide of the present invention. Will not be treatedThe co-cultured cells of (a) were used as basal controls, and the mono-cultured young and old cells were used as age lipid accumulation controls. After treatment and after day 12 of differentiation, according to the manufacturer's instructionsThe detection reagent (Lonza) stained the cells. Briefly, plates were washed with phosphate buffered saline (sigma) and then addedReagents and Hoechst 33342 (Life technologies) and incubated at 37 ℃ for 15 minutes. Finally, fluorescence intensity and number of nuclei were measured by Operetta (Perkin Elmer). Fluorescence was normalized by cell nuclei and results were presented relative to a basal control for co-culture. The results of the percentage of lipid content relative to untreated cells (basal control) are shown in fig. 5 and table 18. Abbreviations: % LA is the percentage of lipid accumulation; CC ═ co-culture control; YC is young control; OC as old control

	％LA
		YC	150.5
OC	85.29
		CC	100.0
PEP-22	133.9
		PEP-23	159.9

Watch 18

The results demonstrate that the peptides PEP-22 and PEP-23 of the present invention increase lipid accumulation in adipocytes compared to the basal control (coculture, CC) without peptide treatment. The percentage of lipid accumulation in PEP-22 and PEP-23 treated cells was similar to that of young cells.

During the aging process, lipid accumulation in adipocytes is reduced due to aging. The peptides of the invention prevent cellular senescence of adipocytes, as they increase lipid accumulation in co-cultured HPAd cells.

Example 19

In vivo studies directed to the evaluation of the anti-wrinkle effect of the peptide PEP-23 of the present invention after long-term application to caucasian skin type female volunteers.

The study was performed for 28 days. Forty-one (41) white female volunteers aged between 35 and 60 years who exhibited skin wrinkles on the face were included in the study. The subjects applied the composition described in example 10 (active cream) on one side of the face (left or right) and a placebo cream with the same composition except the peptide of the invention on the other side of the face. The active cream and placebo cream were applied for 28 days, twice daily (morning and evening). The subjects served as their own reference and the results obtained at times 5 days, 14 days and 28 days were compared with the results obtained at the initial time. Furthermore, the results obtained with the active cream were compared with the results obtained with the placebo cream.

Skin isotropy was assessed by analyzing images of the volunteer's crow's feet regions extracted using a PRIMOS 3D micro-topography imaging system. Isotropy is a determining factor in determining how the collagen fibers of the skin are structured and oriented. A high level of isotropy corresponds to collagen fibers that are uniformly oriented in different directions and is characteristic of young skin. Low levels of isotropy (i.e., anisotropy) are characteristic of aging skin. Therefore, it is desirable to increase the level of skin isotropy to provide a younger appearance.

Images extracted using the PRIMOS 3D microtopography imaging system at day 5, day 14 and after day 28 of product application were analyzed to measure skin isotropy. The results are shown in table 19.

Table 19. skin isotropy increased after 5, 14 and 28 days of product application.

The results demonstrate that after 5, 14 and 28 days of application of the active cream, there is an increase in the isotropy of the skin compared to the initial time (i.e. at the beginning of day 1). In addition, the increase in skin isotropy with the active cream and the placebo cream was higher.

Example 20

In vivo studies directed to the assessment of the effect of PEP-23 peptide on the facial volume of white skin type female volunteers after long-term application to the volunteers.

During the aging process, there is a natural process of facial volume reduction and increased appearance of skin sagging. To evaluate the effect of PEP-23 on facial volume, a 28-day study was performed and the efficacy of the product was evaluated in nineteen (19) white female volunteers between the ages of 35 and 45. The subject applied the composition described in example 10 (active cream) on one side of the face (left or right) and a placebo cream with the same composition except the peptide of the invention on the other half of the face. The active cream and placebo cream were applied for 28 days, twice daily (morning and evening). The subjects served as their own reference and the results obtained at day 14 and 28 were compared with the results obtained at the initial time (starting on day 1). Furthermore, the results obtained with the active cream were compared with the results obtained with the placebo cream.

