ES2649762T3 - Peptide derivatives useful in the treatment, care or cleaning of the skin, mucous membranes, scalp or nails - Google Patents

Abstract

A peptide derivative of the general formula (I) R1-AA1-AA2-AA3-AA4-R2 (I) its stereoisomers, mixtures thereof, or its cosmetically or pharmaceutically acceptable salts, wherein: AA1 is selected from the group consisting of - Glu- and -Arg-; AA2 is selected from the group consisting of -Met-, -Ahx- and -Phg-; AA3 is selected from the group consisting of -Ala- and -Phg-; AA4 is selected from the group consisting of -Ile- and a single link; R1 is selected from the group consisting of H, and R5-C (O) -; and R2 is selected from the group consisting of -NR3R4 and -OR3; wherein R3 and R4 are independently selected from the group consisting of H, and an unsubstituted non-cyclic aliphatic group; wherein R5 is selected from the group consisting of H, and an unsubstituted non-cyclic aliphatic group; in which -Ahx- is ** Formula ** and -Phg- is ** Formula **

Description

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DESCRIPTION

Peptide derivatives useful in the treatment, care or cleaning of the skin, mucous membranes, scalp or nails Field of the invention

The present invention relates to peptide derivatives capable of stimulating the production of endogenous p-defensins and cosmetic and / or pharmaceutical compositions containing these peptide derivatives for the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails, preferably for the treatment of those conditions, disorders and / or pathologies of the skin, mucous membranes, scalp and / or nails resulting from the proliferation of microorganisms or being at risk of proliferation of microorganisms.

Background of the invention

Mammalian skin is its main defense barrier against external aggressions, whether chemical, mechanical or infectious aggressions. Aggressive external agents also include environmental factors such as UV rays, tobacco smoke, pollution and weather. The skin has a cutaneous microbial flora that forms its immune protection system; Any imbalance in the population of this flora entails a functional immune deficit that often involves the invasion of the skin by native bacteria of the skin or by bacteria that are not usually in the skin, thus initiating a process that can result in an infection clinically established Likewise, the flora of the skin has multiple important functions of homeostasis, defense against bacterial infections (by interference), lipid degradation and production of volatile components responsible for body odor.

For example, microorganisms that live as saprophytes on the surface of human skin, in their cracks, scales, stratum corneum and hair follicles, have an important protective role as an additional skin barrier to the superficial layers of cornea and lipid, which determines the permeability between the internal and external environment. This dermal flora is formed by resident and transient microorganisms, and they are bacteria, fungi and parasites.

Resident microorganisms have the ability to multiply and survive adhered to the surface and are dominant constituents of the skin; Examples of them are Corynebacterium bovis, C. mutissium, C. xerosis, C. hoffmani, Propionibacterium avidum, P. granulosum, Acinetobacter, yeast Malassezia furfur, Pityrosporum ovale and P. orbicular, as well as some groups of the Candida family, such as C. glabrata. The saprophyte parasite found in hair follicles, Demodex folliculorum, can be pathogenic.

The transient flora of the skin is mainly represented by Gram-positive bacteria, such as group A Streptococcus, Staphylococcus aureus and the Neisseria genus or fungal flora such as Candida albicans, which is considered pathogenic when it is isolated on the skin.

The normal flora of the skin can be modified by several environmental factors, such as humidity and temperature, age, sex and race, since the characteristics of the skin vary between people, which favors the colonization and proliferation of certain groups of microorganisms . The colonization of the skin depends on the particular characteristics of each topographic area of the body, and the predominance of certain groups of microorganisms also varies according to the latter. In the scalp, for example, there is mixed flora, with bacteria, fungi and parasites, such as Pityrosporum ovale, Staphylococcus, Corynebacterium and Demodex folliculorum. Different groups of microorganisms from the axillary and perianal region, vulva or interdigital spaces can be isolated.

When this microbiological barrier is weakened or destroyed, as in the case of eczema, irritation or aggressive skin treatments, pathogenic microorganisms can colonize the skin or even cross it, thus escaping the non-specific defense mechanisms of the skin. In this way, the presence of cutaneous microbial flora provides the skin with a defense barrier against pathogenic microorganisms due to a phenomenon of nutritional competition and the secretion of substances with enzymatic and / or bactericidal activity.

The proliferation of pathogenic microorganisms such as, for example, Staphylococcus aureus, Streptopyogenes or Propionibacterium acnes or some yeasts implies a deregulation of the cutaneous flora system and can lead to more serious disorders or pathologies in the skin, mucous membranes, scalp and / or nails such as eczema, candidiasis, dermatitis, onychomycosis or dermatosis among others. Also, in wound healing processes there is always a risk of infection, because the defense mechanisms of the skin, mucous membranes, scalp and / or nails are reduced. Wounds may be the result of physical injuries such as cuts, abrasions, burns, irritations, scrapes or exposure to chemical agents, among others, as a result of surgical processes such as surgical incisions or skin grafts among others, as well as result of pathologies and even chronic conditions such as for example diabetic ulcers or venous ulcers among others. In a wound, the amount of inoculum of pathogenic microorganism, the virulence of said pathogens and the host defense mechanisms will determine if the wound will develop an infection, so that during the healing processes the treatment with bactericidal compounds or compounds that stimulate host defenses are therapeutically useful [Edlich, RF, Kenney JG, Morgan RF, Nichter LS, Friedman HI and Rodeheaver G.T. (1986) "Antimicrobial treatment of minor soft tissue lacerations: a critical

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review "Emerg. Med. Clin. of North Am .. 4: 561-80].

In the same way, the growth of pathogenic microorganisms, and specifically the proliferation of Pseudomonas aeruginosa, can also affect the ocular mucous membranes, leading to ocular infections that can produce corneal ulcers. The risk of eye infections increases not only because of poor hygiene habits, especially of the hands, but also because of the daily use of contact lenses [Buehler PO, Schein OD, Stamler JF, Verdier DD and Katz J. (1992) " The increased risk of ulcerative keratitis among disposable soft contact lens users "Arch. Ophthalmol. 110: 1555-1558; Wilhelmus K.R. (1987) "Review of clinical experience with microbial keratitis associated with contact lenses" CLAO J. 13: 211-214].

Some people have a specific risk of getting infections in the skin, mucous membranes, scalp and / or nails because they have a suppressed immune system, such as patients with AIDS or those who are undergoing chemotherapy or radiation therapy. due to carcinogenic processes [Epstein JB and Chow A.W. (1999) "Oral complications associated with immunosuppression and cancer therapies" Infect. Dis. Clin. North Am. 13: 901-23]. In the same way, those in stressful situations often have a suppressed immune system that makes them susceptible to infections in the skin, mucous membranes, scalp and / or nails [Biondi M. and Zannino L.G. (1997) "Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in animals and man: a review" Psychother Psychosom. 66: 3-26].

Bromhidrosis or foul odor is the result of the proliferation of microorganisms in the skin, especially in areas of the skin with a high degree of perspiration, such as armpits, genitals or feet. [Leyden J.J., McGinley K.J., Holzle E., Labows J.N. and Kligman A.M. (1981) "The microbiology of the human axilla and its relationship to axillary odor" J. Invest. Dermatol 77: 413-6]. The characteristic and unpleasant smell of sweat is the result of the breakdown of sweat and wet skin by bacteria and yeasts, and the consequent release of malodorous substances such as steroids, and can be treated with compounds that control or reduce the population microbial of the area in which perspiration occurs [Elsner P. (2006) "Antimicrobials and the Skin Physiological and Pathological Flora" Curr. Probl. Dermatol 33: 35-41].

Another result of the proliferation of microorganisms in the oral cavity is halitosis or bad smell from the mouth. 85% -90% of the origin of halitosis is in oral causes such as periodontal conditions, dentures and poorly adapted restorations or poor dental hygiene. The microflora of the dorsal surface of the tongue and most Gram-negative anaerobic bacteria break down food debris between the teeth, remnants of oral or blood or saliva mucosa cells, producing volatile substances such as simple fatty acids such as acid Butyric acid, propionic acid or valeric acid and sulphurous components such as methylmercaptane or hydrogen sulphide, or protein derivatives such as putrescine and cadaverine. The microorganisms that cause halitosis include Treponema denticola, Prevotella intermedia, Porphyromonas gingivalis, Bacteroides forsythus, Fusobacterium periodonticum or Stomatococcus mucilaginus among others [De Boever E.H. and Loesche W.J. (1995) "Assessing the contribution of anaerobic microflora of the tongue to oral malodor" J. Am. Dent. Assoc. 126: 1384-1393; De Boever E.H., De Uzeda M. and Loesche W.J. (1994) "Relationship between volatile sulfur compounds, BANA-hydrolyzing bacteria and gingival health in patients with and without complaints of oral malodor" J. Clin. Dent. 4: 114-119; Kozlovsky A., Gordon D., Gelemter I., Loesche W.J. and Rosenberg M. (1994) "Correlation between the BANA test and oral malodor parameters" J. Dent. Res. 73: 1036-1042]. To control the bad smell of oral origin, the treatment should be directed towards the elimination of these microorganisms, so that the compounds that control or reduce the microbial population of the oral area will be useful in the treatment of halitosis.

Likewise, the proliferation of pathogenic microorganisms can be reinforced by the reduction of natural mammalian defense systems, and specifically by the reduction of the expression of defensin, the defensins being specific proteins against infections that are located in the skin and mucous membranes. .

Defensins are a class of natural antimicrobial peptides present in plants, insects and in different mammals, including humans. They are small molecules of approximately 30-40 amino acids, which have in common a large number of positively charged amino acids such as arginine, as well as the presence of cysteine residues that form disulfide bonds that give them their three-dimensional structure that contains a set of sheets p antiparallels as a motive [Martin E., Ganz T. and Lehrer RI (1995) "Defensins and other endogenous peptide antibiotics of vertebrates" J. Leukocyte Biol. 58: 128-133; Ganz T. and Lehrer R.I. (1994) "Defensins" Curr. Immunol opinion. 6: 584-589].

In mammals, defensins are classified into two families, according to the pattern of disulfide bonds they have [Harder J., Bartels J., Christophers E. and Schroder J.M. (2001) "Isolation and characterization of human p-defensins-3, a novel inducible peptide antibiotic" J. Biol. Chem. 276: 5707-5713]. In the case of human beings, a-defensins or HNP have three links disulfide between Cys1-Cys6, Cys2-Cys4 and Cys3-Cys5 cysteine residues and are located in neutrophils (HNP1 to HNP4) and in the gastrointestinal tract (HNP5 and HNP6). Human p-defensins or hBDs have three disulfide bonds between Cys1-Cys5, Cys2-Cys4 and Cys3-Cys6 cysteine residues are constitutively expressed in keratinocytes and are located in the kidney, pancreas, saliva, lungs, placenta and skin (hBD1), in the skin, the trachea and lungs (hBD2), in the skin, the trachea, tonsils and tongue (hBD3) and in the testicles and stomach (hBD4).

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HBD2 and hBD3 are the only human defensins that are inducible and are regulated at the transcriptional level in response to contact with microorganisms. These hBDs are overexpressed by differentiated keratinocytes in those places where inflammation and / or infection occurs [Harder J., Bartels J., Christophers E. and Schroder J.M. (1997) "An antibiotic peptide of human skin" Nature 387: 86l]. The proposed mechanism of action for hBD2 is the binding to the target bacterium and its subsequent insertion into the lipid membrane of the microbe, altering the permeability of the membrane and therefore its internal homeostasis. HBD2 is highly effective in killing Gram-negative bacteria, while it only has bacteriostatic activity against Gram-positive bacteria. The spectrum of hBD3 is broader than that of hBD2 and is effective as a bactericide against different Gram-positive and Gram-negative bacteria [Harder J., Bartels J., Christophers E. and Schroder J.M. (2001) "Isolation and characterization of human p-defensin-3, a novel inducible peptide antibiotic" J. Biol. Chem. 276: 5707-5713; Garcia J.R., Jaumann F., Schukz S., Krause A., Rodríguez-Jiménez J., Forssmann U., Adermann K., Kluver E., Vogelmeier C., Becker D., Hedrich R., Forssmann W.G. and Bals R. (2001) "Identification of a novel, multifunctional p-defensin (human p-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction" Cell Tissue Res. 306: 257-264].

There is a direct correlation between the expression of hBD and the incidence of infections in humans. hBD1 and hBD2 are widely expressed in samples of oral inflammation tissue, as well as in primary oral keratinocytes [Harder J., Bartels J., Christophers E. and Schroder J.M. (2001) "Isolation and characterization of human p-defensins-3, a novel inducible peptide antibiotic" J. Biol. Chem. 276: 5707-5713]. In addition, the skin of patients affected by psoriasis, in which epithelial hBDs are overexpressed, has relatively low infection statistics, while in patients with atopic dermatitis, in which hBD expression is suppressed, the lesions are easily infected [Nomura I., Goleva E., Howell MD, Hamid QA, Ong PY, Hall CF, Darse MA, Gao B., Boguniewicz M., Travers JB and Leung D.Y. (2003) "Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes" J. Immunol. 171: 3262-3269; Ong P.Y., Ohtake, T., Brandt C., Strickland I., Boguniewicz M., Ganz T., Gallo R.L. and Leung D.Y. (2002) "Endogenous antimicrobial peptides and skin infections in atopic dermatitis" N. Engl. J. Med. 347: 1151-1160].

The pharmaceutical industry has focused its efforts on the development of a potent pharmacological collection of compounds with bactericidal and / or fungicidal activity to treat infections of the skin, mucous membranes, scalp and / or nails. Such treatments are not free of side effects and also have the disadvantage that their continued use leads to the resistance of pathogenic microorganisms against said compounds. Therefore, it is necessary to develop compounds that control the proliferation of pathogenic microorganisms in the skin, mucous membranes, scalp and / or nails in a more natural, safe and effective way.

A valid alternative to classical treatment with bactericidal and / or antifungal compounds is the induction of endogenous organisms defense systems and, specifically, the induction of endogenous p-defensin expression. The prior art describes that the expression of hBD2 and hBD3 is inducible and can be stimulated by bacteria or yeast extracts [Harder J., Bartels J., Christophers E. and Schroder J.M. (1997) "A peptide antibiotic from human skin" Nature 387: 861], by isoleucine [Fehlbaum P., Rao M., Zasloff M. and Anderson GM (2000) "An essential amino acid induces epithelial p-defensin expression" PNAS 97: 12723-12728] or by alkylamines [Bukowski JF, Morita CT and Brenner M.B. (1999) "" Human gamma delta T cells recognize alkylamines derived from microbes, edible plants, and tea: implications for innate immunity innate "Immunity 11: 57-65].

