Novel compounds

Abstract

The present invention relates to new oligopeptides and derivatives of oligopeptides as well as to their use for the prevention and / or treatment of skin ageing.

Description

[0001] NOVEL COMPOUNDS

[0002] Field of the invention

[0003]

[0001] The present invention relates to new oligopeptides and derivatives of oligopeptides as well as to their use for the prevention and / or treatment of skin ageing.

[0004] Background of the invention

[0005]

[0002] The development of facial expression wrinkles is part of a natural aging process and inter alia caused by repetitive facial muscle contraction.

[0006]

[0003] Today such mimic and age-related wrinkles are often treated with Botox (Botulinum toxin A). Botox is injected in the muscles which are thereby paralyzed. The muscles at the eyes or at the forehead don't operate any more, making the apparition of a forehead wrinkle impossible. However, due to the fact that the treatment with subcutaneously injected Botox has to be conducted by a doctor, this treatment is rather costly. In addition, Botox exerts a high toxicity which is another drawback of this treatment as it can cause severe side effects. In addition, as its effectiveness only lasts for a limited period of time, the treatment has to be repeated regularly.

[0007]

[0004] Thus, consumers are seeking for topical alternatives for the prevention and / or treatment of expression lines and wrinkles in particular of the face caused by muscle contraction.

[0008]

[0005] Sikorski et al, in their article titled "Selective peptidic and peptidomimetic inhibitors of Candida albicans myristoylCoA: Protein N-myristoyltransferase: A new approach to antifungal therapy”, published in Biopolymers, vol. 43(1), 1998, pages 43-71, explore alkylated peptides as potential inhibitors in antifungal therapy against Candida albicans, a technical area very different from the above mentioned treatment of age-related wrinkles. A wide variety of more than 60 peptides is described, most of which comprising at least a Lysine (Lys, K) amino acid or at least a Serine (SER, S) amino acid. Amongst the many peptides are described, in passing, a dipeptide 11-amino-undecanoyl-Ser-Lys-NH2 (32c) and a Lys-containing homoserine (39a), tyrosine (39b), fluoro-methyl-containing analogue (39c) and cis-4- hydroxyproline (40) variant thereof as well as Ser-containing variants thereof wherein the Lys group was varied (41a-g).

[0009]

[0006] Abbott et al, in their article titled "Synthesis and activity of dipeptides, linked to targeting ligands, as specific NK cell enhancers", published in the Journal of Medicinal Chemistry, vol. 41(11), 1998, pages 1909-1926, explores the immunological activity of synthetic dipeptide compounds which selectively activate natural killer (NK) cells. Also this is a technical area very different from the above mentioned treatment of age-related wrinkles. The article mentions a wide variety of analogues of the immunostimulant octadecyl D-alanyl- L-glutamine. One of the variants mentioned in passing is a dipeptide H-D-Ala-L-GIn-linker-R, wherein the linker is NH(CH2)6 and R is NH2 (entry 8 in table 1 ).

[0010]

[0007] WO 2022 / 261220 relates to Proteolysis-targeting chimeras (PROTACs) and methods of using the same for treating conditions characterized by the overexpression or unregulated activity ofthe protein Myeloid Cell Leukemia-1 (Mcl-1). Again a technical area very different from the above mentioned treatment of age-related wrinkles. WO 2022 / 261220 describes compounds of a formula (I), or comprising a substructure of a formula (I), wherein such formula comprises a part A, a linker L and a part B, wherein A comprises an Mcl-1 protein indirect inhibitor moiety; L is a linking group; and B comprises an E3 ubiquitin ligase ligand moiety, wherein the Mcl-1 protein inhibitor moiety thereof, and the E3 ubiquitin ligase ligand moiety thereof are each connected to L. A wide range of more than 400 variations according to formula (I) is provided in the compounds of formulae 1001 to 1460. Such compounds comprise a complex aromatic and halogenated structure as part A, a linker and a variety of structures as part B. Compounds 1085 to 1087 represent a comprehensive molecule comprising a complex aromatic and halogenated structure as part A connected to a complex aromatic and halogenated structure as part B via a peptide linker structure comprising a glycine (Gly) amino acid.

[0011]

[0008] The aim of the present invention was to identify novel muscle-relaxing compounds which can be applied as topical actives for the prevention and / or treatment of mimic and age- related wrinkles and which don't present the disadvantages of Botox. Said compounds should be highly active to minimize cost in use in the final products.

[0012] Summary of the invention

[0013]

[0009] Surprisingly, it has now been found, that certain oligopeptides and derivative thereof are highly active inhibitors ofthe nicotinic acetyl-choline receptor and are thus suitable to treat signs of skin ageing such as in particular mimic and / or age-related wrinkles.

[0014]

[0010] Therefore, the present invention relates to compounds of the general formula (I) R1-AAi-AA2-(AA3)n-(AA4)m-(AA5)i-R2 (I), wherein

[0015] R1 is -H, -CO(CH2)rNH2, -CO(CH2)oCH3, -COphenyl (benzoyl), or -COCH2phenyl, wherein o is 0, 1 , 2 or 3, and r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , most preferably r is 11 ; and

[0016] R2is -NH2, -OH, -OCH3, -OCH2CH3, -NH-(CH2)SNH2, -NH-(CH2)12NHCOCH3, -NH-(CH2)HCONH2, or wherein s is an integer from 6 to 12; and

[0017] AAi, AA2, AA3, AA4 and AA5 are independently from each other an amino acid (AA), and wherein n, m and I are independently of each other either 0 or 1 , as racemates or pure enantiomers, as well as the salts thereof.

[0018] The above claimed compounds are herein sometimes also referred to as oligopeptides and / or derivatives thereof.

[0019]

[0011] The present invention further relates to the use of the previously defined compounds and salts as topically applicable actives or for the preparation of topically applicable products, respectively, as well as topically applicable preparations containing at least one of the previously defined compounds or a salt thereof.

[0020]

[0012] In a preferred embodiment the invention also provides compounds of formula (I) which compounds are selected from the group consisting of compounds of the formulae

[0021] R1-AA1-AA2-R2 (la) or

[0022] R1-AA1-AA2-AA3-R2 (lb),

[0023] - wherein R1 is “NH2- (CH2)r- CO- “, wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and

[0024] - wherein preferably R2 is “-NH2”; and

[0025] - wherein AA1, AA2 and AA3 are independently from each other an amino acid (AA), more preferably wherein at least one of the amino acids AA1, AA2 and AA3 is a phenylalanine, most preferably wherein two adjacent amino acids selected from the amino acids AA1, AA2 and AA3 are phenylalanine. The invention also provides the respective salts of such compounds.

[0026]

[0013] The present invention further provides a method for the production of some of the above peptides that can advantageously be carried out in the liquid phase. Accordingly, the invention further provides a method for the production of a compound of formula (I)

[0027] -wherein R1 is “NH2- (CH2)r- CO- “, wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and

[0028] - wherein preferably R2 is “-NH2”, wherein the production is at least partly carried out in a liquid phase and / or wherein the method comprises a precipitation of such compound from a liquid phase.

[0029]

[0014] As illustrated in the examples, the compounds according to the invention advantageously provide a good nicotinic acetyl-choline receptor inhibition and a good skin permeability and are therefore good topical actives for the prevention and / or treatment of mimic and age-related wrinkles.

[0030] Detailed description of the invention

[0031] Definitions

[0032]

[0015] Unless defined otherwise or clearly indicated by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0033]

[0016] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. to one or at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element. When referring to a noun (e.g. a compound, an additive, etc.) in the singular, the plural is meant to be included. Thus, when referring to a specific moiety, e.g. a ''compound", this means "at least one" of that compound, e.g. "at least one compound", unless specified otherwise.

[0034]

[0017] Throughout the present specification and the accompanying claims, all transitional phrases such as ‘comprising,’ ‘including,’ ‘carrying,’ ‘having,’ ‘containing,’ ‘involving,’ ‘holding,’ ‘composed of’, and variations such as "comprises", "comprise", "includes" and "include" are to be interpreted inclusively and to be understood to be open-ended, i.e., to mean including but not limited to. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. Only the transitional phrases ‘consisting of’ and ‘consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively.

[0035]

[0018] The term 'consisting essentially of as used herein means that the total amount of the listed ingredients ideally sums up to 100 wt. % (weight percent). It is however not excluded that small amount of impurities derived from the ingredients and / or the production process may be present.

[0036]

[0019] Unless explicitly indicated otherwise, the various embodiments of the invention described herein can be cross-combined.

[0037]

[0020] The term "cosmetic composition " or “cosmetic preparation” refers in the present document to a composition suitable for cosmetic purposes. Suitably a cosmetic composition is herein understood to be a composition for cosmetic, that is, non-therapeutic use.

[0021] By an oligopeptide is herein preferably understood a peptide comprising from 2 to 20 amino acids, more preferably a peptide comprising from 2 to 5 amino acids.

[0038]

[0022] Further below the following conventional abbreviations have been used for the amino acid groups:

[0039] “Ala” is Alanine / yl;

[0040] “Bai” or “P-Ala" or “b-Ala” is beta-Alanine / yl, also spelled as p-Alanine / yl,

[0041] “Asp” is Aspartic acid / yl;

[0042] “Asn” is Asparagine / yl;

[0043] “Dab” is 1 ,4-Diaminobutyric acid / yl;

[0044] “Arg” is Arginine / yl;

[0045] “Glu” is Glutamic acid / yl;

[0046] “Gin” is Glutamine / yl;

[0047] “Gly” is Glycine / yl;

[0048] “His” is Histidine / yl;

[0049] “ILe” is Leucine / yl ;

[0050] “Leu” is Isoleucine / yl ;

[0051] “Lys” is Lysine / yl;

[0052] “Met” is Methinoine / yl;

[0053] “Orn” is Ornithine / yl;

[0054] “Phe” is Phenylalanine / yl;

[0055] “Pro” is Proline / yl;

[0056] “Ser” is Serine / yl;

[0057] “Thr” is Threonine / yl;

[0058] “Trp” is Tryptophane / yl;

[0059] “Tyr” is Tyrosine / yl; and

[0060] “Vai” is Valine / yl.

[0061] Compounds of formula (I)

[0062]

[0023] Preferably, in all embodiments of the present invention the residue

[0024] The compounds of formula (I) may form mono- or polyvalent, homogeneous or mixed salts with acids, e.g. with mineral acids such as hydrogen chloride, hydrogen bromide, sulphuric acid or phosphoric acid; or with appropriate carboxylic acids, e.g. .g. aliphatic mono- or dicarboxylic acids, such as formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, glycolic acid, succinic acid, fumaric acid, malonic acid, maleic acid, oxalic acid, phthalic acid, citric acid, lactic acid or tartaric acid; or with aromatic carboxylic acids such as benzoic acid or salicylic acid; or with aromatic-aliphatic carboxylic acids such as mandelic acid or cinnamic acid; or with heteroaromatic carboxylic acids such as nicotinic acid; or with aliphatic or aromatic sulfonic acids such as methanesulfonic acid or toluenesulfonic acid. Dermatologically compatible salts are preferred (also referred to cosmetically acceptable salts). Salts with acetic acid, hydrochloric acid and / or trifluoroacetic acid are particularly preferred. Such salts are easily prepared by a person skilled in the art. Hence, in a preferred embodiment the invention provides a mandelic acid addition salt; a methane sulfonic acid addition salt (also referred to as “MSA” salt); an acetic acid addition salt; a hydrochloric acid addition salt (also referred to as “HQ” salt); or a trifluoroacetic acid addition salt (also referred to as “TFA” salt), of a compound of formula (I). Further preferences for such compounds of formula (I) are described herein above and herein below.

