Peptides, applied in skin, mucosa and/or hair treatment and/or care, and their application in cosmetic or pharmaceutical compositions

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to biotechnology, namely, to peptide for stimulation of Hsp70 (heat shock protein 70) or for protection of skin against ultraviolet radiation. Peptide can be represented by peptide with general formula R1-AA1-AA2-AA3-AA4-R2, its stereoisomers, their mixture and/or their cosmetically or pharmaceutically acceptable salt. AA1 represents -His-; AA2 is selected from the group, consisting of -His-, -Leu- and -Pro-; AA3 represents -Leu-; AA4 is selected from the group, consisting of -Arg- and -Asn-.

EFFECT: claimed invention makes it possible to obtain novel peptide, which is effective for stimulation of Hsp70 synthesis or for protection of skin against ultraviolet radiation.

17 cl, 1 tbl, 16 ex

 

Field of the INVENTION

This invention relates to peptides capable of inducing the expression of heat shock proteins in the skin, mucous membranes and/or hair, and to cosmetic or pharmaceutical compositions which contain these peptides used in the treatment and/or observation of the skin, mucous membranes and/or hair, preferably for the treatment and/or observation of those conditions, disorders and/or diseases of the skin, mucous membranes and/or hair, which are improved or prevented by stimulation of the synthesis of heat shock proteins.

Background of the INVENTION

Skin, mucous membranes and the hair is constantly exposed to stress factors, both chemical and physical nature. Solar radiation, exposure to certain chemicals or high temperatures can have adverse effects on the cells that form the skin, accelerating the aging process and making it look unhealthy. The mechanisms by which ultraviolet radiation (UV) exercise these effects include, among others, the formation of reactive oxygen species, DNA damage and denaturation of proteins.

Denaturation or modification of the protein conformation may entail the occurrence of hydrophobic residues on the protein surface, the situation in which proteins are sensitive to the bulk� units, thus, losing their functionality. It is dangerous for the integrity of cells, and therefore it has certain mechanisms in place to deal with the above situations: all living organisms have mechanisms to prevent damage caused by the accumulation of incorrectly folded proteins [Ananthan J., Goldberg A. L. and Voellmy, R. (1986) "Abnormal proteins serve as eukaryotic stress signals and trigger the activation of heat shock genes" Science 232:522-524].

It was observed that cells respond to stress by increasing the synthesis of so-called stress proteins. This response begins when the cell detects the accumulation of incorrectly folded proteins, giving rise to the increase of transcription of heat shock genes [Lis, J. and Wu, S. (1993) "Protein traffic on the heat shock promoter: parking, stalling, and trucking along" Cell 74:1-4]. The products of these genes are classified into two numerous groups, heat shock proteins and glucoseregulated proteins. The expression "heat shock protein" is derived from the observation of the increase in the synthesis of these proteins in cells incubated with abnormally high temperature. The synthesis of these proteins is increased not only when cells are exposed to higher temperatures, but also in a stressful situation, such as exposure to UV radiation, oxidative stress, osmotic shock, inflammation, hypoxia, exposure to pollutants, such as heavy metals, lack of nutrition � lack of hydration [S. Lindquist (1986) "The heat-shock response" Annu. Rev. Biochem. 55:1151-1191].

Heat shock proteins - a family of proteins classified according to their molecular weight, those that were the subjects of most studies relate to 60 kDa and 70 kDa proteins, due to their selective expression in all cells and their direct involvement in some aspects of the maturation protein. Hsp70 mainly contains two proteins: Hsp73, shape, selectively expressed, and Hsp72, the inducible form, which is transcriptionally regulated by heat shock protein 1 (HSF1). These proteins are also called molecular chaperones for their function in the stacking direction newly synthesized proteins from globaloptions conformation in the final compact structure, avoiding the appearance of conformations susceptible to the formation of aggregates and thus to ensure their proper functionality. Under normal conditions, Hsp70 is located in the nucleus and cytoplasm and temporarily interacts with the newly introduced proteins, it facilitates their packing and facilitates their movement through the Golgi complex and endoplasmic reticulum, with the joint participation of Hsp60. Under stressful conditions, however, Hsp70 forms a complex with unfolded proteins or incorrectly folded proteins to preserve them from degradation and irreversible damage or, conversely, to increase the opportunities for proteolytic�coy attack in case if it is not possible to protect them [S. A. Hayes and Dice, J. F. (1996) "Roles of molecular chaperones in protein degradation" J. Cell. Biol. 132:255-258; M. J. Gething and Sambrook, J. (1992) "Protein folding in the cell", Nature 355:33-45]. Hsp70 or Hsp60 is not done, the formation of coiled protein, they also have some information about the installation; they simply prevent the formation of inappropriate interactions, which can cause incorrect folding or lead to aggregation and, consequently, a loss of functionality.

The mechanism by which a protein adopts its specific conformation, however, is not known.

Also, as supernovae function in restoring the conformation of poorly folded proteins, have been described and the involvement of Hsp70 in the protection and recovery of DNA in the case of damage caused by UV radiation or ionizing radiation [Bases R. (2006) "Heat shock protein 70 enhanced deoxyribonucleic acid base excision repair in human leukemic cells after ionizing radiation" Cell Stress Chaperones 11:240 To 249; P. Niu, Liu L, Gong Z., H. Tan, P. Wang, J. Yuan, Y. Feng, Q. Wei, P. M. Tanguay and T. Wu (2006) "Overexpressed heat shock protein 70 protects cells against DNA damage caused by ultraviolet in a dose-dependent manner" Cell Stress & Chaperones 11:162-169].

Response to stress is a universal conservative cellular defense mechanism, which is reflected in the so-called acquired thermostability, the phenomenon by which cells that have non-lethal heat shock, is able, after the reactivation�vitiligo period in normal temperature growth, to survive the second thermal shock, which would be deadly for the first time [Subjeck, J. R., Sciandra, J. J. and Johnson R. J. (1982) "Heat shock proteins and thermotolerance; a comparison of induction kinetics" Br. J. Radiol. 55:579-584; Angelidis, C. E., Lazaridis I. and Pagoulatos, G. N. (1991) "Constitutive expression of heat-shock protein 70 in mammalian cells confers thermoresistance" Eur. J. Biochem. 199:35-39; G. C. Li, L. Li G., Liu Y. K., Mak, J. Y., Chen L. and Lee W. M. (1991) "Thermal response of rat fibroblasts stably transfected with the human 70-kDa heat shock protein-encoding gene," Proc. Natl. Acad. Sci. USA 88:1681-1685]. It was noticed that this acquired resistance is temporary, it usually lasts from 12 to 24 hours in growing cells and depends on the changes caused by shock initial temperature, such as the levels increase the expression and accumulation shock proteins. Within the Hsp family, it was verified that Hsp70 is responsible for the induction of thermal resistance: specific inhibition, the transcription and synthesis of Hsp72 prevents the protective effects caused by thermal effect [Trautinger P., Kindas-Mugge I. B. Barlan, NeunerP. and Knobler, R. M. (1995) "the 72-kD heat shock protein is a mediator of resistance to ultraviolet light" J. Invest. Dermatol. 105:160-162; Simon MM, Reikerstorfer A., Schwarz A., Krone, C., Luger, T. A., Jaettele M. and Schwarz, T. (1995) "Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release" J. Clin. Invest. 95:926-33].

Subsequently, it was verified that any tool or impact, is able to induce a response to stress, provides cell protection in the face of subsequent exposure environments�TSS, causing stress, regardless of the origin of stress [Kampinga H. H., Brunsting, J. F., Stege, G. J. J., Burgman, P. W. J. J. and Konings A. W. T (1995) "Thermal protein denaturation and protein aggregation in cells made thermotolerant by various chemicals: role of heat shock proteins" Exp.Cell Res. 219:536-546]. External induction of protein expression of shock is, therefore, a possible strategy for the prevention of damage to cellular proteins and thus maintain the integrity of the cell.

There are various diseases described in the literature, which are caused by abnormal protein styling, epidermolysis bullosa [Gu L. H. and P. A. Coulombe (2005) "Defining the properties of the nonhelical tail domain in type ll keratin 5: insight from a bullous disease-causing mutation" Mol Biol Cell. 16:1427-1438], which is caused by improper packing of keratin caused by mutations of some amino acids in its sequence. These diseases are subjects for treatment with compounds that cause an increase in the level of heat shock proteins.

Similarly, compounds which induce increased expression of heat shock proteins, are used in the treatment and/or observation for wounds or as an aid in the healing process and/or re-epithelialization. It is known that wound healing and reconstruction processes there is an increase in the expression of heat shock proteins. In particular, the induction of Hsp expression in case of skin injury specific location keratinocytes � the skin; thus, Hsp70 is considering its synthesis is induced in keratinocytes of the epidermis [Laplante, A. F., Moulin, V., Auger F. A., Landry, J., H. Li, G. Morrow, R. M. Tanguay, and Germain, L. (1998) "Expression of heat shock proteins in mouse skin during wound healing", J. Histochem. Cytochem. 46:1291-301]. It was also observed that external delivery of protein Hsp70 enhances wound healing [Kovalchin, J. T., R. Wang, M. S. Wagh, J. Azoulay, M. Sanders and R. Y. Chandawarkar (2006) "In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-also been other ideas where phagocytosis" Wound Repair Regen. 14:129-137]. It was also described a decrease in the number of Hsp70 in the skin of diabetic patients with poor wound healing and repair [M. S. Bitar, T. Farook, John V. and Francis I. M. (1999) Heat-shock protein 72/73 and impaired wound healing in diabetic and hypercortisolemic states" Surgery 125:594-601; Atalay m, Oksala N., Lappalainen J., Laaksonen D. E., C. K. Sen and Roy, S. (2009) "Heat shock proteins in diabetes and wound healing" Curr. Protein Pept. Sci. 10:85-95; McMurtry A. L, Cho K., Young L. J. - T., C. F. Nelson and Greenhaigh D. G. (1999) "Expression of HSP70 in healing wounds of diabetic and nondiabetic mice" J. surg. Res. 86:36-41]. Thus, the induction of the synthesis of heat shock proteins is a valid strategy for the treatment and/or observation for wounds of the skin and/or mucous membranes and, in particular, in the healing and re-epithelialization of wounds of the skin and/or mucous membranes, which are the result of diabetes.

The involvement of Hsp70 in the regulation of hair growth is also known in the prior art; in particular, in the patent application MX 2007-007622 described the use of compounds inhibiting the synthesis of Hsp70 to slow hair growth. The importance of Hsp70 in the regulation �OST hair provides the use of compounds able to stimulate Hsp synthesis, for the treatment and/or prevention of alopecia, to delay hair loss or to induce their growth and, in particular, for the treatment of baldness caused by chemotherapy for cancer treatment, as described in U.S. patent 2002/0001629.

Abnormal stacking of proteins also affects the skin from the aesthetic point of view. Correct installation of the proteins elastin and collagen is the basis for maintaining the elasticity of the skin and to make skin look smooth and young. The skin of young adults is particularly well adapted to rapid and effective response to a stressful situation, because it is able to synthesize large quantities of Hsp to protect protein folding during synthesis. However, people in older age the ability to maintain the correct laying of the protein is reduced, because with age there is a decrease in the synthesis of Hsp70, which causes the accumulation of damaged proteins or poorly folded, and poor regulation of cell death that causes the skin to look old [Verbeke P, Fonager J, dark BF, Rattan Si. (2001) "Heat shock response and ageing: mechanisms and applications," Cell Biol. Int. 25:845-857]. The effect of abnormal protein folding in the form of skin from an aesthetic point of view is enhanced when the skin is exposed to UV radiation, and refers to the aspect photostorage skin. UV rays are able to deobrat�the IOM destruction of cells, causing cell death. However, it has been shown that exposure to high temperatures has a certain protective effect on the cells, reducing the amount of cell death caused by UVB [TrautingerF., Knobler R., Honigsmann H., M. W. Mayr and Kindas-Mugge 1. (1996) "Increased expression of the 72-kD heat shock protein and reduced sunburn cell formation in human skin after local hyperthermia" J. Invest. Dermatol. 107:442-443]. This exposure to high temperatures causes the synthesis of Hsp. They are responsible for the photoprotective effect on the observed harmful effects of UV radiation. Thus, the induction of synthesis of heat shock proteins is the current treatment strategy and/or the monitoring of the skin and/or hair to reduce, delay and/or prevent signs of aging or photoaging.

Both the cosmetic and pharmaceutical sector performed various tests for the development of compounds able to stimulate the synthesis of heat shock proteins. Role of heat shock proteins in different conditions, disorders and diseases, well-known in the prior art, as can be found, for example, in the periodical publications of Heat Shock Proteins in Biology and Medicine (Research Signpost, India) or Cell Stress and Chaperones (Springer, Netherlands), among others.

It is known that some inhibitors semipretioase able to stimulate the production of heat shock proteins, but their high toxicity prevents their use in therapeutic�ski purposes. Because of this, the industry needs to find funds with these properties, and which also can be used without risk to the health of the patient or client.

Various natural extracts that stimulate the synthesis of Hsps have been described in the prior art, such as rye seed extracts, extracts of Opuntia ficus-indica, extracts that contain mangiferin, (US 2006/0088560) or described in documents US 2004/0228816, US 7128914 or FR 2834887, among others. The difficulty of obtaining extracts with homogeneous quality and known composition and cleaning makes them commercial development complex, especially in the pharmaceutical sector. Also describes the various modified synthetic peptides with aldehyde or a-ketoamine functions, which induce the synthesis of Hsp, such as those described in U.S. patent 5942494. However, the aldehyde function is chemically associated with a large number of ingredients commonly used in compositions for topical application, also demonstrating the problem of low stability in formulations that limit its use in cosmetic or dermofarmatsevtiki sector.

