GENERAL FORMULA PEPTIDE (I) AND PHARMACEUTICAL OR COSMETIC COMPOSITION

专利摘要:
peptide of general formula (i) and pharmaceutical or cosmetic composition. peptides of general formula (i): r1-wn-xm-aa1-aa2-aa3-aa4-yp-zq-r2 (i), their stereoisomers, mixtures thereof and/or their pharmaceutically and cosmetically acceptable salts, a process of preparation, cosmetic or pharmaceutical compositions containing the same and their use in the treatment and/or care of the skin, mucous membranes and/or hair and treatment and/or care of those conditions, disorders and/or diseases that are ameliorated or prevented by stimulation of hsp.
公开号:BR112012009264A2
申请号:R112012009264-2
申请日:2010-10-22
公开日:2021-09-08
发明作者:Cristina Carreño Seraïma；Win Van Den Nest；Ana Sempere Bonete；Antonio Ferrer Montiel；Nuria Almiñana Domenech；Juan Cebrían Puche
申请人:Lipotec S.A.；
IPC主号:

专利说明:

GENERAL FORMULA PEPTIDE (I) AND COMPOSITION
FIELD OF THE INVENTION The present invention relates to peptides capable of inducing the expression of heat shock proteins in the skin, mucous membranes and/or hair, and relates to cosmetic or pharmaceutical compositions containing these peptides used in the treatment and/or care of the skin, rucous membranes and/or hair, preferably for the treatment and/or care of conditions, disorders and/or diseases of the skin, mucous membranes and/or hair that are ameliorated or prevented by a heat shock protein synthesis stimulus.
BACKGROUND OF THE INVENTION The skin, mucous membranes and hair are constantly exposed to stressors, both chemical and physical in nature. Solar radiation, exposure to certain chemical agents or high temperatures can have harmful effects on the cells that make up the skin, accelerating its aging and making it look unhealthy. The mechanisms through which ultraviolet (UV) radiation exerts these effects include the formation of reactive oxygen species, DNA damage, and protein denaturation, among others.
25 The denaturation or alteration in the conformation of the proteins may imply the exposure of hydrophobic residues on the surface of the protein, a situation in which the proteins are susceptible to the formation of aggregates, thus losing their functionality. This is dangerous for cell integrity, 30 and therefore has specialized mechanisms to combat the aforementioned situations: all living organisms have mechanisms to avoid the damage caused by the accumulation of folded proteins [Ananthan J., GoIdberg A.L. and Voellmy R.
b" Wj
2/66 (1986) "Abnormal proteins serve as eukaryotic stress signals and trigger the activation of heat shock genes" Science 232:522-524]. It is observed that cells respond to a stressful situation by increasing the synthesis of so-called stress proteins. This response begins when the r cell detects an accumulation of abnormally folded proteins, resulting in an increase in the transcription of heat shock genes [Lis j. and Wu C. (1993) "Protein traffic on the 10 heat shock promoter: parking, stalling, and trucking along" Cell 74:1-4]. The products of these genes are classified into two broad groups, heat shock proteins and glucose-regulated proteins. The term "heat shock protein" originates from the observation of increased synthesis of these 15 proteins in cells incubated at an unusually high temperature. The synthesis of these proteins is also increased not only when cells are subjected to an increase in temperature, but also in other stressful situations, such as exposure to UV radiation, oxidative stress, osmotic shock, inflammation, hypoxia, exposure to pollutants such as heavy metals, lack of nutrition and lack of hydration [Lindquist S. (1986) "The heat-shock response" Annu. Rev. Biochem. 55:1151-1191].
Heat shock proteins consist of a family of proteins classified according to their molecular weight, those that have undergone the most studies have been . the 60 kDa and 70 kDa proteins, due to their constituent expression in all cells and their direct participation in various aspects of protein maturation. Hsp70 mainly comprises two proteins: Hsp73, the constitutively expressed form, and Hsp72, the inducible form, which is transcriptionally regulated by the ternic shock factor I (HSFI) protein. These proteins are also called bi," h,'
molecular chaperones, due to their function of directing the folding of newly synthesized proteins from a globular-like conformation joined to a compact final structure, avoiding the appearance of conformations susceptible to the formation of aggregates and, therefore, ensuring their correct functionality . Under normal conditions, Hsp70 « is located in the nucleus and cytoplasm and interacts transiently with newly formed proteins, which facilitates its folding and promotes its translocation through the Golgi complex and the endoplasmic reticulum, in a joint action with to Hsp60. Under stressful conditions, however, Hsp70 forms a complex with unfolded or misfolded proteins, in order to rescue them from degradation and irreversible damage, or the opposite, in order to increase the chances of a proteolytic attack. in the case where it is impossible to protect them [Hayes SA and Dice JF (1996) "Roles of molecular chaperones in protein degradation" j. Cell. Biol. 132:255-258; Geting M.J.
and Sambrook J. (1992) "Protein folding in the cell" Nature 20 355:33-45]. Neither Hsp70 nor Hsp60 end up forming part of the final correctly folded protein, nor do they have any specific information about folding; these simply prevent inappropriate interactions from being established, which can cause erroneous CjIl tangles to lead to b 25 aggregations and therefore loss of functionality. However, the mechanism by which the protein . adopts its final conformation. Just as chaperone works to restore the conformation of misfolded proteins, the participation of Hsp70 has been described in processes of protection and repair of DNA in the event of damage caused to it by UV radiation or ionizing radiation [Bases R. (2006) "Heat shock protein 70 enhanced deoxyribonucleic acid base excision E'
repair in human leukemic cells after ionizing radiation" Cell Stress Chaperones 11:240-249; Niu P., Liu L., Gong Z., Tan H., wang F., Yuan J., Feng Y., Wei Q., Tanguay RM and wu T. (2006) "Overexpressed heat shock protein 70 protects cells " 5 against DNA damage caused by ultraviolet C in a dose-dependent manner" Cell Stress & Chaperones 11:162-169]. 6 The stress response constitutes a universally conserved cell defense mechanism that is reflected in the so-called acquired thermotolerance, a phenomenon according to which 10 cells suffering from a non-lethal termination shock are capable, after a period of recovery at temperature of normal growth, of surviving a second heat shock that would have been lethal the first time [subjeck JR, Sciandra JJ and johnson RJ (1982) "Heat shock 15 proteins and thermotolerance,' a comparison of induction kinetics" Br. j. Radiol. 55:579-584; Angelidis C.E., Lazaridis 1. and Pagoulatos G.N. (1991) "Constitutive expression of heat-shock protein 70 in mammalian cells confers thermoresistance" Eur. j. Biochem.199:35-39; Li G.C., 20 Li L.G., Liu Y.K., Mak LT.Y., Chen L.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. academy Sci. USA 88:1681-1685]. It was observed that this acquired thermotolerance is transient, usually lasting 25 between 12 and 24 hours in developing cells, and depends on
W of shock-induced changes in initial temperature, 6 such as levels of increased expression and accumulation of shock proteins. Within the Hsp family, Hsp70 has been found to be responsible for inducing heat tolerance: specific inhibition of both transcription and synthesis of Hsp72 prevents the protective effects induced by heat treatment [Trautinger F., Kindâs-l'4ügge I. , Barlan B., Neuner P.
and Knobler R.M. (1995) "72-kD heat shock protein is a mediator
L of resistance to ultraviolet B light" J. Invest. Dermatol. 105:160-162; Simon MM, Reikerstorfer A., Schwarz A., Krone C., Luger TA, Jãttelâ M. and Schwarz T. (1995) "Heat shock protein 70 overexpression affects the response to ultraviolet " 5 light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release" j. Clinic and Tnvest. 95:926-33].
Subsequently, any agent or treatment capable of inducing a stress response was found to provide the cell with protection despite subsequent exposure to a stress-causing agent, regardless of the source of the stress [Kampinga HH, Brunsting JF, Stege GJJ, Burgman PWjj and Konings A.W.T (1995) "Thermal protein denaturation and protein aggregation in cells made thermotolerant by various chemical role of heat shock proteins" Exp. Cell Res. 219:536-546]. Exogenous induction of shock protein expression is therefore a plausible strategy to prevent damage to cellular proteins and thus maintain integrity.
20 Different diseases are described in the literature that are caused by abnormal protein folding, such as asepidermolysis bullosa [Gu T,.H. and Coulombe P.A. (2005) "Defining the properties of the nonhelical tail domain in type I1 keratin 5: insight from a violent disease-causing 25 inutation" Mol Biol Cell. 16:1427-1438], which is caused by * incorrect folding of keratin caused by mutations of . some amino acids in its sequence. These diseases are subjected to a treatment with compounds that induce an increase in the levels of heat shock proteins.
Likewise, compounds that induce an increase in the expression of heat shock proteins are used in the treatment and/or care of wounds or as adjuvants in healing and/or reepithelialization processes. It is known that the
L wound healing and remediation processes show an increase in the expression of heat shock proteins. Specifically, the induction of Hsp expression in the case of cutaneous trauma is specific for the location of the " 5 keratinocytes in the skin; thus, the synthesis of Hsp70 is seen
H induced in epidermal keratinocytes [Laplante AF, Moulin V., Auger FA, Landry J., Li H., Morrow G., Tanguay RM and Germain L. (1998) "Expression of heat shock proteins in mouse skin during wound healing " j. Histochem. Cytochem. 46:1291-10,301]. External delivery of the Hsp70 protein has also been observed to accelerate wound healing [Kovalchin J.T., Wang R., Wagh M.S., Azoulay J., Sanders M. and Chandawarkar R.Y. (2006) "Tn vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis" 15 Wound Repair Regen. 14:129-137]. A reduction in the amount of Hsp70 in the skin of diabetic patients with healing and remediation of compromised wounds has also been described [Bitar MS, Farook T., john B. and Francis IM (1999) "Heat-shoek protein 72/73 and impaired wound healing in diabetic and 20 hypercortisolemic states" Surgery 125:594-601; Atalay M., Oksala N., Lappalainen J., Laaksonen D.E., Sen C.K. and Roy S.
(2009) "Heat shock proteins in diabetes and wound healing" Curr. Protein Pept. Sci. 10:85-95, McMurtry A.L., C'ho K., Young L.J.-T., Nelson C.F. and Greenhalgh D.G. (1999) > 25 "Expression of HSP70 in healing wounds of diabetic and nondiabetic mice" j. surg. Res. 86:36-41]. Thus, the induction of heat shock protein synthesis is a valid strategy for the treatment and/or care of skin and/or mucous membrane injuries, and specifically in the healing and re-epithelialization of skin and/or mucous membrane injuries. that are a consequence of diabetes. The participation of Hsp70 in the regulation of hair growth is also known in the prior art; P
7/66 specifically MX patent application 2007-007622 describes the application of compounds that inhibit Hsp70 synthesis to reduce hair growth. The implication of Hsp70 in the regulation of hair growth suggests the use of compounds capable of stimulating Hsp synthesis for the treatment and/or prevention of alopecia to delay hair loss or induce
D hair growth and specifically for the treatment of alopecia caused by chemotherapy as a treatment for cancer as described in US patent 2002/0001629 .
10 Abnormal protein folding also has an effect on the skin from an aesthetic point of view. The correct folding of elastin and collagen protein is critical to maintaining skin suppleness and a smooth, youthful appearance. The skin of young adults is particularly well adapted to respond quickly and effectively to stressful situations, as it is able to synthesize large amounts of Hsp to protect protein folding during synthesis. However, in older people, the ability to maintain correct protein folding is reduced, as there is a reduction in Hsp70 synthesis with age, which can cause an accumulation of damaged or poorly folded proteins and poor regulation. cell death that makes the skin look old [Verbeke P, Fonager j, Clark
At 25 BF, Rattan s:r. (2001) "Heat shock response and ageing: mechanisms and applications" Cell Biol. Tnt. 25:845-857]. The effect that abnormal protein folding has on the skin from an aesthetic point of view is exacerbated when the skin is exposed to UV radiation, and contributes to the appearance of photoaged skin. UV radiation is capable of irreversibly damaging cells, causing cell death.
However, exposure to high temperatures has been shown to exert a certain protective effect on K— -
cells, reducing the proportion of UVB-induced cell death [Trautinger F., Knobler R., Hônigsmann H., M.Mayr W. and Kindâs-Mlgge 1. (1996) "Increased expression of the 72-kD heat shock protein and reduced sunburn cell formation in 0 5 human skin after local hyperthermia" j. Investment Dermatol.
4 107:442-443]. This exposure to high temperatures induces Hsp synthesis. These are responsible for the photoprotective effect on the observed harmful effects of UV radiation. Thus, the induction of heat shock protein synthesis is a valid strategy for the treatment and/or care of the skin and/or hair with the aim of reducing, delaying and/or preventing the signs of aging and/or photoaging.
C) cosmetic and pharmaceutical sector performed 15 different tests in the development of compounds capable of stimulating the synthesis of heat shock proteins. The role played by heat shock proteins in different conditions, disorders or diseases is widely known in the prior art, as can be found, for example, in the periodical publication Heat Shock Proteins in Biology and Medicine (Research Signpost, India) or Cell St. :ress and Chaperones (Springer, Netherlands), among others.