Different patents and applications describe the use of plant extracts as agents that induce p-defensin expression. Application FR 2,843,125 A1 of Coletica S.A. and YSL Beauté describes the use of certain plant extracts, including boldo extract, as well as the use of vitamin A and its precursors, a-MSH and its peptide fragments or analogues, calcium and its salts or esters of isoleucine as stimulators of the production of hBD, with the commitment that they do not stimulate the production of proinflammatory molecules and their application in the cosmetic and pharmaceutical field as antifungal or antibacterial agents. International application WO 2005/077349 A1 of Otsuka Pharmaceuticals Co. describes the use of different plant extracts, protein hydrolysates, amino acids, enzymes or proteins as agents that induce hBD synthesis and its use in the cosmetic, food or pharmaceutical field . JP Patent Application 2005-270117 A of Morinaga Co. also describes the use of different plant extracts as agents that stimulate hBD expression.

Other documents such as US Patent Application 2004/0259795 A1 of Gemma Biotechnology Ltd. describe the use of proteins such as milk protein CD14 or its fragments as agents that stimulate defensin synthesis and its application as a medicament or dietary agent for reduce symptoms of sepsis.

The state of the art also describes certain types of small molecules that are capable of inducing hBD synthesis. International application WO 01/68085 A1 of Genaera Corp. and United States Patent Application 2002/0076393 A1 of Magainina Pharmaceuticals Inc. describes the use of the amino acids isoleucine or valine, its stereoisomers and some analogs of said amino acids in the treatment or prevention of infectious diseases through the induction of hBD expression. Similarly, Application EP 1,671,629 A1, also from Otsuka Pharmaceuticals Co., describes the use of certain organic acids, specifically fumaric, malic, citric, ascorbic, lactic, acetic, adipic, tartaric, cinnamic, glutamic or succinic acids such as hBD expression inducers International Patent Application WO 2005/115403 A2 of the Cedars Sinai Medical Center describes a procedure for treating a condition comprising the administration of vitamin D3 or its analogues as

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endogenous stimulators of hBD production and its use in the pharmaceutical or dermopharmaceutical field. The Patent Application FR 2,896,691 A1 of Pierre Fabre Dermo-Cosmétique S.A. describes the use of alkylglucoside esters as inducers of hBD expression and their use in the dermatological or dermocosmetological field.

In the same way, it is known in the state of the art that some microorganisms or microorganism extracts have an efficacy that induces the endogenous expression of hBD. US Patent Application 2005/0196480 A1 by Estee Lauder Companies describes the use of Lactobacillus extracts as stimulators of hBD production, and its application in the cosmetic field for the reduction of skin microflora, acne treatment and reduction of the sensitivity of sensitive skin. International Patent Application WO 2004/055041 A2 of Case Western Reserve University describes a defensin stimulating composition comprising a 12 kDa defensin-inducing peptide associated with fusobacteria and its use for the treatment of infections caused by the human immunodeficiency virus. L'Oréal Application FR 2,879,452 A1 describes the induction capacity of hBD synthesis of a non-photosynthetic, non-fruiting filamentous bacterium, and its use in the cosmetic field. US Patent 6,984,622 B2 of The Regents of the University of California describes the use of lipopolysaccharide or its fragments as agents that stimulate the expression of hBD for the treatment or prevention of eye infections and eye wounds. International Application WO 2007/020884 A1 of Meiji Dairies Corp. describes the use of bifidobacteria and lactic acid bacteria extracts for infection prevention by increasing endogenous levels of p-defensin. JP Patent Application 2006-241023 A of Asahi Breweries Ltd. describes the use of mannose-rich yeast as an agent that induces the synthesis of defensin and its use in the pharmaceutical and food field.

WO 2004/055041 A, GB 2166139A, WO 01/31019 A2, EP 0358485 A2, WO 00/11028 A2, EP 1690869 A1, WO 91/05048 A1, WO 2008/109833 A2, US 2005/181464 A1, WO 2008 / 041863 A1, WO 2007/041689 A2, Judd AK et al. (2004), J. Peptide Res. 64:87, Siemoneit K. et al. (1995), Clinical and Experimental Immunology 101: 278, De Cerio A.L.-D. (1999), International Immunology, 11: 2025, Yang D. et al. (1993), Immunology 78: 582, and Eckard C.P. et al. (2001), Molécules 6: 448 describe peptides that are different from those of the present invention.

None of the documents known in the state of the art describe peptides not derived from natural products capable of inducing hBD expression.

Summary of the invention

The present invention provides a solution to the problem mentioned above. The applicant of the present invention has surprisingly discovered that certain peptide derivatives, whose amino acid sequence is not derived from natural products, are capable of inducing the expression of hBD, particularly the expression of p-defensin-2 and / or p-defensin- 3 human.

The peptide derivatives of the present invention therefore provide a simple, effective and risk-free solution for the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails, which comprises application to the skin, to mucous membranes, scalp and / or nails or oral or parenteral administration to a mammal of a peptide derivative of general formula (I) as defined below.

Peptide derivatives are described according to the general formula (I)

R1-AA1-AA2-AA3-AA4-R2 (I)

their stereoisomers, mixtures thereof, or their cosmetically or pharmaceutically acceptable salts, characterized in that:

AA1 is selected from the group consisting of -Glu- and -Arg-;

AA2 is selected from the group consisting of -Met-, -Ahx and -Phg-;

AA3 is selected from the group consisting of -Ala- and -Phg-;

AA4 is selected from the group consisting of -Ile- and a single link;

R1 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, or unsubstituted aralkyl, and R5 -CO)-; Y

R2 is selected from the group consisting of -NR3R4, -OR3 and -SR3; wherein R3 and R4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted aryl and substituted or unsubstituted aralkyl replaced;

wherein R5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl replaced.

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In a first aspect, the invention relates to a peptide derivative as defined in claim 1.

Another aspect of the present invention is a process for obtaining these peptide derivatives of general formula (I) as defined in claim 1.

Another aspect of the present invention is directed to a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide derivative of general formula (I) as defined in claim 1, its stereoisomers, mixtures thereof or its cosmetic derivatives and pharmaceutically acceptable salts and at least one cosmetic or pharmaceutically acceptable excipient or adjuvant.

In another aspect, the invention is directed to a peptide derivative of general formula (I) as defined in claim 1, its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts, for use in the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails.

Detailed description of the invention

The peptide derivatives of the invention are synthetic peptide derivatives, not derived from natural products, which, as shown in the examples, have an important inducing activity of p-defensin and are therefore useful for the treatment, care and prevention of diseases, disorders and / or pathologies of the skin, mucous membranes, scalp and / or nails, resulting from the proliferation of microorganisms or that are at risk of proliferation of microorganisms.

Definitions

In order to facilitate the understanding of the present invention, the meanings of some terms and expressions as used in the context of the invention are included.

In the present description, the abbreviations used for amino acids follow the rules of the IUPAC-IUB Commission on biochemical nomenclature specified in Eur. J. Biochem. (1984) 138, 9-37 and in J. Biol. Chem. (1989) 264, 633-673.

Thus, for example, Gly represents NH2-CH2-C (O) -OH, Gly- represents NH2-CH2-C (O) -, -Gly represents -NH-CH2- C (O) -OH and -Gly- represents -NH-CH2-C (O) -. The hyphen, which represents the peptide bond, therefore, removes the OH from the amino acid 1-carboxyl group (represented here in the conventional non-ionized form) when placed to the right of the symbol and removes the H from the 2-amino group of the amino acid when placed to the left of the symbol; both modifications can be applied to the same symbol (see Table 1).

Table 1

Symbol

Residue

Symbol

Residue

-Glu-

image 1

-Phg-

image2

-Arg-

image3

-To-

image4

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 -Met-

 i_i 0 * <r / S -Ile- i_i or

 -Ahx

 And i

The abbreviation "Ac-" is used in the present description to designate the acetyl group (CH3-C (O) -) and the abbreviation "Palm-" is used to designate the palmitoyl group (CH3- (CH2) -mC (O ) -).

The term "non-cyclic aliphatic group" is used in the present invention to cover, for example, linear or branched alkyl, alkenyl and alkynyl groups.

The term "alkyl group" refers to a saturated linear or branched group having between 1 and 24, preferably between 1 and 16, even more preferably between 1 and 14, even more preferably between 1 and 12, even more preferably 1, 2 , 3, 4, 5 or 6 carbon atoms and that is attached to the rest of the molecule by means of a single bond, including, for example, methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl and 5-methylhexyl.

The term "alkenyl group" refers to a group having between 2 and 24, preferably between 2 and 16, even more preferably between 2 and 14, even more preferably between 2 and 12, even more preferably 2, 3, 4, 5 or 6 carbon atoms, with one or more carbon-carbon double bonds, preferably with 1, 2 or 3 carbon-carbon double bonds, conjugated or unconjugated, which binds to the rest of the molecule by means of a single bond, including , for example, the vinyl, oleyl and linoleyl group.

The term "alkynyl group" refers to a group having between 2 and 24, preferably between 2 and 16, even more preferably between 2 and 14, even more preferably between 2 and 12, even more preferably 2, 3, 4, 5 or 6 carbon atoms with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, which are attached to the rest of the molecule by means of a single bond, including, by For example, the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentinyl group, such as, for example, 1-pentinyl.

The term "alicyclyl group" is used in the present invention to cover, for example, cycloalkyl or cycloalkenyl or cycloalkynyl groups.

The term "cycloalkyl" refers to a mono- or polycyclic saturated aliphatic group having between 3 and 24, preferably between 3 and 16, even more preferably between 3 and 14, even more preferably between 3 and 12, even

more preferably 3, 4, 5 or 6 carbon atoms and that is attached to the rest of the molecule by means of a bond

simple, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahydroindene, decahydronaphthalene, and dodecahydrofenalene.

The term "cycloalkenyl" refers to a non-aromatic mono- or polycyclic aliphatic group having between 5 and 24, preferably between 5 and 16, even more preferably between 5 and 14, even more preferably between 5 and 12, still more preferably 5 or 6 carbon atoms, with one or more carbon-carbon double bonds, preferably 1.2 or 3 carbon-carbon double bonds, conjugated or unconjugated, and which is attached to the rest of the molecule by means of a single bond, including , for example, the cyclopent-1-en-1-yl group.

The term "cycloalkynyl" refers to a non-aromatic mono- or polycyclic aliphatic group having between 5 and 24,

preferably between 5 and 16, even more preferably between 5 and 14, even more preferably between 5 and 12, even

more preferably 5 or 6 carbon atoms, with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, and which is attached to the rest of the molecule by means of a bond simple, including, for example, the cyclohex-1-in-1-yl group.

The term "aryl group" refers to an aromatic group having between 6 and 30, preferably between 6 and 18, even more preferably between 6 and 10, even more preferably 6 or 10 carbon atoms, comprising 1, 2, 3 or 4 aromatic nuclei, linked by means of a carbon-carbon bond or condensate, including, for example, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthranyl, among others; or to an aralkyl group.

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The term "aralkyl group" refers to an alkyl group substituted with an aromatic group, which has between 7 and 24 carbon atoms and includes, for example, - (CH2) 1-6-phenyl, - (CH2) 1-6 - (1-naphthyl), - (CH2) 1-6- (2-naphthyl) and - (CH2) 1-6- CH (phenyl) 2.

The term "heterocyclyl group" refers to a 3 to 10 membered hydrocarbon ring, in which one or more ring atoms, preferably 1, 2 or 3 ring atoms, is a non-carbon element, such as nitrogen , oxygen or sulfur and that can be saturated or unsaturated. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic cyclic system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms may optionally be oxidized in the heterocyclyl radical; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or totally saturated or aromatic. The term "heterocyclyl" refers more preferably to a 5 or 6 membered ring.

The term "heteroarylalkyl group" refers to an alkyl group substituted with a substituted or unsubstituted aromatic heterocyclyl group, the alkyl group having 1 to 3 carbon atoms and the aromatic heterocyclyl group having between 2 and 24 carbon atoms and of 1 to 3 different carbon atoms and including, for example, - (CH2) 1-6-imidazolyl, - (CH2) 1-6-triazolyl, - (CH2) 1-6-thienyl, - (CH2) 1-6 -furyl, and - (CH2) 1-6-pyrrolidinyl.

As understood in this technical area, there may be a certain degree of substitution on the previously defined radicals. Therefore, there may be substitution in any of the groups of the present invention. References herein to substituted groups in the groups of the present invention indicate that the specified radical may be substituted in one or more positions available with one or more substituents, preferably in 1, 2 or 3 positions, more preferably in 1 or 2 positions, even more preferably in 1 or 2 positions, even more preferably in 1 position. Such substituents include, for example, C1-C4 alkyl; hydroxyl; C1-C4 alkoxy; amino; C1-C4 aminoalkyl; C1-C4 carbonyloxy; C1-C4 oxycarbonyl; halogen such as fluorine, chlorine, bromine and iodine; cyano; nitro; azido; C1-C4 alkylsulfonyl; thiol; C1-C4 alkylthio; aryloxy such as phenoxy; - NRb (C = NRb) NRbRc; wherein Rb and Rc are independently selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl, C6-C18 aryl, C7-C17 aralkyl, 3-10 heterocyclyl members or

amino group protecting group.

Compounds of the invention

The compounds of the invention are defined by the general formula (I)

R1-AA1-AA2-AA3-AA4-R2 (I)

wherein R1, AA1, AA2, AA3, AA4 and R2 have the meaning defined in claim 1.

The reference to "single bond" in the case of AA4 means that the amino acid is absent in this case. Therefore, the peptide derivatives of the invention are tetrapeptide derivatives if AA4 is present or tripeptide derivatives if AA4 is a single bond.

The R1 and R2 groups are linked to amino-terminal and carboxy-terminal ends of the peptide sequences.

According to an embodiment of the present invention, the groups AA1, AA2, AA3 and AA4 are derived from amino acids with an L (levogyrate) configuration. Preferably, R1 is selected from H, acetyl, tert-butanoyl, hexanoyl, 2- methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl. Even more preferably, R1 is H, acetyl, lauroyl, myristoyl or palmitoyl. Even more preferably, the radicals R 1 are acetyl or palmitoyl.