After acquiring the facial topography of the entire face using a 3D device, the increase in the volume of the volunteer's face was evaluated. The volume in the cheek region was analyzed using dedicated software.

Measurements at day 5, day 14 and after day 28 of product application were analyzed to obtain the facial volume in the cheek region. The results are shown in table 20.

Table 20 facial volume decreased after 14 and 28 days of product application.

The results demonstrate that after 5, 14 and 28 days of application of the composition of the invention, the facial volume in the cheek region is increased compared to the initial time. Furthermore, the increase with the active cream was higher than with placebo.

Various aspects and embodiments of the invention are defined by the following numbered clauses:

1. a compound of formula (I):

R₁-W_m-X_n-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_p-Z_q-R₂ (I)，

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

AA₁arg, Lys or no amino acid;

AA₂is Arg or Lys;

AA₃is Gln, Glu, Asn or Asp;

AA₄is Met or Leu;

AA₅glu, Asp or Gln;

AA₆glu, Asp, Gln or no amino acid;

AA₁and AA₆Different;

w, X, Y and Z are each independently any amino acid;

m, n, p and q are each independently 0 or 1;

m + n + p + q is less than or equal to 2;

R₁And R₂Is not an amino acid.

2. The compound of clause 1, wherein the compound is not Arg-Arg-Glu-Leu-Glu-Glu-Leu.

3. The compound of clause 1 or clause 2, wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Are each an L amino acid.

4. The compound of any one of clauses 1 to 3, wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Is a D amino acid.

5. The compound of clause 4, wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆1, 2 or 3 of (a) are D amino acids, and AA₁To AA₆The remainder of (a) is L amino acid.

6. The compound of clause 5, wherein AA₃、AA₄And AA₅1, 2 or 3 of (a) are D amino acids.

7. The compound of clause 6, wherein AA₃、AA₄And AA₅1 or 2 of (a) are D amino acidsAnd AA₁To AA₆Is an L amino acid, and preferably AA₄Is a D amino acid, and AA₁To AA₆The remainder of (a) is L amino acid.

8. The compound of clause 7, wherein the compound has the formula:

R₁-W_m-X_n-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-Y_p-Z_q-R₂ (II)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(III); or

R₁-W_m-X_n-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂ (IV)。

9. The compound according to any one of the preceding clauses wherein R₁Selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₈Alkyl radical, C₂-C₂₄Alkenyl radical, C₃-C₂₄Cycloalkyl groups; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups.

10. The compound of clause 1, wherein the compound is:

Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH₂ (PEP-21)；

Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH₂ (PEP-22)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-23); or

Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH₂ (PEP-24)。

11. A compound according to any one of clauses 1 to 10, a stereoisomer and/or a cosmetically acceptable salt thereof with botulinum toxin and/or with the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂A combination of peptides of (1).

12. A composition comprising a cosmetically effective amount of a compound of formula (I), a stereoisomer and/or a cosmetically acceptable salt thereof according to any one of clauses 1 to 10, or a combination according to clause 11, and at least one cosmetically acceptable excipient or adjuvant.

13. Use of a compound according to any of clauses 1 to 10, stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes.

14. The use according to clause 13, wherein the cosmetic, non-therapeutic treatment and/or care is: treatment and/or prevention of skin aging; reducing and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; and/or reduce and/or prevent facial asymmetry.

15. A method of cosmetically, non-therapeutically treating and/or caring for skin, hair, nails and/or mucous membranes of a subject, the method comprising administering to the subject a cosmetically effective amount of a compound according to any one of clauses 1 to 10, a combination according to clause 11 or a composition according to clause 12.