It is known that some serine protease inhibitors are able to stimulate the production of m 25 heat shock proteins, but their high toxicity prevents their use for therapeutic purposes. Because of this, the industry needs to find agents with these properties that can also be used without risk to the health of the patient or consumer. 30 Different natural extracts that stimulate Hsp synthesis are described in the prior art, such as rye seed extracts, Opuntia ficus-indica extracts, extracts containing mangiferin (US 2006/0088560) or those described in documents US 2004/0228816, US 7128914 or FR 2834887, among others. The difficulties in obtaining extracts with a homogeneous quality and known composition and purity make their industrial development difficult, 4 5 particularly in the pharmaceutical sector. Different modified synthetic peptides are also described with 0-aldehyde or α-ketoester functions that induce hsp synthesis, such as those described in US patent 5942494. However, the aldehyde function is chemically incompatible with a large number of ingredients commonly used in formulations for topical application, also presents problems of low stability in the formulations, which limits their use in the cosmetic or dermopharmaceutical sector. The benefit of the action of heat shock proteins 15 on the skin, wet membranes and/or hair can also be obtained from the direct application of these proteins to the skin, wet membranes and/or hair. In this sense, US patent 5348945 describes the exogenous application of hsp70 protein as a method to reduce the mortality of a tissue subjected to stress situations and, especially, to preserve the tissues that will be used in organ transplants. The topical application of proteins with a high molecular weight presents the difficulty of their low permeability through the skin and hair, making their development difficult in the
K 25 cosmetic or dermopharmaceutical sector. This is due to the fact that despite the large number of . of existing compounds and/or extracts, there is still a need to identify new compounds that stimulate the synthesis of heat shock proteins that are more effective and selective than those known in the prior art. DETAILED DESCRIPTION OF THE INVENTION This invention provides a solution to the aforementioned problem. Applicant of this invention b—
has surprisingly found that synthetic peptides whose sequence does not include aldehyde functionalizations are able to stimulate the synthesis of Hsp70 protein and, therefore, are able to protect the skin, mucous membranes and/or hair against aggressions resulting from exposure to situations These peptides are used in the treatment and/or care of the skin, mucous membranes and/or hair, preferably for the treatment and/or care of those conditions, disorders and/or diseases of the skin, mucous membranes and/or 10 hair that are improved or prevented by heat shock protein stimulation.
DEFINITIONS To facilitate understanding of this invention, the meanings of some terms and expressions used in the context of the invention are included. Within the context of this invention, by "skin" is meant the layers comprising the same from the outermost layer or stratum corneum to the lowest layer or hypodermis, both inclusive. These layers are comprised of different types of cells such as keratinocytes, fibroblasts, melanocytes and/or adipocytes, among others. In the context of this invention, the term "skin" includes the scalp.
In the context of this invention, "care of the skin, mucous membranes and/or hair" comprises the prevention of disorders and/or diseases of the skin, mucous membranes and/or skin. hair. In the context of this invention, the term "aging" refers to the changes experienced by the skin with age (chronoaging) or exposure to the sun (photoaging) or environmental agents such as tobacco smoke, extremely cold or windy weather, pollutants chemicals or pollution, and includes all visible and/or noticeable external b through touch, subject to and without limitation, the development of discontinuities on the skin such as wrinkles, fine lines, cracks, irregularities or roughness, increase in pore size, loss of of elasticity, loss of firmness, loss of resilience, loss of ability to recover from deformation, sagging skin such as sagging cheeks, appearance of bags under the eyes or appearance of a double chin, among others, changes in color of the skin such as marks, redness, bags or the appearance of hyperpigmented areas such as age spots or freckles, among others, abnormal differentiation, hyperkeratinization, elastosis, keratosis and, capillary loss, "orange peel" skin, loss of collagen structuring and other histological changes in the stratum corneum, dermis, epidermis, vascular system 15 (for example, the appearance of varicose veins or telangiectasias) or in those nearby tissues to the skin, among others. The term "photoaging" brings together the set of processes due to prolonged exposure of the skin to ultraviolet radiation that results in premature aging of the skin, and presents the same physical characteristics of aging, according to and without limitation, sagging, loss of firmness, changes in color OLl pigmentation irregularities, abnormal and/or excessive keratinization.
In the context of this invention, "photoprotection" is understood to be the ability of a compound or formulation to prevent or delay the onset of blemishes. symptoms of photoaging when this compound or formulation is applied prior to exposure to UV radiation.
In this description, the abbreviations used for 30 amino acids follow the rules of the IUPAC-IUB joint Commission on Biochemical Nomenclature outlined in Eur. j. Biochein. (1984) 138:9-37 and in j. Biol. Chem. (1989) 264:633-673.
So, for example, Asn represents
NH2-CH(CH2CONH2)-COOH, Asn- represents NH,-CH(CH2CONH2)-CO-, -Asn represents -NH-CH(CH2CONH2)-COOH and -Asn- represents -NjH-cH(cH2coNH2)-co -. therefore, the dash, which represents the peptide bond, eliminates the OH from the I-carboxyl group of the
The 5th amino acid (represented herein in conventional unionized form) when located to the right of the symbol, and * removes the H of the 2-amino group of the amino acid when located to the left of the symbol; both modifications can be applied to the same symbol (see Table 1).
Table 1. Amino acid structures and their three-letter nomenclature code Remaining Symbol Remaining Symbol {Arjt} H° H° _A,,_ hn r _h,,_ UÍJ, R=,,nh _A,n-i" '¢i Nh, hnAnh, ,AÂ, ro -Leu-t I ' -P"o- ('rl 10 the abbreviation "Ac-" is used in this description to name the acetyl group (CH2,-CO-) and the abbreviation "Palm-" is used to name c) palmitoyl group (CH1-(CH2),,-CO-).
The term "non-cyclic aliphatic group" is used in this invention to cover, and not be restricted to, for example, linear or branched alkyl, alkenyl and alkynyl groups.
The term "alkyl group" refers to a group. saturated, linear or branched, having between 1 and 24, preferably between 1 and 16, more preferably between 1 and 20 14, even more preferably between 1 and 12 and even more preferably between 1, 2, 3 , 4, 5 or 6 carbon atoms and which is linked to the remainder of the molecule via a single bond, which includes, for example, and is not limited to methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl, 5-methylhexyl, and the like. The term "alkenyl group" refers to a linear or branched group a that has between 2 and 24, preferably between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, even more preferably 2, 3, 4, 5 or 6 carbon atoms, with a
10 or more carbon-carbon double bonds, preferably with 1, 2 or 3 carbon-carbon double bonds, conjugated or unconjugated, which are linked to the remainder of the molecule through a single bond, which includes, for example, and not restricted to vinyl, oleyl, linoleyl, and
15 similar.
The term "alkynyl group" refers to a straight or branched group having between 2 and 24, preferably,
between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, even more
20 preferably 2, 3, 4, 5 or 6 carbon atoms, with one or more carbon-carbon triple bonds, preferably with 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, which are bonded to the rest of the molecule through a single bond, which includes, for
25 exemplifies, and is not limited to, the ethynyl group, 1-propynyl, 2-. propynyl, l-butynyl, 2-butynyl, 3-butynyl, pentynyl, such
. such as, I-pentynyl, and similar groups.
The term "alicyclic group" is used in this invention to cover, and for example not be restricted to, cycloalkyl or cycloalkenyl or cycloalkynyl groups.
The term "cycloalkyl" refers to a saturated aliphatic or polycyclic group having between 3 and 24,
preferably between 3 and 16, more preferably between 3 and 14, even more preferably between 3 and 12, even more preferably 3, 4, 5 or 6 carbon atoms and which are bonded to the remainder of the molecule via a single bond, which includes, for example, and is not limited to, cyclopropyl, "cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahydroindene, deca-.hydronaphthalene, dodecahydrophenalene, and the like. The term " cycloalkenyl" refers to an aliphatic mono or polycyclic aromatic group having between 5 and 24, preferably between 5 and 16, more preferably between 5 and 14, even more preferably between 5 and 12, even more preferably, 5 or 6 carbon atoms, with one or more carbon-carbon double bonds, preferably with 1, 2 or 3 carbon-carbon double bonds, conjugated or unconjugated, which are linked to the rest of the molecule through a single bond , which includes, for example, and not restricted to similar cyclopent-1-en-1-yl groups and groups.
The term "cycloalkynyl" refers to a non-aromatic mono or polycyclic aliphatic group having between 8 and 20, preferably between 8 and 16, preferably between 8 and 14, even more preferably between 8 and 12, even more preferably, 8 or 9 carbon atoms, with one or more carbon-carbon triple bonds, preferably with 1, 2 or 3 carbon-carbon triple bonds, conjugated or
N 25 unconjugated, which are linked to the rest of the molecule through a single bond, which includes, for example, and no. restricted to, cyclooct-2-yn-i-yl group, and the like. The term "aryl group" refers to an aromatic group having between 6 and 30, preferably between 6 and 18, 30 more preferably between 6 and 10, even more preferably 6 or 10 carbon atoms, which comprises 1, 2, 3 or 4 aromatic rings, linked by a carbon-carbon bond or fused, and which are linked to the remainder of the molecule via a single bond, which includes, for example, and is not limited to phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthranyl, among others. The term "aralkyl group" refers to an " 5 alkyl group substituted by an aromatic group, between 7 and 24 carbon atoms and which includes, for example, and is not restricted to, -(CH 2 ) 1-6- phenyl, -(CH2)1-6-(1-naphthyl), -(CH2)1-6-(2-naphthyl), -(CH2)1-6-CH(phenyl)2, and the like.
The term "heterocyclic group" refers to a 3 to 10 membered heterocyclyl or hydrocarbon ring, wherein one or more of the ring atoms, preferably 1, 2 or 3 of the ring atoms, is an element other than carbon. , such as nitrogen, oxygen or sulfur and may be saturated or unsaturated. For purposes of this invention, heterocyclyl 15 can be a cyclic, monocyclic, bicyclic or tricyclic system which can include fused ring systems; and nitrogen, carbon or sulfur atoms may be optionally oxidized to the heterocyclyl radical; the nitrogen atom may optionally be quaternized; and the heterocyclyl radical may be partially or fully saturated or may be aromatic. With increasing preference, the term heterocyclic refers to a 5- or 6-membered ring.
The term "heteroarylalkyl group" refers to an alkyl group substituted with a heterocyclyl group.
substituted or unsubstituted aromatic P 25, the alkyl group having 1 to 6 carbon atoms and the heterocyclyl group. aromatic has from 2 to 24 carbon atoms and from 1 to 3 non-carbon atoms and which includes, for example, and is not limited to, -(CH2)I-6-imidazolyl, -(cH2)1-6-triazolyl , 30 -(CH2)1-6-thienyl, -(CH2)1-6-furyl, -(CH2)1-6-pyrrolidinyl, and the like. As used in this technical area, there may be a degree of substitution in the groups defined above. Thus,
there may be a substitution in any of the groups of this invention. References herein to the groups substituted on the groups of this invention indicate that the specified radical may be substituted at one or more available " 5 - positions by one or more substituents, preferably at 1, 2 or 3 d positions, more preferably, at 1 or 2 positions, even more preferably at 1. Such substituents include, for example, and are not limited to, C1-C4 alkyl; hydroxyl; C1-C4 alkoxy; amino; C1-C4 aminoalkyl; C1-C4 carbonyloxyl C4; C1-C4 oxycarbonyl; halogen such as fluorine, chlorine, bromine and iodine; cyano; nitro; azido; C1-C4 alkylsulfonyl; thiol; C1-C4 alkylthio, aryloxy, such as phenoxy; -NRb(C) =NRb)NRbRc; where Rb and R, are independently selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-Cl0 cycloalkyl, C6-C18 aryl, aralkyl C7-C17, 3- to 10-membered heterocyclyl or amino protecting group.
COMPOUNDS OF THE INVENTION The compounds of the invention are defined by the general formula (I) R1 - W1 , - X1 , - AM - AA2 - AA3 - AA4 - Yp - Zq-R2 (I) their stereoisomers, mixtures thereof and/or or its 25 cosmetically or pharmaceutically acceptable salts, » characterized by the fact that: ) ÁÀj is -His-; * AÂ2 is selected from the group consisting of -His-, -Leu- and -pro-; 30 AA, is -Leu-; AA4 is selected from the group consisting of -mg- and -Asn-; W, X, Y and Z are independently selected therefrom from the group consisting of coded amino acids and non-coded amino acids;
n, rn, p and q are independently selected from them and have a value between 0 and 1; " 5 n+m+p+q is less than or equal to 2; R1 is selected from the group consisting of 0
H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and R,-CO-, wherein R5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl
substituted, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroarylalkyl; R2 is selected from the group consisting of
-NR3R4, -OR, and -SR1 , wherein R3 and R4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted heteroarylalkyl
25 or unsubstituted, substituted or unsubstituted aryl, and * substituted or unsubstituted aralkyl; B with the proviso that when AA2 is -Leu-, AA4 is -Asn-, Y is -Gln-, then Z is not -Leu-; and with the proviso that when AA2 is -His-, AA4
30 is -Arg-, y or Z :Eor -Tyr-, then p+q is not 1. The R, and R2 groups are attached to the amino-terminal (N-terminal) and carboxy-terminal (C-terminal) ends of the sequences peptides, respectively.
According to a preferred embodiment of this invention, R1 is selected from the group consisting of
H or R5-CO-, wherein R, is selected from the group consisting of substituted or unsubstituted C1-C24 alkyl, " 5 substituted or unsubstituted C2-C24 alkenyl, alkynyl
substituted or unsubstituted C2-C24, substituted or unsubstituted C3-C24 cycloalkyl, substituted or unsubstituted C5-C24 cycloalkenyl, substituted or unsubstituted C8-C24 cycloalkynyl, substituted or unsubstituted C6-C30 aryl
10 unsubstituted, substituted or unsubstituted C7-C24 aralkyl, substituted or unsubstituted heterocyclyl with
3 to 10 ring members, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 different carbon atoms and an alkyl chain of 1 to 6 atoms
15 carbon.
More preferably, R1 is selected from H, acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.
Even more preferably, R1 is H, acetyl, lauroyl, myristoyl
20 or palmitoyl.
In an even more preferred embodiment, R2 is acetyl or palmitoyl.