[0063]

[0025] The compounds of general formula (I) as well as the respective salts thereof may be present as optically pure isomers or as mixtures of different isomers, e.g. as racemates, and / or as mixtures of rotamers.

[0064]

[0026] In all embodiments of the present invention, preferably, AAi, AA2, AA3, AA4 and AA5 are independently from each other chosen from the group consisting of Ala, p-Ala, Asp, Asn, Arg, Gin, Glu, Gly, His, Leu, lie, Lys, Dab, Orn, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and VaL

[0027] In all embodiments of the present invention preferably the amino acids are selected from the group of L-Ala, p-Ala, L-Asp, L-Asn, L-Arg, L-GIn, L-Glu, L-Gly, L-His, L-Leu, L-lle, L- Lys, L-Dab, L-Orn, L-Met, D-or L-Phe, L-Pro, L-Ser, L-Thr, L-Trp, L-Tyr, and L-Val, more preferably from the group of L-Ala, p-Ala, L-Asp, L-Asn, L-GIn, L-Glu, L-Gly, L-His, L-Leu, L- lle, L-Lys, D-or L-Phe, L-Ser, L-Thr, L-Trp, L-Tyr, and L-Val.

[0065]

[0028] In all embodiments of the present invention preferably at least one of the amino acids in compound (I) is phenylalanine (Phe). More preferably, at least one of AA1, AA2, AA3, AA4, and AA5 is Phe, and still more preferably at least two of AA1, AA2, AA3, AA4, and AAsare Phe. Most preferably the compound of formula (I) is a compound comprising two adjacent amino acids that are both phenylalanine (Phe). That is, most preferably the compound of formula (I) comprises a -Phe-Phe- construct. The Phe can be L-Phe or D-Phe. Preferably the Phe is L- Phe.

[0029] According to the present invention, the compounds of general formula I and the respective salts thereof can be manufactured according to methods known per se in peptide chemistry by completely synthesizing the compound of formula (I), possibly cleaving the remaining protective group(s), possibly alkylating a free amino group or converting it into a guanidino function and / or esterifying or amidating a free carboxyl group and / or converting an obtained basic compound into an acid addition salt and / or an obtained acid addition salt into the corresponding conjugate base or into another salt, as also outlined in the examples.

[0066]

[0030] More preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (la), (lb), (Ic) and (Id)

[0067] R1-AA1-AA2-R2 (la), and

[0068] R1-AA1-AA2-AA3-R2 (lb), and R1-AA1-AA2-AA3-AA4-R2 (Ic), and R1-AA1-AA2-AA3-AA4-AA5-R2 (id). wherein all substituents have the same meanings as defined in formula (I).

[0069]

[0031] Preferred compounds of formula (I), more preferably compounds of formula (la), (lb), (Ic) or (Id), in all embodiments of the present invention, are compounds wherein R1 is not H” and / or R2 is not “-NH2”. More preferably either R1 is not “-H” or R2 is not “-NH2”.

[0070]

[0032] Preferred compounds of formula (I), more preferably compounds of formula (la), (lb), (Ic) or (Id), are compounds wherein R1 is not “-H”.

[0071]

[0033] Preferred compounds of formula (I), more preferably compounds of formula (la), (lb), (Ic) or (Id), are compounds wherein

[0072] - R1 is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 ; and / or

[0073] - R2is -NH-(CH2)SNH2, -NH-(CH2)12NHCOCH3, -NH-(CH2)HCONH2, or wherein s is an integer from 6 to 12.

[0074]

[0034] More preferred compounds of formula (I), more preferably compounds of formula (la),

[0075] (lb), (Ic) or (Id), are compounds wherein - Ri is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or

[0076] 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 ; and / or

[0077] - R2is -NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH-(CH2)HCONH2, wherein s is an integer from 6 to 12.

[0078]

[0035] Especially preferred compounds of formula (I), more preferably compounds of formula (la), (lb), (Ic) or (Id), are compounds wherein

[0079] - Ri is -CO(CH2)nNH2,; and / or

[0080] - R2is -NH-(CH2)8-NH2, -NH-(CH2)IQ-NH2or -NH-(CH2)I2-NH2.

[0081]

[0036] Still more preferred compounds of formula (I), more preferably compounds of formula (la), (lb), (Ic) or (Id) are compounds, wherein i) Ri is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 , and

[0082] R2is -NH2, -OH, -OCH3I-OCH2CH3I-NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH- (CH2)HCONH2, or wherein s is an integer from 6 to 12; or ii) Ri is -H, -CO(CH2)rNH2, -CO(CH2)oCH3, -COphenyl (benzoyl), or -COCH2phenyl, wherein o is 0, 1 , 2 or 3, and r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 and R2is -NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH-(CH2)nCONH2, wherein s is an integer from 6 to 1 , more preferably wherein R2is -NH-(CH2)8-NH2, -NH-(CH2)IO-NH2or -NH-(CH2)12-NH2.

[0083]

[0037] Especially preferred compounds of formula (I), more preferably compounds of formula (la), (lb), (Ic) or (Id), in all embodiments of the present invention, are compounds, wherein i) Ri is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 , and

[0084] R2is -NH2; or ii) Ri is -H, and R2is -NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH-(CH2)nCONH2, wherein s is an integer from 6 to 1 , more preferably wherein R2is -NH-(CH2)8-NH2, -NH-(CH2)IO-NH2or -NH-(CH2)I2-NH2.

[0085]

[0038] Even more preferably the compounds of formula (I) are thus selected from the group consisting of i) compounds wherein Ri is “NH2- (CH2)r- CO- “, wherein r is 7, 8, 9, 10 or 11 , most preferably wherein r is 11 , whilst R2is “-NH2”; and ii) compounds wherein Ri is “H-", whilst R2is “-NH-fCHzJs-NHz” wherein s is an integer from 6 to 12, most preferably wherein s is 12; as well as salts thereof.

[0086]

[0039] In an especially preferred embodiment Ri is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11. The skilled person may suitably recognize that wherein Ri is such a group, the Ri group will be bonded to the peptide AAi via the carbonyl group “-CO-“ in a same manner as similar preceding groups Ri. That is, the notations “-CO(CH2)rNH2“ and“NH2-(CH2)r-CO- “ are equal and merely noted in reverse.

[0040] Preferred compounds of formula (I) in all embodiments of the present invention are compounds wherein n is either 0 or 1 and m and I are each 0. Hence, preferred compounds of formula (I) in all embodiments of the present invention are compounds which comprise two or three amino acids in their structure. That is, preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (la) and (lb)

[0087] RI-AAI-AA2-R2(la), and RI-AAI-AA2-AA3-R2(lb).

[0088]

[0041] More preferred compounds of formula (I) in all embodiments of the present invention are compounds wherein n and m and I are each 0. Hence, more preferred compounds of formula (I) in all embodiments of the present invention are compounds which comprise two amino acids in their structure. That is, more preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (la)

[0089]

[0042] Very preferred compounds of formula (I) are thus compounds of formula (la)

[0090] RI-AAI-AA2-R2(la),

[0091]

[0043] Preferred compounds of formula (I) in all embodiments of the present invention are compounds wherein at least one of the amino acids is phenylalanine (Phe) and more preferably at least two of the amino acids are phenylalanine (Phe).

[0044] Particular preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (la)

[0092] RI-AAI-AA2-R2(la), wherein

[0093] Ri is -H, -CO(CH2)rNH2, or -CO(CH2)oCH3, -COphenyl (benzoyl), or-COCH2phenyl, wherein o is 0, 1 or 2 and wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , most preferably r is 9, 10 or 11; and

[0094] R2is -NH2, -NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH-(CH2)HCONH2, or wherein s is an integer from 6 to 12; and

[0095] AAi is chosen from the group consisting of Ala, (3-Ala, Asp, Gly, Lys, Phe, Ser, Trp, Tyr, and Vai, more preferably from the group consisting of Ala, Gly, Phe, Trp and Tyr, most preferably from the group consisting of Gly and Phe; and

[0096] AA2is chosen from the group consisting of Ala, p-Ala, Asn, Gin, Gly, His, Leu, lie, Lys, Phe, Ser, Tyr, and Vai, more preferably from the group consisting of Ala, Gly, Phe, Trp and Tyr, most preferably from the group consisting of Gly and Phe; as well as respective salts thereof.

[0097]

[0045] Preferences for formula (la) are as mentioned above for formula (I).

[0098]

[0046] More preferred compounds are compounds of formula (la) wherein either Ri is not “-H” or R2is not “-NH2”.

[0099]

[0047] More preferred compounds are compounds of formula (la) wherein

[0100] - Ri is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or

[0101] 11 , most preferably r is 9, 10 or 11 ; and / or

[0102] - R2is -NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH-(CH2)HCONH2, wherein s is an integer from 6 to 12.

[0103]

[0048] Particularly preferred compounds are compounds of formula (la), wherein

[0104] - Ri is -CO(CH2)HNH2,; and / or

[0105] - R2is -NH-(CH2)8-NH2, -NH-(CH2)IQ-NH2or -NH-(CH2)I2-NH2.

[0049] Especially preferred compounds of formula (la) are compounds wherein at least one of the amino acids AAi and AA2is a phenylalanine (Phe). More preferred compounds of formula (la) are compounds wherein both amino acids AAi and AA2are a phenylalanine (Phe). The Phe can be L-Phe or D-Phe. Preferably the Phe is L-Phe.

[0106]

[0050] Still more preferably the compound of formula (la) is a compound having the composition:

[0107] Ri-Phe-Gly-R2; or

[0108] Ri-Gly-Phe-R2 ; or

[0109] Ri-Phe-Phe-R2, wherein Ri and R2are as defined above for formula (I).

[0110] Most preferably formula (la) is a compound having the composition Ri-Phe-Phe-R2, wherein Ri and R2are as defined above for formula (I). As indicated above, preferably for compounds of formula (la) preferably either Ri is not “-H” or R2is not “-NH2”. Further preferences for such Ri and R2are as already described above.

[0111]

[0051] Hence, particular preferred compounds of formula (la) are compounds having the composition Ri-Phe-Gly-R2j or R1-Gly-Phe-R2 j or Ri-Phe-Phe-R2, most preferably having the composition Ri-Phe-Phe-R2, wherein i) Ri is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 , and

[0112] R2 is -NH2; or ii) Ri is -H, and R2is -NH-(CH2)SNH2, -NH-(CH2)12NHCOCH3, -NH-(CH2)nCONH2, wherein s is an integer from 6 to 1 , more preferably wherein R2is -NH-(CH2)s-NH2, -NH-(CH2)IO- NH2or -NH-(CH2)12-NH2, as well as salts thereof.

[0113]

[0052] Most preferably the compounds of formula (I) are thus compounds of formula (la) R1-AA1-AA2-R2 (la),

[0114] - wherein preferably the compounds of formula (la) have the composition Ri-Phe-Gly-R2; or Ri-Gly-Phe-R2 ; or Ri-Phe-Phe-R2, most preferably the composition Ri-Phe-Phe-R2; and / or wherein preferably the compounds are selected from the group consisting of

[0115] (i) compounds of formula (la) wherein Ri is “NH2- (CH2)r- CO- “, wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 , whilst R2is “-NH2”; and (ii) compounds of formula (la) compounds wherein Ri is “H-”, whilst R2 is “-NH-(CH2)S- NH2” wherein s is an integer from 6 to 12, most preferably wherein s is 12; as well as salts thereof.