Effect use of heat shock proteins in the skin, mucous membranes and/or hair was also obtained from the direct application of these proteins in the skin, mucous membranes and/or hair. In this sense, U.S. patent 5348945 describes exogenous prima�to the amount of protein Hsp70 as a way of reducing mortality fabric, under stressful situations, and especially for the preservation of tissues used for transplantation. Topical application of proteins with high molecular weight is difficult because of their low permeability through the skin and hair, thus making it difficult for a new development in cosmetic and dermofarmatsevtiki sector.

Therefore, despite the large number of existing compounds and/or extracts, there is still the need to identify new compounds that stimulate the synthesis of heat shock proteins, which are more effective and selective than known in the prior art.

DETAILED DESCRIPTION of the INVENTION

This invention provides a solution for the above problems. The applicant of the present invention unexpectedly found that the synthetic peptides whose sequences do not include the aldehyde functionalization, is able to stimulate the synthesis of Hsp70 protein and, therefore, capable of protecting the skin, mucous membranes and/or hair against aggressive actions arising from the impact of stressful situations. These peptides are used in the treatment and/or observation of the skin, mucous membranes and/or hair, preferably for the treatment and/or observation of such conditions, disorders and/or diseases of the skin, mucous membranes and/or hair, which n�malesuada or warned by the stimulation of heat shock proteins.

Definitions.

To facilitate understanding of the present invention, included are the meanings of some terms and expressions used in the context of the present invention.

In the context of the present invention, "skin" is meant as layers which comprise from outer layer, or stratum corneum, to the bottom layer, or hypodermis, including both. These layers are composed of different cell types such as keratinocytes, fibroblasts, melanocytes and/or adipocytes among others.

In the context of the present invention, the term "skin" includes the scalp.

In the context of the present invention, "the care of the skin, mucous membranes and/or hair contains the prevention of disorders and/or diseases of the skin, mucous membranes and/or hair.

In the context of the present invention, the term "aging" refers to the changes experienced by the skin with age (aging) or by exposure to the sun (photoaging) or to environmental factors such as tobacco smoke, extremely cold or windy weather, chemical pollutants or pollution, and includes all the external visible and/or perceptible through touch changes such as, but not limited to, the development of discontinuities on the skin such as wrinkles, facial wrinkles, cracks, unevenness or roughness, increase in the size of pores, loss elasticos�and, loss of skin firmness, loss of skin elasticity, loss of ability to recover after deformation, sagging skin, such as, among others, the sagging cheeks, the appearance of bags under the eyes or the appearance of a double chin, skin discoloration, such as, among other birthmarks, redness, bags or the appearance of hyperpigmented areas such as age spots or freckles, incorrect differentiation, hyperkeratinization, elastosis, keratosis, hair loss, skin "orange peel" effect, loss of collagen structure and other histological changes of the stratum corneum, dermis, epidermis, vascular system (for example, the appearance of spider veins or telangiectasias) or of those tissues, which among others, are closer to the skin. The expression "photoaging" combines a number of processes caused by prolonged exposure of the skin to UV radiation, which leads to premature aging of the skin, and manifests the same physical characteristics, such as aging, such as, without exception, dullness, sagging, changes in color or irregularities in pigmentation, irregular and/or excessive keratinization.

In the context of the present invention under the "photosamity" understand the ability of the compound or composition to prevent or delay the onset of symptoms of photoaging, when it�unity or the composition is applied before exposure to UV radiation.

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

Thus, for example, Asn represents NH2-CH(CH2CONH2)-COOH, Asn-represents NH2-CH-(CH2CONH2)-CO-, -Asn represents-NH-CH(CH2CONH2)-COOH, and-Asn - represents-NH-CH-(CH2CONH2)-CO-. Consequently, a dash, which represents the peptide bond, HE cleaves the 1-Oh of a carboxyl group of the amino acid (represented here in deionized familiar form), when located to the right of the symbol and cleaves the N 2-th amino group of the amino acid when it is located to the left of the symbol; both modifications can be applied to the same symbol (see Table 1).

Table 1
Structure of amino acids and their three letter product code.
SymbolBalanceSymbolBalanceSymbolBalance
-Arg- -His--Asn-
-Leu--Pro-

The abbreviation "AC-" is used in this description to name the acetyl group (CH3-CO-), and the abbreviation "Palm-" is used to name politologue group (CH3-(CH2)14-CO-).

The expression "non-cyclic aliphatic group" is used in the present invention to encompass, for example, and without limitation, a linear or branched alkyl, alkenyl and alkyline group.

The expression "alkyl group" refers to a saturated, linear or branched group, which has from 1 to 24, preferably from 1 to 16, more preferably from 1 to 14, even more preferably from 1 to 12, yet still more preferably from 1, 2, 3, 4, 5 to 6 carbon atoms and which is linked with the rest of the molecule by a simple bond, including, for example, and without limitation, methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl, 5-etylhexyl and similar�E.

The expression "alkenyl group" refers to linear or branched group, which has from 2 to 24, preferably from 2 to 16, more preferably from 2 to 14, more preferably from 2 to 12, still 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 not conjugated, which is connected with the rest of the molecule through a simple connection, including, for example, and without limitation, vinyl, oleyl, linoleyl and similar groups.

The expression "Alchemilla group" refers to linear or branched group, which has from 2 to 24, preferably from 2 to 16, more preferably from 2 to 14, more preferably from 2 to 12, still 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 non-conjugated, which is connected with the rest of the molecule through a simple connection, including, for example, and without limitation, ethinyl group, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, pentenyl, such as 1-pentenyl and similar groups.

The expression "alicyclic group" is used in the present invention to encompass, e.g.�, and without limitation, cycloalkyl or cycloalkenyl, or cycloalkenyl group.

The expression "cycloalkyl" refers to a saturated mono - or polycyclic aliphatic group which has from 3 to 24, preferably from 3 to 16, more preferably from 3 to 14, more preferably from 3 to 12, still more preferably 3, 4, 5 or 6 carbon atoms and which is linked with the rest of the molecule through a single bond, including, for example, and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahedron, decahydronaphthalene, dodecahydrate and the like.

The expression "cycloalkenyl" refers to non-aromatic mono - or polycyclic aliphatic group which has from 5 to 24, preferably from 5 to 16, more preferably from 5 to 14, more preferably from 5 to 12, still more preferably 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 non-conjugated, which is connected with the rest of the molecule through a single bond, including, for example, and without limitation, cyclopent-1-EN-1-yl group and similar groups.

The expression "cycloalkenyl" refers to non-aromatic mono - or polycycle�certification aliphatic group, which has from 8 to 24, preferably from 8 to 16, more preferably from 8 to 14, even more preferably from 8 to 12, still more preferably 8 or 9 carbon atoms, with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or non-conjugated, which is connected with the rest of the molecule through a single bond, including, for example, and without limitation, cycloocta-2-yn-1-yl group and similar.

The expression "aryl group" refers to an aromatic group which has from 6 to 30, preferably 6 to 18, more preferably 6 to 10, still more preferably 6 or 10 carbon atoms, which contains 1, 2, 3 or 4 aromatic rings, and related carbon-carbon bond or condensed, which is connected with the rest of the molecule through a single bond, including, for example, and without limitation, phenyl, naphthyl, biphenyl, indenyl, tenantry or anfranil among others.

The expression "kalkilya group" refers to an alkyl group, substituted aromatic group with from 7 to 24 carbon atoms and including, for example, and without limitation, -(CH2)1-6-phenyl, -(CH2)1-6-(1-naphthyl), -(CH2)1-6-(2-naphthyl), -(CH2)1-6-CH(phenyl)2and such.

The expression "heterocyclic group" from�OSISA to 3 to 10 member heterocycle or a hydrocarbon ring, in which one or more ring atoms, preferably 1, 2 or 3 ring atoms that are other than carbon elements, such as nitrogen, oxygen or sulfur and can be saturated or unsaturated. For the purposes of the present invention heterocyclyl may be cyclic, monocyclic, bicyclic or tricyclic system, which may include a condensed system of rings; the atoms of nitrogen, carbon or sulfur may not necessarily be oxidized in heterocyclyl radical; the nitrogen atom may not necessarily be quaternity; and heterocyclyl radical may be partially or fully saturated or may be aromatic. With increasing preference for the term heterocyclic refers to a 5 - or 6-membered rings.

The expression "heteroallyl group" refers to an alkyl group, a substituted or unsubstituted aromatic heterocyclyl group, the alkyl group has from 1 to 6 carbon atoms, and aromatic heterocyclyl group - from 2 to 24 carbon atoms and 1 to 3 atoms other than carbon, including, for example, and without limitation, -(CH2)1-6-imidazolyl, -(CH2)1-6-triazolyl, -(CH2)1-6-thienyl, -(CH2)1-6-furyl, -(CH2)1-6-pyrrolidinyl and such.

As used in the art, groups, defined� above, maybe the degree of substitution. Thus, the substitution can be in any of the groups of the present invention. References in this document to groups, substituted groups of the present invention indicate that a particular radical may be substituted at one or more available positions by one or more substituents, preferably 1, 2 or 3 positions, more preferably in 1 or 2 positions, more preferably in 1 position. These substituents include, for example, and without limitation, alkyl (C1-C4; hydroxyl; alkoxyl C1-C4; amino; aminoalkyl C1-C4; carbonyloxy C1-C4; oxycarbonyl C1-C4; halogen, such as fluorine, chlorine, bromine and iodine; cyano; nitro; azido; alkylsulfonyl C1-C4; thiol; alkylthio C1-C4aryloxy, such as phenoxy; -NRb(C=NRb)NRbRc; where Rband Rcare selected independently from the group comprising H, alkyl (C1-C4, alkenyl (C2-C4alkynyl C2-C4cycloalkyl3-C10, aryl (C6-C18aralkyl C7-C17, 3-10-membered-heterocyclyl or a protective group of amino group.

Compounds of the present invention

Compounds of the present invention denoted by the General formula

their stereoisomers, �x mixtures and/or their cosmetically or pharmaceutically acceptable salts, characterized by the fact that:

AA1represents-His-;

AA2selected from the group comprising-His-, -Leu -, and-Pro-;

AA3represents-Leu-;

AA4selected from the group comprising a-Arg - and-Asn-;

W, X, Y and Z is independently selected from among them the group including the encoded amino acids and non-coded amino acids;

n, m, p and q are independently chosen among them and have a value between 0 and 1;

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

R1selected from the group comprising H, substituted or unsubstituted no cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl and R5-CO-, where R5is selected from the group including H, substituted or unsubstituted no cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and a substituted or unsubstituted heteroaromatic;

R2selected from the group including-NR3R4, -OR3and-SR3where R3and R4independently selected from the group comprising H, substituted or unsubstituted no cyclic aliphatic group, substituted or �timesany alicyclic, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;

provided that when AA2represents-Leu-, AA4represents-Asn-, Y is-Gln-, then Z is not-Leu-;

and provided that when AA2represents-His-, AA4represents-Arg-, Y -, or Z represents-Tyr-, then p+q is not equal to 1.

Group R1and R2associated with amino-terminal (N-terminal) and carboxy-terminal (C-terminal) ends of the peptide sequence, respectively.

According to a preferred embodiment of the present invention, R1selected from the group comprising N or R5-CO-, where R5selected from the group comprising substituted or unsubstituted alkyl (C1-C24substituted or unsubstituted of alkenyl C2-C24, a substituted or unsubstituted alkinyl2-C24, a substituted or unsubstituted cycloalkyl3-C24substituted or unsubstituted cycloalkenyl C5-C24, a substituted or unsubstituted cycloalkenyl8-C24substituted or unsubstituted aryl C6-C30, a substituted or unsubstituted aralkyl7-C24substituted or unsubstituted heterocyclyl with 3-10 number�avimi members, and a substituted or unsubstituted heteroallyl with from 2 to 24 carbon atoms, with from 1 to 3 atoms other than carbon and an alkyl chain with 1 to 6 carbon atoms. More preferably, R1selected from H, acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoic, cyclohexanecarboxylic, octanoyl, decanoyl, lauroyl, myristoyl, Palmitoyl, stearoyl, oleoyl and linoleoyl. Even more preferably, R1represents H, acetyl, lauroyl, myristoyl or Palmitoyl. In an even more preferred embodiment, the implementation of R1represents acetyl or Palmitoyl.

According to another preferred embodiment of the Rz represents-NR3R4, -OR3or-SR3where R3and R4independently selected from the group comprising H, substituted or unsubstituted alkyl (C1-C24substituted or unsubstituted of alkenyl C2-C24, a substituted or unsubstituted alkenyl C2-C24, a substituted or unsubstituted cycloalkyl3-C24substituted or unsubstituted cycloalkenyl5-C24, a substituted or unsubstituted cycloalkenyl C8-C24substituted or unsubstituted aryl C6-C30, a substituted or unsubstituted aralkyl C7-C24substituted or unsubstituted heterocyclyl with 3-10 ring members and Thames�nny or unsubstituted heteroallyl with from 2 to 24 carbon atoms and from 1 to 3 atoms, other than carbon, where the alkyl chain contains 1 to 6 carbon atoms. In some cases, R3and R4may be connected by saturated or unsaturated carbon-carbon bond, thus forming a cycle with the nitrogen atom. More preferably, R2represents a-NR3R4or-OR3. More preferably, R3and R4selected from the group comprising H, methyl, ethyl, hexyl, dodecyl or hexadecyl. Even more preferably R3represents H, and R4selected from the group comprising H, methyl, ethyl, hexyl, dodecyl or hexadecyl. According to another preferred embodiment of the R2selected from-HE-NH2.

According to another embodiment of the present invention, R1selected from the group comprising H, acetyl, lauroyl, myristoyl or Palmitoyl, AA2is-L-Leu-, AA4is-L-Arg-, and R2is-NR3R4or-OR3where R3and R4independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R2is-HE-or-NH2. More preferably, R1is acetyl or Palmitoyl and R2is-IT. Even more preferably, n, m, p and q are 0.