In another preferred embodiment, R2 is -
NR3R4, -OR,, or -SR,,, where R, and R4 are independently selected from the group consisting of H, alkyl
25 substituted or unsubstituted Cl-C24, substituted or unsubstituted C2-C24 alkenyl 4 substituted or unsubstituted C2-C24 alkynyl
. substituted or unsubstituted, substituted or unsubstituted C3-C24 cycloalkyl, substituted or unsubstituted Cs-C24 cycloalkenyl, substituted or unsubstituted C8-C24 cycloalkynyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C7-C24 aralkyl, substituted or unsubstituted heterocyclyl having 3 to 10 ring members and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 different carbon atoms wherein the alkyl chain is 1 to 6 carbon atoms. Optionally, R3 and R4 may be linked via a saturated or unsaturated carbon-carbon bond, which forms a ring with the nitrogen atom. More preferably R2 is -NR,R4, or -OR3. More preferably R3 and R, they are
W selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. Even more preferably, R1 is H and R1 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl. According to an even more preferred embodiment, R2 is selected from -OH and -NH2. According to another embodiment of this invention R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl, AA2 is -L-Leu-, AA4 is -L-Arg-, and R2 is -NR3R4 or -OR, wherein R1 and R4 are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R2 is -OH or -NH2 . More preferably, R1 is acetyl or palmitoyl and R2 is -OH.
Even more preferably, n, m, p and q are 0. According to another embodiment of this invention R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl or palmitoyl, aa2 is -L-pro-, AA4 is -L-Arg-, and R2 is -NR3R4 or -OR3 wherein R1 and R4 are independently selected from H, methyl, ethyl, hexyl, m-dodecyl and hexadecyl, preferably R2 is -OH or -NH2 .
W More preferably, R1 is acetyl or palmitoyl and R2 is -OH.
Even more preferably, n, m, p and q are 0. Preferably, the compounds of formula (I) are selected from the group consisting of: pa1m-His-Leu-Leu-Arg-NH 2 , 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, " 5 Ac-His-Leu-Leu-Asn-NH2, Ac-His-Leu-Leu-Asn-OH,
U Ac-His-Leu-Leu-Asn-NH-(CH2)15-CH3, Palm-Hys-Pro-Leu-Arg-NH2, Palrn-His-Pro-Leu-Arg-OH, 10 Ac-His-Pro -Leu-Arg-NH2, Ac-His-Pro-Leu-Arg-OH, Ac-His-Pro-Leu-Arg-NH-(CH2)I5-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, 25 Ac -His-His-Leu-Asn-NH2, * Ac-His-His-Leu-Asn-OH, % Ac-His-His-Leu-Asn-NH-(CH2)15-CH3, Ac-Gly-Gly- His-Pro-Leu-Asn-OH, Ac-His-His-Leu-Asn-Ala-Leu-OH, 30 Ac-Gly-His-His-Leu-Asn-Ala-OH, stereoisomers thereof, mixtures thereof and/or or cosmetically or pharmaceutically acceptable salts thereof.
The peptides of this invention may exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids that form the same may have an L or D configuration or independently racemic with each other. Therefore, it is possible to obtain isomeric mixtures as well as " 5 racemic mixtures or diastereomeric mixtures, or diastereomers or pure enantiomers, depending on the number of
The asymmetric carbons and whose isomers or isomeric mixtures are present. Preferred structures of the peptides of the invention are pure isomers, that is, enantiomers or 10 diastereomers. For example, when it is indicated that AA, may be -His-, it is understood that AA1 is selected from -L-H1S-, -D-H1S- or mixtures of both, racemic or non-racemic. Likewise, when it is said that AA2 can be -Leu-, it is understood that it can be -L-Leu-, -D-Leu- or mixtures of both, racemic or non-racemic. The preparation processes described in that document allow a person skilled in the art to obtain each of the stereoisomers of the peptide of the invention by choosing the amino acid with the appropriate configuration. In the context of this invention, the term "non-encoded amino acids" refers to those amino acids not encoded by the genetic code, whether natural or unnatural, such as, and not restricted to, citrulline, ornithine, sarcosine, desrnosine, norvaline, aminobutyric acid, 2-aminobutyric acid, 4 2-aminoisobutyric acid, 6-aminohexanoic acid, 1-
N-naphthylalanine, 2-naphthylalanine, 2-aminobenzoic acid, 4-aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, cycloserine, 30 carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline, allo-isoleucine, allo-threonine, isonipecotic acid, isoserine, phenylglycine, astatin, B-alanine, norleucine, N-methyl amino acids,
fj3-aminoacids or y-aminoacids among others, as well as derivatives thereof.
A list of unnatural amino acids can be found in the article "Unusual amino acid in peptide synthesis" by D.C.
Roberts and F.
Vellaccio, in The 5 Peptides, Vol. 5 (1983), Chapter VI, Gross E. and Meienhofer" - j., Eds., Academic Press, New York, USA or in the commercial catalogs of companies specialized in the area, such as PolyPeptide Laboratories, Bachem, Novabiochem, Sigma-Aldrich, Peptides International, Advanced ChemTech, Chem-lmpex, 10 Maybridge Chemical, Chirotech Technology, Peninsula Laboratories or RSP Amino acid Analogues among others.
In the context of this invention when n, m, p or q are different by 0 it is clearly understood that the nature of W,
X, Y and/or Z does not make the activity of the peptides of this invention difficult, but either contributes to the stimulation of protein synthesis by heat shock or it has no effect thereon.
In the context of this invention there are also cosmetically or pharmaceutically acceptable salts of the peptides
20 provided by the invention.
The term "cosmetically or pharmaceutically acceptable salts" means a salt permitted for use in animals, and more particularly in humans, and includes those salts used to form base addition salts, if inorganic, for example, and not restricted to , lithium, sodium,
- 25 potassium, calcium, magnesium, manganese, copper, zinc or aluminum among others; if organic such as and not restricted to ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine among others; or acid addition salts, if organic, for example, and not restricted to acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate among others ; or inorganic, for example
[ 23/66 and not restricted to chloride, sulfate, borate or carbonate among others. The nature of the salt is not critical, provided it is cosmetically and pharmaceutically acceptable. Cosmetic and pharmaceutically acceptable salts of the peptides of the invention can be obtained by conventional methods well known in the prior art [Berge S.M., Bighley L.D. and
W Monkhouse D.C. (1977) "Pharmaceutical Salts" j. Pharm. Sci. 66:1-19]. One aspect of this invention pertains to a peptide 10 of the general formula (I), its stereoisomers, mixtures thereof, and/or their cosmetically or pharmaceutically acceptable salts, as described in this invention, for the treatment and/or care of skin, mucous membranes and/or hair.
In another particular aspect, this invention relates to a peptide of general formula (I), its stereoisomers, mixtures thereof, and/or their cosmetically or pharmaceutically acceptable salts, as described in this invention, for the treatment and/or care of these conditions. , disorders and/or diseases that are ameliorated or prevented by stimulating Hsp protein synthesis, specifically Hsp family proteins with a molecular weight between 20klja and 110kDa, more specifically with a molecular weight between 40kDa and 10OkDa and even more specifically proteins Hsp with a molecular weight of between 60kDa and 80kDa and in particular Hsp with a molecular weight of 70JcDa or Hsp70. In a preferred embodiment, conditions, disorders and/or diseases that are ameliorated or prevented by a heat shock stimulus of protein synthesis are selected from the group consisting of epidermolysis bullosa and alopecia, including alopecia caused by treatment of cancer chemotherapy.
In another particular aspect, this invention relates to a peptide of general formula (I), its stereoisomers, mixtures thereof, and/or their cosmetically or pharmaceutically acceptable salts, as described in this invention, for the treatment and/or care of the skin, mucous membranes and/or hair, which reduce, delay, and/or prevent " 5 damage to cells induced by UV radiation, heat stress, oxidative stress, osmotic shock, inflammation, hypoxia,
W exposure to pollutants, lack of nutrition and lack of hydration.
In another aspect, this invention relates to a peptide of general formula (I), its stereoisomers, mixtures thereof, and/or their cosmetically or pharmaceutically acceptable salts, as described in this invention, for the treatment and/or care of the skin, mucous membranes and/or hair, which reduce and/or prevent the signs of aging and/or photoaging. In another aspect, this invention relates to a peptide of general formula (I), its stereoisomers, mixtures thereof, and/or their cosmetically or pharmaceutically acceptable salts, as described in this invention, for the treatment and/or care of the skin and /or mucous membranes, which stimulate healing and/or re-epithelialization of wounds, preferably wounds that are a result of diabetes. In another particular aspect, this invention relates to a peptide of general formula (I), its
W stereoisomers, mixtures thereof, and/or cosmetically or pharmaceutically acceptable salts thereof, as described in this invention, for the treatment and/or care of skin and/or hair that retard and/or prevent hair loss or induce hair growth. hair.
PREPARATION PROCESSES The synthesis of the peptides of the invention, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be carried out according to conventional methods, known in the prior art, such as solid phase peptide synthesis methods [Stewart JM and Young JD (1984 ) "Solid Phase Peptiae Synthesis, 2nd edition "Pierce" 5 Chemical Company, Rockford, Illinois; Bodanzsky M. and Bodanzsky A. (1984) "The practice of Peptide Synthesis" - Springer Verlag, New York; Lloyd-Williams P., Albericio F. and Giralt E. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA], solution synthesis, a combination of methods for the synthesis of solid phase and solution synthesis or enzymatic synthesis [Kullmann W. (1980) "Proteases as catalysts for enzymic syntheses of opioid peptides" j.Biol.Chem. 255:8234 to 8238]. The peptides can also be obtained through the fermentation of a bacterial strain, genetically modified or not, to produce the desired sequences, through the controlled hydrolysis of proteins of animal or plant origin, preferably of plant origin, to release fragments of peptide that contain at least the desired sequence.
20 For example, a method for obtaining the peptides of the invention of formula (I) comprises the steps of: coupling an amino acid at the protected N-terminus and at the free C-terminus, in an amino acid with the free N-terminus -terminal and the C-terminal end protected or attached to a solid support;
B remove the N-terminal end protecting group; repeating the coupling and removal sequence of the N-terminal protecting group until the desired peptide sequence is obtained; — remove the cleavage protecting group or C-terminal end of the solid support. Preferably, the C-terminal end is attached to a solid support and the process is conducted in solid phase and therefore includes coupling an amino acid to the protected N-terminal α5-terminus and the C-terminal free end at m an amino acid with the free N-terminus and the C-terminus attached to a polymer support; removal of the protecting group from the N-terminal end; and repeating that sequence as many times as necessary to obtain a peptide of the desired length, and, finally, followed by cleavage of the synthesized polypeptide from the original polymer support.
The functional groups of amino acid side chains are suitably protected with temporary or permanent protecting groups through the synthesis, and can be deprotected simultaneously or orthogonally to the process of cleaving the peptide from the polymer support. Alternatively, solid phase synthesis can be accomplished by a convergent strategy that couples a peptide to the polymer support or to a peptide or amino acid previously attached to the polymer support. Convergent synthesis strategies are widely known to the person skilled in the art and are described in 25 Lloyd-Williams P., Álbericio F. and Giralt E. in "Convergent
P solid-phase peptide synthesis" (1993) Tetrahedron 49:11065 to 11133. The process may comprise the additional stages of deprotecting the ends and/or cleaving the N-terminus and/or C-terminus of the peptide from the support. of polymer in a different order, using standard procedures and conditions known in the prior art, after which the functional groups at these ends can be modified.
Optional modification of the N-terminal and/or C-terminal ends may be carried out with the peptide of formula (I) attached to the polymeric support or once the peptide has been cleaved from the polymeric support. 5 Optionally, R1 can be introduced by reacting the N-terminal end of the peptide of the invention with an e compound Rl-j, where Rl is as described above and j is a leaving group, for example, and not restricted to, the tosyl group, the mesyl group and the halogen groups, among others; 10 through a nucleophilic substitution reaction, in the presence of a base and suitable solvent, in which the fragments that have the functional groups not involved in the formation of the NC bond are adequately protected with temporary or permanent protective groups.
Optionally and/or additionally, such R2 radicals may be introduced by reacting an HR2 compound wherein R2 is -OR3, -NR3R4 or -SR3, with a complementary fragment corresponding to the peptide of formula (I) wherein R2 is - OH in the presence of a suitable solvent and a base such as, N,N-diisopropylethylamine (DIEA) or triethylamine or an additive such as 1-hydroxybenzotriazole (HOBt) or I-hydroxyazabenzotriazole (HOAt) and a dehydrating agent such as a carbodiimide, a uronium salt, a phosphonium salt or an amidinium salt, among others, or by previous acyl halide formation with, for example, thionyl chloride, and,
P hereby obtain a peptide according to the invention of . general formula (I), wherein the fragments having the functional groups not involved in NC bond formation are suitably protected with temporary or permanent protecting groups, c)1j, alternatively, other radicals R2 may be introduced by the simultaneous incorporation into the process of cleavage of the peptide from the polymeric support.
A person skilled in the art will readily understand that the steps of deprotection/cleavage of the C-terminal and N-terminal ends and their subsequent derivatization can be performed in a different order, according to procedures known in the prior art [Smith 5 MB and March j. (1999) "March's Advanced Organic Chemistry Reactions, Mechanisms and Structure", 5th Edition, john wiley &
W Sons, 2001).
The term "protecting group" refers to a group that blocks an organic functional group and can be released under controlled conditions. Protecting groups, their relative reactivity and the conditions under which they remain inert are known to the person skilled in the art.
Examples of representative protecting groups for the amino group are amides such as amide acetate, amide benzoate, amide pivalate; carbamates, such as benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ), para-nitrobenzyloxycarbonyl (pNZ), tert-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc) ), 9-20 fluorenylmethyloxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), Trityl (Trt), methoxytrityl (Mtt), 2,4-dinitrophenyl (Dnp), N-[1-(4,4-dimethyl-2,6- dioxocyclohex-1-ylidene)ethyl (Dde), 1-(4,4-dimethyl-2,6-dioxo-cyclohexylidene)-3-methylbutyl (ivyl), 1-(1-adamanti1)-1-methylethoxycarbonyl (Adpoc ), among others, preferably Boc m or Fmoc. b Examples of representative protecting groups for the carboxyl group are esters such as tert-butyl ether (tBu), allyl ester (All), triphenylmethyl ester (trityl ester, Trt), cyclohexyl ester (CHX), benzyl ester ( Bzl), ortho-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzyl ether, trimethylsilylethyl ester, 2-phenylisopropyl ester, fluorenylmethyl ester (Fm), 4-
(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl (Dmab), among others; the protecting groups of the invention are the All, tBu, CHX, Bzl and Trt esters. " 5 The side chains of trifunctional amino acids can be protected during the synthetic process with groups
P temporary or permanent protectors orthogonal to the protecting groups at the N-terminal and C-terminal ends.