[0116]

[0053] (The skilled person may suitably recognize that in the preference of the embodiment of the preceding paragraph, where R1 is NH2- (CH2)r- CO- wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 , the R1 group in the compounds of group (i) will be bonded to the peptide AA1 via the carbonyl group “-CO-" in a same manner as similar preceding groups R1. That is, the notations “-CO(CH2)rNH2“ and “NH2-(CH2)r-CO- “ are equal and merely noted in reverse.)

[0117]

[0054] Most preferred compounds of formula (la) are compounds having the composition R1- Phe-Gly-R2; or Ri-Gly-Phe-R2 ; or Ri-Phe-Phe-R2, most preferably having the composition R1- Phe-Phe-R2, wherein

[0118] R1 is -CO(CH2)rNH2, wherein r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably r is 11 , and

[0119] R2 is -NH2, as well as salts thereof.

[0120]

[0055] The compounds of formula (la) as illustrated herein were found to be very active inhibitors of the nicotinic acetyl-choline receptor and thus very suitable to treat signs of skin ageing such as in particular mimic and / or age-related wrinkles. In addition, these compounds can advantageously be produced in a low cost manner with high yields.

[0121]

[0056] Without wishing to be bound by any kind of theory it is believed that the advantages of the compounds of formula (la) may still be obtained if a third amino acid, and optionally a fourth or fifth amino acid, is added.

[0122]

[0057] Hence, in a preferred embodiment the compounds of formula (I) are compounds wherein n is 1 ; m is 0 and I is 0.

[0123]

[0058] Further particular preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (lb)

[0124] R1-AA1-AA2-AA3-R2 (lb), wherein

[0125] R1 is -H or -CO(CH2)rNH2, wherein r is 9, 10 or 11 , and

[0126] R2 is -NH2 or -NH-(CH2)SNH2, wherein s is an integer from 8 to 12, and

[0127] AA1 is chosen from the group of Gly and Phe, and

[0128] AA2 is chosen from the group of Gly and Phe, and AA3 is chosen from the group of Gly and Phe; as well as respective salts thereof.

[0129]

[0059] As indicated above, preferably for compounds of formula (lb) preferably either Ri is not “-H” or R2 is not “-NH2”. Further preferences for R1 and R2 are as already described above.

[0060] In another preferred embodiment the compounds of formula (I) are compounds wherein n is 1 ; m is 1 and I is 0.

[0130]

[0061] Hence, also preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (Ic)

[0131] R1-AA1-AA2-AA3-AA4-R2 (Ic), wherein

[0132] R1 is -H or -CO(CH2)rNH2, wherein r is 9, 10 or 11 ; and

[0133] R2 is -NH2 or -NH-(CH2)SNH2, wherein s is an integer from 8 to 12; and

[0134] AA1 is chosen from the group consisting of Ala, Asp, Asn, Glu, Lys, Phe and Tyr; and AA2is chosen from the group consisting of Asn, Gly, Leu, Tyr and Vai; and

[0135] AA3is chosen from the group consisting of Asn, Leu, Lys, Phe, Tyr and Vai; and

[0136] AA4 is chosen from the group consisting of Ala, Asp, Glu, Gly, Lys and Tyr; as well as respective salts thereof.

[0137]

[0062] As indicated above, preferably for compounds of formula (Ic) preferably either R1 is not “-H” or R2 is not “-NH2”. Further preferences for such R1 and R2 are as already described above.

[0138]

[0063] In another preferred embodiment the compounds of formula (I) are compounds wherein n is 1 ; m is 1 and I is 0.

[0139]

[0064] Hence, also preferred compounds of formula (I) in all embodiments of the present invention are compounds of formula (Id)

[0140] RI-AAI-AA2-AA3-AA4-AA5-R2 (Id), wherein

[0141] R1 is -H, -CO(CH2)rNH2, wherein r is 9, 10 or 11 ; and

[0142] R2 is -NH2 or -NH-(CH2)SNH2, wherein s is an integer from 8 to 12; and

[0143] AA1 is chosen from the group of Glu and Phe; and

[0144] AA2is chosen from the group of Gly and Thr; and

[0145] AA3is chosen from the group of Phe and Thr; and

[0146] AA4 is chosen from the group Phe and Thr; and

[0147] AA5 is chosen from the group of Glu and Gl; as well as respective salts thereof.

[0148]

[0065] As indicated above, preferably for compounds of formula (Id) preferably either R1 is not “-H” or R2 is not “-NH2”. Further preferences for such R1 and R2 are as already described above.

[0066] Most preferred compounds of formula (la) in all embodiments of the present invention are the compounds outlined in table 1 as well as the respective salts thereof.

[0149] Table 1

[0150]

[0067] Of the above, the compound H2N-(CH2)n-CO-Phe-Phe-NH2 and optional salts thereof are most preferred. This compound was found to be an especially active inhibitor of the nicotinic acetyl-choline receptor and thus very suitable to treat signs of skin ageing such as in particular mimic and / or age-related wrinkles. In addition, this compound can be produced in a very cost-efficient and therefore economically attractive manner. The compound therefore combines a good activity and minimal costs.

[0151]

[0068] Most preferred compounds of formula (lb) in all embodiments of the present invention are the one listed in table 2 as well as the respective salts thereof.

[0152] Table 2

[0069] Most preferred compounds of formula (Ic) in all embodiments of the present inventions are the ones listed in table 3 as well as the respective salts thereof.

[0153] Table 3

[0070] Most preferred compounds of formula (Id) in all embodiments of the present invention are the ones listed in table 4 as well as the respective salts thereof.

[0154] Table 4

[0155]

[0071] In the above tables, the abbreviations are used as follows: Ac means acetyl,

[0156] Bal means p-Alanine, Bu means butyl,

[0157] Bz means benzoyl,

[0158] Bn means benzyl, and

[0159] PhAc means phenylacetyl.

[0160] In addition, if nothing else is stated, the amino acids as referred to in tables 1-4 are the respective natural (L-) amino acids.

[0161]

[0072] Most preferably the compounds of formula (I) are selected from the group consisting of compounds of the formulae

[0162] R1-AA1-AA2-R2 (la) or

[0163] R1-AA1-AA2-AA3-R2 (lb), wherein R1 is “NH2- (CH2)r- CO- “, wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and wherein R2is “-NH2”.

[0164] In these most preferred compounds the R1 group is suitably bonded via the above carbonyl group to free amino group at the N-terminus of the first amino acid of the peptide, AA1. In addition, the R2 group is suitably bonded via the nitrogen atom to the free carbonyl group at the C-terminus of the last amino acid of the peptide.

[0165] Hence, such compounds most preferably are compounds of a formula :

[0166] O

[0167] NH - (CH ) -C-AA1-AA - NH wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11, still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11.

[0168] Preferences for the amino acids are as described herein before in this and other paragraphs. As indicated above, preferably at least one of the amino acids in such compound is phenylalanine (Phe). More preferably at least two adjacent amino acids are phenylalanine (Phe). The Phe can be L-Phe or D-Phe. Preferably the Phe is L-Phe.

[0169] Most preferably, the compound is a compound of a formula :

[0170] O

[0171] NH2- (CH2)r- C-AArAA2- NH2 wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11, still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and preferably at least one of AAi and AA2 is Phe, and still more preferably both of AA1 and AA2 are Phe. The Phe can be L-Phe or D-Phe. Preferably the Phe is L-Phe.

[0172] As illustrated in the examples the above compounds can be conveniently prepared in the liquid phase. Therefore these compounds can advantageously be produced in a very cost-efficient and therefore economically attractive manner. These compounds therefore combine a good activity and minimal costs.

[0173] Of the above, the compounds H2N-(CH2)ii-CO-Phe-Phe-NH2, H2N-(CH2)n-CO-Phe-Gly-NH2 and H2N-(CH2)n-CO-Gly-Phe-NH2 and optional salts thereof are most preferred. H2N-(CH2)n- CO-Phe-Phe-NH2 or a salt thereof is most preferred. These compounds were found to be especially active inhibitors of the nicotinic acetyl-choline receptor and thus very suitable to treat signs of skin ageing such as in particular mimic and / or age-related wrinkles.

[0174]

[0073] The invention further advantageously provides compounds of the formulae R1-AA1-AA2-R2 (la) or R1-AA1-AA2-AA3-R2 (lb),

[0175] - wherein R1 is “NH2 - (CH2)r- CO- “, wherein r is equal to or more than 7, more preferably wherein r is equal to or more than 8, still more preferably wherein r is equal to or less than 20, even more preferably wherein r is equal to or less than 15 and yet more preferably wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and

[0176] - wherein R2 is -NH2, -OH, -OCH3 or -OCH2CH3, more preferably wherein R2 is “-NH2”; and

[0177] - wherein AA1, AA2and optionally AA3are independently from each other an amino acid (AA), more preferably wherein at least one of the amino acids AA1, AA2and optionally AA3is a phenylalanine, even more preferably wherein at least two of the amino acids AA1, AA2 and optionally AA3 are phenylalanine, most preferably wherein two adjacent amino acids selected from the amino acids AA1, AA2and optionally AA3are phenylalanine. The invention also provides the respective salts of such compounds. Further preferences for such compounds and such salts are as described elsewhere in the description.

[0178]

[0074] Two especially preferred compounds according to the invention are the compounds of structural formulae (II) and (III) depicted below, representing respectively H2N-(CH2)n-CO- Phe-Phe-NH2 and H2N-(CH2)n-CO-Gly-Phe-NH2. Hence, the invention also provides the compounds of formula (II) and (III) and / or optionally any potential acid addition salt thereof.

[0179] Method for synthesis

[0180]

[0075] The invention further provides a method for the production of a compound of formula (I), respectively a compound of formula (la), (lb), (Ic) or (Id), with preferences as described herein, wherein Ri is “NH2- (CH2)r- CO- “, wherein r is equal to or more than 7, more preferably wherein r is equal to or more than 8, still more preferably wherein r is equal to or less than 20, even more preferably wherein r is equal to or less than 15 and yet more preferably wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 , whilst R2 is “-NH2”, wherein the production is at least partly carried out in a liquid phase and / or wherein such a method comprises a precipitation of such compound from a liquid phase.

[0181]

[0076] Preferences for the compounds are as described herein above.

[0182]

[0077] Preferably the liquid phase comprises or consists of a medium comprising or consisting of at least a preferably polar, preferably aprotic, preferably water-soluble solvent. More preferably such a solvent would be selected from the group consisting of: acetone, acetonitrile, dimethylimidazolidone, dimethylpropyleneurea, dimethylsulfoxide (DMSO), N-methyl pryrrolidine, pyridine, sulfolane, and mixtures thereof. More preferably the liquid phase comprises or consists of a medium comprising at least 30 volume %, more preferably at least 50 volume %, even more preferably at least 70 volume %, and most preferably at least 90 volume % of such a preferably polar, preferably aprotic, preferably water-soluble solvent.

[0183] Cosmetic compositions

[0184]

[0078] The compounds of the present invention, respectively the respective salts thereof with the definitions and preferences as given herein can be incorporated into cosmetic composition useful for improving skin appearance and physiology such as e.g. to reduce fine lines, wrinkles and other symptoms associated with aged or photodamaged skin, to treat stretch marks or to tighten and / or firm skin by inhibiting the expression of the nicotinic acetyl-choline receptor in human skin.

