Dimeric compounds attachable to keratinous tissues

Abstract

The present disclosure relates to novel compounds, processes and useful intermediates for preparing and using them, to topical compositions comprising them and to various uses of these compounds. These compounds are based on seco-iridoid-based derivatives and can be utilized to reliably and efficiently graft amino-functionalized compounds such as hyaluronic acid onto keratinous tissues such as skin or hair in a fast and irreversible manner. The key compounds comprise two 3,4-saturated 2H-pyran moieties which are linked to each other. The general concept is illustrated below using a genipin derivative as an example: Formula (I) In a first step, the genipin derivative is linked to the amino group of the active ingredient by reaction of one of the two 3,4-saturated 2H-pyran moieties: Formula (II) In a second step, the resulting compound is then reacted with the amino groups of the keratinous tissue to attach the active ingredient to the keratinous tissue: Formula (III)

Description

[0001] DIMERIC COMPOUNDS ATTACHABLE TO KERATINOUS TISSUES

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims benefit from the European Patent Applications Nos. EP24219629.3, 24219630.1, 24219631.9, and 24219632.7, all titled: “Compounds attachable to keratinous tissues” and all filed on December 12, 2024, their content being incorporated herein in their entirety by reference thereto; as well as the benefit of the European Patent Applications EP25177118.4, and EP25194313.0, both titled: “Compounds attachable to keratinous tissues”, filed on May 16, 2025, their content also being incorporated herein in their entirety by reference thereto. The contents of disclosure of the PCT applications filed by the present applicant on the same day with the Canadian Patent Office having the titles “Bicyclic compounds attachable to keratinous tissues”, “1,5-Dicarbonylic compounds attachable to keratinous tissues”, “Derivatives of elenolic acid attachable to keratinous tissues”, “Insect repellants attachable to keratinous tissues” and “Retinal derivatives attachable to keratinous tissues” are also being incorporated herein in their entirety by reference thereto.

[0004] TECHNICAL FIELD

[0005] The present disclosure relates to seco-iridoid-based compounds which can be utilized to reliably and efficiently graft amine-functionalized compounds onto keratinous tissues such as skin or hair in a fast and irreversible manner. In many instances, the seco-iridoid-based compounds do not noticeably add a color of their own, i.e. the amine-functionalized compounds can be unobtrusively linked to skin and hair. The seco-iridoid-based compounds are, in particular, derivatives of genipin. The disclosure relates to the compounds as such, to topical compositions comprising these compounds and to various methods and applications for these compounds. The present disclosure also relates to new genipin-based intermediates which are particularly useful in efficiently preparing the aforementioned compounds. BACKGROUND

[0006] Genipin is the naturally occurring compound methyl (1R,4aS,7aS)-1-hydroxy-7-(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (CAS RN. 6902-77-8). It has the following structure, and for the purposes of the present disclosure, the following ring atom numbering will be used:

[0007]

[0008] Genipin can be coupled to keratinous tissues such as skin and hair. For instance, keratin in skin comprises lysine amino acids having aliphatic amino side chains. These amino side chains react with genipin according to the below representative reaction scheme:

[0009] R = lysine

[0010]

[0011] When bound to skin, genipin develops an intense blue color. For this reason, genipin is used as a colorant in semi-permanent inks.

[0012] WO 2023 / 102652 Al discloses that genipin and related seco-iridoids and iridoids can be hydrogenated to provide compounds which bind to skin without adding color of their own. The publication is incorporated herein in its entirety by reference thereto.

[0013] In their extensive research regarding genipin chemistry, the present inventors have further found that a broad range of synthetic 3,4-saturated 2H-pyran derivatives can be reliably and efficiently coupled to keratinous tissues such as skin and hair. This robust coupling chemistry can be attributed to the 3,4-saturated 2H-pyran moiety of genipin and is largely unaffected by the further substitution of the 3,4-saturated 2H-pyran moiety. This finding is further supported in the literature which describes that e.g. oleuropein and aucubin activated by P-glucosidase have very strong protein-denaturing, protein-crosslinking, and amino acid-alkylating activities, see Konno et al., PNAS, 1999, 96 (16) 9159-9164. Deglycosylated oleuropein (also called oleuropein aglycone) and deglycosylated aucubin have the following structures, all comprising 3,4-saturated 2H-pyran moieties:

[0014] OH

[0015]

[0016] Regarded in isolation, the aforementioned 3,4-saturated 2H-pyran moiety is a derivative of, in IUPAC nomenclature, a 3,4-dihydro-2H-pyran moiety. When referring to the atoms of the 3,4-saturated 2H-pyran moieties, the following ring numbering will be used throughout the present disclosure.

[0017] 4

[0018]

[0019] The present inventors have found that it is the 2-hydroxy-3,4-saturated 2H-pyran moiety itself which provides the robust coupling to keratinous tissues. This finding can be rationalized when considering the coupling mechanism of this moiety. This will in the following be explained using genipin as an example. Genipin exists in a number of tautomers, including the ring-opened 1,5-dialdehydic tautomer which has some similarity to the well-known cross-linking agent glutaraldehyde:

[0020]

[0021] Ring-open dialdehydic tautomer Glutaraldehyde Like glutaraldehyde, genipin can be coupled to keratinous tissues. For instance, keratin in skin comprises lysines having aliphatic amino side chains. These amino side chains react with genipin according to the below representative reaction scheme:

[0022] R - lysine

[0023]

[0024] The crosslinking reaction of genipin can theoretically proceed by a number of reaction pathways. A mechanistic study by Adamo et al., RSC Adv., 2014, 4, 11029, concluded that the predominant reaction pathway proceeds via the more reactive ring-opened 1,5 -dial dehy die tautomer of genipin:

[0025]

[0026] R = lysine The coupling to keratinous tissues is also irreversible due to the high stability of the generated 1,4-dihydropyridine moiety and due to fact that its formation involves the elimination of two equivalents of water.

[0027] Other 3,4-saturated 2H-pyran derivatives are also subject to the aforementioned ring-opening tautomerism and the reactive ring-opened 1,5-dialdehydic tautomers readily undergo the same coupling reaction as genipin. This explains why structurally very diverse 3,4-saturated 2H-pyran derivatives can bind to keratinous tissues. Utilizing the robustness of this coupling chemistry, the present inventors have made available a reliable and effective platform for topically coupling a very diverse range of active ingredients including, for instance, humectants, insect repellents and pharmaceuticals, to keratinous tissues such as skin or hair. This is the subject-matter of WO 2024 / 250111 Al and WO 2024 / 250112 Al which are incorporated herein in their entirety by reference thereto. A representative example of how an active ingredient is attached to keratinous tissue via such an anchoring compound is shown below:

[0028]

[0029] R moiety representing the active ingredient

[0030] The broken bond indicates attachment to the keratinous tissue

[0031] Typically, as one of the last steps in the synthesis, the active ingredient is coupled to the 3,4-saturated 2H-pyran anchoring moiety. However, in some cases, the active ingredient may comprise functional groups which are interfering with the anchoring moiety. For instance, in case the active ingredient is functionalized with an amino group, it is necessary to protect the hemiacetal of the 4-saturated 2H-pyran moiety such that that the amine-functionalized compound does not competitively react with the hemiacetal group instead of the functional group foreseen for coupling the amine-functionalized active ingredient to the anchoring moiety:

[0032]

[0033] R = amine-functionalized moiety representing the active ingredient

[0034] While protecting the hemiacetal group prior to linking the active ingredient to the anchoring moiety is a feasible strategy, the present inventors have found that deprotecting the hemiacetal is often proceeding sluggishly and / or in low yields. This is inefficient since the deprotecting step is one of the final reaction steps and, thus, low yields in such a step substantially reduce the overall efficiency of the synthesis.

[0035] While strategies for chemo-selectively coupling functional groups are generally available, their practical implementation is often demanding and there is no literature precedence for genipin-like compounds. Moreover, the obtained chemo-selectivity is usually not 100%, i.e. sideproducts are obtained and further purification steps are required. These purification steps may also be demanding, for instance for polymers and, in particular, for water-soluble polymers such as hyaluronic acid, and for water-soluble active ingredients.

[0036] Finally, the aforementioned issue of a sluggishly proceeding and low-yielding deprotecting step is of general relevance, and a synthetical approach that reduces or avoids the necessity for protecting groups would be desirable.

[0037] SUMMARY OF THE INVENTION

[0038] In a first aspect, the present disclosure relates to a compound comprising two 3,4-saturated 2H-pyran moieties. The first 3,4-saturated 2H-pyran moiety is according to formula (la) and the second 3,4-saturated 2H-pyran moiety is according to formula (lb),

[0039]

[0040] (la) According to the present disclosure, this compound is intended as an anchor for coupling the active ingredient to keratinous tissues such as skin or hair. The moiety according to formula (la) is intended to couple to the amine-functionalized active ingredient. The moiety according to formula (lb) is intended to couple to the keratinous tissues. The moieties according to formulae (la) and (lb) are linked to each other, i.e. when the moiety according to formula (la) has coupled to the amine-functionalized active ingredient and when the moiety according to formula (lb) has coupled to the keratinous tissue, the active ingredient is anchored to the keratinous tissue. Returning to the definition of the individual substituents of the formulae (la) and (lb), at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 and at least one of Li'-Ar, Ly-Ay, L3-A3', L4-A4', Ls'-As', Lg'-Ag' and L7-A7' jointly represent a bridging linker group LBRIDGE which is covalently binding the moiety according to formula (la) to the moiety according to formula (lb). LBRIDGE is not particularly limited and further examples will be provided below. The remainder of substituents in formulae (la) and (lb) represent, each independently from the others:

[0041] Li, L2, L3, L4, L5, Lg, L7, absent or a linker group

[0042] Lr, L2', L3', L4', L5', Lg' and L7'

[0043] Ai, Ar, A4, A4', As and As' hydrogen, a C1-C30 moiety, hydroxyl, amino, or a halogen

[0044] A2, A2', A3, and A3' as for Ai or L2-A2 and L3-A3 jointly represent oxo;

[0045] Ag, Ag', A7 and A7' hydrogen or a C1-C30 moiety;

[0046] R1and R2hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

[0047]

[0048] The compound according to this first aspect may be provided as such or as a tautomer and / or as a pharmaceutically acceptable salt thereof.

[0049] In a second aspect, the present disclosure relates to a compound for covalently binding an active ingredient to skin and / or hair, wherein the compound comprises a 3,4-saturated 2H-pyran moiety which is defined as indicated for formula (lb) in the first aspect. The compound according to this second aspect further comprises a moiety according to formula (Ic) or (Id) which comprises the active ingredient,

[0050]

[0051] (Ic) (Id)

[0052] The active ingredient is not particularly limited, but is advantageously selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a color-imparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair. The compound may be provided as such or as a tautomer and / or a pharmaceutically acceptable salt thereof. The compound of this second aspect is otherwise analogous to the anchor compound provided in the first aspect, except that an active ingredient comprising (or being linked to) an amino group has been reacted with one of its 3,4-saturated 2H-pyran moieties yielding a dihydropyridine derivative according to formula (Ic) or a pyridinium derivative according to formula (Id). Accordingly, the definition of the substituents in the formulae (Ic) and (Id) is analogous to the definitions of the substituents in formula (la). More specifically, at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag, and L7-A7 and at least one of Lr-Ar, Ly-Ay, Ls'-As', L4'-A4', Lg'-Ag' and L7-A7' jointly represent a bridging linker group LBRIDGE’ which is covalently binding the moiety of formula (Ic) or (Id) to the moiety of formula (lb). LBRIDGE’ is not particularly limited and is in particular identical to LBRIDGE. LS- represents a linker group or is absent. R represents the active ingredient a) as such, or b) as a precursor thereof, in which case the linker group Ls- is present and cleavable to release the active ingredient from the compound after the application of the compound to the skin and / or the hair. The remainder of the substituents is defined as indicated for formula (la) in the first aspect.

[0053] In a third aspect, the present disclosure relates to a process of preparing a compound according to the second aspect. The process comprises coupling a compound according to the first aspect and an active ingredient comprising an amino group, wherein the process comprises the following steps: a) mixing the compound according to the first aspect in one or more solvents to obtain a reaction mixture; b) agitating the reaction mixture and bringing the active ingredient into reactive contact with the compound according to the first aspect in said reaction mixture such that the compound according to the first aspect is present in stoichiometric excess with respect to the active ingredient until substantially all or all of the amino groups of the active ingredient have reacted with the compound according to the first aspect or until a reagent is added which terminates the coupling reaction between the active ingredient and the compound according to the first aspect in the reaction mixture.

[0054] In a related fourth aspect, the present disclosure provides a process of preparing a compound comprising a 3,4-saturated 2H-pyran moiety according to formula (le),

[0055]

[0056] or a tautomer and / or a pharmaceutically acceptable salt thereof, for covalently binding a water-soluble polymer to skin and / or hair; wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 represents LFG-PWS, wherein Pws represents the water-soluble polymer and LFG represents a linker group which binds the water-soluble polymer to the 3,4-saturated 2H-pyran moiety; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing LFG-PWS is defined as indicated for formula (lb) in the first aspect; the process comprising reacting: i) a precursor of the water-soluble polymer comprising a first functional group with ii) a precursor compound comprising a second functional group and a 3,4-saturated 2H-pyran moiety, such that the first and second functional groups generate the linker group LFG; wherein the precursor compound is represented by the following formula (If),

[0057] / A1

[0058] A2-L2lr1

[0059] A3-L3VYL6-A6

[0060] A4 - L4 7X^,0

[0061] A5-L5b o— R1

[0062] Ly

[0063] SA7

[0064]

[0065] (If)

[0066] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 represents a linker group comprising the second functional group; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 not representing the linker group comprising the second functional group is defined as indicated for formula (lb) in the first aspect; and wherein the first and second functional groups are more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety of both the compound according to formula (le) and the precursor compound according to formula (If). In a fifth aspect, the present disclosure provides a topical composition comprising a topically acceptable excipient and a compound according to formula (le), or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein the compound is obtainable by carrying out the process of the fourth aspect and wherein the topical composition comprises residual educts and / or one or more further reaction products obtainable by carrying out said process. Related to this, there is also provided a compound comprising a 3,4-saturated 2H-pyran moiety according to formula (le),

[0067]

[0068] or a tautomer and / or a pharmaceutically acceptable salt thereof; for covalently binding a water-soluble polymer to skin and / or hair; wherein one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 represents LFG-PWS, wherein Pws represents the water-soluble polymer and LFG represents a linker group which binds the water-soluble polymer to the 3,4-saturated 2H-pyran moiety; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing LFG-PWS is defined as indicated for formula (lb) in the first aspect; wherein LFG comprises one of the moieties shown in Figure 5; and wherein the wavy bonds represent bonds directly or indirectly connecting to the water-soluble polymer or to the remainder of the moiety of formula (le) with the proviso that, in case two wavy bonds are attached to N, none of them connects to hydrogen.

[0069] In a sixth aspect, the present disclosure provides intermediates which are particularly useful as intermediates in the synthesis of compounds according to the first to fifth aspects. Accordingly, in a sixth aspect, there is provided a compound of formula (XV),

[0070]

[0071] wherein Bi represents C(=O)Z1, C(=S) Z1, CH(=O), or an acetal or hemiacetal thereof; CH2-Z2; or Z2; wherein Z1represents -OH, -SH or -NH2; and wherein Z2represents OH, SH, F, Cl, Br, I, N3; or a tautomer and / or a salt thereof.

[0072] The compounds of the sixth aspect may also be used to efficiently prepare genipin derivatives carrying an active ingredient. Accordingly, in a seventh aspect, there is provided a compound comprising a 3,4-saturated 2H-pyran moiety of formula (XVI),

[0073]

[0074] A20—L20—B2(XVI),

[0075] or a tautomer and / or a pharmaceutically acceptable salt thereof; for covalently binding an active ingredient to skin and / or hair; wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, UVA- and / or UVB-absorbing moiety, a color-imparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair; wherein B2 represents CH2, C(=O), (C=S), (C=NRc), or a C1-C4 acetal moiety selected from the group consisting of an 0,0-acetal, an O, N-acetal, an O, S-acetal, an N, N-acetal, an S, N-acetal, and an S, S-acetal, wherein the C1-C4 acetal moiety is attached to the adjacent methylene group of the remainder of the 3,4-saturated 2H-pyran moiety by a carbon atom, wherein Rcrepresents H, C1-C6alkyl or phenyl, wherein L20 is absent or represents a linker that is attached to B2 by O, N, C, S, B or P, more specifically by O, N, C or S, and in particular by O, N or S; and wherein A20 represents the active ingredient a) as such, or b) as a precursor thereof, wherein the compound of formula (XVI) is cleavable to release the active ingredient from the precursor after the application of the compound to the skin and / or the hair. In an eighth aspect, the present disclosure provides a topical composition comprising a compound of the present disclosure, wherein the topical composition further comprises an excipient that is suitable for topical administration.

[0076] In a ninth aspect, the present disclosure provides a process for preparing a topical composition comprising the compounds of the present disclosure, in particular the compounds of the second, sixth and seventh aspect, wherein the topical composition further comprises an excipient that is suitable for topical administration, the process comprising providing said compound and mixing it with an excipient suitable for topical administration.

[0077] In a tenth aspect, the present disclosure relates to the use of a compound or topical composition according to any of the aspects and / or embodiments disclosed herein for covalently binding an active ingredient to keratinous tissue, in particular to skin and / or hair.

[0078] In an eleventh aspect, the present disclosure provides the compounds and / or topical compositions disclosed herein for use in medicine, in particular for treating a skin-associated disease and / or a hair-associated disease.

[0079] DESCRIPTION OF DRAWINGS

[0080] Fig. 1 to 10 disclose synthetical approaches to compounds according to the present disclosure.

[0081] Fig. 11 discloses the UV / Vis spectrum of the dimer compound, the dimer compound linked to an amino-functionalized compound and said dimer compound further coupled to lysine as a model for keratinous tissue.

[0082] Fig. 12 shows the reaction scheme of the dimer compound (1) with hyaluronic acid.

[0083] DETAILED DESCRIPTION

[0084] The present inventors have developed novel compounds and processes for coupling 3,4- saturated 2H-pyran anchoring moieties to synthetically challenging amino group-containing active ingredients such as amino-functionalized hyaluronic acid. These compounds and processes completely or at least largely avoid the use of protecting groups, in particular in the last steps of the synthesis.

[0085] The present inventors have further identified novel intermediates in the synthesis of 3,4-saturated 2H-pyran anchoring moieties which can be prepared from the naturally occurring genipin without using protecting groups. These intermediates are particularly useful in the preparation of the aforementioned anchoring moieties for the synthetically challenging amino group-containing active ingredients since the overall efficiency of the synthesis is further increased. However, they will also have utility in the preparation of other 3,4-saturated 2H-pyran anchoring moieties.

[0086] Accordingly, in a first aspect, the present disclosure relates to a compound comprising two 3,4-saturated 2H-pyran moieties. The first 3,4-saturated 2H-pyran moiety is according to formula (la) and the second 3,4-saturated 2H-pyran moiety is according to formula (Ib),

[0087]

[0088] (la) (Ib)

[0089] According to the present disclosure, this compound is intended as an anchor for coupling the active ingredient to keratinous tissues such as skin or hair. The moiety according to formula (la) is intended to couple to the amine-functionalized active ingredient. The moiety according to formula (Ib) is intended to couple to the keratinous tissues. The moieties according to formulae (la) and (Ib) are linked to each other, i.e. when the moiety according to formula (la) has coupled to the amine-functionalized active ingredient and when the moiety according to formula (Ib) has coupled to the keratinous tissue, the active ingredient is anchored to the keratinous tissue. The general concept is illustrated below using a genipin derivative as both the moiety according to formula (la) and the moiety according to formula (lb):

[0090] In a first step, the aforementioned anchor is provided, both moieties according to formula (la) and (lb) are based on the same hydrogenated genipin derivative and are linked to each other via a spacer (labelled “L”).

[0091]

[0092] The anchor is then linked to the amino group of the active ingredient by reaction of one of the two 3,4-saturated 2H-pyran moieties:

[0093] O - L - O

[0094]

[0095] In this form, the active ingredient can optionally be formulated and stored until it is applied to the keratinous tissue, e.g. skin. Once applied, it will react with the amino groups of the keratinous tissue and attach the active ingredient to the keratinous tissue:

[0096]

[0097] As described, the moieties according to formulae (la) and (lb) are linked to each other.

[0098] Returning to the definition of the individual substituents of the formulae (la) and (lb), at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Ls-As and L7-A7 and at least one of Lr-Ar, Ly-Ay, Ls'-As', L4'-A4', LS'-AS', Lg'-Ag' and L7-A7' jointly represent a bridging linker group LBRIDGE which is covalently binding the moiety according to formula (la) to the moiety according to formula (lb). LBRIDGE is not particularly limited and further examples will be provided below. For the sake of clarity, the above-depicted reaction scheme is referring to a “spacer L” which is used for illustrative purposes only and which is not to be confused with the bridging linker group LBRIDGE as referred to in the first aspect. LBRIDGE is defined with reference to the 3,4-saturated 2H-pyran moi eties proper, i.e. in the above illustrative example LBRIDGE is jointly represented by the combination of substituents L3-A3' and L4-A4' in formula (la) and the combination of substituents L3-A3 and L4-A4 in formula (lb). In other words, the linker group LBRIDGE is represented by cyclopentanetriyl-CFL-CFh-CCh-L-ChC-CFh-CFh-cyclopentane-triyl.

[0099] The remainder of substituents in formulae (la) and (lb) represent, each independently from the others:

[0100] Li, L2, L3, L4, L5, Lg, L7, absent or a linker group

[0101] Lr, L2', L3', L4', Ls', Lg' and L7'

[0102] Ai, Ar, A4, A4', As and As' hydrogen, a C1-C30 moiety, hydroxyl, amino, or a halogen

[0103] A2, A2', A3, and A3' as for Ai or L2-A2 and L3-A3 jointly represent oxo;

[0104] Ag, Ag', A7 and A7' hydrogen or a C1-C30 moiety;

[0105] R1and R2hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

[0106]

[0107] The compound according to this first aspect may be provided as such or as a tautomer and / or as a pharmaceutically acceptable salt thereof. In a second aspect, the present disclosure relates to a compound for covalently binding an active ingredient to skin and / or hair, wherein the compound comprises a 3,4-saturated 2H-pyran moiety which is defined as indicated for formula (lb) in the first aspect.

[0108] The compound according to this second aspect further comprises a moiety according to formula (Ic) or (Id) which comprises the active ingredient,

[0109]

[0110] (Ic) (Id)

[0111] The active ingredient is not particularly limited, but is advantageously selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a color-imparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair. The compound may be provided as such or as a tautomer and / or a pharmaceutically acceptable salt thereof.

[0112] The compound of this second aspect is otherwise analogous to the anchor compound provided in the first aspect, except that an active ingredient comprising (or being linked to) an amino group has been reacted with one of its 3,4-saturated 2H-pyran moieties yielding a dihydropyridine derivative according to formula (Ic) or a pyridinium derivative according to formula (Id). Accordingly, the definition of the substituents in the formulae (Ic) and (Id) is analogous to the definitions of the substituents in formula (la). More specifically, at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag, and L7-A7 and at least one of Lr-Ar, L2-A2', L3-A3', L4-A4', Lg'-Ag' and L7-A7' jointly represent a bridging linker group LBRIDGE’ which is covalently binding the moiety of formula (Ic) or (Id) to the moiety of formula (lb). LBRIDGE’ is not particularly limited and is in particular identical to LBRIDGE and / or as defined for LBRIDGE in the further embodiments that will be provided below.

[0113] Ls- represents a linker group or is absent. R represents the active ingredient a) as such, or b) as a precursor thereof, in which case the linker group Ls- is present and cleavable to release the active ingredient from the compound after the application of the compound to the skin and / or the hair. The remainder of the substituents is defined as indicated for formula (la) in the first aspect of the present disclosure.

[0114] If the active ingredient comprises an amino group, it may be directly attached to the moiety of formula (la). In this case, Ls- may be absent. If the active ingredient does not comprise an amino group, it may be indirectly connected to the moiety of formula (la) by attaching a connecting group to the active ingredient which comprises an amino group. After connecting the active ingredient to the moiety of formula (la), said connecting group then constitutes Ls-. Accordingly, in both formulae (Ic) and (Id), Ls- is either absent or represents a linker group.

[0115] It should be understood that the R representing the active ingredient as such according to the above option a) means that the moiety representing the active ingredient is capable of providing its effect or activity while being bound to the keratinous tissue such as skin and / or hair (more precisely while being attached to the remainder of the compound in the form as it is covalently bound to the tissue). As an example, a hyaluronic acid-based skin moisturizer is able to provide its moisturizing effect while being bound to the skin since the polar polymer provides its waterretaining effect irrespective of whether the hyaluronic acid is bound to the skin or not. However, this should not be understood as excluding the possibility that the active ingredient is chemically modified while being bound to skin. For instance, the hyaluronic acid may be partially hydrolyzed to liberate low-molecular fragments of hyaluronic acid which may penetrate deeper into the skin to provide a further moisturizing or metabolic effect in deeper skin layers.

[0116] The term “precursor” in the above option b) is to be given its ordinary meaning in the art as a moiety that participates in a chemical reaction that produces another compound (namely the active ingredient) that is no longer part of the compound of the second aspect in the form as it is covalently bound to the keratinous tissue such as skin and / or hair. Alternative terms include e.g. the term “prodrug” in case the active ingredient is a pharmaceutical. It should also be understood that the precursor will be cleaved to the corresponding active ingredient. For brevity, the precursor corresponding to an active ingredient will in the following also be referred to as “the corresponding precursor thereof’ or simply “precursor”. However, it should be understood that, unless specified otherwise, the term “precursor” is meant to refer to the precursor corresponding to the active ingredient which is mentioned in the respective context. Moreover, it should be understood that the compound comprising a precursor of an active ingredient means that the active ingredient is providing its effect or activity after its corresponding active ingredient has been cleaved from the remainder of the compound in the form as it is covalently bound to skin and / or hair. As an example, a precursor of a fragrance will provide its olfactory effect only after being released from the skin or hair. However, this should not be construed as excluding the possibility that a precursor may already provide a reduced effect or activity or an otherwise altered effect or activity before being cleaved from the remainder of the compound in the form as it is covalently bound to skin and / or hair.

[0117] In the first and second aspects, R1and R2represent, independently from each other, hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair. The primary purpose of providing a protective group hydrolysable under physiological conditions is to increase the storage stability of the compound, at least in a neutral or slightly alkaline formulation, more specifically in a formulation having a pH of 7.0 or higher, of 7.5 or higher, of 8.0 or higher or of 8.5 or higher. However, once applied to the skin or hair with their lower pH environment, R' / R2should be hydrolysed to the more reactive hemi-acetal which then binds to the skin and / or the hair. When referring in this context to “physiological conditions” it should be understood that this refers to the pH conditions encountered at the locus where the compound according to the second aspect is supposed to bind to (skin or hair). Moreover, it should be understood that the hydrolysis under physiological conditions takes place in an amino-acid rich environment such as collagen which is the predominant skin protein. Collagen comprises a complex mixture of the following amino acids: alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine. These amino-acids, and in particular those with nucleophilic side chains such as lysine, will further facilitate hydrolysis.

[0118] Accordingly, a group qualifies as “protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair”, if the compound comprising the group in question as R1or R2hydrolyses to the corresponding hemi-acetal (and its tautomers) by more than 10 mol%, more specifically by more than 50 mol%, and in particular by more than 80 mol%, when incubating 0.1 mmol / mL of the compound for 24 hours at 37°C in any one of the following three solutions: a) a phosphate buffer solution, pH 5.5; an aqueous solution of bovine collagen type I (1 mg / mL, adjusted to pH 5.5); and c) an aqueous solution of lysine (1 mg / mL, adjusted to pH 5.5 using a phosphate buffer solution). The conversion can be monitored by any suitable means, including nuclear magnetic resonance spectroscopy (NMR), high-performance liquid chromatography (HPLC), optionally coupled to mass spectrometer (MS) or a UV / vis. The aforementioned conversion ratio in mol% can also be determined using any suitable means, including the aforementioned methods. Additionally or alternatively, a group qualifies as “protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair” if the compound cannot be comprehensively washed off from a sample of (explanted) porcine skin or from a hair sample by water, soap, and / or isopropanol after incubating the compound (or a topical composition comprising the compound) on the porcine skin sample or on a hair sample at 37°C for 24 hours.

[0119] As said, the compound according to the second aspect is intended to be topically applied to skin and / or hair. As used herein, the term “skin” refers to skin, including lips and the oral cavity, and skin appendages. Skin appendages are epidermal and dermal-derived components of the skin and include nails, sweat glands, and sebaceous glands. As used herein, the term “hair” refers to hair and other fibrous keratinous materials such as eyebrows and eye lashes. In some embodiments, the skin is mammalian skin and in particular human skin. In some embodiments, the hair is mammalian hair and in particular human hair.

[0120] As also said, the compound according to the second aspect, once it has been topically applied to skin and / or hair, can covalently bind to the skin and / or the hair by the reaction of its 3,4-saturated 2H-pyran moiety with amino groups which are present on the skin and / or the hair. Whether the compound has covalently bound to the skin and / or the hair by reaction of its 3,4-saturated 2H-pyran moiety can be determined by any suitable means. For instance, if the compound cannot be comprehensively washed off from an (explanted) sample of porcine skin or from a hair sample by water, soap, and / or isopropanol after incubating the compound (or a topical composition comprising said compound) on the respective porcine skin or hair sample at 37°C for 24 hours, the compound can be considered to have covalently bound by reaction of its 3,4-saturated 2H-pyran moiety to skin or hair. Additionally or alternatively, the compound can be considered to achieve this feature if it passes a suitable in-vitro test, in particular placing 0.1 mol / L of the compound in an aqueous or methanolic solution having a pH of about 5.5 and further containing 0.1 mmol / mL lysine at 37°C for 24 hours, wherein the compound passes the test if it is converted by more than 10 mol%, more specifically by more than 50 mol%, and in particular by more than 75 mol%, to its corresponding 1,4-dihydropyridine derivative. The conversion can be monitored by any suitable means, including nuclear magnetic resonance spectroscopy (NMR), high-performance liquid chromatography (HPLC), optionally coupled to mass spectrometer (MS) or a UV / vis detector. The aforementioned conversion ratio in mol% can also be determined using any suitable means, including the aforementioned methods. It should further be understood that the reaction of the compound of the second aspect proceeds via its 3,4-saturated 2H-pyran moiety in its hemiacetal form, i.e. when R1represents hydrogen. Accordingly, the aforementioned in-vitro test may, for those compounds according to the second aspect in which R1does not represent hydrogen, also alternatively be performed with the corresponding derivative in which R1represents hydrogen.