The guanidine group of the arginine 10 side chain can be protected with the nitro group, allyloxycarbonyl (Alloc), para-toluenesulfonyl (tosyl, Tos), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (pbf) or 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), among others; 15 the imidazolyl group of the histidine side chain can be protected with the thosyl group (Tos), the tert-butyloxycarbonyl group (Boc), the trityl group (Trt), the methoxytrityl group (Mtt) or the 2,4-dinitrophenyl group (Dnp) among others; and the amide group of the asparagine side chain may be protected with the trityl group (Trt) or the xanthyl group (Xan) or is used unprotected.
In a preferred embodiment, the protecting group strategy used is the strategy in which the amino groups are protected by Boc, the carboxyl groups are protected by Bzl, chx or All esters, the arginine side chain is n protected by Mtr or Tos , the asparagine side chain is used unprotected and the histidine side chain is protected by Tos or Dnp. In another preferred embodiment, the protecting group strategy used is the strategy in which the amino groups are protected by Fmoc, the carboxyl groups are protected by tBu, All or Trt esters, the side chain of arginine is protected by Pmc or Pbf, the side chain of asparagine by
Trt and the side chain of histidine by Trt or Mtt. Examples of these and other protecting groups, their introduction and replacement, can be found in the literature [Greene T.W. and Wuts P.G.M., (1999) "Protective groups in '5 organic synthesis" John Wiley & Sons, New York; Atherton B.
W and Sheppard R.C. (1989) "Solid Phase Peptide Synthesis: A practical approach" TRL Oxford University Press]. The term "protecting groups" also includes polymeric supports in solid phase synthesis.
10 When the synthesis takes place wholly or partially in the solid phase, possible solid supports used in the process of the invention may involve polystyrene supports, polystyrene grafted polyethylene glycol, and the like, for example, and without restriction to, p-methylbenzhydrylamine resins 15 ( MBHA) [Matsueda GR and Stewart JM (1981) "A p-methylbenzhydrylamine resin for improved solid-phase synthesis of peptide amides" Peptides 2:45 to 50], 2-chlorotritile resins [Barlos K., Gatos D., Kallitsis J., Papaphotiu G., Sotiriu P., Wenqing Y. and Schâfer W. (1989) "Darstellung 20 geschützter peptid-Fragment unter Einsatz substituerter Triphenylmethyl-Harze" Tetrahedron Lett. 30:3943 to 3946, · Barlos K., Gatos D., Kapolos S., Papaphotiu G., Schâfer W. and Wenqing Y. (1989) "Veresterung von partiell geschützten Peptid-Fragmenten mit Harzen. Einsatz von 25 2-Chlorotrity1chlorid zur Synthese von Leul -Gastrin T" ^ Tetrahedron Lett. 30:3947 to 3951], TentaGei® resins (Rãpp "Polynere GmbH), CherriMatrix® resins (Matrix Innovation, Inc), and the like, which may or may not include a variable linker, such as 5-(4-aminomethyl-3, 5-dimethoxy phenoxy)valeric (PAL) 30 [Alberício F., Kheib-Cordonier N., Biancalana S., Gera L., Masada Rl, Hudson d. and Barany G. (1990) "preparation and application of the
5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy phenoxy)va1eric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions" j. Org. Chem. 55:3730 a 3743], 2-(AM) [R:ink H. (1987)" 5 "Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methylester resin" Tetrahedron Lett.
W 28:3787 to 3790], Wang [Wang S.S. (1973) "p-Alkoxybenzyl Alcohol Resin and p-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis of Protected Peptide Fragments" 10 j.Am.Chem.Soc. 95:1328 to 1333], and the like, allowing deprotection and simultaneous cleavage of the peptide from the polymeric support.
COSMETIC OR PHARMACEUTICAL COMPOSITIONS In this regard, another aspect of the invention is a cosmetic or pharmaceutical composition comprising at least one peptide of general formula (1), stereoisomers thereof, mixtures thereof, and/or cosmetically and pharmaceutically acceptable salts thereof together with at least one cosmetically or pharmaceutically acceptable adjuvant.
Such compositions may be prepared by conventional means known to those skilled in the art ["Harry's Cosmeticology'", Eighth edition (2000) Rieger M.M., ed., New York Chemical Pub., NY, USA; "Remington: The Science and Practice of Pharmacy", Twentieth Edition (2003) Genaro A.R., 25th ed., Lippincott Williams & Wilkins, Philadelphia, USA]. » The peptides of this invention have solubility. variable in water, according to the nature of its sequence or any possible modifications at the N-terminal and/or C-terminal ends. Accordingly, the peptides of this invention may be incorporated into the compositions by aqueous solution, and those which are not water-soluble may be solubilized in conventional cosmetically or pharmaceutically acceptable solvents, for example, and not restricted to,
ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.
The cosmetically or pharmaceutically effective amount of the peptides of the invention which must be administered, as well as their dosage, will depend on numerous factors, including the age, condition of the patient, the nature or severity of the condition, disorder or disease being treated, cared for, or treated. and/or prevented, the route and frequency of administration and the particular nature of the peptides to be used "Cosnetically and pharmaceutically effective amount" is understood to mean a non-toxic but sufficient amount of the peptide or peptides of the invention to provide the desired effect. The peptides of the invention are used in the cosmetic or pharmaceutical composition of this invention in cosmetically or pharmaceutically effective concentrations to achieve the desired effect; in a preferred form versus the total weight of the composition, between 0.00000001% (by weight ) and 20% (by weight); preferably between 0.000001% (by weight) and 20% (by weight), more preferably between 0.0001% (by weight ) and 10% (by weight) and even more preferably between 0.0001% (by weight) and 5% (by weight).
The peptides of the invention may also be incorporated into cosmetic and pharmaceutical delivery systems and/or sustained release systems. m The term "delivery systems" refers to a - diluent, adjuvant, excipient or carrier with which the peptide of the invention is administered. Such cosmetic or pharmaceutical carriers may be liquids, such as water, oils or surfactants, including those of petroleum, animal, vegetable or synthetic origin, such as and not restricted to peanut oil, soybean oil, mineral oil, sesame, castor oil, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosidases, maltosides, fatty alcohols, nonoxynols, polyoxamers, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, digitonin and the like. In "Remington's Pharmaceutical" 5 Sciences by E.W. Martin, diluents, adjuvants or excipients are described as appropriate carriers.
The term "sustained release" is used in a conventional sense referring to a delivery system for a compound that provides for gradual release of that compound over a period of time and preferably, although not necessarily, with relatively low levels of compound release. constant over a period of time. Examples of sustained release or delivery systems are liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, milliparticles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed surfactant micelles , mixed surfactant-phospholipid micelles, 20 millispheres, microspheres and nanospheres, lipospheres, milliccapsules, microcapsules and nanocapsules, as well as microemulsions and nanoemulsions, which can be added to achieve greater penetration of the active ingredient and/or improve its pharmacokinetic and pharmacodynamic properties . You
Preferred extended-release or delivery systems are liposomes, mixed surfactant-phospholipid micelles and microemulsions, more preferably water-in-oil microemulsions with a reverse micelle internal structure.
Sustained-release systems can be prepared by methods known in the prior art, and compositions containing the same can be administered, for example, by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches and microelectric patches, or by systemic administration, for example, and not restricted to, orally or parenterally, including nasal, rectal or subcutaneous implantation or injection, or implantation or direct injection into a specific part of the body, and preferably should release a
W relatively constant amount of the peptides of the invention. The amount of peptide contained in the sustained release system will depend, for example, on where the composition is to be administered, the kinetics and duration of release of the peptide of the invention, as well as the nature of the condition, disorder and/or disease being treated. and/or cared for.
The peptides of this invention can also be adsorbed on organic polymers or solid mineral supports such as, and not restricted to, talc, bentonite, silica, starch or maltodextrin among others. Compositions containing the peptides of the invention can also be incorporated into cloths, non-woven cloths and medical devices that are in direct contact with the skin, thus releasing the peptides of the invention either by biodegradation of the cloth binding system, non-woven cloth tissue or medical device, or friction between them and the body, due to body moisture, skin pH or body temperature. In addition, cloths and non-woven cloths can be used to produce garments that are in direct contact with the body. Preferably, the cloths, non-woven cloths and medical devices containing the peptides of the invention are used for the treatment and/or care of those conditions, disorders and/or diseases which are ameliorated or prevented by a stimulation of Hsp synthesis. . Examples of cloths, non-woven cloths, garments, medical devices and means for immobilizing the peptides thereto, among which are the delivery systems and/or the programmed release systems described above, can be found in the literature and are known in the art. prior art [Schaab CK (1986) "Impregnating Fabrics with Microcapsules", HAPPT May 1986; Nelson G. (2002) " 5 "Application of microencapsulation in textiles" Int. j.
and Pharm. 242:55 to 62; "Biofunctional Textiles and the Skin" (2006) Curr. problem Dermatol. v.33, Hipler U.C. and Elsner P., eds. S. Karger AG, Basel, Switzerland; Malcolm R.K.; McCullagh S.D., woolfson A.D., Gorman S.P., jones D.S., Cuddy j. (2004) 10 "Controlled release of an antibacterial drug model from a novel self-lubricating silicone biomaterial" j. Cont. Release 97:313 to 320]. Cloths, non-woven cloths, garments and medical devices of choice are bandages, gauzes, T-shirts, socks, pantyhose, underwear, belts, gloves, diapers, sanitary towels, dresses, covers, tissues, adhesive plasters, non-woven plasters adhesives, occlusive plasters, microelectric plasters and/or face masks.
Cosmetic or pharmaceutical compositions that contain the peptides of this invention, their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, can be used in different types of topically or transdermally applied compositions, optionally including cosmetically or 25 pharmaceutically acceptable substances necessary to formulate the desired administration form [Faülí i Trillo c. (1993) in - "Tratado de Farmacia Galénica" P Luzán 5, S.A. Ediciones, Madrid]. Topical or transdermal application compositions 30 may be produced in any solid, liquid or semi-solid formulation, such as and not restricted to creams, multiple emulsions such as and not restricted to oil and/or silicone in water emulsions, water-in-oil and/or silicone emulsions, water/oil/water or water/silicone/water type emulsions, and oil/water/oil or silicone/water/silicone type emulsions, anhydrous compositions, aqueous dispersions, oils, milks , balms, spurs, lotions, gels, gels " 5 in cream, hydroalcoholic solutions, hydroglycolic solutions,
W hydrogels, ointments, serums, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, ointments, powders, sticks, pencils and sprays or aerosols (sprinkles), including leave-on and wash-off formulations. These 10 topical or transdermal application formulations can be incorporated using techniques known to those skilled in the art into different types of solid accessories such as, and not restricted to, bandages, gauzes, t-shirts, socks, pantyhose, underwear, belts, gloves, diapers, sanitary napkins, drapes, covers, wipes, adhesive plasters, non-adhesive plasters, occlusive plasters, microelectric plasters or face masks, or they can be incorporated into different make-up products such as make-up bases, such as fluid bases and compact foundations, make-up removal lotions, make-up removal milks, under-eye concealers, eye shadows, lipsticks, lip balms, lip gloss and powders, among others.
Cosmetic and pharmaceutical compositions of the invention may include agents that enhance percutaneous absorption of the peptides of this invention, such as and
R restricted to, dimethylsulfoxide, dimethylacetamide, . dimethylformamide, surfactants, azone (1-dodecylazacycloheptaneo-2-one), alcohol, urea, ethoxydiglycol, acetone, propylene glycol or polyethylene glycol, among others.
In addition, the cosmetic or pharmaceutical compositions of this invention can be applied to local areas to be treated by means of iontophoresis, sonophoresis, electroporation, microelectric patches, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or needleless injections by means of pressure, such as oxygen pressure injections, or any combination thereof, to achieve greater penetration of the peptide of the invention. The "5" area of application will be determined by the nature of the condition,
M disorder and/or disease to be treated and/or cared for. Furthermore, cosmetic compositions containing the peptides of this invention, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be used in 10 different types of formulations for oral administration, preferably in the field of oral cosmetics and pharmaceutical drugs, such as and unrestricted. a, 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 gelatins and any other manner known to one skilled in the art. Particularly, the peptides of the invention may be incorporated into any form of functional food or fortified food, such as, and not restricted to, diet bars or compact or non-compact powders. These powders can be dissolved in water, juices, soft drinks, dairy products, soy products or can be incorporated into diet bars. The peptides of this invention can be formulated
H 25 with common excipients and adjuvants for oral compositions or food supplements, such as and not restricted to, - fat components, aqueous components, humectants, preservatives, texturizing agents, flavors, flavors, antioxidants and colorings common in the food industry.
Cosmetic or pharmaceutical compositions which contain the peptides of the invention, their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts may also be administered topically or transdermally, as well as by any other suitable route with, for example, oral or parenteral route, for which they will include the pharmaceutically acceptable excipients necessary for the formulation of the b
5 desired form of administration.
In the context of this invention,
The term "parenteral" includes nasal, auricular, ophthalmic, rectal, urethral, vaginal, subcutaneous, intradermal, intravascular injections, such as intravenous, intramuscular, intraocular, intravitreal, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intrameningeal , intra-articular, intrahepatic, intrathoracic, intratracheal, intrathecal and intraperitoneal and any other similar injection or infusion technique.