[0185]

[0079] Thus in another embodiment, the present invention relates to the use of a compound according to the present invention with all the definitions and preferences as given herein as a cosmetic active, in particular for the prevention and / or treatment of skin ageing such in particular of the prevention and treatment of mimic and / or age-related wrinkles in human skin.

[0080] In a further embodiment, the present invention relates to cosmetic compositions comprising at least one compound according to the present invention with all the definitions and preferences as given herein.

[0186]

[0081] The term ‘prevention of skin ageing’ as used herein refers to a prophylactic use to reduce the risk to develop visible manifestations of skin ageing such as in particular wrinkles, fine lines, sagging, and laxity, even more preferably for the prevention of mimic and / or age- related wrinkles in human skin.

[0187]

[0082] The term ‘treatment of skin ageing’ as used herein refers to a reduction of the visible manifestations of skin ageing such as in particular wrinkles, fine lines, sagging, and laxity, even more preferably for the prevention and / or treatment of mimic and / or age-related wrinkles in human skin.

[0188]

[0083] The (total) amount of the compound(s) of formula (I) or a respective salt thereof in the cosmetic composition can easily be adjusted by a person skilled in the art in order to achieve the desired beneficial effect. Preferably, the amount of the compound of formula (I) in the cosmetic compositions according to the present invention is at least 0.5 ppm based on the total weight of the cosmetic composition. In all embodiments of the present invention the amount of the compound of formula (I) is preferably selected in the range of about 0.5 and 5000 ppm, more preferably in the range of 1 and 1000 ppm, most preferably in the range of 1 to 100 ppm, based on the total weight of the cosmetic composition.

[0189]

[0084] The compounds of the present invention can be used as a solution, a dispersion, an emulsion or encapsulated in carriers such as macro-, micro- or nanocapsules, in liposomes or chylomicrons, or enclosed in macro-, micro- or nanoparticles or in microsponges or absorbed on powdered organic polymers, talc, bentonite and further inorganic carriers.

[0190]

[0085] Preferably, the compounds according to the present invention are either incorporated as such or in the form of a solution (blend) comprising the compounds according to the present invention into cosmetic compositions. Particularly suitable solutions are for examples the ones formed with a polyalcohol, such as e.g. glycerin, butylene glycol and propylene glycol and the like. Such solutions generally comprise the compounds according to the present invention in an amount of 1000-2500 ppm. Such solutions can be prepared according to standard procedures in the art. Such solutions may further contain water and further stabilizers and / or additives.

[0191]

[0086] In a further embodiment, the invention also relates to a method for the prevention and / or treatment of skin ageing, preferably for prevention and / or treatment of mimic and / or age- related wrinkles in human skin, said method comprising the step of applying a cosmetic composition according to the present invention with all the definitions and preferences given herein to the affected area.

[0192]

[0087] In another embodiment the present invention relates to the use of a compound of formula (I) with all the definitions and preferences as given herein to reduce and / or inhibit the expression of the nicotinic acetyl-choline receptor.

[0193]

[0088] The term ‘cosmetic composition’ preferably refers to compositions which are used to treat, care for or improve the appearance of the skin and / or the scalp. Particular advantageous cosmetic compositions are skin care compositions.

[0194]

[0089] The cosmetic compositions according to the invention are preferably intended for topical application, which is to be understood as the external application to keratinous substances, such as in particular the skin and even more in particular the face.

[0195]

[0090] The term ‘cosmetically acceptable carrier’ as used herein refers to a physiologically acceptable medium which is compatible with keratinous substances. Suitable carriers are well known in the art and are selected based on the end-use application. Preferably, the carriers of the present invention are suitable for application to skin (e.g., sunscreens, creams, milks, lotions, masks, serums, hydrodispersions, foundations, creams, creamgels, or gels etc.). Such carriers are well-known to one of ordinary skill in the art, and can include one or more compatible liquid or solid filler diluent, excipient, additive or vehicle which are suitable for application to skin. The exact amount of carrier will depend upon the level of the compound of formula (I) and any other optional ingredients that one of ordinary skill in the art would classify as distinct from the carrier (e.g., other active components). The compositions of the present invention preferably comprise from about 75% to about 99.999%, more preferably from about 85% to about 99.99%, still more preferably from 90% to about 99%, and most preferably, from about 93% to about 98%, by weight of the composition, of a carrier.

[0196]

[0091] The cosmetic compositions of the present invention can be formulated into a wide variety of product types, including creams, waxes, pastes, lotions, milks, mousses, gels, oils, tonics, and sprays, emulsions, ointments, face masks or a plasters for transdermal application. Preferably the compounds of formula (I) are formulated into emulsions, lotions, creams, gels, and tonics. These product forms may be used for a number of applications, including, but not limited to, hand and body lotions, facial moisturizers, anti-ageing preparations, make-ups including foundations, and the like. Any additional components required to formulate such products vary with product type and can be routinely chosen by one skilled in the art.

[0197]

[0092] If compositions of the present invention are formulated as an aerosol and applied to the skin as a spray-on product, a propellant is added to the composition.

[0198]

[0093] The cosmetic compositions according to the present invention can be prepared by conventional methods in the art such as e.g. by admixing a compound of formula (I) with all the definitions and preferences given herein with the cosmetically acceptable carrier.

[0199]

[0094] The cosmetic compositions of the invention (including the carrier) may comprise further conventional cosmetic adjuvants and additives, such as preservatives / antioxidants, fatty substances / oils, water, organic solvents, silicones, thickeners, softeners, emulsifiers, antifoaming agents, aesthetic components such as fragrances, surfactants, fillers, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorings / colorants, abrasives, absorbents, chelating agents and / or sequestering agents, essential oils, skin sensates, astringents, pigments or any other ingredients usually formulated into such compositions.

[0200]

[0095] In accordance with the present invention, the cosmetic compositions according to the invention may also comprise further cosmetically active ingredients conventionally used in cosmetic compositions. Exemplary active ingredients encompass skin lightening agents; UV- filters, agents for the treatment of hyperpigmentation; agents for the prevention or reduction of inflammation; firming, moisturizing, soothing, and / or energizing agents as well as agents to improve elasticity and skin barrier.

[0201]

[0096] Examples of cosmetic excipients, diluents, adjuvants, additives as well as active ingredients commonly used in the skin care industry which are suitable for use in the cosmetic compositions of the present invention are for example described in the International Cosmetic Ingredient Dictionary & Handbook by Personal Care Product Council (http: / / www.personalcarecouncil.org / ), accessible by the online INFO BASE (http: / / online.personalcarecouncil.org / jsp / Home.jsp), without being limited thereto.

[0202]

[0097] The necessary amounts of the active ingredients as well as the cosmetic excipients, diluents, adjuvants, additives etc. can, based on the desired product form and application, easily be determined by the skilled person. The additional ingredients can either be added to the oily phase, the aqueous phase or separately as deemed appropriate.

[0203]

[0098] The cosmetically active ingredients useful herein can in some instances provide more than one benefit or operate via more than one mode of action.

[0204]

[0099] Of course, one skilled in this art will take care to select the above mentioned optional additional ingredients, adjuvants, diluents and additives and / or their amounts such that the advantageous properties intrinsically associated with the combination in accordance with the invention are not, or not substantially, detrimentally affected by the envisaged addition or additions.

[0205]

[0100] The cosmetic compositions according to the present invention may be in the form of a suspension or dispersion in solvents or fatty substances, or alternatively in the form of an emulsion or micro emulsion (in particular of oil-in-water (O / W) or water-in-oil (W / O) type, silicone-in-water (Si / W) or water-in-silicone (W / Si) type, PIT-emulsion, multiple emulsion (e.g. oil-in-water-in oil (O / W / O) or water-in-oil-in-water (W / O / W) type), pickering emulsion, hydrogel, alcoholic gel, lipogel, one- or multiphase solution or vesicular dispersion or other usual forms, which can also be applied by pens, as masks or as sprays.

[0206]

[0101] If the cosmetic composition is an emulsion, such as in particular an O / W, W / O, Si / W, W / Si, O / W / O, W / O / W multiple or a pickering emulsion, then the amount of the oily phase present in such cosmetic emulsions is preferably at least 10 wt.-%, such as in the range of 10 to 60 wt.-%, preferably in the range of 15 to 50 wt.-%, most preferably in the range of 15 to 40 wt.-%, based on the total weight of the cosmetic composition.

[0207]

[0102] In one embodiment, the cosmetic compositions according to the present invention are advantageously in the form of an oil-in-water (O / W) emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier. The preparation of such O / W emulsions is well known to a person skilled in the art.

[0208]

[0103] If the cosmetic composition according to the invention is an O / W emulsion, then it contains advantageously at least one O / W- or Si / W-emulsifier selected from the list of, glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl-3-methylglycosedistearate. Further suitable emulsifiers are phosphate esters and the salts thereof such as cetyl phosphate (e.g. as Amphisol® A from DSM Nutritional Products Ltd.), diethanolamine cetyl phosphate (e.g. as Amphisol® DEA from DSM Nutritional Products Ltd.), potassium cetyl phosphate (e.g. as Amphisol® K from DSM Nutritional Products Ltd.), sodium cetearylsulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glycerides phosphate and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as an emulsifier. For example, PVP eicosene copolymer, acrylates / C 10-30 alkyl acrylate crosspolymer, and mixtures thereof.

[0209]

[0104] The at least one O / W, respectively Si / W emulsifier is preferably used in an amount of 0.5 to 10 wt. %, in particular in the range of 0.5 to 6 wt.-%, such as more in particular in the range of 0.5 to 5 wt.-%, such as most in particular in the range of 1 to 4 wt.-%, based on the total weight of the cosmetic composition.

[0210]

[0105] Particular suitable O / W emulsifiers to be used in the cosmetic compositions according to the invention encompass phosphate ester emulsifiers such as advantageously 8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, ceteareth-2 phosphate, ceteareth-5 phosphate, ceteth-8 phosphate, ceteth-10 phosphate, cetyl phosphate, C6-10 pareth-4 phosphate, C12- 15 pareth-2 phosphate, C12-15 pareth-3 phosphate, DEA-ceteareth-2 phosphate, DEA-cetyl phosphate, DEA-oleth-3 phosphate, potassium cetyl phosphate, deceth-4 phosphate, deceth- 6 phosphate and trilaureth-4 phosphate.

[0211]

[0106] A particular suitable O / W emulsifier to be used in the cosmetic compositions according to the invention is potassium cetyl phosphate e.g. commercially available as Amphisol® K at DSM Nutritional Products Ltd Kaiseraugst.

[0212]

[0107] Another particular suitable class of O / W emulsifiers are non-ionic self-emulsifying systems derived from olive oil e.g. known as (INCI Name) cetearyl olivate and sorbitan olivate (chemical composition: sorbitan ester and cetearyl ester of olive oil fatty acids) sold under the tradename OLIVEM 1000.

[0213]

[0108] In one particular embodiment, the invention relates to cosmetic compositions with all the definitions and preferences given herein in the form of O / W emulsions comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier wherein the O / W emulsifier is potassium cetyl phosphate. The amount of oily phase in such O / W emulsions is preferably at least 10 wt.-%, more preferably in the range of 10 to 60 wt.-%, most preferably in the range of 15 to 50 wt.-%, such as in the range of 15 to 40 wt.-%.

[0214]

[0109] The cosmetic compositions according to the invention in general have a pH in the range of 3 to 10, preferably a pH in the range of 4 to 8 and most preferably a pH in the range of 4 to 7.5. The pH can easily be adjusted as desired with suitable acids, such as e.g. citric acid, or bases, such as sodium hydroxide (e.g. as aqueous solution), triethanolamine (TEA Care), Tromethamine (Trizma Base) and Aminomethyl Propanol (AMP-Ultra PC 2000), according to standard methods in the art.