[0121] The term “moisturizer” refers to a compound / moiety which is capable of directly binding water (via hydrogen bonding) in the respective keratinous tissue (skin or hair) or of reducing evaporation of water from the skin. Accordingly, the term encompasses moisturizes, emollients and occlusives as these terms are used and understood in the art.

[0122] The term “pesticide” refers to its common meaning in the art and in particular refers compounds capable of killing, incapacitating, repelling or in any other way ameliorating a risk to mammalian (human) health, comfort or well-being posed by invertebrates, in particular insects.

[0123] The term “skin whitening agent” refers to the common meaning in the art and in particular refers to a compound which is chemically and / or metabolically able to lighten the color tone of the skin. The term “skin whitening agent” does not refer to pigments or dyes or optical brighteners.

[0124] The term “fragrance” refers to the common meaning in the art and in particular refers to a volatile compound which is capable of providing an olfactory impression, in particular an olfactory impression comprising one or more of the seven fundamental odors (floral, fruity, minty, nutty, pungent, sweet, and woody).

[0125] The term “pharmaceutical” refers to the common meaning in the art and in particular refers to a compound capable / intended for use in the diagnosis, cure, mitigation, treatment, therapy, or prevention of a disease in mammals, in particular humans and domestic and farm animals.

[0126] re The term “UVA- and / or UVB-absorbing moiety” refers to the common meaning in the art and in particular refers to a moiety which reduces the amount of UVA- and / or UVB-radiation that can pass through the compound.

[0127] The term “color-imparting moiety” refers to the common meaning in the art and in particular refers to moiety which imparts a color-impression perceivable by the human eye.

[0128] The term “cosmetic hair coating” refers to a compound / moiety which is capable of providing a coating onto hair which provides a cosmetic benefit to the subject. Accordingly, the term encompasses coatings imparting a hair conditioning effect, gloss or shine, an anti-frizz effect, or a reinforcing (styling) effect.

[0129] The term “primer for attaching dyes to the hair” refers to a compound / moiety which provides a functional group to the hair which is suitable for anchoring a colorant (dye or pigment) and / or compounds which can be developed into dyes or pigments. Said anchoring is preferably, but not necessarily, a covalent binding. In other words, the term “primer for attaching dyes to the hair” refers to a compound / moiety comprising a functional group which is suitable for reacting with and in particular suitable to covalently bind to a colorant, or a compound / moiety which can be converted into a colorant by reacting with a color developer.

[0130] In a third aspect, the present disclosure relates to a process of preparing a compound according to the second aspect. The process is generally directed to utilizing an excess amount of the precursor according to the first aspect such that the reaction of only one of the precursor’s two 3,4-saturated 2H-pyran moieties is favored. While other approaches, such as providing the precursor with two 3,4-saturated 2H-pyran moieties of different reactivity towards an amino group, are in principle feasible, the present inventors have found that utilizing an excess amount of the precursor works surprisingly well. Moreover, in many instances, any remaining unreacted precursor can be extracted from the reaction mixture, making the process very efficient since the extracted precursor can be reused in the next reaction batch.

[0131] In more detail, the process comprises coupling a compound according to the first aspect and an active ingredient comprising an amino group, wherein the process comprises the following steps: a) Mixing the compound according to the first aspect in one or more solvents to obtain a reaction mixture; b) agitating the reaction mixture and bringing the active ingredient into reactive contact with the compound according to the first aspect in said reaction mixture such that the compound according to the first aspect is present in stoichiometric excess with respect to the active ingredient until substantially all or all of the amino groups of the active ingredient have reacted with the compound according to the first aspect or until a reagent is added which terminates the coupling reaction between the active ingredient and the compound according to the first aspect in the reaction mixture.

[0132] Specific embodiments of the first three aspects will be described in more detail in the following:

[0133] The compounds of the present disclosure are i.a. defined by reference to combinations of substituents of linkers groups (referenced as Li, Lr, etc.) which are connecting further, typically terminal, substituents (referenced as Ai, Ar, etc.) to a 3,4-saturated 2H-pyrane moiety. It should be understood that, in some embodiments, such a linker can also be absent. In these embodiments, the corresponding other (terminal) substituent is attached to the respective 3,4-saturated 2H-pyran moiety. In other instances, the linker is present and serves to connect the corresponding further (terminal) substituent to the respective 3,4-saturated 2H-pyran moiety. In this case, the linker is attached to the respective 3,4-saturated 2H-pyran moiety and the further (terminal) substituent is attached to linker, i.e. said further (terminal) substituent is merely connected to the respective 3,4-saturated 2H-pyran moiety. In still other instances, two of the linkers of the same respective 3,4-saturated 2H-pyran moiety are jointly representing a cyclic moiety to which the two respective further (terminal) substituents are attached. It should be understood that this means that the linkers and the carbon atoms of the respective 3,4-saturated 2H-pyran moiety j ointly form the cyclic moiety. To give a non-limiting example, in case L3 and L4 in formula (lb) jointly represent a ring, said ring is fused to the respective 3,4-saturated 2H-pyran moiety and the corresponding substituents A3 and A4 are either directly attached to said ring or indirectly connected to said ring via attachment to a further portion of the respective linker L3 or L4 which is, in turn, directly attached to the said ring. To give a more concrete example, L3 and L4 in formula (lb) may jointly represent (together with the two carbon atoms of the 3,4-saturated 2H-pyran moiety to which L3 and L4 are attached) a cyclopentane moiety and A3 may be directly attached to said cyclopentane whereas A4 is indirectly connected to said cyclopentane via a further part of L4 which may be a methylene oxy moiety. In this example, the compound would be represented by the below formula (other substituents are truncated for better readability):

[0134]

[0135] A— O

[0136] It should be understood that the exact position of the other (terminal) substituents (A3 and A4 in the above example) or the position of the remainder of the respective linkers (if present; L3 and L4 in the above example) on the formed cyclic moiety are not particularly limited and can vary. It should also be understood that the formed cyclic moiety can optionally be further substituted and that these optional substituents may also form a further ring (in this case, the cyclic moiety is a bridged bicyclic moiety). More specific examples of such bicyclic moieties will be given further below.

[0137] In the following, the present disclosure will be primarily discussed with reference to the moiety of formula (lb) in order to avoid excessive redundance in the disclosure. However, it should be understood that, unless specifically indicated otherwise, the same disclosure equally but optionally applies to the moieties of formulae (la), (Ic) and (Id), and, vide infra, to the moieties of formulae (le) and (If). With respect to formulae (la), (Ic) and (Id), the corresponding substituents are identified by a prime, i.e. a more specific disclosure regarding to e.g. substituent Li in e.g. formula (lb) equally applies to substituents Lr in formulae (la), (Ic) and (Id).

[0138] In some embodiments, each occurrence of Li to L7 and Lr to L7' which is not a part of LBRIDGE and LBRIDGE’ is, independently from each other, absent or representing an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms. For the sake of avoiding doubt, here and elsewhere in the present disclosure, the reference to “Li to L7” is to be understood as referring to “Li, L2, L3, L4, L5, Lg and L7” and the reference to” Lr to LT” is to be understood as referring to “Lr, L2', L3', L4', Ls-, Lg' and LT” In some embodiments, it may be particularly advantageous that one or more, and in particular all, of the remainder of Li to L7 and Lr to L7' which are not representing a part of LBRIDGE and LBRIDGE’ are, independently for each embodiment, defined as follows: Li is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0139] Lr is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0140] L2 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0141] L2' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0142] L3 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0143] L3' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0144] L4 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0145] L4' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0146] L5 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0147] Ls' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0148] Le is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or Lg' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0149] L7 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0150] L7' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms.

[0151] In some embodiments, Li and Lg are present and form a ring; and / or Li and L3 are present and form a ring; and / or L3 and L4 are present and form a ring; and / or L4 and L7 are present and form a ring; and / or L4 is present and forms a ring with R1. In some embodiments, Lr and Lg- are present and form a ring; and / or Lr and L3' are present and form a ring; and / or L3' and L4' are present and form a ring; and / or L4' and L7' are present and form a ring; and / or L4' is present and forms a ring with R2. It may be particularly advantageous that said ring is a 5-, 6-, 7- or 8-membered ring, more specifically a 5-, 6-, or 7-membered ring, and in particular a 5- or 6-membered ring. As explained above, the aforementioned rings are fused to the respective 3,4-saturated 2H-pyran moiety, i.e. the referenced number of ring atoms includes the respective two carbon atoms that are shared with the 3,4-saturated 2H-pyran moiety. The presence of such rings, more specifically of rings formed by Li and L3, by L3 and L4, and by L4 and L7, and in particular of a ring formed by L3 and L4, restrict the conformational freedom of the ring-opened 1,5-dicarbonyl tautomer and favors the close proximity of the 1,5-dicarbonyl positions, thus, may facilitate the ring-closing reaction to form the 1,4-dihydropyridine that ultimately binds the compound to the keratinous tissue.

[0152] It should be understood that, when referring, here and elsewhere in the present disclosure, to any of Li to L7 and any of Lr and L7' forming (a) ring(s) or being a part of (a) ring(s), or a like language, this / these ring(s) may be optionally further substituted. This applies to all such rings of the present disclosure, irrespective of whether the ring is a hydrocarbon ring, a heterocyclic ring, a (hetero)aromatic ring, a bicyclic ring, a tricyclic ring, a bridged ring, or the like. It should also be understood that these further optional substituents are not particularly limited unless expressly indicated otherwise in a specific embodiment. In some embodiments, said ring is a hydrocarbon ring or a heterocyclic ring comprising one or more heteroatoms selected from O, N and S; more specifically an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, an optionally substituted cycloheptyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, an optionally substituted tetrahydrofuranyl ring or an optionally substituted tetrahydropyranyl ring. In some embodiments, it may be particularly preferred that said ring is a bridged bicyclic ring, more specifically a bicyclic ring having a bridge which comprises one or two bridging atoms; more specifically wherein the bridging atoms are, independently from each other, selected from C, N, O and S, more specifically from C, N and O, and in particular from C and N.

[0153] In particular, said bicyclic ring comprises a methylene or ethylene bridge, more specifically a methylene which is optionally substituted once or twice with a moiety selected, independently from each other, from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, C1-C4-hydroxyalkyl, and C1-C4 alkylsulfonic acid; and in particular wherein the bicyclic ring comprises a methylene bridge which is optionally substituted twice with methyl. Such bicyclic rings are conveniently accessible from the chiral pool of the terpene family, more specifically the pinene family, and are advantageous in that they improve the efficiency of the synthesis by facilitating the stereoselective synthesis of the compounds of the present disclosure, are typically readily available and are in many cases well tolerated by human beings.

[0154] In some embodiments, said bicyclic ring comprises a bridge of the formula -N(-R')-, wherein R' represents H or a C1-C30 moiety, more specifically C1-C12 alkyl, more specifically Ci-Cs alkyl, and in particular C1-C4 alkyl. Such bicyclic rings are accessible from the family of tropinone alkaloids and are advantageous in that they introduce a secondary or tertiary amino functionality in the bicyclic ring which will be protonated under physiological conditions and, thus, can be used to improve the water-solubility of the compound. Moreover, tropinone derivatives are readily available by the Robinson synthesis.

[0155] In some embodiments, said bicyclic ring is further substituted to comprise a further (third) ring which is fused to said bicyclic ring. In some embodiments, it may be particularly advantageous that said further ring is an aliphatic, unsaturated or aromatic hydrocarbon ring, a saturated or unsaturated heterocyclic ring, or a heteroaromatic ring, wherein the heteroatoms of the heterocyclic or heteroaromatic ring are, independently from each other, selected from C, N, O and S, more specifically from C, N and O, and in particular from C and N. Examples of such tricyclic rings are conveniently accessible from e.g. lawsone and lawsone derivatives.

[0156] In some embodiments, the respective two of Ai to A? and Ar to A?' corresponding to the two linker groups of Li to L7 and Lr to L7' which are forming the (bicyclic) ring are attached to said (bicyclic) ring by a bond. For the sake of avoiding doubt, here and elsewhere in the present disclosure, the reference to “Ai to A7” is to be understood as referring to “Ai, A2, A3, A4, As, Ae and A7” and the reference to ”Ar to AT” is to be understood as referring to “Ar, AT, A3', Ar, As', A& and AT”.

[0157] As indicated above, in case two linkers form a ring, a further part of the linker(s) forming said ring can represent a substituent of said ring that then carries the respective moiety Ai to A7 or Ar to A. Concretely, in some embodiments, the respective two of Ai to A7 and Ar to AT corresponding to the two linker groups of Li to L7 and Lr to L7' which are forming the (bicyclic) ring are connected to said (bicyclic) ring by a linker group which is a part of respective linker group Li to L7 and Lr to LT, respectively, which is forming the (bicyclic) ring. Said linker group can alternatively be referred to as a “further linker group” or an “ancillary linker element” of the respective linker group Li to L7 and Lr to L7'.

[0158] Said linker group (or further linker group, or ancillary linker element) is not particularly limited. In some embodiments, said linker group is selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)1-4-, -(CH2)1-4-O- and -O-(CH2)1-4-, or combinations thereof.

[0159] In some embodiments, the ring is optionally substituted and / or optionally bridged as defined in any one of the aforementioned ring-related embodiments with the further proviso that the (bridged) ring, together with its optional substituents and linker groups (or further linker groups, or ancillary linker elements), comprises less than 30, more specifically less than 16, and in particular less than 12 carbon atoms; less than 12, more less than 8, and in particular less than 6 oxygen atoms; less than 8, more specifically less than 6, and in particular less than 4 nitrogen atoms; less than 6, more specifically less than 4, and in particular less than 3 sulfur atoms; less than 6, more specifically less than 4, and in particular less than 3 phosphorus atoms; less than 6, more specifically less than 4, and in particular less than 3 boron atoms; and less than 10, more specifically less than 8, and in particular less than 6 halogen atoms. It should be understood that the aforementioned numbers are meant to define the size of the linker moieties, i.e. the number of carbon atom is counted excluding the carbon atoms shared with the 3,4-disaturated 2H-pyrane ring.

[0160] In some embodiments, each of Li, L2, L3, L4, Ls, Lg and L7 is attached to its respective carbon atom of the 3,4-saturated 2H-pyran moiety by a carbon atom, by an oxygen atom, or by a nitrogen atom, more specifically by a carbon atom, or by an oxygen atom, and in particular by a carbon atom.

[0161] In some embodiments, both Lg and L7 are absent and As and A7 represent hydrogen. Such embodiments may be particularly advantageous, because the 3,4-saturated 2H-pyran moiety can ring-open to a reactive 1,5-dialdehyde which readily reacts with primary amines.

[0162] In some embodiments, L3 and L4 and / or L3’ and L4’ are present and (each) form an optionally substituted 5-, 6-, 7- or 8-membered ring comprising, in combination with its optional substituents, 1 to 12 carbon atoms, more specifically 1 to 10 carbon atoms, and in particular 1 to 8 carbon atoms, in particular an optionally substituted cyclopentyl, an optionally substituted cyclohexyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, an optionally substituted tetrahydrofuranyl ring or an optionally substituted tetrahydropyranyl ring. These substitution patterns may be particularly advantageous in view of skin irritation potential since they mimic the well-tolerated genipin structure. In some embodiments, it may be particularly advantageous that L3 and L4 are present and represent an optionally substituted 5-or 6-membered ring, in particular cyclopentyl, cyclopentenyl, tetrahydrofuranyl, cyclohexyl, or cyclohexenyl, to which A3 and A4 are attached, optionally via a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)I-4-, -(CH2)I-4-O- and -O-(CH2)I-4-, or combinations thereof.

[0163] In some embodiments, L7 is absent and A7 represents hydrogen or the C1-C30 moiety. In some embodiments, Lg is absent and Ag represents hydrogen or the C1-C30 moiety. In some embodiments, Lg and L7 are absent and A7 represents hydrogen and Ag represents the C1-C30 moiety. In some embodiments, Lg and L7 are absent and A7 represents the C1-C30 moiety and Ag represents hydrogen. In some embodiments, Lg and L7 are absent and A7 and Ag both independently represent the C1-C30 moiety. It may be particularly advantageous, in some embodiments, that Lg and L7 are absent and A7 represents hydrogen and Ag represents the Ci- Cso moiety or that Lg and L7 are absent and A7 represents the C1-C30 moiety and As represents hydrogen since this substitution pattern retains the initial high reactivity of an aldehyde group. It may be further particularly advantageous, in some embodiments, that Lg and L7 are absent and Ai represents hydrogen and As represents the C1-C30 moiety since this substitution pattern is conveniently synthetically accessible, as discussed below in the experimental section.

[0164] In some embodiments, both Ls and L7 are absent and one of As and Ai represents hydrogen and the other represents the C1-C30 moiety.

[0165] In some embodiments, Lg and L7 are absent and Ag represents hydrogen and Ai represents the C1-C30 moiety. In some embodiments, Lg and L7 are absent and Ag represents theCi-Cso moiety and Ai represents hydrogen. These embodiments may be particularly advantageous, because they are readily synthetically available reliable and well-proven chemistry while maintaining good reactivity towards primary amines. Concrete examples will be given further below.

[0166] In some embodiments, it may be advantageous that both Lg- and L7' are absent and both Ag' and AT represent hydrogen whereas, in case Lg and L7 are absent, at least one of Ag and Ai represents the C1-C30 moiety. In this way, one of the 3,4-dihydro-2H pyrane moiety opens to a reactive 1, 5-dial dehy de whereas the other opens to a mixed 1,5-ketoalehyde or a 1,5-diketone which are somewhat less reactive. This may facilitate the selective coupling to one of the two 3,4-dihydro-2H pyrane moieties in the process according to the third aspect.

[0167] In some embodiments, none of the substituent combinations L1-A1 and L4-A4 represent hydrogen and / or none of the substituent combinations Lr-Ar and L4-A4' represent hydrogen. Like glutardialdehyde, 3,4-saturated 2H-pyran derivatives may undergo side-reactions which result in oligomerized or polymerized side-products which are undesirable in view of a potential skin irritation or skin sensitization. One maj or pathway for the generation of these side products is that, once the ring-opened form of the 3,4-saturated 2H-pyran derivatives has reacted to an imine, its tautomeric enamine can bind - via the nucleophilic carbon atom of the enamine - to other 3,4-saturated 2H-pyran derivatives. However, if both C-3 and C-5 (i.e. the carbon atoms to which L1-A1 and L4-A4 or Lr-Ar and L4’-Ar are attached) are not carrying a hydrogen atom, the subsequent elimination of hydrogen to a stable intermediate is no longer possible and this reaction pathway to oligomerized and polymerized side products is effectively suppressed. In some embodiments, it may be particularly advantageous that at least one of L1-A1, L3-A3, L4-A4, Le-Ae and L7-A7 and at least one of Lr-Ar, Ls'-As', L4'-A, Le'-Ae- and L7-A7' j ointly represent the bridging linker group LBRIDGE and / or the bridging linker group LBRIDGE’.

[0168] In some embodiments, it may be particularly advantageous that at least one of L1-A1, L3-A3, L4-A4 and Lg-Ag and at least one of Lr-Ar, L3-A3', L4-A4' and Le-Ar jointly represent the bridging linker group LBRIDGE and / or the bridging linker group LBRIDGE’.

[0169] In some embodiments, it may be particularly advantageous that at least one of L1-A1, L3-A3 and L4-A4 and at least one of Lr-Ar, L3-A3' and L4- A j ointly represent the bridging linker group LBRIDGE and / or the bridging linker group LBRIDGE’.

[0170] In some embodiments, it may be particularly advantageous that L3-A3 and L4-A4 and L3-A3' and L4-A4' jointly represent the bridging linker group LBRIDGE and / or the bridging linker group LBRIDGE’.

[0171] In some embodiments, it may be particularly advantageous that L1-A1 and Lr-Ar jointly represent the bridging linker group LBRIDGE and / or the bridging linker group LBRIDGE’.

[0172] In some embodiments, LBRIDGE and / or LBRIDGE’ is a Ci-Ceo moiety or a polymer. The exact structure of LBRIDGE and / or LBRIDGE’ is not particularly limited. In some embodiments, LBRIDGE and / or LBRIDGE’ is a linker comprising one or more hydroxyl groups and / or n polyethylene ether repeat units, wherein n = 2 to 100, more specifically 2 to 36, and in particular 2 to 12. Such a linker would be advantageous for improving the water-solubility. Additionally or alternatively, in some embodiments, LBRIDGE and / or LBRIDGE’ comprises an optionally further substituted chain of 3 or more, more specifically of 4 or more, and in particular of 5 or more, rotatable single bonds. Such a linker would be advantageous since it spaces apart the 3,4-saturated 2H-pyran moieties / derivatives and imparts flexibility between them. These properties may be helpful in linking the compound of the first aspect to a large and bulky active ingredient (such as a polymer) and subsequently linking such a large compound to the keratinous tissue. Additionally or alternatively, in some embodiments, LBRIDGE and / or LBRIDGE’ comprises ahydrocarbon moiety consisting of at least 6 carbon atoms, more specifically at least 9 carbon atoms, and in particular at least 12 carbon atoms, with the remainder of atoms of said hydrocarbon moiety being only hydrogen atoms. Such a linker would be advantageous since it imparts a lipophilic character and facilitates penetration into deeper layers of the skin,

[0173] Moreover, in some embodiments, LBRIDGE and / or LBRIDGE’ is a Ci-Ceo moiety, in particular an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 60 carbon atoms, more specifically 1 to 48 carbon atoms, and in particular 1 to 36 carbon atoms, 0 to 50, more specifically 0 to 40, and in particular 0 to 20 oxygen atoms; 0 to 30, more specifically 0 to 20, and in particular 0 to 10 nitrogen atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 sulfur atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 silicon atoms; and 0 to 20, more specifically 0 to 10, and in particular 0 to 5 halogen atoms.

[0174] Moreover, in some embodiments, LBRIDGE and / or LBRIDGE’ comprises an oligomer or a polymer. In some embodiments, LBRIDGE and / or LBRIDGE’ comprises an oligomer or a polymer of ethylene glycol and / or propylene glycol or a silicone oligomer or silicone polymer such a polydimethylsiloxane.

[0175] In some embodiments, it may be particularly advantageous that LBRIDGE and / or LBRIDGE’ comprises a linker group selected from the group consisting of: -O-; -S-; -NH-; an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 16 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms, 0 to 16, more specifically 0 to 12, and in particular 0 to 8 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 silicon atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms; or combinations thereof.

[0176] In some embodiments, it may be particularly advantageous that LBRIDGE comprises a linker group having an -A'-B-A- structure, wherein A' represents the moiety coupling the linker to the remainder of the moiety of formula (la), wherein A represents the moiety coupling the linker to the remainder of the moiety of formula (lb), and wherein B represents a moiety linking A and A' to each other. Likewise, in some embodiments, it may be particularly advantageous that LBRIDGE’ comprises a linker group having an -A'-B-A- structure, wherein A' represents the moiety coupling the linker to the remainder of the moiety of formula (Ic) or (Id), wherein A represents the moiety coupling the linker to the remainder of the moiety of formula (lb), and wherein B represents a moiety linking A and A' to each other.

[0177] In some embodiments, it may be particularly advantageous that A and A' comprise, independently from each other, a carbon ester, in particular a monoester, 1,1 -di ester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; a disulfide; a carbon amide, in particular a peptide or a N-Mannich base; a secondary or tertiary amine; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amide; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; a phosphonic acid amide; a boronic ester, a borinic ester, a boric ester; an aromatic, saturated or unsaturated heterocycle, in particular an oxazol; a triazole; a benzothiazole, or a coumarin; or combinations thereof.

[0178] B is not particularly limited. In some embodiments, B represents a Ci-Ceo moiety, in particular an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 60 carbon atoms, more specifically 1 to 48 carbon atoms, and in particular 1 to 36 carbon atoms, 0 to 50, more specifically 0 to 40, and in particular 0 to 20 oxygen atoms; 0 to 30, more specifically 0 to 20, and in particular 0 to 10 nitrogen atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 sulfur atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 silicon atoms; and 0 to 20, more specifically 0 to 10, and in particular 0 to 5 halogen atoms. In some embodiments, B represents oligomer or a polymer, more specifically an oligomer or a polymer of ethylene glycol and / or propylene glycol or a silicone oligomer or silicone polymer such a polydimethylsiloxane. In some embodiments, it may be particularly advantageous that B represents an aliphatic hydrocarbon, more specifically a saturated hydrocarbon moiety comprising 1 to 12 carbon atoms and optionally 1 to 12 oxygen atoms.

[0179] In some embodiments, it may be particularly advantageous that A and A' comprise, independently from each other, -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, or combinations thereof; and that B represents -(CH2)i-i2-, -(CH2-O-)i-i2-, -(CH2-CH2-O-)i-i2, -(CH2-CH2-CH2-O-)i-i2-, -(CH(CH3)-CH2-O-)i-i2-; and combinations thereof. In some embodiments, the compound according to the first aspect comprises a moiety according to formula (la) and a moiety according to formula (lb), wherein the moiety according to formula (la) and the moiety according to formula (lb) are identical, more specifically identical with the optional exclusion of the at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 and the at least one of Li-Ar, L2-A2', L3-A3', L4-A4', L5-A5', Le-Ae- and L7-A7' which jointly represent the bridging linker group LBRIDGE. Such compounds, which may be considered as dimers, may be beneficial in that both 3,4-dihydropyrane moieties have the same reactivity and result in the same compound according to the second aspect of the present disclosure. In other words, using such a compound will result in the same compound of the second aspect, irrespective of whether the first moiety according to formula (la) and a second moiety according to formula (lb) react with the active ingredient. Having such a well-defined coupling chemistry may also be advantageous in view of potential skin irritation and safety considerations.

[0180] Likewise, for the same reasons, it may be particularly advantageous that, in some embodiments, the compound according to the second aspect comprises a moiety according to formula (Ic) and a moiety according to formula (lb), wherein L1-A1, L2-A2, L3-A3, L4-A4, Le-Ae and L7-A7 are identical to the corresponding Lr-Ar, L2-A2', L3-A3', L4-A4', Le-Ae' and L7-A7' with the optional exclusion of the at least one of L1-A1, L2-A2, L3-A3, L4-A4, Le-Ae and L7-A7 and the at least one of Lr-Ar, L2-A2', L3-A3', L4-A4', Le-Ae' and L7-A7' which jointly represent the bridging linker group LBRIDGE’. In some embodiments, it may be particularly advantageous that the compound according to the second aspect comprises a moiety according to formula (Id) and a moiety according to formula (lb), wherein L1-A1, L3-A3, L4-A4, Le-Ae and L7-A7 are identical to the corresponding Lr-Ar, L2-A2', L3-A3', L4-A4', Le-Ae' and L7-A7' with the optional exclusion of the at least one of L1-A1, L2-A2, L3-A3, L4-A4, Le-Ae and L7-A7 and the at least one of Lr-Ar, L3-A3', L4-A4', Le-Ae' and L7-A7' which jointly represent the bridging linker group LBRIDGE’.

[0181] The Linker Group Ls'

[0182] The compound according to the second aspect comprises an active ingredient (or a precursor thereof) that is to be anchored to the keratinous tissue such as skin and / or hair. According to formulae (Ic and Id), said active ingredient (or a precursor thereof) is optionally attached to the remainder of the compound via the linker group Ls'. The linker group Ls' is not particularly limited and can be freely selected.

[0183] In some embodiments, Ls' comprises one or more of, two or more of, three or more of, four or more of, five or more, six or more, or all of:

[0184] - 1 to 12 carbon atoms, more specifically 1 to 8 carbon atoms, and in particular 1 to 4 carbon atoms;

[0185] - 1 to 12 oxygen atoms, more specifically 1 to 8 oxygen atoms, and in particular 1 to 4 oxygen atoms;

[0186] - 1 to 8 nitrogen atoms, more specifically 1 to 6 nitrogen atoms, and in particular to 3 nitrogen atoms;

[0187] - 1 to 3 sulfur atoms, more specifically 1 or 2 sulfur atoms, and in particular 1 sulfur atom; - 1 to 3 phosphorus atoms, more specifically 1 or 2 phosphorus atoms, and in particular 1 phosphorus atom;

[0188] - 1 to 12 silicon atoms, more specifically 1 to 8 silicon atoms, and in particular to 1 to 6 silicon atoms; and

[0189] - 1 or 2 boron atoms, and in particular 1 boron atom.

[0190] In some embodiments, after the compound according to the second aspect has bound to the skin and / or the hair, Ls- is biostable. When referring in this context to “biostable”, it should be understood that Ls- is not subject to biodegradation under physiological conditions encountered after application of the compound to the skin and / or the hair for 14 days which is a typical time span before the natural desquamation of the skin removes any bound compounds from the skin. It should be understood that, when referring in this context or another context to “physiological conditions”, it is in particular referred to the ambient conditions, in particular pH, enzymatic and temperature conditions, encountered at the locus where the compound according to the second aspect is supposed to bind to keratinous tissues in e.g. the hair of the (mammalian, in particular human) subject to be treated.

[0191] In some embodiments, after the compound according to the second aspect has bound to the skin and / or the hair, Ls- is cleavable, more specifically cleavable under physiological conditions encountered after its application to the skin and / or the hair. In some embodiments, it may be particularly advantageous that Ls- can be cleaved under physiological conditions to provide the active ingredient from the corresponding precursor over a plurality of hours or days. In some embodiments, the plurality of hours is 8 hours or more, more specifically 12 hours or more, and in particular 24 hours or more. In some embodiments, the plurality of days is 2 days or more, more specifically 3 days or more, and in particular 7 days or more.