An analysis of the different pharmaceutical forms of administration
15 of the active ingredients and excipients necessary to obtain the same can be found, for example, in the "Treaty of Galénica Pharmacy", C.
Faulí i Trillo, 1993, Luzán 5, S.A.
Editions, Madrid.
Among the cosmetic or pharmaceutical adjuvants
Acceptable substances contained in the cosmetic or pharmaceutical compositions described in this invention include additional ingredients commonly used in compositions for the treatment and/or care of skin, mucous membranes and/or hair such as, and not restricted to, heat shock proteins, other stimulating agents. of heat shock protein synthesis, acetylcholine receptor aggregation inhibitors,
- muscle contraction inhibitory agents, anticholinergic agents, elastase inhibitory agents, matrix metalloproteinase inhibitory agents, inhibitory agents or
30 melanin synthesis stimulants, depigmenting or bleaching agents, pro-pigmentation agents, self-tanning agents, anti-aging agents, NO synthase inhibitory agents, 5α-reductase inhibitory agents,
lysyl and/or prolyl hydroxylase inhibitors, antioxidants, free radical scavengers and/or anti-smog agents, scavengers of reactive carbonyl species, anti-glycation agents, anti-smog agents. 5 histamines, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners such as urectants, moisture retaining substances, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermal hydrolytic enzymes, 10 vitamins, amino acids, proteins, pigments or colorants, dye, gelling polymers, thickeners, surfactants, softening agents, anti-wrinkle agents, agents capable of reducing or treating bags under the eyes, exfoliating agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents which stimulate the synthesis of dermal or epidermal macromolecules and/or capable of inhibiting or preventing their degradation, such as, for example, collagen synthesis stimulating agents, elastin synthesis stimulating agents, decorin synthesis stimulating agents, stimulating agents synthesis of laminin, agents and defensin synthesis stimulants, aquaporin synthesis stimulating agents, hyaluronic acid synthesis stimulating agents,
N 25 fibronectin synthesis, sirtuin synthesis stimulating agents, agents that stimulate the synthesis of lipids and · stratum corneum components (ceramides, fatty acids, etc.), agents that inhibit collagen degradation, other agents that inhibit degradation of elastin, agents that inhibit serine proteases such as cathepsin G, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate adipocyte proliferation, agents that stimulate melanocyte proliferation, agents that stimulate keratinocyte differentiation, agents that stimulate adipocyte differentiation, agents that inhibit acetylcholinesterase, skin relaxant agents,
P 5 glycosaminoglycan synthesis stimulants, anti-
P hyperkeratosis, comedolytic agents, antipsoriatic agents, DNA repair agents, DNA protecting agents, stabilizers, anti-itch agents, agents for the treatment and/or care of sensitive skin, firming agents, anti-stretch marks agents, binding agents, agents that regulate sebum production, lipolytic agents or agents that stimulate lipolysis, anti-cellulite agents, antiperspirant agents, agents that stimulate healing, adjunct healing agents, agents that stimulate re-epithelialization, adjunct re-epithelialization agents, tissue growth factors cytokine, calming agents, anti-inflammatory and/or analgesic agents, anesthetic agents, agents that act on capillary circulation and/or microcirculation, agents that stimulate angiogenesis, 20 agents that inhibit vascular permeability, venotonic agents, agents that act on metabolism cells, agents to improve the dermoepidermal junction, agents that induce growth agents, hair growth inhibiting or retarding agents, hair loss delaying agents, preservatives, perfumes, chelating agents, plant extracts, essential oils, marine extracts, agents · obtained from a biofermentation process, mineral salts extracts of cell 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 the other components of the composition and especially with the peptides of the general formula (I) contained in the composition of this invention.
Furthermore, the nature of these additional ingredients should not unacceptably alter the benefits of the peptides of this invention. The nature of these additional ingredients may be synthetic or natural, such as plant extracts or obtained by a biotechnological process or a combination of one. synthetic process and a biotechnological process. Additional examples can be found in the CTFA International Cosmetic Ingredient Dictionary & Handbook, 12" Edition (2008).
In the context of this invention, biotechnological process is understood to be any process that produces the active ingredient or part thereof, in an organism or part thereof. A further aspect of this invention relates to a cosmetic or pharmaceutical composition which contains a cosmetically or pharmaceutically effective amount of at least a peptide according to general formula (I), its stereoisomers, mixtures thereof and/or their cosmetic salts. or pharmaceutically acceptable and also a cosmetically or pharmaceutically effective amount of at least one extract, synthetic compound or biofermentation product that stimulates Hsp synthesis, such as, and not restricted to, 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 Arteinia, m 25 jojoba seed oil, grape seed extracts, green tea extracts, geranylgeranilacetone, cel-astrol, zinc and its - salts, 2-cyclopenten-1-one, proteasome inhibitors such as and not restricted to bortezomib; prostaglandins and their derivatives, hydroxylamine and its derivatives such as and not restricted to bimoclomol; chalcone and its derivatives, hyperosmotic agents such as and not restricted to, 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.
A further aspect of this invention pertains to a cosmetic or pharmaceutical composition that contains a cosmetically or pharmaceutically effective amount of at least
minus one peptide according to general formula (I), its a-stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts and also a cosmetically or pharmaceutically effective amount of at least one extract which is an anti-wrinkle and/or anti-wrinkle agent or anti-aging agent such as and not restricted to extracts of Vitis vinifera, Rosa canina, Curcuma longa, Tris pallida,
Theobroma cacao, Ginkgo biloba, Leontopodium Alpinum or Dunaliella salina among others or, in addition, at least one synthetic compound or biofermentation product that is an anti-wrinkle agent and/or an anti-aging agent such as and not restricted to MatMxyl" [ INCI· Palmitoyl pentapeptide-4],
Matrixyl 3000" [INCI: Palmitoyl Tetrapeptide-7, Palmitoyl Oligopeptide], EssenskinT" [INCI: Calcium Hydroxymethionine], Renovage [INCI: Teprenone] or Dermaxyl" [INCI:
20 Palmitoyl Oligopeptide] marketed from Sederma, Vialox" [INCI: Pentapeptide 3], Syn"Ake" [INCI-Dipeptide ® Diaminobutyroyl Benzylamide Diacetate], Syn-Coll [INCI: Palmitoyl Tripeptide-5], Phytaluronate [INCI: ® Carob tree (Keratonia siliqua)] or Preregen [INCI:
25 Glycine Protein Soy (Soybean), Oxide Reductases] commercialized with Pentapharm/DSM, Myoxinol" [INCI:
- Hydrolyzed Hibiscus Esculentus Extract], Syniorage" [INCI: Acetyl Tetrapeptide-ll], Dermican"" [INCI: Acetyl Tetrapeptide-9] or DN-AGE" LS [INCI:
30 Cassia Alata] sold by Laboratoires ® Sérobiologiques/Cognis, Algisum C [INCI: Methylsilanol Manuronate] or Hydroxyprolysilane CN" [INCI: Methylsilanol Hydroxyproline Aspartate] sold by Exsymol,
Argireline" [INCI: Acetyl Hexapeptide-8], SNAP 7 [INCI: Acetyl Heptapeptide-4], SNAP-8 [INCI: Acetyl Octapeptide-3], Leuphasyl" [INCI. Pentapeptide-18], Inyline" [INCI proposal: Acetyl Hexapeptide 25], Aldenine" [INCI hydrolyzed wheat protein, hydrolyzed soy protein, bO Tripeptide-l], preventheliaTM [INCI: Diaminopropionoyl Tripeptide 33], Decorinyl" [ INCI: Tripeptide 10 Citrulline], Trylagen" [INCI: Pseudoalteromonas Yeast Extract, Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, 10 Tripeptide 10 Citr"ulin, Tripeptide 1], Eyeseryl" [INCI: Acetyl Tetrapeptide-5], AC29 Peptide [INCI: Acetyl Tripeptide-30 Citrulline], Relistase"" [INCI Proposal: Acetyl Tetrapeptide-30], Lipocrornan-6 [INCI: Dimethylmethoxy Chromanol], Chromabright"" [INCI: Dimethylmethoxy Chromanyl 15 Palmitate], Antarcticine" [ INCI. Pseudoalteromonas Yeast Extract] or Vilastene"M [INCI: Lysine HCl, Lecithin, Tripeptide-1O Citrulline] sold from ® Lipotec, Kollaren [INCI: Tripeptide-1, Dextran] sold from Institut Europeen de Biologie 20 Cellulaire, Collaxyl "IS [INCI: Hexapeptide 9], Laminixyl IS"" [INCI: Heptapeptide], Orsirtine"" GL [INCI: Oryza Sativa Extract (Rice)], D'OrientineT" IS [INCI: Phoenix Dactylífera Seed Extract ( Date palm)], Phytoquintescine"" [INCI: Spelled Extract (Triticum
D 25 Monococcum)] or Quintescine"" IS [INCI: Dipeptide-4] marketed from vincience/lSP, BONT-L-Peptide [INCI: - Palmitoyl Hexapeptide-19] marketed from Infinitec Activos, Deepaline" PVB [INCI: Palmitoyl Hydrolyzed Wheat Protein] or Sepilift" DPHP [INCI· Dipalmitoyl 30 Hydroxyproline] sold from Seppic, Gatuline" Expression [INCI: Acmella oleracea Extract], Gatuline" In-Tense [INCI: Spilanthes Acmella Flower Extract] or Gatuline" Age Defense 2 [INCI: Juglans Seed Extract
Regia (Nogueira)] marketed with Gattefossé, ThalassineT" [INCI: Algae Extract] marketed with Biotechmarine, ChroNOline" [INCI: Caprooil Tetrapeptide-3] or Timulen-4 [INCI: Acetyl Tetrapeptide-2] marketed
5 from Atrium Innovations/Unipex Group, EquiStat [INCI: 0 Pyrus Malus Fruit Extract, Soy Glycine Serpent Extract] or Juvenesce [INCI: Ethoxydig1icol and Caprylic Triglyceride, Retinol, Ursolic Acid, Phytonadione, Ilomastat] sold together à 10 Coletica/Engelhard/BASF, Ameliox [INCI: Carnosine, Tocopherol, Silybum Marianum Fruit Extract] or phytoCellTec Malus Domestica [INCI: Malus Domestica Fruit Cell Culture] sold from Mibelle Biochemistry, Bioxilift [INCI: Extract of pimpinella Anisum] or SMS Anti-15 Wrinkle" [INCI: Annona Squamosa Seed Extract] marketed from Silab, Ca' channel antagonists such as and not restricted to, alverine, manganese or magnesium salts, certain secondary amines or tertiary, retinol and its derivatives, idebenone and its derivatives, Coenzyme Q1O and its derivatives, boswellic acid and its derivatives, GHK and its derivatives and/or salts, carnosine and its derivatives, DNA repair enzymes such as o and not restricted to, photolyase, T4 endonuclease V, or chloride channel agonists among others.
K 25 Additionally, this invention relates to a cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide according to general formula (I), its stereoisomers, mixtures thereof and/or their cosmetic salts. 30 or pharmaceutically acceptable, and, in addition, a cosmetically or pharmaceutically effective amount of at least one extract or combination of extracts that stimulate healing and/or re-epithelialization or adjuncts to healing and/or re-epithelialization such as, without restriction to, extracts of Centella asiatica, Rosa moschata, Echinacea angustifolia, Symphytum officinal, Equisetum arvense, Hypericum perforatum, Mimosa tenuiflora, Aloe vera, Polyplant" Epithelizing [INCI: " 5 Calendula officinalis, Hypericurn perforatum, Chamornilla & recutita, Rosmarinus officinalis] marketed by Provital, Cytokinol " LS 9028 [INCI: Hydrolyzed Casein, Hydrolyzed Yeast Protein, Lysine HCl] marketed by Labor atories Serobiologiques/Cognis or 10 Deliner" [INCI: Zea mays Nucleus extract (corn)] marketed by Coletica/Engelhard/BASF among others, and/or a cosmetically or pharmaceutically effective amount of at least one synthetic compound, extract or product of biofermentation that stimulate healing and/or re-epithelialization such as, without restriction to, cadherins, integrins, selectins, hyaluronic acid receptors, immunoglobulins, fibroblast growth factor, connective tissue growth factor, platelet-derived growth factor , vascular endothelial growth factor 20, epidermal growth factor, insulin-like growth factor, keratinocyte growth factors, colony-stimulating factors, transforming growth factor beta, tumor necrosis factor alpha, interferons, interleukins, metalloproteinases 25 matrix, protein tyrosine phosphatase receptors,
K Antarcticine" [INCI: Pseudoalteromonas Yeast Extract] or Decorinyl" [INC"Ú Tripeptide 10 Citrulline], marketed by Lipotec, among others, or a mixture thereof.