[0215]

[0110] The amount of the cosmetic composition to be applied to the skin is not critical and can easily be adjusted by a person skilled in the art. Preferably the amount is selected in the range of 0.1 to 3 mg / cm2skin, such as preferably in the range of 0.1 to 2 mg / cm2skin and most preferably in the range of 0.5 to 2 mg / cm2skin.

[0216]

[0111] The compounds of the present invention as well as the cosmetic compositions containing the same are preferably used as skin care products, in particular against the formation and aggravation of wrinkles and against all consequences of natural or accelerated (sun rays, pollution) skin aging.

[0217]

[0112] As outlined above, the compounds of formula (I) according to the present invention can be composed with at least one additional skin care active. Particular suitable skin care actives to be used with the compounds according to the present invention are listed below:

[0218]

[0113] Farnesol ([2E,6E]-3,7,11-trimethyl-2,6,10-dodecatrien-1-ol and as used herein "farnesol" includes isomers and tautomers of such): The cosmetic compositions of the present invention may contain a safe and effective amount of farnesol. Farnesol is a naturally occurring substance which is believed to act as a precursor and / or intermediate in the biosynthesis of squalene and sterols, especially cholesterol. Farnesol is also involved in protein modification and regulation (e.g., farnesylation of proteins), and there is a cell nuclear receptor which is responsive to farnesol.

[0219]

[0114] Phytantriol: The cosmetic compositions of the present invention may contain a safe and effective amount of phytantriol. Phytantriol is the common name for the chemical known as 3,7,11 ,15-tetramethylhexadecane-1 ,2,3-triol. Phytantriol is useful, e.g., as a spider vessel / red blotchiness repair agent, a dark circle / puffy eye repair agent, sallowness repair agent, a sagging repair agent, an anti-itch agent, a skin thickening agent, a pore reduction agent, an oil / shine reduction agent, a post-inflammatory hyperpigmentation repair agent, a wound-treating agent, an anti-cellulite agent, and an agent for regulating skin texture, including wrinkles and fine lines.

[0220]

[0115] Desquamation actives: A safe and effective amount of a desquamation active may be added to the compositions of the present invention, more preferably from about 0.1 wt.-% to about 10 wt.-%, even more preferably from about 0.2 wt.-% to about 5 wt.-%, also preferably from about 0.5 wt.-% to about 4 wt.-%, based on the composition. Desquamation actives enhance the skin appearance benefits of the present invention. For example, the desquamation actives tend to improve the texture of the skin (e.g., smoothness). One desquamation system that is suitable for use herein contains sulfhydryl compounds and zwitterionic surfactants and is described in U.S. Pat. No. 5,681 ,852 to Bissett, cited herein by reference. Another desquamation system that is suitable for use herein contains salicylic acid and zwitterionic surfactants and is described in U.S. Pat. No. 5,652,228 to Bissett, cited herein by reference. Zwitterionic surfactants such as described in these applications are also useful as desquamatory agents herein, with cetyl betaine being particularly preferred.

[0221]

[0116] Anti-acne actives: The compositions of the present invention may contain a safe and effective amount of one or more anti-acne actives. Examples of useful anti-acne actives include resorcinol, sulfur, salicylic acid, benzoyl peroxide, erythromycin, zinc, etc.

[0222]

[0117] Anti-wrinkle actives / anti-atrophy actives: The compositions of the present invention may further contain a safe and effective amount of one or more anti-wrinkle actives or antiatrophy actives. Exemplary anti-wrinkle / anti-atrophy actives suitable for use in the compositions of the present invention include sulfur-containing D and L amino acids and their derivatives and salts, particularly the N-acetyl derivatives, a preferred example of which is N- acetyl-L-cysteine; thiols, e.g., ethane thiol; hydroxy acids (e.g., alpha-hydroxy acids such as lactic acid and glycolic acid or beta-hydroxy acids such as salicylic acid and salicylic acid derivatives such as the octanoyl derivatives), phytic acid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g., phenol and the like), vitamin B3 compounds and retinoids which enhance the horny tissue appearance benefits of the present invention, especially in regulating keratinous tissue condition, e.g., skin condition.

[0223] (a) Vitamin B3 compounds: The compositions of the present invention may contain a safe and effective amount of a vitamin B3 compound. Exemplary derivatives of the foregoing vitamin B3 compounds include nicotinic acid esters, including non-vasodilating esters of nicotinic acid (e.g., tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide.

[0224] (b) Retinoids: The compositions of the present invention may also contain a retinoid. As used herein, "retinoid" includes all natural and / or synthetic analogs of vitamin A or retinol-like compounds which possess the biological activity of vitamin A in the skin, as well as the geometric isomers and stereoisomers of these compounds. The retinoid is preferably retinol, retinol esters (e.g., C2 to C22 alkyl esters of retinol, including retinyl palmitate, retinyl acetate, retinyl propionate), retinal, and / or retinoic acid (including all-trans retinoic acid and / or 13-cis- retinoic acid), more preferably retinoids other than retinoic acid. Other suitable retinoids are tocopheryl retinoate [tocopherol ester of retinoic acid (trans- or cis-), adaptalene{6-[3-(1- adamantyl)-4-methoxyphenyl]-2-naphthoic acid), and tazarotene(ethyl 6-[2-(4,4- dimethylthiochroman-6-yl)-ethinyl]nicotinate). Preferred retinoids are retinol, retinyl palmitate, retinyl acetate, retinyl propionate, retinal and combinations thereof. The compositions of the present invention may contain a safe and effective amount of the retinoid, such that the resultant composition is safe and effective for regulating horny tissue condition, preferably for regulating visible and / or tactile discontinuities in skin, more preferably for regulating signs of skin aging, even more preferably for regulating visible and / or tactile discontinuities in skin texture associated with skin aging.

[0225] (c) Hydroxy acids: The compositions of the present invention may contain a safe and effective amount of a hydroxy acid. Preferred hydroxy acids for use in the compositions of the present invention include salicylic acid and salicylic acid derivatives.

[0226]

[0118] Bakuchiol: The cosmetic compositions of the present invention may advantageously further contain bakuchiol. That is, the invention advantageously also provides a cosmetic composition comprising one or more oligopeptides and / or derivatives of such oligopeptides as claimed herein in combination with bakuchiol.

[0227]

[0119] Peptides: Additional peptides, including but not limited to di-, tri-, tetra- and pentapeptides and derivatives thereof, may be included in the compositions of the present invention in amounts that are safe and effective. As used herein, "peptides" refers to both naturally occurring peptides and synthesized peptides and also includes peptide mimetics and metal complexes of "peptides". Also useful herein are naturally occurring and commercially available compositions that contain peptides.

[0228] Suitable peptides for use herein include the SYN®-Peptide range available from DSM Nutritional Products Ltd such as SYN®-HYCAN (Tetradecyl Aminobutyroylvalylaminobutyric Urea Trifluoroacetate), SYN®-AKE (Dipeptide Diaminobutyroyl Benzylamide Diacetate), SYN®-COLL (Palmitoyl Tripeptide-5), SYN®-UP (Amidinobenzyl Benzylsulfonyl D-Seryl Homophenylalaninamide Acetate); palmitoyl-Gly-His-Lys commercially available as Biopeptide CL™; as well as Matrixyl (palmitoyl-Lys-Thr-Thr-Lys-Ser) available from Sederma, France, Acetyl Hexapeptide-1 (e.g. commercially available as Munapsys from Lipotrue) and Acetyl Hexapeptide-8 (e.g. commercially available as Argireline / Argireline amplified peptide solution at Lubrizol), and Nasturtium officinale Extract (commercially available as Myoline® by Silab).

[0229] The invention therefore also provides a cosmetic composition comprising

[0230] - one or more oligopeptides according to the invention, suitably according to formula (I), more preferably according to formula (la), (lb), (Ic) or (Id), as described herein; and

[0231] - one or more oligopeptides selected from the group consisting of Tetradecyl Aminobutyroylvalylaminobutyric Urea Trifluoroacetate, Dipeptide Diaminobutyroyl Benzylamide Diacetate,

[0232] Palmitoyl Tripeptide-5, Amidinobenzyl Benzylsulfonyl D-Seryl Homophenylalaninamide Acetate, palmitoyl-Gly-His-Lys and pal mitoyl-Lys-Thr-Thr-Lys-Ser.

[0120] Antioxidants / radical scavengers: The compositions of the present invention may include a safe and effective amount of an antioxidant / radical scavenger. The antioxidant / radical scavenger is especially useful for providing protection against UV radiation which can cause increased scaling or texture changes in the stratum corneum and against other environmental agents which can cause skin damage.

[0233] Antioxidants / radical scavengers such as ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium or magnesium ascorbyl phosphate, ascorbyl sorbate, tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename Trolox™), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., N,N- diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid and its salts, lycine pidolate, arginine pidolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, 1 -methionine, proline, superoxide dismutase, silymarin, tea extracts, grape skin / seed extracts, melanin, and rosemary extracts may be used. Preferred antioxidants / radical scavengers are selected from tocopherol and esters of tocopherol, such as tocopherol acetate.

[0234]

[0121] Flavonoids: The compositions of the present invention may optionally contain a flavonoid compound. Examples of suitable flavonoids include, but are not limited to, unsubstituted flavanone, mono-hydroxy flavanones (e.g., 2'-hydroxy flavanone, 6-hydroxy flavanone, 7-hydroxy flavanone, etc.), mono-alkoxy flavanones (e.g., 5-methoxy flavanone, 6-methoxy flavanone, 7-methoxy flavanone, 4'-methoxy flavanone, etc.), unsubstituted chaicone (especially unsubstituted trans-chalcone), mono-hydroxy chaicones (e.g., 2'- hydroxy chaicone, 4'-hydroxy chaicone, etc.), di-hydroxy chaicones (e.g., 2',4-dihydroxy chaicone, 2',4'-dihydroxy chaicone, 2,2'-dihydroxy chaicone, 2',3-dihydroxy chaicone, 2', 5'- dihydroxy chaicone, etc.), and tri-hydroxy chaicones (e.g., 2',3',4'-trihydroxy chaicone, 4,2',4'-trihydroxy chaicone, 2,2',4'-trihydroxy chaicone, etc.), unsubstituted flavone, 7,2'- dihydroxy flavone, 3',4'-dihydroxy naphthoflavone, 4'-hydroxy flavone, 5,6-benzoflavone, and 7,8-benzoflavone, unsubstituted isoflavone, daidzein(7,4'-dihydroxy isoflavone), 5,7- dihydroxy-4 '-methoxy isoflavone, soy isoflavones (a mixture extracted from soy), unsubstituted coumarin, 4-hydroxycoumarin, 7-hydroxy coumarin, 6-hydroxy-4-methyl coumarin, unsubstituted chromone, 3-formyl chromone, 3-formyl-6-isopropyl chromone, unsubstituted dicoumarol, unsubstituted chromanone, unsubstituted chromanol, and mixtures thereof. Preferred for use herein are unsubstituted flavanone, methoxy flavanones, unsubstituted chaicone, 2',4-dihydroxy chaicone, and mixtures thereof. More preferred are unsubstituted flavanone, unsubstituted chaicone (especially the trans-isomer), and mixtures thereof.