According to another embodiment of the present invention, R1selected from the group include�her H acetyl, lauroyl, myristoyl or Palmitoyl, AA2is a-L-Pro-, AA4is a-L-Arg -, and R2represents a-NR3R4or-OR3where R3and R4independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R2is a-HE-or-NH2. More preferably, R1represents acetyl or Palmitoyl and R2is a-HE. Even more preferably, n, m, p and q are equal to 0.

Preferably the compound of formula (I) selected from the group including:

Palm-His-Leu-Leu-Arg-NH2,

Palm-His-Leu-Leu-Arg-OH,

Ac-His-Leu-Leu-Arg-NH2,

Ac-His-Leu-Leu-Arg-OH,

Ac-His-Leu-Leu-Arg-NH-(CH2)15-CH3,

Palm-His-Leu-Leu-Asn-NH2,

Palm-His-Leu-Leu-Asn-OH,

Ac-His-Leu-Leu-Asn-NH2,

Ac-His-Leu-Leu-Asn-OH,

Ac-His-Leu-Leu-Asn-NH-(CH2)15-CH3,

Palm-His-Pro-Leu-Arg-NH2,

Palm-His-Pro-Leu-Arg-OH,

Ac-His-Pro-Leu-Arg-NH2,

Ac-His-Pro-Leu-Arg-OH,

Ac-His-Pro-Leu-Arg-NH-(CH2)15-CH3,

Palm-His-Pro-Leu-Asn-NH2,

Palm-His-Pro-Leu-Asn-OH,

Ac-His-Pro-Leu-Asn-NH2,

Ac-His-Pro-Leu-Asn-OH,

Ac-His-Pro-Leu-Asn-NH-(CH2)15-CH3,

Palm-His-His-Leu-Arg-NH2,

Palm-His-His-Leu-Arg-OH,

Ac-His-His-Leu-Arg-NH2,

Ac-His-His-Leu-Arg-OH,

Ac-His-His-Leu-Arg-NH-(CH2)15-CH3,

Palm-His-His-Leu-Asn-NH2,

Palm-His-His-Leu-Asn-OH,

Ac-His-His-Leu-Asn-NH2,

Ac-His-His-Leu-Asn-OH,

Ac-His-His-Leu-Asn-NH-(CH 2)15-CH3,

Ac-Gly-Gly-His-Pro-Leu-Asn-OH,

Ac-His-His-Leu-Asn-Ala-Leu-OH,

Ac-Gly-His-His-Leu-Asn-Ala-OH,

their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts.

The peptides of the present invention can exist as stereoisomers or mixtures of stereoisomers; for example, amino acids that form them, may be L-, D-configuration or be racemic independently from each other. Therefore, it is possible to obtain a mixture of isomers as well as racemic mixtures or diastereomeric mixture, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and which isomers or isomeric mixtures are present. The preferred structures of the peptides of the present invention are pure isomers, i.e. enantiomers or diastereomers.

For example, when it is stated that AA1maybe-His-, it is clear that AA1selected from-L-His-, -D-His - or their mixture is racemic or nonracemic. In the same way, when specified AA2maybe-Leu-, it is clear that it can be-L-Leu-, -D-Leu - or mixtures thereof, may be racemic or nonracemic. The methods of preparation described in this document allow a specialist in this prior art to obtain each of the stereoisomers of the peptide of the present invention, by choosing the amino acid with the appropriate config�radiation.

In the context of the present invention, the expression "non-coded amino acid" refers to those not encoded by the genetic code amino acids, natural or unnatural, such as, and not limited to, citrulline, ornithine, sarcosine, desmosine, Norvaline, 4-aminobutyric acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 6-aminohexanoic acid, 1-nafcillin, 2-nafcillin, 2-aminobenzoic acid, 4-aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamyl acid, thienylene, hydroxyproline, ALLO-isoleucine, ALLO-threonine, isonicotinoyl acid, Soeren, phenylglycine, astatin, β-alanine, norleucine, N-methyl amino acids, β-amino acids and γ-amino acids, among others, as well as their derivatives. A list of unnatural amino acids can be found in the article "Unusual amino acids in peptide synthesis" by D. C. Roberts and F. Vellaccio, in The Peptides, Vol.5 (1983), Chapter VI, Gross E. and Meienhofer J., Peg., Academic Press, New York, USA or in the commercial directories of companies specializing in this area, such as a PolyPeptide Laboratories, Bachem, Novabiochem, Sigma-Aldrich, Peptides International, Advanced ChemTech, Chem-lmpex, Maybridge Chemical, Chirotech Technology, Peninsula Laboratories or RSP Amino Acid Analogues among others.

In the context of the present invention, when n, m, p or q is not 0, it is clear that the nature of W, X, Y and/and�and Z does not make the activity of the peptides of the present invention is difficult but it or helps to stimulate the synthesis of heat shock proteins, or has no effect on him.

In the context of the present invention, there is also a cosmetically or pharmaceutically acceptable salts of the peptides provided by the present invention. The expression "cosmetically or pharmaceutically acceptable salt" means a salt that is approved for use in animals and, in particular, on people, and includes salt used for formation of salts of attaching the base, or inorganic, for example, and without limitation, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, among others; or organic, such as, and without limitation, ethylamine, diethylamine, Ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine among others; or for the formation of salts by joining acids, or organic, for example, and without limitation, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, triptorelin, oxalate, pamoate or gluconate among others; or inorganic, for example and without limitation, chloride, sulfate, borate or carbonate among others. The nature of the salt is not critical provided that it is cosmetically and pharmaceutically acceptable. Cosmetically and pharmaceutically acceptable salts of the peptides on�present invention can be obtained by the conventional methods, well known in this art [Berge S. M., Bighley L. D., and Monkhouse, D. C. (1977) "Pharmaceutical Salts" J. Pharm. Sci. 66:1-19].

Aspect of the present invention relates to a peptide of General formula (I), its stereoisomers, their mixtures and/or its cosmetically or pharmaceutically acceptable salts, as described in the present invention for the treatment and/or observation of the skin, mucous membranes and/or hair.

In another particular aspect, the present invention relates to a peptide of General formula (I), its stereoisomers, their mixtures and/or its cosmetically or pharmaceutically acceptable salts, as described in the present invention for the treatment and/or observation of such conditions, disorders and/or diseases which improve or are prevented by stimulating the synthesis of Hsp protein, in particular proteins of the Hsp family with a molecular weight between 20 kDa and 110 kDa, more specifically, with a molecular weight between 40 kDa and 100 kDa, and more specifically proteins Hsp with a molecular weight of between 60 kDa and 80 kDa, and especially Hsp with a molecular weight of 70 kDa or Hsp70.

In a preferred embodiment, the condition, disorder and/or diseases which improve or are prevented by stimulating the synthesis of heat shock proteins selected from the group including epidermolysis epidermis and alopecia, including alopecia caused by cancer treatment hamiota�the Apia.

In another particular aspect the present invention relates to a peptide of General formula (I), its stereoisomers, their mixtures and/or its cosmetically or pharmaceutically acceptable salts, as described in the present invention for the treatment and/or observation of the skin, mucous membranes and/or hair, which reduce, delay or prevent the cellular damage caused by UV radiation, thermal stress, oxidative stress, osmoticheski shock, inflammation, hypoxia, exposure to pollutants, lack of nutrition and lack of hydration.

In another aspect, the present invention relates to a peptide of General formula (I), its stereoisomers, their mixtures and/or its cosmetically or pharmaceutically acceptable salts, as described in the present invention for the treatment and/or observation of the skin, mucous membranes and/or hair, which reduce and/or prevent the signs of aging or photoaging.

In another aspect, the present invention relates to a peptide of General formula (I), its stereoisomers, their mixtures and/or its cosmetically or pharmaceutically acceptable salts, as described in the present invention for the treatment and/or observation of the skin and/or mucous membranes which stimulate healing and/or re-epithelialization of wounds, especially wounds that are sleds�of diabetes.

In another aspect, the present invention relates to a peptide of General formula (I), its stereoisomers, their mixtures and/or its cosmetically or pharmaceutically acceptable salts, as described in the present invention for the treatment and/or observation of the skin and/or hair, which retard or prevent the loss of hair or induce hair growth.

Manufacturing process

The synthesis of the peptides of the present invention, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be performed in accordance with conventional methods known in the art, such as methods of solid-phase peptide synthesis [Stewart J. M. 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], synthesis in solution, a combination of solid-phase synthesis and synthesis in solution or enzymatic synthesis [Kullmann W. (1980) "Proteases as catalysts for enzymic syntheses of opioid peptides" J. Biol. Chem. 255:8234-8238]. The peptides can also be obtained by fermentation of a bacterial strain obtained through genetic engineering or not, to obtain the required sequence by controlled hydrolysis of proteins of animal or vegetable origin, preferably of plant origin�, for the isolation of peptide fragments containing at least the sequence.

For example, a method of producing peptides of formula (I) of the present invention contains the following steps:

- linking amino acids with protected N-terminal end and a free C-terminal end of the amino acid with a free N-terminal end and the C-terminal end protected or bound to a solid substrate;

- removal of the protective group of the N-terminal end;

- repeat the sequence of binding and removing the protective group of the N-terminal end until the required peptide sequence;

- removal of the protective group of the C-terminal end or cleavage from the solid substrate.

Preferably, the C-terminal end bound to a solid substrate, and the process is carried out on the solid phase and, therefore, involves the binding of an amino acid with a protected N-terminal end and a free C-terminal end of the amino acid with a free N-terminal end and the C-terminal end associated with the polymer substrate; removing the protective group from the N-terminal end; and repetition of this sequence as many times as necessary to obtain a peptide of desired length, and finally, the subsequent cleavage of the synthesized peptide from the original�Noah polymeric substrate.

Functional groups of the side chains of amino acids during the synthesis is adequately protected with temporary or permanent protective groups, and the protection can be removed simultaneously or orthogonal with respect to the process of cleavage of the peptide from the polymeric substrate.

Alternatively, solid-phase synthesis can be performed convergent strategy of attaching the peptide to a polymer substrate, or a peptide or amino acid, previously associated with the polymer substrate. The strategy of convergent synthesis is widely known to those skilled in this technical field and are described in Lloyd-Williams P., Albericio F. and Giralt E. in "Convergent solid-phase peptide synthesis" (1993) Tetrahedron 49:11065-11133.

The method may further include the stage of removal of the protective groups from the N-terminal and/or C-terminal ends and/or separation of the peptide from the polymeric substrate in a different order, using standard methods and conditions known in the prior art, after which the functional groups of these ends can be modified. Optional modification of the N-terminal and/or C-terminal ends can be performed with the peptide of formula (I), associated with the polymer substrate or immediately after separation of the peptide from the polymeric substrate.

Optional, R1can be introduced by reaction of the N-terminal end of the peptide of the present Fig�t with R 1-J, where R1- represents, as described above, and J represents a leaving group, for example, and without limitation, tonilou group, mailnow group and halogen groups among others; the reaction of nucleophilic substitution in the presence of an appropriate base and solvent, where the fragments that have the functional groups not involved in the formation of N-C bonds, respectively protected with temporary or permanent protective groups.

Optionally and/or additionally, the radicals R2can be introduced into the reaction of a compound HR2where R2is a-OR3, -NR3R4or-SR3with a complementary fragment, which corresponds to the peptide of formula (I) in which R2is a-HE, in the presence of suitable solvent and base, such as N,N-diisopropylethylamine (DIEA) or triethylamine or an additive such as 1-hydroxy-benzotriazole (HOBt) or 1-gidroksibenzotriazola (HOAt) and a dehydrating means, such as carbodiimide, salt Urania, salt or phosphonium salt of amidine, among others, or prior learning of allhelgona, for example, thionylchloride, and thereby obtaining a peptide in accordance with the General formula (I) of the present invention, where fragments that have the functional group, not involved in education�R N-C bonds, suitably protected with temporary or permanent protective groups, or alternatively other radicals R2can be entered simultaneously switching in the process of separation of the peptide from the polymeric substrate.

Specialists in the art will easily be understood that the steps of removing the protective groups/branches of the C-terminal and N-terminal ends and their subsequent derivatization can be performed in a different order in accordance with methods known in the prior art [Smith M. B. and March J. (1999) "March's Advanced Organic Chemistry Reactions, Mechanisms and Structure", Izd, John Wiley & Sons, 2001].

The expression "protective group" refers to a group that blocks functional organic group and may be removed under controlled conditions. Protective groups, their relative reactivity and the conditions in which they remain inert, known to specialists in this field of technology.

Examples of typical protective groups for the amino group are amides, such as amylacetate, lebensohl, amideast; carbamates, such as benzyloxycarbonyl (Cbz or Z), 2-Chlorobenzyl (CIZ), para-nitrobenzenesulfonyl (pNZ), tert-butyloxycarbonyl (Boc), 2,2,2-Trichloroisocyanuric (Troc), 2-(trimethylsilyl)ethoxycarbonyl (TEOS), 9-fluorenylmethoxycarbonyl (Fmoc) or allyloxycarbonyl (Apos), trityl (TP), methoxytrityl (Mtt), 2,4-dinitrophenyl(Dnp), N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-Illidan)ethyl (Dde), 1-(4,4-dimethyl-2,6-diokso-cyclohexylidene)-3-methylbutyl (ivDde), 1-(1-adamantyl)-1-methylethanolamine (Adpoc), among others, preferably Boc or Fmoc.

Examples of typical protective groups for a carboxyl group are esters, such as complex tert-butyl ether (tBu), allyl complex ether (EN), complex triphenylmethyl ester (compound tritely ester, Trt), complex cyclohexyloxy ester (chx), complex benzyl ether (Bzl), complex ortho-nitrobenzyloxy ether complex pair-nitrobenzyloxy ether complex pair-methoxybenzyloxy ether complex trimethylsilylethynyl ether complex 2-phenylisopropylamine ether complex fluorenylmethyl ether (Fm), complex 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohex)-3-methylbutyl]amino)benzyl ester (Dmab), among others; preferred protective groups of the present invention are the All, tBu, cHx, Bzl and Trt esters.

