Hydrogenated genipin derivatives attachable to keratinous tissue

Abstract

The present application relates to topical compositions comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application wherein the compound capable of covalently binding to the skin is a compound of formula (I) or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein R1 represents hydrogen or a protecting group that is hydrolysable under physiological conditions upon application of the topical composition to the skin; wherein L1, L2 and L3, independently of each other, represent a linking group or are absent, and wherein A1, A2 and A3, independently of each other, represent: a) a C1-C30 moiety, H, hydroxyl, amino or halogen, or b) a C1-C60 moiety or a polymeric moiety; wherein at least one of A1, A2 and A3 is a C1-C60 moiety or a polymeric moiety of group b); wherein the C1-C60 portion or polymeric portion of group b): b1) is configured to act as a skin moisturizer, an insecticide, a skin whitening agent or a drug; and / or b2) is configured to act as a skin moisturizer, an insecticide, a skin whitening agent, a fragrance or a drug upon cleavage from the 3, 4-dihydro-2H-pyran moiety; and wherein L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond at the alpha position of the carbon atoms marked as "a" and "b", respectively. (I);

Description

Cross-references to related applications

[0001] This application claims the benefit of European patent applications No. EP23178139.4 and No. 23178138.6, both filed on 7 June 2023, entitled “Compounds attachable tokeratinous tissues”, the contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to compounds that can be reliably and effectively grafted onto keratinized tissues such as skin. More specifically, this disclosure relates to conjugated molecules comprising an active ingredient and specially selected anchoring moieties that, once attached to the keratinized tissue, do not form a broad conjugated π system. Therefore, the coupled anchoring moieties do not impart color and allow the compounds of this disclosure to remain visually inconspicuous after coupling to the tissue. This disclosure also relates to topical compositions comprising these compounds, as well as various methods and applications of these compounds. Background Technology

[0003] Genipin is a naturally occurring compound (1R,4aS,7aS)-1-hydroxy-7-(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopentadienano[c]pyran-4-carboxylic acid methyl ester (CAS RN.6902-77-8) and has the following structure:

[0004]

[0005] Genipin can be irreversibly coupled to keratinocytes. For example, keratin in the skin contains lysine residues with aliphatic amino side chains. These amino side chains react with the cyclic hemiacetal structure of genipin according to the following representative reaction scheme:

[0006]

[0007] The resulting conjugated genipin derivative is dark blue. Due to its dark blue color, genipin is commercially used as a tattoo dye in semi-permanent tattoos.

[0008] This skin-coupling property makes genipin an interesting candidate for conjugating various active ingredients, such as moisturizers, insecticides, especially insect repellents, skin brighteners, fragrance precursors, and drugs, to the skin. However, the deep blue color is not aesthetically pleasing to many, especially if applied to the face or a large area of ​​skin. Therefore, despite carrying many functional groups that could easily be used to attach active ingredients, genipin has not yet been seriously considered as a means of attaching active ingredients to the skin.

[0009] However, there is a great need for compounds that allow active ingredients to adhere to the skin discreetly. Summary of the Invention

[0010] In their extensive research on genipin chemistry, the inventors concluded that a wide range of genipin derivatives can be reliably and efficiently coupled to keratinized tissues such as skin. This robust coupling chemistry is attributable to the 3,4-dihydro-2H-pyran moiety and is largely unaffected by further substitution of the 3,4-dihydro-2H-pyran moiety. This finding is further supported by literature describing, for example, oleuropein and aucubin activated by β-glucosidase as having very strong protein denaturing, protein cross-linking, and lysine alkylation activities, which are very similar to but stronger than those of glutaraldehyde; see Konno et al., PNAS, 1999, 96(16) 9159-9164. Deglycosylated oleuropein and aucubin have the following structures:

[0011]

[0012] Therefore, the inventors have recognized that various 3,4-dihydro-2H-pyran derivatives can be effectively and irreversibly coupled to the skin.

[0013] Furthermore, in their research, the inventors surprisingly discovered that the hydrogenated genipin derivatives remained substantially colorless after reaction with lysine. A representative example is shown in the following reaction scheme:

[0014]

[0015] The colorless (or nearly colorless, and therefore visually imperceptible) state of skin-coupled hydrogenated genipin derivatives can be explained by the fact that the 1,4-dihydropyridine moiety formed with lysine does not have a π-electron system conjugated with the double bond present in the cyclopentene moiety of genipin (and not present in hydrogenated genipin).

[0016] Therefore, the inventors have concluded that, provided the 3,4-dihydro-2H-pyran derivative is selected such that the 1,4-dihydropyridine moiety, which avoids binding to the skin, forms a conjugated π-electron system, various 3,4-dihydro-2H-pyran derivatives will inconspicuously bind to, for example, the skin. Thus, 3,4-dihydro-2H-pyran derivatives that meet this requirement are particularly useful as visually imperceptible anchoring portions to effectively, irreversibly, and inconspicuously couple active ingredients to keratinocytes, such as the skin.