[0192] In some embodiments, after the compound according to the second aspect has bound to the skin and / or the hair, Ls- is cleavable under conditions preselected for said use. The term “cleavable under conditions preselected for said use” should be understood as referring to conditions not normally encountered in said specific use and, thus, are suitable for defining conditions for a triggering event which results in Ls- being cleaved or starting to being cleaved. In particular, such preselected conditions include: cleavable upon elevation of temperature to higher than 37 °C (i.e. higher than body surface temperature); cleavable upon exposure to daylight; cleavable upon exposure to UVA- and / or UVB-light; cleavable upon exposure to acids; cleavable upon exposure to an oxidizing agent suitable for oxidizing said functional group; cleavable upon exposure to a reducing agent suitable for reducing said functional group; cleavable upon applying an enzyme; and cleavable upon exposure to salts. To give an example, when using the compound according to the second aspect for applying a fragrance to hair, Ls- may be an ester group which starts to be hydrolyzed in the presence of moisture (originating from the wet hair) and at temperatures of greater than 40°C (as encountered when hair is dried with a hair dryer). Another example is the use of compound according to the second aspect for applying a pharmaceutical to skin, wherein Ls- is a coumarin moiety which photodegrades to liberate the pharmaceutical from its prodrug moiety upon exposure to daylight. The use of coumarin-based linkers for light-triggered drug release is reviewed in e.g. Johan et al., Pharmaceuticals (Basel), 2022, 15(6):655, which is incorporated herein in its entirety by reference thereto.

[0193] In some embodiments, Ls- is hydrolysable at the physiological pH of mammalian skin, more specifically of human skin, and in particular at a pH of between about 5 to about 6. A suitable in-vitro test is incubating 0.1 mmol / mL of the compound according to the second aspect for 24 hours at 37°C in any of the following three solutions: a) a phosphate buffer solution, pH 5.5; an aqueous solution of bovine collagen type I (1 mg / mL, adjusted to pH 5.5); and c) an aqueous solution of lysine (1 mg / mL, adjusted to pH 5.5 using a phosphate buffer solution), wherein the group in question qualifies as hydrolysable if a notable amount of the group is hydrolysed (e.g. more than 5 mol%, or more than 10 mol%). The conversion can be monitored by any suitable means, including nuclear magnetic resonance spectroscopy (NMR), high-performance liquid chromatography (HPLC), optionally coupled to mass spectrometer (MS) or a UV / vis detector. The aforementioned conversion ratio in mol% can also be determined using any suitable means, including the aforementioned methods.

[0194] In some embodiments, Ls' is enzymatically cleavable under physiological conditions after the compound according to the second aspect is topically applied onto mammalian, more specifically human skin, in particular enzymatically cleavable by enzymes present in the mammalian, more specifically human skin. A suitable in-vitro test is placing 0.1 mol / L of the compound according to the second aspect in an aqueous solution having a pH of about 5.5 at 37°C for 24 hours and further containing 50 U of esterase activity, wherein the group in question qualifies as enzymatically cleavable if a notable amount of the group is cleaved (e.g. more than 5 mol-%, or more than 10 mol-%). The conversion can be monitored by any suitable means, including nuclear magnetic resonance spectroscopy (NMR), high-performance liquid chromatography (HPLC), optionally coupled to mass spectrometer (MS) or a UV / vis detector. The aforementioned conversion ratio in mol% can also be determined using any suitable means, including the aforementioned methods.

[0195] In some embodiments, Ls- can be cleaved to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof.

[0196] In some embodiments, Ls- can be cleaved to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; to the active ingredient.

[0197] In some embodiments, Ls- can be cleaved to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to the active ingredient; and to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime, to the remainder of the compound according to the second aspect (in the form as bound to skin or hair). In some embodiments, Ls- comprises a carbon ester, in particular a monoester, 1,1 -diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; a disulfide; a carbon amide, in particular a peptide or a N-Mannich base; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amide; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; a phosphonic acid amide; a boronic ester, a borinic ester, a boric ester; an oxazol, a triazole, a benzothiazole, or a coumarin.

[0198] In some embodiments, Ls- may be a functional group mentioned in chapter 6 of the textbook Prodrug Design Perspectives, Approaches and Applications in Medicinal Chemistry, 1sted., 2015, ISBN: 9780128035191, which is incorporated herein (for the aforementioned purpose and in its entirety) by reference thereto. Process conditions for attaching the active ingredient to the compound according to the first aspect

[0199] According to the third aspect of the present disclosure, the compound according to the first aspect of the disclosure is coupled to an active ingredient comprising an amino group, providing a compound according to the second aspect of the present disclosure.

[0200] When referring, here and elsewhere in the present disclosure, to the active ingredient comprising an amino group, it should be understood that this refers to the active ingredient comprising an amino group, to a precursor of the active ingredient, wherein the precursor comprises an amino group, to the active ingredient attached to a linker group Ls” or to a precursor of the active ingredient attached to a linker group Ls”, wherein Ls” defined as disclosed above for Ls- except that Ls” terminates with an amino group. The exact type of the active ingredient comprising an amino group will be governed by the type of compound according to the second aspect of the present disclosure that is provided by the process.

[0201] In some embodiments, the rate of addition of the active ingredient is controlled such that the compound of the first aspect is present in constant or increasing stoichiometric excess in relation to the active ingredient. In some embodiments, it may be advantageous that the rate of addition of the active ingredient is controlled such that the compound of the first aspect is present throughout the entire process in a stoichiometric ratio to the active ingredient comprising the amino group of at least about 3:1, more specifically at least about 5:1, even more specifically at least about 10:1, and in particular at least about 20:1. It should be understood that the stoichiometric ratio refers to the molar equivalent of the total number of amino groups of the active ingredient which are present in the reaction mixture to the molar amount of the compound of the first aspect. The present inventors have found that these ratios are already adequate to provide selective coupling of the amino groups to one of two identical 3,4-disaturated 2H-pyrane moieties of the compound of the first aspect.

[0202] In some embodiments, the active ingredient is added together with a first solvent as a first solution. Concomitantly or after a portion of the first solution has been added to the reaction mixture, a second replenishing solution which comprises the compound of the first aspect in a second solvent is added to the reaction mixture. Moreover, the concentration of the compound of the first aspect in said second solution and its rate of addition is adjusted to (substantially) maintain the concentration of the compound of the first aspect in the reaction mixture constant.

[0203] In some embodiments, the reaction mixture is an aqueous reaction mixture. In some embodiments, the first solvent is water.

[0204] In some embodiments, the reaction is terminated by adding a reagent which reacts with any remaining amino groups under formation products which are no longer capable of reacting with a 3,4-saturated 2H-pyrane moiety. The reagent may be either more reactive than the respective 3,4-saturated 2H-pyrane moieties and / or it may be added in molar excess to the 3,4-saturated 2H-pyrane moieties remaining in the reaction mixture. In some embodiments, it may be particularly advantageous that the reagent which terminates the coupling reaction between the active ingredient and the compound of aspect 1 is an acid; an alkylating agent; a reagent that converts an amino group to its corresponding acid amide such as ethylenediaminetetraacetic dianhydride, a phosphoric acid anhydride, or a mixed anhydride of carboxylic acid of phosphoric acid; a reagent that converts an amino group to its corresponding imine. For instance, benzaldehydes which are substituted one, twice or trice with a sulfonate group are reported in Chem. Sci., 2024, 15, 10408-10415, to have an equilibrium in water that is 100% on the imine side. The compounds described therein are incorporated herein by reference thereto. The reagents can optionally also be used in combination.

[0205] In some embodiments, in formulae (la) and (lb) of the compound of the first aspect, the moieties Li-Ai, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not being part of the bridging linker group LBRIDGE are identical to the respective moieties Lr-Ar, L2-A2', L3-A3', L4-A4', Ls-As-, Lg-Ag- and L7-A7' not being part of the bridging linker group LBRIDGE’. In other words, the reaction of the compound according to the first aspect does not comprise further moieties which are reactive in the process according to the third aspect. This may be beneficial in obtaining a consistent product with a defined and reproducible composition.

[0206] In some embodiments, the moiety of formula (la) is more reactive towards the amino groups of the active ingredient than the moiety of formula (lb), more specifically R2may represent H and R1may represent the protective group. This may be beneficial in further improving selectivity of the coupling reaction. Synthesis of compound according to the first aspect of the disclosure

[0207] The synthesis of the compound according to the first aspect of the present disclosure is not particularly limited. However, the present inventors have found that, a synthetic approach starting from genipin and involving protection and deprotection steps is typically suffering from very poor yields. The present disclosure provides a novel process for preparing compounds according to the first aspect of the present disclosure which is higher yielding, because it is not involving any protection and deprotection steps for genipin.

[0208] The process is outlined in Figure 1 and elaborated further in the experimental section. Briefly, genipin aldehyde (Fig.1 - Al), the synthesis of which has been disclosed in WO 2024 / 168437 Al, is reacted with malonic acid in a Doebner modification of the Knoevenagel condensation to provide product (Fig.l - A2), followed by hydrogenation of its diene. The resulting hydrogenated genipin derivative having a C2-extended carboxylic acid (Fig.1 - A3) can be converted to its acid chloride (by e.g. the Ghosez’s reagent) or another activating reagent and linked to each other via a linker group such as di ethylene glycol resulting in a monoester (Fig.1 - A4). This monoester can be reacted with another acid chloride of the C2-extended carboxylic acid to yield a compound according to the first aspect (Fig.1 - A5). The reaction is described in more detail in the experimental section. It is surprisingly high-yielding and does not require the use of any protecting groups. Alternatively, two equivalents of the acid chloride of the C2-extended carboxylic acid can be reacted with diethylene glycol (or another linker group).

[0209] Moreover, while this synthetical approach would in principle also work with genipin acid (Fig.1 - Bl) or hydrogenated genipin acid (Fig.l - B2), the present inventors have found that the genipin acid is competitively undergoing an intramolecular cyclization with its hemiacetal group to yield the hemiacetal lactones (Fig.1 - B3 and B4) as major side-products. The present inventors have further found that the extension of the carboxylic acid side chain completely suppresses the intramolecular cyclization when extending the sidechain by two carbon atoms. The present inventors have further found that extending the side chain by two or more carbon atoms is also possible in good yields and without having to apply a protecting group to the hemiacetal by using a Wittig-type reaction (data not shown). However, the Wittig reaction is not as atom-efficient as the Doebner modification of the Knoevenagel condensation and introduces an ester ((Fig.l - Cl; or like group such as an acetal (not shown)) which needs to be subsequently cleaved or converted to provide the corresponding carboxylic acid. Moreover, such a deprotection would need to be chemo-selective in order to retain the carboxymethyl group attached to C-4 of the genipin derivative.

[0210] Thus, the C2-extended hydrogenated carboxylic acid is a particularly suitable intermediate to provide, starting from the safe and readily available genipin, a compound according to the first aspect of the present disclosure in a convenient and robust approach. Moreover, the lack of a protecting group for the hemiacetal of the C2-extended hydrogenated carboxylic acid is particularly suitable for the process according to the third aspect of the present disclosure which is based (although not exclusively) on the concept of introducing an amine-carrying active ingredient into a compound according to the first aspect of the present disclosure in which the 3,4-disaturated 2H-pyrane moiety is not carrying a protecting group at Ri and / or R2.

[0211] Moreover, the C2-extended hydrogenated carboxylic acid can be readily further functionalized to provide a large number of linkers. Accordingly, in some embodiments, the compound (or use of such said compound) according to the first, second and / or third aspects relates to a compound comprising at least one moiety of formula (lb'),

[0212] O O^

[0213] \ ^l o

[0214] C-A'-B-A / Y

[0215]

[0216] °H(Ib')>

[0217] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein A, B and A' represent the A-B-A' structure as defined above; and wherein C represents a moiety of formula (la) or of formula (Ic) or (Id) as defined above.

[0218] Further details of an exemplary reaction according to the third aspect are provided in the experimental section.

[0219] Process according to the fourth aspect using functional groups of orthogonal reactivity

[0220] In a fourth aspect, the present disclosure provides an alternative approach of coupling an active ingredient, more specifically a water-soluble polymer, to a compound comprising a 3,4-saturated 2H-pyran moiety such that said pyran moiety is preserved for coupling the compound to keratinous tissue such as skin and / or hair and which also does not rely on a protecting / deprotecting-step in the coupling of the polymer to said pyran moiety.

[0221] The general concept is illustrated below using a genipin derivative and hyaluronic acid: In this non-limiting example, the hyaluronic acid is thiol-functionalized, i.e. the water-soluble hyaluronic acid comprises thiol groups. It will be in the following abbreviated as “HA-SH”. The genipin derivative is an ester of the aforementioned C2-extended hydrogenated carboxylic acid and the readily available 5-norbomene-2-methanol. 5-Norbomene-2-methanol is a ring-strained olefin and, thus, highly reactive in a thiol-ene reaction. This reaction proceeds readily in an aqueous solution under (light-induced) catalysis of water-soluble riboflavin phosphate (i.e. phosphorylated Vitamin B2) to provide a genipin derivative that is linked to HA-SH via a thioether linking group. Since the thiol group and the norbomene group do not react with the 3,4-disaturated 2H-pyrane moiety, at least not under formation of a stable product, the presence of the thiol groups on the hyaluronic acid is not expected to be noticeably accompanied by undesirable side reactions which degrade the 3,4-disaturated 2H-pyrane moiety:

[0222]

[0223] In other words, the reactivity of the thiol group and the norbomene functional groups are more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety. Accordingly, the present disclosure provides a process of preparing a compound comprising a 3,4-saturated 2H-pyran moiety according to formula (le),

[0224]

[0225] or a tautomer and / or a pharmaceutically acceptable salt thereof, for covalently binding a water-soluble polymer to skin and / or hair; wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 represents LFG-PWS, wherein Pws represents the water-soluble polymer and LFG represents a linker group which binds the water-soluble polymer to the 3,4-saturated 2H-pyran moiety; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing LFG-PWS is defined as indicated for formula (lb) in the first aspect;

[0226] the process comprising reacting:

[0227] i) a precursor of the water-soluble polymer comprising a first functional group with ii) a precursor compound comprising a second functional group and a 3,4-saturated 2H- pyran moiety,

[0228] such that the first and second functional groups generate the linker group LFG;

[0229] wherein the precursor compound is represented by the following formula (If),

[0230]

[0231] (

[0232] or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0233] wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 represents a linker group comprising the second functional group; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing the linker group comprising the second functional group is defined as indicated for formula (lb) in the first aspect; and wherein the first and second functional groups are more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety of both the compound according to formula (le) and the precursor compound according to formula (If).

[0234] In some embodiments, it may be particularly advantageous that the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 not representing LFG-PWS are defined as indicated herein for any of the specific embodiments of the formula (lb) with the proviso that the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag correspond to those of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 which are not jointly representing a bridging linker group LBRIDGE with and at least one of Lr-Ar, L2-A2', L3-A3', L4- 4', L5-A5', Lg-Ag- and LT- AT.

[0235] When referring to the first and second functional groups being more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety of both the compound according to formula (le) and the precursor compound according to formula (If), it should be understood that this refers to the reactivity of said functional group as it is attached to its compound. The skilled person can readily determine suitable combinations of first and second functional groups by generally considering whether a reaction can principally take place at all and, in case of doubt, by carrying out trial experimentation. For the avoidance of doubt, when referring to the first and second functional groups being more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety of both the compound according to formula (le) and the precursor compound according to formula (If), it should be understood that this refers to the reactivity under the given reaction conditions and, additionally or alternatively, under conditions as applied to the skin and / or hair. Suitable test conditions for testing the reactivity include water at a pH of e.g. about 5, a concentration of the water-soluble polymer of e.g. about 1 mg / ml and a temperature of e.g. about 37°C. The amount of the compound according to formula (le) with respect to the water-soluble polymer can be appropriately selected, e.g. such that at least 0.2 molar equivalents of the second functional group are present per molar equivalent of the 3,4-saturated 2H-pyran moiety, more specifically at least 0.4 molar equivalents, still more specifically at least 0.6 molar equivalents, and in particular at least at least 1 molar equivalent. The first and second functional groups can be considered being more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety of both the compound according to formula (le) and the precursor compound according to formula (If), if at least 60 mol.%, more specifically at least 80 mol.%, and in particular at least 90 mol.%, of said molar equivalent of the 3,4-saturated 2H-pyran moiety remain intact at the end of the reaction which is characterized by a conversion of at least 95 mol.% of the stoichiometrically limiting compound, and / or by reaching a steady-state of the reagents which is characterized by less than 2 mol.-% conversion per hour, and / or after a reaction time of at least 24 hours. The way of determining the progress of the reaction is not particularly limited and includes any suitable means, for instance NMR spectroscopy, HPLC, GC / MS and TLC.

[0236] In some embodiments, the water-soluble polymer has a number average molecular weight of at least 1000 g / mol, more specifically at least 2000 g / mol, and in particular at least 5000 g / mol. In some embodiments, it may be particularly advantageous that the water-soluble polymer is a polysaccharide; more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid; and in particular hyaluronic acid; and copolymers thereof, in particular copolymers comprising polyethylene glycol.

[0237] In some embodiments, the water-soluble polymer comprises a polysaccharide, more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid; and in particular hyaluronic acid.

[0238] In some embodiments, the reaction is carried out in an aqueous solvent.

[0239] As said, the identification of suitable combinations of first and second functional groups can be guided by generally considering whether a reaction can principally take place at all. Suitable examples of the first functional group of the precursor of the water-soluble polymer include, in some embodiments, a secondary amine, a thiol, a (meth)acrylate, an alkyne, an alkene, a Michael acceptor, an azide, an epoxy, a hydrazide, a carboxylic acid, an ester of a N-hydroxylamine, of a N-hydroxylamide, of a N-hydroxyimide or of a N-hydroxyl heteroaromatic, a 1,2, 4, 5 -tetrazine, a catechol, a hydroquinone, or an aldehyde.

[0240] Suitable examples of the second functional group of the precursor compound according to formula (If) include a secondary amine, a thiol, a (meth)acrylate, an alkyne, an alkene, a Michael acceptor, an azide, an epoxy, a hydrazide, a carboxylic acid, an ester of a N-hydroxylamine, of a N-hydroxylamide, of a N-hydroxylimide or of a N-hydroxyl heteroaromatic, a 1,2, 4, 5 -tetrazine, a catechol, a hydroquinone, or an aldehyde. In some embodiments, it may be particularly advantageous that the reaction between the first and second functional groups generating the linker group LFG is not an addition-elimination reaction involving a nucleophilic attack of the first or second functional group on the respective other of said first or second functional group that is followed by the elimination of a hydroxyl group.

[0241] In some embodiments, the reaction between the first and second functional groups generating the linker group LFG is a cycloaddition reaction, a radical reaction, an addition reaction reducing ring strain, a Michael addition reaction, a redox-reaction, a photochemical reaction, or a combination thereof. Suitable examples of these reaction types are well-known to the skilled person.

[0242] As one exemplary embodiment of a cycloaddition reaction, Figure 2 shows a hyaluronic acid which is azido-functionalized, i.e. the water-soluble hyaluronic acid comprises azide groups. It will be in the following abbreviated as “HA-N3”. The compound of formula (If) is a propargyl ester of the aforementioned C2-extended hydrogenated carboxylic acid. The coupling reaction yielding a compound according to formulae (le) is a Huisgen 1,3-dipolar cycloaddition which proceeds reliably and efficiently in aqueous media using Cu(I) as a catalyst. Neither the azide group nor the propargyl react with the 3,4-disaturated 2H-pyrane moiety, i.e. the coupling reaction between these groups is not expected to be noticeably accompanied by undesirable side reactions which degrade the 3,4-disaturated 2H-pyrane moiety. Othe suitable examples include the cycloaddition reactions include the inverse-electron demand Diels Alder reaction of dienes with 1,2,4,5-tetrazines or the reaction of ring-strained enes such as norbomene with 1,2,4,5-tetrazines.

[0243] As an illustrative example of a radical reaction, reference can be made to the aforementioned thiol-ene reaction between HA-SH and the aforementioned 5 -norbomene-2 -methanol which proceeds via a radical mechanism. Other examples are well-known to the skilled person, for instance the thiol-ene reaction between HA-SH and (meth)acrylate or thiol-yne reaction between HA-SH and an alkyne such as the aforementioned propargyl ester.

[0244] As an illustrative example of an addition reaction reducing ring strain, reference can be made to aforementioned thiol-ene reaction between HA-SH and the aforementioned 5 -norbomene-2 -methanol which proceeds so efficiently by reducing ring strain of the norbomene-2-methanol. Other examples are well-known to the skilled person, for instance the thiol-ene reaction between HA-SH and cyclooctatetraene (COT) and the cycloaddition of azide to cyclooctyne. As a further exemplary embodiment, Figure 3 shows the conversion of genipin aldehyde to a secondary amine which is subsequently reacted with an epoxy-functionalized hyaluronic acid. The nucleophilic addition of the secondary amine to an epoxide is fast and proceeds in high yields since it is reducing ring strain of the epoxide. At the same time, while a secondary amine can, in principle, react with the 3,4-saturated 2H-pyran moiety, the addition of the secondary amine is reversible and cannot readily result in the formation of a stable product such as a 1,4-dihydropyridine.

[0245] As an example of a Michael addition reaction, the hetero-Michael addition such as the thia- and ozo-Michael addition represents an advantageous embodiment since, as explained above, the thiols and secondary amines do not readily react with 3,4-saturated 2H-pyran moiety, at least not to stable products. Specifically, in their ring-open 1,5-diacarbonylic form, the 1,2-addition of thiols or secondary amines to a 3,4-saturated 2H-pyran moiety results in intermediate hemi-thioacetals and hemi-aminals which are meta-stable and cannot readily eliminate water. In their ring-closed form, the 3,4-saturated 2H-pyran moiety is a poor Michael acceptor since Michael additions are thermodynamically controlled and the presence of the ether-group favors the reverse Michael elimination for the 3,4-saturated 2H-pyran moiety. As an exemplary embodiment, Figure 4 shows the conversion of the aforementioned C2-extended hydrogenated carboxylic acid with PEG dithiol (Mnranges which are commercially available from e.g. Sigma Aldrich include 1000, 1500 and 3400 g / mol) to a thiol-compound according to formula (If) which is subsequently coupled with hyaluronic acid that is functionalized with maleimide groups (“HA-Maleimide”). Other suitable pairs of the first and second functional group include e.g. thiols or secondary amines in combination with enones such as (meth)acrylates or benzoquinones.

[0246] As an illustrative example of a redox-reaction reaction, reference can be made to the oxidative coupling of the first and second functional groups being thiols, under formation of a disulfide group. Other suitable pairs of the first and second functional groups include catechols as first and second functional groups and the combination of catechol with tyrosol. As an illustrative example of a photochemical reaction, reference can be made to the aforementioned thiol-ene reaction between HA-SH and the aforementioned 5-norbomene-2-methanol which proceeds via a photo-initiated mechanism.

[0247] In some embodiments, it may be particularly advantageous that the reaction between the first and second functional groups generating the linker group LFG is a cycloaddition, more specifically a [3+2] cycloaddition, a [2+3] cycloaddition, a [4+1] cycloaddition, a [4+2] cycloaddition, or a [2+2+2] cycloaddition; and in particular a (Hetero-)Diels-Alder reaction, an Inverse Electron Demand (Hetero-)Diels-Alder reaction, or a Huisgen 1,3-dipolar cycloaddition.

[0248] In some embodiments, it may be advantageous that the reaction between the first and second functional groups generating the linker group LFG is a nucleophilic or radical addition reaction to a C-C-double bond or C-C-triple bond, in particular a thiol-ene reaction, athiol-yne reaction; or a (hetero-)Michael addition, more specifically a thia- or aza-Michael addition, and in particular a thia-Michael addition.

[0249] In some embodiments, it may be particularly advantageous that the reaction between the first and second functional groups generating the linker group LFG is an addition reaction reducing ring strain, more specifically an addition reaction to an epoxy, an N-alkyl aziridine, a norbomene, an oxanorbomene or a cyclooctatetraene.

[0250] In some embodiments, it may be particularly advantageous that the reaction between the first and second functional groups generating the linker group LFG comprises a redox reaction; in particular: wherein the first or second functional group comprises a catechol or a hydroquinone and the respective second or first functional group comprises a nucleophile, in particular a secondary amine or a thiol; and wherein the reaction comprises oxidizing the catechol or the hydroquinone to 1,2-benzoquinone or 1,4-benzoquinone, followed by nucleophilic addition of the nucleophile in a (hetero)-Michael addition, and optionally further followed by rearomatization.

[0251] In some embodiments, it may be particularly advantageous that the process comprises adding a catalyst which facilitates the reaction between the first and second functional groups generating the linker group LFG, in particular a catalyst that is not a Bronsted acid. Not adding a Bronsted acid as a catalyst may have the additional advantage that the ring-opening reaction of 3,4-disaturated 2H-pyrane moiety to the more reactive 1,5-dicarbonyl is not facilitated, further improving selectivity towards the reaction between the first and second functional groups.

[0252] In some embodiments, the process is carried out at a temperature range of -15°C and 35°C, more specifically between -7°C and 30°C, and in particular between 0 °C and 25°C. In these temperature windows, the competing reactions between the 3,4-disaturated 2H-pyrane moieties are generally slow enough to allow discrimination between the reaction of the first and second functional groups and reactions of the 3,4-disaturated 2H-pyrane moieties.

[0253] Topical compositions according to the fifth aspect based on coupling functional groups of orthogonal reactivity

[0254] The aforementioned reactions between the first and second functional groups are typically high yielding and based on well-tolerated functional groups. As such, it may not be necessary to remove residuals of the coupling reaction. To give an example, the thiol-ene reaction shown in Figure 1 may be characterized by residual norbomenes, thiols and phosphorylated Vitamin B2, all of which are well tolerated. As another example, the reaction of secondary amines with epoxies shown in Figure 3 will leave behind residual epoxy which will degrade to a diol and an amine, i.e. also well-tolerated compounds. Therefore, it is often possible to avoid a purification of the polymeric compound of formula (le) after the coupling reaction. Therefore, the compound of formula (le), a tautomer and / or a pharmaceutically acceptable salt thereof, may be formulated to a topical composition after the reaction between the first and second functional groups generating the linker group LFG without further purification, more specifically without ultrafiltration, dialysis or use of an ion exchange resin or absorbing agent, in particular without ultrafiltration or dialysis.

[0255] Accordingly, in a fifth aspect, there is provided a topical composition comprising a topically acceptable excipient and a compound according to formula (le), or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein the compound is obtainable by carrying out the process of the fourth aspect and wherein the topical composition comprises residual educts and / or one or more further reaction products obtainable by carrying out said process. Compounds according to the fifth aspect based on coupling functional groups of orthogonal reactivity

[0256] In many instances, the concept of utilizing functional groups of orthogonal reactivity will require an appropriate selection of combinations of different functional groups which will result in specific functional groups linking the water-soluble polymer to the remainder of the compound. Accordingly, in the fifth aspect, there is also provided a compound comprising a 3,4-saturated 2H-pyran moiety according to formula (le),

[0257] A2L2

[0258] Lg- A6

[0259] AS- L5O-R

[0260]

[0261] or a tautomer and / or a pharmaceutically acceptable salt thereof; for covalently binding a water-soluble polymer to skin and / or hair; wherein one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 represents LFG-PWS, wherein Pws represents the water-soluble polymer and LFG represents a linker group which binds the water-soluble polymer to the 3,4-saturated 2H-pyran moiety; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing LFG-PWS is defined as indicated for formula (lb) in the first aspect; wherein LFG comprises one of the moieties shown in Figure 5; and wherein the wavy bonds represent bonds directly or indirectly connecting to the water-soluble polymer or to the remainder of the moiety of formula (le) with the proviso that, in case two wavy bonds are attached to N, none of them connects to hydrogen.

[0262] In some embodiments, at least one of the substituent combinations Lg-Ag and L7-A7 represents the C1-C30 moiety.

[0263] In some embodiments, it may be particularly advantageous that the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing LFG-PWS are defined as indicated herein for any of the specific embodiments of the formula (lb) with the proviso that the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag not representing LFG-PWS correspond to those of Li- Ai, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 which are not jointly representing a bridging linker group LBRIDGE with at least one of Lr-Ar, Ly-Ay, Ls'-As', L4'-A4', Ls'-As', Lg'-Ag' and L7 -A7'.

[0264] In some embodiments, the water-soluble polymer has a number average molecular weight of at least 1000 g / mol, more specifically at least 2000 g / mol, and in particular at least 5000 g / mol. In some embodiments, it may be particularly advantageous that the water-soluble polymer is a polysaccharide; more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid; and in particular hyaluronic acid; and copolymers thereof, in particular copolymers comprising polyethylene glycol.

[0265] In some embodiments, it may be particularly advantageous that the water-soluble polymer is a polysaccharide, more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid; and in particular hyaluronic acid.

[0266] Specific 3,4-disaturated 2H-pyrane moieties for all aspects of the present disclosure

[0267] In the following more specific embodiments of the 3,4-saturated 2H-pyrane moieties of the present disclosure are provided. In order to avoid excessive redundance in the disclosure, the moieties are discussed primarily in context of formula (lb). However, it should be understood that, unless specifically indicated otherwise, the same disclosure equally applies to the moieties of formulae (la), (Ic), (Id), (le) and (If). In case of formulae (la), (Ic) and (Id), the corresponding substituents are identified by a prime, i.e. disclosure regarding to e.g. substituent Li equally applies to substituents Lr in formulae (la), (Ic) and (Id). The same applies to the following specific 3,4-disaturated 2H-pyrane moieties of formulae (II) to (XIII), where the corresponding substituents are identified by the next higher row of ten, i.e. disclosure regarding below formulae (II) to (XIII) is meant to apply to formulae (lb), (le) and (If) with the proviso that Lnand An in below formulae (II) to (XIII) apply to Ln-10 and An-io in formulae (lb), (le) and (If) and to Ln-10’ and An-io’ in formulae (la), (Ic) and (Id). To give an example, the substituent Ln in e.g. formula (II) is meant to correspond to substituents Li in formulae (lb), (le) and (If) and to substituents Lr in formulae (la), (Ic) and (Id). Finally, in view of the requirement of the first, second and third aspects that the two moieties are connected to each other via the bridging linker groups LBRIDGE and LBRIDGE’, respectively, and the requirement in the fourth and fifth aspect that one of the substituents is representing LFG-PWS or representing the linker group comprising the second functional group, it should be understood that the disclosure of below formulae (II) to (XIII) is not meant to override these requirements, but that at least one of the substituents defined for formulae (II) to (XIII) is to be replaced or meant to represent a part of LBRIDGE, a part of LBRIDGE’, LFG-PWS and the linker group comprising the second functional group, respectively.