[0235]

[0122] Anti-cellulite agents: The compositions of the present invention may also contain a safe and effective amount of an anti-cellulite agent. Suitable agents may include, but are not limited to, xanthine compounds (e.g., caffeine, theophylline, theobromine and aminophylline).

[0236]

[0123] Skin-tanning actives: Dihydroxyacetone (also known as DHA or 1 ,3-dihydroxy-2- propanone) or erythrulose available from DSM Nutritional Products Ltd.. DHA and erythrulose can be administered in combination.

[0237]

[0124] Skin-lightening agents: Suitable skin-lightening agents comprise those known in the art, including kojic acid, arbutin, alpha-arbutin, ascorbic acid and derivatives thereof (e.g., magnesium ascorbyl phosphate or sodium ascorbyl phosphate) and extracts (e.g., mulberry extract, placental extract).

[0238]

[0125] Skin-soothing and skin-healing actives: The compositions of the present invention may comprise a skin-soothing or skin-healing active. Skin-soothing or skin-healing actives suitable for use herein include candelilla wax, panthenoic acid derivatives (including panthenol, dexpanthenol, ethyl panthenol), aloe vera, allantoin, bisabolol (e.g., alpha bisabolol), dipotassium glycyrrhizinate, liquorice (the plant genus / species Glycyrrhiza glabra) family, including glycyrrhetic acid, glycyrrhizic acid and derivatives thereof (e.g., salts and esters), plant sterols (e.g., phytosterol), chamomile, red clover extract and sea alga extract.

[0239]

[0126] Antimicrobial and antifungal actives: The compositions of the present invention may contain an antimicrobial or antifungal active. Such actives are capable of destroying microbes, preventing the development of microbes or preventing the pathogenic action of microbes. Preferred examples of actives useful herein include those selected from salicylic acid, benzoyl peroxide, 3-hydroxy benzoic acid, glycolic acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, phytic acid, N-acetyl-L-cysteine, lipoic acid, azelaic acid, arachidonic acid, benzoylperoxide, tetracycline, ibuprofen, naproxen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, 2,4,4'- trichloro-2'-hydroxy diphenyl ether, 3,4,4-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neocycin sulfate and mixtures thereof.

[0240]

[0127] Sunscreen actives: Exposure to ultraviolet light can result in excessive scaling and texture changes of the stratum corneum. Therefore, the compositions of the present invention may optionally contain a sunscreen active. As used herein, "sunscreen active" includes both sunscreen agents and physical sunblocks. Suitable sunscreen actives may be organic or inorganic. Inorganic sunscreens useful herein include the following metallic oxides: titanium dioxide, zinc oxide, zirconium oxide, iron oxide and mixtures thereof, such as PARSOL® TX or PARSOL® ZX, both commercially available from DSM Nutritional Products Ltd.

[0241] Examples of organic sunscreens suitable to be incorporated in toie compositions according to the present invention are 2-ethylhexyl-p-methoxycinnamate (e.g. commercially available as PARSOL® MCX), 4,4'-t-butyl methoxydibenzoyl-methane (e.g. commercially available as PARSOL® 1789), polysilicone-15 (e.g. commercially available as PARSOL® SLX), 2- hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid, digalloyltrioleate, 2,2-dihydroxy— 4-methoxybenzophenone, ethyl-4-(bis(hydroxy-propyl))aminobenzoate,

[0242] 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (e.g. commercially available as PARSOL® 340), 2-ethylhexylsalicylate (commercially available as PARSOL® EHS), glyceryl-p- aminobenzoate, 3,3,5-trimethylcyclohexylsalicylate (e.g. commercially available as PARSOL HMS), methylanthranilate, p-dimethylaminobenzoic acid or aminobenzoate, 2-ethylhexyl-p- dimethylaminobenzoate, 2-phenylbenzimidazole-5-sulfonic acid or salts thereof (e.g. commercially available as PARSOL® HS), 2-(p-dimethylaminophenyl)-5- sulfonicbenzoxazoic acid, 2,2'-methylene-bis-[6-(2H-benzotriazol-2-yl)-4-(1 ,1 ,3,3- tetramethylbutyl)-phenol] (e.g. commercially available as PARSOL® MAX), 2,4-Bis-[(4-(2- ethylhexyloxy)-2-hydroxy)-phenyl]-6-(4-methoxyphenyl)-1 ,3,5-triazin (e.g. commercially available as PARSOL® SHIELD) and mixtures of these compounds. The exact amounts of the sunscreen active will vary depending upon the sunscreen or sunscreens chosen and the desired Sun Protection Factor (SPF).

[0243]

[0128] Conditioning agents: The compositions of the present invention may contain a conditioning agent selected from humectants, moisturizers or skin conditioners. These materials include, but are not limited to, guanidine, urea, glycolic acid and glycolate salts (e.g., ammonium and quaternary alkyl ammonium), salicylic acid; lactic acid and lactate salts (e.g., ammonium and quaternary alkyl ammonium); aloe vera in any of its variety of forms (e.g., aloe vera gel); polyhydroxy alcohols such as sorbitol, mannitol, xylitol, erythritol, glycerol, hexanetriol, butanetriol, propylene glycol, butylene glycol, hexylene glycol and the like; polyethylene glycols; sugars (e.g., melibiose) and starches, sugar and starch derivatives (e.g., alkoxylated glucose, fructose, glucosamine), saccharide isomerate (Pentavitin®), hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine, panthenol, allantoin and mixtures thereof.

[0244] Preferably, the conditioning agent is selected from panthenol, dexpanthenol, saccharide isomerate, allantoin and combinations thereof. Use

[0245]

[0129] The compounds such as the compounds of formula’s (I), la), (lb), (Ic) and / or (Id) and / or salts thereof and / or cosmetic compositions as described herein comprising such compound(s) can advantageously be used for the prevention and / or treatment of skin ageing. Preferably the prevention and / or treatment of skin ageing is the prevention and / or treatment of mimic and / or age-related wrinkles in human skin.

[0246]

[0130] Hence, herein is also provided a method for the prevention and / or treatment of skin ageing, preferably of mimic and / or age-related wrinkles in human skin, said method comprising applying a compound and / or cosmetic composition as described herein to the affected area.

[0247]

[0131] Further provided is a use of at least one compound such as the compounds of formula’s (I), la), (lb), (Ic) and / or (Id) and / or salts thereof for the preparation of a cosmetic composition, preferably a skin care product, more preferably for the prevention and / or treatment of skin ageing.

[0248]

[0132] Further preferences for the compounds are as described elsewhere in this description.

[0249] Examples

[0250] Abbreviations:

[0251] Ac Acetyl (acetic acid N-terminal modification)

[0252] Ala Alanine / yl

[0253] Arg Arginine / yl

[0254] Bal beta-Alanine / yl

[0255] P-Ala or b-Ala beta-Alanine / yl

[0256] Bu Butyryl (butyric acid N-terminal modification)

[0257] Bz Benzoyl / Benzoic acid (N-terminal modification)

[0258] C8 a,® disubstituted octan, -(CHzJs-

[0259] C12 a, co disubstituted dodecan, -(CH2)12-

[0260] DCM Dichloromethane

[0261] DIPEA Diisopropyl ethyl amine

[0262] DMF Dimethylformamide

[0263] Glu Glutamic acid / yl

[0264] Gin Glutamine / yl

[0265] Gly Glycine / yl

[0266] His Histidine / yl

[0267] HPLC high pressure liquid chromatography ILe Leucine / yl

[0268] Leu Isoleucine / yl

[0269] Lys Lysine / yl

[0270] MeOH Methanol

[0271] Met Methinoine / yl

[0272] NH-C11 -CO amino dodecanoic acid / dodecanoyl

[0273] NMP 1-Methyl-2-pyrrolidone

[0274] PhAc Phenylacetic acid (N-terminal modification)

[0275] Phe Phenylalanin / yl

[0276] Pro Proline / yl

[0277] Ser Serine / yl

[0278] TBTU coupling reagent

[0279] Thr Threonine / yl

[0280] Trp Tryptophane / yl

[0281] Tyr Tyrosine / yl

[0282] Vai Valine / yl

[0283] Example 1 (Synthesis and nicotinic acetyl-choline receptor inhibition assay)

[0284] In example 1 a series of 57 peptides were prepared as illustrated by Table 5 below. The peptides were produced according to a general procedure as detailed below. Subsequently their ability to act as an active inhibitor of the nicotinic acetyl-choline receptor was tested.

[0285] Resin loading C12

[0286] Dodecane-1 ,12-diamine (45 g, 1 Eq, 0.22 mol) was dissolved in 400 ml Dichloromethane (DCM), warmed to approximately 35°C and 250ml 1-Methyl-2-pyrrolidone (NMP) was added. 1-chloro-2-(chloro(phenyl)(p-tolyl)methyl)benzene (15 g, 0.11 Eq, 24 mmol) was added in 3 portions. The mixture was shaken for 3 hours, solvent was filtered off and resin was washed two times with DCM.

[0287] Subsequently the Resin was washed two times with DCM+ 0.04% DIPEA, then a solution of MeOH / DIPEA / DCM 2:1 :17 was added and the resin shaken for 10 minutes. The procedure was repeated with a new mixture, after that resin was washed again with DCM, DMF, and 2x DCM.

[0288] Resin was checked with 2,4,6-Trinitrobenzene sulfonic acid (TNBS) Test and found to be strongly Positive, then washed two times using Iso-propyl ether (IPE), then dried overnight in vacuum.

[0289] The yield was 18.05g resin, loading was calculated to be 1.15mmol / g. In the above and below, 1 ,12-Ci2 diamine was used as an illustrative example. The below peptides, including 1 ,8-Cs diamine, 1,9-Cg diamine, 1,10-Cw diamine, and 1 ,11-Cn diamine were prepared in the same way, using the respective equivalents as well.

[0290] Synthesis of Fmoc-12amino lauric acid

[0291] 25 gram (g) 12-aminododecanoic acid (1 Eq, 0.12 mol) was suspended in a 1L round bottom necked flask with 400ml water and 15g Na2CO3 (1.2 Eq, 0.14 mol). Diluted with 200ml 1 ,4— Dioxane, but still a suspension. 47 g Fmoc-OSU (47 g, 1.2 Eq, 0.14 mol) was dissolved in 200ml 1 ,4-Dioxane by slightly warming. (Fluorenylmethoxycarbonyl-succinimide (Fmoc-OSu) is a mixed carbamate reagent with CAS number 82911-69-1 , commercially available from Sigma Aldrich).

[0292] When adding Fmoc-OSu into the amine suspension, it became very thick soon, likely due to product precipitation. The suspension was stirred stronger and Fmoc-OSu addition was continued. After adding 200 ml dioxane and 200ml THF reaction mixture became almost clear. Reaction mixture was diluted with 500 ml water, pH was adjusted to 1 using 2M HCI and extracted with 250 ml EtOAc. Aqueous phase was reextracted with 150 ml EtOAc.

[0293] Combined organic phases were washed neutral with water and brine, dried over Na2SO4. Solvents were removed in vacuum, residue was dissolved in 300ml EtOAc at 70°C and allowed to cool to RT, diluted with 150ml EtOAc, and agitated on the rotary evaporator (without vacuum) overnight.

[0294] The following day reaction mixture were filtered over glas slit filter. Filter cake was washed three times with IPE, checked for purity by HPLC, dried in vacuum until weight constant.