A further aspect of this invention relates to a cosmetic or pharmaceutical composition which comprises a cosmetically or pharmaceutically effective amount of at least one peptide according to general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable, and, in addition, a cosmetically or pharmaceutically effective amount of at least one extract or combination of extracts which delay hair loss or which induce hair growth such as, without restriction to, extracts of Tussilago farfara or Achillea millefolium, and/or a cosmetically or pharmaceutically effective amount of at least one compound that delays hair loss or that
10 induces hair growth, such as, and not limited to, nicotinic acid esters such as C3-C6 alkyl nicotinates such as methyl or hexyl nicotinate, benzyl nicotinate, or tocopherol nicotinate; non-steroidal and steroidal anti-inflammatory agents, such as, and not limited to,
hydrocortisone, its salts and derivatives or niflumic acid; retinoids such as, and not limited to, all transretinoic acids or tretinoin, isotretinoin, retinol, or vitamin A, and derivatives thereof, such as acetate, palmitate, propionate, motretinide, etretinate, and trans retinoate of
20 zinc; antibacterial agents such as, and not limited to, macrolides, pyranosides, and tetracycline, erythromycin; calcium channel antagonists such as, without restriction to, cinnarizine and diltiazem; hormones such as, and not limited to,
estriol, its analogues or tyrosine, its analogues and/or its
25 salts; antiandrogenic agents such as, and not limited to, m oxendolone, spironolactone or diethylstilbestrol;
- antiradicals such as, and not restricted to, dimethylsulfoxide; esterified oligosaccharides such as, and not restricted to,
those described in EP 0211610 and EP 0064012; 30 hexasaccharide acid derivatives such as, and without restriction to glucose saccharide acid or those described in the EP document
0375388; glucosidase inhibitors such as, and not restricted to, D-glucaro-1,5-lactam or those described in the EP document
0334586; proteoglycan inhibitors and such as, and not restricted to, L-galacton-1,4-lactone or those described in EP 0277428 ; tyrosine kinase inhibitors such as, and not restricted to, 1-amide-1-cyano(3,4-dihydroxyphenyl)ethylenQ or those described in EP 0403238, diazoxides such as, and not restricted to, 7-(acetylthio)- 4',5'-dihydrospiro[androst-4-.ene-17,2'-(3H)furan]-3-one, 3-methyl-7-chloro[2H]-1,2,4-benzothiadiazine or 1,1-spiroxazone dioxide; phospholipids such as, and without restriction to, lecithin; salicylic acid and its derivatives, hydroxyl carboxylic or keto carboxylic acids and their esters, lactones and their salts; anthralin, eicosa-
5,8,1l-trienoic acid and its esters or amides or minoxidil and its derivatives among others, or mixtures thereof.
A further aspect of this invention relates to a
15 cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide according to general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, and,
20 additionally, a cosmetically or pharmaceutically effective amount of at least one sunscreen such as,
and without restriction to, anthranilates, cinnamates, salicylates, dibenzoylmethane derivatives, camphor derivatives, triazine derivatives, benzophenone derivatives, diphenylacrylate derivatives, benzotriazole derivatives, benzylmalonate derivatives, benzimidazole derivatives , imidazolines,
· ' Benzoallyl derivatives, p-aminobenzoic acid derivatives, polymers and silicones, alkyl styrene derivatives, metal oxide nanopigments such as, and not limited to,
30 titanium oxide or zinc oxide or filters based on carbon nanotubes, among others, or mixtures thereof.
Another further aspect of this invention relates to a cosmetic or pharmaceutical composition which comprises a cosmetically or pharmaceutically effective amount of at least one peptide according to general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically salts. and, in addition, a cosmetically or pharmaceutically effective amount of at least one Hsp family protein, such as, and not restricted to, Hsp70, including Hsp72 and Hsp73, Hsp60, Hsp27 or Hsp90 among others.
APPLICATIONS 10 An aspect of this invention relates to the use of at least one of the peptides of the general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts in the preparation of a cosmetic or pharmaceutical composition for the treatment 15 and/or care of the skin, mucous membranes and/or hair- Another aspect of this invention relates to the use of at least one of the peptides of general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts in the preparation of a cosmetic or pharmaceutical composition for the treatment and/or care of those conditions, disorders and/or diseases which are ameliorated or prevented by stimulating Hsp protein synthesis, specifically Hsp family proteins having a molecular weight between 20kDa and 1lokDa , specifically a
K 25 molecular weight between 40kDa and 100kDa and even more specifically Hsp proteins with a molecular weight between 60kDa and 80kDa, and in particular Hsp with a molecular weight of 70kDa or Hsp70.
In a preferred modality, conditions, disorders and/or diseases that are ameliorated or prevented by stimulation of heat shock protein stimulation are selected from the group consisting of epodermolysis bullosa and alopecia, including alopecia married to chemotherapy treatment for cancer.
According to a preferred embodiment, this invention relates to the use of a peptide of formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts in the preparation of a cosmetic or pharmaceutical composition for the treatment and/or care of the skin, mucous membranes and/or hair that reduces, delays and/or prevents cell damage induced by UV radiation, heat stress, oxidative stress, osmotic shock, inflammation, hypoxia, exposure to pollutants, deficiency of nutrition and lack of hydration.
According to a preferred embodiment, this invention relates to the use of a peptide of formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts in the preparation of a cosmetic or pharmaceutical composition for the treatment and /or skin and/or hair care that reduces, delays or prevents the signs of aging and/or photoaging.
Similarly, this invention relates to the use of at least one of the peptides of formula (I), their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts in the preparation of a cosmetic or pharmaceutical composition for the treatment and /or care of the skin, rucous membranes and/or hair, which 25 stimulate wound healing and/or re-epithelialization,
R preferably those injuries which are a result of - diabetes. According to a preferred embodiment, this invention relates to the use of a peptide of formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts in the preparation of a cosmetic or pharmaceutical composition for the treatment and /or skin and/or hair care that delays and/or prevents hair loss or induces hair growth. Examples of cosmetic or pharmaceutical compositions for treating and/or caring for the skin, mucous membranes and/or hair include creams, multiple emulsions such as, and without restriction to, oil and/or silicone in water, water-in-oil and water emulsions. /or silicone emulsions, water/oil/water or water/silicone/water type emulsions, and oil/water/oil or silicone/water/silicone type emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams , lotions, gels, gels 10 in cream, hydroalcoholic solutions, hydroglycolic solutions, hydrogels, lininients, serums, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, ointments, powders, bars, pencils and sprays or aerosols ( sprays), including "rinse off" 15 and "rinse off" formulations, bandages, gauzes, t-shirts, socks, pantyhose, underwear, belts, gloves, diapers, sanitary napkins, clothing, quilts, tissues, adhesive tapes, non-adhesive, occlusive tape, space microelectric wipes or face masks, makeup products such as makeup foundations, fluid foundations and compact foundations, makeup removal lotions, makeup removal milks, under-eye concealers, shadows, lipsticks, lip balms, shine lips and powders among others.
25 Compositions containing the peptides thereof. invention may be applied to the skin or may be administered orally or parenterally as needed to treat and/or care for a condition, disorder and/or disease.
The pharmaceutical or cosmetic compositions related to this invention can be applied to the skin by iontophoresis, sonophoresis, electroporation, microelectric plaster, mechanical pressure, pressure gradient
Osmotic, occlusive cure, microinjections or needleless pressure injections, such as pressure injections of the peptide of the invention. A further aspect of this invention relates to a
The 5 method of treatment and/or care of the skin, mucous membranes
W and/or hair which comprises administering the cosmetically or pharmaceutically effective amount of at least one peptide of general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic composition or pharmaceutical company that contains the same. A further aspect of this invention relates to a method for the treatment and/or care of such conditions, disorders and/or diseases of mammals, preferably hurnans, which are ameliorated or prevented by stimulation of synthesis and heat shock protein, preferably Hsp70; which comprises administering an effective amount of at least one peptide of general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical composition containing the same.
In a preferred embodiment, conditions, disorders, and/or pathologies that are ameliorated or prevented by heat shock protein synthesis and stimulation are » selected from a group consisting of epidermolysis bullosa and alopecia, which includes alopecia caused by chemotherapy treatment for cancer Another further aspect of this invention pertains to a method for treating and/or caring for skin, mucous membranes and/or hair that reduces, delays, and/or prevents radiation-induced cell damage. UV, heat stress, oxidative stress, osmotic shock, inflammation, hypoxia, exposure to pollutants, lack of nutrition and lack of hydration; which comprises administering an effective amount of at least one peptide of general formula (I), its stereoisomers, mixtures of the themselves and/or their salts cosmetically or pharmaceutically
5 acceptable, preferably in the form of a cosmetic or pharmaceutical composition containing the same.
According to a further aspect, this invention relates to treatment and/or care that reduces, delays and/or prevents signs of aging and/or photoaging,
10 which comprises administering an effective amount of at least one peptide of general formula (I), its stereoisomers,
mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical composition containing the same.
Another further aspect of this invention relates to a method for treating and/or caring for the skin and/or mucous membranes that stimulates healing and/or re-epithelialization of wounds, preferably wounds that are a
20 consequence of diabetes, and which comprises administering an effective amount of at least one peptide of general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic composition or pharmaceutical containing the same.
Another additional aspect of this invention relates to
" a method for treating and/or caring for skin and/or hair that delays and/or prevents hair loss or induces hair growth, which comprises administering an effective amount
30 of at least one peptide of general formula (I), its stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, preferably in the form of a cosmetic or pharmaceutical composition containing the same.
In a more particular aspect, the treatment and/or care of this invention is carried out by topical or transdermal application; preferably, topical or transdermal application is performed by means of iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive healing, microinjections, needleless injections by means of pressure, by means of microelectric patches or any combination. of the same.
10 In another particular aspect, the treatment and/or care is performed by oral administration.
In another particular aspect, the treatment and/or care is performed by parenteral application.
The frequency of application or administration can vary widely, depending on the needs of each subject and the severity of the condition, disorder or disease being treated or cared for, with a recommended range of application or administration from once a month to ten times. per day, preferably from once a week to four times a day, more preferably from three times a week to three times a day, even more preferably once or twice a day.
The following specific examples provided herein illustrate the nature of this invention. These 25 examples are included for illustrative purposes only and are not
B should be built with limitations on the invention claimed herein. EXAMPLES
GENERAL METHODOLOGY 30 All reagents and solvents are of synthesis quality and are used without further treatment.
ABBREVIATIONS The abbreviations used for amino acids follow the T
IUPAC-IUB Joint Commission on Biochemical Nomenclature rules outlined in Eur. jj Biochem. (1984) 138:9 to 37 and in lj.
Biol.
Chem. (1989) 264:633 to 673. Resin; Ac, acetyl; DNA, acid 6
5-deoxyribonucleic acid; Adpoc, 1-(1-adamantyl)-1-methylethoxy-
6 carbonyl; All, alila; Alloc, allyloxycarbonyl; A-M, 2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid; Arg, arginine; Asn, asparagine, Boc, tert-butyloxycarbonyl; 2-Brz, 2-bromobenzyloxycarbonyl; Bzl, benzyl; Cbz, 10 carboxybenzyl; CHx, cyclohexyl; C1Trt-®, 2-chlorotrityl resin; C1z, 2-chlorobenzyl; cps, centipoise; C-terminal, carboxy-terminal; DCM, dichloromethane; Dde, N-[1"(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl; 2,6-diClZ, 2,6-dichlorobenzyl; DIEA, N,1V-diisopropylethylamine; DIPCDI, 15N ,N-diisopropylcarbodiimide; Dmab, 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl; DMEM, Dulbecco's modified Eagle medium; DMF, N, N-dimethylformamide;
DMSO, dimethyl sulfoxide; Dnp, 2,4-dinitrophenol; DPPC, dipalmitoylphosphatidylcholine; EDTA, acid
20 ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; equiv, equivalent; ESI-MS, cornionization mass spectrometry; Fm, fluorenylmethyl; Fmoc, 9-fluorenylmethyloxycarbonyl; Gln, glutamine; grp, glucose-regulated proteins, His, histidine; HOAt, 1-hydroxy-7-
and 25 azabenzotriazole; HOBt, I-hydroxybenzotriazole; HPLC, high performance liquid chromatography; hsp, proteins from
" heat shock; INCI, International Nomenclature of Cosmetic Ingredients; 1vDde, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl; kDa, kiloDalton; Leu,
30 leucine; MBHA, p-methylbenzhydrylamine; MeCN, acetonitrile; MeOH, methanol; MLV, multilaminar vesicles; MPD, minimum pigmentation dose; Mtt, methoxytrityl or methyltrityl; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolin bromide;
N-terminal, amino-terminal; PAL, 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid; Palm, palmitoyl; PBS, phosphate buffer saline; pNZ, p-nitrobenzyloxycarbonyl; Pro, proline; rpm, revolutions per " 5 minute; qs, sufficient amount; q.s.p., amount
W enough for; tBu, tert-butyM; Teoc, 2-(trimethylsilyl)ethyloxycarbonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TIS, triisopropylsilane; Troc, 2,2,2-trichloroethyloxycarbonyl; 10 Trt, triphenylmethyl or trityl; Trt, trityl; Tyr, tyrosine; ULV, unilaminar vesicles; UV, ultraviolet; Z, benzyloxycarbonyl.
CHEMICAL SYNTHESIS All synthetic processes were performed in 15 polypropylene syringes fitted with polyethylene ® discs, porous or Pyrex reactors fitted with porous spikes. Solvents and soluble reagents were removed by suction. The Fmoc group was removed with piperidine-DMF (2:8, v/v) (1 x min, 1 x 5 min, 5 ml/g resin) [Lloyd-Williams P., 20 Albericio F. and Giralt E. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton, Ft, USA]. Washes between stages of deprotection, coupling, and, again, deprotection, were performed with DMF (3 x 1 min) each time using 10 ml solvent/g resin. Coupling reactions were performed with 3 ml solvent/g resin. Coupling control was performed by - performing the ninhydrin test [Kaiser E., Colescott RL, Bossinger CD and Cook PI (1970) "Color test for detection of free terminal amino groups in the solid-phase synthesis of 30 peptide" Anal . Biochem. 34:595-598] or chloranil test [Christensen T. (1979) "A qualitative test for monitoring coupling completeness in solid-phase peptide synthesis using chloranil" Acta Chem. Scan 33B:763 to 766]. All synthetic reactions and washes were performed at room temperature. HPLC chromatographic analysis was performed with Shirnadzu equipment (Kyoto, Japan) using a temperature-controlled reversed phase * 5 column at 30°C (250 x 4.0 mm, Kromasil Cb, 5 µm, Akzo Nobel, Sweden). Extraction was performed using a gradient of acetonitrile (+0.07% TFA) in water (+0.1% TFA) at a flow rate of 1 ml/min and detection was performed at 220 nm.
EXAMPLE 1 Obtain FmOC-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-O-2-ClTrt-®, where A-A, is -L-H1S-; AA2 is -L-H1s-, -L-Leu- or -L-Pro-; 1LA3 is -1>Leu-; AA, is -L-Arg- or -L-,i'lsn-; and n, m, p and q are 0.