[0017] Finally, the active ingredient can be stably bound to a 3,4-dihydro-2H-pyran derivative, or the active ingredient can be bound to a 3,4-dihydro-2H-pyran derivative such that it is released over time, for example by attaching the active ingredient to a functional group on the 3,4-dihydro-2H-pyran derivative via hydrolysis or enzymatic cleavage. Suitable functional groups that provide sustained release properties are well known in the art and are readily available to those skilled in the art; see, for example, V. Redasani and S. Bariwidely, Prodrug Design - Perspectives, Approaches and Applications in Medicinal Chemistry, 1st ed., 2015, ISBN: 9780128035191, the full text of which is incorporated herein by reference.

[0018] Therefore, in a first aspect, this disclosure relates to a topical composition comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin is a compound of formula (I).

[0019] (I).

[0020] In the compound of formula (I), R 1 L1, L2, and L3 represent hydrogen or a protecting group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; L1, L2, and L3 independently represent linking groups or are absent. A1, A2, and A3 independently represent the following portions:

[0021] Group a): C1-C 30 Partial, H, hydroxyl, amino, or halogen; or

[0022] Group b): C1-C 60 Partial or polymeric portion.

[0023] Group b) C1-C 60 The active ingredient / component is carried in part or in a polymer portion. Therefore, at least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric portion.

[0024] Group b) C1-C 60 The partial or polymeric portion is further subdivided into two subgroups, b1) and b2).

[0025] C1-C of group b1) 60 Some or polymeric components are formulated to act as skin moisturizers, insecticides, skin brighteners, or drugs.

[0026] In other words, this means that, here and for all other aspects of this disclosure, group b1) of C1-C 60 The partial or polymeric portion is a skin moisturizing portion, a portion that provides insecticidal activity, a skin whitening portion, or a pharmaceutically active portion, while also adhering to the remaining portion of the 3,4-dihydro-2H-pyran portion.

[0027] Additionally or alternatively, this means that, herein and for all other aspects of this disclosure, C1-C of group b1) 60 Some or polymeric components are skin moisturizers, insecticides, skin brighteners, or drugs.

[0028] Additionally or alternatively, this means that, herein and for all other aspects of this disclosure, C1-C of group b1) 60 A skin moisturizer, insecticide, skin brightener, or drug whose partial or polymeric portion is attached to the remaining portion of the 3,4-dihydro-2H-pyran moiety.

[0029] C1-C of group b2) 60 The portion or polymer portion is configured to act as a skin moisturizer, insecticide, skin whitening agent, fragrance or medicine after cleavage from the 3,4-dihydro-2H-pyran portion.

[0030] In other words, this means that, here and for all other aspects of this disclosure, group b2) of C1-C 60 The partial or polymeric portion provides its skin moisturizing activity, its insecticidal activity, its skin whitening activity, its olfactory effect, or its pharmaceutical activity after being cleaved or released from the remainder of the 3,4-dihydro-2H-pyran moiety.

[0031] Additionally or alternatively, this means that, herein and for all other aspects of this disclosure, C1-C of group b2) 60 The partial or polymeric portion is a skin moisturizer, insecticide, skin whitening agent, fragrance, or pharmaceutical after being cleaved or released from the remainder of the 3,4-dihydro-2H-pyran moiety.

[0032] Additionally or alternatively, this means that, herein and for all other aspects of this disclosure, C1-C of group b2) 60 A partial or polymeric moiety is a skin moisturizer, insecticide, skin brightener, fragrance, or drug that can be cleaved or released from the remainder of the 3,4-dihydro-2H-pyran moiety after the compound has been covalently bonded to the skin.

[0033] Although in some cases, such as in the case of fragrances, the attached active ingredient only becomes active after release, the two subgroups b1) and b2) are not necessarily mutually exclusive. For example, a polyol wetting agent can provide its activity when attached to the 3,4-dihydro-2H-pyran moiety, or it can provide its activity when released from the 3,4-dihydro-2H-pyran moiety.

[0034] As noted above, the 3,4-dihydro-2H-pyran derivatives of this disclosure are chosen such that the 1,4-dihydropyridine moiety that binds to the skin is substantially prevented from forming a conjugated π-electron system. Therefore, the compounds of this disclosure are limited such that L1-A1 and L2-A2 do not represent portions containing unsaturated CC or CN bonds at the α positions of the carbon atoms labeled “a” and “b”, respectively.

[0035] The compounds in the above formula may also exist in their tautomer form and / or in pharmaceutically acceptable salt form.

[0036] In a second aspect, this disclosure relates to compounds of formula (I) or their tautomers and / or pharmaceutically acceptable salts.

[0037] (I);

[0038] in

[0039] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0040] L1, L2, and L3 represent the linking group independently or not at all.

[0041] A1, A2, and A3 represent each other independently.

[0042] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0043] b)C1-C 60 Partial or polymeric components;

[0044] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0045] Group b) C1-C 60 Partial or polymeric portion

[0046] b1) is configured to act as a drug; and / or

[0047] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0048] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0049] Used in medicine.