Side chains of trifunctional amino acids can be protected during the synthesis process with temporary or permanent protective groups, the orthogonal protective groups of the N-terminal and C-terminal ends.

The guanidine group of the arginine side chain can be protected by a nitro group, allyloxycarbonyl (ARS), para-toluensulfonyl (tosyl, Tos), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), 2,2,4,6,7-pent�methylpiperazine-5-sulfonyl (Pbf) or 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), among others; imidazolinone group histidinol side chain can be protected toiley group (Tos), tert-butyloxycarbonyl unit (Qau), trailvoy group (Trt), methoxytrityl group (Mtt) or 2,4-dinitrophenyl group (Dnp), among others; and the amide group of the asparagine side chain can be protected trailvoy group (Trt) or cantilenas group (Xan) or used unprotected.

In a preferred embodiment of the implementation strategy used protective group is a strategy where the amino protecting by Boe, a carboxyl protecting group by Bzl, cHx or an ester, arginine side chain protecting through Mtr or Tos, aspartic side chain using unprotected and histidinol side chain protecting Tos or Dnp.

In another preferred embodiment, the implementation strategy used protective group is a strategy where protect the amino group by Fmoc, the carboxyl protecting group by tBu, NA or Trt esters, arginine side chain protecting through Pmc or Pbf, aspartic side chain through Trt and histidinol side chain through Trt or Mtt.

Examples of these and other additional protective groups, their insertion and removal, can be found in the literature [Greene T. W. and Wuts P. G. M., (1999) "Protective groups in organic synhesis" John Wiley & Sons, New York; Atherton B. and Sheppard R. C. (1989) "Solid Phase Peptide Synthesis: A practical approach" IRL Oxford University Press]. The expression "protective group" also includes a polymeric substrate used in solid-phase synthesis.

When the synthesis takes place totally or partially in solid phase, the possible solid substrate used in the method of the present invention, may include a polystyrene substrate, a polyethylene glycol grafted to polystyrene and similar, for example, and without limitation, R-methylbenzhydrylamine (MVNA) resin [Matsueda G. R. and Stewart J. M. (1981) "A p-methylbenzhydrylamine resin for improved solid-phase synthesis of peptide amides" Peptides 2:45-50], 2-Hortative resin [Barlos, K., Gatos D, Kallitsis J., Papaphotiu G., Sotiriu P., Wenqing Y. and W. Schafer (1989) "Darstellung geschutzter Peptid-Fragmente unter Einsatz substituierter Triphenylmethyl-Harze" Tetrahedron Lett. 30:3943-3946; K. Barlos, D. Gatos, Kapolos S., Papaphotiu G., Schafer W. and Wenqing Y. (1989) "Veresterung von partiell geschutzten Peptid-Fragmenten mit Harzen. Einsatz von 2-Chlorotritylchlorid zur Synthese von Leu1 - Gastrin I" Tetrahedron Lett. 30:3947-3951], resins TentaGel® (Rapp Polymere GmbH), ChemMatrix resin® (Matrix Innovation, Inc), etc., which may include or may not include a labile linker, such as 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) [Albericio F., Kneib-Cordonier N., Biancalana S., Gera L, Masada R. I., Hudson D. and Barany G. (1990) "Preparation and application of the 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy phenoxy)valeric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions" J.Org. Chem. 55:3730-3743], 2-(AM) [Rink H. (1987) "Solid-phase synthesis of protected peptide fragments using a 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] and etc., allowing the simultaneous removal of the protective groups and the separation of the peptide from the polymeric substrate.

Cosmetic or pharmaceutical composition

In this respect, another aspect of the present invention is a cosmetic or pharmaceutical composition, which contains at least a peptide of the General formula (I), its stereoisomers, mixtures thereof, and/or its cosmetically or pharmaceutically acceptable salts together with at least one cosmetically or pharmaceutically acceptable auxiliary means. These compositions can be obtained by conventional means, known to those skilled in the art ["Harry's Cosmeticology", 8 ed. (2000) Rieger M. M., ed., New York Chemical Pub., NY, US; "Remington: The Science and Practice of Pharmacy", 20th ed. (2003) Genaro A. R., ed., Lippincott Williams & Wilkins, Philadelphia, US].

The peptides of the present invention have variable solubility in water, in accordance with the nature of their sequence or any possible modifications in the N-terminal and/or C-terminal ends. Therefore, the peptides of the present invention may be incorporated in the composition by means of an aqueous solution, and those that are not soluble in water, can be dissolved in a cosmetically or pharmaceutically acceptable common solution�the teli, for example, and without limitation, ethanol, propanol, isopropanol, propylene glycol, glycerin, butyleneglycol, or polyethylene glycol, or any combination thereof.

Cosmetically or pharmaceutically effective amount of the peptides of the present invention that are required as input, as well as its dosage will depend on many factors, including age, condition of patient, the nature or severity of the condition, disorder or disease, which requires treatment to be monitored and/or prevented, the route and frequency of administration and the particular nature of the peptides used.

"Cosmetically and pharmaceutically effective amount" is understood as meaning non-toxic, but sufficient amount of the peptide or peptides of the present invention to obtain the desired effect. The peptides of the present invention are used in cosmetic or pharmaceutical compositions of the present invention in a cosmetically or pharmaceutically effective concentrations to achieve the desired effect; in a preferred form, of the total weight of the composition, from 0,00000001% by weight to 20% by weight; preferably 0.000001% by weight to 20% by weight, more preferably from 0.0001% by weight to 10% by weight and even more preferably from 0.0001% by weight to 5% (by weight).

The peptides of the present invention may also be incorporated in cosmetic�Chia or pharmaceutical delivery systems and/or sustained release system.

The expression "delivery system" refers to a diluent, auxiliary means auxiliary substance or carrier, which is administered the peptide of the present invention. These cosmetic or pharmaceutical carriers can be liquids, such as water, oils or surfactants, including petroleum, animal, vegetable or synthetic origin, such as, and without limitation, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, esters sorbitan, ether sulfates, sulfates, betaine, glycosides, maltoside, fatty alcohols, nonoxinol, poloxamer, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin and the like. In "Remington's Pharmaceutical Sciences", E. W. Martin, diluents, auxiliaries or excipients are described as suitable carriers.

The phrase "sustained release" is used in the conventional sense in respect of the delivery system of connections, which provides for the gradual release of the compound over a period of time and preferably, though not necessarily, with relatively constant levels of release of the compound over a period of time.

Examples of delivery systems or sustained release are liposomes, mixed liposomes, oleosomes, niosomes, economy, mill�particles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed micelles of surfactant-phospholipid, military, microspheres and nanospheres, liposphere, millicapsules, microcapsules and nanocapsules, as well as microemulsions and nano-emulsion that can be added to achieve better penetration of the current beginning of the drug substance and/or improve its pharmacokinetic and pharmacodynamic properties. The preferred delivery systems or sustained release are liposomes, mixed micelles of surfactant-phospholipid and microemulsions, more preferably a microemulsion-type "water in oil" with the internal structure of reverse micelles.

The sustained release system can be obtained by methods known in the art, and compositions that contain them, you can enter, for example, by topical or transdermal administration, including patches, non-sticky lining, sealed lining, micro-electric pads or by systemic administration, for example, and without limitation, oral or parenteral, including nasal, rectal or subcutaneous implantation or injection, or direct implantation of Il� injection to a specific part of the body, and preferably they should release a relatively constant quantity of the peptides of the present invention. The amount of peptide contained in the sustained release system will depend, for example, from where you need to enter the composition, the kinetics and duration of release of the peptide of the present invention, as well as the nature of the condition, disorder and/or disease that must be treated and/or subjected to surveillance.

The peptides of the present invention can also be adsorbed on solid organic polymers or solid mineral substrates, such as, and without limitation, talc, bentonite, silica, starch or maltodextrin, among others.

Compositions which contain the peptides of the present invention, can also be incorporated into the fabric, non-woven fabric and medical devices that are in direct contact with the skin, thus releasing the peptides of the present invention or by biodegradation of the binding system to the fabric, non-woven fabric or medical device or by friction between them and the body, because the body moisture, skin pH or body temperature. In addition, tissue and nonwoven materials can be used to create clothing that is in direct contact with the body. Preferably, fabric, non-woven fabrics and medical devices, aderrasi� peptides of the present invention, used for the treatment and/or observation of such conditions, disorders and/or diseases which improve or are prevented by the stimulation of Hsp synthesis.

Examples of fabrics, non-woven materials, clothing, medical devices and means for immobilizing peptides in them, among which are the delivery systems and/or sustained release system described above can be found in the literature and known in the prior art [Schaab C. K. (1986) "Impregnating Fabrics With Microcapsules", HAPPI may 7986; Nelson G. (2002) "Application of microencapsulation in textiles" Int. J. Pharm. 242:55-62; "Biofunctional Textiles and the Skin" (2006) m & as.Probl. Dermatol. v.33, U. C. Hipler and ElsnerP., peg. S. KargerAG, Basel, Switzerland; Malcom R. K.; McCullagh S. D., Woolfson AD., German S. P., Jones D. S. J. Cuddy (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 materials, clothing, and medical devices are bandages, gauze, t-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bedspreads, wipes, plasters, non-sticky lining, leak-proof lining, micro-electric pads and/or mask.

Cosmetic or pharmaceutical compositions which contain the peptides of the present invention, their stereoisomers, their mixtures and/or their cosmetically or pharmaceutically acceptable salts, can be applied in different types of compositions for local or transdermal when�of anenia, not necessarily including a cosmetically or pharmaceutically suitable excipients required for the formation of the desired shape of the introduction [Fault i Trillo C. (1993) in "Tratado de Farmacia Galenica", Luzan 5, S. A. Ediciones, Madrid].

Compositions for local or transdermal application may be obtained from any solid, liquid or semi-solid composition, such as, and without limitation, creams, heterogeneous emulsion, such as, and without limitation, emulsion-type oil and/or silicone in water, emulsions of the type water in oil and/or silicone, emulsions of the type water/oil/water or water/silicone/water emulsion type and oil/water/oil or silicone/water/silicone, anhydrous compositions, aqueous dispersions, oils, milks, balsams, foams, lotions, gels, cream gels, hydroalcoholic solutions, water-glycol solutions, hydrogels, liniments, sera, Soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, pomades, powders, pieces, pencils and sprays or aerosols (sprays), including leave-in and rinse-off formulations. These formulations for local or transdermal application can be enabled using techniques known to those skilled in the art, different types of solid accessories such as, and without limitation, bandages, gauze, t-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bedspreads, traps�, patches, non-sticky lining, leak-proof lining, micro-electric pads or facial mask, or you can include them in different makeup, such as Foundation cream, such as liquid Foundation and compact Foundation, the compositions for removing makeup, cleansing milk for removing makeup, corrective remedy under eyes, eye shadows, lipsticks, hygienic lipsticks, lip gloss and powder, among others.

Cosmetic and pharmaceutical compositions of the present invention may include features that increase the absorption through the skin peptides of the present invention, such as, and without limitation, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylsulfate-2-it), alcohol, urea, ethoxydiglycol, acetone, propylene glycol or polyethylene glycol, among others. In addition, cosmetic or pharmaceutical compositions of the present invention can be applied to restricted areas for treatment by means of iontophoresis, sonophoresis, electroporation, micro-electric pads, mechanical pressure, osmotic pressure gradient, jointing tools, microinjections or bezgolosyh injections by means of pressure, such as injections by means of pressure of oxygen, or any combination thereof, to achieve �Otsego penetration of the peptide of the present invention. The scope may be determined by the nature of the condition, disability and/or illness, which neobhodimo be subjected to treatment or observation.

In addition, cosmetic compositions containing the peptides of the present invention, their stereoisomers or their cosmetically or pharmaceutically acceptable salts, can be applied in different types of formulations for oral administration, preferably in the form of oral cosmetics and pharmaceutical drugs, such as, and without limitation, capsules, including gelatin capsules, soft capsules, hard capsules, tablets, including sugar coated tablets, powders, granules, chewing gum, solutions, suspensions, emulsions, syrups, polysaccharide films, jellies or gelatin and any other forms known to those skilled in the art. In particular, the peptides of the present invention can be included in any form of functional food or vitaminsforyou food product, such as, and without limitation, dietary bars or compact or non-compact powders. These powders can be dissolved in water, juices, aerated water, dairy products, soy or derivatives can be included in diet bars. The peptides of the present invention can be formulated with such additives and auxiliary�patients remedies for oral compositions or food supplements, such as, and without limitation, fat components, aqueous components, wetting means, preservatives, improvers consistency, flavor additives, fragrances, antioxidants and colorants common in the food industry.

Cosmetic or pharmaceutical compositions containing the peptides of the present invention, their stereoisomers, their mixtures and/or their cosmetically or pharmaceutically acceptable salts, can also be used for local or transdermal manner, or by any other suitable means, as for example oral or parenteral route, for which they will include the pharmaceutically acceptable excipients necessary to produce a desired form of administration. In the context of the present invention, the phrase "parenteral introduction in case" includes nasal, auricular, ocular, rectal, urethral, vaginal, subcutaneous, intradermal, intravascular injections, such as intravenous, intramuscular, intraocular, intravitreal, intracerebral, intraspinal, bone marrow, intracranial, intracervically, intracerebral, intermembranous, intra-articular, intrahepatic, intrathoracic, intratracheal, intrathecal and vnutribrjushinnye, and any another similar injection or infusion technique. The review of the different pharmaceutical f�rmam the introduction of active ingredients and excipients required to obtain them can be found, for example, in "Tratado de Farmacia Galenica", C. Fault i Trillo, 1993, Luzan 5, S. A. Ediciones, Madrid.