The amount of 5.71 g of Fmoc-L-Arg(Pbf)-OH or 15 5.25 g of Fmoc-L-Asn(Trt)-OH (8.8 mmol; 1 equivalent) dissolved in 55 ml of DCM to which 1.3 ml of DIEA (7.6 mmol; 0.86 equivalent) was added to the dry 2-chlorotrityl resin (5.5 g; 8.8 mmol). They were stirred for 5 minutes, after which 2.5 ml of DIEA was added (14.6 20 mmol; 1.66 equivalent). The mixture was allowed to react for 40 minutes. Remaining chloride group were blocked by treatment with 4.4 ml of MeOH.
The N-terminal Fmoc group was deprotected as described in the general methods and 7.77 g of Fmoc-L-Leu-OH (22
W 25 mmol; 2.5 equivalent) were coupled to the peptidyl resin in the presence of DIPCDI (3.39 ml, 22 mmol, 2.5 equivalent) and "HOBt (3.37 g, 22 mmol, 2.5 equivalent) using DMF as a solvent for 1 hour. The resin was then washed as described in the general methods and the deprotection treatment of the Frnoc group 30 was repeated to couple the next amino acid. Following the described protocols, 13.63 g of Fmoc-L-H1s(Trt) -OH, 7.77 g of Fmoc-L-Leu-OH or 7.42 g of Fmoc-L-Pro-OH (22 mmol; 2.5 equivalent) were sequentially coupled; and subsequently 13.63 g of Fmoc- L-His(Trt)-OH (22 mmoles; 2.5 equivalent), each coupling being in the presence of 3.37 g of HOBt (22 mmoles; 2.5 equivalent) and 3.39 ml of DIPCDI (22 mmoles; 2 .5 equivalent) and 5 After synthesis, the peptidyl-resins were washed 0 with DCM (5 x 3 min) and dried by a stream of nitrogen.
EXAMPLE 2 Obtain moc-Wn-Xm-m1-m2-m3-•-4-Yp-zq-m-MBm-®, where AA, is -L-H1s-; AA2 is -L-H1S-, -L-ljeu- or -L-Pro-; AA3 is -10 L-Leu-; AA4 is -L-Arg- or -L-Asn-; en, m, p and q are 0. A 6.85g amount of the Fmoc-AM-MBHA resin with a functionalization of 0.73 mmol/g (5 mmol) was treated with piperidine-DMF according to the general protocol described for remover the Fmoc group. 16.22 g of Fmoc-L-Arg(Pbf)-OH or 14.92 g of Frnoc-L-Asn(Trt)-OH (25 mmol; 5 equivalent) were incorporated into the deprotected resin in the presence of DIPCDI (3, 85 ml; 25 mmol; 5 equivalent) and HOBt (3.85 g; 25 mmol; 5 equivalent) with q using DMF as a solvent for 1 hour.
The resin was then washed as described in the general methods and the Fmoc group deprotection treatment was repeated to couple the next amino acid. Following previously described protocols, 8.84 g of Fmoc-L-Leu-OH (25 mmol; 5 equivalent); 15.49 g of Fmoc-L-H1s(Trt)-OH, 8.84 g of Fmoc-L-Leu-OH or 8.44 g of Fmoc-L-pro-OH (25 mmol; ≥ 5 equivalents); and subsequently 15.49 g of Fmoc-L-" His(Trt)-OH (25 mmoles; 5 equivalents) were sequentially coupled to each coupling in the presence of 3.85 g of HOBt (25 mmoles; 5 equivalents) and 3.85 ml of DIPCDI (25 30 mmol; 5 equivalent) After synthesis, the peptidyl-resins were washed with DCM (5 x 3 min) and dried by a stream of nitrogen.
EXAMPLE 3
General process for removing the N-terminal protecting group from Fmoc.
The N-terminal Fmoc group of the peptidyl-resins obtained in Examples 1 and 2 was deprotected as described
W 5 in general methods (20% piperidine in DMF, 1 x 5 min + 1 x and 20 minutes). The peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (x 1 min) and dried under vacuum. EXAMPLE 410 Process for introducing the group R1 palmitoyl into the peptidyl resins obtained in Example 3. An amount of 2.56 g of palmitic acid (10 mmol; 10 equivalent) pre-dissolved in DMF (1 ml) was added to 1 mmol of the peptidyl-resins obtained in Example 33, in the presence of 1.53 g of HOBt (10 mmol; 10 equivalent) - 15 and 1.54 ml of DIPCDI {10 mmol; 10 equivalent). They were allowed to react for 15 hours, after which time the resins were washed with THF (5 x 1 min), DCM (5 x 1 min), DMF (5 x 1 min), MeOH (5 x 1 min). , DMF (5 x 1 min), THF (5 x 120 min), DMF (5 x 1 min), DCM (4 x 1 min), ether (3 x 1 min), and dried under vacuum.
EXAMPLE 5 Process for introducing the R1 acetyl group into the peptidyl-resins obtained in Example 3.
25 1 mmol of the peptidyl-resins obtained in Example 3 were treated with 25 equivalents of acetic anhydride in the
K presence of 25 equivalents of DIEA with the use of 5 ml of DMF as a solvent. They were allowed to react for 30 minutes, after which the peptidyl-resins were washed with 30 DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried under vacuum. - EXAMPLE 6 Process of cleaving the polymeric support of the peptidyl-resins obtained in Examples 3, 4 and 5. An amount of 200 mg of the dry peptidyl-resins obtained in Examples 3, 4 and 5 was treated with 5 ml of TFA:TIS: H2O (90:5:5) for 2 hours at room temperature under
U 5 stirring. The filtrates were collected in 50 ml of ether
The cold diethyl, filtered through polypropylene syringes fitted with porous polyethylene discs and washed 5 times with 50 ml of diethyl ether. The final precipitates were dried under vacuum.
10 HPLC analysis of the peptides obtained in gradients of MeCN (+0.07% TFA) in H,O (+0.1% TFA) showed a purity exceeding 80% in all cases. The identity of the peptides obtained was confirmed by ESI-MS.
EXAMPLE 715 The process of cleaving the polymeric support and functionalization with substituted R2 amine: Obtain AC-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-NH-(CH2)15-CH1 , where AA, , is -L-H1S-; AA2 is -L-H1s-, -L-Leu- or -L-Pro-; AA, is -L-Leu-; AA4 is -L-Arg- or -L-Asn-; and n, m, p and q are 0.
20 The peptides AC-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-OH with fully protected side chains were obtained by treating 150 mg of peptidyl-resins AC-Wn-Xm-AA,-AA2-AA3 -AA4-Yp-Zq-O-2-ClTrt-® from Example 5, previously dissected under vacuum in the presence of KOH, with 3 ml of a 3% solution
F 25 of TFA in DCM for 5 minutes. The filtrates were collected in 50 ml of cold diethyl ether and the treatment was repeated three times. The ether solutions were evaporated to dryness at reduced pressure and room temperature, the precipitates were redissolved in 50% MeCN in H2O and lyophilized. 10 mg of the crude peptides were weighed into a flask and 3 equivalents of hexadecylamine and 25 ml of anhydrous DMF were added, two equivalents of DIPCDI were added, and allowed to react under magnetic stirring in
47°C. The reactions were monitored by HPLC until the initial products disappeared, which were complete after 24 to 48 hours. Solvents were evaporated to dryness and co-evaporated twice with DCM. Residues 5 obtained [AC-Wn-Xm-AA1rAA2-AA3-AA4-Yp-Zq-NH-(CH2)15-CH3 with
The fully protected side chains] were redissolved in 25 ml of a mixture of TFA-DCM-anisole (49:49:2) and allowed to react for 30 minutes at room temperature.
250 ml of cold diethyl ether were additional, the solvents 10 were evaporated under reduced pressure and two additional coevaporations with ether were carried out. Residues were dissolved in a mixture of 50% MecN in H2O and lyophilized.
The HPLC analysis of the peptides obtained in "15 gradients of MeCN (+0.07% TFA) in H,O (+0.1% TFA) showed a purity exceeding 65% in all cases. The identity of the peptides obtained was confirmed by ESI-MS.
EXAMPLE 8 Hsp70 Synthesis Stimulation Assay.
20 The stimulation of Hsp70 synthesis was evaluated in a human keratinocyte cell line in the presence of the peptides of the invention. Cells were inoculated (10 6 cells/plate in 6 wells) and incubated for 24 hours in DMEM, after which peptides were added at 200µM in 25 h culture medium and incubated for another 16 to 24 hours. The proteasome inhibitor MG-132 in 10µM was used as a positive control and vehicle (culture medium) as a negative control. After the incubation period, the cells were washed with PBS, lysed and centrifuged at 12,000 rpm at 30 4°C for 10 minutes. Supernatants were collected, and Hsp70 levels were determined by performing a competitive ELISA assay following commercial kit protocols (Human/Mouse DuoSet Total HSP70 IC Elisa Kit, R&D
Systems Inc.) Table 2 provides details of peptides which show Hsp70 stimulation level values greater than 15%. Hsp70 levels were normalized to those
G 5 mean baseline values.
. Table 2. Increase in Hsp70 levels Treatment Increase in Hsp70 vehicle 0°: MG-132 294°: pa1m-L-His-L-Pro-L-Leu-L-Asn-NH2 15% Ac-L-H1s-L -His-L-Leu-L-Asn-NH-(CH2 ),-CH, 17% Ac-L-His-L-Leu-L-Leu-L-Arg-OH 28% Ac-L-His -L-Pro-L-Leu-L-Arg-OH 42% Ac-L-His-L-Leu-L-Leu-L-Arg-NH, 21% EXAMPLE 9 Ac-L-His Photoprotective Efficacy Assay -L-Pro-L-Leu-L-Arg-OH and Ac-L-His-L-Leu-L-Leu-L-Arg-OH in human keratinocyte cultures.
10 Keratinocytes were cultured for 24 hours in 96-well plates for single layer formation and cells were pre-incubated in darkness 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 vehicle (culture medium) for 2 hours at 37°C. Subsequently the cells were irradiated with UVB at an energy of 800 j/m2. A vehicle control plate was kept in the dark without radiation for the same time at room temperature. After c) period of . irradiation, the cell medium was replaced with fresh medium and the cells were incubated for an additional 24 hours. THE
Cell viability was determined by the MTT method, in which 5 mg/ml of the MTT solution was added to each well and the plate was incubated for 4 hours at 37 °C, after which time the medium was removed, 100 µL of DMSO was additional and the plate was shaken at room temperature for 15 minutes. The optical density of each well was measured at 570 nm in a spectrophotometer.
The photoprotective efficacy 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
V 5 in relation to the response of irradiated control cells and
P not irradiated.
Table 3. Photoprotective efficacy of the peptides of the invention Treatment Viability of Efficacy Photoprotective cell Non-irradiated vehicle 100.0% Irradiated vehicle 73.9% Ac-L-His-L-Pro-L- 97.2% 32% Leu-L- Arg-OH Ac-L-His-L-Leu-L- 87.7% 19% Leu-L-Arg-OH EXAMPLE 10 m Preparation of a cosmetic composition containing Palm-L-His-L-Pro-L -Leu-L-Asn-NH2.
INGREDIENT (INCI nomenclature) % BY WEIGHT WATER (AQUA) q.s.p. 100 CONSERVATIVES 0.45 IMIDAZOLIDINYL UREA 0.095 EDTA DISODIUM 0.14 GLYCERIN 4.75 PROPYLENE GLYCOL 2.85 B WATER (AQUA), POLYACRYLAMIDE, C13-14 ISOPRAFINE, LAURET-7 2.85 ETHYLHEXYL COCOATE 4.75 TRIGLYCERIDE/CAPRYLIC 4.75 C DIMETHICONE 1.9 D TRIETHANOLAMINE qs E FRAGRANCE (PERFUME) 0.19 F Palm-L-His-L-Pro-L-Leu-L-Asn-NH2 0.01%, 5 P BUTYLENGLYCOL,
ALCOHOL DESNAT 10 "A""phase a was dissolved in an appropriate reactor. In another reactor, phase B was mixed, formed by Sepigel" 305 [INCI: Aqua (Water), Polyacrylamide, C13-Cl4 isoparaffin, Lauret-7] , Myritol" 308 [INCI: Caprylic/Capric Triglyceride] and ethylhexyl cocoate and once homogenized it was added to phase A under stirring. Then phase C was added under stirring, and subsequently phase f was added at 35°C. was adjusted to 5.5 to 7.0 with D phase and E phase was added.
EXAMPLE 11 Preparation of Liposoins Containing Ac-L-His-L-Leu-, L-Leu-L-Arg-OH.
INGREDIENT (INCI Nomenclature) % BY WEIGHT PHOSPHATIDYLCHOLINE 4.0 Ac-L-His-L-Leu-L-Leu-L-Arg-OH 0.2 CONDOM 0.50 AQUA (WATER) q.s.p. 100 Dipalmitoylphosphatidylcholine (DPPC) was weighed and dissolved in chloroform. The solvent was evaporated under vacuum until obtaining a thin phospholipid layer, and this layer was hydrated under treatment at 55°C with an aqueous solution of the peptide at the desired concentration (which contains Phenonip"), and MLV liposomes were obtained. ULV liposomes were obtained by submerging the liposomes in an ultrasound bath at 55°C for 8 cycles of 2 minutes at 5 minute intervals.The size of the ULV liposomes was reduced by passing a high pressure extrusion system through them.
EXAMPLE 12 Preparation of a composition in the form of a liposome gel containing Ac-L-His-L-Leu-L-Leu-L-Arg-OH. The liposomes from Example 11 were dispersed in water with preservatives (EDTA, imidazolidinyl urea and Phenonip) under gentle agitation. Hispagel" 200 was added [INCI: Aqua (Water), glycerin, glyceryl polyacrylate] and gently stirred until a homogeneous mixture was obtained.