[0295] Yield was: 42g white solid

[0296] Synthesis of free peptides (General Procedure)

[0297] 0.5 mmol of the preloaded 1 ,x Cxdiamine chlorotrityl resin (where x was respectively 8, 9, 10, 11 , and 12 as explained above) was loaded in the Peptide synthesizer and coupled with 1.25 equivalent (eq) of the respective amino acids, coupling, washing and deprotection steps were done automatically. Once the peptide sequence was assembled, crude peptide was cleaved from the resin using 95% TFA. The crude mixture was then purified by preparative-HPLC, pure fractions were pooled and lyophilised.

[0298] With this method, the examples from Table 5: 2,3, 5-17, 25-39, 47-54 were obtained. As an Illustrative Example: 241 mg H-Phe-Lys-NH-C12-NH2 *3TFA was obtained as a white lyophilizate. The TFA salt could be converted into acetate or hydrochloride as described below in the “typical Procedure for conversion from TFA into hydrochloride” and the Typical Procedure for conversion from TFA into acetate” .

[0299] Synthesis of N-acylated peptides (General Procedure)

[0300] 0.5 mmol of the preloaded 1 ,x Cx diamine chlorotrityl resin was loaded in the Peptide synthesizer and coupled with 1 .25 eq of the respective amino acids, coupling, washing and deprotection steps were done automatically. Once the peptide sequence was fully assembled, the A / -terminal acid was coupled to the peptide using TBTU as a coupling reagent, no deprotection this time, (for acetylated peptides, a mixture of Acetic anhydride, Pyridine / DMF is used) The crude peptide was cleaved from the resin using 95% TFA, and the mixture was then purified by preparative-HPLC.

[0301] As an Illustrative Example: 309mg Bu-Lys-Phe- NH-C12-NH2 *2TFA was obtained as a white lyophilizate and could be converted into acetate or hydrochloride as described below in the “typical Procedure for conversion from TFA into hydrochloride” and the Typical Procedure for conversion from TFA into acetate”.

[0302] Examples from Table 5: 1 ,4, 18-24 were obtained in this manner.

[0303] Synthesis of amidated peptides (General Procedure)

[0304] 0.5 mmol of the aminomethy resin was loaded in the Peptide synthesizer and coupled with 1.25 eq of the respective amino acids, coupling, washing and deprotection steps were done automatically. Once the peptide sequence was fully assembled, the Fmoc-12-amino lauric acid is coupled to the peptide using TBTU as a coupling reagent, no deprotection this time. The crude peptide was cleaved from the resin using 95% TFA, and the mixture was then purified by preparative-HPLC.

[0305] As an Illustrative Example: 130 mg H2N-(CH2)n-CO-Phe-Phe-NH2 *2TFA was obtained as a white lyophilizate and can be converted into acetate or hydrochloride as described below in the “typical Procedure for conversion from TFA into hydrochloride” and the Typical Procedure for conversion from TFA into acetate”.

[0306] Examples from table 5 entries 42 - 46 were obtained in this manner.

[0307] Synthesis of C-terminal acylated diamines (General Procedure)

[0308] Boc-Phe-Gly-OH (2.41 g, 2 Eq, 7.49 mmol) was preactivated with TBTU (1.80 g, 1.5 Eq, 5.61 mmol) and DIPEA (2.42 g, 3.26 mL, 5 Eq, 18.7 mmol) for 4min. Dodecane-1 ,12-diamine (750 mg, 1 Eq, 3.74 mmol) was added and the reaction takes place and is allowed to react. After aqueous workup using water, 0.5M NaHCOs, 2x water, 0.5M HCI, 3x water, the crude mixture was purified using prep HPLC (50x300mm C18 column): Gradient: 28% AcN to 63% AcN in 15min.

[0309] From the fractions 24-30 Boc-Phe-Phe-NH-(CH2)12-NH2 *TFA was isolated. AcN was removed in vacuum and compound extracted into EtOAc phase. EtOAc was removed in vacuum and residue was dissolved in 5ml Ac2O / Pyridine / DMF 1 :1 :10 mixture for 15 min. after aqueous workup using EtOAc / diluted HCI, solvent was removed in vacuum and excess of TFA was added 10 mins to remove Boc protection group. Product was purified and lyophilized. 302 mg of H-Phe-Phe-NH-(CH2)12-NH-Ac *TFA was isolated and can be converted into acetate or hydrochloride as described below.

[0310] The example from table 5 entry 40 was obtained in this manner.

[0311] From the fractions 72-78 Boc-Phe-Phe-NH-(CH2)12-NH-Phe-Phe-Boc was isolated by extraction into EtOAc phase. Solvent was removed in vacuum and excess of TFA was added 10 mins to remove Boc protection group. Product was purified and lyophilized. 206 mg of Boc- Phe-Phe-NH-(CH2)12-NH-Phe-Phe-H *2TFA was isolated and can be converted into acetate or hydrochloride as described below.

[0312] The example from table 5 entry 41 was obtained in this manner.

[0313] All examples 1-58 can be converted into acetates and / or hydrochlorides by standard methods in the art as outlined below.

[0314] Typical Procedure for conversion from TFA into hydrochloride

[0315] Ac-Phe-Phe- NH-(CH2)12-NH2 *TFA (65 mg, 100 pmol) is dissolved in a mixture of 2ml AcN and 2ml water. After adding 2N HCI (36.65 mg, 502.7 pL, 10 Eq, 1 .00 mmol). And diluting with 15ml of water, the solution is lyophilized.

[0316] 61 mg of Ac-Phe-Phe- NH-(CH2)12-NH2 *HCI, a white powder is obtained.

[0317] Typical Procedure for conversion from TFA into acetate

[0318] Ac-Phe-Phe- NH-(CH2)12-NH2 *TFA (65 mg, 100 pmol) is dissolved in a mixture of 2ml AcN and 2ml water. After adding 2g Biorad Ion exchange resin, in acetate form, the mixture is slightly agitated for 2 hours, the the resin is filtered, washed 2x with 3ml of water and the solution is lyophilized. Yield: 57 mg of Ac-Phe-Phe- NH-(CH2)12-NH2 *AcOH, a white powder is obtained. Method of the nicotinic acetyl-choline receptor inhibition assay

[0319] The assay is based on an automated patch clamp assay on the human nicotinic acetylcholine receptor (nAChR) containing the alphal , betal , delta, and epsilon subunits. The receptor is stably expressed in HEK293 cells. Cells are harvested, washed, and resuspended and then applied to the instrument. The assay is performed at room temperature, cells are held at -60 mV. The antagonist effect is measured as follows: establish a baseline response using the ECso concentration of acetylcholine (ACh). The inhibitor peptides are then co-applied with the ECso concentration of ACh for 2 seconds after the cells were incubated with the inhibitor peptides for 30 seconds. This is followed by a 30 second wash step. The process is repeated with the next ascending concentration of test compound. Peak inward currents in response to the ACh additions in the presence of test compound are measured. All inhibitor data are normalized to the baseline peak current induced by addition of ECao. The results are depicted in Table 5. The Half Maximal Inhibitory Concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function.

[0320] * If nothing else is mentioned, the respective AA code refers to the respective natural AA, i.e. the respective L-forms.

[0321] As illustrated by the entries 42, 43 and 44, especially good results were obtained where the compound is H2N-(CH2)ii-CO-Phe-Phe-NH2, H2N-(CH2)ii-CO-Gly-Phe-NH2 or H2N- (CH2)n-CO-D-Phe-D-Phe-NH2or a salt thereof.

[0322] Example 2 (comparative)

[0323] To test the potency of prior art dipeptide Diaminobutyroyl Benzylamide Diacetate (also referred to as “Beta-Ala-Pro-Dab-NHBz”), this prior art dipeptide was submitted to the same nicotinic acetyl-choline receptor inhibition assay (nACh Receptor) assay, as described above for

[0324] Example 1. The test was carried out in duplicate. The results are provided below in Table 6. As illustrated by these results, the oligopeptides according to the invention as illustrated in Table 5 result in an improved inhibition as compared to the prior art oligopeptides listed in Table 6. Table 6

[0325] Example 3 (in-silico measurement of skin permeability)

[0326] In this example an in-silico comparison of the skin permeability was made between the peptides according to the invention and the peptides as mentioned in the prior art, namely H- D-Ala-L-Gln-NH(CH2)e-NH2, 11-amino-undecanoyl-Ser-Lys-NH2 and Dipeptide diaminobutyroyl benzylamide (beta-Ala-Pro-Dab-NHBz).

[0327] The skin permeability parameter LogKp was computed using the QikProp program within the Schrodinger Small-Molecule Drug Discovery Suite. The computations were done with the most prominent protonation states predicted at pH=7.0 using the LigPrep program using the PROPKA algorithm. The results are reflected in Table 7.

[0328] Table 7

[0329] Higher values (i.e. less negative values) of QLogKp correlate with a better skin permeability, meaning the substance is more readily able to penetrate through the skin's lipid barrier. The compounds of the current invention clearly show better skin permeability according to this analysis. Hence, the compounds in the present invention are superior to those mentioned in the prior art. Example 4 (in-silico prediction of binding affinity using a 3D receptor model)

[0330] In this example an in-silico comparison of the binding of the peptide to an in-silico 3D receptor model was made between the peptides according to the invention and the peptides as mentioned in the prior art, namely H-D-Ala-L-Gln-NH(CH2)e-NH2, 11-amino-undecanoyl-Ser- Lys-NH2 and Dipeptide diaminobutyroyl benzylamide (beta-Ala-Pro-Dab-NHBz). (That is, in this in silico test it was compared how strong a peptide was bonded to the receptor, whereas in Table 5 it was tested how well the action of the receptor was inhibited. Although these tests are different, a correlation is expected.)

[0331] A molecular model of the muscle-type nicotinic acetylcholine receptor was retrieved from the Protein Data Bank (PDB ID 6UWZ) and prepared using the Protein Preparation Wizard in the Schrodinger Small-Molecule Drug Discovery Suite. Docking to the ion channel portion of the receptor was done using the Glide program in standard-precision mode using structures prepared in the previous step (LogKp prediction). The ten best-scored binding modes per compound were visually inspected and retained if they presented an orientation with their aliphatic chain pointed towards the ion channel port. The results are reflected in Table 8.

[0332] Table 8

[0333] In these results, lower values (i.e. more negative values) correlate with a better binding.

[0334] From the results in Table 8 it can be seen that compounds with long amine chains such as the ones in the present invention were shown to have an improved bonding to the ion channel port portion of the receptor model. The dipeptide diaminobutyroyl benzylamide as well as the dipeptide H-D-Ala-L-Gln-NH(CH2)6-NH2 (entry 8 in Abbott et al.) do not show proper bonding to the ion channel pore of the receptor and were omitted from a numerical comparison. The dipeptide 11-amino-undecanoyl-Ser-Lys-NH2 (entry 32c in Sikorski et al.) showed worse binding affinity (i.e. a higher docking score) than the compounds in the present invention. Hence, the above in-silico experiments is predicting that the compounds in the present invention will be expected to have superior inhibition characteristics compared to those mentioned in the prior art.

[0335] Example 5 (synthesis in liquid phase)

[0336] The below provides an example of how the synthesis of the compounds of entries 42-44 of Table 5 is advantageous over the synthesis of other compounds in Table 5. As illustrated the compounds of entries 42-44 of Table 5 can advantageously be synthesized in the liquid phase with high yields whereas the other compounds in Table 5 cannot be efficiently synthesized in this manner.