[0050] In a third aspect, this disclosure relates to compounds of formula (I) or their tautomers and / or pharmaceutically acceptable salts.

[0051] (I);

[0052] in

[0053] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0054] L1, L2, and L3 represent the linking group independently or not at all.

[0055] A1, A2, and A3 represent each other independently.

[0056] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0057] b)C1-C 60 Partial or polymeric components;

[0058] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0059] Group b) C1-C 60 Partial or polymeric portion

[0060] b1) is configured to act as a drug; and / or

[0061] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0062] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0063] Used to treat skin-related diseases, allergic conditions, pain, or inflammation.

[0064] In a fourth aspect, this disclosure relates to compounds of formula (I) or their tautomers and / or pharmaceutically acceptable salts.

[0065] (I);

[0066] in

[0067] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0068] L1, L2, and L3 represent the linking group independently or not at all.

[0069] A1, A2, and A3 represent each other independently.

[0070] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0071] b)C1-C 60 Partial or polymeric components;

[0072] At least one of A1, A2, and A3 is a C1-C group configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran. 60 Partial or polymeric portion; and

[0073] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0074] Used in medicine, particularly for skin-related diseases, allergic conditions, pain, or inflammation, in which the drug is released within hours or days.

[0075] In a fifth aspect, this disclosure relates to the use of the topical composition according to the first aspect as a skin moisturizer, insecticide, particularly an insect repellent, skin brightener, or fragrance.

[0076] In a sixth aspect, this disclosure relates to a method of using a topical composition comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin may be a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0077] (I);

[0078] in

[0079] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0080] L1, L2, and L3 represent the linking group independently or not at all.

[0081] A1, A2, and A3 represent each other independently.

[0082] a)C1-C30 Partial, H, hydroxyl, amino or halogen, or

[0083] b)C1-C 60 Partial or polymeric components;

[0084] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0085] Group b) C1-C 60 Partial or polymeric portion

[0086] b1) is configured to act as a skin moisturizer, insecticide, or skin brightener; and / or

[0087] b2) is configured to act as a skin moisturizer, insecticide, skin brightener, or fragrance after partial cleavage from 3,4-dihydro-2H-pyran; and

[0088] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0089] The method involves applying a topical composition to the skin.

[0090] In a seventh aspect, this disclosure relates to a method of treating domestic or farm animals, the method comprising applying a topical composition to the skin and / or fur of the domestic or farm animal, wherein the topical composition comprises a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin may be a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0091] (I);

[0092] in

[0093] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0094] L1, L2, and L3 represent the linking group independently or not at all.

[0095] A1, A2, and A3 represent each other independently.

[0096] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0097] b)C1-C 60 Partial or polymeric components;

[0098] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0099] Group b) C1-C 60 Partial or polymeric portion

[0100] b1) is configured to act as an insecticide; and / or

[0101] b2) is configured to act as an insecticide after partial cleavage from 3,4-dihydro-2H-pyran; and

[0102] L1-A1 and L2-A2 do not indicate portions containing unsaturated CC or CN bonds at the α positions of carbon atoms labeled "a" and "b" respectively.

[0103] In the eighth aspect, this disclosure specifically relates to the compounds of this disclosure themselves, i.e., independent of topical compositions. Attached Figure Description

[0104] Figure 1 A reaction scheme for synthesizing compounds of this disclosure containing erythritol as an active component is shown.

[0105] Figure 2 A reaction scheme for synthesizing compounds of this disclosure comprising p-methane-3,8-diol as an active component is shown.

[0106] Figure 3 A reaction scheme for synthesizing compounds of this disclosure containing minoxidil as an active component is shown.

[0107] Figure 4 A reaction scheme for synthesizing compounds of this disclosure containing desloratadine as an active component is shown.

[0108] Figures 5 to 9 and Figure 11 UV spectra of compounds containing the 3,4-dihydro-2H-pyran moiety (some of which are compounds according to this disclosure) and UV spectra of their corresponding lysine conjugates are shown.

[0109] Figure 10 and Figure 12 The adhesion of the compounds of this disclosure to pig skin is shown. Detailed Implementation

[0110] In a first aspect, this disclosure relates to a compound capable of covalently binding to the skin, and more particularly to said compound contained in a topical composition further comprising an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin is a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0111] (I).

[0112] The term "compound capable of covalently binding to the skin" has its common meaning in the art, and particularly refers to a compound that can undergo a chemical reaction in which it covalently binds to the amino side chain of an amino acid such as lysine. Additionally or alternatively, a compound is "capable of covalently binding to the skin" if, after incubating the compound (or a topical composition containing the compound) on pig skin at 37°C for 24 hours, the compound (or the topical composition containing the compound) cannot be completely washed off from the (explanted) pig skin by water, soap, and / or isopropanol. Additionally or alternatively, a compound is "capable of covalently binding to the skin" if, when 0.1 mol / L of the compound is placed in an aqueous solution at 37°C for 24 hours at a pH of about 5 and also containing 0.1 mol / L lysine, the compound is converted to its corresponding 1,4-dihydropyridine derivative in greater than 10 mol%.