In a preferred embodiment, R2 is selected from the group consisting of -NR3R4 and -OR3, in which R3 and R4 are the same or different. More preferably, R3 and R4 are selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. More preferably, R3 is H and R4 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. Even more preferably, R2 is selected from -OH and -NH2. Even more preferably, R1 is acetyl and R2 is -OH.

According to an embodiment of the present invention, AA1 is -Glu-, AA2 is -Met-, AA3 is -Ala- and AA4 is -Ile-.

According to another embodiment of the present invention, AA1 is -Arg-, AA2 is -Ahx-, AA3 is -Ala- and AA4 is a single bond.

According to another embodiment of the present invention, AA1 is -Arg-, AA2 is -Phg-; AA3 is -Phg- and AA4 is a simple link.

According to another embodiment of the present invention, R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl, AA1 is -L-Glu-, AA2 is -L-Met-, AA3 is -L-Ala -, AA4 is -L-Ile- and R2 is -NR3R4 or -OR3, in which R3 and R4 are independently selected from the groups H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R2 is -OH or -NH2 . Even more preferably, R1 is acetyl and R2 is -OH.

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According to another embodiment of the present invention, R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl, AA1 is -L-Arg-, AA2 is -Ahx-, AA3 is -L-Ala-, AA4 is a single bond and R2 is - NR3R4 or -OR3, where R3 and R4 are independently selected from the groups H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R2 is -OH or -NH2. Even more preferably, R1 is acetyl and R2 is -OH.

According to another embodiment of the present invention, R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl, AA1 is -L-Arg-, AA2 is -L-Phg- or -D-Phg-, AA3 is -L-Phg- or -D-Phg-, AA4 is a single bond and R2 is -NR3R4 or -OR3, where R3 and R4 are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl groups , preferably R2 is -OH or -NH2. Even more preferably, R1 is acetyl and R2 is -OH.

The compounds of formula (I) are preferably selected from the group consisting of:

Ac-Arg-Phg-Phg-OH,

Ac-Glu-Phg-Ala-OH,

Ac-Arg-Phg-Ala-Ile-OH,

Ac-Arg-Ahx-Phg-Ile-OH,

H-Glu-Met-Ala-Ile-OH,

Ac-Arg-Met-Phg-Ile-OH,

Ac-Arg-Phg-Ala-OH,

Ac-Glu-Phg-Ala-Ile-OH,

Ac-Glu-Met-Phg-Ile-OH,

Ac-Arg-Ahx-Ala-OH,

Ac-Arg-Phg-Phg-NH- (CH2) 15-CH3,

Palm-Glu-Met-Ala-Ile-NH2,

Ac-Arg-Ahx-Ala-Ile-OH,

Ac-Arg-Phg-Phg-Ile-OH,

Ac-Glu-Phg-Phg-Ile-OH,

Ac-Arg-Met-Ala-Ile-OH,

Y

Ac-Glu-Met-Ala-Ile-OH.

The peptide derivatives of the present invention may exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids that form them can have an L-, D- configuration, or they can be racemic independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemic mixtures or diastereomeric mixtures, or pure diastereoisomers or enantiomers, depending on the number of asymmetric carbons and on which isomers or isomeric mixtures are present. Preferred structures of the peptide derivatives of the invention are pure isomers, that is, enantiomers or diastereoisomers.

For example, when it is indicated that AA1 may be -Glu-, it is understood that AA1 is selected from -L-Glu-, -D-Glu- or racemic or non-racemic mixtures of both. Similarly, when it is indicated that AA2 may be -Met-, it is understood that it may be -L-Met-, -D-Met- or racemic or non-racemic mixtures of both. The methods described herein allow the person skilled in the art to obtain each of the stereoisomers of the peptide derivative of the invention by choosing the amino acid with the appropriate configuration.

Therefore, the compounds of formula (I) are even more preferably selected from the group consisting of:

Ac-L-Arg-L-Phg-L-Phg-OH,

Ac-L-Arg-L-Phg-D-Phg-OH,

Ac-L-Arg-D-Phg-L-Phg-OH,

Ac-L-Arg-D-Phg-D-Phg-OH,

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Ac-L-Glu-L-Phg-L-Ala-OH,

Ac-L-Glu-D-Phg-L-Ala-OH,

Ac-L-Arg-L-Phg-L-Ala-L-Ile-OH,

Ac-L-Arg-D-Phg-L-Ala-L-Ile-OH,

Ac-L-Arg-Ahx-L-Phg-L-Ile-OH,

Ac-L-Arg-Ahx-D-Phg-L-Ile-OH,

H-L-Glu-L-Met-L-Ala-L-Ile-OH,

Ac-L-Arg-L-Met-L-Phg-L-Ile-OH,

Ac-L-Arg-L-Met-D-Phg-L-Ile-OH,

Ac-L-Arg-L-Phg-L-Ala-OH,

Ac-L-Arg-D-Phg-L-Ala-OH,

Ac-L-Glu-L-Phg-L-Ala-L-Ile-OH,

Ac-L-Glu-D-Phg-L-Ala-L-Ile-OH,

Ac-L-Glu-L-Met-L-Phg-L-Ile-OH,

Ac-L-Glu-L-Met-D-Phg-L-Ile-OH,

Ac-L-Arg-Ahx-L-Ala-OH,

Ac-L-Arg-L-Phg-L-Phg-NH- (CH2) 15-CH3,

Ac-L-Arg-L-Phg-D-Phg-NH- (CH2) 15-CH3,

Ac-L-Arg-D-Phg-L-Phg-NH- (CH2) 15-CH3,

Ac-L-Arg-D-Phg-D-Phg-NH- (CH2) 15-CH3,

Palm-L-Glu-L-Met-L-Ala-L-Ile-NH2,

Ac-L-Arg-Ahx-L-Ala-L-Ile-OH,

Ac-L-Arg-L-Phg-L-Phg-L-Ile-OH,

Ac-L-Arg-L-Phg-D-Phg-L-Ile-OH,

Ac-L-Arg-D-Phg-L-Phg-L-Ile-OH,

Ac-L-Arg-D-Phg-D-Phg-L-Ile-OH,

Ac-L-Glu-L-Phg-L-Phg-L-Ile-OH,

Ac-L-Glu-L-Phg-D-Phg-L-Ile-OH,

Ac-L-Glu-D-Phg-L-Phg-L-Ile-OH,

Ac-L-Glu-D-Phg-D-Phg-L-Ile-OH,

Ac-L-Arg-L-Met-L-Ala-L-Ile-OH,

Ac-L-Glu-L-Met-L-Ala-L-Ile-OH, and

their mixtures or their cosmetically or pharmaceutically acceptable salts.

Cosmetically or pharmaceutically acceptable salts of the peptide derivatives provided by this invention are also within the scope of the present invention. The term "cosmetically or pharmaceutically acceptable salts" means a salt generally admitted for use in animals and more particularly in humans and includes salts used to form base addition salts, or inorganic base addition salts, such as for example lithium, sodium, potassium, calcium, magnesium or aluminum, among others, or organic base addition salts, such as, for example, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine,

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arginine, lysine, histidine or piperazine, among others, or acid addition salts, whether organic acid addition salts such as, for example, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate , succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate, among others, or inorganic acid addition salts, such as, for example, chloride, sulfate, borate or carbonate among others. The nature of the salt is not critical, provided it is cosmetically or pharmaceutically acceptable. Cosmetically or pharmaceutically acceptable salts of the peptide derivatives of the invention can be obtained by conventional procedures well known in the state of the art [Berge S.M., Bighley L.D. and Monkhouse D.C. (1977) "Pharmaceutical Salts" J. Pharm. Sci. 66: 1-19].

Preparation Procedures

The synthesis of the peptide derivatives of the invention, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be carried out in accordance with conventional procedures known in the state of the art, such as by solid phase peptide synthesis procedures [Stewart JM and Young J.D. (1984) "Solid Phase Peptide Synthesis, 2nd edition" Pierce Chemical Company, Rockford, Illinois; Bodanzsky M. and Bodanzsky A. (1984) "The practice of Peptide Synthesis" Springer Verlag, New Cork; Lloyd-Williams P., Albericio F. and Giralt E. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA], solution synthesis, a combination of solid phase synthesis and procedures of synthesis of enzymatic synthesis solutions or procedures [Kullmann W. (1980) "Proteases as catalysts for enzymic syntheses of opioid peptides" J.Biol.Chem. 255: 8234-8238]. Peptide derivatives can also be obtained by fermentation of a bacterial strain modified or unmodified by genetic engineering in order to produce the desired sequences, or by controlled hydrolysis of proteins of animal or plant origin, preferably of plant origin, which releases peptide fragments that It contains at least the desired sequence.

For example, a process for obtaining the peptide derivatives of the invention of formula (I) comprises the steps of:

to. Couple an amino acid with the protected N-terminal end and the free C-terminal end to an amino acid with the free N-terminal end and the protected C-terminal end or attached to a solid support;

b. Elimination of the protective group of the N-terminal end;

C. Repeat the coupling sequence and remove the protective group from the N-terminal end a.-b. until the desired sequence is obtained -AA1-AA2-AA3-AA4-sequence;

d. Elimination of the protective group of the C-terminal end or excision of the solid support.

The C-terminal end is preferably attached to a solid support and the process is carried out in a solid phase and therefore comprises coupling an amino acid with the protected N-terminal end and the free C-terminal end on an amino acid with the end. Free N-terminal and the C-terminal end attached to a polymeric support; remove the protective group from the N-terminal end; and repeat this sequence as many times as necessary in order to obtain a tripeptide or a tetrapeptide, finally followed by excision of the synthesized peptide from the original polymeric support.

The functional groups of the amino acid side chains, if any, are adequately protected with temporary or permanent protecting groups throughout the synthesis, and can be unprotected simultaneously or orthogonally with the process of the cleavage of the peptide from the polymeric support.

The solid phase synthesis can alternatively be carried out by means of a convergent strategy that couples a dipeptide or a tripeptide to the polymeric support or to a dipeptide or amino acid previously attached to the polymeric support. Convergent synthesis strategies are widely known to those skilled in the art and are described in Lloyd-Williams P., Albericio F. and Giralt E. in "Convergent solid phase peptide synthesis" (1993) Tetrahedron 49: 11065-11133.

An example of a process for obtaining the peptide derivatives of the invention of formula (I) R1-AA1-AA2-AA3-AA4-R2 (I)

understand the stages of

- sequentially reacting a fragment of formula (II)

PG1-AAn-OH (II)

having the free C-terminal carboxyl group or a reactive derivative thereof, in which PG1 is a protective group of the N-terminal group and AAn is an amino acid structural unit (-AA1-, -AA2- or -AA3-) as has been previously described, with a complementary fragment (III) having an amino group at the N-terminal end with at least one free hydrogen atom,

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H-AAm-Sop (III)

wherein Sop is a protective group or a solid support and AAm is an amino acid structural unit -AA3- or -AA4- as previously described, with the consequent formation of an amide bond and the expansion of the peptide chain in an amino acid to form the fragment of formula (IV),

PG1-AAn-AAm-Sop (IV)

- wash the fragment thus obtained,

- the cleavage of the protective group PG1 of the fragment thus formed to obtain a fragment (V) with the free N-terminal end and

H-AAn-AAm-Sop (V)

- repeat the coupling, washing and cleavage sequence of the protecting group as many times as necessary until obtaining a precursor of formula (VI)

PG-AA1-AA2-AA3-AA4-Sop (VI)

wherein PG is a protecting group, and Sop and AA1-AA2-AA3-AA4 have the meaning described above.

The process may comprise the additional steps of deprotection and / or excision of the fragment support (VI) for the N-terminal and C-terminal ends in an indifferent order, using standard procedures and conditions known in the art, after which functional groups of said ends can be modified. The optional modification of the amino and carboxy terminal ends can be carried out with the peptide of formula (I) anchored to the polymeric support or once the peptide has been cleaved from the polymeric support. For example, the N-terminal end can be deprotected first to give a fragment of formula (VII).

H-AA1-AA2-AA3-AA4-Sop (VII)

Optionally, other types of radicals R1 can be introduced by reacting (VII) with a compound R1-X, in which R1 has the meaning described above and X is a labile group, such as for example the tosyl, mesyl and halogen among others, by means of a nucleophilic substitution reaction in the presence of a suitable base and solvent and in which the functional groups of said fragments that do not participate in the formation of the NC bond, if any, are adequately protected with protective groups Temporary or permanent.

The resulting fragment can be deprotected or cleaved from the solid support, as appropriate, to provide a compound of formula (VIII), which is a peptide of formula (I) in which R2 is -OH, -NH2 or -SH. Optionally and / or additionally, other radicals R2 can be introduced by the reaction of a compound HR2 in which R2 is -OR3, -NR3R4 or -SR3, with a complementary fragment (IX) corresponding to the compound of formula (VIII) in which R2 is -OH

R1 -AA1 -AA2-AA3-AA4-OH (IX)

in the presence of a suitable solvent and a base such as for example N, N-diisopropylethylamine or triethylamine or an additive such as for example 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazole (HOAt) and a dehydrating agent, such as for example a carbodiimide, an uranium salt, a phosphonium salt or an amidinium salt, among others, or through the prior formation of an acyl halide with, for example, thionyl chloride, to thereby obtain a peptide derivative according to the invention of the general formula (I), in which the functional groups of said fragments that do not participate in the formation of the NC bond, if any, are adequately protected with temporary or permanent protecting groups, or alternatively other R2 radicals can be introduced by means of the simultaneous incorporation into the process to cleave the peptide derivative from the polymeric support.

One skilled in the art will readily understand that the deprotection / cleavage stages of the C and N-terminal ends and their subsequent derivation can be carried out in an indifferent order, according to processes known in the art [Smith, M.B. and March, J. (1999) "March's Advanced Organic Chemistry Reactions, Mechanisms and Structure", 5th Edition, John Wiley & Sons, 2001].

The term "protecting group" refers to a group that blocks an organic functional group and that can be removed under controlled conditions. Those skilled in the art know the protecting groups, their relative reactivities and the conditions in which they remain inert.

Examples of representative protecting groups for the amino group are amides, such as acetate amide, benzoate amide, pivalate amide; carbamates, such as benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl (pNZ), tert-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), 2- (trimethylsilyl) ethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc) -fluorenylmethyloxycarbonyl (Fmoc), among others; preferably Boc or Fmoc.