INGREDIENT (INCI Nomenclature) % BY WEIGHT LIPOSOMES CONTAINING Ac-L-His-L-Leu-L-Leu-L- 10.00 Arg-OH (1%) DISODIUM EDTA 0.15 IMIDAZOLIDINYL UREA 0.10 PRESERVATIVE 0.50
AQUA (WATER) 29.25 AQUA (WATER), GLYCERIN, POLYACRYLATE OF 60.00
GLTCERIL EXAMPLE 13 Composition of a face cream containing AC-L-H1S-. L-Pro-L-Leu-L-Arg-OH.
. INGREDIENT (INCI Nomenclature) % BY WEIGHT A BUTYROSPERMUM PARKII 3.5 to 4.5 CETEARYL ETHYLHEXANOATE 3 to 5 GLYCERYL STEARATE SE 1.5 to 2.5 SQUALAN 0.5 to 1 PEG-1OO STEARATE 1 POLYSORBATE 60 0 .30 CETYL PALMITATE 1.5 to 2.5 DIMETHICONE 2.5 to 3.5 CETERYL ALCOHOL 1.5 to 2.5 PALMITE ACID 0.5 B AQUA (WATER) 2 GLYCERIN 1.5 to 2.5 BUTYLENE GT , ICOLS 1 to 3 MANNITOL 0.5 to 1.5 HYDROGENATED LECITINE 0.5 to 1.5 PROPYLENE GLYCOL 0.5 to 1.5 C CARBOMER 0.4 ETHYLHEXYL PALMITATE 1.5 to 2.5 D TROMETAMINE 0, 4 AQUA (WATER) 1 AND CONDOMS qs F Ac-L-His-L-Pro-L-Leu-L-Arg-OH 0.001 AQUA (WATER) qsplOO Preparation 5 - Mix Phase A components and heat to 70°C. - Mix Phase B components and heat to 70 °C.
W - Add Phase C to agitate Phase B with the homogenizer (Silverson) for 5 minutes. - Add Phase A little by little to the mixture of phases B and C with a homogenizer and keep homogenizing for 15 minutes.
- Start cooling to 30 to 35°C under gentle agitation. At 50°C add Phase D. Keep stirring. At 35 to 38°C add Phases e and F which were previously solubilized. EXAMPLE 14b 5 Preparation of a mixed micelle composition. which contains Ac-L-His-L-Leu-L-Leu-L-Arg-OH. The phase A ingredients were weighed into a container suitable for the entire sample and briefly heated to about 30°C to help dissolve some of the preservatives. Next, the components of phase B were added and homogenized under moderate agitation.
Phase C was then added under continuous stirring, after which Phase D (Oramix® CG 110 [INCI: Aqua (Water), Capryl/Capryl Glucoside]) was added with slow stirring to avoid foaming. The pH was adjusted to 5.5 to 6.5.
_fN,G,R,E,D,I,E,N,T,E _ (.N,o,m,e,n,clat,u,ra _ d,e _ I,N,C,I. - His-L-Leu-L-Leu-L-Arg-OH 0.025 LECITIN 4.0 C XANTHAN GUM 0.4 D AQUA (WATER), 30 CAPRYLYL/CAPRIL GLUCOSIDE EXAMPLE 150 microemulsion composition containing palm-L -His-L-Pro-L-Leu-L-Asn-NH2 .
H 20 Phase B ingredients were weighed into a suitable container for complete sampling. Next, phase D was added to phase B and homogenized under continuous stirring. Phase A was then added to the mixture. Finally, phase C was added.
INGREDIENT (Nomenclatu,r,a_d,e_I,N,C,I.) _ %_E,M_P,E,S,O _
A DIETHYLHEXYL SODIUM SULFOSUCYANATE 1.35 ISOSTEARIC ACID 7.65 B AQUA (WATER) 0.2 ALCOHOL DESNAT 0.8 C ETHYLHEXYL COCOATE q.s.p. 100 D palln-L-His-L-Pro-L-Leu-L-Asn-NH2 0.005 EXAMPLE 16 Composition of a hair lotion containing AC-L-His-L-Leu-L-Leu-L-Arg-OH . Mix Phase A components slowly under agitation. Slowly add Phase B to Phase A under stirring until homogenization is complete.
INGREDIENT (INCI nomenclature) % BY WEIGHT ALCOHOL DESNAT. 50 to 60 PANTHENOL 0.05 to 0.15 ZINC RICTHNOLEATE 0.05 to 0.10 FRAGRANCE 0.02 Ac-L-His-L-Leu-L-Leu-L-Arg-OH 0.01 B AQUA ( WATER) qsplOO
R u

权利要求:
Claims (15)
[1]
1. GENERAL FORMULA PEPTIDE (I) R1 - Wn - Xm - AA1 - AA2 - AA3 - AA4 - Yp - Zq -R2 (I) its stereoisomers, mixtures thereof and/or their pharmaceutically or cosmetically acceptable salts, characterized by: AA1 is - His -; AA2 is selected from the group consisting of – His -, - Leu - and –Pro - AA3 is –Leu -; AA4 is selected from the group consisting of –Arg - and –Asn -; W, X, Y and Z are independently selected therefrom from the group consisting of coded amino acids and non-coded amino acids; n, m, p and q are independently selected therefrom and have a value between 0 and 1; n+m+p+q is less than or equal to 2; R1 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-CO- wherein R5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted allicyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl substituted and substituted or unsubstituted heteroarylalkyl; R2 is selected from the group consisting of
-NR3R4, -OR3 and -SR3, wherein R3 and R4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted allicyl, substituted or unsubstituted heterocyclyl, substituted heteroarylalkyl or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl; with the proviso that when AA2 is -Leu-, AA4 is -Asn- and Y is -Gln-, then Z is not -Leu-; and with the proviso that when AA2 is -His-, AA4 is -Arg- and Y or Z is -Tyr-, then p+q is not 1.
[2]
A PEPTIDE according to claim 1, characterized in that R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl and palmitoyl, AA2 is -L -Leu-, AA4 is -L -Arg -, and R2 is -NR3R4 or -OR3 wherein R3 and R4 are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl.
[3]
A PEPTIDE according to claim 1, characterized in that R1 is selected from the group consisting of H, acetyl, lauroyl, myristoyl and palmitoyl, AA2 is -L -Pro -, AA4 is -L -Arg -, and R2 is -NR3R4 or -OR3 wherein R3 and R4 are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl.
[4]
4. PEPTIDE according to any one of claims 1 to 3, characterized by the treatment and/or care for the skin, mucous membranes and/or hair.
[5]
5. PEPTIDE according to claim 4, characterized by the treatment and/or care for those conditions, disorders and/or diseases of the skin, mucous membranes and/or hair that are ameliorated or prevented by stimulating the synthesis of at least one protein of thermal shock.
[6]
A PEPTIDE according to claim 5, characterized in that said heat shock protein has a molecular weight between 20kDa and 110kDa.
[7]
A PEPTIDE according to any one of claims 4 to 6, characterized in that said treatment and/or care reduces, delays and/or prevents cell damage due to UV radiation, heat stress, oxidation stress, osmotic shock, inflammation, hypoxia, exposure to pollutants, lack of nutrition and lack of hydration and/or signs of aging and/or photoaging.
[8]
A PEPTIDE according to any one of claims 4 to 7, characterized in that said treatment and/or care delays and/or prevents hair loss or induces hair growth.
[9]
A PEPTIDE according to any one of claims 4 to 7, characterized in that said treatment and/or care stimulates healing and/or re-epithelization of wounds.
[10]
10. PHARMACEUTICAL OR COSMETIC COMPOSITION, characterized in that it comprises a cosmetically or pharmaceutically effective amount of at least one peptide of the general formula (I), its stereoisomers, mixtures thereof and/or their pharmaceutically and cosmetically acceptable salts as defined in any of the claims 1 to 3, and at least one cosmetically or pharmaceutically acceptable excipient or adjuvant.
[11]
11. COMPOSITION, according to claim 10, characterized by the peptide of the general formula (I), its stereoisomers, mixtures thereof and/or their pharmaceutically and cosmetically acceptable salts, is incorporated into a pharmaceutical or cosmetic delivery system or delivery system. sustained release selected from the group consisting of liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, millycapsules, microcapsules, nanocapsules, sponges, cyclodextrins, vesicles, micelles, mixed surfactant micelles, mixed surfactant phospholipid micelles, millispheres, microspheres, nanospheres , lipospheres, microemulsions, nanoemulsions, miniparticles, milliparticles, microparticles, nanoparticles, 5 solid lipid nanoparticles and nanostructured lipid carriers or is found adsorbed on a soluble organic polymer or solid mineral support selected from the group consisting of talc, bentonite, silica, starch and maltodextrin.
[12]
12. COMPOSITION according to any one of claims 10 to 11, characterized in that said composition is presented in a formulation selected from the group consisting of creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions , gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions, hydrogels, ointments, serums, soaps, shampoos, conditioners, serums, ointments, mousses, skin creams, powders, bars, pencils, sprays, aerosols, capsules, gelatine capsules , soft capsules, hard capsules, tablets, sugar-coated tablets, granules, chewing gum, solutions, suspensions, emulsions, syrups, polysaccharide films, jellies and gelatins.
[13]
13. COMPOSITION, according to any one of claims 10 to 12, characterized in that said composition is found incorporated in a product selected from the group consisting of concealers for the region below the eye, make-up base, make-up removal lotions, milk of removing makeup, eye shadows, lipsticks, lip gloss, lip balms and powders.
[14]
14. COMPOSITION according to any one of claims 10 to 12, characterized by the peptide of the general formula (I), its stereoisomers, mixtures thereof and/or their pharmaceutically and cosmetically acceptable salts, is incorporated into a tissue, non-tissue tissue or a medical device.
[15]
A COMPOSITION according to any one of claims 10 to 14, wherein said composition further comprises a cosmetically or pharmaceutically effective amount of at least one adjuvant selected from the group comprised of heat shock proteins, other shock protein stimulating agents heat, acetylcholine receptor aggregation inhibitors, muscle contraction inhibiting agents, anticholinergic agents, elastase inhibiting agents, matrix metalloproteinase inhibiting agents, melanin synthesis inhibiting or stimulating agents, depigmentation or bleaching agents, pro-pigmentation agents, self-tanning agents, anti-aging agents, NO synthesis inhibiting agents, 5α-reductase inhibiting agents, lysyl and/or prolyl hydroxylase inhibiting agents, antioxidants, free radical scavengers and/or anti-aging agents. air pollution, reactive carbonyl species scavengers, antiglycation agents, antihistamine agents, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners, humectants, moisture retaining substances, alpha-hydroxy acids, beta-hydroxy acids, moisturizers, epidermal hydrolytic enzymes, vitamins , amino acids, proteins, pigments or coloring agents, dyes, gelling polymers, thickeners, surfactants, softening agents, anti-wrinkle agents, agents capable of reducing or treating dark circles, exfoliating agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents , bacteriostatic agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and/or capable of inhibiting or preventing their degradation, collagen synthesis stimulating agents, elastin synthesis stimulating agents, decorin synthesis stimulating agents, synthesis stimulating agents of laminin, 5 stimulating agents defensin synthesis stimulating agents, aquaporin synthesis stimulating agents, hyaluronic acid synthesis stimulating agents, fibronectin synthesis stimulating agents, sirtuin synthesis stimulating agents, agents that stimulate the synthesis of lipids and stratum corneum components, ceramides, fatty acids, agents that inhibit collagen degradation, agents that inhibit elastin degradation, agents that inhibit serine proteases such as cathepsin G, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate adipocyte proliferation, agents that stimulate melanocyte proliferation, agents that stimulate keratinocyte differentiation, agents that stimulate adipocyte differentiation, agents that inhibit acetylcholinesterase, skin relaxant agents, glycosaminoglycan synthesis stimulating agents, antihyperkeratosis agents, comedolytic agents, antipsoriasis agents , repair agents DNA, DNA protecting agents, stabilizers, anti-itching agents, agents for the treatment and/or care of sensitive skin, solidifying agents, anti-stretch branding agents, binding agents, agents that regulate sebum production, lipolytic agents or agents that stimulate lipolysis, anti-cellulite agents, antiperspirant agents, healing-stimulating agents, adjunctive healing agents, re-epithelization-stimulating agents, adjunctive re-epithelization agents, cytokine growth factors, soothing agents, anti-inflammatory and/or analgesics, anesthetic agents, agents that act on the circulation and/or capillary microcirculation, agents that stimulate angiogenesis, agents that inhibit capillary permeability, venotonic agents, agents that act on cellular metabolism, agents to improve epidermal junction 5, agents that induce hair growth , hair growth delaying or inhibiting agents, hair loss delaying agents, co preservatives, perfumes, chelating agents, plant extracts, essential oils, marine extracts, agents obtained from a biofermentation process, mineral salts, cell extracts and sunscreens, mineral or organic photoprotective agents active against ultraviolet A and/or B rays or mixtures of the same.

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法律状态:
2021-09-21| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2021-09-28| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE AS 9A, 10A E 11A ANUIDADES. |

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2022-01-18| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2647 DE 28-09-2021 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

优先权:

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申请号 | 申请日 | 专利标题

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US25434009P| true| 2009-10-23|2009-10-23|

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ES200930896A|ES2358829B1|2009-10-23|2009-10-23|USEFUL PEPTIDES IN THE TREATMENT AND / OR CARE OF SKIN, MUCOSES AND / OR HAIR AND ITS USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS.|

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US61/254,340|2009-10-23|

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ES200930896|2009-10-23|

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PCT/EP2010/006454|WO2011047868A2|2009-10-23|2010-10-22|Peptides used in the treatment and/or care of the skin, mucous membranes and/or hair and its use in cosmetic or pharmaceutical compositions|

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