[0113] Although the features described in the foregoing paragraphs explicitly refer to “skin,” the term “topical composition” should not be construed as excluding compositions also (or primarily or even exclusively) formulated / intended for use with skin appendages. Skin appendages are epidermal and dermal components of the skin and include hair, nails, sweat glands, and sebaceous glands.

[0114] In the compound of formula (I), R 1 The term "protective group that is hydrolyzable under physiological conditions after application of the topical composition to the skin" refers to hydrogen or a protective group that is hydrolyzable under physiological conditions after application of the topical composition to the skin. When "physiological conditions" is used in the context, it should be understood that this refers specifically to the pH conditions encountered at the site where the compound of formula (I) binds to the subject (skin or skin appendages) to be treated. Additionally or alternatively, the term "protective group that is hydrolyzable under physiological conditions after application of the topical composition" refers to a group that hydrolyzes when 0.1 mol / L of the compound of formula (I) is placed in an aqueous solution at a pH of about 5 for 24 hours, wherein the group under consideration is considered to meet the definition of "protective group that is hydrolyzable under physiological conditions after application of the topical composition" if more than 10 mol% is converted to the corresponding hemiacetal of the group under consideration.

[0115] A1, A2, and A3 independently represent the following parts:

[0116] Group a): C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0117] Group b): C1-C 60 Partial or polymeric portion.

[0118] Group b) C1-C60 The active ingredient / component is carried in part or in a polymer portion. Therefore, at least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric portion.

[0119] Group b) C1-C 60 The partial or polymeric portion is further subdivided into two subgroups, b1) and b2). The C1-C fraction of subgroup b1) is... 60 Some or polymeric portions are formulated to act as skin moisturizers, insecticides, skin brighteners, or pharmaceuticals. In other words, the active ingredient / component is able to provide its activity by attaching to the remainder of the 3,4-dihydro-2H-pyran moiety. (Group b2) C1-C 60 A portion or polymer portion is configured to act as a skin moisturizer, insecticide, skin brightener, fragrance, or pharmaceutical after cleavage from the 3,4-dihydro-2H-pyran moiety. In other words, the active ingredient / component is able to provide its activity after release from the remainder of the 3,4-dihydro-2H-pyran moiety. Although in some cases, such as in fragrances, the attached active ingredient is only active after release, the two subgroups b1) and b2) are not necessarily mutually exclusive. For example, a polyol wetting agent can provide its moisturizing activity both when attached to the 3,4-dihydro-2H-pyran moiety and when released from it.

[0120] When referring to group b2) C1-C 60 When a portion or polymeric moiety is cleaved (or released) from the 3,4-dihydro-2H-pyran moiety, it should be understood that this means the 3,4-dihydro-2H-pyran moiety includes (or at least partially includes) L1, L2 and / or L3 (if present) and any remaining A1 to A3 moiety. Furthermore, it should be understood that this refers to cleavage (or release) under physiological conditions encountered by the compound after the topical composition has been applied to the skin (or skin appendages). When “physiological conditions” is used in the context, it should be understood that this specifically refers to environmental conditions, particularly pH, enzyme, and temperature conditions, encountered at the site where the compound of hypothetical formula (I) binds to keratinized tissue in the stratum corneum and / or epidermis of, for example, a subject to be treated (mammal, particularly human). Additionally or alternatively, the C1-C of group b2) can be evaluated on an isolated porcine skin model at 37°C. 60 The ability of a portion or polymeric part to be cleaved from the 3,4-dihydro-2H-pyran moiety.

[0121] As noted above, the 3,4-dihydro-2H-pyran derivatives of this disclosure are chosen such that the 1,4-dihydropyridine moiety that binds to the skin is substantially prevented from forming a conjugated π-electron system. Therefore, the compounds of this disclosure are limited such that L1-A1 and L2-A2 do not represent portions containing unsaturated CC or CN bonds at the α positions of the carbon atoms labeled “a” and “b”, respectively.

[0122] A1, A2, and A3 can represent C1-C independently of each other. 30 A portion, that is, a portion according to group a). The term is not particularly limited as commonly understood in the art, and refers to any portion containing 1 to 30 carbon atoms. The presence of additional heteroatoms, i.e., atoms that are not C, such as H, O, and N, may be included in the portion.

[0123] A1, A2, and A3 can independently represent C1-C of groups b1) and / or b2). 60 Partial or polymeric portion. Similarly, the term C1-C. 60 The term "part" is not particularly limited by its common understanding in the art and refers to any part containing 1 to 60 carbon atoms. The presence of additional heteroatoms, i.e., atoms that are not C, such as H, O, and N, can be included in C1-C2. 60 In addition, the term "polymer moiety" is not particularly limited to its common understanding in the art, and refers to any oligomer (defined herein as having more than 3 and at most 8 repeating units) or polymer moiety (defined herein as having more than 8 repeating units). A polymer moiety, i.e., a polymer, will generally contain carbon and / or silicon, but does not exclude the presence of additional heteroatoms, i.e., atoms that are not C or Si, such as H, O, N, etc., which may be included in the polymer moiety.