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Examples of representative groups for the carboxyl group are esters, such as tert-butyl ester (tBu), allyl ester (All), triphenylmethyl ester (trityl ester (Trt)), cyclohexyl ester (cHex), ester of benzyl (Bzl), o-nitrobenzyl ester, p-nitrobenzyl ester, p-methoxybenzyl ester, trimethylsilylethyl ester, among others; Preferred protecting groups of the invention are allyl, tert-butyl, cyclohexyl, benzyl and trityl esters.

The trifunctional amino acids, if any, are protected during the synthetic process with temporary or permanent orthogonal protecting groups with the amino- and carboxy-terminal protecting groups. The arginine guanidine group can be protected with 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl (Pbf), to- toluenesulfonyl (tosyl, Tos) or the 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) group, among others, and the carboxyl group of glutamic acid can be protected with the tert-butyl group (tBu), the trityl group ( Trt), the cyclohexyl group (cHex), the benzyl group (Bzl) or the allyl group (All), among others.

In a preferred embodiment, the strategy of the protective group used is the strategy in which the amino groups are protected by means of Boc, the carboxyl groups are protected by Bzl, cHex or All and the arginine side chain is protected with Mtr or Tos and the glutamic side chain with Bzl, cHex or All.

In another preferred embodiment, the strategy of the protective group used is the strategy in which the amino groups are protected by means of Fmoc, the carboxyl groups are protected by tBu, All or Trt and the arginine side chain is protected with Pmc or Pbf. and the glutamic side chain with tBu, All or Trt.

Examples of these and additional protecting groups, their introduction and their elimination are described in the literature [Greene T.W. and Wuts P.G.M., (1999) "Protective groups in organic synthesis" John Wiley Sons, New York; Atherton B. and Sheppard R.C. (1989) IRL Oxford University Press] .Solid Phase Peptide Synthesis: A practical approach. "The term" protecting groups "also includes polymeric supports used in solid phase synthesis.

When the synthesis is carried out totally or partially in the solid phase, solid supports to be used in the process of the invention can be mentioned: supports made of polystyrene, polystyrene grafted with polyethylene glycol and the like, such as for example p-methylbenzhydrylamine resins (MBHA) [Matsueda GR and Stewart J.M. (1981) "A p-methylbenzhydrylamine resin to improve solid phase synthesis of peptide amides" Peptides 2: 4550], 2-chlorotrityl resins [Barlos K., Cats D., Kallitsis J., Papaphotiu G., Sotiriu P., Wenqing Y. and Schafer W. (1989) "Darstellung geschützter Peptid-fragmente unter Einsatz substituierter Triphenylmethylharze" Tetrahedron Lett. 30: 3943-3946; Barlos K., Cats D., Kapolos S., Papaphotiu G., Schafer W. and Wenqing Y. (1989) "Veresterung von partiell geschützten Peptid-fragmenten mit Harzen. Einsatz von 2-Chlorotritylchlorid zur Synthese von Leu15 - gastrin I" Tetrahedron Lett. 30: 3947-3951], TentaGel® resins (Rapp Polymere GmbH), ChemMatrix® resins (Matrix Innovation, Inc) and the like, which may or may not include a labile linker such as 5- (4-aminomethyl-3,5- acid) valeric dimethoxyphenoxy) (PAL) [Albericio F., Kneib-Cordonier N., Biancalana S., Gera L., Masada RI, Hudson D. and Barany G. (1990) “Preparation and application of acid 5- (4- ( 9-fluorenylmethyloxycarbonyl) aminomethyl-3,5-dimethoxyphenoxy) -valeric (PAL) for solid phase synthesis of C-terminal amide peptide under mild conditions "J. Org. Chem. 55: 3730-3743], acid 2 - [4-aminomethyl- (2,4-dimethoxyphenyl)] phenoxyacetic (aM) [Rink H. (1987) Solid-phase synthesis of protected peptide fragments using to trialkoxy-diphenyl-methylester resin "Tetrahedron Lett. 28: 3787-3790], Wang [Wang S.S. (1973) "p-Alkoxybenzyl Alcohol Resin and p-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis of Protected Peptide Fragments" J.Am.Chem.Soc. 95: 1328-1333], allowing simultaneous deprotection and cleavage of the polymeric support peptide.

Cosmetic or pharmaceutical compositions

The peptide derivatives of the invention can be administered to stimulate the synthesis of hBD by any means that causes the contact of the peptide derivatives with the site of action thereof in the body of a mammal, preferably the body of humans, and in the form of a composition that contains them.

In this sense, another aspect of the invention is a cosmetic or pharmaceutical composition comprising at least one peptide derivative of general formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts together with at least one cosmetically or pharmaceutically acceptable adjuvant. Such compositions may be prepared by conventional procedures known to those skilled in the art ["Harry's Cosmeticology", Eighth edition (2000) Rieger M.M., ed., New York Chemical Pub., NY, US; "Remington: Science and Practice of Pharmacy", Twentieth edition (2003) Genaro A.R., ed., Lippincott Williams & Wilkins, Philadelphia, USA].

The peptide derivatives of the present invention have a variable water solubility, depending on the nature of their sequence or the possible modifications at the amino- and / or carboxy-terminal ends they have. The peptide derivatives of the present invention can therefore be incorporated into the compositions by means of an aqueous solution and those that are not soluble in water can be solubilized in conventional cosmetically or pharmaceutically acceptable solvents such as for example ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.

The cosmetic or pharmaceutically effective amount of the peptide derivatives of the invention that must be administered to treat a condition, disorder and / or pathology, as well as their dosage will depend on a series of

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factors, including the age, the patient's condition, the severity of the disorder or pathology, the route and frequency of administration and the particular nature of the peptide derivatives to be used.

A "cosmetic or pharmaceutically effective amount" is understood as a non-toxic but sufficient amount of peptide derivative or derivatives to provide the desired effect. The peptide derivatives of the invention are used in the cosmetic or pharmaceutical composition of the present invention in cosmetic or pharmaceutically effective concentrations to achieve the desired effect; preferably, with respect to the total weight of the composition, between 0.00000001% (by weight) and 20% (by weight); preferably between 0.000001% (by weight) and 20% (by weight), more preferably between 0.0001% (by weight) and 10% (by weight) and more specifically between 0.0001% (by weight) and 5 % (in weigh).

The peptide derivatives of the invention can also be incorporated into cosmetic or pharmaceutical sustained release systems and / or delivery systems.

The term "administration systems" refers to a diluent, adjuvant, excipient or vehicle with which the peptide derivative of the invention is administered. Such cosmetic or pharmaceutical vehicles can be liquids, such as water, oils or surfactants, including those of petroleum, animal, vegetable or synthetic origin, such as for example peanut oil, soybean oil, mineral oil, sesame oil, oils of castor, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylene, polyethylene glycols, dextrose and glycerol. "Remington's Pharmaceutical Sciences" by E.W. Martin describes diluents, adjuvants or excipients as suitable carriers.

The term "sustained release" is used in the conventional sense, in relation to an administration system for a compound that provides for the gradual release of said compound over a period of time and preferably, but not necessarily, with constant compound release levels. over a period of time.

Examples of sustained release or release systems are liposomes, miliparticles, microparticles, nanoparticles and solid lipid nanoparticles, sponges, vesicles, micelles, microspheres, microspheres and nanospheres, lipospheres, millicapsules, microcapsules and nanocapsules, as well as microemulsions and nanoemulsions, which can be add in order to achieve greater penetration of the active ingredient and / or improve its pharmacokinetic and pharmacodynamic properties.

Sustained release formulations can be prepared by methods known in the state of the art and the compositions containing them can be administered, for example, by topical administration, including adhesive patches and non-adhesive patches, or by systemic administration, such as for example by oral, nasal, rectal route, subcutaneous implantation or injection, or direct implant or injection into a specific part of the body, and should preferably release a relatively constant amount of the peptide derivatives of the invention. The amount of peptide derivative contained in the sustained release formulation will depend, for example, on the site of administration, on the kinetics and duration of release of the peptide derivative of the invention, as well as on the nature of the condition, disorder and / or pathology to treat or prevent.

The peptide derivatives of the present invention can also be adsorbed on solid organic polymers or solid mineral supports such as for example talc, bentonite, silica, starch or maltodextrin, among others.

The peptide derivatives of the invention can also be incorporated into tissues, nonwoven fabrics and medical devices that are in direct contact with the skin, mucous membranes, scalp and / or nails of the body, so as to release the peptide derivatives of the invention. either by the biodegradation of the tissue anchoring system, non-woven fabric or medical devices or by the friction of the latter with the body, by the body moisture, by the pH of the skin or by the body temperature. Similarly, fabrics and nonwoven fabrics can be used to make garments that are in direct contact with the body. Preferably, the tissues, nonwoven fabrics and medical devices containing the peptide derivatives of the invention are used for the treatment, care and / or cleaning of those skin conditions, disorders and / or pathologies resulting from the proliferation of microorganisms. or that are at risk of proliferation of microorganisms, or in the treatment of open wounds.

Examples of fabrics, nonwoven fabrics, clothing, medical devices and means for immobilizing peptide derivatives, including administration systems and / or sustained release systems described above, are described in the literature and are known in the state of the technique [Schaab CK (1986) ")" Impregnating Fabrics With Microcapsules ", HAPPi May 1986; Nelson G. (2002)" Application of microencapsulation in textiles "Int. J. Pharm. 242: 55-62;" Biofunctional Textiles and the Skin "(2006 ) Curr. Probl. Dermatol. V.33, Hipler UC and Elsner P., eds. S. Karger AG, Basel, Switzerland; Malcom RK, McCullagh SD, Woolfson AD, Gorman SP, Jones DS and Cuddy J. (2004) "Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial" J. Cont. Release 97: 313-320]. Preferred fabrics, non-woven fabrics, clothing and medical devices are bandages, gauze , t-shirts, socks, pantyhose, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bedspreads, wipes, hydrogels, adhesive patches, non-adhesive patches and / or facial masks.

Cosmetic or pharmaceutical preparations containing the peptide derivatives of the present invention, their

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stereoisomers, their mixtures or their cosmetically or pharmaceutically acceptable salts can be used in different types of topical or transdermal application formulations that will optionally include the cosmetically or pharmaceutically acceptable excipients necessary for the formulation of the desired pharmaceutical form [Faulí i Trillo C. (1993) in "Treaty of Farmacia Galenica", Luzán 5, SA Editions, Madrid].

Formulations of topical or transdermal application can be presented in any solid, liquid or semi-solid dosage form, such as, for example, creams, multiple emulsions such as for example oil and / or silicone emulsions in water, water in oil emulsions and / or silicone, water / oil / water or water / silicone / water type emulsions and oil / water / oil or silicone / water / silicone type emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels , hydroalcoholic solutions, liniments, serums, soaps, shampoos, ointments, foams, ointments, powders, sticks, pencils and sprayers or aerosols, including wash and rinse formulations. These formulations of topical or transdermal application can be incorporated by means of techniques known to those skilled in the art to different types of solid accessories such as for example wipes, hydrogels, adhesive patches, non-adhesive patches or facial masks, or they can be incorporated to different makeup line products, such as foundation for makeup, make-up lotions, make-up milks, correctors, eye shadows, lipsticks, lip protectors, bars and lip powders, among others. The cosmetic or pharmaceutical compositions containing the peptide derivatives of the present invention can also be incorporated into products for the treatment, care and / or cleaning of nails and cuticles such as nail polishes, nail removal lotions and lotion removal lotions. cuticles, among others.

The cosmetic or pharmaceutical compositions of the invention may include agents that increase the percutaneous absorption of the peptide derivatives of the present invention, such as, for example, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylazacycloheptan-2-one), alcohol, acetone, propylene glycol or polyethylene glycol, among others. The cosmetic or pharmaceutical compositions object of the present invention can also be applied to local areas to be treated by iontophoresis, sonophoresis, electroporation, occlusive treatment, microinjections or needle-free injections by means of pressure, such as pressure injections of oxygen or any combination thereof, in order to achieve greater penetration of the peptide derivative of the invention. The area of application will be determined by the nature of the condition, disorder and / or pathology to be prevented or treated.

The cosmetic compositions containing the peptide derivatives of the present invention, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can also be used in different types of formulations for oral administration, preferably in the form of oral cosmetics, such as capsules, including capsules, gelatin, tablets, including sugar-coated tablets, powders, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, jellies or jellies, as well as in any other presentation known to a person skilled in the art. In particular, the peptide derivatives of the invention can be incorporated into any form of functional food or fortified food, such as for example, in nutritive bars or in compact or non-compact powders. Such powders can be solubilized in water, soda, dairy products, soy derivatives, or they can be incorporated into nutritional bars. The peptide derivatives of the present invention can be formulated with the usual excipients and adjuvants for oral compositions or food supplements, such as, for example, fatty components, aqueous components, humectants, preservatives, texturizers, flavors, aromas, antioxidants and dyes common in The food industry.

The cosmetic or pharmaceutical compositions containing the peptide derivatives of the invention, their stereoisomers, their mixtures or their cosmetically or pharmaceutically acceptable salts can be administered topically or transdermally in addition to any other suitable route, for example orally or parenteral route. , for which purpose they will include the pharmaceutically acceptable excipients necessary for the formulation of the desired dosage form. In the context of the present invention, the term "parenteral" includes the nasal route, the rectal route, subcutaneous injections, intradermal injections, intravascular injections, such as for example intravenous, intramuscular, intravitreal, spinal, intracranial, intraarticular, intrathecal and intraperitoneal, as well as any other similar injection or infusion technique. A review of the different pharmaceutical dosage forms of active ingredients and of the excipients necessary to obtain it is found, for example, in the Galician Pharmacy Treaty, C. Faulí i Trillo, 1993, Luzán 5, S.A. Editions, Madrid.