[0268] In some embodiments, one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (II),

[0269] / A-n

[0270] A i2IT11

[0271] A _| V^ / Lie-Aie

[0272] A13 L13-r

[0273] A14— L14-^\^O

[0274] A15 A O— R3

[0275] *~1\

[0276]

[0277] A17

[0278] (ID.

[0279] The compound may be present as tautomer and / or a pharmaceutically acceptable salt thereof. The remainder of substituents not representing a part of the bridging linker group LBRIDGE, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, is representing:

[0280] L11, L13, L14, L15and L17absent or a linker group, in particular as defined in any preceding embodiment, wherein, in said preceding embodiments, L11 corresponds to L1 and / or L1', L13 corresponds to L3 and / or L3’, L14 corresponds to L4 and / or L4’, Lis corresponds to Lg and / or Lgy and L17 corresponds to L7 and / or L7’. An, A13 and A14 hydrogen, hydroxyl, halogen, or a C1-C30 moiety, in particular as defined in any preceding embodiment, wherein, in said preceding embodiments, An corresponds to Ai and / or Ar, A13 corresponds to A3 and / or A3’ and A14 corresponds to A4 and / or A4’.

[0281] A 12 and A15 hydrogen or halogen, and in particular hydrogen;

[0282]

[0283] Ai6 and A17 hydrogen or a C1-C30 moiety;

[0284] optionally with the further proviso that at least one of the substituent combinations L16-A16and L17-A17represents hydrogen;

[0285] R3hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

[0286]

[0287] In some embodiments, it may be particularly advantageous that none of the substituent combinations L11-A11and L14-A14represents hydrogen. Like glutardialdehyde, 3,4-saturated 2H-pyran derivatives may undergo side-reactions which result in oligomerized or polymerized side-products which are undesirable in view of a potential skin irritation or skin sensitization. One major pathway for the generation of these side products is that, once the ring-opened form of the 3,4-saturated 2H-pyran derivatives has reacted to an imine, its tautomeric enamine can bind - via the nucleophilic carbon atom of the enamine - to other 3,4-saturated 2H-pyran derivatives. However, if both C-3 and C-5 (i.e. the carbon atoms to which L11-A11and L14-A14are attached) are not carrying a hydrogen atom, the subsequent elimination of hydrogen to a stable intermediate is no longer possible and this reaction pathway to oligomerized and polymerized side products is effectively suppressed.

[0288] In some embodiments, it may be further particularly advantageous that L13 and L14 jointly form a cyclopentyl ring, a cyclohexyl ring or a cycloheptyl ring, in particular a cyclopentyl ring, a cyclohexyl ring or a cycloheptyl ring as defined in in any of the embodiments according to the first aspect. As explained above, the aforementioned rings are fused to the respective 3,4-saturated 2H-pyran moiety, i.e. the referenced number of ring atoms includes the respective two carbon atoms that are shared with the 3,4-saturated 2H-pyran moiety. The presence of such rings, restrict the conformational freedom of the ring-opened 1,5-di carbonyl tautomer and favors the close proximity of the 1,5-dicarbonyl positions, thus, may facilitate the ring-closing reaction to form the 1,4-dihydropyridine that ultimately binds the compound to the keratinous tissue.

[0289] In some embodiments, it may be particularly advantageous that A12, A15 and R3represent hydrogen. Such a substitution pattern will facilitate linking the 3,4-saturated 2H-pyran moiety to the keratinous tissue or the amino-functionalized active ingredient since both the initial ring- opening to the 1,5-dicarbonyl derivative as well as the formation of the 1,4-dihydropyridine moiety are facilitated.

[0290] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (III),

[0291]

[0292] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, A11, A13, A14, A16, A17, L13, L14, L16and L17are defined as in any preceding disclosure; X represents O or S, and in particular O; and Lxis absent or represents -O-, -S-, -NH-, or an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 10 carbon atoms, 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms; and the hydrocarbon moiety is attached to the (C=X)-moiety via a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom.

[0293] Compounds of formula (III) may be particularly advantageous since the (thio-)carbonyl group facilitates the ring-opening to the more reactive 1,5-dicarbonyl tautomer. Moreover, it blocks the C-5 position in the 3,4-saturated 2H-pyran moiety and allows to delocalize charge in the cascade of reactions towards the 1,4-dihydropyridine derivative, both of which are beneficial in suppressing the formation of oligomers and polymers which may be facilitated in case the C-5 position is substituted with hydrogen. In some embodiments, it may be advantageous that the substituent combination C(=X)-Lx-An represents a C1-C16 moiety selected from a carboxylic acid or a salt thereof, a carboxylic acid ester; a ketone; more specifically a moiety selected from: -COOH or a salt thereof; -COORa, -C(O)-Ra, -C(O)-NH2, -C(O)NHRa, -C(O)NRa2, wherein Rarepresents a moiety comprising 1 to 16 carbon atoms, and optionally one or more of: 1 to 8 oxygen atoms, 1 to 6 nitrogen atoms, 1 to 3 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms and 1 to 5 halogen atoms; more specifically a moiety comprising 1 to 6 carbon atoms, and optionally one or more of: 1 to 4 oxygen atoms, 1 to 3 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms, and 1 to 3 halogen atoms; and wherein NRa2 may alternatively represent an optionally substituted saturated or unsaturated nitrogen heterocycle comprising, in combination with its optional substituents, 1 to 12, more specifically 1 to 10, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 1 to 4, more specifically 1 to 3, and in particular 1 or 2 nitrogen atoms; 0 to 3, more specifically 0 to 2, and in particular 0 or 1 sulfur atoms; and 0 to 5, more specifically 0 to 4, and in particular 0 to 3 halogen atoms. Compounds of this embodiment may be particularly beneficial since they mimic genipin, oleuropein and elenolic acid which are generally regarded as safe.

[0294] In some embodiments, it may be particularly advantageous that C(=X)-Lx-An represents -COORaas defined immediately above; more specifically -COORa, wherein Ra represents a hydrocarbon moiety comprising 1 to 8 carbon atoms, and optionally one or more of: 1 to 4 oxygen atoms, 1 to 4 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms, and 1 to 3 halogen atoms; and in particular -COORa, wherein Ra represents Ci-C4-alkyl, such as methyl or ethyl. Compounds of this embodiment may be particularly beneficial since they are essentially structurally genipin, oleuropein and elenolic acid which are generally regarded as safe.

[0295] In some embodiments, it may be advantageous that L13 and L14 form a ring, in particular a 5-memberered or 6-membered ring. Compounds of this embodiment may be particularly beneficial since they are essentially structurally identical at C-5 to genipin which is generally regarded as safe. In some embodiments, it may be particularly advantageous that A13 and Au are attached to said ring by a bond or by a linker group which is, independently from the other, selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)i-4-, -(CH2)I-4-O- and -O-(CH2)i-4-, and combinations thereof. Compounds of this embodiment may be particularly beneficial since they are still structurally closer to genipin and / or can be obtained by derivatization of genipin.

[0296] In some embodiments, it may be advantageous that X represents O; Lxand Lu form an optionally substituted 6-membered ring, more specifically an optionally substituted cyclohexenone ring or an optionally substituted fused ring system comprising a cyclohexendione and a phenyl ring which is fused to the cyclohexendione. Compounds of this embodiment may be particularly beneficial since they are structurally close to genipin and can be conveniently obtained by semi-synthetic approach starting from pinene-derivatives which are readily available and generally considered to be safe. Further examples will be given below. In some of these embodiments, it may further be particularly advantageous that Au represents H; and wherein An is attached to the 6-membered ring via a linker group comprising 1 to 12 carbon atoms, and optionally one or more of: 1 to 4 oxygen atoms, 1 to 4 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms, and 1 to 5 halogen atoms.

[0297] In some embodiments, it may be advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (IV),

[0298]

[0299] (IV)

[0300] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, L11, L13, L14, A11, A13, A14, A16and A17are defined as in any preceding disclosure; n represents an integer of 0 or 1, and in particular 0; the dashed bond represents a single or a double bond, and in particular a single bond; and, independently from each other, each instance of Lyis absent or represents a linker group, in particular a linker group selected from the group consisting of: -O-; -S-; -NH-; an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 10 carbon atoms, 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms; or combinations thereof. In some embodiments, it may further be particularly advantageous that independently from each other, each instance of Lyis absent or represents a linker group which is selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)1-4-, -(CH2)1-4-O- and -O-(CH2)1-4-, and combinations thereof. Compounds of this embodiment may be particularly beneficial since they are structurally close to genipin and can be conveniently obtained from genipin itself or by semi-synthetic approach starting from pinene-derivatives which are readily available and generally considered to be safe.

[0301] In some embodiments, it may be advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (V),

[0302]

[0303] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, X, Lx, Ly, L16, L17, A11, A13, A14, A16and A17are defined as in any preceding disclosure. Compounds of this embodiment may be particularly beneficial since they are structurally close to genipin and can be conveniently obtained from genipin itself and / or are structurally close to genipin which is generally considered to be safe. Moreover, when attached to skin and / or hair, compounds of this embodiment were found to be colorless, i.e. attach to the skin and / or hair in an unobtrusive fashion.

[0304] In some embodiments, it may be advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (VI),

[0305]

[0306] (VI),

[0307] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, X, Lx, Ly, L16, A11, A14and A16and are defined as in any preceding disclosure. Compounds of this embodiment may be particularly beneficial since they are structurally close to genipin and can be conveniently obtained from genipin itself and / or are structurally close to genipin which is generally considered to be safe. Moreover, when attached to skin and / or hair, compounds of this embodiment were found to be colorless, i.e. attach to the skin and / or hair in an unobtrusive fashion.

[0308] In some embodiments, it may be particularly advantageous that L17is absent and A17represents hydrogen. In some embodiments, it may be particularly advantageous that the substituent combination Lx-A11 represents O-C1-C4-alkyl, and in particular O-CH3. Compounds of this embodiment may be particularly beneficial since they are structurally closest to genipin providing the above-referenced benefits. In some embodiments, it may be particularly advantageous that Lyrepresents linker group which is selected from the group consisting of: -O-, -C(O)-, -CO2-, -O-C(O)-, -(CH2)i-4-, -(CH2)I-4-O- and -O-(CH2)i-4-, and combinations thereof. In some embodiments, it may be most advantageous that additionally the substituent combination -Ly-Ai4 represents -(CH2)2-4-C(=O)-O-Ai4, -(CH2)2-4-C(=O)-NH-Ai4 or -(CH2)2-4-O-A14. In some embodiments, it may be particularly advantageous that Lyrepresents a linker group which is selected from the group consisting of: -O-, -C(O)-, -CO2-, -O-C(O)-, -(CH2)I-4-, -(CH2)I-4-O- and -O-(CH2)I-4-, and combinations thereof. In some embodiments, it may be most advantageous that additionally the substituent combination -Ly-Ai4 represents -(CH2)2-4-C(=O)-O-Ai4, -(CH2)2-4-C(=O)-NH-Ai4 or -(CH2)2-4-O-Ai4. Compounds of these embodiments may be particularly beneficial since they can be efficiently prepared from genipin without requiring a protecting group strategy. In some embodiments, it may be particularly advantageous that Ly-A14 represents a part of the bridging linker group LBRIDGE or LBRIDGE’, represents LFG-PWS, and represents the linker group comprising the second functional group, respectively. For the sake of clarity, this disclosure -and like disclosure elsewhere in the present disclosure - refers back to the corresponding formula referenced in the respective context, i.e. presently means that, if formula (VI) represents a moiety of formula (la) or of formula (lb), Ly-A14 represents a part of the bridging linker group LBRIDGE; if formula (VI) represents a compound of formula (le), Ly-Ai4 represents LFG-PWS; and if formula (VI) represents a compound of formula (If), Ly-Ai4 represents the linker group comprising the second functional group.

[0309] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (VII),

[0310]

[0311] A17L17

[0312] (VII),

[0313] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, L11, L16, L17, A11, A16and A17and are defined as in any preceding disclosure. Compounds of this embodiment may be particularly beneficial since they are structurally close to genipin and can be conveniently and stereo-selectively obtained from the chiral terpenoid myrtenal which is generally considered to be safe and is available at low cost. Moreover, when attached to skin and / or hair, compounds of this embodiment will be colorless, i.e. attach to the skin and / or hair in an unobtrusive fashion. An exemplary synthesis is shown in Figure 6.

[0314] In some embodiments, it may be particularly advantageous that L17is absent and A17represents hydrogen. In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (VIII),

[0315]

[0316] A17L17

[0317] (VIII) 5

[0318] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, L11, L16, L17, A11, A13, A16and A17are defined as in any preceding disclosure; wherein the dashed bond represents a single or a double bond, and in particular a single bond; and wherein Lyis defined as in any preceding embodiment and attached to any one of the carbon atoms marked with a or in case the dashed bond represents a single bond and to the carbon atoms marked with a in case the dashed bond represents a double bond. Compounds of this embodiment may be particularly beneficial since they are structurally close to genipin and can be conveniently obtained from the terpenoid perilladehyde which is generally considered to be safe and is available at low cost. Moreover, when attached to skin and / or hair, compounds of this embodiment will be colorless, i.e. attach to the skin and / or hair in an unobtrusive fashion. The compounds are generally available following the same synthetical approach as shown for myrtenal in Figure 6, but using perilladehyde as the Michael acceptor.

[0319] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (IX),

[0320]

[0321] (IX),

[0322] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, each instance of Ly, L13, L14, L17, A11, A13, A14, A16, and A17 are defined as in any preceding disclosure. Compounds according to this embodiment may be particularly beneficial since the cyclic structure of the cyclohexan-1,3-dione-derivative sterically constrains the ring-opened 1,5 -dicarbonyl compound and, by allowing only the formation of the Z-enol, may facilitate ring-closure to the 3,4-saturated dihydropyran during synthesis, thus, shifting the overall equilibrium towards the product side. The compounds are generally available following the same synthetical approach shown in Figure 6, but using a cy cl ohexan-l,3-di one-derivative as the Michael donor.

[0323] In some embodiments, it may be particularly advantageous that L17 is absent and A17 represents hydrogen.

[0324] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (X),

[0325]

[0326] (X) 5

[0327] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, each instance of Ly, L13, L14, L17, A11, A13, A14, A16, and A17 are defined as in any preceding disclosure. An exemplary synthetical approach is shown in Figure 7 using a lawsone derivative as the Michael acceptor and camphor as the Michael donor. Both lawsone derivatives and camphor derivatives are readily available at low cost and generally regarded as safe.

[0328] In some embodiments, it may be particularly advantageous that L17 is absent and A17 represents hydrogen.

[0329] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (XI),

[0330]

[0331] (XI),

[0332] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, Ln, L13, Lie, An, A13 and Aie are defined as in any preceding disclosure. An exemplary synthetical approach is shown in Figure 8, starting from camphor, 4-(dimethylamino)benzaldehyde and an acetoacetate ester, the latter of which can e.g. be further functionalized to provide the compounds according to the present disclosure. Moreover, the synthetical approach is highly flexible and can be readily adapted. All components are readily available at low cost and generally regarded as safe. The chiral camphor derivative will further provide stereoselectivity to the synthesis (not shown) which will facilitate purification and, thus, also overall yields. In some embodiments, it may be particularly advantageous that L13 represents an optionally substituted phenyl. The intermediate benzylidene camphor derivative shown in Figure 8 can be reliably and robustly obtained in high yields from a larger number of aldehydes. Changing the aromatic aldehyde allows conveniently introducing further functionalities: For instance, the 4-(dimethyl-amino)benzaldehyde provides a group that is protonated at a physiological pH, i.e. improves water solubility. A hydroxybenzaldehyde derivative could provide a further functional group for attaching compounds of interest. Moreover, in case L13 represents an optionally substituted phenyl, the compounds will further provide a UV-absorbing effect.

[0333] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (XII),

[0334]

[0335] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, Ly, Ln, L13, Lie, An, A13, A14 and Aie are defined as in any preceding disclosure. An exemplary synthetical approach is shown in Figure 9, starting from tropinone, benzaldehyde and an acetoacetate ester, the latter of which can be further functionalized to provide the compounds according to the present disclosure. Moreover, the synthetical approach is highly flexible and can be readily adapted. All components are readily available at low cost and generally regarded as safe. The bulky tropinone will further provide stereoselectivity to the synthesis (not shown) which will facilitate purification and, thus, also overall yields. Tropinone will also improve water-solubility since the amine group will be protonated. In some embodiments, it may be particularly advantageous that L13 represents an optionally substituted phenyl. The intermediate benzylidene tropinone derivative shown in Figure 9 can be reliably and robustly obtained in high yields from a larger number of aromatic aldehydes. Changing the aromatic aldehyde allows conveniently introducing further functionalities: A hydroxy benzaldehyde derivative could e.g. provide a further functional group for attaching compounds of interest. Moreover, in case L13 represents an optionally substituted phenyl, the compounds will further provide a UV-absorbing effect.

[0336] In some embodiments, it may be particularly advantageous that one or both moieties of formulae (la) and (lb), or the compound of formula (le) or (If) is a compound / moiety of formula (XIII),

[0337]

[0338] (XIII)

[0339] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, Ln, Lie, An and Aie are defined as in any preceding embodiment. An exemplary synthetical approach is shown in Figure 10 using starting from the chiral pinene derivative nopinone and a formylated monoester of malonic acid, the latter of which can e.g. be further functionalized to provide the compounds according to the present disclosure. All components are readily available at low cost and generally regarded as safe. The chiral nopinone will further provide stereoselectivity to the synthesis (not shown) which will facilitate purification and, thus, also improve overall yields. In some embodiments, it may be particularly advantageous that the substituent combination Ln-An represents (C=O)-Lx-An, wherein Lxand An are defined as indicated above with respect to formula (III). Compounds of this embodiment are particularly reactive due to the electron-withdrawing and resonance-stabilizing effect of the carbonyl group as well as its ability to shift the keto-enol equilibrium of the resulting 4-pyridone to the 4-hydroxy pyridine derivative is further facilitating the coupling to the amino-functionalized active ingredient and / or the keratinous tissue such as skin or hair.

[0340] Specific compounds, in particular for the 1st to 3rd aspect of the present disclosure

[0341] In some embodiments according to the first, second and third aspect, it may be particularly advantageous that the compound according to the first aspect is a compound according to the following formula (XIV),

[0342]

[0343] (XIV) or a tautomer and / or a pharmaceutically acceptable salt thereof; and wherein each instance of R3 represents, independently from each other, R3 as defined in any preceding embodiment, and in particular represents H; wherein each instance of Z represents, independently from each other, represents O or S or C=Z represents a methylene group; and wherein B represents the linker group B as defined in any of the above embodiments of the present disclosure; in particular CH2-(OCH2)i-i2 or (CH2)i-i2, more specifically CH2-(OCH2)I-S or (CH2)I-6, and in particular CH2-(OCH2)I-6 or (CH2)2-4.

[0344] Physiologically hydrolysable protective group R1, R2and R3in all aspects of the present disclosure

[0345] In some embodiments, R1, R2and / or R3may represent the protective group hydrolysable under physiological conditions. The choice of said protective group is not particularly limited. Of note, glucoside moieties such as pyranosyl were found to not be suitable as protective groups since the glucosidic bond between the glucoside moiety and the 3,4-saturated 2H-pyran moiety (which is part of two acetals) is not readily hydrolyzed. However, suitable leaving groups can be readily determined by following one or more of the following principles:

[0346] a) Small protective groups which do not hinder the accessibility of the acetal group (of which R1, R2and / or R3is a part) by water and nucleophiles which are natively present on the skin and / or the hair, and in particular the accessibility by the n-butyl amino group of lysine, will favor the rate of hydrolysis.

[0347] b) Protective groups which represent good leaving groups, in particular protective groups which are able to delocalize or stabilize a positive or negative charge, such as an acyl moiety, will favor the rate of hydrolysis.

[0348] c) Protective groups which themselves can be hydrolysed or decompose under conversion of the ether bond to the 3,4-saturated 2H-pyran moiety can also be utilized. Examples include silyl groups.

[0349] In some embodiments, R1, R2and R3, independently from each other, represents Ci-6 acyl, in particular C1-3 acyl or trifluoracetyl; C1-6 alkyl, in particular methyl or ethyl; or a silyl group, in particular trimethoxysilyl triethoxysilyl, and / c / v-butyldimethylsilyl.

[0350] In some embodiments, it is most advantageous that R1, R2and R3represent hydrogen.

[0351] Specific embodiments of the C1-C30 moiety in all aspects of the present disclosure

[0352] In any of the embodiments of the present disclosure, and independently from each other for each occurrence of the C1-C30 moiety in the present disclosure, it may be advantageous that the C1-C30 moiety comprises 1 to 30, more specifically 1 to 16, and in particular 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 phosphorus atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 boron atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.

[0353] In some embodiments, it may further be advantageous that, again independently from each other, for each occurrence of the C1-C30 moiety in the present disclosure, the C1-C30 moiety is bound a) to the respective Li to L7 and Lr to L7' via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or, b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the Ci-C30 moiety is attached.

[0354] In some embodiments, it may be particularly advantageous that, again independently from each other, for each occurrence of the C1-C30 moiety in the present disclosure, the C1-C30 moiety is selected from a saturated or unsaturated, cyclic or acyclic (hetero)alkyl or (hetero)aryl, each comprising 1 to 30, more specifically 1 to 16, and in particular 1 to 12, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms; and, optionally, wherein the C1-C30 moiety is bound a) to the respective Li to L7 and Lr to L7' via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or, b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the Ci-C30 moiety is attached.

[0355] In some embodiments, it may be particularly advantageous that, again independently from each other, for each occurrence of the C1-C30 moiety in the present disclosure, the C1-C30 moiety is selected from a saturated or unsaturated (hetero)alkyl comprising 1 to 12, more specifically 1 to 8, and in particular 1 to 4, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 nitrogen atoms; 0 or 1 sulfur atom; and 0 to 5, more specifically 0 to 4, and in particular 0 to 3 halogen atoms; and wherein the C1-C30 moiety is bound a) to the respective Li to L7 and Lr to L7' via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or, b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the C1-C30 moiety is attached.

[0356] Compound according to the sixth aspect of the disclosure

[0357] As explained above, the C2-extended hydrogenated carboxylic acid can surprisingly efficiently be prepared with excellent yields and without relying on protecting groups. These intermediates are not only highly useful for the synthesis of compounds according to the first to third aspects, but also for the synthesis of compounds according to the fourth and fifth aspects, and still further unrelated uses. Moreover, the C2-extended hydrogenated carboxylic acid can be further functionalized efficiently without relying on a protecting group strategy, making efficiently available a diverse range of highly useful intermediates.

[0358] Accordingly, in a sixth aspect, there is provided a compound of formula (XV),

[0359]

[0360] wherein Bi represents C(=O)Z1, C(=S) Z1, CH(=O), or an acetal or hemiacetal thereof; CH2-Z2; or Z2; wherein Z1represents -OH, -SH or -NH2; and wherein Z2represents OH, SH, F, Cl, Br, I, N3; or a tautomer and / or a salt thereof.

[0361] Compounds according to this embodiment can be efficiently obtained from genipin via the aforementioned C2-extended hydrogenated carboxylic acid by further functionalization of its carboxylic acid group without having to rely on protecting groups.

[0362] In some embodiments, it may be particularly advantageous that Bi represents C(=O)Z1and Z1represents -OH.

[0363] Compound according to the seventh aspect of the disclosure

[0364] The compounds of the sixth aspect may also be used to efficiently prepare genipin derivatives carrying an active ingredient. Accordingly, in a seventh aspect, there is provided a compound comprising a 3,4-saturated 2H-pyran moiety of formula (XVI),

[0365]

[0366] A20—L20—B2(XVI), or a tautomer and / or a pharmaceutically acceptable salt thereof; for covalently binding an active ingredient to skin and / or hair; wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, UVA- and / or UVB-absorbing moiety, a color-imparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair; wherein B2 represents CH2, C(=O), (C=S), (C=NRc), or a C1-C4 acetal moiety selected from the group consisting of an 0,0-acetal, an O, N-acetal, an O, S-acetal, an N, N-acetal, an S, N-acetal, and an S, S-acetal, wherein the C1-C4 acetal moiety is attached to the adjacent methylene group of the remainder of the 3,4-saturated 2H-pyran moiety by a carbon atom, wherein Rcrepresents H, C1-C6alkyl or phenyl, wherein L20 is absent or represents a linker that is attached to B2 by O, N, C, S, B or P, more specifically by O, N, C or S, and in particular by O, N or S; and wherein A20 represents the active ingredient a) as such, or b) as a precursor thereof, wherein the compound of formula (XVI) is cleavable to release the active ingredient from the precursor after the application of the compound to the skin and / or the hair.

[0367] In some embodiments, it may be particularly advantageous that L20 is defined as indicated for Ls- in any embodiment of the present disclosure.

[0368] In some embodiments, it may be particularly advantageous that A20 is an active ingredient as defined in any of the embodiments of the present disclosure.

[0369] In some embodiments, it may further be particularly advantageous that B2 represents -C(=O) and L20 represents a linker that is attached to B2 by O, S or N.

[0370] In some embodiments, B2 is selected from CH2, C(=O) and (C=S).

[0371] In some embodiments, L20 is absent. In some embodiments, it may be further advantageous in view of the efficiency of the synthesis that the active ingredient is attached to B2 by O, N or S.

[0372] In some embodiments, it may be particularly advantageous that B2 is selected from CH2, C(=O) and (C=S), L20 is absent and the active ingredient is attached to B2 by O, N or S. In such embodiments, the subsequent reaction steps of the intermediate compounds according to the sixth aspect of the disclosure are kept at a minimum. In some embodiments, B2 represents a C1-C4 acetal moiety selected from the group consisting of an 0,0-acetal, an O, S-acetal, or an S, S-acetal. Examples of such acetal moieties are shown below, wherein the broken bond represents the bond to the methylene group of the remainder of the 3,4-saturated 2H-pyran moiety:

[0373]

[0374] Active ingredients of the present disclosure

[0375] In the following, the active components linked to the remainder of the compounds according to the present disclosure will be discussed. For reasons of simplicity of language, in some instances, reference to the active ingredient will be made as if the active ingredient is an individual compound instead of a moiety attached to the remainder of the compound according to, in particular, the 2nd, 4thand 7thaspect of the present disclosure. It should be understood that this is to be interpretated as a reference to a moiety that is attached to the remainder of said compound, by e.g. elimination of a hydrogen atom from the active ingredient.

[0376] It should be further understood that the below disclosure regarding the active components is freely combinable with the above disclosure relating to the compounds the present disclosure.

[0377] It should also be understood that the below disclosure of active ingredients also applies to the respective precursors thereof, unless expressly stated to the contrary.

[0378] In some embodiments, the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a color-imparting moiety, a cosmetic hair coating agent and a primer for attaching dyes to hair. In some embodiments, it may be particularly advantageous that the active ingredient is the moisturizer, the skin moisturizer or the hair moisturizer, respectively.

[0379] The concrete structure and / or mass of the active ingredient or the precursor thereof is not particularly limited since the anchoring moieties are robustly linking to keratinous tissues such as skin and / or hair independently therefrom. In some embodiments, the active ingredient or the precursor thereof is a Ci-Ceo moiety. In some embodiments, the active ingredient or the precursor thereof is a polymeric moiety.

[0380] Humectants, Emollients, Occlusives, in particular hyaluronic acid

[0381] In some embodiments, the active ingredient is a moisturizer, a skin moisturizer or a hair moisturizer, respectively.

[0382] In some embodiments, the active ingredient comprises a plurality of hydrogen bonding groups selected from the group consisting of hydroxyl groups, ether groups, carboxylic acids, amines and amides; and their salts. In some embodiments, the plurality of hydrogen bonding groups comprises three or more, more specifically 4 or more, and in particular 6 or more hydrogen bonding groups. In some embodiments, the ratio of C-atoms to the sum of hydrogen bonding groups comprised in the active ingredient is between about 4: 1 to 1: 1, more specifically between about 3:1 to about 1:1 and in particular between about 2:1 to about 1:1. In some embodiments, the active ingredient has a molecular weight of at least 60 g / mol, more specifically at least 90 g / mol, and in particular at least 120 g / mol. In some embodiments, the active ingredient has a molecular weight of 60 g / mol to 2000 g / mol, more specifically 90 g / mol to 1600 g / mol, and in particular 120 g / mol to 1200 g / mol. In some embodiments, the ratio of C-atoms to the sum of heteroatoms comprised in the active ingredient is between about 4:1 to 1:2, more specifically between about 3: 1 to about 1:1.5, and in particular between about 2: 1 to about 1:1, wherein the heteroatoms are selected from nitrogen and oxygen. In some embodiments, the active ingredient comprises:

[0383] a polyol, more specifically a polyol having n hydroxyl groups with n being 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 8 or more, 10 or more, 12 or more, or 16 or more; a mono- or polyvalent carboxylic acid comprising one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid or citric acid;

[0384] a sugar, more specifically a triose, a tetrose, a pentose a hexose, a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide;

[0385] a sugar alcohol, more specifically a sugar alcohol comprising between 2 and 24 carbon atoms, in particular ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, or maltotetraitol; or

[0386] a sugar acid, more specifically an aldonic acid, an ulosonic acid, an uronic acid or an aldaric acid; or a salt thereof; or an ester thereof, in particular a C1-C4-alkylester thereof; or an amide thereof; or

[0387] a water-soluble polymer is a polysaccharide; more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid; and in particular hyaluronic acid; and copolymers thereof, in particular copolymers comprising polyethylene glycol.

[0388] In some embodiments, it may be particularly advantageous that the active ingredient is a hyaluronic acid, more specifically a hyaluronic acid having a weight-average or a number-average, and in particular a number-average, molecular weight of between 3000 and 3 million kDa, more specifically between 5000 and 2 million kDa, and in particular between 10,000 and 1.5 million kDa.

[0389] In some embodiments, the active ingredient is an emollient or an occlusive.