[0124] A1, A2, and A3 can independently represent C1-C of group b1). 60 A partial or polymeric portion configured to act as a skin moisturizer, insecticide, skin brightener, or pharmaceutical. The functional language is intended to suggest C1-C. 60 Partial or polymeric portions (or more specifically, the entire compound after covalent bonding to keratinous materials such as skin) can provide the mentioned effects (skin moisturizing, insecticidal, skin whitening, or pharmacological effects).

[0125] A1, A2, and A3 can also independently represent C1-C of group b2). 60 A partial or polymeric portion configured to act as a skin moisturizer, insecticide, skin brightener, fragrance, or pharmaceutical after cleavage from the 3,4-dihydro-2H-pyran moiety. The functional language is intended to suggest a sequence from C1-C...60 Compounds that are partially or released from polymer portions (or more specifically, from the whole compound after covalent bonding to keratinous materials such as skin) can provide the aforementioned effects (skin moisturizing effect, insecticidal effect, skin whitening effect, olfactory effect, or pharmacological effect).

[0126] In some embodiments, A1, A2, and A3 may independently represent the polymer portion of group b1) or b2) configured to act as a skin moisturizer. The functional language is intended to suggest that the polymer portion (or more specifically, the entire compound after covalent bonding to a keratinous material such as skin) is capable of providing skin moisturizing effects.

[0127] The term "skin moisturizer" refers to a compound / part that can directly bind to water in the skin (via hydrogen bonding) or reduce water evaporation from the skin. Therefore, the term encompasses moisturizers, emollients, and occlusives, as these terms are used and understood in the art.

[0128] The term “pesticide” is used in its general sense in the art, and in particular refers to compounds that can kill, incapacitate, repel, or otherwise improve the health, comfort, or well-being of mammals (humans) caused by invertebrates (especially insects).

[0129] The term "skin brightener" has its common meaning in the art, and in particular refers to compounds that can chemically and / or metabolically brighten the skin tone. The term "skin brightener" does not refer to pigments or dyes or optical brighteners.

[0130] The term "fragrance" is used in the general sense in this field, and in particular refers to volatile compounds that can provide an olfactory impression, especially an olfactory impression comprising one or more of the seven basic odors (floral, fruity, minty, nutty, spicy, sweet and woody).

[0131] The term "drug" is used in its general sense in the art, and in particular refers to compounds that are capable of / intended to be used for the diagnosis, cure, relief, treatment, therapy or prevention of diseases in mammals, particularly humans and domestic and farm animals.

[0132] L1, L2, and L3 independently represent the linking group or its absence. The term "linking group" is not particularly limited and refers to any chemical group that covalently links the 3,4-dihydro-2H-pyran moiety to the corresponding moiety A1, A2, and A3, respectively. For clarity, it should be understood that L1 and L2 are linked to the 3,4-dihydro-2H-pyran moiety by a single bond, i.e., the ring positions marked "a" and "b" indicate the methine ("CHR3").

[0133] In some embodiments, L1, L2, and L3 (if present and independent of each other) may represent optionally substituted hydrocarbon moieties, each of which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0134] In some embodiments, L1, L2, and L3 may also form optionally substituted cyclic structures. In some embodiments, L1 and L2 are present and form 5-, 6-, 7-, or 8-membered rings, particularly cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0135] In some embodiments, L1 and L2 form optionally substituted 5- or 6-membered rings and, together with their substituents, contain 2 to 14 carbon atoms, more specifically 3 to 12, and particularly 4 to 8 carbon atoms. For clarity, it should be understood that when L1 and L2 form 5- or 6-membered rings, two of the ring carbons originate from the 3,4-dihydro-2H-pyran moiety and are therefore not included in the total carbon number of L1 and L2. Two examples are given: if L1 and L2 form a tetrahydrofuranyl group, the number of carbon atoms is 2. If L1 and L2 form a cyclopentyl group monosubstituted with a -CH2-OH group, the number of carbon atoms is 4.

[0136] In some embodiments, it may be particularly advantageous that L1 and L2 are present and form an optionally substituted 5- or 6-membered ring, particularly cyclopentyl or cyclohexyl, with A1 and A2 optionally attached to the ring via groups selected from: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 - or combinations thereof. In some embodiments, it may be most advantageous that L1 and L2 are present and form a cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl ring, and A1 and A2 are optionally attached to the ring via groups selected from: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 - or a combination thereof.

[0137] In some embodiments, the compound capable of covalently binding to the skin is a compound of formula (II) or its tautomers and / or a pharmaceutically acceptable salt.