[0337] Prophetic preparation of compounds of entries 1-41 and 43 to 57 of Table 5 in liquid phase

[0338] In this prophetic example it is explained what the disadvantages are of carrying out synthetic steps in liquid phase to prepare the compounds of entries 1-41 and 43 to 57 in Table 5 the The compounds of entries 1-41 and 43 to 57 in Table 5 are reflected with the general formula AA-(AA)x-NH-(CH2)y-NH2).

[0339] Desymmetrisation of H2N-(CH2)X-NH2 could be carried out as follows:

[0340] Use could be made of solvents like dioxane, dichloromethane or chloroform. However, these solvents are less desirable from a Safety perspective as they are or are suspected Carcinogenic, Mutagenic and Reprotoxic (CMR). Yield maximization is expected to be difficult, as adding an excess of the amine protecting group tert-butyloxycarbonyl (Boc), chemically present as a di-tert-butyl dicarbonate (BOC2O), will result in the formation of undesired bis-Boc- diamine, which needs to be removed. Therefore the reaction would need to be stopped when starting material is still present and not too much of the bis-Boc-diamine is formed.

[0341] Prophetically, raw yield (referred to the diamine) is maximum 60%. However, chromatic purification is still required, and the desired mono-Boc-Diamine is isolated in a yield range of 25 -35%. Aqueous workup is difficult due to the detergent like properties of the target compound.

[0342] Presuming a peptide synthesis and final Boc deprotection of approx. 90% each, a maximum total yield of 0.90 * 0.90 * 0.35 *0.90 * 0.90 = 23 mol % is expected to be obtained referred to the long chain moiety (1 ,12 diamine in this case). Actual preparation of compounds of entries 1-41 and 43 to 57 of Table 5 in solid phase

[0343] In practice, synthesis steps on solid phase were carried out to prepare the compounds of entries 1-41 and 43 to 57 in Table 5 (reflected with the general formula AA-(AA)x-NH-(CH2)y- NH2).

[0344] Loading of resin with diamine was performed with 10 equivalents of diamine (to prevent bridging two adjacent functionalized sites with one molecule of diamine). As reuse of the diamine surplus did not work, the maximum obtained yield related to the diamine was 10%. Rest is Standard peptide synthesis, standard cleavage from resin, (all approx. 95%)

[0345] Values of entry 39 are used as illustrative example: a total yield of 44.5% was achieved, taking into account the 10 fold excess used for preparing the resin, isolated yield referred to the long chain moiety (in this case 1 ,12 diamine) is only 4.5 mol %

[0346] Actual preparation of the compound of entry 42 of Table 5 in liquid phase

[0347] Advantageously, for the compounds of entries 42 to 44 of Table 5 it was possible to carry out the synthetic steps in liquid phase with high yields. The compounds of entries 42 to 44 of Table 5 are reflected with the general formula H2N-(CH2)y-C(=O)-AA-(AA)x-OH / NH2

[0348] Synthesis steps to prepare the H2N-(CH2)y-C(=O)-AA-(AA)x-OH / NH2 are illustrated below with the preparation of the compound of entry 42.

[0349] Instead of the above mentioned diamine, an omega amino fatty acid was used. Boc protection, coupling and Boc-deprotection were all performed in polar aprotic solvents without CMR classification like acetone, acetonitrile, dimethylimidazolidone, dimethylpropyleneurea, DMSO, ethylacetate, N-Methyl Pryrrolidine, pyridine, and / or sulfolane, whereafter workup consisted of a simple precipitation after pH adjustment and an isolated yield of more than 90% w / w on a 100g scale was obtained. No further chromatographic purification was required. The total isolated yield obtained was 92% * 89% * 88%= 72 mol % referred to the long chain moiety (in this case, 12 amino lauric acid).

[0350] The compounds of entries 42 to 44, and especially entry 42, of Table 5 are therefore very advantageous as they allow for a more cost efficient manner of preparation. Hence, said compounds are both highly active and allow one to minimize cost in use in the final products.

[0351] Example 6 (Cosmetic composition)

[0352] Table 9 and 10 outline exemplary O / W emulsions, wherein each can be prepared comprising each of the exemplified compounds 1-57. Table 9 Anti-ageing creams Table 10 Facial day cream with SPF

Claims

CLAIMS1 . A compound of formula (I)R1-AA1-AA2-(AA3)n-(AA4)m-(AA5)l-R2 (I), whereinR1 is -H, -CO(CH2)rNH2, -CO(CH2)oCH3, -COphenyl (benzoyl), or -COCH2phenyl, wherein o is 0, 1 , 2 or 3, and r is 7, 8, 9, 10, 11 or 12, more preferably r is 7, 8, 9, 10 or 11 , most preferably r is 11 ; andR2is -NH2, -OH, -OCH3, -OCH2CH3, -NH-(CH2)SNH2, — NH-(CH2)I2NHCOCH3,-NH-(CH2)IICONH2>orwherein s is an integer from 6 to 12; andAA1, AA2, AA3IAA4 and AAsare independently from each other an amino acid (AA), wherein n, m and I are independently of each other either 0 or 1.

2. The compound according to claim 1 , characterized in having the formula (la)RI-AAI-AA2-R2(la), whereinR1 is -H, -CO(CH2)rNH2, or -CO(CH2)oCH3, -COphenyl (benzoyl), or -COCH2phenyl, wherein o is 0, 1 or 2 and r is 9, 10 or 11 ;R2is -NH2, -NH-(CH2)SNH2, -NH-(CH2)I2NHCOCH3, -NH-(CH2)IICONH2, orwherein s is an integer from 6 to 12;AA1 is chosen from the group of Ala, p-Ala, Asp, Gly, Lys, Phe, Ser, Trp, Tyr, and Vai; andAA2is chosen from the group of Ala, p-Ala, Asn, Gin, Gly, His, Leu, lie, Lys, Phe, Ser, Tyr, and VaL3. The compound according to claim 1 or claim 2, whereinRi is -CO(CH2)rNH2, wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and / orR2is -NH-(CH2)SNH2or -NH-(CH2)12NHCOCH3, wherein s is 6, 7, 8, 9, 10, 11 or 12, more preferably wherein s is 8, 9, 10, 11 or 12, most preferably wherein s is 12.

4. The compound according to claim 1 , characterized in having the formula (lb)RI-AAI-AA2-AA3-R2(lb), whereinRi is -H or -CO(CH2)rNH2, wherein r is 9, 10 or 11 ;R2is -NH2or -NH-(CH2)SNH2, wherein s is an integer from 8 to 12;AAi is chosen from the group of Gly and Phe;AA2is chosen from the group of Gly and Phe; andAA3is chosen from the group of Gly and Phe.

5. The compound according to claim 1 , characterized in having the formula (Ic)Ri-AA-i-AA2-AA3-AA4-R2(IC), whereinRi is -H or -CO(CH2)rNH2, wherein r is 9, 10 or 11 ;R2is -NH2or -NH-(CH2)SNH2, wherein s is an integer from 8 to 12;AAi is chosen from the group consisting of Ala, Asp, Asn, Glu, Lys, Phe and Tyr;AA2is chosen from the group consisting of Asn, Gly, Leu, Tyr and Vai;AA3is chosen from the group consisting of Asn, Leu, Lys, Phe, Tyr and Vai; andAA4 is chosen from the group consisting of Ala, Asp, Glu, Gly, Lys and Tyr.

6. The compound according to claim 1 , characterized in having the formula (Id)RI-AAI-AA2-AA3-AA4- AA5-R2(Id), whereinRi is -H, -CO(CH2)rNH2, wherein r is 9, 10 or 11 ;R2is -NH2or -NH-(CH2)SNH2, wherein s is an integer from 8 to 12;AAi is chosen from the group of Glu and Phe;AA2is chosen from the group of Gly and Thr;AA3is chosen from the group of Phe and Thr;AA4 is chosen from the group Phe and Thr; and AA5is chosen from the group of Glu and Gly.

7. The compound according to claim 1 , wherein the compound is selected from the group consisting of compounds of the formulaeR1-AA1-AA2-R2 (la) orR1-AA1-AA2-AA3-R2 (lb),- wherein R1 is “NH2- (CH2)r- CO- “, wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and- wherein preferably R2 is “-NH2”; and- wherein AA1, AA2and AA3are independently from each other an amino acid (AA).

8. The compound according to anyone of claims 1 to 7, wherein at least one of respectively AA1, AA2, AA3, AA4, and AA5is Phe, and more preferably wherein at least two of respectively AA1, AA2, AA3, AA4, and AA5 are Phe.

9. The compound according to claim 1 , claim 2, claim 3, claim 7 or claim 8, wherein the compound isH2N-(CH2)ii-CO-Phe-Phe-NH2 ; orH2N-(CH2)ii-CO-Gly-Phe-NH2; orH2N-(CH2)ii-CO-Phe-Gly-NH2; or a mixture thereof ; or a salt of any of these.

10. The compound according to anyone of claims 1 to 9, wherein the compound is in the form of a mono- or polyvalent, homogenous or mixed salt.11 . The compound according any one of claims 1 to 10, wherein the compound is present as a salt with an inorganic and / or organic acids, preferably a salt with acetic acid, hydrochloric acid and / or trifluoroacetic acid.

12. A cosmetic composition comprising at least one compound according to anyone of claim 1 to 11 and a cosmetically acceptable carrier.

13. The cosmetic composition according to claim 12, wherein the total amount of the at least one compound according to anyone of claim 1 to 11 is selected in the range of 0.5 and 5000 ppm (w / w), preferably in the range of 1 and 1000 ppm (w / w), most preferably in the range of 1 to 100 ppm (w / w), based on the total weight of the cosmetic composition.

14. The cosmetic composition according to claim 12 or 13, wherein the composition is in the form of an emulsion, a cream, a wax, a paste, an ointment, a lotion, a milk, a mousse, a gel, an oil, a tonic, a face mask or a plaster for transdermal application or a spray.

15. The cosmetic composition according to anyone of claims 12 to 14, wherein the composition further comprises at least one active selected from the group consisting of desquamation actives, anti-acne agents, vitamin B3 compounds, retinoids, di-, tri-, tetra- and pentapeptides and derivatives thereof, hydroxy acids, radical scavengers, soothing agents, skin-tanning actives, skin-whitening agents, anti-cellulite agents, flavonoids, antimicrobial actives, skin-healing agents, antifungal actives, sunscreens, conditioning agents, farnesol, phytantriol, and mixtures thereof.

16. Use of a compound according to anyone of claims 1 to 11 or a cosmetic composition according to any one of claims 12 to 15 for the prevention and / or treatment of skin ageing.

17. The use according to claim 16, wherein the prevention and / or treatment of skin ageing is the prevention and / or treatment of mimic and / or age-related wrinkles in human skin.

18. A method forthe prevention and / ortreatment of skin ageing, preferably of mimic and / or age-related wrinkles in human skin, said method comprising applying a cosmetic composition according to anyone of claims claim 12 to 15 to the affected area.

19. Use of at least one compound according to any one of claims 1 to 11 for the preparation of a cosmetic composition, preferably a skin care product, more preferably for the prevention and / or treatment of skin ageing.

20. A method for the production of a compound according to any one of claims 1 to 11-wherein Ri is “NH2- (CH2)r- CO- wherein r is 7, 8, 9, 10, 11 or 12, more preferably wherein r is 7, 8, 9, 10 or 11 , still more preferably wherein r is 8, 9, 10 or 11 , yet more preferably wherein r is 9, 10 or 11 , most preferably wherein r is 11 ; and- wherein preferably R2 is “-NH2”, wherein the production is at least partly carried out in a liquid phase and / or wherein the method comprises a precipitation of the compound from a liquid phase.