Among the cosmetically or pharmaceutically suitable auxiliaries contained in the cosmetic or pharmaceutical compositions described in the present invention include additional ingredients commonly used in compositions for the treatment and/or observation of the skin, mucous membranes and/or hair, such as, and without limitation, heat shock proteins, other means of stimulating the synthesis of heat shock proteins, inhibitors of the aggregation of the acetylcholine receptor, means inhibiting the muscle contraction, anticholinergic means, inhibiting elastase, means inhibiting the matrix metalloproteinases, a means of stimulating or inhibiting the synthesis of melanin, whitening or depigmenting means propagandise means, bronzer, funds, aging, remedies that inhibit MO-synthase, means inhibiting 5A-reductase, and means inhibiting lysyl - and/or prolylhydroxylase, antioxidants, scavengers of free radicals and/or agents against atmospheric pollution, scavengers of reactive carbonyl groups, artiglierie funds, antihistamine tools, antiviral agents, Antip�residenee funds emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners such as moisturizing agents, substances that retain moisture, alphahydroxy acid, betahydroxylase, moisturizers, epidermal hydrolytic enzymes, vitamins, amino acids, proteins, pigments or colorants, dyes, gelling polymers, thickeners, surfactants, emollients, means the port of wrinkles, remedies that can reduce or treat bags under the eyes, exfoliating, antibacterial agents, antifungal means, fungistatic means, a bactericidal agent, a bacteriostatic agent, the funds, stimulating the synthesis of dermal or epidermal macromolecules and/or capable of inhibiting or preventing their degradation, such as, for example, agents that stimulate the synthesis of collagen, agents that stimulate the synthesis of elastin, agents that stimulate the synthesis decorin, a means of stimulating the synthesis of laminin, a means of stimulating defensin synthesis, agents that stimulate the synthesis of aquaporins, agents that stimulate the synthesis of hyaluronic acid, agents that stimulate the synthesis of fibronectin, agents that stimulate the synthesis of sirtuins, agents that stimulate the synthesis of lipids and components of the stratum corneum (CERA�IDA, fatty acids, etc.), means that inhibit the degradation of collagen, other remedies that inhibit the degradation of elastin, means which inhibit semipretioase, for example, cathepsin G, a means of stimulating fibroblast proliferation, agents that stimulate the proliferation of keratinocytes, agents that stimulate the proliferation of adipocytes, a means of stimulating the proliferation of melanocytes, a means of stimulating the differentiation of keratinocytes, agents that stimulate the differentiation of adipocytes, means which inhibit acetylcholinesterase, means causing relaxatio skin, agents that stimulate the synthesis of glycosaminoglycan, a means that prevents hyperkeratosis, zit remedies, antipsoriatic drugs, DNA-reducing agents, DNA-protective agents, stabilizers, protivochesotocnaya funds, funds for the treatment and/or monitoring of sensitive skin, firming funds, funds against stretch marks, bonding agent, means for regulating the secretion of sebaceous glands, lipolytic funds or a means of stimulating lipolysis, anti-cellulite remedies, remedies for hyperhidrosis, a means to promote healing, aid healing, agents that stimulate the re-epithelialization, tools to help re-epithelialization, op�cinavia growth factors, sedatives, anti-inflammatory and/or analgesics, anesthetic funds, agents acting on capillary circulation and/or microcirculation, agents that stimulate angiogenesis, the funds that inhibit vascular permeability, venotonizirutee funds, funds that affect cell metabolism, a means of enhancing the dermal-epidermal connection, means of inducing hair growth remedies that inhibit or slow hair growth, means slowing down hair loss, preservatives, fragrances, chelating means, plant extracts, essential oils, extracts from seaweed, the funds the resulting fermentation processes, mineral salts, cell extracts and sunscreens (organic or mineral photoprotective agents active against ultraviolet rays A and/or b), among others, provided that they are physically and chemically compatible with other components of the composition and especially with the peptides of General formula (I) contained in the composition of the present invention. In addition, the nature of these additional ingredients should not change an inappropriate way, the effects of the peptides of the present invention. The nature of these additional ingredients can be synthetic or natural, for example, a plant extract� or obtained by biotechnological process or a combination of synthetic and biotechnological process process. Additional examples can be found in the CTFA International Cosmetic Ingredient Dictionary &Handbook, 12 ed. (2008). In the context of the present invention biotechnological process is understood as any process that produces an active ingredient or a part of the body or its parts.

An additional aspect of the present invention relates to cosmetic or pharmaceutical composition containing a cosmetically or pharmaceutically effective quantity of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, and also a cosmetically or pharmaceutically effective quantity of at least one extract, synthetic compounds or bio-enzymatic product that stimulates the synthesis of Hsp, such as, and without limitation, extracts of Opuntia ficus indica, Salix alba, Lupinus spp., Secale cereale, extracts of red algae of the genus Porphyra, extracts of crustaceans of the genus Artemia, seed oil, jojoba oil, extracts of grape seeds, extracts of green tea, geranylgeranylation, celastrol, zinc and its salts, 2-cyclopenten-H-he, the proteasome inhibitors, such as, and without limitation, bortezomib; prostaglandins and their derivatives, hydroxylamine and its derivatives, such as, and without limitation, bioglobal; Halcon and its derivatives, hyperosmotic agents such as, and without limitation�t, sorbitol and its derivatives, mannitol and its derivatives or glycerol and its derivatives, isosorbide, urea or salicylic acid and its derivatives, among others, or mixtures thereof.

An additional aspect of the present invention relates to cosmetic or pharmaceutical compositions containing a cosmetically or pharmaceutically effective quantity of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, and also a cosmetically or pharmaceutically effective quantity of at least one extract, which is anti-wrinkle and/or anti-aging agent, such as, and without limitation, extracts of Vitis vinifera, Rosa canina, Curcuma longa, Iris pallida, Theobroma cacao, Ginkgo biloba, Leontopodium Alpinum or Dunaliella salina among others, or in addition, at least one synthetic compound or biofermentnyh product which is a wrinkle and/or anti-aging agent, such as, and without limitation, Matrixyl® [INCI: Palmitoyl Pentapeptide-4], Matrixyl 3000® [INCI: Palmitoyl tetrapeptide-7, Palmitoyl Oligopeptide], Essenskin™ [INCI: hydroxylation calcium], Renovage [INCI: teprenone] or Dermaxyl® [INCI: Palmitoyl Oligopeptide], sold by Sederma, Vialox® [INCI: Pentapeptide-3], Syn-Ake [INCI: dipeptide diaminobutyric benzylated diacetate], Syn®-Coll [INCI: PAL�Michail Tripeptide-5], Phytaluronate [INCI: gum, carob (Ceratonia Siliqua)] or Preregen® [INCI: glycine soy protein (Soybean), oxidoreductase] sold by Pentapharm/DSM, Myoxinol™ [INCI: hydrometerology extract of Hibiscus Esculentus], Syniorage™ [INCI: acetyl tetrapeptide-11], Dermican™ [INCI: acetyl tetrapeptide-9] or DN-AGE™ LS [INCI: extract of the leaves of Cassia Alata] marketed by laboratories serobiologiques/Cognis (Laboratories Serobiologiques/Cognis), Algisum C9[INCI: methylsilanol-mannuronate] or Hydroxyprolisilane CN® [INCI: methylsilanol hydroxyproline aspartate] sold by Exsymol, Argireline® [INCI: acetyl Hexapeptide-8], SNAP-7 [INCI: acetyl heptapeptide-4], SNAP-8 [INCI: acetyl OCTA-peptide-3], LeuphasyI® [INCI: Pentapeptide-18], Inyline™ [proposed INCI name: acetyl Hexapeptide-25], Aldenine® [INCI: hydrolyzed wheat protein, hydrolyzed soy protein, Tripeptide-1], Preventhelia™ [INCI: diaminopropanol Tripeptide-33], Decorinyl® [INCI: Tripeptide-10 citrulline], Trylagen® [INCI: extract enzyme Pseudoaltei-omonas, hydrolyzed wheat protein, hydrolyzed soy protein, Tripeptide-10 citrulline, Tripeptide-1], Eyeseryl® [INCI: acetyl tetrapeptide-5], Peptide IS [INCI: acetyl Tripeptide-30 citrulline], Relistase™ [proposed INCI name: acetyl tetrapeptide-30], Lipochroman-6 [INCI: dimethylmethoxy of chromanol], Chromabright™ [INCI: dimethylmethoxy chromanol a palmitate], Antarcticine® [INCI: extract of Pseudoalteromonas ferment] or Vilastene™ [INCI: lysine HCL, lecithin, Tripeptide-10 citrulline], marketed Lipotec, Kollaren® [INCI: Tripeptide-1, text�EN], sold by Institut Europeen de Biologie Cellulaire, Collaxyl®IS [INCI: Hexapeptide-9], Laminixyl IS™ [INCI: heptapeptide], Orsirtine™ GL [INCI: extract Oryza Sativa (rice)], D Orientine™ IS [INCI: extract of seeds of Phoenix Dactylifera (date palm)], Phytoquintescine™ [INCI: extract of wheat odnosemyanka (Triticum Monococcum)] or Quintescine™ IS [INCI: dipeptide-4] marketed Vincience/ISP, BONT-L-Peptide [INCI: the Palmitoyl Hexapeptide-19] marketed Infinitec Activos, Deepaline™ PVB [INCI: Palmitoyl hydrolyzed wheat protein] or Sepilift® DPHP [INCI: dipalmitoyl hydroxyproline], sold by Seppic, Gatuline® Expression [INCI: extract of Acmella oleracea], Gatuline® In-Tense [INCI: Spilanthes flower extract Acmella] or Gatuline® Age Defense 2 [INCI: seed extract, Juglans Regia (walnut)] sold by Gattefosse, Thalassine™ [INCI: extract of marine algae] sold Biotechmarine, ChroNOIine™ [INCI caproyl tetrapeptide-3] or Thymulen-4 [INCI: acetyl tetrapeptide-2] marketed Atrium Innovations/Unipex Group, EquiStat [INCI: fruit extract Pyrus Malus, glycine extract of soybean seeds] or Juvenesce [INCI: ethoxydiglycol and Caprylic triglyceride, retinol, ursolic acid, phytonadione, ilomastat] sold by Coletica/Engelhard/BASF, Ameliox [INCI: cartonin, tocopherol, fruit of the Silybum Marianum extract] or PhytoCellTec Malus Domestica [INCI: cell culture Malus Domestica fruit], sold Mibelle Biochemistry, Bioxilift [INCI: Pimpinella Anisum extract] or SMS Anti-Wrinkle® [INCI: extract of seeds of Annona Squamosa] sold by Silab, antagonists of the CA2+channel, such as, and without limitation, alverin, salts of manganese or magnetic�I, known secondary or tertiary amines, retinol and its derivatives, idebenone and its derivatives, coenzyme Q10 and its derivatives, Boswellia acid and its derivatives, GHK and its derivatives and/or salts, carnosine and its derivatives, DNA repair enzymes, such as, and without limitation, photolyase, T4 endonuclease V or antagonists and chloride channel among others.

In addition, this invention relates to a cosmetic or pharmaceutical composition, which contains a cosmetically or pharmaceutically effective quantity of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, and also a cosmetically or pharmaceutically effective quantity of at least one extract or combination of extracts that stimulate healing and/or re-epithelialization or facilitate the healing and/or re-epithelialization, such as, and without limitation, extracts of Centella asiatica, Rosa moschata, Echinacea angustifolia, Symphytum officinal, Equisetum arvense, Hypericum perforatum, Mimosa tenuiflora, Aloe vera, Polyplant® Epithelizing [INCI: Calendula officinalis, Hypericum perforatum, Chamomilla recutita, Rosmarinus officinalis] marketed Provital, Cytokinol® LS 9028 [INCI: hydrolyzed casein, hydrolyzed yeast protein, lysine HCL] marketed by laboratories serobiologiques/Cognis (Laboratories Serobiologiques/Cognis) or Deliner® [INCI: extract of grains of Zea mays (maize)], about�awaymy Coletica/Engelhard/BASF, among others, and/or a cosmetically or pharmaceutically effective quantity of at least one synthetic compound, extract or biofermentation product that stimulate healing and/or re-epithelialization, such as, and without limitation, cadherin, integrins, selectins, receptors hialuronowy acids, immunoglobulins, fibroblast growth factor, growth factor connective tissue growth factor, platelet growth factor, vascular endothelial, epidermal growth factor, insulin-like growth factor, growth factors, keratinocyte, colony-stimulating factors, transforming factor-beta growth factor-alpha tumor necrosis, interferons, interleukins, matrix metalloproteinase, protein receptor tyrosine phosphatase, Antarcticine® [INCI: extract of Pseudoalteromonas ferment] or Decorinyl® [INCI: Tripeptide-10 citrulline], marketed Lipotec, among others, or a mixture thereof.