[0390] In some embodiments, the active ingredient comprises: a Cio-Ceo moiety, more specifically a C15-C60 moiety and in particular a C20-C60 moiety; or an oligo- or polysiloxane, in particular a poly(di-Ci-C4-alkyl)siloxane. In some embodiments, the active ingredient is the Ci-Ceo moiety and has a molecular weight of 140 g / mol to 2000 g / mol, more specifically 160 g / mol to 1600 g / mol, and in particular 180 g / mol to 1200 g / mol. In some embodiments, the active ingredient has more than 30 carbon atoms. In some embodiments, the active ingredient comprises a saturated or unsaturated Cio-Ceo aliphatic moiety, more specifically a Cis-Ceo aliphatic moiety, and in particular a C20-C60 aliphatic moiety. In some embodiments, the ratio of C-atoms to the sum of heteroatoms comprised in the active ingredient is between about 60:1 to 5:1, more specifically between about 50:1 to about 10:1, and in particular between about 40:1 to about 20:1, wherein the heteroatoms are selected from nitrogen and oxygen. In some embodiments, the Ci-Ceo moiety is a sphingosine or a derivative thereof, in particular a ceramide or a sphingomyelin.

[0391] Pesticides

[0392] In some embodiments, the active ingredient is a pesticide.

[0393] In some embodiments, the pesticide may be an insect repellant. For the purposes of the present disclosure, an insect repellent is a chemical used to control insects without killing or incapacitating them, in particular by making the host (i.e. the subject to which the insect repellant is applied) less attractive to the insect.

[0394] In some embodiments, the pesticide may be an insecticide. For the purposes of the present disclosure, an insecticide is a chemical used to control insects by killing or incapacitating them.

[0395] In some embodiments, the insect repellant or insecticide may act against an ectoparasite and / or a hematophagous insect, in particular a hematophagous insect selected from the group consisting of mosquitoes, ticks, mites, gnats, fleas, chiggers, leeches and bugs. Ectoparasites are organisms that live on the skin of a host, from which they derive their sustenance.

[0396] Skin whitening agents

[0397] In some embodiments, the active ingredient is a skin whitening agent.

[0398] In some embodiments, the skin whitening agent acts by chemically or metabolically whitening the skin, in particular by providing a bleaching effect or decreasing melanin production. In some embodiments, the skin whitening agent is selected from corticosteroids, in particular clobetasol derivatives, fluocinolone derivative, or betamethasone; a vitamin A derivative, in particular tretinoin, isotretinoin, alitretinoin, retinol or retinal; a hydroxyphenol derivative, in particular hydroquinone; an aliphatic dicarboxylic acid, in particular azelaine; alpha-hydroxy-acids, in particular lactic and glycolic acid; and vitamin C.

[0399] Fragrances In some embodiments, the active ingredient is the fragrance. It should be understood that the fragment is present in the form of its precursor. In some embodiments, the precursor is a Ci-Ceo moiety comprising a functional group which couples the Ci-Ceo moiety to the corresponding Li, L2, L3, L4, Ls, Le, L7, or Ls’ moiety or, if the corresponding Li, L2, L3, L4, Ls, Le or L7 moiety is absent, to the 3,4-saturated-2H-pyran moiety, or, if the corresponding Ls’ moiety is absent, to the respective cycloalkane moiety. In some embodiments, the Ci-Ceo moiety is cleaved under physiological conditions on skin and / or hair to an aldehyde, a ketone, a thiol, a hydroxy, a carboxy, or an amine. In some embodiments, the functional group is an imine, an acetal, a 1,1-diester, an enolether, an ester, an amide, a thioester, or a thioacetal. In some embodiments, the Ci-Ceo moiety has a molecular weight after being cleaved off of less than 400 g / mol, more specifically less than 300 g / mol, and in particular less than 200 g / mol. In some embodiments, the fragrance is not benzyl alcohol or hexanol.

[0400] Pharmaceuticals

[0401] In some embodiments, the active ingredient is a pharmaceutical.

[0402] In some embodiments, the pharmaceutical is suitable for treating a skin-associated disease and / or a hair-associated disease. In some embodiments, the skin-associated disease is selected from acneiform eruptions, autoinflammatory syndromes, chronic blistering, conditions of the mucus membranes, conditions of the skin appendages, conditions of the subcutaneous fat, congenital anomalies, connective tissue diseases, abnormalities of dermal fibrous and elastic tissue, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, disturbances of pigmentation, endocrine-related skin conditions, eosinophilic cutaneous conditions, skin lesions, skin cancer, erythemas, genodermatoses, infection-related cutaneous conditions, lichenoid eruptions, lymphoid-related cutaneous condition, melanocytic nevi and neoplasms, monocyte- and macrophage-related cutaneous conditions, mucinoses, neurocutaneous conditions, Noninfectious immunodeficiency-related cutaneous conditions, Nutrition-related cutaneous conditions, Papulosquamous hyperkeratotic cutaneous conditions, Palmoplantar keratodermas, pruritus, psoriasis, reactive neutrophilic cutaneous conditions, skin conditions resulting from errors in metabolism, skin conditions resulting from physical factors, urticaria, dandruff, desquamation disorders, and vascular-related cutaneous conditions; and / or the hair-associated disease is selected from dandruff and alopecia. In some embodiments, the active ingredient is an agonist of a retinoid receptor, more specifically a retinoic acid receptor, a retinoid X receptor and / or a RAR-related orphan receptor. In some embodiments, the active ingredient comprises a vitamin A vitamer, more specifically a vitamer selected from the group of retinol, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene and / or bexarotene, in particular retinol, retinal and / or adapalene.

[0403] Cosmetic hair coating agents

[0404] In some embodiments, the active ingredient is a cosmetic hair coating agent.

[0405] In some embodiments, the cosmetic hair coating agent provides a conditioning effect to the hair. Compounds / moieties providing a hair-conditioning effect are well-known in the art. Suitable examples include compounds / polymers having long hydrocarbon or siloxane backbones which help to lubricate the surface of the hair, thereby reducing the sensation of roughness and assisting combing. Conventional conditioners often also contain quaternary cationic groups. These groups have a dual purpose: First, they help in attaching conventional conditioners to the hair. The outermost layer of a hair is rich in cysteine groups which are mildly acidic. When the hair is washed these groups can deprotonate, giving the hair a negative charge. Positively charged quaternary ammonium species can then become attached to the hair via electrostatic interactions. This functionality is of lesser importance for the present disclosure since the compounds attach to hair in a different manner. However, the surface coating of cationic groups also results in the hair being repelled from each other electrostatically which reduces clumping. Accordingly, while not essential, the active ingredient may also benefit from the presence of the quaternary cationic groups.

[0406] In some embodiments, the cosmetic hair coating agent provides a gloss effect (or shine) to the hair. Compounds / moieties providing a gloss-effect or shine effect are well-known in the art. Typical examples include polymer having a high refractive index and examples (copolymers comprising poly ether blocks and poly siloxane blocks) are, for instance, disclosed in European Patent Application EP 3 162 408 Al which is incorporated herein in its entirety by reference thereto. In some embodiments, the cosmetic hair coating agent provides a reinforcing effect to the hair. When referring to a reinforcing effect, it is meant that the hair is physically coated with e.g. a polymer to make it thicker and that the hair is provided with a coating that improves the styling performance of the hair (much like e.g. a styling gel would). Compounds providing such reinforcing effects are well-known in the art and include vinyl (co-)polymers such as polyvinyl pyrrolidone or a copolymer of dimethylamino-ethylmethacrylate and polyvinyl pyrrolidone. Such (co-)polymers are capable of forming hydrogen bonds along the entire polymer chain which provides the styling effect. Other suitable polymers include derivatives of polyethylene glycol. A reinforcing (styling) effect such as curling can also be provided by enriching the surface with moieties provided with one or more thiols. Examples of such moieties include cysteine and cysteine derivatives. These thiols can be oxidized to dithiols (just as in a conventional perm) with an oxidizing agent (such as an peroxide) to provide the hair with a desired shape.

[0407] In some embodiments, the cosmetic hair coating agent provides an anti-frizz effect to the hair. When referring to an anti-frizz effect, it is meant that the frizziness of the hair is reduced. Compounds / moieties providing an anti-frizz effect are also well-known in the art and include compounds that can act as antistatic agents. Suitable compounds are well-known in the art and in particular encompass compounds / polymers which contain quaternary cationic groups and poly carboxylic acids or poly carboxylates, in particular a polyitaconate.

[0408] Accordingly, in some embodiments, the cosmetic hair coating agent may in particular be further characterized as follows:

[0409] In some embodiments, the cosmetic hair coating agent provides a conditioning effect to the hair. In some embodiments, the cosmetic hair coating agent provides a gloss effect to the hair. In some embodiments, the cosmetic hair coating agent provides an anti-frizz effect to the hair. In some embodiments, the cosmetic hair coating agent provides a reinforcing effect to the hair.

[0410] In some embodiments, the cosmetic hair coating agent represents a Ci-Ceo moiety, in particular a Ci-Ceo moiety having a molecular weight of 60 g / mol to 2000 g / mol, more specifically 90 g / mol to 1600 g / mol, and in particular 120 g / mol to 1200 g / mol; or a polymeric moiety. In some embodiments, the cosmetic hair coating agent is a sphingosine or a derivative thereof, in particular a ceramide or a sphingomyelin. In some embodiments, the cosmetic hair coating agent is positively charged and / or comprises a cation, in particular a quaternary cation. In some embodiments, the cosmetic hair coating agent is negatively charged and / or comprises an anion, in particular a sulfate ion or a carboxylate ion. In some embodiments, the cosmetic hair coating agent is a polymeric moiety, in particular a polymeric moiety that is positively charged and / or comprises a cation, in particular a quaternary cation. In some embodiments, the cosmetic hair coating agent is a polyquatemium, in particular polyquatemium-16, polyquatemium-46, polyquatemium-11, poly quatemi um-28, polyquatemium-6, polyquatemium-7, polyquatemium-22, polyquatemium-39, polyquatemium-2, polyquatemium-17, or polyquatemium- 18. In some embodiments, the cosmetic hair coating agent is a poly carboxylic acid or a polycarboxylate, in particular a polyitaconate. In some embodiments, the cosmetic hair coating agent comprises a polyether, more specifically a poly-(Ci-C6)ether, and in particular polymers of ethylene oxide and / or propylene oxide. In some embodiments, the cosmetic hair coating agent comprises a poly siloxane, more specifically a poly(di-Ci-C4-alkyl)siloxane and derivatives thereof. In some embodiments, the cosmetic hair coating agent comprises a copolymer comprising polyether blocks and polysiloxane blocks.

[0411] Primers for attaching dyes to hair

[0412] Hair dyes and also reactive hair dyes are well-known in the art. The compounds of the present disclosure can be utilized to provide functional groups to the hair surface and / or its interior which subsequently allow the (covalent) attachment of dyes and pigments to the hair which are otherwise not attachable to hair, or only under aggressive conditions which may damage the hair.

[0413] Moreover, the compounds of the present disclosure can also be utilized to provide a more gentle hair dying method. Conventional hair dyes require a rather aggressive treatment of the hair to open the hair cuticle such that dye precursors can access the core of the hair. The dye precursors deposited in the core of the hair are then developed into a color using oxidative or reductive developers, followed by a treatment with a conditioner to restore the cuticle layer to encapsulate the dye in the core of the hair. However, this process is far from perfect and permanently damages the hair. The compounds of the present disclosure can be utilized to covalently bind

[0414] -11- such dye precursors to the hair surface and / or its interior under milder conditions, and the bound dye precursors can then be developed into dyes using the established developers.

[0415] To summarize, the compounds of the present disclosure may be used for priming the hair by covalently binding functional groups to the hair which are subsequently utilized to attach colorants (dyes or pigments) to the hair or by covalently binding dye precursors to the hair which are subsequently converted into (the desired) color by applying a color developer. Both of these concepts are to be understood as concepts for attaching dyes to the hair, in accordance with the present disclosure.

[0416] Utilizing the compounds of the present disclosure for attaching two types of primer are of particular relevance, namely a) enriching the hair with functional groups which are naturally occurring in hair (hydroxyl, amines, sulfides, etc.) but not in sufficient number to adequately attach colorants to the hair; and, additionally or alternatively, b) providing functional groups not naturally occurring in hair (e.g. aromatic diamines, aminophenols and resorcinol derivatives) to use their functionality to attach colorants to the hair or to develop them to dyes using a developer.

[0417] The above concept of hair dyeing may be particularly gentle to the hair, in particular since the core of the hair does not need to be made accessible to entrap the dye in the core of the hair.

[0418] Accordingly, in some embodiments, in particular relating to uses of the compounds of the present disclosure for covalently binding the one or more active ingredients to hair, represents the active ingredient which is a primer for attaching dyes to the hair.

[0419] In some embodiments, the primer comprises one or more functional groups, in particular hydroxyl, thiol or amino groups, and the use comprises treating the hair with a second composition comprising a colorant (a dye or a pigment) which is capable of covalently binding to said one or more functional groups, optionally in the presence of a coupling agent, in particular an oxidizing agent or a reducing agent. In some embodiments, the coupling agent is comprised in the second composition. In some embodiments, the coupling agent is comprised in a third composition. In some embodiments, the primer comprises a thiol group, the second composition comprises a colorant comprising a thiol group which is capable of covalently binding with the thiol group of the primer under formation of a disulfide bond, optionally in the presence of a coupling agent, in particular an oxidizing agent.

[0420] In some embodiments, the primer comprises one or more ionic functional groups, and the use comprises treating the hair with a second composition comprising a colorant (a dye or a pigment) which is capable of binding to said one or more ionic functional groups by ion-ion interactions and / or by forming a chelate.

[0421] In some embodiments, the primer comprises one or more dye precursors, and the use comprises treating the hair with a second composition comprising a developer which is reacting with the one or more dye precursors to provide a colorant, optionally in the presence of a coupling agent, in particular an oxidizing agent or a reducing agent. In some embodiments, the developer is said oxidizing agent or said reducing agent. In some embodiments, the coupling agent is comprised in the second composition. In some embodiments, the coupling agent is comprised in a third composition.

[0422] In some embodiments, the primer is a Ci-Ceo moiety, in particular a Ci-Ceo moiety having a molecular weight of 60 g / mol to 2000 g / mol, more specifically 90 g / mol to 1600 g / mol, and in particular 120 g / mol to 1200 g / mol.

[0423] In some embodiments, the primer is an aromatic moiety comprising two or more functional groups selected from hydroxyls, primary, secondary or tertiary amines, and ethers.

[0424] In some embodiments, the primer is selected from resorcinol, m-aminophenol, 2-methyl-5-aminophenol, p-phenylenediamine, 2,4-diaminoanisole, 1,5-dihydroxynaphthalene, 4-methoxy-3-aminophenol, 2,4-diaminophenoxyethanol, m-diethylaminophenol and p-amino-o-cresol; and derivatives thereof.

[0425] In some embodiments, the dye precursor is selected from para-phenylenediamine and paraaminophenol. In some embodiments, the dye precursor is a precursor (or a derivative thereof) as disclosed in the review article by Morel et al., in Chem. Rev. 2011, 111, 4, 2537-2561, which is incorporated herein in its entirety by reference thereto.

[0426] In some embodiments, the oxidizing agent is a peroxide, in particular hydrogen peroxide.

[0427] In some embodiments, the reducing agent is a thiol-based reducing agent, and in particular a thiol-based reducing agent selected from the group consisting of thioglycolic acid, cysteine, thiolactate, and salts thereof.

[0428] In some embodiments, the compound of the present disclosure is less than 14 Angstrom, more specifically less than 12 Angstrom, and in particular less than 9 Angstrom, in size. The small size of the molecules may help in penetrating the hair which has been likened to a molecular sieve with a sieve hole size of 14.8 Angstrom in the literature.

[0429] UVA and / or UVB-absorbing moieties and color-imparting moieties

[0430] In some embodiments, the active ingredient is a color-imparting moiety or a UVA and / or UVB-absorbing moiety.

[0431] In some embodiments, the color-imparting moiety has at least one absorption peak within the wavelength range of 380 to 790 nm, more specifically at least one absorption peak within the wavelength range of 380 to 790 nm having an absorbance value of more than 0.5 when measured at a concentration of 2 mM.

[0432] In some embodiments, the UVA- and / or UVB-absorbing moiety has at least one absorption peak within the wavelength range of 280 to 379 nm, more specifically at least one absorption peak within the wavelength range of 280 to 379 nm having an absorbance value of more than 0.5 when measured at a concentration of 2 mM.

[0433] In some embodiments, the color-imparting moiety is: a) an optionally substituted (hetero)aromatic moiety comprising, in combination with its optional substituents, 4 to 40 carbon atoms; or b) an optionally substituted conjugated moiety comprising, in combination with its optional substituents, 6 to 40 carbon atoms and at least 3 conjugated C-C double bonds. In some embodiments, the UVA and / or UVB absorbing moiety is: a) an optionally substituted (hetero)aromatic moiety comprising, in combination with its optional substituents, 4 to 36 carbon atoms; or b) an optionally substituted conjugated moiety comprising, in combination with its optional substituents, 4 to 36 carbon atoms, and at least 2 conjugated C-C double bonds.

[0434] In some embodiments, at least one of A1, A2, A3, A4, A5, A6, A7and A8represents a chromophore (dye moiety), more specifically selected from an azo group; a diazo group; a diphenylamine group; a nitroarylamine group; an azine group; an oxazine group; an acridine group; an indoline group; a sulfur dye group, in particular a thiazine group, a thiazole group, a thiazone group, a thianthrene group, or a phenothiazonethioanthrone group; a quinoid or quinone group; an anthraquinoid or anthraquinone group; a xanthene group; a naphthostyryl group; a diaryl methyl or triarylmethyl group; a benzodifuranone-based group; a formazan group; a phthalocyanine group; or a metal complex.

[0435] In some embodiments, the UVA- and / or UVB-absorbing moiety as one of the active ingredients or of the precursors thereof which is selected / derived from: a benzophenone group, a benzotriazole group, a benzone group, salicylic acid or a salicylic acid derivative, a benzocaine group, an esculin or an esculin derivative, a ferulic acid or a ferulic acid derivative, octinoxate or an octinoxate derivative, or octocrylene or an octocrylene derivative.

[0436] No or low color anchoring compound

[0437] The compounds of the present disclosure do not necessarily have to be colorless when bound to skin or hair. For instance, if the compounds are used to bind active ingredients to farm animals, color does not play a prominent role and may even be desirable. However, in particular in uses for humans, it may be beneficial that the compounds of the present disclosure, in the form as they are bound to skin or hair, are colorless (or nearly colorless and, thus, not visually perceivable on the skin and hair) or do not add more color than already provided by the active ingredient and / or the precursor comprised in the compound.

[0438] Accordingly, in some embodiments, the compound of the present disclosure, after having covalently bound to the skin and / or the hair, is not observable to the human eye on the skin and / or the hair. This may, for instance, be tested with a test sample of explanted porcine skin to which the compound has been covalently bound.

[0439] Suitable test conditions include a visual inspection, optionally by a test panel of 5 of more panelists, in a dark room under artificial light conditions of 3000 Kelvin and an intensity of 1000 Lux. The test sample may be prepared by applying a methanolic solution of the compound of the present disclosure onto explanted porcine skin at a concentration of 1 pmol / in2(=0.156 pmol / cm2), followed by incubation at 25°C and at 50% relative humidity for 24 hours. At the concentration of 1 pmol / in2, hydrogenated genipin and oleuropein aglycone bind to skin without being visually perceivable whereas skin-bound genipin is still perceivable at about 0.07 pmol / in2. For compounds of the present disclosure comprising oligomeric or polymeric active ingredients or precursors, the number-average molecular weight of the compound can be determined by any suitable means, for instance high-pressure liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), MALDI mass spectrometry, size exclusion chromatography (SEC), gel permeation chromatography (GPC),1H- or13C-NMR, or diffusion-ordered NMR spectroscopy (DOSY). Alternatively, for compounds of the present disclosure comprising oligomeric or polymeric active ingredients or precursors, the test sample may also be prepared by applying the equivalent of 3 mg of the compound of the present disclosure in a methanolic solution onto an area of 1 in2(= 6.45 cm2) of explanted porcine skin, followed by incubation at 25°C and at 50% relative humidity for 24 hours.

[0440] Alternatively or additionally, a comparative test can be performed: The compound of the present disclosure can be considered to have bound to the skin and / or the hair as not observable to the human eye, if the compound of the present disclosure is not observable at such a high concentration that oleuropein aglycone is starting to be observable. Suitable test conditions again include a visual inspection, optionally by a test panel of 5 of more panelists, in a dark room under artificial light conditions of 3000 Kelvin and an intensity of 1000 Lux. The test samples may be prepared by applying a methanolic solution of the compounds onto samples of explanted porcine skin at a series of diluted concentrations, optionally including concentrations of 5 and 10 pmol / in2(=0.780 pmol / cm2and 1.56 pmol / cm2), followed by incubation of each sample at 25°C and at 50% relative humidity for 24 hours. In some embodiments, the compound of the present disclosure, after having covalently bound to lysine, does not show UV / vis absorption peaks having an extinction of more than 0.5 within the wavelength range of 380 to 790 nm in a 2 mM methanolic solution.

[0441] In some embodiments, the compound of the present disclosure, after having covalently bound to lysine, does not show UV / vis absorption peaks having an extinction higher than oleuropein aglycone in the wavelength range of 380 to 790 nm when both compounds are tested at the same concentration.

[0442] Functionalized linking groups LBRIDGE and LBRIDGE’

[0443] Referring back to the bridging linker group LBRIDGE’ according to the second aspect of the present disclosure, the present disclosure also provides for embodiments in which said bridging linker group is further functionalized to attach further active ingredients, or precursors thereof, to the same molecule.

[0444] In some embodiments, LBRIDGE’ further comprises one or more further moieties according to formula (Ic) or (Id), and in particular one or more further moieties according to formula (Ic). In some embodiments, it may be particularly advantageous that LBRIDGE’ further comprises one or more linker groups L9 which each, and independently from each other, comprise a further moiety according to formula (Ic) or (Id) comprising a further active ingredient, wherein said further active ingredient is present: a) as such, or b) as a precursor thereof, in which case said linker group L9 is cleavable to release said active ingredient from the compound after the application of the compound to the skin and / or the hair.

[0445] In some embodiments, each instance of L9 comprises, independently from each other, one or more of, two or more of, three or more of, four or more of, five or more, or all of:

[0446] 1 to 12 carbon atoms, more specifically 1 to 8 carbon atoms, and in particular 1 to 4 carbon atoms;

[0447] 1 to 4 oxygen atoms, more specifically 1 to 3 oxygen atoms, and in particular 1 or 2 oxygen atoms;

[0448] 1 to 4 nitrogen atoms, more specifically 1 to 3 nitrogen atoms, and in particular 1 or 2 nitrogen atoms;

[0449] 1 to 3 sulfur atoms, more specifically 1 or 2 sulfur atoms, and in particular 1 sulfur atom; 1 to 3 phosphorus atoms, more specifically 1 or 2 phosphorus atoms, and in particular 1 phosphorus atom

[0450] 1 or 2 boron atoms, and in particular 1 boron atom.

[0451] In some embodiments, it may be particularly advantageous that the compound has bound to the skin and / or the hair, at least one and in particular all of L9 are, independently from each other: (i) biostable; or (ii) cleavable, more specifically cleavable under physiological conditions encountered after its application to the skin and / or the hair, and / or cleavable under conditions preselected for said use, in particular cleavable upon elevation of temperature to higher than 42 °C, cleavable upon exposure to daylight, cleavable upon exposure to UVA- and / or UVB-light, cleavable upon exposure to acids, cleavable upon exposure to an oxidizing agent suitable for oxidizing said functional group, cleavable upon exposure to a reducing agent suitable for reducing said functional group, or cleavable upon exposure to salts. In some embodiments, at least one and in particular all of L9 are hydrolysable at the physiological pH of mammalian skin, more specifically of human skin, and in particular at a pH of between about 5 to about 6. In some embodiments, at least one and in particular all of L9 are enzymatically cleavable under physiological conditions after the compound is topically applied onto mammalian, more specifically human skin, in particular enzymatically cleavable by enzymes present in the mammalian, more specifically human skin.

[0452] In some embodiments, at least one and in particular all of L9 provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; after cleavage of L9.

[0453] In some embodiments, at least one and in particular all of L9 are provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; to said active ingredient after cleavage of L9. In some embodiments, it may be particularly advantageous that, independently for each instance of L9, after cleavage of said L9: L9 provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to said active ingredient; and L9 provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to the remainder of the compound.

[0454] In some embodiments, at least one and in particular all of L9 comprise a carbon ester, in particular a monoester, 1,1 -diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; a disulfide; a carbon amide, in particular a peptide or aN-Mannich base; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amide; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; a phosphonic acid amide; a boronic ester, a borinic ester, a boric ester; an oxazol, a triazole, a benzothiazole, or a coumarin.

[0455] Further aspects of the present disclosure

[0456] In an eighth aspect, the present disclosure provides a topical composition comprising a compound of the present disclosure, wherein the topical composition further comprises an excipient that is suitable for topical administration.

[0457] Any of the specific compounds disclosed herein; in particular the compounds disclosed in the second, fifth, sixth and seventh aspect, or the compounds obtained by or obtainable by the process of the fourth aspect; also represent specific embodiments according to this eighth aspect of the present disclosure.

[0458] The topical composition is not particularly limited and includes any such composition for topical administration. Topical administration in the sense of the present disclosure refers to any local (i.e. not systemic) administration, whether through ointments, gels, creams, lotions, or other similar formulations, of the compounds or compositions of the present disclosure, including administration directly to the external epidermis or dermis of a subject, including administration to skin appendages such as hair but excluding oral, rectal, intrapulmonary and intranasal administration. As one form of topical composition, the present disclosure further pertains in some embodiments to the compounds or compositions of the present disclosure for use as a cosmetic.

[0459] In the present application, a cosmetic or a cosmetic use means that the composition is suitable for external use (i.e. extracorporeal use, e.g. not ingested) and is in particular suitable for application to the skin or hair. In some embodiments, the term “cosmetic” is referring to an article intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance. In some embodiments, the reference to a cosmetic use is excluding a medical use. In some embodiments, the reference to a cosmetic use means that the compounds of the present disclosure, and / or the composition comprising them, complies with Regulation (EC) N° 1223 / 2009 of the European Union and / or with The Modernization of Cosmetics Regulation Act of 2022 of the USA.

[0460] Generally, the aforementioned compositions can be formulated in any form known in the art for cosmetic (topical) administration. Hence, the composition can be applied in any topical form, such as in the form of aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic / sunscreen and skin care formulation. The composition can also be water-resistant (e.g. waterproof).

[0461] The topical composition may also be present in the form of a patch or a carrier comprising the topical composition. Examples of a patch include an adhesive label or thin foil on which the composition is coated or printed. Examples of a carrier include a non-woven material or a hydrogel in which the composition is impregnated.

[0462] The compositions of this disclosure may contain one or more of the compounds of the present disclosure described herein in the range of 0.005 wt.-% to 99 wt.-% with the balance made up from the suitable excipients. The contemplated compositions may contain 0.01 wt.-% to 99 wt.-% of any one of the compounds provided herein, in one embodiment 0.1 to 95 wt.-%, in another embodiment 75 to 85 wt.-%, in a further embodiment 20 to 80 wt.-%, wherein the balance may be made up of any excipient described herein, or any combination of these excipients. The topical composition according to the present disclosure further comprises an excipient suitable for topical administration. The excipient is not particularly limited. In some embodiments, the excipient suitable for topical administration comprises one or more excipients selected from water, ethanol, isopropanol, n-propanol, ethylene glycol, diethylene glycol, a propylene glycol, pentylene glycol, diethylene glycol monoethyl ether, DMSO, and glycerol.

[0463] In some embodiments, the topical composition can also be a pre-dispersed composition comprising the compound of this disclosure and a liquid carrier. These compositions can be a solution (e.g., free of any undissolved solid particles), a dispersion (e.g., containing a liquid phase and a solid precipitant phase), or an emulsion.

[0464] In some embodiments, the topical composition may contain water and / or organic solvents as suitable carriers and excipients. In one example, the liquid composition can be sterile and / or prepared from a sterile aqueous solution for infusion.

[0465] In some embodiments, the topical composition may also include a surface-active agent, such as an alkylbenzene sulfonate, an alkyl sulfate, an alkyl ether sulfate, a soap, an ethoxylate, an alkyl alcohol, a lignosulfonate, or a triglyceride. The composition may also include a solid matrix. Suitable examples of a matrix component include a sugar, a sugar alcohol (e.g., sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydrolysates), a polymer, or a combination of two or more thereof.

[0466] In some embodiments, the composition may also include a skin penetration enhancer. A “skin penetration enhancer” as used herein refers to a substance that penetrates into skin (penetrant) to reversibly decrease its barrier resistance. In some embodiments, a skin penetration enhancer can also enhance the solubility of the penetrant to increase loading, which may, for example, enhance the flux of the penetrant across the skin. Non-limiting examples of a skin penetration enhancer include an alcohol, an amide, an ester, an ether alcohol, a fatty acid, a glycol, a pyrrolidone, a sulphoxide, and a terpene.

[0467] In some embodiments, it may be particularly beneficial that the topical composition comprises trehalose. Trehalose is a disaccharide otherwise known as a-D-glucopyranosyl-a-D-glucopyranoside. Unlike other disaccharides or sugar analogs that have been used in moisturizers for the skin, the present inventors have found that trehalose, besides providing a moisturizing effect, also facilitates the penetration of anchor compounds into the deeper layers of the skin, thereby enhancing the attachment and long-lasting effect of the compounds of the present disclosure.

[0468] In some embodiments, the composition may also include a preservative; a thickening agent, more specifically a gelling agent, and in particular xanthan gum; a film-forming agent and / or a humectant.

[0469] As used herein, a “preservative” refers to an agent that protects the topical composition against decay, discoloration, and / or spoilage. Nonlimiting examples of a preservative include ascorbic acid, an ascorbate, a palmitate, citric acid, a benzoate, a benzoic acid, a sorbate, sorbic acid, methylisothiazolinone, phenoxyisopropanol, chlorhexidine and its derivatives, ethylenediaminetetraacetic acid (EDTA), butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), a sulfite, a bisulfite, a metabisulfite, propylparaben, an isothiazoline, a paraben, phenoxyethanol, tocopherol, or combinations thereof.