Cosmetic or pharmaceutically acceptable adjuvants contained in the cosmetic or pharmaceutical compositions described in the present invention include additional ingredients commonly used in compositions for the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails, such as, for example, agents that stimulate or inhibit the synthesis of melanin, bleaching or depigmenting agents, propigmentation agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, antioxidant agents, free radical scavengers and / or atmospheric antipollution agents, glycation antiagents, emulsifying agents, emollients, organic solvents, propellant liquids, skin conditioners such as, for example, humectants, moisture-retaining substances, alpha hydroxy acids, beta hydroxy acids, humectants, vitamins, pigments or dyes dyes gelific before, thickeners, surfactants, softeners, anti-wrinkle agents, agents capable of reducing or treating eye bags, exfoliating agents, antimicrobial agents, fungicidal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents that stimulate the synthesis of dermal macromolecules or

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epidermal and / or capable of inhibiting or preventing its degradation, such as collagen synthesis stimulating agents, elastin synthesis stimulating agents, decorin synthesis stimulating agents, laminin synthesis stimulating agents, others agents that stimulate the synthesis of defensin, agents that stimulate the synthesis of chaperone, agents that stimulate the synthesis of hyaluronic acid, agents that stimulate the synthesis of lipids and components of the stratum corneum (ceramides, fatty acids, etc.), agents that inhibit collagen degradation, agents that inhibit elastin degradation, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate keratinocyte differentiation, agents that stimulate angiogenesis, relaxant agents the skin, agents that stimulate the synthesis of glycosaminoglycans, repair agents DNA ration, DNA protection agents, anti-pruritus agents, agents for the treatment of sensitive skin, firming agents, anti-stretch agents, astringent agents, agents that regulate sebum production, lipolysis stimulating agents, anti-cellulite agents, agents that stimulate healing, adjuvant healing agents, cytokine growth factors, calming agents, anti-inflammatory agents, agents that act on capillary circulation and / or microcirculation, agents that act on cell metabolism, agents intended to improve dermoepidermal binding, preservatives , perfumes, chelants, plant extracts, essential oils, marine extracts, agents from a biofermentation process, mineral salts, cellular extracts and sunscreens (organic or mineral photoprotective agents active against ultraviolet rays A and / or B) among others , as long as they are physically and chemically co compatible with the remaining components of the composition and especially with the peptide derivatives of general formula (I) contained in the composition of the present invention. Similarly, the nature of said additional ingredients should not unacceptably alter the benefits of the peptide derivatives of the present invention. Such additional ingredients may be synthetic or natural, such as, for example, plant extracts, or they may come from a biofermentation process. Additional examples are described in the CTFA Cosmetic Ingredient Handbook, Eleventh Edition (2006).

A further aspect of the present invention relates to a cosmetic or pharmaceutical composition containing a cosmetic or pharmaceutically effective amount of at least one peptide derivative of the invention, its stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts and also cosmetics. or pharmaceutically the effective amount of at least one extract with inducing activity of defensin synthesis, such as, for example, extracts or hydrolysates of Aloe vera, roasted amaranth, Rehmannias radix, arnica, gardenia, carrot, orange, peach, pineapple, mint, gentian, hibiscus flower, walnut leaf, pumpkin, peony, quinoa, boldo, sarsaparilla, sunflower, elderberry, seaweed, corn hydrolyzate, soy hydrolyzate or rice hydrolyzate, among others, and / or also a cosmetic amount or pharmaceutically effective of at least one compound, extract or product from a biofermentation process with the effectiveness of the stimulator of the expression of defensin, such as isoleucine and its isomers and derivatives, valine and its isomers and derivatives, calcium and its salts, a-MSH and fragments contained in the amino acid sequence of a-MSH, vitamin A and its derivatives and precursors, vitamin D3 and its derivatives, jasmonic acid, fumaric acid, malic acid, citric acid, ascorbic acid, lactic acid, acetic acid, adipic acid, tartaric acid, cinnamic acid, glutamic acid, succinic acid, inulin, alkyl glucosides, poly -D- Glutamic acid, glycine, L-methionine, L-alanine, L-citrulline, lactoprotein, casein, lactoperoxidase, lysozyme, polyphenol, Lactobacillus extract, fusobacterium extract or non-photosynthetic filamentous bacteria, non-fruiting, among others.

The cosmetic or pharmaceutical composition of the invention may also additionally contain a cosmetic or pharmaceutically effective amount of at least one bactericidal and / or bacteriostatic agent and / or a fungicidal agent and / or a fungistatic agent, such as, for example, caprylglycol, imidazolidinyl urea , Methyl 4-hydroxybenzoate [INCI: methylparaben], ethyl 4-hydroxybenzoate [INCI: ethylparaben], propyl 4-hydroxybenzoate [INCI: propylparaben], butyl 4-hydroxybenzoate [INCI: butylparaben], 4-hydroxybenzoate 4 [INCI: isobutylparaben], 1,3-bis (hydroxymethyl) -5,5-dimethylimidazolidine-2,4-dione [INCI: DMDM Hydantoin], benzyl 4-hydroxybenzoate [INCI: benzylparaben], benzyl alcohol, dehydroacetic acid, benzoic acid, sorbic acid, salicylic acid, formic acid, propionic acid, 2-bromo-2-nitropropan-1,3-diol, 3-p-chlorophenoxy-1,2-propanediol [INCI: chlorophenine], dichlorobenzyl alcohol, butylcarbamate of iodopropyl chloride of benzalkonium, benzethonium chloride, chlorhexidine, ethanol, isopropanol, methanol, 1,2-hexanediol, 1,2-octanediol, pentylene glycol, glycerin laurate, glycerin caprylate, glycerin caprate, benzoyl peroxide, chlorhexidine trichlosin , phenoxyethanol, terpinen-4-ol, atherpineol, resorcinol, stiemycin, erythromycin, neomycin, clindamycin and its esters, tetracyclines, metronidazole, azelaic acid, tolnaphtate, nystatin, clotrimazole, ketoconazole, zinc pyrithione, zinc oxide, isotiazone, zinc , selenium sulfide, benzylhemiformal, boric acid, sodium borate 6,6-dibromo-4,4-dichloro-2,2'-methylenediphenol [INCI: bromochlorophen], 5-bromo-5-nitro-1,3-dioxane , tosyl chloramide sodium [INCI: chloramine T], chloroacetamide, p-chloro-m-cresol, 2-benzyl-4-chlorophenol [INCI: chlorophene], dimethyl oxazolidine, dodecyldimethyl-2-phenoxyethylammonium bromide [INCI: domiphen bromide ], 7-ethylbicyclooxazolidine, glutaraldehyde, N- (4-chlorophenyl) -N- [4-chloro-3- (trifluoromethyl ) phenyl] -urea [INCI: cloflucarban], hexetidine, 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one [INCI: Hinokitiol],

Isopropylmethylphenol, mercury salts, aluminum salts, nisin, phenoxysopropanol, or -phenylphenol, 3-heptyl-2 - [(3-heptyl-4-methyl-3H-thiazol-2-ylidene) methyl] -4-methylthiazolium iodide [ INCI: Quaternium-73], silver chloride, sodium iodate, thymol, undecylenic acid, diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, lactoperoxidase, glucose oxidase, lactoferrin and / or a cosmetic or pharmaceutically effective amount of at least one natural extract or an essential oil with bactericidal, bacteriostatic, fungicidal and / or intrinsic fungistatic activity, such as extracts of Allium sativum, Calendula officinalis, Chamomilla recutita, Echinacea purpura, Hyssopus Officinalis, Melaleuca alternifolia or tea tree oil, among others, in order to combine the bactericidal effect and / or

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bacteriostatic p-defensins with the effect of such agents.

Similarly, the cosmetic or pharmaceutical compositions of the present invention may additionally contain a cosmetic or pharmaceutically effective amount of at least one analgesic compound and / or an anti-inflammatory compound for the purpose of reducing swelling and irritation associated with inflammatory processes that occur with The proliferation of microorganisms. Such compounds include synthetic compounds such as hydrocortisone, clobetasol, dexamethasone, prednisone, paracetamol, acetylsalicylic acid, amoxiprine, benorilate, choline salicylate, diflunisal, phalamine, methyl salicylate, magnesium salicylate, salsalate, diclofenac, aceclofenac, aceclofenac, aceclofenac, aceclofenac, aceclofenac, aceclofenac etodolac, indomethacin, sulindac, tolmetine, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ioxoprofen, naproxen, oxaprozin, thiaprophenic acid, supphene, mefenamic acid, meclofenamophenone, methanobutanamone, nabophenazoaone, meclophenazoaone, methanobutaonamate, naprophenonazone , sulfinpyrazone, pyroxicam, iornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, licofelone, omega-3 fatty acids and their biometabolites, morphine, codeine, oxycodone, hydrodynamine, oxydodine, oxydodine brupenorphine, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, tricyclic antidepressants, amitriptyline, carbamazepine, gabapentin, pregabalin, bisabolol, panthenol, biotin, lauryrimodipropionate disodium tocopherylphosphate, cyclopyroxylamine, nordihydroguaarretic acid, coenzyme Q10 or intrinsic or anti-oligomeric activity, natural oils or anti-aliphatic activity, or anti-aromatics, or intrinsic, anti-aromatics, or anti-oligosacic acid, such as anti-oxyglycerides, or natural or synthetic anti-aromatics, such as anti-oxyglycerides, such as essential oils such as madecassosida, equinacin, amaranth seed oil, sandalwood oil, placenta extract, peach tree leaf extract, Aloe vera, Arnica montana, Artemisia vulgaris, Asarum Máximum, Calendula officinalis, Capsicum, Centipeda cunninghamii, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, Harpagophytum procumbens, Hypericum perforatum, Lilium candidum, Malva sylvestris, Melaleuca alternifolia, Origanum majorana, Salix alba, Silybum marianum, Tanacetum parthenium or Uncaria guianensis.

In addition, the present invention relates to a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide derivative according to the general formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically salts. acceptable and also a cosmetic or a pharmaceutically effective amount of at least one extract or combination of extracts with healing and / or re-epithelial activity or effective as coadjuvants in healing and / or re-epithelialization processes, such as, for example, Centella asiatica, Rosa moschata extracts , Echinacea angustifolia, Symphytum officinal, Equisetum arvense, Hypericum perforatum, Mimosa tenuiflora, Aloe vera, Polyplant® Epithelizer [INCI: Calendula Officinalis, Hypericum Perforatum, Chamomilla Recutita, Rosmarinus Officinalis] marketed by Provital® Cytoine: , Hydrolyzed yeast protein, Lysine HCl ] marketed by Laboratories Serobiologiques or Deliner® [INCI: Zea May (Corn) Kernel Extract] marketed by Coletica / Engelhard, among others, and / or also a cosmetic or pharmaceutically effective amount of at least one synthetic compound, extract or product from a biofermentation process with healing and / or reepithelising or effective activity as an adjuvant in healing and / or re-epithelialization procedures, such as caderins, integrins, selectins, hyaluronic acid receptors, immunoglobulins, fibroblast growth factor, growth factor of connective tissue, vascular endothelial growth factor, epidermal growth factor, insulin growth factor, keratinocyte growth factors, colony stimulating factors, beta transforming growth factors, tumor tumor necrosis factors alpha, interferons, interleukins, matrix metalloproteinases , tyrosine protein receptors phosphatase, Antarcticina® [INCI: Pseudoalteromonas Ferment Extract] or Decorinyl® [INCI: Tripeptide-10 Citrulline], marketed by Lipotec, among others.

Applications

A cosmetic or pharmaceutical procedure not included by the invention for the treatment and / or care of those conditions, disorders and / or pathologies of mammals, preferably human beings, which benefit from a stimulation of the synthesis of endogenous defensin and / or of the cleaning associated with said treatments are described herein; which comprises the administration of an effective amount of at least one peptide derivative of the general formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical composition containing them. Also described is a cosmetic or pharmaceutical method not understood by the invention to stimulate the body's defenses, preferably the skin, mucous, scalp and / or nail defenses. Similarly, a cosmetic or pharmaceutical procedure for stimulating the skin's defenses, mucous membranes, scalp and / or nails after surgical intervention, after treatment with intense pulsed light therapy is described herein. (IPL), after a monochromatic pulse (laser) treatment, after a treatment with chemical descaling agents or after overexposure to aggressive external agents, such as for example overexposure to the sun or extreme cold or extreme heat.

Similarly, a cosmetic or pharmaceutical procedure not included in the invention is described for the treatment and / or care of those conditions, disorders and / or pathologies of the skin, mucous membranes, scalp and / or nails resulting from the proliferation of microorganisms or at risk for the proliferation of microorganisms and / or the cleaning associated with said treatments, which includes the application to the skin, mucous membranes, scalp and / or nails or the oral or parenteral administration of a cosmetic or pharmaceutical composition containing the less a peptide derivative of the invention, its stereoisomers, its mixtures or its cosmetically or pharmaceutically acceptable salts.

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Preferably, among the conditions, disorders and / or pathologies of the skin, mucous membranes, scalp and / or nails to be treated and / or cared for caused by the proliferation of microorganisms or that are at risk of proliferation of microorganisms, are acne, erysipelas, herpes, dandruff, vitiligo, bacterial dermatosis, fungal dermatosis, eczema, sensitive skin, atopic dermatitis, seborrheic dermatitis, rash, genitalocrural candidiasis, mucosal candidiasis, such as vaginal candidiasis, interdigital candidiasis or associated candidiasis to diabetes, bacterial vaginosis, impetigo, folliculitis, boils, papulopustular rosacea, paronychia, pityriasis versicolor, staphylococcal scalded skin syndrome, erythrasma, dermatophytosis, such as marginalized Hebra eczema, ringworm, ringworm, ringworm of the body, ringworm or athlete's foot, gingivitis, dental cavities, periodontitis, triclosporonosis cut white line or stone, nail mycosis or onychomycosis, the infectious complications that occur in the healing processes of ulcers, wounds or burns, ophthalmological infections, skin disorders resulting from antibiotic treatments or antifungal treatments, or resulting from occupational exposure or sports high risk or resulting from hormonal deregulations such as pregnancy or infectious complications that occur in immunocompromised people, such as people with AIDS or undergoing cancer treatment or in stressful situations, among others, halitosis, bromhydrosis, oily hair and / or scalp, or any other condition, disorder and / or pathology of the skin, mucous membranes, scalp and / or nails caused by the proliferation of Actinomyces, Aspergillus spp., Candida albicans, Clostridium difficile, Clostridium pefringens, Demodex folliculorum, Epidermophyton floccosum, Escheric hia coli, Gardnerella vaginalis, Klebsiella spp., Malazessia furfur, Mycobacterium spp., Peptostreptococcus spp., Pityrosporum ovale, Propionibacterium acnes, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus streptogenesis streptogenesis, Streptogenesis streptococcus streptomygenesis Tinea corporis, Trichophyton interdigitale, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton yaoundei or Trichosporon cutaneum, among others. Additional examples of microorganisms and conditions, disorders and / or pathologies of the skin, mucous membranes, scalp and / or nails are described in "The Skin Microflora and Microbial Skin Disease", Noble WC, ed. University of London, Cambridge University Press, United Kingdom.