In an additional aspect, the present relates to a cosmetic or pharmaceutical composition, which contains a cosmetically or pharmaceutically effective quantity of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, and, in addition, a cosmetically or pharmaceutically effective quantity of at least one extract or combination of extracts, �have a quiet slow hair loss or increase hair growth, such as without limitation extracts of Tussilago farfara, or Achillea millefolium, and/or a cosmetically or pharmaceutically effective quantity of at least one compound that slows hair loss or inducing hair growth, such as, without limitation, esters of nicotinic acid, for example, alkylsulfonate3-C6such as methyl or exillerating, benzylsuccinic or tocopherylacetate; steroidal and non-steroidal anti-inflammatory agents such as, without limitation hydrocortisone, its salts and derivatives, or niflumova acid; retinoids, such as, without limitation, all-TRANS-retinoic acid, or tretinoin, isotretinoin, retinol or vitamin a and its derivatives, such as acetate, palmitate, propionate, matricine, etretinate and zinc TRANS retinal; antibacterial agents such as, without limitation macrolides, pyranoside and tetracycline, erythromycin; calcium channel antagonists such as, without limitation, Cinnarizine and diltiazem; hormones such as, without limitation estriol, its analogues or tyrosine, its analogues and/or its salts; antiandrogenov means, such as without limitation oxendolone, spironolactone, or diethylstilbestrol; antiradical, such as without limitation, dimethyl sulfoxide; esterified oligosaccharides, such as without limitation those described in prior�mentah EP 0211610 and EP 0064012; derivatives hexasaccharide acids, such as, without limitation glucose sahariana acid or those described in document EP 0375388; glucosidase inhibitors, such as, without limitation 0 glucaro-1,5-lactam or those described in document EP 0334586; inhibitors of glycosaminoglycan and proteoglycan, such as without limitation L-galactono-1,4-lactone or those described in document EP 0277428; tyrosine kinase inhibitors, such as without limitation 1-amide-1-cyano(3,4-dihydroxyphenyl)ethylene or what is described in the document EP 0403238, diazoxide, such as without limitation 7-(acetylthio)-4',5'-dihydrospiro[androst-4-ene-17,2'-(3H)furan]-3-one, 3-methyl-7-chloro[2H]-1,2,4-benzothiadiazin or spiroxazine 1,1-dioxide; phospholipids, such as, without limitation lecithin; salicylic acid and its derivatives, hydroxycarboxylic or clockability acids and their esters, lactones and their salts; anthralin, acoso-5,8,11-triene acids and their esters or amides, or Minoxidil and derivatives thereof, among others, or mixtures thereof.

In an additional aspect, the present relates to a cosmetic or pharmaceutical composition, which contains a cosmetically or pharmaceutically effective quantity of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, and, moreover, cosmetic, etc�Cesky or pharmaceutically effective amount of at least one sunscreen, such as without limitation anthranilate, cinnamates, salicylates, derivatives dibenzoylmethane, camphor derivatives, triazine derivatives, benzophenone derivatives, derivatives of β,β'-diphenylacetate, benzotriazole derivatives, derivatives of benzylmalonate, derivatives of benzimidazole, imidazoline, derivatives of bentolila, derivatives of p-aminobenzoic acid, polymers and silicones, derivatives of alkylthiols, nanopigments of metal, such as without limitation titanium oxide or zinc oxide or filters based on carbon nanotubes among others, or mixtures thereof.

In an additional aspect, the present relates to a cosmetic or pharmaceutical composition, which contains a cosmetically or pharmaceutically effective quantity of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, and, in addition, a cosmetically or pharmaceutically effective quantity of at least one protein of the Hsp family, such as without limitation Hsp70, including Hsp72 and Hsp73, Hsp60, Hsp27 or HspQO among others.

Application

Aspect of the present invention relates to the use of at least one peptide according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts in cooked�Institute of cosmetic or pharmaceutical compositions for the treatment and/or care of skin, mucous membranes and/or hair.

Another aspect of the present invention relates to the use of at least one of the peptides according to General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts in the preparation of cosmetic or pharmaceutical compositions for the treatment and/or care for these conditions, disorders and/or diseases which improve or are prevented by stimulating the synthesis of Hsp protein, in particular proteins of the Hsp family of molecular weight from 20 kDa to 110 kDa, in particular with a molecular weight from 40 kDa to 100 kDa, and more specifically proteins Hsp with a molecular weight of 60 kDa to 80 kDa, and in particular Hsp with a molecular weight of 70 kDa or Hsp70.

In a preferred embodiment, the condition, disorder and/or diseases which improve or are prevented by the stimulation of the heat shock protein, selected from the group formed epidermolysis epidermtm and alopecia, including alopecia caused by cancer treatment with chemotherapy.

According to a preferred embodiment of the present invention relates to the use of the peptide of formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts in the preparation of cosmetic or pharmaceutical to�positions for the treatment and/or care of skin, mucous membranes and/or hair, which reduce, delay or prevent the cellular damage caused by UV radiation, thermal stress, oxidative stress, osmotic shock, inflammation, hypoxia, effects of pollutants, lack of nutrition and lack of hydration.

According to a preferred embodiment of the present invention relates to the use of the peptide of formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts in the preparation of cosmetic or pharmaceutical compositions for the treatment and/or care of skin, mucous membranes and/or hair, which reduce, delay or prevent the signs of aging and/or photoaging.

Similarly, the present invention relates to the use of the peptide of formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts in the preparation of cosmetic or pharmaceutical compositions for the treatment and/or care of skin, mucous membranes and/or hair, which stimulate healing and/or re-epithelialization of wounds, preferably such wounds that result from diabetes.

According to a preferred embodiment of the present invention relates to the use of the peptide of formula (I), its stereoisomer�ditch their mixtures and/or its cosmetically or pharmaceutically acceptable salts in the preparation of cosmetic or pharmaceutical compositions for the treatment and/or care of skin, mucous membranes and/or hair, which inhibit and/or prevent the loss of hair or induce hair growth.

Examples of cosmetic or pharmaceutical compositions for the treatment and/or care of skin, mucous membranes and/or hair include creams, a lot of emulsions, such as, without limitation emulsion of oil and/or silicone in water, emulsions of water-in-oil and/or silicone type emulsions, water/oil/water or water/silicone/water, and the type of emulsions oil/water/oil or silicone/water/silicone, anhydrous compositions, aqueous dispersions, oils, milk, balms, foams, lotions, gels, cream gels, aqueous-alcoholic solutions, water-glycol solutions, hydrogels, liniments, sera, Soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, pomades, powders, bars of soap, pencils and sprays or aerosols (sprays), including remaining in place and rinse-off formulations, bandages, gauze, t-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, bandages, sheets, cloths, adhesive plasters, neagative lining, leak-proof lining, micro-electric pads or masks, cosmetic products, for example, cosmetic, etc�ski bases, such as fluid foundations and compact foundations, make-up remover lotions, make-up removing milk, correctors under the eyes, eye shadow, lipstick, hygienic lipsticks, lip glosses and powders among others.

The compositions containing the peptides of this invention may be applied cutaneous or can be administered orally or parenterally, as it is necessary for the treatment and/or care for a condition, disorder and/or disease.

Cosmetic or pharmaceutical compositions covered by this invention, can be applied by cutaneous iontophoresis, sonophoresis, electroporation, micro-electric pads, mechanical pressure, osmotic pressure gradient, occlusive treatment, microinjections or injections without a needle by means of pressure, such as injections by oxygen pressure, or any combination thereof to obtain a greater penetration of the peptide of the present invention.

An additional aspect of the present invention relates to a method of treatment and/or care of skin, mucous membranes and/or hair, which contains the use of cosmetically or pharmaceutically effective quantity of at least one peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical�ticheskii compositions containing them.

An additional aspect of the present invention relates to a method of treatment and/or care for these conditions, disorders and/or diseases of mammals, preferably humans, which improve or are prevented by stimulating the synthesis of heat shock proteins, preferably Hsp70; which contains the introduction of an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical compositions containing them.

In a preferred embodiment of the implementation, condition, disorder and/or pathology, which improve or are prevented by stimulating the synthesis of heat shock proteins selected from the group formed by epidermolysis epidermtm and alopecia, including alopecia caused by cancer treatment with chemotherapy.

Another additional aspect of the present invention relates to a method of treatment and/or care of skin, mucous membranes and/or hair, which reduces, retards or prevents the cellular damage caused by UV radiation, thermal stress, oxidative stress, osmotic shock, inflammation, hypoxia, effects of pollutants, lack of food and lack of hydrate�AI; which contains an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical compositions containing them.

According to an additional aspect of the present invention relates to treatment and/or care reduces, delays or prevents the signs of aging and/or photoaging, which includes the use of an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical compositions containing them.

In another additional aspect, the present invention relates to a method for the treatment and/or care of skin and/or mucous membranes which stimulates the healing and/or re-epithelialization of wounds, preferably of injuries that are a consequence of diabetes, and which contains an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical compositions containing them.

In another additional�the DIY aspect, the present invention relates to a method for the treatment and/or care of skin and/or hair, which slows and/or prevents the loss of hair or induce hair growth, which contains an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical compositions containing them.

In a more particular aspect, the treatment and/or care of the present invention is made of an external or transdermal introduction; preferably, the outer or transdermal application is performed via iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive treatment, microinjections or injection without the needle through pressure, through micro-electric pads, or any combination thereof.

In another particular aspect, the treatment and/or care was performed by oral administration.

In another particular aspect, the treatment and/or care was performed by parenteral use.

The frequency of application or administration may vary considerably depending on the needs of each subject and the severity of the condition, disorder or disease that treat or care recipients with the recommended application or introduction, in the range from once a month to ten times a day, preferred�Uo from once per week to four times per day more preferably from three times a week to three times a day, preferably once or twice a day.

The following specific examples cited here illustrate the nature of this invention. These examples are included for illustrative purposes only and should not be construed as limitations stated herein of the present invention.

EXAMPLES

The General methodology

All reagents and solvents have a synthetic quality and used without further treatment.

Abbreviations

Abbreviations used for amino acids follow IUPAC-IUB Joint Commission on Biochemical Nomenclature rules outlined in Eur.J. Biochem. (1984) 138:9-37 and in J. Biol. Chem. (1989) 264:633-673.

®, resin; AC, acetyl; DNA, deoxyribonucleic acid; Adpoc, 1-(1-adamantyl)-1-methylethanolamine; AHN, allyl; Alloc, allocerror; AM, 2-[4-aminomethyl-(2,4-dimethoxyphenyl)]venexiana acid; Arg, arginine; Asn, asparagine, Boc, tert-butyloxycarbonyl; 2-BrZ, 2-bromobenzyloxycarbonyl; Bzl, benzyl; Cbz, carboxybenzoyl; chx, cyclohexyl; CITrt-®, 2-chlorotrityl resin; CIZ, 2-Chlorobenzyl; cps, CPS; C-terminal, carboxy-terminal; DCM, dichloromethane; Dde, N,N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1 - Illidan)ethyl; 2,6-diCIZ, 2,6-dichlorobenzyl; DIEA, N,N-diisopropylethylamine; DIPCDI, N,N'-diisopropylcarbodiimide; Dmab, 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohex)-3-methylb�Teal]amino)benzyl; DMEM, modified according to the method of Dulbecco medium eagle; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; Dnp, 2,4-dinitrophenol; DPPC, dipalmitoylphosphatidylcholine; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; EQ., equivalent; ESI-MS, mass spectrometry with ionization by elektrorazpredelenie; Fm, fluorenylmethyl; Fmoc, 9 - fluorenylmethoxycarbonyl; Gin, glutamine; Dr, glucose-regulating proteins, His, histidine; HOAt, 1-hydroxy-7-asobancaria; HOBt, 1-hydroxy-benzotriazole; HPLC, high performance liquid chromatography; Hsp, heat shock proteins; INCI, international nomenclature of cosmetic ingredients; ivDde, 1-(4,4-dimethyl-2,6-dioxocyclohex)-3-methyl-butyl; kDa, kDa; Leu, leucine; MUNA, R-methylbenzhydrylamine; MeCN, acetonitrile; MeOH, methanol; MLV, multi-layer vessels; MPD, minimum pigment dose; Mtt, methoxytrityl or medicrity; MTT, 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium; N-terminal, aminoterminal; PAL, 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid; Palm, Palmitoyl; PBS, phosphate-saline buffer solution; pNZ, p-nitrobenzenesulfonyl; Pro, Proline; rpm, revolutions per minute; qs sufficient quantity; q.s.p., sufficient for; tBu, tert-butyl; theos, 2-(trimethylsily)ethoxycarbonyl; TFA, trifluoroacetate acid; THF, tetrahydrofuran; TIS, triisopropylsilane; Thus, 2,2,2-trichlo�ethoxycarbonyl; Trt, triphenylmethyl or trityl; Trt, trityl; Tight, tyrosine; ULV, single layer vessels; UV, ultraviolet; Z, benzyloxycarbonyl.

Chemical synthesis

All synthetic processes were carried out in polypropylene syringes fitted with porous polyethylene discs, or Rugen® reactors, equipped with porous tablets. Solvents and soluble reagents were removed by suction. Fmoc group was removed with piperidine-DMF (2:8, V/V) (1×1 min, 1 x 5 min, 5 ml/g resin) [Lloyd-Williams P., Albehcio F. and Giralt E. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA]. Laundering between stages of deprotection, binding, and, again, deprotection, were carried out with DMF (3 x 1 min), each time using 10 ml solvent/g resin. Binding reactions were performed with 3 ml solvent/g resin. Control binding was performed by conducting a ninhydrin test [Kaiser E., Colescott R. L., Bossinger, C. D. and Cook, P. I. (1970) Color test for detection of free terminal am/no groups in the solid-phase synthesis of peptides" Anal. Biochem. 34:595-598] or chloraniline test [Christensen T. (1979) "A qualitative test for monitoring coupling completeness in solid-phase peptide synthesis using chloranil" Acta Chem. Scand. 33B:763-766]. All synthetic reactions and washing was performed at room temperature.

HPLC chromatographic analyses were performed with Shimadzu equipment (Kyoto, Japan), using a column for reversed-phase chromatography, thermostated at 30°C (250×4.0 mm, Kromasil CE, 5 µm, Akzo Nobel, Sweden). The elution was done�but using a gradient of acetonitrile (+0,07% TFA) in water (+0.1% of TFA) at a flow rate of 1 ml/min and the diagnosis was performed at 220 nm.

EXAMPLE 1

Obtaining Fmoc-Wn-Xm,-AA1-AA2-AA3-AA4-Yp-Zq-O-2-CITrt-®, where AA1is a-L-His-; AA2is a-L-His-, -L-Leu - or-L-Pro-; AA3is a-L-Leu-; AA4is a-L-Arg - or-L-Asn-; and n, m, p and q equal to 0.