[0470] As used herein, a “thickening agent” refers to an agent that increases the viscosity of a liquid. In some embodiments, the thickening agent increases the viscosity of the liquid without substantially changing other properties of the topical composition. Non-limiting examples of thickening agents include starches; gums (e.g., natural and synthetic gums); in particular xanthan gum; cellulosics; and arabinogalactan; and combinations thereof.

[0471] As used herein in context of the formulation of a topical composition, a “humectant” refers to a substance that attracts water. For example, a humectant may attract water to bring moisture to the skin and / or to bind moisture to the skin. Non-limiting examples of humectants include polyhydric alcohols, for example, poly alkylene glycols (e.g., alkylene polyols and their derivatives), alpha hydroxy acids, sugars, Aloe vera gel, vegetable oil, lithium chloride, allantoin, urea, and dicyanamide, and combinations thereof.

[0472] As used herein, a “film-forming agent” refers to a compound that can produce a continuous fdm on skin, more specifically a continuous film on skin upon drying of the topical composition. Non-limiting examples of film-forming agents include (volatile) silicone resins, polyvinylpyrrolidone, (meth)acrylates, acrylamides, copolymers of (meth)acrylates and / or acrylamides, isododecane resins, and combinations thereof. Non-limiting examples of (volatile) silicone resins include polymethylsilsesquioxane, trimethylsiloxysilicate, polypropylsilsesquioxane, dimethicone, cyclopentasiloxane, dimethiconol crosspolymer, polysilicone-6, polysilicone-8, polysilicone-11, and polysilicone-14. Non-limiting examples of copolymers include acrylates copolymer, styrene / acrylates copolymer, acrylates / Ci2-22 alkyl methacrylate copolymer, acrylates / polytrimethylsiloxymethacrylate copolymer, polyvinylpyrrolidone / vinyl acetate (VP / VA) copolymer, VP / dimethiconylacrylate / polycarbamyl / polyglycol ester, VP / dimethylaminoethylmethacrylate copolymer, VP / dimethyl amino ethylmethacrylate / polycarbamyl polyglycol ester, VP / eicosene copolymer, VP / hexadecene copolymer, VP / methacrylamide / vinyl imidazole copolymer, VP / polycarbamyl polyglycol ester, VP / VA copolymer, polyester-1, polyester-2, polyester-3, polyester-4, polyester-5, polyester-7, polyester-8, and polyester-10.

[0473] In some embodiments, it may be particularly advantageous to use more than one fdm-forming agent, more specifically two or more film-forming agents, and in particular three or more filmforming agents. Using a plurality of film-forming agents may be particularly advantageous to provide a reliable and strong film-forming property under the diverse conditions of use and in view of the diverse skin types. The formation of a film slows drying of the topical composition and wet or moist conditions facilitate the coupling of the compounds of the present disclosure to the keratinous tissue such as skin or hair.

[0474] The topical compositions can be applied to the skin of the subject using inkjet printing directly onto a skin transfer substrate such as a patch. The composition in this case is applied to the transfer substrate using printer nozzles. In some embodiments, the composition may also be contained in a pen-like applicator since this may allow more selective localized delivery. It may be particularly advantageous that the pen-like applicator comprises one or more features disclosed in WO 2023 / 023851 Al, the content of which are incorporated herein in its entirety by reference thereto. More specifically, in some embodiments, the pen-like applicator is an ink applicator having one or more of the device features as disclosed in any of claims 1 to 50 of WO 2023 / 023851 Al, the respective content of said claims is incorporated herein in its entirety by reference thereto for the purposes of further defining the aforementioned pen-like applicator.

[0475] In some embodiments, it may be particularly advantageous that the topical composition is contained in a pen-like applicator and that the topical composition comprises more than one film-forming agent, more specifically two or more film-forming agents, and in particular three or more film-forming agents.

[0476] In some embodiments, the topical formulation comprising the compound of the present disclosure is storage stable (i.e., the compound of the present disclosure retains its original chemical structure at greater than 95 mol.-%) for a period of time from greater than 1 month, more specifically greater than 3 months, and in particular greater than 6 months, when stored at 21°C and 25% RH. In some embodiments, aqueous solubility of the compound of formula (I) is from about 1 g / L to about 100 g / L, from about 5 g / L to about 50 g / L, or from about 10 g / L to about 100 g / L.

[0477] In some embodiments, it may be particularly advantageous that the topical composition is not too “runny” in order to facilitate that the topical formulation is retained locally on the skin at the site of administration. Accordingly, it may be particularly advantageous that the topical composition is having a dynamic viscosity, measured at 37°C, of more than 2 mPa s, more specifically more than 10 mPa s, and in particular more than 50 mPa s, for instance, in the range of 2 mPa s to 50,000 mPa s, more specifically in the range of 10 mPa s to 20,000 mPa s, and in particular in the range of 50 mPa s to 10,000 mPa s. Suitable measuring methods are well-known in the art and include ASTM D-2196-20, using test method A at 30 rpm, or DIN EN ISO 2555:2018-09, at 30 rpm, on a rotational viscosimeter, for instance ViscoQC 100, optionally equipped with a PTD 100 Cone-Plate for smaller sample sizes, obtainable from Anton Paar GmbH, Germany.

[0478] In some embodiments, the topical composition is a skin care composition. In some embodiments, the topical composition is a hair care composition. In some embodiments, said skin care composition or hair care composition is enclosed in a container. In some embodiments, the container is sealed and / or releasable after opening. In some embodiments, the container comprises a label and / or is provided with packaging.

[0479] In a ninth aspect, the present disclosure provides a process for preparing a topical composition comprising the compounds of the present disclosure, in particular the compounds of the second, sixth and seventh aspect, wherein the topical composition further comprises an excipient that is suitable for topical administration, the process comprising providing said compound and mixing it with an excipient suitable for topical administration. In some embodiments, it may be particularly beneficial that the topical composition is the topical composition as defined above for the eighth aspect.

[0480] Any of the specific compounds disclosed herein, in particular for the second, fourth, fifth, sixth and seventh aspect, also represent specific embodiments according to this ninth aspect of the present disclosure.

[0481] In a tenth aspect, the present disclosure relates to the use of a compound or topical composition according to any of the aspects and / or embodiments disclosed herein for covalently binding an active ingredient to keratinous tissue, in particular to skin and / or hair.

[0482] Any of the specific compounds and / or topical compositions disclosed herein also represent specific embodiments according to this tenth aspect of the present disclosure.

[0483] In an eleventh aspect, the present disclosure provides the compounds and / or topical compositions disclosed herein for use in medicine, in particular for treating a skin-associated disease and / or a hair-associated disease.

[0484] Any of the specific compounds and / or topical compositions disclosed herein also represent specific embodiments according to this eleventh aspect of the present disclosure.

[0485] Methods of preparing the compounds of the present disclosure

[0486] The methods of preparing the compounds of the present disclosure are not particularly limited.

[0487] Particularly suitable are the syntheses disclosed in the detailed description and the figures. However, alternative approaches are readily available to the skilled person in view of the teaching of the present disclosure.

[0488] Further Definitions As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value). For example, "about 20" means or includes amounts from 18 to and including 22.

[0489] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention includes each and every individual sub-combination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.

[0490] Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.

[0491] As used herein, the term “Cn-Cmmoiety”, as it is used in e.g. C1-C30 moiety, C1-C16 moiety, Ci-Ceo moiety etc., refer to any carbon-containing moiety having the referenced number of carbon atoms. It should be understood that the reference to a “Cn-Cmmoiety” is a closed definition and defines a finite moiety, i.e. a “Cn-Cmmoiety” is a moiety which, with respect to the number of carbon atoms, contains between n and m carbon atoms, but not more or less carbon atoms. However, it should be further understood that a “Cn-Cmmoiety” may optionally comprise further atom species not being C, i.e. atom species such a H, O, S, and N and others may be contained in the Ci-Ceo moiety.

[0492] As used herein, any reference to a moiety comprising a specified number or a specified range of an atom species, such as e.g. “a C1-C30 moiety comprising 1 to 12 oxygen atoms”, should be understood as defining a finite moiety, i.e. a moiety which, with respect to said atom species, contains said atom species in said specified amount. So, the aforementioned “C1-C30 moiety comprising 1 to 12 oxygen atoms” refers to a C1-C30 moiety containing between 1 to 12 oxygen atoms. However, it should be further understood that said moiety may optionally comprise further atom species besides the specified atom species, i.e. the aforementioned “C1-C30 moiety containing between 1 to 12 oxygen atoms” may optionally comprise further atom species not being C and not being O, i.e. atom species such H, S, and N and others. In case a specified range of a specified atom species starts with zero (“0”), the presence of the referenced atom species is optional. To give an example, a “C1-C30 moiety comprising 0 to 12 oxygen atoms and 0 to 4 nitrogen atoms” is to be understood a s reference to a C1-C30 moiety optionally containing 1 to 12 oxygen atoms and optionally containing 1 to 4 nitrogen atoms.

[0493] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, «-propyl, isopropyl, «-butyl, / c / 7-butyl. isobutyl, sec-butyl; higher homologs such as 2-methyl-l-butyl, «-pentyl, 3-pentyl, / 7-hexyl. 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, more specifically from 1 to 4 carbon atoms, even more specifically from 1 to 3 carbon atoms, and in particular 1 to 2 carbon atoms.

[0494] As used herein, the term “Cn-m acyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched, having n to m carbons.

[0495] As used herein, the term “amino” refers to a group of formula -NH2.

[0496] As used herein, the term “halogen” refers in particular to F, Cl, Br and I.

[0497] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the ^-configuration. In some embodiments, the compound has the ^-configuration.

[0498] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0499] As used herein, the term “tautomer” is attributed its ordinary meaning in the art and, in particular, comprises the corresponding ring-opened 1,5-di carbonyls (i.e. keto / keto, keto / aldehyde and aldehyde / keto). Moreover, the term is also meant to encompass those constitutional isomers of the compound of formula (I) which are accessible by an intramolecular nucleophilic ring-closure of the said 1,5-dicarbonyls, as well as their respective tautomers.

[0500] As used herein, a “salt” or “pharmaceutically acceptable salt” of a compound of any one of the formulae disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of any one of the formulae include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, mal onate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthal ene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of any one of the formulae disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; tri ethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N, N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some embodiments, the compounds of any one of the formulae disclosed herein, or salts thereof, are substantially isolated.

[0501] The terms “protecting group” and “protective group” refer to a moiety that reversibly chemically modifies a functional group in order to obtain chemoselectivity or in order to reduce degradation in one or more subsequent chemical reactions. Suitable protecting groups are well known in the art (see, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N. Y, 1999, which is incorporated herein by reference in its entirety).

[0502] As used herein, “color” refers to wavelengths of electromagnetic radiation visible to the human eye and “colorless” and like expressions such as “not perceivable by the human eye”, “not visually perceivable” or “not observable” refers to the absence of wavelengths of electromagnetic radiation visible to the human eye. EXPERIMENTAL SECTION

[0503] 1. Synthesis of genipin anchor dimer compound (1)

[0504]

[0505] Step 1: Extended genipin acid from genipin aldehyde

[0506] Genipin aldehyde (5.0 g, 1 equivalent) was added to a round bottom flask equipped with a Teflon™ stir bar and dissolved in pyridine (30 mL, 0.75 M). Malonic acid was then added (8.12 g, 3.5 equivalents) followed by piperidine (0.31 mL, 0.14 equivalents). The mixture was heated at 60 °C and capped with a rubber septum punctured with a 22G needle to vent any built-up pressure. The reaction was monitored for complete consumption of genipin aldehyde by TLC. After 2 hours the reaction was complete and diluted with 250 mL of dichloromethane. The reaction mixture was added to a separatory funnel and washed with IM HC1 (4 x 50 mL) and then brine to remove any pyridine. The organic phase was dried with anhydrous sodium sulfate and concentrated to give an oil. The oil was resuspended in a minimal amount of dichloromethane and dry-loaded onto silica. The product was isolated via flash column chromatography (5 % MeOH / DCM) as an off-white solid (80 % yield).

[0507] 'H NMR (400 MHz, CDCh): 87.66-7.40 (m, 2H), 6.56-6.37 (m, 1H), 6.00 (d, 15.8 Hz, 1H, 2 isomers), 5.78-4.82 (m, 1H), 3.75 (s, 3H, 2 isomers), 3.33-2.74 (m, 3H), 2.35 (dd, J = 18.4, 9.5 Hz, 1H, 2 isomers).

[0508] Step 2: Hydrogenation of extended genipin acid

[0509] The extended genipin acid was reduced under continuous flow conditions by dissolving in ethanol (0.05 M) and running through a 70 mm column of 10% Pd / C at 1 mL / min and 2 bar of hydrogen gas. The eluent was concentrated and clean without further purification (89 % yield). 'H NMR (400 MHz, CDCb): 8 7.46-7.39 (m, 1H), 5.56-4.79 (d, 1H, 4 isomers combined), 3.76-3.69 (s, 3H, 4 isomers from methyl ester), 2.84 (m, 1H), 2.64-2.37 (m, 2H), 2.33-2.12 (m, 2H), 2.12-1.90 (m, 2H), 1.90-1.49 (m, 2H), 1.49-1.34 (m, 1H), 1.22 (m, 1H).

[0510] HRMS (DART+): Calculated for C13H19O6 [M+H]+: 271.1176 m / z. found: 271.1180 m / z

[0511] Step 3: Formation of ethylene glycol ester

[0512] A 100 mL Schlenk flask was flame dried and equipped with a magnetic stir bar. A solution of the hydrogenated extended genipin anchor (1.00 g, 1 equivalent) in anhydrous acetonitrile (10.6 mL, 0.35 M) was added and brought to 0 °C. Ghosez reagent was added to the solution and allowed to stir at 0 °C for 1 hour. Then 11 mL of ethylene glycol (51 equivalents) was added followed by pyridine (7 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and monitored by TLC. Once complete, the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel with 1 M HC1 to remove excess pyridine and ethylene glycol. The ethyl acetate layer was washed with 1 M HC1 (3x). The combined aqueous layer was back extracted with ethyl acetate (3x). The combined ethyl acetate layer was dried with sodium sulfate, fdtered, and concentrated in vacuo to an oil. The crude oil was dry-loaded onto silica and purified via gradient flash column chromatography (hexane / ethyl acetate 0 / 100 -> 100 / 0) (65 % yield).

[0513] 'H NMR (400 MHz, CDCh): 87.46-7.36 (m, 1H), 5.56-4.73 (d, 1H, 4 isomers), 4.34-4.15 (m, 2H, ethylene glycol CH2), 3.83 (m, 2H, ethylene glycol CH2), 3.71 (s, 3H, methyl ester CH3), 2.82 (m, 1H), 2.56-2.35 (m, 2H), 2.30-2.05 (m, 3H), 2.02-1.49 (m, 5H), 1.46-1.31 (m, 1H), 1.22 (m, 1H).

[0514] HRMS (DART+): Calculated for C16H23O7 [M+H]+: 315.1438 m / z. found: 315.1448 m / z

[0515] Step 4: Formation of extended anchor genipin dimer compound (1)

[0516] A 50 mL Schlenk flask was flame dried and equipped with a magnetic stir bar. A solution of the hydrogenated extended genipin anchor (500 mg, 1 equivalent) in anhydrous acetonitrile (10.6 mL, 0.35 M) was added and brought to 0 °C. Ghosez reagent was added to the solution and allowed to stir at 0 °C for 1 hour. Then a solution of hydrogenated genipin-ethylene linker (735 mg in 5 mL anhydrous acetonitrile) was added followed by pyridine (3 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and monitored by TLC. Once complete, the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel with 1 M HC1 to remove excess pyridine and ethylene glycol. The ethyl acetate layer was washed with 1 M HC1 (3x). The combined aqueous layer was back extracted with ethyl acetate (3x). The combined ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo to an oil. The crude oil was dry-loaded onto silica and purified via gradient flash column chromatography (hexane / ethyl acetate 0 / 100 — > 100 / 0) (65 % yield).

[0517] 'H NMR (400 MHz, CDCh): 87.47-7.36 (m, 2H), 5.55-4.71 (m, 2H), 4.36-4.21 (m, 4H), 3.74-3.66 (s, 6H, isomers), 2.82 (2H), 2.53-2.33 (m, 4H), 2.32-2.05 (m, 4H), 2.02-1.58 (m, 10H), 1.46-1.31 (m, 2H), 1.23-1.15 (m, 2H).

[0518] HRMS (ESI+): Calculated for C28H42NO12 [M+NH4]+: 584.2702 m / z. found: 584.2705 m / z

[0519] 2. Sequential reaction of the genipin anchor dimer compound (1) with two different amines

[0520] Reaction with hexylamine in the presence of excess of dimer compound (1), yielding compound (2):

[0521]

[0522] The dimer compound (1) (100 mg, 5 equivalents) was added to a 2 Dram (= 7.4 mL) vial equipped with a Teflon™ stir bar and dissolved in methanol with 3 drops of water. Then hexylamine was added with a micropipette (4.6 pl, 1 equivalent). The reaction was stirred at room temperature for 24 hours and purified by flash column chromatography.

[0523] HRMS (ESI+): Calculated for C34H50NO10 [M+H]+: 632.3429 m / z. found: 632.3434 m / z Reaction with L-lysine in the presence of compound (2). yielding compound (3):

[0524]

[0525] Compound (2) (9.7 mg, 1 equivalent) was added to a 2 Dram (= 7.4 mL) vial equipped with a Teflon™ stir bar and dissolved in methanol with 3 drops of water. Then L-lysine (2.25 mg, 1 equivalent) was added and the mixture was stirred at room temperature for 24 hours and purified by preparative thin layer chromatography.

[0526] HRMS (ESI+): Calculated for C40H60N3O10 [M+H]+: 742.4273 m / z. found: 742.4278 m / z

[0527] The resulting UV / Vis spectra are shown in Figure 11.

[0528] From the MS and UV / Vis data, it can be concluded that an amino-functionalized compound can be selectively coupled to a compound of the second aspect and that the second 3,4-saturated 2H-pyran moiety retains its ability to bind to keratinous tissue such as skin and / hair (as demonstrated by the model compound lysine).

[0529] Reaction of dimer compound (1) with amino-functionalized hyaluronic acid (15% degree of substitution with ethylene diamine)

[0530] An overview of the reaction is shown in Figure 12. Specifically, to a 20 mL scintillation vial equipped with a Teflon™ stir bar was added hydrogenated anchor dimer (190 mg, 5 equivalents relative to the number of amino groups in 7 mg of the 10 kDa hyaluronic acid polymer) and dissolved in a minimal volume methanol. In a separate vial, hyaluronic acid amine (15% degree of substitution) is weighed out (7 mg) and dissolved in a minimal amount of water. The solution of hyaluronic acid is added to the stirring solution of dimer compound (1). The solution turns turbid upon addition of the aqueous hyaluronic acid. Additional methanol is added until the solution is homogeneous. The final volumes required were 4 mL MeOH and 2 mL water. The solution was stirred at room temperature for 66 hours. Once complete, the reaction was concentrated in vacuo to a gel. The gel was separated between water and ethyl acetate in a small vial. The top layer of ethyl acetate was carefully removed with a Pasteur pipette. Fresh ethyl acetate was added, and the process of removal was repeated until TLC showed no more unreacted dimer compound (1) in either layer. Then the residual ethyl acetate is concentrated for re-use and the aqueous mixture is lyophilized to obtain a white solid (7.7 mg) comprising the dimer compound (1).

[0531] OTHER EMBODIMENTS

[0532] It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0533] The present disclosure also relates to the following embodiments which are supplementary to and freely combinable with the above specification:

[0534] 1. A compound comprising two 3,4-saturated 2H-pyran moieties, wherein the first moiety is according to formula (la) and the second moiety is according to formula (lb),

[0535]

[0536] (lb)

[0537] or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 and at least one of Li'-Ar, L2-A2', L3-A3', L4-A4', L5-A5', Lg-Ag- and L7-A7' jointly represent a bridging linker group LBRIDGE which is covalently binding the moiety according to formula (la) to the moiety according to formula (lb);

[0538] wherein the remainder of substituents represents, each independently from the others: Li, L2, L3, L4, L5, Lg, L7, absent or a linker group

[0539] Lr, L2', L3', L4', L5', Lg- and L7'

[0540] Ai, Ar, A4, A4', As and As- hydrogen, a C1-C30 moiety, hydroxyl, amino, or a halogen

[0541] A2, A2', A3, and A3' as for Ai or L2-A2 and L3-A3 jointly represent oxo; Ag, Ag', A7 and A?- hydrogen or a C1-C30 moiety;

[0542] R1and R2hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

[0543]

[0544] A compound for covalently binding an active ingredient to skin and / or hair, wherein the compound comprises a 3,4-saturated 2H-pyran moiety which is defined as indicated for formula (lb) in embodiment 1 and a moiety according to formula (Ic) or (Id) which comprises the active ingredient,

[0545]

[0546] (Id) or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0547] wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a colorimparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair; wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 and at least one of Lr-Ar, L2-A2', L3-A3', L4-A4', Lg-Ag- and L7-A7' jointly represent a bridging linker group LBRIDGE’ which is covalently binding the moiety of formula (Ic) or (Id) to the moiety of formula (lb),

[0548] wherein, in both formulae (Ic) and (Id):

[0549] Ls' represents a linker group or is absent;

[0550] R represents the active ingredient

[0551] a) as such, or

[0552] b) as a precursor thereof, in which case the linker group Ls- is present and cleavable to release the active ingredient from the compound after the application of the compound to the skin and / or the hair; and

[0553] the remainder of the substituents is defined as indicated for formula (la) in embodiment 1.

[0554] A process of preparing a compound of embodiment 2, the process comprising coupling a compound of embodiment 1 and an active ingredient comprising an amino group, wherein the process comprises the following steps:

[0555] mixing the compound of embodiment 1 in one or more solvents to obtain a reaction mixture,

[0556] agitating the reaction mixture and bringing the active ingredient into reactive contact with the compound of embodiment 1 in said reaction mixture such that the compound of embodiment 1 is present in stoichiometric excess to the active ingredient until:

[0557] substantially all or all of the amino groups of the active ingredient have reacted with the compound of embodiment 1, or

[0558] a reagent is added which terminates the coupling reaction between the active ingredient and the compound of embodiment 1 in the reaction mixture.

[0559] A process of preparing a compound comprising a 3,4-saturated 2H-pyran moiety according to formula (le),

[0560]

[0561] or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0562] for covalently binding a water-soluble polymer to skin and / or hair;

[0563] wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 represents LFG-PWS, wherein Pws represents the water-soluble polymer and LFG represents a linker group which binds the water-soluble polymer to the 3,4-saturated 2H-pyran moiety; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 not representing LFG-PWS is defined as indicated for formula (lb) in embodiment 1;

[0564] the process comprising reacting:

[0565] iii) a precursor of the water-soluble polymer comprising a first functional group with

[0566] iv) a precursor compound comprising a second functional group and a 3,4- saturated 2H-pyran moiety,

[0567] such that the first and second functional groups generate the linker group LFG; wherein the precursor compound is represented by the following formula (If),

[0568] >7

[0569]

[0570] (If)

[0571] 5

[0572] or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0573] wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 represents a linker group comprising the second functional group; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not representing the linker group comprising the second functional group is defined as indicated for formula (lb) in embodiment 1; and

[0574] wherein the first and second functional groups are more reactive towards each other than towards the 3,4-saturated 2H-pyran moiety of both the compound according to formula (le) and the precursor compound according to formula (If).

[0575] A topical composition comprising a topically acceptable excipient and a compound according to formula (le), or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein the compound is obtainable by carrying out the process of embodiment 4 and wherein the topical composition comprises residual educts and / or one or more further reaction products obtainable by carrying out said process.

[0576] The compound, process or topical composition according to any preceding embodiment, wherein each occurrence of the C1-C30 moiety, independently from each other, comprises 1 to 30, more specifically 1 to 16, and in particular 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 phosphorus atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 boron atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms; and / or wherein the C1-C30 moiety is bound

[0577] a) to the respective Li to L7 and Lr to L7- via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or,

[0578] b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the Ci- C30 moiety is attached.

[0579] The compound, process or topical composition according to embodiment 6, wherein each occurrence of the C1-C30 moiety is, independently from each other, selected from a saturated or unsaturated, cyclic or acyclic (hetero)alkyl or (hetero)aryl, each comprising 1 to 30, more specifically 1 to 16, and in particular 1 to 12, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms; and, optionally, wherein the C1-C30 moiety is bound

[0580] a) to the respective Li to L7 and Lr to L7' via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or,

[0581] b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the Ci- C30 moiety is attached.

[0582] The compound, process or topical composition according to embodiment 7, wherein each occurrence of the C1-C30 moiety is, independently from each other, selected from a saturated or unsaturated (hetero)alkyl comprising 1 to 12, more specifically 1 to 8, and in particular 1 to 4, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 nitrogen atoms; 0 or 1 sulfur atom; and 0 to 5, more specifically 0 to 4, and in particular 0 to 3 halogen atoms; and

[0583] wherein the C1-C30 moiety is bound

[0584] a) to the respective Li to L7 and Lr to L7' via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or,

[0585] b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the Ci- C30 moiety is attached.

[0586] The compound, process or topical composition according to any preceding embodiment, wherein both Lg and L7 are absent and wherein As and A7 represent hydrogen.

[0587] The compound, process or topical composition according to any preceding embodiment, wherein each occurrence of Li to L7 and Lr to L7' which is not a part of LBRIDGE and LBRIDGE’ and not representing LFG is, independently from each other, absent or representing an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms. ll. The compound, process or topical composition according to any preceding embodiment, wherein one or more, and in particular all, of the remainder of Li to L7 and Lr to L7' which are not representing a part of LBRIDGE and LBRIDGE’ and not representing LFG are, independently for each embodiment, defined as follows:

[0588] Li is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0589] Lr is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0590] L2 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0591] L2' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0592] L3 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0593] L3' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0594] L4 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0595] L4' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0596] L5 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0597] L5' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0598] -we Lg is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0599] Lg' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0600] L7 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms; and / or

[0601] L7' is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon.

[0602] The compound, process or topical composition according to any preceding embodiment, wherein:

[0603] Li and Lg are present and form a ring; and / or

[0604] Li and L3 are present and form a ring; and / or

[0605] L3 and L4 are present and form a ring; and / or

[0606] L4 and L7 are present and form a ring; and / or

[0607] L4 is present and forms a ring with R1.

[0608] The compound, process or topical composition according to any preceding embodiment, wherein:

[0609] Lr and Lg- are present and form a ring; and / or

[0610] Lr and L3' are present and form a ring; and / or

[0611] L3' and L4' are present and form a ring; and / or

[0612] L4' and L7' are present and form a ring; and / or

[0613] L4' is present and forms a ring with R2.

[0614] The compound, process or topical composition according to embodiment 12 or 13, wherein, independently for each occurrence, the ring is a 5-, 6-, 7- or 8-membered ring, more specifically a 5-, 6-, or 7-membered ring, and in particular a 5- or 6-membered ring. The compound, process or topical composition according to embodiment 14, wherein the ring is a hydrocarbon ring or a heterocyclic ring comprising one or more heteroatoms selected from O, N and S; more specifically an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, an optionally substituted cycloheptyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, an optionally substituted tetrahydrofuranyl ring or an optionally substituted tetrahydropyranyl ring.

[0615] The compound, process or topical composition according to embodiment 14 or 15, wherein the ring is a bridged bicyclic ring, more specifically a bicyclic ring having a bridge which comprises one or two bridging atoms; more specifically wherein the bridging atoms are, independently from each other, selected from C, N, O and S, more specifically from C, N and O, and in particular from C and N.

[0616] The compound, process or topical composition according to embodiment 16, wherein the bridged bicyclic ring comprises a methylene bridge which is optionally substituted once or twice with a moiety selected, independently from each other, from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4-hydroxyalkyl, and C1-C4 alkylsulfonic acid; and in particular wherein the bridged bicyclic ring comprises a methylene bridge which is optionally substituted twice with methyl.

[0617] The compound, process or topical composition according to embodiment 16, wherein the bridged bicyclic ring comprises a bridge of the formula -N(-R')-, wherein R' represents H or a C1-C30 moiety.

[0618] The compound, process or topical composition according to any one of embodiments 12 to 18, wherein the ring is further substituted to comprise a further ring which is fused to said ring.

[0619] The compound, process or topical composition according to embodiment 19, wherein the further ring is a an aliphatic, unsaturated or aromatic hydrocarbon ring, a saturated or unsaturated heterocyclic ring, or a heteroaromatic ring, wherein the heteroatoms of the heterocyclic or heteroaromatic ring are, independently from each other, selected from C, N, O and S, more specifically from C, N and O, and in particular from C and N. The compound, process or topical composition according to any one of embodiments 12 to 20, wherein the respective two of Ai to A? and Ar to A?' corresponding to the two linker groups of Li to L? and Lr to L7' which are forming the (bicyclic) ring are, independently from each other, attached to said (bicyclic) ring by a bond or a linker group.

[0620] The compound, process or topical composition according to embodiment 21, wherein one of the two of Ai to A7 and Ar to A7' corresponding to the two linker groups of Li to L7 and Lr to L7' which are forming the (bicyclic) ring is representing hydrogen and is attached to said (bicyclic) ring by a bond and wherein the other of the two of Ai to A7 and Ar to A7' corresponding to the two linker groups of Li to L7 and Lr to L7' which are forming the (bicyclic) ring is attached to said (bicyclic) ring by a bond or a linker group.

[0621] The compound, process or topical composition according to embodiment 21 or embodiment 22, wherein said linker group is selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)1-4-, -(CH2)1-4-O- and -O-(CH2)1-4-, or combinations thereof.

[0622] The compound, process or topical composition according to any one of embodiments 12 to 23, wherein the ring is optionally substituted and / or optionally bridged as defined in any one of embodiments 12 to 23 with the further proviso that the (bridged) ring, together with its optional substituents and linker groups, comprises less than 30, more specifically less thanl6, and in particular less than 12 carbon atoms; less than 12, more less than 8, and in particular less than 6 oxygen atoms; less than 8, more specifically less than 6, and in particular less than 4 nitrogen atoms; less than 6, more specifically less than 4, and in particular less than 3 sulfur atoms; less than 6, more specifically less than 4, and in particular less than 3 phosphorus atoms; less than 6, more specifically less than 4, and in particular less than 3 boron atoms; and less than 10, more specifically less than 8, and in particular less than 6 halogen atoms.