[0138] (II);

[0139] Where R 1 L3, A1, and A3 are as defined for compounds of formula (I);

[0140] Among them (R) 2 ) n Each of the n moieties is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, amino, or halogen.

[0141] Where n is an integer selected from 1 and 2; and

[0142] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof; and

[0143] Where R 4 Selected from H or C1-C4-alkyl.

[0144] In some embodiments, the compound capable of covalently binding to the skin is a compound of formula (III) or its tautomers and / or a pharmaceutically acceptable salt.

[0145] (III);

[0146] Where R 1 L3, A1, and A3 are as defined for compounds of formula (I); and

[0147] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof; and

[0148] Where R 4 Selected from H or C1-C4-alkyl.

[0149] In some implementations, the compound capable of covalently binding to the skin is a compound of formula (IV) or its tautomers and / or a pharmaceutically acceptable salt.

[0150] (IV);

[0151] Where R 1 A1 is as defined for compounds of formula (I);

[0152] Among them (R) 2 ) n Each of the n moieties is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, amino, or halogen.

[0153] Where n is an integer selected from 1 and 2;

[0154] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof;

[0155] Where R 3 The term represents a hydrocarbon moiety with hydrogen or optional substitution, said hydrocarbon moiety and its optional substituents comprising 1 to 14 carbon atoms; and

[0156] Where R 4 Selected from H or C1-C4-alkyl.

[0157] In some implementations, the compound capable of covalently binding to the skin is a compound of formula (V) or its tautomers and / or a pharmaceutically acceptable salt.

[0158] (V);

[0159] Where R 1 A1 is as defined for compounds of formula (I);

[0160] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4-O-, -O-(CH2) 1-4 -or combinations thereof;

[0161] Where R 3 The term represents a hydrocarbon moiety with hydrogen or optional substitution, said hydrocarbon moiety and its optional substituents comprising 1 to 14 carbon atoms; and

[0162] Where R 4 Selected from H or C1-C4-alkyl.

[0163] The usefulness of the compounds disclosed herein will be illustrated by way of example through the following examples. Of course, other applications will be apparent to those skilled in the art and will be conventionally available based on the guidance given in this disclosure.

[0164] The first embodiment relates to a compound intended to provide a moisturizing effect. Skin moisturizers are well known in cosmetics and include a variety of compounds capable of binding water in the stratum corneum. Examples include polyols such as glycerin, pentaerythritol, and sorbitol, as well as other hydrogen-bonded compounds such as urea. Pentaerythritol is carried as C1-C in group b). 60 Some of the compounds according to this disclosure are shown below:

[0165]

[0166] It is well known that genipin derivatives bind to the stratum corneum. Due to the large number of hydroxyl groups, it is expected that the compounds according to this disclosure will provide a long-lasting moisturizing effect on the skin. Even though the pentaerythritol moiety remains attached to the skin via the 3,4-dihydro-2H-pyran moiety, a moisturizing effect will still occur. Therefore, this moiety is an example of group b1). Furthermore, the ester group connecting the pentaerythritol moiety to the rest of the compound can be cleaved by esterases abundant in the skin. Therefore, this moiety is also an example of a moiety that simultaneously belongs to group b2). If it is desired that the pentaerythritol moiety belongs only to group b1), another functional group can be selected. For example, an ether bond can be considered instead of an ester bond.

[0167] An overview of the chemical synthesis of the above compounds is as follows: Figure 1 As shown. The synthesis of compounds (1) and (2) is disclosed in co-pending international application WO 2023 / 102652 A1. (2) can be converted from thionyl chloride to the corresponding acyl chloride, which can then be coupled with pentaerythritol to produce ester (3). Ester (3) can be hydrolyzed in acidic aqueous solution under mild heating to produce target compound (4).

[0168] In the experimental section, it was demonstrated that the wetting agent glycerin and the emollient decanol can be linked to hydrogenated genipin derivatives, and that the resulting conjugates can be conjugated to the skin. Specifically, the following compounds were synthesized and conjugated to the skin.

[0169]

[0170] The second embodiment relates to compounds designed to provide insecticidal effects, more specifically, insect repellent effects.

[0171] p-Menthane-3,8-diol (PMD) is an insect repellent that can be applied directly to skin or clothing. It is highly effective against a wide range of arthropods, such as mosquitoes, ticks, midges, flies, and fleas, and is colorless. The chemical structure of PMD is reproduced below:

[0172]

[0173] PMD's insecticidal efficacy is comparable to that of N,N-diethyl-m-methylbenzamide (DEET). However, like DEET, it only provides a short-lived effect lasting up to 6-8 hours. This is mainly due to PMD's relatively high volatility.

[0174] Efforts have been made to increase the retention time of PMD on the skin. Of particular interest is the recent research that has revealed that by chemically binding PMD to acrylic copolymers topically applied to the skin, PMD can be retained in the stratum corneum for up to 5 days (Shah, SI et al., Pharmaceutics 2021, 13, 403). More specifically, the authors demonstrated that acryloyl chloride can be conjugated to the secondary alcohol of PMD via ester bonds, and the resulting conjugated monomer can be crosslinked to the copolymer carrying the PMD conjugation. The authors further demonstrated that esterases can release PMD from the copolymer in in vitro tests and when the copolymer is applied to porcine skin in an in vitro test.