A cosmetic or pharmaceutical method not included in the invention for preventing or treating infections of the nails and / or cuticles comprising the application to the nails and / or cuticles of a cosmetic or pharmaceutical composition containing at least one peptide derivative of the invention, its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts.

A cosmetic or pharmaceutical method not covered by the invention is described to prevent or treat bromhydrosis comprising oral or parenteral administration or application to the areas affected by perspiration, preferably in the armpits, genitals or feet, of a cosmetic composition or Pharmaceutical containing at least one peptide derivative of the invention, its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts.

Similarly, a cosmetic or pharmaceutical method not covered by the invention to prevent or treat mucosal infections, comprising the application to the mucosa or oral or parenteral administration of a cosmetic or pharmaceutical composition containing at least one peptide derivative of the invention, its stereoisomers, its mixtures or its cosmetically or pharmaceutically acceptable salts.

A cosmetic or pharmaceutical method not included by the invention for the treatment of mucous membranes of the oral cavity or for oral hygiene is also described, which comprises the application to the oral cavity or the oral or parenteral administration of a cosmetic or pharmaceutical composition that It contains at least one peptide derivative of the invention, its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts. Preferably, the oral hygiene composition is a composition for the treatment or prevention of halitosis, gingivitis and / or periodontitis.

A cosmetic or pharmaceutical method not covered by the invention is described for the treatment of vaginal mucous membranes or for personal hygiene, comprising the application to the genitals or oral or parenteral administration of a cosmetic or pharmaceutical composition containing at least one derivative. peptide of the invention, its stereoisomers, its mixtures or its cosmetically or pharmaceutically acceptable salts.

A cosmetic or pharmaceutical method not covered by the invention for the treatment of the ocular mucosa or for ocular hygiene is described, comprising the application to the eyes or the oral or parenteral administration of a cosmetic or pharmaceutical composition containing at least one peptide derivative. of the invention, its stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts.

A cosmetic or pharmaceutical method not included by the invention for the treatment of hair and / or scalp or for hair hygiene, preferably for the treatment or hygiene of oily hair and scalp, for the treatment or the hygiene of hair and scalp affected by dandruff or for the treatment or hygiene of seborrheic conditions, which includes the application to the scalp and hair or the oral or parenteral administration of a cosmetic or pharmaceutical composition containing at least one derivative peptide of the invention, stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts.

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The compositions containing the peptide derivatives of the present invention, their stereoisomers, their mixtures or their cosmetically or pharmaceutically acceptable salts can be applied to the skin, mucous membranes, scalp and / or nails or can be administered orally or parenterally, depending on the requirements for the treatment of a condition, disorder and / or pathology, or can be administered daily to maintain homeostasis of the microbial flora of the skin, mucous membranes, scalp and / or nails. Homeostasis of the microbial flora is understood as the self-regulation of the levels of microbial flora present in healthy skin, healthy mucous membranes, healthy scalp or healthy nails, which vary according to body area, between 104 and 106 CFU / cm2 [Selwyn S. (1980) "Microbiology and ecology of human skin" Practitioner 224: 1059-1062], and is basically made up of staphylococci, micrococci and diphtheroids [Noble WC and Somerville D.A. in "Microbiology of Human Skin" 1974, W.B. Saunders Company Ltd., ed, London, United Kingdom].

The frequency of application or administration can vary widely, depending on the needs of each subject, an application or administration interval is suggested from once a month to ten times a day, preferably from once a week to four times a day, more preferably three times a week to three times a day, even more preferably once or twice a day.

A further aspect of the present invention relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for use in the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails.

The present invention further relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for use in stimulating the body's defenses, preferably the defenses of the skin, mucous membranes, scalp and / or nails. Preferably, the stimulation of the body's defenses is mediated by the induction of endogenous p-defensin expression, and more preferably by the induction of human p-defensin-2 and / or p-defensin-3 expression.

The present invention further relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for use in stimulating the skin's defenses, mucous membranes, the scalp and / or nails after surgery, after treatment with intense pulsed light therapy (IPL), after treatment with monochromatic pulse light (laser), after treatment with chemical descalers or after overexposure to aggressive external agents, such as overexposure to the sun or extreme cold or extreme heat.

Similarly, another aspect of the present invention relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for use in the treatment, care and / or cleaning of those conditions, disorders and / or pathologies of the skin, mucous membranes, scalp and / or nails resulting from the proliferation of microorganisms or being at risk of proliferation of microorganisms. Preferably, the cosmetic or pharmaceutical compositions are for use in the treatment, care and / or cleaning of those areas of the skin, mucous membranes, scalp and / or nails affected by acne, erysipelas, herpes, dandruff, vitiligo, bacterial dermatosis, dermatosis fungal, eczema, sensitive skin, atopic dermatitis, seborrheic dermatitis, diaper erythema or genitocrural candidiasis, mucosal candidiasis, such as for example vaginal candidiasis, interdigital candidiasis or candidiasis associated with diabetes, bacterial vaginosis, impetigo, folliculitis, furuncles, rosacea paronychia, pityriasis versicolor, staphylococcal scalded skin syndrome, erythrasma, dermatophytosis, such as eg marginalized strand eczema, ringworm of the scalp, ringworm of the body, ringworm or athlete's foot, gingivitis, dental cavities, periodontitis, cutaneous trichosporonosis or white stone, nail mycosis or onychomycosis, infectious complications that occur in the healing processes of ulcers, wounds or burns, ophthalmological infections, skin disorders resulting from antibiotic treatments or antifungal treatments, or resulting from occupational exposure or high-risk sports, or resulting from hormonal deregulations, such as pregnancy, or infectious complications that occur in immunosuppressed people, such as for example people with AIDS or undergoing cancer treatment or in stressful situations, including halitosis, bromhidrosis, oily hair and / or scalp, or any other condition, disorder and / or pathology of the skin, mucous membranes, scalp and / or nails caused by proliferation of Actinomyces, Aspergillus spp., Candida albicans, Clostridium difficile, Clostridium pefringens, Demodex folliculorum, Epidermophyton floccosum, Escherichia coli, Gardnerella vaginalis, Gardnerella vaginalis, Gardnerella vaginalis, Gardnerella vaginalis, Gardnerella vaginalis ., Malazessia furfur, Mycobacterium spp., Peptostreptoco ccus spp., Pityrosporum ovale, Propionibacterium acnes, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Streptococcus pyogenes, Streptococcus sanguis, Streptopyogenes, Tinea capitis Trichtetron, Trichontia trichophytosis, Tinea corichitis trichteum, Trichontitis trichoponia , among others.

In a further embodiment, the present invention relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for use in the prevention or treatment of infections of the nails and / or cuticles.

According to another embodiment, the peptide derivatives of general formula (I), their stereoisomers, their mixtures or

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its cosmetically or pharmaceutically acceptable salts are used in the preparation of a cosmetic or pharmaceutical composition to prevent or treat infections of the mucous membranes, preferably infections of the mucous membranes of the oral cavity, such as for example gingivitis or periodontitis, or infections of the vaginal mucosa , such as vaginal candidiasis or bacterial vaginosis.

In another additional embodiment, the present invention relates to at least one of the peptide derivatives of general formula (I), its stereoisomers, or its cosmetically or pharmaceutically acceptable salts for use in oral hygiene. Preferably, the cosmetic or pharmaceutical composition is used for the treatment or prevention of halitosis, gingivitis and periodontitis. Examples of a cosmetic or pharmaceutical composition for oral hygiene include toothpastes, mouth rinses to rinse the mouth or chewing gum, among others.

A further aspect of the present invention relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for use in body hygiene, for personal hygiene or hair hygiene. Preferably, cosmetic or pharmaceutical compositions for hair hygiene are selected from the group consisting of compositions for oily hair or scalp hygiene, compositions for the treatment or prevention of dandruff and compositions for the hygiene of seborrheic conditions. Examples of a cosmetic or pharmaceutical composition for hair hygiene include shampoos, hair lotions, hair toners or scalp conditioners, among others. Preferably, cosmetic or pharmaceutical compositions for body hygiene are selected from the group consisting of compositions for oily skin hygiene. Examples of a cosmetic or pharmaceutical composition for body hygiene include soaps, shower gels, facial cleansing gels, antibacterial aftershave gels, body or facial milks, astringent lotions or creams for oily skin. Examples of a cosmetic or pharmaceutical composition for personal hygiene include soaps or personal hygiene gels.

A further embodiment of the present invention relates to at least one of the peptide derivatives of general formula (I), their stereoisomers, mixtures thereof, or their cosmetically or pharmaceutically acceptable salts for use in the treatment, reduction and / or Bromhidrosis prevention. Examples of a cosmetic or pharmaceutical composition for the treatment, prevention and / or reduction of bromhydrosis include deodorants and antiperspirants.

The following specific examples provided herein serve to illustrate the nature of the present invention. These examples are included for illustrative purposes only and should not be construed as limitations of the invention claimed herein.

Examples

General Methodology

All reagents and solvents are of quality for synthesis and are used without further treatment. Abbreviations

The abbreviations used for amino acids follow the rules of the IUPAC-IUB Commission on Biochemical Nomenclature specified in Eur. J. Biochem. (1984) 138, 9-37 and in J. Biol. Chem. (1989) 264, 633-673.

Ac, acetyl; DNA, deoxyribonucleic acid; Ahx, £ -aminohexanoic acid or 6-aminocaproic acid; Al, allyl; Alloc, allyloxycarbonyl; Ala, Alanine; AM, 2- [4-aminomethyl- (2,4-dimethoxyphenyl)] -phenoxyacetic acid; Arg, arginine; RNA, ribonucleic acid; MRNA, messenger ribonucleic acid; Boc, tert-butyloxycarbonyl; Bzl, benzyl; Cbz, benzyloxycarbonyl; UFC, colony forming units; cHex, cyclohexyl; ClTrt, 2-chlorotrityl resin; DCM, dichloromethane; DIEA, N, N-diisopropylethylamine; DIPCDI, N, N'-diisopropylcarbodiimide; DMEM, Eagle medium modified by Dulbecco; DMF, N, N-dimethylformamide; DPPC, dipalmitoylphosphatidylcholine; EDTA, ethylenediaminetetraacetic acid; equivalent; ESI-MS, electrospray ionization mass spectrometry; FBS, fetal bovine serum; Fmoc, 9-fluorenylmethyloxycarbonyl; G418, geneticin; Glu, glutamic acid; hBD, human p-defensins; HNP, human a-defensins; HOAt, 1-hydroxazabenzotriazole; HOBt, 1-hydroxybenzotriazole; HPLC, high performance liquid chromatography; Ile, isoleucine; INCI, International Nomenclature of Cosmetic Ingredients; IPL, intense pulse light; LPS, lipopolysaccharide of Pseudomona aeruginosa; MBHA, p-methylbenzhydrylamine resin; MeCN, acetonitrile; MeOH, methanol; Met, methionine; mLV, multilamellar vesicles; MSH, melanocyte stimulating hormone; Mtr, 4-methoxy-2,3,6-trimethylbenzenesulfonyl; NMP, N-methylpyrrolidone; PAL, 5- (4-aminomethyl-3,5-dimethoxyphenoxy) valeric acid; Palmitoil palm; Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Phg, phenylglycine; Pmc, 2,2,5,7,8-pentamethylchroman-6-sulfonyl; ®, resin; RpMI-1640, medium of Roswell Park Memorial Institute; RT-PCR, reverse transcription polymerase chain reaction; AIDS, acquired immunodeficiency syndrome; spp., species; tBu, tert-butyl; Teoc, 2- (trimethylsilyl) ethyloxycarbonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TIS, triisopropylsilane; Cough, para-toluenesulfonyl or tosyl; Troc, 2,2,2-trichlorethyloxycarbonyl; Trt, triphenylmethyl or trityl; ULAs, luminescence absorption units; ULV, unilamellar vesicles; UV, ultraviolet.

Chemical synthesis

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All synthetic processes are carried out in polypropylene syringes equipped with porous polyethylene discs, in Pyrex® reactors equipped with a porous plate, or in an ACT396Q automatic synthesizer (Advanced Chemtech, Inc). Solvents and soluble reagents are removed by suction. The removal of the Fmoc group is carried out with piperidine-DMF (2: 8, v / v) (1 x 1 min, 1 x 5 min, 5 mL / g resin) [Lloyd-Williams P., Albericio F. and Giralt, E. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA]. Washing between the deprotection, coupling and deprotection steps was carried out with DMF (3 x 1 min) using 10 ml of solvent / g of resin each time. The coupling reactions were carried out with 3 mL of solvent / g of resin. Coupling control is carried out by means of the ninhydrin test [Kaiser E., Colescott R.L., Bossinger C.D. and Cook P.I. (1970) "Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides". Anal. Biochem 34: 595-598]. All transformations and synthetic washes were carried out at room temperature.

Example 1 - General procedure to synthesize peptidyl resins

Synthesis of Fmoc-AA1-AA2-AA3-AA4-O-2-ClTrt-® and Fmoc-AA1-AA2-AA3-AA4-AM-MBHA-®.

250 mg of commercial resins HL-Ile-O-2-ClTrt-®, HL-Ala-O-2-ClTrt-®, HL-Phg-O-2-ClTrt-®, HD-Phg-O-2- ClTrt-® and Fmoc-AM-MBHA-® were weighed and distributed in 12, 6, 6, 6 and 24 wells respectively, of the 96-position reactor of an ACT396Q multiple synthesizer. The synthesis of the peptides was programmed through the commercial software Advanced Chemtech v.1.36.03. A stock solution of each of the amino acids Fmoc-Ahx-OH, Fmoc-L-Ala-OH, Fmoc-D-Ala-OH, Fmoc-L-Arg (Pbf) -OH, Fmoc-D-Arg (Pbf) -OH, Fmoc-L-Glu (OtBu) -OH, Fmoc-D- Glu (OtBu) -OH, Fmoc-L-Ile-OH, Fmoc-D-Ile-OH, Fmoc-L-Met-OH, Fmoc -D-Met-OH, Fmoc-L-Phg-OH and Fmoc-D-Phg-OH was prepared in DMF at a concentration of 0.5 M containing 0.5 M HOBt, as well as a solution of 1 mM DIPCDI and a 20% piperidine in DMF. In each case, the incorporation cycles of each amino acid were programmed with the following sequence: washes (DMF, 3 x 2 min), deprotection (20% piperidine in DMF, 1 x 5 min + 1 x 20 min), DMF washes , 3 x 2 min), coupling of the desired amino acid (5 equiv of Fmoc-amino acid, 5 equiv of DIPCDI, 60 min) and washes (DMF, 3 x 2 min).