5,71 g of Fmoc-L-Arg(Pbf)-OH or 5.25 g of Fmoc-L-Asn(Trt)-OH (8.8 mmol; 1 EQ.) dissolved in 55 ml of DCM to which was added to 1.3 ml of DIEA (7.6 mmol; 0,86 EQ.), been associated with dry 2-chlorotrityl resin (5.5 g; 8.8 mmol). They were mixed for 5 minutes, then added 2.5 ml of DIEA (14,6 mmol; from 1.66 EQ.). The mixture was allowed to react for 40 min. Remaining chloride groups were blocked by treatment 4.4 ml MeOH.

The N-terminal Fmoc group was removed as described in General methods, and 7.77 g of Fmoc-L-Leu-OH (22 mmol; 2.5 EQ.) were associated with the peptidyl-resin in the presence of DIPCDI (3.39 in ml, 22 mmol, 2.5 EQ.) and HOBt (3.37 g, 22 mmol, 2.5 EQ.) using DMF as the solvent for 1 hour. The resin is then washed as described in the General methods, and processing to remove the Fmoc group was repeated to attach the following amino acid. After the described protocols is 13.63 g of Fmoc-L-His(Trt)-OH, of 7.77 g of Fmoc-L-Leu-OH or of 7.42 g of Fmoc-L-Pro-OH (22 mmol; 2.5 EQ.) were connected in series; and subsequently is 13.63 g of Fmoc-L-His(Trt)-OH (22 mmol; 2.5 EQ.) each was connected in the presence of 3.37 g of HOBt (22 mmol; 2.5 EQ.) and 3,39 ml DIPCDI (22 mmol; 2.5 to e�V.).

After synthesis, peptidyl resin was washed DCM (5×3 min) and dried by nitrogen stream.

EXAMPLE 2

Obtaining Fmoc-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-AM-MBHA-®, where AA1is a-L-His-; AA2is a-L-His-, -L-Leu - or-L-Pro-; AA3is a-L-Leu-; AA4is a-L-Arg - or-L-Asn-; and n, m, p and q equal to 0.

Of 6.85 g of Fmoc-AM-MBHA resin with a functionalization of 0.73 mmol/g (5 mmol) was treated with piperidine-DMF according to the described General Protocol in order to remove the Fmoc group. 16,22 g of Fmoc-L-Arg(Pbf)-OH or of 14.92 g of Fmoc-L-Asn(Trt)-OH (25 mmol; 5 EQ.) include in the resin with remote protective groups in the presence of DIPCDI (3,85 ml; 25 mmol; 5 EQ.) and HOBt (3.85 g; 25 mmol; 5 EQ.) using DMF as the solvent for 1 hour.

Then the resin was washed as described in the General methods, and processing to remove the Fmoc group repeat to attach the following amino acid. After the previously described protocols is 8.84 g of Fmoc-L-Leu-OH (25 mmol; 5 EQ.); 15,49 g of Fmoc-L-His(Trt)-OH, 8.84 g of Fmoc-L-Leu-OH or 8.44 g of Fmoc-L-Pro-OH (25 mmol; 5 EQ.); and then 15,49 g of Fmoc-L-His(Trt)-OH (25 mmol; 5 EQ.) connected in series in the presence of 3.85 g HOBt (25 mmol; 5 EQ.) and 3,85 ml DIPCDI (25 mmol; 5 EQ.).

After synthesis, peptidyl resin was washed DCM (5×3 min) and dried by nitrogen stream.

EXAMPLE 3

The General process of removing the N-terminal Fmoc protecting groups.

the N-terminal Fmoc group peptidyl resins, obtained in Example 1 was removed from protection as described in the General methods (20% piperidine in DMF, 1×5 min + 1×20 min). Peptidyl resin was washed DMF (5×1 min), DCM (4×1 min), diethyl ether (4×1 min) and dried in vacuum.

EXAMPLE 4

The process of introducing palmitoleic group, R1in peptidyl resin obtained in Example 3.

2,56 g of palmitic acid (10 mmol; 10 EQ.) pre-dissolved in DMF (1 ml), was added to 1 mmol peptidyl resins obtained in Example 3 in the presence of 1.53 g of HOBt (10 mmol; 10 EQ.) and 1.54 ml of DIPCDI (10 mmol; 10 EQ.). They allow to react for 15 hours, after which the resin was washed THF (5×1 min), DCM (5×1 min), DMF (5×1 min), MeOH (5×1 min), DMF (5×1 min), THF (5×1 min), DMF (5×1 min), DCM (4×1 min), ether (3×1 min), and dried in vacuum.

EXAMPLE 5

The process of introducing acetyl group, R1in peptidyl resin obtained in Example 3.

1 mmol peptidyl resins obtained in Example 3 was treated with 25 EQ. the acetic anhydride in the presence of 25 equiv. DIEA, using 5 ml of DMF as solvent. They were allowed to react for 30 min, after which peptidyl resin was washed DMF (5×1 min), DCM (4×1 min), diethylamino (4×1 min) and dried in vacuum.

EXAMPLE 6

The process of cleavage from the polymer carrier peptidyl resins obtained in Example 5.

200 mg dried peptidyl resins obtained in P�the imera 5, were treated with 5 ml of TFA:TIS:H2O (90:5:5) for 2 hours at room temperature with stirring. The filtrates were collected in 50 ml cold diethylether, they were filtered through a polypropylene syringes equipped with porous polyethylene discs, and washed 5 times with 50 ml of diethylether. The final precipitates were dried in vacuum.

The HPLC analysis of the obtained peptides in gradients of MeCN (+0.07% TFA) in H2O (+0.1% TFA) in all cases showed a purity of 80%. Identification of the obtained peptides was carried out by ESI-MS.

EXAMPLE 7

The process of cleavage from the polymer carrier and functionalization substituted with an amine R2: Obtaining Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-NH-(CH2)15-CH3where AA1is a-L-His-; AA2is a-L-His-, -L-Leu - or-L-Pro-; AA3is a-L-Leu-; AA4is a-L-Arg - or-L-Asn-; u n, m, p, u q is equal to 0.

The peptides Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-OH with fully protected side chains are obtained by processing 150 mg peptidyl resins Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-O-2-ClTrt-® of Example 5, previously dried under vacuum in the presence of KOH, with 3 ml of 3% solution of TFA in DCM for 5 min. the Filtrates collected in 50 ml cold�th diethylether, and the treatment is repeated 3 times. The ethereal solutions are evaporated to dryness under reduced pressure at room temperature, the precipitates were dissolved in 50% MeCN in H2O and lyophilizers. 10 mg of the obtained raw peptides are weighed into a flask and add 3 EQ. hexadecylamine and 25 ml of anhydrous DMF. Add 2 EQ. DIPCDI and leave for the reaction in a magnetic stirrer at 47°C. the Reaction is controlled by HPLC until the dissolution of the original products, which is completed in 24-48 hours. The solvents were evaporated to dryness and twice together evaporated with DCM. The obtained residues [Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-NH-(CH2)15-CH3with fully protected side chains] were dissolved in 25 ml of a mixture of TFA-DCM-anisole (49:49:2) and left to react for 30 min at room temperature. Add 250 ml of cold diethylether, the solvents evaporated under reduced pressure and carry out two additional co-evaporation with ether. The residues are dissolved in a mixture of 50% MeCN in H2O and lyophilizers.

EXAMPLE 8

Analysis of the stimulation of the synthesis of Hsp70.

Stimulation of the synthesis of Hsp70 was assessed in cell lines of human keratinocytes in the presence of peptides of the present invention. Cells were seeded (106cells/6-hole championship course, which tablet) and incubated for 24 hours in DMEM, after which the peptide was added to 200 µm in cultures� - filled, medium and incubated for another 16-24 hours. 10 μm of the proteasome inhibitor MG-132 was used as a positive control, and medium (the culture medium) as a negative control. After an incubation period, the cells were washed with PBS, literally and centrifuged at 12,000 rpm. min at 4°C for 10 min, the Supernatants collected, and identification of Hsp70 levels was conducted during the competitive ELISA, following the protocols of a commercial kit (DuoSet IC human/mouse total HSP70 ELISA kit, R&D Systems Inc.)

Table 2 gives details of the peptides that showed the magnitude of Hsp70 stimulation level is greater than 15%. Hsp70 levels were normalized with respect to average underlying value.

EXAMPLE 9

Analysis of photoprotective efficiency Ac-L-His-L-Pro-L-Leu-L-Arg-OH and Ac-L-His-L-Leu-L-Leu-L-Arg-OH in cultures of human keratinocytes.

Human keratinocytes were kept in culture for 24 hours in 96-of linkovich tablets for monolayer formation, and the cells were plaincourault in the dark with 0.1 mm Ac-L-His-L-Pro-L-Leu-L-Arg-OH, Ac-L-His-L-Leu-L-Leu-L-Arg-OH in culture medium or with medium (the culture medium) for 2 hours at 37°C. Subsequently, cells were irradiated with UVB at radiant exposure of 800 j/m2. Control the tablet with the carrier kept in the dark without the same exposure time at room temperature. After a period of irradiation of the cell medium was replaced with fresh medium, and cells will complement�flax were incubated for 24 hours. Cell viability was determined by MTT method by adding 5 mg/ml MTT to each well and incubating the tablet for 4 hours at 37°C, then the medium was removed, added to 100 ál of DMSO, and the plate was stirred at room temperature for 15 min, the Optical density of each well was measured at 570 nm on a spectrophotometer.p>

Photoprotective efficiency was determined by comparing the viability obtained in cells treated with Ac-L-His-L-Pro-L-Leu-L-Arg-OH or Ac-L-His-L-Leu-L-Leu-L-Arg-OH, relative to the response of irradiated and non-irradiated control cells.

EXAMPLE 10

Preparation of cosmetic compositions containing Palm-L-His-L-Pro-L-Leu-L-Asn-NH2.

Phase And dissolved in a suitable reactor. In another phase reactor In a mixed form with Sepigel®305 [INCI: Aqua (Water), polyacrylamide, C13-C14 the isoparaffin, the award-7], Myritol®308 [INCI: Caprylic/Capric Triglyceride] and ethylhexyl by cocoaton and immediately homogenized, it is slowly added to phase A while stirring. Then phase C was added with stirring, and subsequently add phase F at 35°C. Set pH 5.5-7.0 with the addition of phase D and phase E.

EXAMPLE 11

Preparation of liposomes containing Ac-L-His-L-Leu-L-Leu-L-Arg-OH.

Dipalmitoylphosphatidyl�n (DPPC) is weighed and dissolved in chloroform. The solvent was evaporated in vacuo to obtain a good phospholipid layer, and this layer is hydrated by treatment at 55°C with an aqueous solution of the peptide in the desired concentration (containing Phenonip®and receive MLV liposomes. ULV liposomes obtained by immersion of the MLV liposomes in an ultrasonic bath at 55°C for 8 cycles of 2 min at intervals of 5 min. Size ULV liposomes is reduced by passing them through an extrusion system with high pressure.

EXAMPLE 12

Preparation of the composition in the form of a liposomal gel containing Ac-L-His-L-Leu-L-Leu-L-Arg-OH.

The liposomes of Example 11 was dispersed in water with preservatives (EDTA, imidazolidinyl ureido urea and Phenonip®) with mild stirring. Add Hispagel®200 [INCI: Aqua (Water), glycerin, glyceryltrinitrate] and lightly mix until you get a homogeneous mixture.

EXAMPLE 13

The composition of the cream containing Ac-L-His-L-Pro-L-Leu-L-Arg-OH.

Cooking

- 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 while stirring with a homogenizer (Silverson) for 5 minutes.

- Add Phase And gradually to the mixture of phases b and C with homogenizer and maintain homogenization for 15 minutes.

- Start cooling to 30-35°C with mild stirring. At 50°C add Phase D. Continue per�smeshivanie. At 35-38°C add Phase E and F, which have been previously dissolved.

EXAMPLE 14

Preparation of the composition of mixed micelles containing Ac-L-His-L-Leu-L-Leu-L-Arg-OH.

The ingredients of phase A are weighed in a flask, suitable for the whole sample, and slightly heated to 30°C to help dissolve some of the preservatives. Then add components of phase b and homogenized with moderate stirring.

Then add phase C under continuous stirring, then add phase D (Oramix® CG 110 [INCI: Aqua (Water), Caprylyl/Capryl Glucoside]) with slow stirring to avoid the formation of foam.

the pH was maintained at the level of 5.5-6.5.

EXAMPLE 15

Microemulsion composition containing Palm-L-His-L-Pro-L-Leu-L-Asn-NH2.

The ingredients of phase b are weighed in a flask, suitable for the whole sample. Then phase D is added to phase b and homogenize with constant stirring. Then added to the mixture of phase A. Finally, add phase C.

EXAMPLE 16

The composition of a capillary lotion containing Ac-L-His-L-Leu-L-Leu-L-Arg-OH.

Mix the components of Phase A slowly while stirring. Slowly add Phase b to Phase A while stirring until homogenization is complete.

1. Peptide for stimulation of the synthesis of Hsp70 (heat shock protein 70), or to protect�you skin from ultraviolet radiation with the General formula (I)
R1-AA1-AA2-AA3-AA4-R2
(I)
its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, characterized in that
AA1represents-His-;
AA2selected from the group consisting of-His-, -Leu -, and-Pro-;
AA3represents-Leu-;
AA4selected from the group consisting of-Arg - and-Asn-;
R1selected from the group consisting of H, substituted non-cyclic aliphatic group selected from the group consisting of acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoic, octanoyl, decanoyl, lauroyl, myristoyl, Palmitoyl, stearoyl, oleoyl and linoleoyl or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl, unsubstituted aralkyl and R5-CO-, where R5selected from the group consisting of H, unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and unsubstituted heteroallyl;
R2selected from the group consisting of-NR3R4, -OR3and-SR3where R3and R4independently selected from the group�s, consisting of H, unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, unsubstituted heterocyclyl, unsubstituted heteroaromatic, substituted or unsubstituted aryl and unsubstituted aralkyl.