[0623] The compound, process or topical composition according to any one of embodiments 1 to 24, wherein both Lg and L7 are absent and both As and A7 represent hydrogen. The compound, process or topical composition according to any one of embodiments 1 to 24, wherein Lg and L? are absent and wherein one of As and A? represents hydrogen and the other of As and A? represents the C1-C30 moiety.

[0624] The compound, process or topical composition according to embodiment 26, wherein Lg is absent and Ag represents hydrogen and wherein L7 is absent and A7 represents the Ci- C30 moiety.

[0625] The compound, process or topical composition according to embodiment 26, wherein Lg and L7 are absent and wherein As represents the C1-C30 moiety and A7 represents hydrogen.

[0626] The compound, process or topical composition according to any preceding embodiment, wherein none of the substituent combinations L1-A1 and L4-A4 represent hydrogen and / or wherein none of the substituent combinations Lr-Ar and L4-A4' represent hydrogen.

[0627] The compound, process or topical composition according to any preceding embodiment, wherein R1and / or R2represent hydrogen, Ci-g acyl, a silyl group, or Ci-g alkyl; and in particular hydrogen.

[0628] The compound, process or topical composition according to any one of embodiments 1 to 30, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (II),

[0629]

[0630] An

[0631] (ID,

[0632] or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0633] L11, L13, L14, L16 and L17 absent or a linker group, in particular as defined in any preceding embodiment, wherein, in said preceding embodiments, L11 corresponds to L1 and / or L1', L13 corresponds to L3 and / or L3’, L14 corresponds to L4 and / or L4’, Lis corresponds to Lg and / or Lgy and L17 corresponds to L7 and / or L7’. An, A13 and A14 hydrogen, hydroxyl, halogen, or a C1-C30 moiety, in particular as defined in any preceding embodiment, wherein, in said preceding embodiments, An corresponds to Ai and / or Ar, A13 corresponds to A3 and / or A3’ and A14 corresponds to A4 and / or A4’.

[0634] A12 and A15 hydrogen or halogen, and in particular hydrogen; A16 and A17 hydrogen or a C1-C30 moiety;

[0635] optionally with the further proviso t rat at least one of the substituent combinations L16-A16 and L17-A17 represents hydrogen;

[0636] R3hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

[0637]

[0638] The compound, process or topical composition according to embodiment 31, wherein none of the substituent combinations L11-A11 and L14-A14 represents hydrogen.

[0639] The compound, process or topical composition according to embodiment 31 or 32, wherein L13 and L14 jointly form a cyclopentyl ring, a cyclohexyl ring or a cycloheptyl ring, in particular a cyclopentyl ring, a cyclohexyl ring or a cycloheptyl ring as defined in any one of embodiments 15 to 24.

[0640] The compound, process or topical composition according to any one of embodiments 31 to 33, wherein A12, A15 and R3represent hydrogen. The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (III),

[0641]

[0642] A’7(III),

[0643] or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0644] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0645] R3, A11, A13, A14, A16, A17, L13, L14, L16 and L17 are defined as in any preceding embodiment;

[0646] X represents O or S, and in particular O; and

[0647] Lxis absent or represents -O-, -S-, -NH-, or an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 10 carbon atoms, 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms; and

[0648] the hydrocarbon moiety is attached to the (C=X)-moiety via a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom.

[0649] The compound, process or topical composition according to embodiment 35, wherein the substituent combination C(=X)-Lx-An represents a C1-C16 moiety selected from a carboxylic acid or a salt thereof, a carboxylic acid ester; a ketone; more specifically a moiety selected from:

[0650] -COOH or a salt thereof; -COORa, -C(O)-Ra,

[0651] -C(O)-NH2, -C(O)NHRa, -C(O)NRa2,

[0652] wherein Rarepresents a moiety comprising 1 to 16 carbon atoms, and optionally one or more of: 1 to 8 oxygen atoms, 1 to 6 nitrogen atoms, 1 to 3 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms and 1 to 5 halogen atoms; more specifically a moiety comprising 1 to 6 carbon atoms, and optionally one or more of: 1 to 4 oxygen atoms, 1 to 3 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms, and 1 to 3 halogen atoms,

[0653] wherein NRa2may alternatively represent an optionally substituted saturated or unsaturated nitrogen heterocycle comprising, in combination with its optional substituents, 1 to 12, more specifically 1 to 10, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 1 to 4, more specifically 1 to 3, and in particular 1 or 2 nitrogen atoms; 0 to 3, more specifically 0 to 2, and in particular 0 or 1 sulfur atoms; and 0 to 5, more specifically 0 to 4, and in particular 0 to 3 halogen atoms.

[0654] The compound, process or topical composition according to embodiment 36, wherein C(=X)-Lx-A11 represents -COORa as defined in embodiment 36; more specifically -COORa, wherein Rarepresents a hydrocarbon moiety comprising 1 to 8 carbon atoms, and optionally one or more of: 1 to 4 oxygen atoms, 1 to 4 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms, and 1 to 3 halogen atoms; and in particular -COORa, wherein Ra represents Ci-C4-alkyl, such as methyl or ethyl.

[0655] The compound, process or topical composition according to any one of embodiments 35 to 37, wherein L13 and L14 form a ring, in particular a 5-memberered or 6-membered ring.

[0656] The compound, process or topical composition according to embodiment 38, wherein A13 and A14 are attached to the ring by a bond or by a linker group which is, independently from the other, selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)I-4-, -(CH2)I-4-O- and -O-(CH2)I-4-, and combinations thereof.

[0657] The compound, process or topical composition according to any one of embodiments 35 to 39, wherein X represents O; Lxand L14 form an optionally substituted 6-membered ring, more specifically an optionally substituted cyclohexenone ring or an optionally substituted fused ring system comprising a cyclohexendione and a phenyl ring which is fused to the cyclohexendione.

[0658] The compound, process or topical composition according to embodiment 40, wherein Ai6 represents H; and wherein An is attached to the 6-membered ring via a linker group comprising 1 to 12 carbon atoms, and optionally one or more of: 1 to 4 oxygen atoms, 1 to 4 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 phosphorous atoms, 1 or 2 boron atoms, and 1 to 5 halogen atoms.

[0659] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (IV),

[0660]

[0661] (IV)

[0662] or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0663] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0664] R3, L11, L13, L17, A11, A13, A14, A15 and A17 are defined as in any preceding embodiment; n represents an integer of 0 or 1, and in particular 0;

[0665] the dashed bond represents a single or a double bond, and in particular a single bond; and, independently from each other, each instance of Lyis absent or represents a linker group, in particular a linker group selected from the group consisting of:

[0666] -O-;

[0667] -S-;

[0668] -NH-;

[0669] an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 10 carbon atoms, O to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms;

[0670] or combinations thereof.

[0671] The compound, process or topical composition according to embodiment 42, wherein, independently from each other, each instance of Lyis absent or represents a linker group which is selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)i-4-, -(CH2)I-4-O- and -O-(CH2)i-4-, and combinations thereof.

[0672] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (V),

[0673] A13X^XLX—A11

[0674] I I

[0675] Ai\ kJL / O

[0676] Ly — X

[0677]

[0678] A— 17 LL17r3

[0679] (V),

[0680] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0681] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0682] R3, X, Lx, Ly, L13, L17, A11, A13, A14, A16 and A17 are defined as in any preceding embodiment.

[0683] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (VI), A— Ly

[0684]

[0685] (VI),

[0686] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0687] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0688] R3, X, Lx, Ly, L16, A11, A14 and A16 and are defined as in any preceding embodiment.

[0689] The compound, process or topical composition according to embodiment 45, wherein L16 is absent and A16 represents hydrogen; and / or wherein Ly-A14 represents a part of the bridging linker group LBRIDGE or LBRIDGE’, represents LFG-PWS, and represents the linker group comprising the second functional group, respectively.

[0690] The compound, process or topical composition according to embodiment 45 or embodiment 46, wherein the substituent combination Lx-A11 represents O-C1-C4-alkyl, and in particular O-CH3.

[0691] The compound, process or topical composition according to any one of embodiments 45 to 47, wherein Lyrepresents a linker group which is selected from the group consisting of: -O-, -C(O)-, -CO2-, -O-C(O)-, -(CH2)1-4-, -(CH2)1-4-O- and -O-(CH2)1-4-, and combinations thereof.

[0692] The compound, process or topical composition according to any one of embodiments 45 to 47, wherein the substituent combination -Ly-Ai4 represents -(CH2)2-4-C(=O)-O-A14, -(CH2)2-4-C(=O)-NH-A14 or -(CH2)2-4-O-A14.

[0693] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (VII),

[0694]

[0695] A17L17

[0696] (VII),

[0697] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0698] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0699] R3, L11, L13, L17, A11, A15 and A17 and are defined as in any preceding embodiment.

[0700] The compound, process or topical composition according to embodiment 50, wherein L11 is absent and A11 represents hydrogen.

[0701] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (VIII),

[0702] A _ I

[0703]

[0704] «17 u17

[0705] (VIII) 5

[0706] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0707] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0708] R3, L11, L13, L17, A11, A13, A15 and A17 are defined as in any preceding embodiment; wherein the dashed bond represents a single or a double bond, and in particular a single bond; and wherein Lyis defined as in any preceding embodiment and attached to any one of the carbon atoms marked with a or in case the dashed bond represents a single bond and to the carbon atoms marked with a in case the dashed bond represents a double bond.

[0709] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (IX),

[0710]

[0711] (IX),

[0712] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0713] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0714] R3, each instance of Ly, L13, L14, L17, A11, A13, A14, A16, and A17 are defined as in any preceding embodiment.

[0715] The compound, process or topical composition according to embodiment 53, wherein L17 is absent and A17 represents hydrogen.

[0716] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (X),

[0717]

[0718] (X)

[0719] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0720] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0721] R3, each instance of Ly, L13, L14, L17, A11, A13, A14, A16, and A17 are defined as in any preceding embodiment.

[0722] The compound, process or topical composition according to embodiment 53, wherein L17 is absent and A17 represents hydrogen.

[0723] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (XI),

[0724]

[0725] (XI),

[0726] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0727] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent: R3, L11, L13, L16, A11, A13 and A16 are defined as in any preceding embodiment.

[0728] The compound, process or topical composition according to embodiment 57, wherein L13 represents an optionally substituted phenyl, more specifically phenyl or a phenyl which, in combination with its optional substituents, comprises 6 to 12, more specifically 6 to 10, and in particular 6 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 nitrogen atoms; 0 to 3, more specifically 0 to 2, and in particular 0 or 1 sulfur atoms; and 0 to 5, more specifically 0 to 4, and in particular 0 to 3 halogen atoms; and in particular phenyl or phenyl mono- or disubstituted with (a) hydroxyl group(s).

[0729] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (XII),

[0730]

[0731] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0732] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0733] R3, Ly, L11, L13, L16, A11, A13, A14 and A16 are defined as in any preceding embodiment.

[0734] The compound, process or topical composition according to embodiment 59, wherein L13 represents an optionally substituted phenyl, more specifically phenyl or a phenyl which, in combination with its optional substituents, comprises 6 to 12, more specifically 6 to 10, and in particular 6 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 nitrogen atoms; 0 to 3, more specifically 0 to 2, and in particular 0 or 1 sulfur atoms; and 0 to 5, more specifically 0 to 4, and in particular 0 to 3 halogen atoms; and in particular phenyl or phenyl mono- or disubstituted with (a) hydroxyl group(s).

[0735] The compound, process or topical composition according to any preceding embodiment, wherein one or both moieties of formulae (la) and (lb), the compound of formula (le) and / or (If) is a compound / moiety of formula (XIII),

[0736]

[0737] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0738] wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, not representing LFG-PWS, and not representing the linker group comprising the second functional group, respectively, represent:

[0739] R3, L11, L16, A11and A16are defined as in any preceding embodiment.

[0740] The compound, process or topical composition according to embodiment 61, wherein L11-A11represents (C=O)-Lx-A11, wherein Lxand A11are defined as indicated above with respect to formula (III) in any one of embodiments 35 to 37.

[0741] The compound according to embodiment 1, and optionally further according to any one of embodiments 6 to 62, wherein the bridging linker group LBRIDGE is a Ci-Ceo moiety or a polymer.

[0742] The compound according to embodiment 63, wherein the bridging linker group LBRIDGE is a Ci-Ceo moiety, in particular an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 60 carbon atoms, more specifically 1 to 48 carbon atoms, and in particular 1 to 36 carbon atoms, 0 to 50, more specifically 0 to 40, and in particular 0 to 20 oxygen atoms; 0 to 30, more specifically 0 to 20, and in particular 0 to 10 nitrogen atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 sulfur atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 silicon atoms; and 0 to 20, more specifically 0 to 10, and in particular 0 to 5 halogen atoms.

[0743] The compound according to embodiment 64, wherein the bridging linker group LBRIDGE is a linker group selected from the group consisting of:

[0744] -O-;

[0745] -S-;

[0746] -NH-;

[0747] an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 16 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms, 0 to 16, more specifically 0 to 12, and in particular 0 to 8 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 silicon atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms;

[0748] or combinations thereof.

[0749] The compound according to any one of embodiments 63 to 65, wherein the bridging linker group LBRIDGE is a linker group having an -A'-B-A- structure, wherein A' represents the moiety coupling the linker to the remainder of the moiety of formula (la), wherein A represents the moiety coupling the linker to the remainder of the moiety of formula (lb), and wherein B represents a moiety linking A and A' to each other.

[0750] The compound according to embodiment 66, wherein A and A' comprise, independently from each other, a carbon ester, in particular a monoester, 1,1 -di ester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; a disulfide; a carbon amide, in particular a peptide or a N-Mannich base; a secondary or tertiary amine; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amide; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; a phosphonic acid amide; a boronic ester, a borinic ester, a boric ester; an aromatic, saturated or unsaturated heterocycle, in particular an oxazol; a triazole; a benzothiazole, or a coumarin; or combinations thereof. The compound according to embodiment 66 or 67, wherein B represents an aliphatic hydrocarbon, more specifically a saturated hydrocarbon moiety comprising 1 to 12 carbon atoms and optionally 1 to 12 oxygen atoms.

[0751] The compound according to any one of embodiments 66 to 68, wherein A and A' comprises, independently from each other, -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, or combinations thereof; and B represents -(CH2)i-i2-, -(CH2-O-)1-12-, -(CH2-CH2-O-)1-12, -(CH2-CH2-CH2-O-)i-i2-, -(CH(CH3)-CH2-O-)I-I2-;

[0752] and combinations thereof.

[0753] The compound according to any one of embodiments 1 or 63 to 69, wherein the compound comprises the first moiety according to formula (la) and the second moiety is according to formula (lb), wherein the first moiety and the second moiety are identical.

[0754] The compound according to embodiment 1, wherein the compound is according to the following formula (XIV),

[0755]

[0756] (XIV)

[0757] or a tautomer and / or a pharmaceutically acceptable salt thereof; and

[0758] wherein each instance of R3 represents, independently from each other, R3 as defined in any preceding embodiment, and in particular represents H;

[0759] wherein each instance of Z represents, independently from each other, O or S or C=Z represents a methylene group; and

[0760] wherein B represents the linker group B as defined in any one of embodiments 66 to 69; in particular CH2-(OCH2)1-12or (CH2)1-12, more specifically CH2-(OCH2)1-8or (CH2)1-6, and in particular CH2-(OCH2)1-6or (CH2)2-4. The compound according to embodiment 2, and optionally further according to any one of embodiments 6 to 62, wherein the bridging linker group LBRIDGE’ is optionally as defined for LBRIDGE in any of embodiments 63 to 71, with the proviso that, if present, A' represents the moiety coupling the linker to the remainder of the moiety of formula (Ic) or (Id) and A represents the moiety coupling the linker to the remainder of the moiety of formula (lb).

[0761] The compound according to embodiment 72, wherein the active ingredient or the precursor thereof is a Ci-Ceo moiety; or wherein the active ingredient or the precursor thereof is a polymeric moiety.

[0762] The compound according to embodiment 72 or 73, wherein Ls- comprises one or more of, two or more of, three or more of, four or more of, five or more, six or more, or all of: - 1 to 12 carbon atoms, more specifically 1 to 8 carbon atoms, and in particular 1 to 4 carbon atoms;

[0763] - 1 to 12 oxygen atoms, more specifically 1 to 8 oxygen atoms, and in particular 1 to 4 oxygen atoms;

[0764] - 1 to 8 nitrogen atoms, more specifically 1 to 6 nitrogen atoms, and in particular to 3 nitrogen atoms;

[0765] - 1 to 3 sulfur atoms, more specifically 1 or 2 sulfur atoms, and in particular 1 sulfur atom;

[0766] - 1 to 3 phosphorus atoms, more specifically 1 or 2 phosphorus atoms, and in particular 1 phosphorus atom;

[0767] - 1 to 12 silicon atoms, more specifically 1 to 8 silicon atoms, and in particular to 1 to 6 silicon atoms;

[0768] - 1 or 2 boron atoms, and in particular 1 boron atom.

[0769] The compound according to embodiment 74, wherein, after the compound has bound to the skin and / or the hair, Ls- is:

[0770] (i) biostable; or

[0771] (ii) cleavable,

[0772] more specifically cleavable under physiological conditions encountered after its application to the skin and / or the hair, and / or cleavable under conditions preselected for said use, in particular cleavable upon elevation of temperature to higher than 42 °C, cleavable upon exposure to daylight, cleavable upon exposure to UVA- and / or UVB-light, cleavable upon exposure to acids, cleavable upon exposure to an oxidizing agent suitable for oxidizing said functional group, cleavable upon exposure to a reducing agent suitable for reducing said functional group, or cleavable upon exposure to salts.

[0773] The compound according to any one of embodiments 72 to 75, wherein Ls- is hydrolysable at the physiological pH of mammalian skin, more specifically of human skin, and in particular at a pH of between about 5 to about 6.

[0774] The compound according to any one of embodiments 72 to 76, wherein Ls- is enzymatically cleavable under physiological conditions after the compound is topically applied onto mammalian, more specifically human skin, in particular enzymatically cleavable by enzymes present in the mammalian, more specifically human skin.

[0775] The compound according to any one of embodiments 75 to 77, wherein Ls- provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; after cleavage of Ls-.

[0776] The compound according to any one of embodiments 75 to 78, wherein Ls- provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; to said active ingredient after cleavage of Ls-.

[0777] The compound according to embodiment 79, wherein, after cleavage of Ls-:

[0778] Ls- provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to said active ingredient; and Ls' provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to the remainder of the compound.

[0779] The compound according to any one of embodiments 72 to 80, wherein Ls- comprises a carbon ester, in particular a monoester, 1,1 -diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; a disulfide; a carbon amide, in particular a peptide or a N-Mannich base; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amide; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; a phosphonic acid amide; a boronic ester, a borinic ester, a boric ester; an oxazol, a triazole, a benzothiazole, or a coumarin.

[0780] The process of embodiment 3, and optionally further according to any one of embodiments 6 to 81, wherein the bridging linker group LBRIDGE is optionally as defined in any of embodiments 63 to 71, with the proviso that, if present, A' represents the moiety coupling the linker to the remainder of the moiety of formula (Ic) or (Id) and A represents the moiety coupling the linker to the remainder of the moiety of formula (lb).

[0781] The process according to embodiment 82, wherein the rate of addition of the active ingredient is controlled such that the compound of embodiment 1 is present in constant or increasing stoichiometric excess in relation to the active ingredient.

[0782] The process according to embodiment 82 or 83, wherein the rate of addition of the active ingredient is controlled such that the compound of embodiment 1 is present throughout the entire process in a stoichiometric ratio to the active ingredient comprising the amino group of at least about 3:1, more specifically at least about 5:1, even more specifically at least about 10:1, and in particular at least about 20:1; wherein the stoichiometric ratio is defined as the molar equivalent of the total number of amino groups of the active ingredient which are present in the reaction mixture to the molar amount of the compound of embodiment 1. The process according to any one of embodiments 82 to 84, wherein the active ingredient is added together with a first solvent as a first solution,

[0783] wherein concomitantly or after a portion of the first solution has been added to the reaction mixture, a second replenishing solution comprising the compound of embodiment 1 in a second solvent is added to the reaction mixture, and

[0784] wherein the concentration of the compound of embodiment 1 in the second solution and its rate of addition is adjusted to (substantially) maintain the concentration of the compound of embodiment 1 in the reaction mixture constant.

[0785] The process according to any one of embodiments 82 to 85, wherein the reaction mixture is an aqueous reaction mixture.

[0786] The process according to any one of embodiments 82 to 86, wherein the reagent which terminates the coupling reaction between the active ingredient and the compound of embodiment 1 is an acid; an alkylating agent; a reagent that converts an amino group to its corresponding acid amide such as ethylenediaminetetraacetic dianhydride, a phosphoric acid anhydride, or a mixed anhydride of carboxylic acid of phosphoric acid; a reagent that converts an amino group to its corresponding imine such as a benzaldehyde substituted one, twice or trice with a sulfonate group; or a combination thereof.

[0787] The process according to any one of embodiments 82 to 87, wherein, in formulae (la) and (lb) of the compound of embodiment 1, the moieties Li-Ai, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 not being part of the bridging linker group LBRIDGE are identical to the respective moieties Lr-Ar, L2-A2', L3-A3', L4- 4', L5-A5', Lg-Ag- and L7-A7' not being part of the bridging linker group LBRIDGE’.

[0788] The process according to any one of embodiments 82 to 87, wherein the moiety of formula (la) is more reactive towards the amino groups of the active ingredient than the moiety of formula (lb), more specifically wherein R2represents H and R1represents the protective group.

[0789] The process of embodiment 4, and optionally further according to any one of embodiments 6 to 81 with the proviso that Ls' as defined in any of the embodiments 74 to 81 is to be understood as representing LFG and with the further proviso that the “active ingredient” as defined in embodiments 79 and 80 is to be understood as referring to “water-soluble polymer”.

[0790] The process of embodiment 90, wherein the water-soluble polymer has a number average molecular weight of at least 1000 g / mol, more specifically at least 2000 g / mol, and in particular at least 5000 g / mol.

[0791] The process of embodiment 90 or 91, wherein the water-soluble polymer is a polysaccharide; more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid; and in particular hyaluronic acid; and copolymers thereof, in particular copolymers comprising polyethylene glycol.

[0792] The process of any one of embodiments 90 to 92, wherein the water-soluble polymer comprises a polysaccharide, more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid; and in particular hyaluronic acid.

[0793] The process of any one of embodiments 90 to 93, wherein the first functional group of the precursor of the water-soluble polymer is selected from the group consisting of: a secondary amine, a thiol, a (meth)acrylate, an alkyne, an alkene, a Michael acceptor, an azide, an epoxy, a hydrazide, a carboxylic acid, an ester of aN-hydroxylamine, of aN-hydroxylamide, of a N-hydroxyimide or of a N-hydroxyl heteroaromatic, a 1,2,4,5-tetrazine, a catechol, a hydroquinone, or an aldehyde.

[0794] The process of any one of embodiments 90 to 94, wherein the second functional group of the precursor compound is selected from the group consisting of: a secondary amine, a thiol, a (meth)acrylate, an alkyne, an alkene, a Michael acceptor, an azide, an epoxy, a hydrazide, a carboxylic acid, an ester of a N-hydroxylamine, of a N-hydroxylamide, of a N-hydroxylimide or of a N-hydroxyl heteroaromatic, a 1,2,4,5-tetrazine, a catechol, a hydroquinone, or an aldehyde.

[0795] The process of any one of embodiments 90 to 95, wherein the reaction is carried out in an aqueous solvent. The process of any one of embodiments 90 to 96, wherein the reaction between the first and second functional groups generating the linker group LFG is not an additionelimination reaction involving a nucleophilic attack of the first or second functional group on the respective other of said first or second functional group that is followed by the elimination of a hydroxyl group.

[0796] The process of any one of embodiments 90 to 97, wherein the reaction between the first and second functional groups generating the linker group LFG is a cycloaddition reaction, a radical reaction, an addition reaction reducing ring strain, a Michael addition reaction, a redox-reaction, a photochemical reaction, or a combination thereof.

[0797] The process of any one of embodiments 90 to 98, wherein the reaction between the first and second functional groups generating the linker group LFG is a cycloaddition, more specifically a [3+2] cycloaddition, a [2+3] cycloaddition, a [4+1] cycloaddition, a [4+2] cycloaddition, or a [2+2+2] cycloaddition; and in particular a (Hetero-)Diels-Alder reaction, an Inverse Electron Demand (Hetero-)Diels-Alder reaction, or a Huisgen 1,3-diploar cycloaddition.

[0798] The process of any one of embodiments 90 to 99, wherein the reaction between the first and second functional groups generating the linker group LFG is a nucleophilic or radical addition reaction to a C-C-double bond or C-C-triple bond, in particular a thiol-ene reaction, a thiol-yne reaction; or a (hetero-)Michael addition.

[0799] The process of any one of embodiments 90 to 100, wherein the reaction between the first and second functional groups generating the linker group LFG is an addition reaction reducing ring strain, more specifically an addition reaction to an epoxy, an N-alkyl aziridine, a norbomene, an oxanorbomene or a cyclooctatetraene.

[0800] The process of any one of embodiments 90 to 101, wherein the reaction between the first and second functional groups generating the linker group LFG comprises a redox reaction; in particular:

[0801] wherein the first or second functional group comprises a catechol or a hydroquinone and the respective second or first functional group comprises a nucleophile, in particular a secondary amine or a thiol; and wherein the reaction comprises oxidizing the catechol or the hydroquinone to 1,2- benzoquinone or 1,4-benzoquinone, followed by nucleophilic addition of the nucleophile in a (hetero)-Michael addition, and optionally further followed by rearomatization.

[0802] The process of any one of embodiments 90 to 102, wherein the process comprises adding a catalyst which facilitates the reaction between the first and second functional groups generating the linker group LFG, in particular a catalyst that is not a Bronsted acid.

[0803] The process of any one of embodiments 90 to 103, wherein the process is carried out at a temperature range of -15°C and 35°C, more specifically between -7°C and 30°C, and in particular between 0 °C and 25°C.

[0804] The process of any one of embodiments 90 to 104, wherein the compound of formula (le), a tautomer and / or a pharmaceutically acceptable salt thereof, is formulated to a topical composition after the reaction between the first and second functional groups generating the linker group LFG without further purification, more specifically without ultrafiltration, dialysis or use of an ion exchange resin or absorbing agent, in particular without ultrafiltration or dialysis.

[0805] The process of any one of embodiments 90 to 105, wherein LFG comprises one of the moieties specified in Figure 5, wherein the wavy bonds represent bonds directly or indirectly connecting to the water-soluble polymer or to the remainder of the moiety of formula (le) with the proviso that, in case two wavy bonds are attached to N, none of them connects to hydrogen.

[0806] A topical composition according to embodiment 5, wherein LFG comprises one of the moieties recited in embodiment 106.

[0807] A compound comprising a 3,4-saturated 2H-pyran moiety according to formula (le),

[0808]

[0809] or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0810] for covalently binding a water-soluble polymer to skin and / or hair;

[0811] wherein one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 represents LFG-PWS, wherein Pws represents the water-soluble polymer and LFG represents a linker group which binds the water-soluble polymer to the 3,4-saturated 2H-pyran moiety; wherein the remainder of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 not representing LFG-PWS is defined as indicated for formula (lb) in embodiment 1; wherein LFG comprises one of the moi eties recited in embodiment 106.

[0812] The compound of embodiment 108, wherein the compound is defined as indicated in one or more of the embodiments 90 to 93.

[0813] The compound, process or topical composition according to any preceding embodiment, wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a colorimparting moiety, a cosmetic hair coating agent and a primer for attaching dyes to hair.

[0814] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a moisturizer, a skin moisturizer or a hair moisturizer, respectively.

[0815] The compound, process or topical composition according to embodiment 111, wherein the active ingredient comprises a plurality of hydrogen bonding groups selected from the group consisting of hydroxyl groups, ether groups, carboxylic acids, amines and amides; and their salts. The compound, process or topical composition according to embodiment 112, wherein the plurality of hydrogen bonding groups comprises 3 or more, more specifically 4 or more, and in particular 6 or more hydrogen bonding groups.

[0816] The compound, process or topical composition according to embodiment 112 or 113, wherein the ratio of C-atoms to the sum of hydrogen bonding groups comprised in the active ingredient is between about 4: 1 to 1: 1, more specifically between about 3: 1 to about 1: 1 and in particular between about 2: 1 to about 1:1.

[0817] The compound, process or topical composition according to any one of embodiments 110 to 114, wherein the active ingredient has a molecular weight of at least 60 g / mol, more specifically at least 90 g / mol, and in particular at least 120 g / mol.

[0818] The compound, process or topical composition according to any one of embodiments 110 to 115, wherein the ratio of C-atoms to the sum of heteroatoms comprised in the active ingredient is between about 4: 1 to 1:2, more specifically between about 3:1 to about 1:1.5, and in particular between about 2:1 to about 1:1, wherein the heteroatoms are selected from nitrogen and oxygen.

[0819] The compound, process or topical composition according to any one of embodiments 110 to 116, wherein the active ingredient comprises:

[0820] a polyol, more specifically a polyol having n hydroxyl groups with n being 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 8 or more, 10 or more, 12 or more, or 16 or more;

[0821] a mono- or polyvalent carboxylic acid comprising one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid or citric acid;

[0822] a sugar, more specifically a triose, a tetrose, a pentose a hexose, a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide;

[0823] a sugar alcohol, more specifically a sugar alcohol comprising between 2 and 24 carbon atoms, in particular ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, or maltotetraitol; a sugar acid, more specifically an aldonic acid, an ulosonic acid, an uronic acid or an aldaric acid; or a salt thereof; or an ester thereof, in particular a C1-C4-alkylester thereof; or an amide thereof;

[0824] a water-soluble polymer which is a polysaccharide; more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid; and in particular hyaluronic acid; and copolymers thereof, in particular copolymers comprising polyethylene glycol; more specifically wherein the active ingredient is:

[0825] a hyaluronic acid, more specifically a hyaluronic acid having an average molecular weight of between 3000 and 3 million kDa, more specifically between 5000 and 2 million kDa, and in particular between 10,000 and 1.5 million kDa.