After the synthesis was finished, the peptidyl resins were washed with DCM (5 x 3 min) and dried by a stream of nitrogen.

Example 2 - General procedure for cleaving the protective group Fmoc N-terminal Synthesis of H-AA1-AA2-AA3-AA4-O-2-ClTrt-® and H-AA1-AA2-AA3-AA4-AM-MBHA-®.

50 mg of the peptidyl resins obtained in Example 1 were divided into aliquots and the N-terminal Fmoc group was deprotected as described in the general procedures (20% piperidine in DMF, 1 x 5 min + 1 x 20 min) . The peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

Example 3 - Procedure to introduce the palmitoyl group R1

Synthesis of Palm-AA1-AA2-AA3-AA4-O-2-ClTrt-® and Palm-AA1-AA2-AA3-AA4-AM-MBHA-®.

10 equivalents of palmitic acid predisolved in 1 mL of DMF, in the presence of 10 equiv of HOBt and 10 equiv of DIPCDI, were incorporated into 50 mg of the peptidyl resins obtained in Example 1, the N-terminal Fmoc group being previously deprotected as It is described in the general procedures. They were allowed to react for 15 h, after which the peptidylresins were washed with THF (5 x 1 min), DCM (5 x 1 min), DMF (5 x 1 min), MeOH (5 x 1 min), DMF ( 5 x 1 min), THF (5 x 1 min), DMF (5 x 1 min), DCM (4 x 1 min), ether (3 x 1 min) and dried under vacuum.

Example 4 - Procedure to introduce the acetyl group R1

Synthesis of Ac-AA1-AA2-AA3-AA4-O-2-ClTrt-® and Ac-AA1-AA2-AA3-AA4-AM-MBHA-®.

50 mg of the peptide resins obtained in Example 1, the previously unprotected N-terminal Fmoc group were treated as described in the general procedures, with 25 equivalents of acetic anhydride in the presence of 25 equiv of DIEA using 0.5 mL of DMF as a solvent They were allowed to react for 30 minutes, after which the peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

Example 5 - Procedure for excision of the polymeric support

Obtaining of H-AA1-AA2-AA3-AA4-OH, Ac-AA1-AA2-AA3-AA4-OH, Palm-AA1 -AA2-AA3-AA4-OH, H-AA1- AA2-AA3-AA4- NH2, Ac-AA1 -AA2-AA3-AA4-NH2 and Palm-AA1-AA2-AA3-AA4-NH2.

25 mg of the dried peptidyl resins obtained in Examples 2, 3 and 4 were treated with 0.5 mL of TFA-TIS-H2O (90: 5: 5) for 2 h at room temperature with stirring. The filtrates were collected in 10 mL of cold diethyl ether, filtered through polypropylene syringes equipped with porous polyethylene discs and washed 5 times

with 10 mL of diethyl ether. The final precipitates were dried in vacuo.

HPLC analysis of the peptides obtained in MeCN gradients (+ 0.07% TFA) in H2O (+ 0.1% TFA) showed purity greater than 80% in all cases. The identity of the peptides obtained was confirmed by ES-MS.

5 Example 6 - Procedure for excision of the polymeric support and functionalization with the substituted amine R2. Obtaining Ac-AA1 -AA2-AA3-AA4-NH- (CH2) 15-CH3.

The Ac-AA1-AA2-AA3-AA4-OH peptide derivatives were obtained with the side chains completely protected by treatment of the Ac-AA1-AA2-AA3-AA4-O-2-ClTrt-® peptide resins of Example 4, previously dried under vacuum in the presence of KOH, with a 3% solution of TFA in DCM for 5 minutes. The filtrates were collected in cold diethyl ether and the treatment was repeated three times. The ether solutions were evaporated in vacuo to dryness and at room temperature, the precipitates were resuspended in 50% MeCN in H2O and lyophilized. 10 mg of the raw products obtained in a flask were weighed, 3 equiv. of hexadecylamine and 25 mL of anhydrous DMF. 2 equiv of DIPCDI were added and allowed to react with magnetic stirring at 47 ° C. The reactions were monitored by HPLC by the disappearance of the initial products, completing after 24-48 h. The solvents were evaporated to dryness and coevaporated twice with DCM. The remains obtained [Ac-AA1-AA2-AA3-AA4-NH- (cH2) 9-CH3 with fully protected side chains] were resuspended in 25 mL of a mixture of TFA-DCM-anisole (49: 49: 2) and allowed to react for 30 minutes at room temperature. 250 mL of cold diethyl ether was added, the solvents were evaporated under reduced pressure and two additional coevaporations were carried out with ether. The residues were dissolved in a mixture of 50% MeCN in H2O and lyophilized.

HPLC analysis of the peptide derivatives obtained in MeCN gradients (+ 0.07% TFA) in H2O (+ 0.1% TFA) showed purity greater than 80% in all cases. The identity of the peptide derivatives obtained was confirmed by ES-MS.

Example 7

Composition of a facial cream containing Ac-L-Arg-Ahx-L-Ala-OH.

INGREDIENT (INCI Nomenclature) ____________________% BY WEIGHT

TO BUTYROSPERMUM PARKII 3,5-4,5

TO CETEARYL ETHYLHEXANOATE 3-5

A GLICERIL ESTEARATO S, E, 1,5-2,5

30 A SCALEAN 0.5-1

A PEG-100 ESTEARATO 1

A POLYSORBATE 60 0.30

TO CETILL PALMITATE 1,5-2,5

A DIMETICONE 2,5-3,5

35 A CETEARIL ALCOHOL 1,5-2,5

A PALMYTIC ACID 0.5

B AQUA (WATER) 2

B GLYCERINE 1.5-2.5

B BUTILENGLYCOL 1-3

40 B MANITOL 0.5-1.5

B HYDROGEN LECITINE 0.5-1.5

B PROPYLENE GLYCOL 0.5-1.5

C CARBOMER 0.4

C ETHYHEXYL PALMITATE 1,5-2,5

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 D TROMETAMINE

 0.4

 D AQUA (WATER)

 one

 AND PRESERVANTS

 c.s.

 F Ac-L-Arg-Ahx-L-Ala-OH

 0.10

 F AQUA (WATER)

 c.s.100

Preparation

- Mix the components of phase A and heat to 70 ° C.

- Mix the components of phase B and heat to 70 ° C.

- Add phase C to phase B by stirring with a homogenizer (Silverson) for 5 minutes.

- On the mixture of phases B and C, gradually add phase A with a homogenizer and maintain homogenization for 15 minutes.

- Start cooling at 30-35 ° C with gentle agitation. Add phase D at 50 ° C. Keep stirring. Add Phases E and F previously solubilized at 35-38 ° C.

Example 8

Preparation and composition of liposomes containing Ac-L-Glu-L-Met-L-Ala-L-Ile-OH.

Dipalmitoylphosphatidylcholine (DPPC) was weighed and dissolved and dissolved in chloroform. The solvent was evaporated under reduced pressure until a thin phospholipid layer was obtained, and this layer was hydrated by treatment at 55 ° C with an aqueous solution of the peptide derivative at the desired concentration (containing Phenonip®), obtaining MLV liposomes. ULV liposomes were obtained by immersing MLV liposomes in an ultrasonic bath at 55 ° C for 8 cycles of 2 min at 5 min intervals. The size of the ULV liposomes was reduced by passing them through an extrusion system under high pressure.

INGREDIENT (INCI Nomenclature) ___________________________% BY WEIGHT

DIPALMITOILPHOSFATIDILCOLINA 4.0

Ac-L-Glu-L-Met-L-Ala-L-Ile-OH 0.2

PHENOXYETHANOL, METHYLPARABENE, ETHYLPARABENE, BUTILPARABEN,

PROPILPARABENO, ISOBUTILPARABENO 0,5

____________AQUA (WATER) __________________________________________________ c.s.100

Example 9

Preparation of a liposome gel-shaped composition containing Ac-L-Glu-L-Met-L-Ala-L-Ile-OH.

The liposomes of Example 8 were dispersed in water with preservatives (EDTA, imidazolidinyl urea and Phenonip®) under gentle agitation. Hispagel® 200 [INCI: Water, glycerin and glyceryl polyacrylate] was added and stirred gently

until a homogeneous mixture was obtained.

INGREDIENT (INCI Nomenclature) ____________________% BY WEIGHT

LIPOSOMES CONTAINING

Ac-L-Glu-L-Met-L-Ala-L-Ile-OH (1%) 10.00

DISODIC EDTA 0.15

IMIDAZOLIDINIL UREA 0.10

PHENOXYETHANOL, METHYLPARABENE, ETHYLPARABEN,

BUTILPARABENO, PROPILPARABENO, ISOBUTILPARABENO 0,50

AQUA (WATER) 29.25

AQUA (WATER), GLYCERINE, POLYCRYLATE GLYCERILE

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Example 10

Composition for the treatment of nails containing Palm-L-Arg-Ahx-L-Ala-OH

INGREDIENT (INCI Nomenclature) ____________________% BY WEIGHT

A CETEARIL ALCOHOL / CETEARIL SODIUM SULFATE 10

A PRUNUS DULCIS 0.05

A BUTYROSPERMUM PARKII 0,5

TO ZINC OXIDE 0.5

TOCOPHEROL ACETATE 0.1

A 0.1-0.3 METHYLPARABEN

B GLYCERINE 13

B AQUA (WATER) 10

B HYDROLYZED SOY PROTEIN 0.1

C Palm-L-Arg-Ahx-L-Ala-OH 0.1

C AQUA (WATER) ________________________________________ c.s. 100

Preparation

- Mix the components of phase A and heat to 70 ° C.

- Mix the components of phase B and heat to 70 ° C.

- Add Phase A in the stirring phase B with a homogenizer (Silverson) for 5 minutes and maintain the homogenization for 15 minutes.

- Start cooling at 30-35 ° C with gentle agitation. Add the previously solubilized phase C at 35-38 ° C.

Example 11

Composition of a body lotion containing Palm-L-Arg-Ahx-L-Ala-NH ?.

INGREDIENT (INCI Nomenclature) ____________________% BY WEIGHT

 TO CETEARIL ETILHEXANOATE

 3-5

 A GLICERIL ESTEARATO SE.

 2.5

 TO PEG-100 ESTEARATE

 one

 TO SCALE

 2

 TO DIMETICONE

 0.5-1

 TO CETHYL ALCOHOL

 0.4-0.8

 B AQUA (WATER)

 one

 B BUYLENE GLYCOL

 1-3

 B GLYCERINE

 0.5-2

 B PROPYLENE GLYCOL

 0.5-1.5

 C CARBOM

 0.2

 C ETILEXIL PALMITATE

 0.5-1.5

 C ACRILATES / C10-30 CROSPOLYMER RENT ACRYLATE 0.1

 D AQUA (WATER)

 one

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 D TROMETAMINE

 0.25

 AND PRESERVANTS

 c.s.

 F Palm-L-Arg-Ahx-L-Ala-NH2

 0.10

 F AQUA (WATER)

 c.s. 100

Preparation

- Mix the components of phase A and heat to 70 ° C.

- Mix the components of phase B and heat to 70 ° C.

- Add phase C in phase B stirring with a homogenizer (Silverson) for 5 minutes.

- On the mixture of phases B and C, gradually add phase A with a homogenizer and maintain homogenization for 15 minutes.

- Start cooling at 30-35 ° C with gentle agitation. Add phase D at 50 ° C. Keep stirring. Add Phases E and F previously solubilized at 35-38 ° C.

Example 12

Composition of a hair lotion containing Ac-L-Arg-Phg-Phg-NH- (CH?) I5-CH3.

INGREDIENT (INCI Nomenclature) ___________________% BY WEIGHT

TO DESNAT ALCOHOL. 50-60

APENTENOL 0.05-0.15

ZINC ARICINOLATE 0.05-0.10

A FRAGRANCE 0.02

B AQUA (WATER) c.s.100

B Ac-L-Arg-Phg-Phg-NH- (CH?) I5-CH3 ________________________ 0.01

Preparation

- Mix the components of Phase A.

- Mix the components of Phase B.

- Slowly add Phase B in Phase A with stirring until complete homogenization. Example 13

Composition of a mouthwash containing Ac-L-Arg-Phg-Phg-OH

INGREDIENT (INCI Nomenclature) _____________% BY WEIGHT

Ac-L-Arg-Phg-Phg-OH 0.10

SODIUM SACARINE 0,01-0,03

SORBITOL 4-6

PROPYLENE GLYCOL 8-12

PEG-60 HYDROGENATED CASTOR OIL 1-3

AQUA (WATER) ___________________________________ c.s.100

Preparation

- Mix the components until complete homogenization. Example 14

Activation assay of the hBD2 promoter in a stable cell line by the compounds of general formula (I) obtained in Examples 5 and 6.

The A549 human epithelial cell line was cultured using RPMI-1640 medium supplemented with FBS and Penicillin-Streptomycin. It was routinely cultivated by dividing the cultures twice a week at a 1:10 dilution using Trypsin-EDTA. 106 cells of the A549 line were seeded in a 60 mm disc treated with polylysine. After 24 h they were co-transfected with 10 | jg of a gene construct formed by the hBD2 gene promoter followed by the protein luciferase gene (pGL3-hBD2promotor-Luc), and the pcDNA3B DNA plasmid containing the gene resistance to a geneticine antibiotic ratio to pcDNA3B.1 / promoter-Luc pGL3-hBD2 of 1: 5. 25 jL of Lipofectamine ™ 2000 were used for transfection. After 24 hours, selection 10 was started with complete medium supplemented with the antibiotic G418-Geneticin®, the selection medium was renewed every 2 days. Different clones were isolated, which were characterized and selected based on luciferase activity.

The stable lines selected were cultured using complete medium for the parental line supplemented with G418. They were routinely grown by dividing the cultures twice a week in a 1:10 dilution using Trypsin-EDTA.