2. The peptide according to claim 1, characterized in that selected from the group consisting of H, acetyl, lauroyl, myristoyl and Palmitoyl, AA2is-L-Leu-, A is-L-Arg-, and R2is-NR3R4or-OR3where R3and R4independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl.

3. The peptide according to claim 1, characterized in that R1selected from the group consisting of H, acetyl, lauroyl, myristoyl and Palmitoyl, AA2is a-L-Pro-,
AA4is a-L-Arg-, and R2represents a-NR3R4or-OR3where R3and R4independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl.

4. The peptide according to any of claims. 1-3 for the treatment and/or care of skin, mucous membranes and/or hair.

5. The peptide according to claim 4 for the treatment and/or care for these conditions, disorders and/or diseases of the skin, mucous membranes and/or hair, which are improved or prevented by stimulating the synthesis of Hsp70.

6. The peptide according to claim 5, wherein the condition, disorder and/or disease that ul�Claudia or prevented by stimulating the synthesis of Hsp70, selected from the group formed epidermolysis epidermtm and baldness.

7. The peptide according to claim 4, characterized in that said treatment and/or care reduces, delays and/or prevent cell damage caused by UV radiation, thermal stress, oxidative stress, osmotic shock, inflammation, hypoxia, exposure to pollutants, lack of nutrition and lack of hydration and/or aging and/or photoaging.

8. The peptide according to claim 4, where said treatment and/or care reduces, delays and/or prevent the loss of hair or induce hair growth.

9. The peptide according to claim 4, where said treatment and/or care stimulate healing and/or re-epithelialization of wounds.

10. A cosmetic composition, which contains a cosmetically effective amount of at least one peptide for the stimulation of the synthesis of Hsp70 or to protect the skin from ultraviolet radiation of the General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically acceptable salts according to any one of claims. 1-3 and at least one cosmetically suitable excipient or adjuvant.

11. A composition according to claim 10, characterized in that the peptide with General formula (I), its stereoisomers, mixtures thereof and/or their cosmetically acceptable salts are included in cosmetic delivery system or a system with a slow release, �selected from the group consisting of liposomes, mixed liposomes, oleosa, NREN, ethos, millicapsules, microcapsules, nanocapsules, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, surfactant-phospholipid mixed micelles, mallister, microspheres, nanospheres, lipofen, microemulsions, nano-emulsions, miniparticles, milicast, microparticles, nanoparticles, solid lipid nanoparticles and nanostructured lipid carriers, or be adsorbed on solid organic polymers or solid mineral substrate selected from the group consisting of talc, bentonite, silica, starch and maltodextrin.

12. A composition according to claim 10, characterized in that said composition includes a composition selected from the group consisting of creams, heterogeneous emulsions, anhydrous compositions, aqueous dispersions, oils, milk, balms, foams, lotions, gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions, hydrogels, liniments, sera, Soaps, shampoos, conditioners, serums, ointments, mousses, lipsticks, powders, bulk Soaps, pencils, sprays, aerosols, capsules, gelatin capsules, soft capsules, hard capsules, tablets, tablets, sugar-coated, granules, chewing gum, solutions, suspensions, emulsions, syrups, polysaccharide films, jellies and gelatins.

13. Composicao p. 10, characterized in that said composition is included in a product selected from the group consisting of corrective tools under eyes, creams, lotions, makeup remover, milk makeup remover, eye shadow, lipsticks, lip gloss, hygienic lipsticks and powders.

14. A composition according to claim 10, characterized in that the peptide of General formula (I), its stereoisomers, mixtures thereof and/or its cosmetically acceptable salts introduced into the fabric, non-woven fabric or medical device.

15. A composition according to any one of claims. 10-14, characterized in that said composition further comprises a cosmetically effective amount of at least one auxiliary selected from the group including heat shock proteins, other means of stimulating the synthesis of heat shock proteins, inhibitors of the aggregation of the acetylcholine receptor, means inhibiting the muscle contraction, anticholinergic agents, means, inhibiting elastase, means inhibiting the matrix metalloproteinases, a means of stimulating or inhibiting melanin synthesis, whitening or depigmenting means propagandise means, means for tanning, aphrodisiac, anti-aging, aphrodisiac, inhibiting NO-synthase, tools, inhibiting 5α-reductase, and means inhibiting lysyl - and/or proli�the hydroxylase, antioxidants, scavengers of free radicals and/or agents against atmospheric pollution, scavengers of reactive carbonyl groups, artiglierie funds, antihistamine tools, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners, moisturizing agents, substances that retain moisture, alphagalactosidase, betahydroxylase, moisturizers, epidermal hydrolytic enzymes, vitamins, amino acids, proteins, pigments or colorants, dyes, gelling polymers, thickeners, surfactants, emollients, anti-wrinkle, tools, able to reduce or treat bags under the eyes, exfoliating, antibacterial agents, antifungal means, fungistatic means, a bactericidal agent, a bacteriostatic agent, 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 decorin, a means of stimulating the synthesis of laminin, a means of stimulating defensin synthesis, agents that stimulate Synthe� aquaporins, agents that stimulate the synthesis of hyaluronic acid, agents that stimulate the synthesis of fibronectin, agents that stimulate the synthesis of sirtuins, agents that stimulate the synthesis of lipids and components of the stratum corneum, ceramides, fatty acids, means which inhibit the degradation of collagen, means which inhibit the degradation of elastin, means which inhibit semipretioase, such as cathepsin G, a means of stimulating fibroblast proliferation, agents that stimulate the proliferation of keratinocytes, agents that stimulate the proliferation of adipocytes, a means of stimulating the proliferation of melanocytes, a means of stimulating the differentiation of keratinocytes, agents that stimulate the differentiation of adipocytes, means which inhibit acetylcholinesterase, means causing relaxation of the skin, agents that stimulate the synthesis of glycosaminoglycan, a means that prevents hyperkeratosis, zit remedies, antipsoriatic drugs, DNA-reducing agents, DNA-protective agents, stabilizers, protivochesotocnaya funds, funds for the treatment and/or care of sensitive skin, firming funds, funds against stretch marks, bonding agent, means for regulating the secretion of sebaceous glands, lipolytic funds or a means of stimulating lipolysis, prot�satellite funds funds from sweating, agents that stimulate the healing process, aid healing, agents that stimulate the re-epithelialization, tools to help re-epithelialization, cytokine growth factors, sedatives, anti-inflammatory and/or analgesics, anesthetic funds, agents acting on capillary circulation and/or microcirculation, agents that stimulate angiogenesis, the funds that inhibit vascular permeability, venotonizirutee funds, funds that affect cell metabolism, a means of enhancing the dermal-epidermal connection, means of inducing hair growth remedies that inhibit or slow hair growth, remedies, slowing down hair loss, preservatives, fragrances, chelating means, plant extracts, essential oils, algae extracts, funds received as a result of fermentation processes, mineral salts, cell extracts and sunscreens, organic or mineral photoprotective agents active against ultraviolet rays A and/or b or mixtures thereof.

16. Pharmaceutical composition which contains a pharmaceutically effective amount of at least one peptide for the stimulation of the synthesis of Hsp70 or to protect the skin from ultraviolet radiation of the General formula (I), its stereoisomer�s, their mixtures and/or its pharmaceutically acceptable salt according to any one of claims. 1-3 and at least one pharmaceutically suitable excipient or adjuvant.

17. A composition according to claim 16, characterized in that the peptide with General formula (I), its stereoisomers, mixtures thereof and/or their pharmaceutically acceptable salts are included in a pharmaceutical delivery system or a system with a slow release, selected from the group consisting of liposomes, mixed liposomes, oleosa, NREN, ethos, millicapsules, microcapsules, nanocapsules, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, surfactant-phospholipid mixed micelles, mallister, microspheres, nanospheres, lipofen, microemulsions, nano-emulsions, miniparticles, milicast, microparticles, nanoparticles, solid lipid nanoparticles and nanostructured lipid carriers, or be adsorbed on solid organic polymers or solid mineral substrate selected from the group consisting of talc, bentonite, silica, starch and maltodextrin.



 

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EFFECT: obtaining of bicin derivatives.

24 cl, 11 dwg, 2 tbl, 21 ex

-interleukin" target="_blank">

The invention relates to compounds of General formulaand-

< / BR>
< / BR>
where n = 0, 1, or 2, m and m' = 1 or 2; R11is

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or

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R2'= R2= H, R3is-CH2Ar or 5-15 membered non-aromatic monocyclic group which may contain from 0 to 2 endocycles nitrogen atoms; R4is a branched (C1-5) alkyl group; R5choose from a group comprising-C(O)R7, -C(O)OR9, -C(O)C(O)R7; R7selected from the group: phenyl, naphthyl, isoquinoline, and phenyl may be substituted with halogen, (C1-6) alkoxy, 1,2-methylenedioxy or - N(H)C(O)(C1-6)-alkyl, R9independently selected from straight line (C1-5) alkyl group, optionally substituted by phenyl; R12and R13independently selected from the group comprising-R7-C(O)-R7and-C(O)-N(H)-R7or R12and R13together form a 4-8-membered saturated cyclic group, f is -interleukin (ICE), method of inhibiting ICE activity, methods of treating or preventing IL-mediated diseases

The invention relates to new compounds of General formula I

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in which R1selected from the group consisting of hydrogen, unsubstituted or optionally substituted aralkyl, unsubstituted or optionally substituted orelkinoservisa, unsubstituted or optionally substituted allyloxycarbonyl, unsubstituted or optionally substituted alkyl and hydroxyamino group; R2selected from the group consisting of hydrogen, unsubstituted or optionally substituted orelkinoservisa, unsubstituted or optionally substituted allyloxycarbonyl, aminosidine group; R3selected from the group consisting of hydrogen, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R4selected from the group consisting of unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R5and R6that may be the same or different, each independently selected from the group consisting of hydrogen, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted cycle>and R6taken together with the nitrogen atom to which they are attached, form an unsubstituted or optionally substituted heterocyclic group; R7selected from the group consisting of hydrogen, hydroxy, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R8selected from the group consisting of hydrogen, hydroxy, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl, and R9selected from the group consisting of hydrogen, hydroxy, amino and a group of the formula-X-Y, in which X is selected from the group consisting of unsubstituted or optionally substituted (C1-C6)-alkylene and unsubstituted or optionally substituted phenylene, and Y denotes a group of formula-a-b or a-B, where a is selected from the group consisting of unsubstituted or optionally substituted (C1-C6)-alkylene, imino and unsubstituted or optionally substituted (C1-C6)-alkylamino, and selected from the group consisting of hydrogen, amino, amidino, acylmethyl, unprotected or optionally protected bis (phosphono)methyl, provided that R7, R8and R are not simultaneously represent

The invention relates to compounds of formula I (the values of the radicals defined in the description), their prodrugs and their pharmaceutically acceptable salts

The invention relates to compounds of formula (I) and (II) the value of the radicals R1-R18presented in the description, with the ability to inhibit prenyltransferase

The invention relates to new compounds of General formula 1: R1- SO2- B - X - Z - C(O) - Y, where R1represents a (1-12C)alkyl, which optionally may be substituted CF3, (7-15C)aralkyl or Campari; represents a bond, an amino acid of formula-NH-CH[(CH2)pC(O)OH]-C(O)-, where R = 1, 2, or 3, D-3-Tiq, or L - or D-amino acid containing a hydrophobic or neutral side chain; X represents an amino acid with a hydrophobic side chain, glutamine, cyclic amino, -NR2-CH2-C(O) -, or a group:

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where n = 2, 3 or 4, W represents CH; R3represents H, (1-6C)alkyl; Z represents a lysine or 4-aminocyclohexanol; Y represents-NH-(1-6C)alkylene-C6H5, -OR4where R4represents H, (2-6C)alkyl, or NR5R6and R5and R6independently represent H, (1-6C)alkoxy or (1-6C)alkyl, optionally substituted with halogen, or R5and R6together represent a (3-6C)alkylene, or R5and R6together with the nitrogen atom to which they are attached, represent< / BR>
where V carts is naphthyl-SO2-Asp-Pro-Lys[COCO]-OH,having anticoagulant activity; and the pharmaceutical composition having inhibitory by combinationally

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oxazolopyrimidine compounds of formula (I) , in which A is selected from NH, O and S; R1 is selected from (C1-C6)-alkyl, (C3-C7)-cycloalkyl-CtH2t and Het-CtH2t-, where t is selected from 0, 1, 2 and 3; R2 is selected from phenyl and residue of aromatic 5-member - 6-member monocyclic heterocycle, which includes 1, 2 similar or different ring heteroatoms, selected from N, O and S, in which one of ring nitrogen atoms can carry atom of hydrogen or substituent R21, and in which phenyl and aromatic heterocycle residue are optionally substituted in one or more ring carbon atoms with one or more similar or different substituent R22; R3 is selected from (C1-C6)-alkyl, or R3 represents residue of saturated or unsaturated 3-member - 10-member, monocyclic or bicyclic ring, which includes 0, 1, 2 or 3 similar or different ring nitrogen atoms can carry hydrogen atom or (C1-C4)-alkyl substituent and one or two ring sulphur atoms can carry one or two oxo groups, and in which ring residue is optionally substituted in one or more ring carbon atoms with similar or different substituents R31, on condition that R3 cannot be (C1-C6)-alkyl, if A represents S; other values of radicals are given in i.1 of formula.

EFFECT: compounds of formula (I) are suitable for wound healing.

16 cl, 2 tbl, 9 ex

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