[0826] The compound, process or topical composition according to embodiment 117, wherein the active ingredient has a molecular weight of 60 g / mol to 2000 g / mol, more specifically 90 g / mol to 1600 g / mol, and in particular 120 g / mol to 1200 g / mol.

[0827] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is an emollient or an occlusive.

[0828] The compound, process or topical composition according to embodiment 119, wherein the active ingredient comprises:

[0829] a Cio-Ceo moiety, more specifically a Cis-Ceo moiety and in particular a C20-C60 moiety; or

[0830] an oligo- or polysiloxane, in particular a poly(di-Ci-C4-alkyl)siloxane.

[0831] The compound, process or topical composition according to embodiment 120, wherein the active ingredient is the Ci-Ceo moiety and has a molecular weight of 140 g / mol to 2000 g / mol, more specifically 160 g / mol to 1600 g / mol, and in particular 180 g / mol to 1200 g / mol.

[0832] The compound, process or topical composition according to embodiment 120 or 121, wherein the active ingredient has more than 30 carbon atoms. The compound, process or topical composition according to any one of embodiments 119 to 122, the active ingredient comprises a saturated or unsaturated Cio-Ceo aliphatic moiety, more specifically a Cis-Ceo aliphatic moiety, and in particular a C20-C60 aliphatic moiety.

[0833] The compound, process or topical composition according to any one of embodiments 119 to 123, wherein the ratio of C-atoms to the sum of heteroatoms comprised in the active ingredient is between about 60:1 to 5:1, more specifically between about 50:1 to about 10:1, and in particular between about 40:1 to about 20:1, wherein the heteroatoms are selected from nitrogen and oxygen.

[0834] The compound, process or topical composition according to any one of embodiments 119 to 124, wherein the Ci-Ceo moiety is a sphingosine or a derivative thereof, in particular a ceramide or a sphingomyelin.

[0835] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a pesticide, more specifically an insect repellant, an insecticide which optionally acts against an ectoparasite and / or a hematophagous insect, in particular a hematophagous insect selected from the group consisting of mosquitoes, ticks, mites, gnats, fleas, chiggers, leeches and bugs.

[0836] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is the skin whitening agent, more specifically wherein the skin whitening agent acts by chemically or metabolically whitening the skin, in particular by providing a bleaching effect or decreasing melanin production; and, in particular, wherein the skin whitening agent is selected from corticosteroids, in particular clobetasol derivatives, fluocinolone derivative, or betamethasone; a vitamin A derivative, in particular tretinoin, isotretinoin, alitretinoin, retinol or retinal; a hydroxyphenol derivative, in particular hydroquinone; an aliphatic dicarboxylic acid, in particular azelaine; alpha-hydroxy-acids, in particular lactic and glycolic acid; and vitamin C.

[0837] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a fragrance in the form of a precursor. The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a pharmaceutical, more specifically a pharmaceutical suitable for treating a skin-associated disease and / or a hair-associated disease, wherein the skin-associated disease is optionally selected from acneiform eruptions, autoinflammatory syndromes, chronic blistering, conditions of the mucus membranes, conditions of the skin appendages, conditions of the subcutaneous fat, congenital anomalies, connective tissue diseases, abnormalities of dermal fibrous and elastic tissue, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, disturbances of pigmentation, endocrine-related skin conditions, eosinophilic cutaneous conditions, skin lesions, skin cancer, erythemas, genodermatoses, infection-related cutaneous conditions, lichenoid eruptions, lymphoid-related cutaneous condition, melanocytic nevi and neoplasms, monocyte- and macrophage-related cutaneous conditions, mucinoses, neurocutaneous conditions, Noninfectious immunodeficiency-related cutaneous conditions, Nutrition-related cutaneous conditions, Papulosquamous hyperkeratotic cutaneous conditions, Palmoplantar keratodermas, pruritus, psoriasis, reactive neutrophilic cutaneous conditions, skin conditions resulting from errors in metabolism, skin conditions resulting from physical factors, urticaria, dandruff, desquamation disorders, and vascular-related cutaneous conditions; and wherein the hair-associated disease is optionally selected from dandruff and alopecia.

[0838] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a cosmetic hair coating agent, more specifically wherein the cosmetic hair coating agent is providing a conditioning effect to the hair; wherein the cosmetic hair coating agent is providing a gloss effect to the hair; wherein the cosmetic hair coating agent is providing an anti-frizz effect to the hair; and / or wherein the cosmetic hair coating agent is providing a reinforcing effect to the hair.

[0839] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a primer for attaching dyes to the hair; more specifically a primer comprising hydroxyl groups, thiol groups, and / or amino groups which reacts in the presence of an oxidizing agent with a dye precursor under formation of a dye.

[0840] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is a UVA- and / or UVB-absorbing moiety and has at least one absorption peak within the wavelength range of 280 to 379 nm, more specifically at least one absorption peak within the wavelength range of 280 to 379 nm having an absorbance value of more than 0.5 when measured at a concentration of 2 mM.

[0841] The compound, process or topical composition according to embodiment 110, wherein the active ingredient is the color-imparting moiety and has at least one absorption peak within the wavelength range of 380 to 790 nm, more specifically at least one absorption peak within the wavelength range of 380 to 790 nm having an absorbance value of more than 0.5 when measured at a concentration of 2 mM.

[0842] The compound, process or topical composition according to any one of the preceding embodiments 1 to 132, wherein the compound, after having covalently bound to the skin and / or the hair, is not observable to the human eye on the skin and / or hair when illuminated with artificial light of 3000 Kelvin and an intensity of 1000 Lux.

[0843] The compound, process or topical composition according to any one of the preceding embodiments 1 to 132 or 134, the compound, after having covalently bound to lysine, does not show absorption peaks having an extinction of more than 0.5 within the wavelength range of 380 to 790 nm in 2 mM methanolic solution.

[0844] The compound according to embodiment 2, and optionally further according to any one of embodiments 6 to 62 and 110 to 135, wherein the linker group LBRIDGE’ is optionally as defined in any of embodiments 63 to 71, with the proviso that, if present, A' represents the moiety coupling the linker to the moiety of formula (Ic) or (Id) and A represents the moiety coupling the linker to the moiety of formula (lb).

[0845] The compound according to embodiment 136, wherein LBRIDGE’ further comprises one or more further moieties according to formula (Ic) or (Id), and in particular one or more further moieties according to formula (Ic).

[0846] The compound according to embodiment 136 or 137, wherein LBRIDGE’ further comprises one or more linker groups L9 which each, and independently from each other, comprise a further moiety according to formula (Ic) or (Id) comprising a further active ingredient, wherein said further active ingredient is present: a) as such, or

[0847] b) as a precursor thereof, in which case said linker group L9 is cleavable to release said active ingredient from the compound after the application of the compound to the skin and / or the hair.

[0848] The compound according to embodiment 138, wherein each instance of L9 comprises, independently from each other, one or more of, two or more of, three or more of, four or more of, five or more, or all of:

[0849] - 1 to 12 carbon atoms, more specifically 1 to 8 carbon atoms, and in particular 1 to 4 carbon atoms;

[0850] - 1 to 4 oxygen atoms, more specifically 1 to 3 oxygen atoms, and in particular 1 or 2 oxygen atoms;

[0851] - 1 to 4 nitrogen atoms, more specifically 1 to 3 nitrogen atoms, and in particular 1 or 2 nitrogen atoms;

[0852] - 1 to 3 sulfur atoms, more specifically 1 or 2 sulfur atoms, and in particular 1 sulfur atom;

[0853] - 1 to 3 phosphorus atoms, more specifically 1 or 2 phosphorus atoms, and in particular 1 phosphorus atom

[0854] - 1 or 2 boron atoms, and in particular 1 boron atom.

[0855] The compound according to embodiment 139, wherein, after the compound has bound to the skin and / or the hair, at least one and in particular all of L9 are, independently from each other:

[0856] (i) biostable; or

[0857] (ii) cleavable,

[0858] more specifically cleavable under physiological conditions encountered after its application to the skin and / or the hair, and / or

[0859] cleavable under conditions preselected for said use, in particular cleavable upon elevation of temperature to higher than 42 °C, cleavable upon exposure to daylight, cleavable upon exposure to UVA- and / or UVB-light, cleavable upon exposure to acids, cleavable upon exposure to an oxidizing agent suitable for oxidizing said functional group, cleavable upon exposure to a reducing agent suitable for reducing said functional group, or cleavable upon exposure to salts. The compound according to any one of embodiments 138 to 140, wherein at least one and in particular all of L9 are hydrolysable at the physiological pH of mammalian skin, more specifically of human skin, and in particular at a pH of between about 5 to about 6.

[0860] The compound according to any one of embodiments 138 to 140, wherein at least one and in particular all of L9 are enzymatically cleavable under physiological conditions after the compound is topically applied onto mammalian, more specifically human skin, in particular enzymatically cleavable by enzymes present in the mammalian, more specifically human skin.

[0861] The compound according to any one of embodiments 138 to 142, wherein at least one and in particular all of L9 provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; after cleavage of L9.

[0862] The compound according to any one of embodiments 138 to 140, wherein at least one and in particular all of L9 are provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime; or salts thereof; to said active ingredient after cleavage of L9.

[0863] The compound according to embodiment 144, wherein, independently for each instance of L9, after cleavage of said L9:

[0864] L9 provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to said active ingredient; and

[0865] L9 provides a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, a boronic acid, a borinic acid, a boric acid, or an oxime to the remainder of the compound. The compound according to any one of embodiments 138 to 145, wherein at least one and in particular all of L9 comprise a carbon ester, in particular a monoester, 1,1 -diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; a disulfide; a carbon amide, in particular a peptide or a N-Mannich base; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amide; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; a phosphonic acid amide; a boronic ester, a borinic ester, a boric ester; an oxazol, a triazole, a benzothiazole, or a coumarin.

[0866] A compound of formula (XV),

[0867]

[0868] wherein B1 represents C(=O)Z1, C(=S)Z1, CH(=O), or an acetal or hemiacetal thereof; CH2-Z2; or Z2;

[0869] wherein Z1represents -OH, -SH or -NH2; and

[0870] wherein Z2represents OH, SH, F, Cl, Br, I, N3;

[0871] or a tautomer and / or a salt thereof.

[0872] The compound of embodiment 147, wherein Bi represents C(=O)Z1and Z1represents - OH.

[0873] A compound comprising a 3,4-saturated 2H-pyran moiety of formula (XVI),

[0874] ^

[0875]

[0876] 20 20 or a tautomer and / or a pharmaceutically acceptable salt thereof;

[0877] for covalently binding an active ingredient to skin and / or hair;

[0878] wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, UVA- and / or UVB-absorbing moiety, a colorimparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair; wherein B2 represents CH2, C(=O), (C=S), (C=NRc), or a C1-C4 acetal moiety selected from the group consisting of an 0,0-acetal, an O, N-acetal, an O, S-acetal, an N, N-acetal, an S, N-acetal, and an S, S-acetal, wherein the C1-C4 acetal moiety is attached to the adjacent methylene group of the remainder of the 3,4-saturated 2H-pyran moiety by a carbon atom,

[0879] wherein Rc represents H, C1-C6alkyl or phenyl,

[0880] wherein L20 is absent or represents a linker that is attached to B2 by O, N, C, S, B or P, more specifically by O, N, C or S, and in particular by O, N or S; and

[0881] wherein A20 represents the active ingredient

[0882] a) as such, or

[0883] b) as a precursor thereof, wherein the compound of formula (XVI) is cleavable to release the active ingredient from the precursor after the application of the compound to the skin and / or the hair.

[0884] The compound according to embodiment 149, wherein L20 is defined as indicated for Ls- in any of the embodiments 74 to 81.

[0885] The compound according to embodiment 149 or 150, wherein A20 is an active ingredient as defined in any of embodiments 110 to 135.

[0886] The compound according to any one of embodiments 149 to 151, wherein B2 is selected from CH2, C(=O) and (C=S).

[0887] The compound according to any one of embodiments 149 to 152, wherein L20 is absent and wherein the active ingredient is attached to B2 by O, N or S.

[0888] The compound according to any one of embodiments 149 to 153, wherein B2 is selected from CH2, C(=O) and (C=S), L20 is absent and the active ingredient is attached to B2 by O, N or S. A topical composition comprising a compound as defined in embodiment 2, and optionally further according to one or more of embodiments 6 to 62, 72 to 81, 108 to 146 and / or 149 to 151, and an excipient that is suitable for topical administration.

[0889] The topical composition of any one of embodiments 5, 107 or 155, wherein the topical composition is having a dynamic viscosity of more than 2 mPa·s, more specifically more than 10 mPa·s, and in particular more than 50 mPa·s; or in the range of 2 mPa·s to 50,000 mPa·s, more specifically in the range of 10 mPa·s to 20,000 mPa·s, and in particular in the range of 50 mPa·s to 10,000 mPa·s; wherein the dynamic viscosity is measured at 37°C according to ASTM D-2196-20, using test method A at 30 rpm, or DIN EN ISO 2555:2018-09, at 30 rpm, on a rotational viscosimeter, for instance ViscoQC 100, optionally equipped with a PTD 100 Cone-Plate for smaller sample sizes, obtainable from Anton Paar GmbH, Germany.

[0890] The topical composition of any one of embodiments 5, 107, 155 or 156, wherein the topical composition comprises trehalose.

[0891] The topical composition of any one of embodiments 5, 107, 155 to 157, wherein the topical composition is present in the form of a patch or in the form of an ink comprised in a pen-like applicator.

[0892] A process for preparing a topical composition according to any one of embodiments 5, 107, or 155 to 158, the process comprising providing a compound as defined in embodiment 2 or as defined in formula (le) of embodiment 4, and optionally further according to one or more of embodiments 6 to 62, 72 to 81, 108 to 146 and / or 149 to 151, and mixing it with an excipient suitable for topical administration.

[0893] Use of a compound as defined in embodiment 2 or as defined in formula (le) of embodiment 4, and optionally further according to one or more of embodiments 6 to 62, 72 to 81, 108 to 146 and / or 149 to 151, for covalently binding an active ingredient, and in particular a water-soluble polymer, specifically hyaluronic acid, to keratinous tissue, in particular to skin and / or hair. Use of a compound as defined in embodiment 2 or as defined in formula (le) of embodiment 4, and optionally further according to one or more of embodiments 6 to 62, 72 to 81, 108 to 146 and / or 149 to 151, in medicine, more specifically...

Claims

1. CLAIMS1. A compound comprising two 3,4-saturated 2H-pyran moieties, wherein the first moiety is according to formula (la) and the second moiety is according to formula (lb),4. 6.(la) (lb)7.or a tautomer and / or a pharmaceutically acceptable salt thereof,8.wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Lg-Ag and L7-A7 and at least one of Li'-Ar, L2-A2', L3-A3', L4-A4', L5-A5', Lg-Ag' and L7-A7' jointly represent a bridging linker group LBRIDGE which is covalently binding the moiety according to formula (la) to the moiety according to formula (lb);9.wherein the remainder of substituents represents, each independently from the others: Li, L2, L3, L4, L5, Lg, L7, absent or a linker group10.Lr, L2', L3', L4', L5', Lg' and L7'11.Ai, Ar, A4, A4', As and As' hydrogen, a C1-C30 moiety, hydroxyl, amino, or a halogen12.A2, A2', A3, and A3' as for Ai or L2-A2 and L3-A3 jointly represent oxo; Ag, Ag', A7 and A7' hydrogen or a C1-C30 moiety;13.R1and R2hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

15.

2. A compound for covalently binding an active ingredient to skin and / or hair, wherein the compound comprises a 3,4-saturated 2H-pyran moiety which is defined as indicated for formula (lb) in claim 1 and a moiety according to formula (Ic) or (Id) which comprises the active ingredient,18. 20.(Ic) (Id)21.or a tautomer and / or a pharmaceutically acceptable salt thereof;22.wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a colorimparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair; wherein at least one of L1-A1, L2-A2, L3-A3, L4-A4, L5-A5, Le-Ae and L7-A7 and at least one of Li'-Ar, Ly-Ay, Ls'-As', L4'-A4', Le'-Ae' and L7-A7' jointly represent a bridging linker group LBRIDGE’ which is covalently binding the moiety of formula (Ic) or (Id) to the moiety of formula (lb),23.wherein, in both formulae (Ic) and (Id):24.Ls- represents a linker group or is absent;25.R represents the active ingredient26.a) as such, or27.b) as a precursor thereof, in which case the linker group Ls- is present and cleavable to release the active ingredient from the compound after the application of the compound to the skin and / or the hair; and28.the remainder of the substituents is defined as indicated for formula (la) in claim 1.

3. A process of preparing a compound of claim 2, the process comprising coupling a compound of claim 1 and an active ingredient comprising an amino group, wherein the process comprises the following steps:30.mixing the compound of claim 1 in one or more solvents to obtain a reaction mixture, agitating the reaction mixture and bringing the active ingredient into reactive contact with the compound of claim 1 in said reaction mixture such that the compound of claim 1 is present in stoichiometric excess to the active ingredient until:31.substantially all or all of the amino groups of the active ingredient have reacted with the compound of claim 1, or a reagent is added which terminates the coupling reaction between the active ingredient and the compound of claim 1 in the reaction mixture.

4. The compound or process according to any preceding claim, wherein each occurrence of the C1-C30 moiety, independently from each other, comprises 1 to 30, more specifically 1 to 16, and in particular 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 phosphorus atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 boron atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms; and / or wherein33.the C1-C30 moiety is bound34.a) to the respective Li to L7 and Lr to L7' via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, or,35.b) if the respective Li to L7 and Lr to L7' is absent, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom to the carbon atom of ring to which the Ci- C30 moiety is attached.

5. The compound or process according to any preceding claim, wherein each occurrence of Li to L7 and Lr to L7' which is not a part of LBRIDGE and LBRIDGE’ is, independently from each other, absent or representing an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 8 carbon atoms.

6. The compound or process according to any preceding claim, wherein:38.Li and Lg are present and form a ring; and / or39.Li and L3 are present and form a ring; and / or40.L3 and L4 are present and form a ring; and / or41.L4 and L7 are present and form a ring; and / or42.L4 is present and forms a ring with R1;43.and / or wherein:44.Lr and Lg' are present and form a ring; and / or45.Lr and L3' are present and form a ring; and / or46.L3' and L4' are present and form a ring; and / or L4- and L7' are present and form a ring; and / or47.L4' is present and forms a ring with R2; and in particular wherein48.independently for each occurrence, the ring is a 5-, 6-, 7- or 8-membered ring, more specifically a 5-, 6-, or 7-membered ring, and in particular a 5- or 6-membered ring.

7. The compound or process according to claim 6, wherein the ring is a bridged bicyclic ring, more specifically a bicyclic ring having a bridge which comprises one or two bridging atoms; more specifically wherein the bridging atoms are, independently from each other, selected from C, N, O and S, more specifically from C, N and O, and in particular from C and N.

8. The compound or process according to claim 6 or claim 7, wherein the respective two of Ai to A7 and Ar to A7' corresponding to the two linker groups of Li to L7 and Lr to L7' which are forming the (bicyclic) ring are, independently from each other, attached to said (bicyclic) ring by a bond or a linker group; and / or51.wherein the ring is optionally substituted and / or optionally bridged as defined in claim 6 or 7 with the further proviso that the (bridged) ring, together with its optional substituents and linker groups, comprises less than 30, more specifically less thanl6, and in particular less than 12 carbon atoms; less than 12, more less than 8, and in particular less than 6 oxygen atoms; less than 8, more specifically less than 6, and in particular less than 4 nitrogen atoms; less than 6, more specifically less than 4, and in particular less than 3 sulfur atoms; less than 6, more specifically less than 4, and in particular less than 3 phosphorus atoms; less than 6, more specifically less than 4, and in particular less than 3 boron atoms; and less than 10, more specifically less than 8, and in particular less than 6 halogen atoms; and / or52.wherein said linker group is selected from the group consisting of: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2)1-4-, -(CH2)1-4-O- and -O-(CH2)1-4-, or combinations thereof.

9. The compound or process according to any one of claims 1 to 8, wherein one or both moieties of formulae (la) and (lb) is a moiety of formula (II),54. 56.(ID,57.or a tautomer and / or a pharmaceutically acceptable salt thereof;58.wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE represent:59.Ln, L13, LU, Lie and L17 absent or a linker group, in particular as defined in any preceding claim, wherein, in said preceding claims, Ln corresponds to Li and / or Lr, L13 corresponds to L3 and / or L3’, L14 corresponds to L4 and / or L4’, Lie corresponds to Lg and / or Lg’, and L17 corresponds to L7 and / or L7’.60.An, A13 and A14 hydrogen, hydroxyl, halogen, or a C1-C30 moiety, in particular as defined in any preceding claim, wherein, in said preceding claims, An corresponds to Ai and / or An, A13 corresponds to A3 and / or A3 ’ and A14 corresponds to A4 and / or A4’. A12 and A15 hydrogen or halogen, and in particular hydrogen; A16 and A17 hydrogen or a C1-C30 moiety;61.optionally with the further proviso t rat at least one of the substituent combinations Lig- Ais and L17-A17 represents hydrogel 1;62.R3hydrogen or a protective group hydrolysable under physiological conditions after application of the compound to the skin and / or the hair.

64.

10. The compound or process according to any preceding claim, wherein one or both moieties of formulae (la) and (lb) is a moiety of formula (III),Xx^Lx— An67.1-16“ A-I668.Ai 3— Li 369.A14— Li 4 k.070.0-R371.I1772.A1774.

75. (III),76.or a tautomer and / or a pharmaceutically acceptable salt thereof;77.wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’, represent:78.R3, An, A13, A14, Ais, A17, L13, L14, LIS and L17 are defined as in any preceding claim; X represents O or S, and in particular O; and79.Lxis absent or represents -O-, -S-, -NH-, or an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 10 carbon atoms, 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms; and80.the hydrocarbon moiety is attached to the (C=X)-moiety via a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom;81.and, in particular,82.wherein one or both moieties of formulae (la) and (lb) is a moiety of formula (IV),84.

85. (IV)86.587.or a tautomer and / or a pharmaceutically acceptable salt thereof; wherein the remainder of substituents not representing a part of the bridging linker group LBRIDGE or LBRIDGE’ represent:88.R3, Ln, Lis, Ln, An, A13, AU, Ais and An are defined as in any preceding claim; n represents an integer of 0 or 1, and in particular 0;89.the dashed bond represents a single or a double bond, and in particular a single bond; and, independently from each other, each instance of Lyis absent or represents a linker group, in particular a linker group selected from the group consisting of:90.-O-;91.-S-;92.-NH-;93.an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 18 carbon atoms, more specifically 1 to 12 carbon atoms, and in particular 1 to 10 carbon atoms, 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 sulfur atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; and 0 to 8, more specifically 0 to 6, and in particular 0 to 5 halogen atoms;94.or combinations thereof.

11. The compound or process according to claim 1, and optionally further according to any one of claims 3 to 10, wherein the bridging linker group LBRIDGE is a Ci-Ceo moiety or a polymer; and / or96.the compound or process according to any one of claims 2 to 10, wherein the bridging linker group LBRIDGE’ is a Ci-Ceo moiety or a polymer; in particular97.wherein the bridging linker group LBRIDGE and / or the bridging linker group LBRIDGE’ is a Ci-Ceo moiety, in particular an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 60 carbon atoms, more specifically 1 to 48 carbon atoms, and in particular 1 to 36 carbon atoms, 0 to 50, more specifically 0 to 40, and in particular 0 to 20 oxygen atoms; 0 to 30, more specifically 0 to 20, and in particular 0 to 10 nitrogen atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 sulfur atoms; 0 to 10, more specifically 0 to 8, and in particular 0 to 6 phosphorous atoms; 0 to 4, more specifically 0 to 3, and in particular 0 to 2 boron atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 silicon atoms; and 0 to 20, more specifically 0 to 10, and in particular 0 to 5 halogen atoms.

12. The compound according to claim 1 or the process of claim 3, wherein the compound comprising the moiety according to formula (la) and the moiety according to formula (lb) is a compound according to the following formula (XIV),100.

101. (XIV) or a tautomer and / or a pharmaceutically acceptable salt thereof; and102.wherein each instance of R3 represents, independently from each other, R3 as defined in claim 9, and in particular represents H;103.wherein each instance of Z represents, independently from each other, O or S or C=Z represents a methylene group; and104.wherein B represents a linker group, in particular CH2-(OCH2)i-i2 or (CH2)i-i2, more specifically CH2-(OCH2)i-s or (CH2)I-6, and in particular CH2-(OCH2)I-6 or (012)2-4.

13. The compound or process according to any one of claims 2 to 12, wherein the active ingredient or the precursor thereof is a Ci-Ceo moiety; or wherein the active ingredient or the precursor thereof is a polymeric moiety.

14. The compound or process according to any one of claims 2 to 13, wherein Ls- comprises one or more of, two or more of, three or more of, four or more of, five or more, six or more, or all of:107.- 1 to 12 carbon atoms, more specifically 1 to 8 carbon atoms, and in particular 1 to 4 carbon atoms;108.- 1 to 12 oxygen atoms, more specifically 1 to 8 oxygen atoms, and in particular 1 to 4 oxygen atoms; - 1 to 8 nitrogen atoms, more specifically 1 to 6 nitrogen atoms, and in particular to 3 nitrogen atoms;109.- 1 to 3 sulfur atoms, more specifically 1 or 2 sulfur atoms, and in particular 1 sulfur atom;110.- 1 to 3 phosphorus atoms, more specifically 1 or 2 phosphorus atoms, and in particular 1 phosphorus atom;111.- 1 to 12 silicon atoms, more specifically 1 to 8 silicon atoms, and in particular to 1 to 6 silicon atoms;112.- 1 or 2 boron atoms, and in particular 1 boron atom.

15. The compound or process according to any one of claims 2 to 14, wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, a UVA- and / or UVB-absorbing moiety, a color-imparting moiety, a cosmetic hair coating agent and a primer for attaching dyes to hair;114.more specifically, wherein the active ingredient is a moisturizer; and,115.in particular, wherein the active ingredient comprises:116.a polyol, more specifically a polyol having n hydroxyl groups with n being 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 8 or more, 10 or more, 12 or more, or 16 or more;117.a mono- or polyvalent carboxylic acid comprising one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid or citric acid;118.a sugar, more specifically a triose, a tetrose, a pentose a hexose, a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide;119.a sugar alcohol, more specifically a sugar alcohol comprising between 2 and 24 carbon atoms, in particular ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, or maltotetraitol;120.a sugar acid, more specifically an aldonic acid, an ulosonic acid, an uronic acid or an aldaric acid; or a salt thereof; or an ester thereof, in particular a C1-C4-alkylester thereof; or an amide thereof;121.a water-soluble polymer which is a polysaccharide; more specifically a glycosaminoglycan, such as chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid; and in particular hyaluronic acid; and copolymers thereof, in particular copolymers comprising polyethylene glycol; more specifically wherein the active ingredient is:122.a hyaluronic acid, more specifically a hyaluronic acid having an average molecular weight of between 3000 and 3 million kDa, more specifically between 5000 and 2 million kDa, and in particular between 10,000 and 1.5 million kDa.

16. The compound or process according to any one of claims 2 to 15, wherein the compound, after having covalently bound to the skin and / or the hair, is not observable to the human eye on the skin and / or hair when illuminated with artificial light of 3000 Kelvin and an intensity of 1000 Lux; and / or wherein the compound, after having covalently bound to lysine, does not show absorption peaks having an extinction of more than 0.5 within the wavelength range of 380 to 790 nm in 2 mM methanolic solution.

17. A compound of formula (XV),126. 128.wherein B1 represents C(=O)Z1, C(=S)Z1, CH(=O), or an acetal or hemiacetal thereof; CH2-Z2; or Z2;129.wherein Z1represents -OH, -SH or -NH2; and130.wherein Z2represents OH, SH, F, Cl, Br, I, N3;131.or a tautomer and / or a salt thereof.

18. A compound comprising a 3,4-saturated 2H-pyran moiety of formula (XVI),134. 135.A20 (XVI), or a tautomer and / or a pharmaceutically acceptable salt thereof;136.for covalently binding an active ingredient to skin and / or hair;137.wherein the active ingredient is selected from a moisturizer, a pesticide, a fragrance, a pharmaceutical, a skin whitening agent, UVA- and / or UVB-absorbing moiety, a colorimparting moiety, a cosmetic hair coating agent, and a primer for attaching dyes to hair; wherein B2 represents CH2, C(=O), (C=S), (C=NRc), or a C1-C4 acetal moiety selected from the group consisting of an 0,0-acetal, an O, N-acetal, an O, S-acetal, an N, N-acetal, an S, N-acetal, and an S, S-acetal, wherein the C1-C4 acetal moiety is attached to the adjacent methylene group of the remainder of the 3,4-saturated 2H-pyran moiety by a carbon atom,138.wherein Rc represents H, C1-C6alkyl or phenyl,139.wherein L20 is absent or represents a linker that is attached to B2 by O, N, C, S, B or P, more specifically by O, N, C or S, and in particular by O, N or S; and140.wherein A20 represents the active ingredient141.a) as such, or142.b) as a precursor thereof, wherein the compound of formula (XVI) is cleavable to release the active ingredient from the precursor after the application of the compound to the skin and / or the hair;143.in particular wherein B2 is selected from CH2, C(=O) and (C=S), L20 is absent and the active ingredient is attached to B2 by O, N or S.

19. A topical composition comprising a compound as defined in claim 2 or claim 18 and an excipient that is suitable for topical administration.

20. The topical composition of claim 19, wherein the topical composition is having a dynamic viscosity of more than 2 mPa s, more specifically more than 10 mPa s, and in particular more than 50 mPa s; or in the range of 2 mPa s to 50,000 mPa s, more specifically in the range of 10 mPa s to 20,000 mPa s, and in particular in the range of 50 mPa s to 10,000 mPa s; wherein the dynamic viscosity is measured at 37°C according to ASTM D-2196- 20, using test method A at 30 rpm, or DIN EN ISO 2555:2018-09, at 30 rpm, on a rotational viscosimeter, for instance ViscoQC 100, optionally equipped with a PTD 100 Cone-Plate for smaller sample sizes, obtainable from Anton Paar GmbH, Germany; and / orwherein the topical composition comprises trehalose; and / or146.wherein the topical composition is present in the form of a patch or in the form of an ink comprised in a pen-like applicator.

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