The ability to activate the hBD2 promoter was determined by the luciferase activity assay since a transcriptional agent that induces the synthesis of hBD2 produces the production of the luciferase enzyme by activating the hBD2 gene promoter contained in the pGL3 construct -hBD2promotor-Luc, observing an increase in luminescence. Selected stable cell lines were seeded at 20,000 cells per plate. After 24 h the plates were washed and incubated for 24 hours in RPMI-1640 medium

20 modified without L-isoleucine with different peptide derivatives at a concentration of 0.5 mM. LPS (100 were used

jg / mL) and L-isoleucine (25 jg / mL) as positive controls with the same treatment as peptide derivatives. Once the incubation period was over, the Steady-Glo Luciferase Assay System (Promega Corp.) reagent was added to the cells, following the protocol of the trading company. The luminescent signal (ULAs / s) produced by the reaction between the luciferase and its substrate was quantified with a LUMIstar Galaxy (BMG plate luminometer)

25 Labtechnologies). Based on the values of luciferase activity (ULAs / s), standardized with controls

negative, hBD2 promoter activation was determined. Table 1 details the activity of the compounds of general formula (I) that show an increase in luminescence equal to or greater than 20%.

Table 1.

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Compound_________________

Control_____________________

LPS

L-Ile

Ac-L-Arg-Phg-Phg-OH

Ac-L-Glu-Phg-L-Ala-OH

Ac-L-Arg-Phg-L-Ala-L-Ile-OH

Ac-L-Arg-Ahx-Phg-L-Ile-OH

H-L-Glu-L-Met-L-Ala-L-Ile-OH

Ac-L-Arg-L-Met-Phg-L-Ile-OH

Ac-L-Arg-Phg-L-Ala-OH

Ac-L-Glu-Phg-L-Ala-L-Ile-OH

Ac-L-Glu-L-Met-Phg-L-Ile-OH

Ac-L-Arg-Ahx-L-Ala-OH

Palm-L-Glu-L-Met-L-Ala-L-Ile-NH2

Ac-L-Arg-Ahx-L-Ala-L-Ile-OH

Ac-L-Arg-Phg-Phg-L-Ile-OH

Ac-L-Glu-Phg-Phg-L-Ile-OH

Increase in luminescence _______ 100%

185%

127%

120%

121%

125%

125%

125%

127%

127%

130%

131%

135%

137%

137%

138%

138%

145%

Ac-L-Arg-Phg-Phg-NH- (CH2) 15-CHa

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Ac-L-Arg-L-Met-L-Ala-L-Ile-OH 153%

Ac-L-Glu-L-Met-L-Ala-L-Ile-OH __________ 196%

Example 15

Quantification of hBD2 mRNA secreted in human keratinocytes after incubation with Ac-L-Glu-L-Met-L-Ala-L-Ile-OH, Ac-L-Arg-Phg-Phg-OH and Ac-L-Arg -Ahx-L-Ala-OH.

Quantification of the amount of secreted mRNA was carried out by a real-time quantitative RTPCR assay. 3x106 cells of a human keratinocyte line, seeded in 25 cm2 flasks were used. The cells were washed and incubated for 16h-24h with different peptide derivatives at a concentration of 1 mm or 0.25 mm in a volume of 3 mL of medium. DMEM LPS (100 pg / mL) and L-Ile (200 pg / mL) were used as positive controls. The cell supernatants were stored at -80 ° C, to analyze the level of secreted hBD2 protein and the total RNA was extracted from the cells with the RNeasy kit (Quiagen) following the protocol of the trading company.

A back transcription reaction was carried out in a Mastercycler thermal cycler from 1 pg of total RNA of each sample, using the GeneAmp RNA PCR kit (Applied Biosystems) according to the commercial company protocol and subsequently a PCR in real time it was carried out by testing with the SYBR Green I fluorophore in an ABI PRIS M 7700 Sequence Detector (Applied Biosystems).

The amount of mRNA was quantified by standardization by normalizing it with respect to endogenous 18S ribosomal RNA values. These values were normalized in turn with respect to untreated cells and were represented as the relative level of hBD2 mRNA.

Table 2.

Compound __________________ The relative level of hBD2 mRNA

 Control

 100%

 LPS

 192%

 L-Ile

 125%

 1 mm Ac-L-Glu-L-Met-L-Ala-L-Ile-OH

 323%

 0.25 mm Ac-L-Arg-Ahx-L-Ala-OH

 126%

 0.25 mm Ac-L-Arg-Phg-Phg-OH

 201%

Example 16

Quantification of hBD2 secreted in human keratinocytes after incubation with Ac-L-Glu-L-Met-L-Ala-L-Ile-OH, Ac-L-Arg-Phg-Phg-OH and Ac-L-Arg -Ahx-L-Ala-OH.

The amount of hBD2 secreted by human keratinocytes was quantified by means of an ELISA using the commercial Human Development Kit BD-2 ELISA (Peprotech) from cell supernatants from Example 15.

Based on the absorbance data obtained, the hBD2 protein level was calculated after calibration with recombinant hBD2. The hBD2 values obtained were standardized with respect to the values of the control assays (untreated cells).

Table 3.

Compound _________________________ Relative level of hBD2

 Control

 100%

 LPS

 143%

 L-Ile

 134%

 1 mm Ac-L-Glu-L-Met-L-Ala-L-Ile-OH

 129%

 0.25 mm Ac-L-Arg-Ahx-L-Ala-OH

 126%

 0.25 mm Ac-L-Arg-Phg-Phg-OH

 116%

Claims (14)

1. A peptide derivative of the general formula (I) R1-AA1-AA2-AA3-AA4-R2 (I) their stereoisomers, their mixtures, or their cosmetically or pharmaceutically acceptable salts, in which: 5 AA1 is selected from the group consisting of -Glu- and -Arg-; AA2 is selected from the group consisting of -Met-, -Ahx- and -Phg-; AA3 is selected from the group consisting of -Ala- and -Phg-; AA4 is selected from the group consisting of -Ile- and a single link; R1 is selected from the group consisting of H, and R5-C (O) -; Y 10 R2 is selected from the group consisting of -NR3R4 and -OR3; wherein R3 and R4 are independently selected from the group consisting of H, and an unsubstituted non-cyclic aliphatic group; wherein R5 is selected from the group consisting of H, and an unsubstituted non-cyclic aliphatic group; in which -Ahx- is fifteen and -Phg- is image 1 2. The peptide derivative according to claim 1, wherein AA1 is -Glu-, AA2 is -Met-, AA3 is -Ala- and AA4 is -Ile-. 3. A peptide derivative according to claim 1, wherein AA1 is -Arg-, AA2 is -Ahx-, AA3 is -Ala- and AA4 is a simple link 4. The peptide derivative according to claim 1, wherein AA1 is -Arg-, AA2 is -Phg-, AA3 is -Phg- and AA4 is a single bond. 5. The peptide derivative according to any one of claims 1 to 4, selected from the group consisting of Ac-L-Arg-L-Phg-L-Phg-OH, Ac-L-Arg-L-Phg-D-Phg-OH, Ac-L-Arg-D-Phg-L-Phg-OH, Ac-L-Arg-D-Phg-D-Phg-OH, 30 Ac-L-Glu-L-Phg-L-Ala-OH, Ac-L-Glu-D-Phg-L-Ala-OH, Ac-L-Arg-L-Phg-L-Ala-L-Ile-OH, Ac-L-Arg-D-Phg-L-Ala-L-Ile-OH, Ac-L-Arg-Ahx-L-Phg-L-Ile-OH, image2 5 10 fifteen twenty 25 30 35 40 Ac-L-Arg-Ahx-D-Phg-L-Ile-OH, H-L-Glu-L-Met-L-Ala-L-Ile-OH, Ac-L-Arg-L-Met-L-Phg-L-Ile-OH, Ac-L-Arg-L-Met-D-Phg-L-Ile-OH, Ac-L-Arg-L-Phg-L-Ala-OH, Ac-L-Arg-D-Phg-L-Ala-OH, Ac-L-Glu-L-Phg-L-Ala-L-Ile-OH, Ac-L-Glu-D-Phg-L-Ala-L-Ile-OH, Ac-L-Glu-L-Met-L-Phg-L-Ile-OH, Ac-L-Glu-L-Met-D-Phg-L-Ile-OH, Ac-L-Arg-Ahx-L-Ala-OH, Ac-L-Arg-L-Phg-L-Phg-NH- (CH2) i5-CHa, Ac-L-Arg-L-Phg-D-Phg-NH- (CH2) i5-CHa, Ac-L-Arg-D-Phg-L-Phg-NH- (CH2) i5-CH3, Ac-L-Arg-D-Phg-D-Phg-NH- (CH2) i5-CH3, Palm-L-Glu-L-Met-L-Ala-L-Ile-NH2, Ac-L-Arg-Ahx-L-Ala-L-Ile-OH, Ac-L-Arg-L-Phg-L-Phg-L-Ile-OH, Ac-L-Arg-L-Phg-D-Phg-L-Ile-OH, Ac-L-Arg-D-Phg-L-Phg-L-Ile-OH, Ac-L-Arg-D-Phg-D-Phg-L-Ile-OH, Ac-L-Glu-L-Phg-L-Phg-L-Ile-OH, Ac-L-Glu-L-Phg-D-Phg-L-Ile-OH, Ac-L-Glu-D-Phg-L-Phg-L-Ile-OH, Ac-L-Glu-D-Phg-D-Phg-L-Ile-OH, Ac-L-Arg-L-Met-L-Ala-L-Ile-OH, Ac-L-Glu-L-Met-L-Ala-L-Ile-OH, and their mixtures or their cosmetically or pharmaceutically acceptable salts. 6. A process for obtaining a peptide derivative of general formula (I), its stereoisomers, mixtures thereof, or its cosmetically or pharmaceutically acceptable salts as defined in any of claims 1 to 5, in which it is carried out in solid phase or in the solution phase. 7. A cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide derivative of general formula (I), its stereoisomers, mixtures thereof, or its cosmetically or pharmaceutically acceptable salts, as defined in any of the claims 1 to 5, and at least one cosmetic or pharmaceutically acceptable excipient or adjuvant. 8 8. The cosmetic or pharmaceutical composition according to claim 7, wherein the peptide derivative of the general formula (I), its stereoisomers, mixtures thereof, or its cosmetically or pharmaceutically acceptable salts, are incorporated into an administration system or a Cosmetic or pharmaceutically acceptable sustained release system selected from the group consisting of liposomes, millicapsules, microcapsules, nanocapsules, sponges, vesicles, micelles, microspheres, microspheres, nanospheres, lipospheres, microemulsions, nanoemulsions, miliparticles, microparticles, nanoparticles and solid lipid nanoparticles and / or cosmetically adsorbed or 5 10 fifteen twenty 25 30 35 40 Four. Five fifty a pharmaceutically acceptable solid support or a solid organic polymer selected from the group consisting of talc, bentonite, silica, starch and maltodextrin. 9. The cosmetic or pharmaceutical composition according to any one of claims 7 to 8, wherein it is selected from the group consisting of creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels , hydroalcoholic solutions, liniments, serums, soaps, shampoos, ointments, foams, ointments, powders, bars, pencils, sprays, sprays, capsules, gelatin capsules, tablets, sugar-coated tablets, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, jellies and jelly. 10. The cosmetic or pharmaceutical composition according to any one of claims 7 to 8, wherein it is a product selected from the group consisting of correctors, makeup bases, makeup remover lotions, makeup remover milks, eye shadows, lipsticks, Lip protectors, powders, nail polishes, nail polish removal lotions, cuticle removal lotions, deodorants and antiperspirants. 11. The cosmetic or pharmaceutical composition according to any one of claims 7 to 8, wherein the peptide derivative of general formula (I), its stereoisomers, mixtures thereof, or its cosmetically or pharmaceutically acceptable salts, are incorporated into a tissue , a non-woven tissue or a medical device. 12. The cosmetic or pharmaceutical composition according to any one of claims 7 to 11, wherein it additionally comprises a cosmetic or pharmaceutically effective amount of at least one active agent selected from the group consisting of agents that stimulate or inhibit the synthesis of melanin , bleaching or depigmenting agents, propigmentation agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, antioxidant agents, free radical sequestering agents and / or atmospheric anti-pollution agents, anti-glycation agents, emulsifying agents, emollients , organic solvents, liquid propellants, skin conditioners such as humectants, moisture-retaining substances, alpha hydroxy acids, beta hydroxy acids, humectants, vitamins, pigments or dyes, dyes, gelling polymers, thickeners, surfactants, softeners, wrinkle agents , or cap agents aces to reduce or to treat eye bags, exfoliating agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or capable of inhibiting or preventing their degradation, agents that stimulate the synthesis of collagen, agents that stimulate the synthesis of elastin, agents that stimulate the synthesis of decorin, agents that stimulate the synthesis of laminin, agents that stimulate the synthesis of defensin, agents that stimulate the synthesis of chaperones, agents that stimulate the synthesis of hyaluronic acid, agents that stimulate the synthesis of lipids and components of the stratum corneum, agents that stimulate angiogenesis, agents that inhibit the degradation of collagen, agents that inhibit the degradation of elastin, agents that stimulate proliferation of fibroblasts, agents that stimulate proliferation on keratinocytes, agents that stimulate the differentiation of keratinocytes, skin relaxants, agents that stimulate the synthesis of glycosaminoglycans, DNA repair agents, DNA protective agents, anti-pruritus agents, agents for the treatment of sensitive skin, firming agents , anti-stretch agents, astringent agents, agents that regulate sebum production, agents that stimulate lipolysis, anti-cellulite agents, agents that stimulate healing, coadjuvant agents of circulation, cytokine growth factors, soothing agents, anti-inflammatory agents, agents that they act on the capillary circulation and / or the microcirculation, agents that act on the cellular metabolism, agents destined to improve the dermoepidermal union, preservatives, perfumes, chelating agents, plant extracts, essential oils, marine extracts, agents coming from a process of biofermentation, mineral salts , cellular extracts and sunscreens (organic or mineral photoprotective agents that are active against ultraviolet rays A and / or B), or mixtures thereof. 13. A peptide derivative of the general formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts, according to any one of claims 1 to 5, for use in the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails. 14. The peptide derivative for use according to claim 13, wherein the treatment, care and / or cleaning consisting of the stimulation of the defenses of the skin, mucous membranes, scalp and / or nails. 15. The peptide derivative for use according to any of claims 13 to 14, wherein the treatment, care and / or cleaning of the skin, mucous membranes, scalp and / or nails is of the conditions, disorders and / or pathologies resulting from the proliferation of microorganisms or from being at risk of proliferation of microorganisms.