[0175] Therefore, compounds of this disclosure comprising PMD bound to the remainder of the molecule via ester groups are suitable candidates for the sustained release of PMD into the skin. Specific exemplary compounds are shown below:

[0176]

[0177] An overview of the chemical synthesis of the above compounds is as follows: Figure 2 As shown. The synthesis of compounds (1) and (2) is disclosed in co-pending international application WO 2023 / 102652 A1. (2) can be converted to the corresponding acyl chloride, for example, by thionyl chloride, and then coupled with PMD to produce ester (3). Ester (3) can be hydrolyzed in acidic aqueous solution under mild heating to produce target compound (4).

[0178] As supported by the article by Shah, SI et al. in Pharmaceuticals 2021, 13, 403, it can be expected that the ester groups that link PMD to the rest of the compound will be cleaved by esterases in the skin, and that PMD will be released into the stratum corneum over time to provide its insect-repellent effect.

[0179] In the experimental section, it was demonstrated that the insect repellent picaridin can be linked to a hydrogenated genipin derivative, and that the resulting conjugate can be conjugated to the skin. Specifically, the following compounds were synthesized and conjugated to the skin.

[0180]

[0181] The third embodiment relates to compounds designed to provide pharmaceutical effects, more specifically treating / preventing hair loss.

[0182] Minoxidil and its derivatives, such as kopexil, are applied topically to treat hair loss. Minoxidil is typically applied twice daily to the scalp as an alcoholic solution (ethanol and propylene glycol). The compound is generally well-tolerated, but common side effects include dandruff and contact dermatitis, caused by frequent exposure to the drying properties of ethanol and propylene glycol. Therefore, to minimize side effects and improve patient compliance, a topical delivery system for minoxidil requiring less frequent application would be desirable.

[0183] Minoxidil has the following chemical structure:

[0184]

[0185] The article by Stoica et al. in Bioorganic & Medicinal Chemistry Letters, 2016, 26(4), 1145-1150, provides a convenient method for coupling minoxidil with an alcohol by activating the compound with N,N-carbonyldiimidazole (CDI). This synthetic route allows for the easy acquisition of the following compounds disclosed herein:

[0186]

[0187] An overview of the chemical synthesis of the above compounds is as follows: Figure 3 As shown. The synthesis of compound (3) is disclosed in co-pending international application WO 2023 / 102652 A1. Minoxidil (1) is activated by CDI to compound (2), which then reacts with (3) to produce urethane (4). (4) is hydrolyzed in an acidic aqueous solution under mild heating to produce the target compound (5), which couples minoxidil to the remainder of the compound via a monosubstituted urethane group.

[0188] Monosubstituted carbamate groups are frequently used in prodrugs and can be cleaved by esterases (see review by Gosh et al., J. Med. Chem., 2015, 58, 7, 2895–2940). Therefore, the above-mentioned compounds are promising candidates for providing sustained release of minoxidil into the skin.

[0189] The fourth embodiment also relates to compounds intended to provide pharmaceutical effects, more specifically treating allergic conditions.

[0190] Desloratadine, the metabolically active form of loratadine, is a highly potent antihistamine administered orally at a dose of 5 mg once daily. Topical formulations of desloratadine are currently under investigation. Mohamed et al., Pharmaceuticals 2023, 16(4), 578, describe good skin penetration of desloratadine when used as a transdermal gel formulation. They found that the gel formulation had higher bioavailability and slower elimination compared to the tablet formulation. The bioavailability of the gel formulation was 2.4–3.2 times that of the tablet formulation. This means that a very low daily dose of approximately 2 mg of desloratadine may be sufficient to provide adequate anti-allergic effects, making desloratadine even more attractive as a pharmaceutical component of the compounds disclosed herein, as it can alleviate the systemic side effects associated with oral administration of desloratadine.

[0191] Desloratadine has the following chemical structure:

[0192]

[0193] An overview of the chemical synthesis of the above compounds is as follows: Figure 4 As shown. The synthesis of compound (2) is disclosed in co-pending international application WO 2023 / 102652 A1. Desloratadine (1) is coupled with CDI to form compound (2) to produce carbamate (3). Compound (3) is hydrolyzed in an acidic aqueous solution under mild heating to produce target compound (4), which couples desloratadine to the remainder of the compound via an N,N-disubstituted carbamate group. This synthetic route allows for the readily available production of the following compounds of this disclosure:

[0194]

[0195] The N,N-disubstituted carbamate groups used in the above compounds are frequently used in prodrugs (e.g., bambuterol) and can be cleaved by esterases, resulting in a relatively long sustained release (see review by Gosh et al., J. Med. Chem., 2015, 58, 7, 2895–2940). Therefore, the above compounds are promising candidates for providing long-term release of desloratadine into the skin. Thus, a prolonged reservoir effect can be expected, potentially allowing for lower frequency of administration, particularly such as weekly administration. In practice, this can be accomplished by applying a transdermal patch overnight, which transfers and anchors the desloratadine-containing compound onto the skin. From there, it is released via enzymatic activity in the skin over, for example, a period of one week.