16. The compound of clause 1 or clause 2, wherein AA₁Is Arg and/or AA₂Is Arg.

17. The compound of any of clauses 1, 2 or 16, wherein AA₃Gln or Asp.

18. The compound of any one of clauses 1, 2, 16 or 17, wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Are each an L amino acid.

19. The compound of any one of clauses 1, 2, 16 or 17, wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆Is a D amino acid.

20. The method of clause 19The compound of (1), wherein AA₁、AA₂、AA₃、AA₄、AA₅And AA₆1, 2 or 3 of (a) are D amino acids, and AA₁To AA₆The remainder of (a) is L amino acid.

21. The compound of clause 20, wherein AA₃、AA₄And AA₅1, 2 or 3 of (a) are D amino acids.

22. The compound of clause 21, wherein AA₃、AA₄And AA₅1 or 2 of (a) is a D amino acid, and AA₁To AA₆Is an L amino acid, and preferably AA₄Is a D amino acid, and AA₁To AA₆The remainder of (a) is L amino acid.

23. The compound of clause 22, wherein the compound has the formula:

R₁-W_m-X_n-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-Y_p-Z_q-R₂ (II)；

R₁-W_m-X_n-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂(III); or

R₁-W_m-X_n-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-Y_p-Z_q-R₂ (IV)。

24. The compound according to any one of clauses 1, 2 or 16-23, wherein R₁Selected from the group consisting of H and R₅-CO-wherein R is₅Selected from the group consisting of C₁-C₁₈Alkyl radical, C₂-C₂₄Alkenyl radical, C₃-C₂₄Cycloalkyl groups; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups.

25. The compound of clause 24, wherein R₁Selected from the group consisting of: H. acetyl, or palmitoyl, lauroyl, or myristyl; and R is₂is-NR₃R₄OR-OR₃Wherein R is₃And R₄Independently selected from the group consisting of H and C₁-C₁₆Alkyl groups.

26. The compound of clause 25, wherein R₁Selected from the group consisting of H, acetyl or palmitoyl; and R is₂is-NH₂or-OH, wherein R₃Is H, R₄Is H, and preferably R₁Is acetyl, R₂Is NH₂。

27. The compound of clause 1, wherein the compound is:

Ac-L-Arg-L-Arg-L-Gln-L-Met-L-Glu-L-Glu-NH₂ (PEP-21)；

Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH₂ (PEP-22)；

Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP-23); or

Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH₂ (PEP-24)。

28. A compound according to any one of clauses 1, 2 or 16 to 27, stereoisomers and/or cosmetically acceptable salts thereof and botulinum toxin and/or with the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂A combination of peptides of (1).

29. A composition comprising a cosmetically effective amount of a compound of formula (I), a stereoisomer and/or a cosmetically acceptable salt thereof according to any one of clauses 1, 2 or 16 to 27, or a combination according to claim 28, and at least one cosmetically acceptable excipient or adjuvant.

30. Use of a compound according to any of clauses 1, 2 or 16 to 27, stereoisomers and/or cosmetically acceptable salts thereof for the cosmetic, non-therapeutic treatment and/or care of the skin, hair, nails and/or mucous membranes.

31. The use according to clause 30, wherein the cosmetic, non-therapeutic treatment and/or care is: treatment and/or prevention of skin aging; reducing and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; and/or reduce and/or prevent facial asymmetry.

32. A method of cosmetically, non-therapeutically treating and/or caring for skin, hair, nails, and/or mucous membrane of a subject, the method comprising administering to the subject a cosmetically effective amount of a compound according to any one of clauses 1, 2, or 16 to 27, the combination according to clause 28, or the composition according to clause 29.

33. The method of clause 15 or clause 32, wherein the non-therapeutic cosmetic treatment and/or care is: treatment and/or prevention of skin aging; reducing and/or preventing skin wrinkles; stimulating collagen synthesis and/or preventing collagen loss; improving or maintaining skin firmness; treating and/or preventing the appearance of skin sagging; and/or reduce and/or prevent facial asymmetry.

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