[0196] As can be seen from the above embodiments, the compounds disclosed herein offer broad applicability and flexibility in the topical application of active ingredients to the keratinocytes.

[0197] Other aspects, features, and implementation schemes of this disclosure will now be discussed.

[0198] In some implementations, group b) of C1-C 60 Partial or polymeric portions may contain C1-C 60 Functional groups that are coupled to the corresponding L1, L2 or L3 moieties in a part or polymeric form, or functional groups that are coupled to the 3,4-dihydro-2H-pyran moieties if the corresponding L1, L2 or L3 moieties are not present.

[0199] In some embodiments, the functional group may include a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, or a combination thereof; more specifically, a carbon atom, an oxygen atom, a nitrogen atom, or a combination thereof; and particularly carbon atom and / or oxygen atom.

[0200] In some embodiments, the functional group may contain one or more, two or more, three or more, four or more, or all of the following: 1 to 12 carbon atoms, more specifically 1 to 6 carbon atoms, and particularly 1 to 3 carbon atoms; 1 to 12 oxygen atoms, more specifically 1 to 6 oxygen atoms, and particularly 1 to 3 oxygen atoms; 1 to 4 nitrogen atoms, more specifically 1 to 3 nitrogen atoms, and particularly 1 to 2 nitrogen atoms; 1 to 3 sulfur atoms, more specifically 1 to 2 sulfur atoms, and particularly 1 sulfur atom; 1 to 3 phosphorus atoms, more specifically 1 to 2 phosphorus atoms, and particularly 1 phosphorus atom.

[0201] In some embodiments, the functional groups may be cleavable under physiological conditions after the topical composition has been applied to the skin. When “physiological conditions” is used in the context, it should be understood that this specifically refers to the pH conditions encountered at the sites where the compound of formula (I) binds to keratinocytes and / or keratinized tissue in the stratum corneum and / or epidermis of the subject to be treated (mammal, particularly human). In some embodiments, the functional groups may be hydrolyzable at the physiological pH of mammalian skin, more specifically human skin, and particularly at a pH of about 5 to about 6. A suitable in vitro test is to place 0.1 mol / L of the compound of formula (I) in an aqueous solution at a pH of about 5 at 37°C for 24 hours, wherein if a significant amount of the group is hydrolyzed (e.g., more than 5 mol%, or more than 10 mol%), the group under consideration meets the criteria for hydrolysis.

[0202] In some embodiments, after the topical composition is applied to the skin, the functional groups may be enzymatically cleavable under physiological conditions, particularly by enzymes present in human skin. When “physiological conditions” is used in the context, it should be understood that this specifically refers to the conditions encountered at the site where the compound of formula (I) binds to the stratum corneum and / or keratinized tissue in the epidermis of, for example, a subject to be treated (mammal, particularly human). A suitable in vitro test is to place 0.1 mol / L of the compound of formula (I) in an aqueous solution at pH about 5 and containing 50 U of esterase activity at 37°C for 24 hours, wherein if a significant amount of the group is cleaved (e.g., more than 5 mol-%, or more than 10 mol-%), the group under consideration meets the criteria for enzymatic cleavage.

[0203] In some embodiments, the functional group may be configured to cleave into hydroxyl, primary or secondary amine, carboxylic acid, thiol, aldehyde, ketone, thiocarbonate, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, olefin or oxime; or salts thereof.

[0204] In some embodiments, the functional group may be configured to, upon cleavage, provide a hydroxyl, primary or secondary amine group, carboxylic acid, thiol, aldehyde, ketone, thiocarbonate, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, olefin or oxime; or salts thereof; to the C1-C group attached to group b). 60 Provided on the corresponding L1, L2, or L3 portion of the partial or polymeric portion, or on the 3,4-dihydro-2H-pyran portion if the corresponding L1, L2, or L3 portion does not exist.

[0205] In some embodiments, the functional group may be configured to, upon cleavage, provide a hydroxyl, primary or secondary amine group, carboxylic acid, thiol, aldehyde, ketone, thiocarbonate, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, olefin or oxime; or salts thereof; to the C1-C of group b). 60 On a portion or polymer portion.

[0206] In some embodiments, the functional group may include carbon esters, particularly monoesters, 1,1-diesters, carbonates or carbamates; ethers or thioethers, particularly acetals, hemiacetals, glycosidic groups or thioacetals; carbamates, particularly peptides or N-Mannich bases; enols; enamines; imines; oximes; sulfates; sulfonates; sulfonamides; phosphates; phosphonates; phosphatases; or phosphonamides.

[0207] In some implementations, the functional group may be the functional group mentioned in Chapter 6 of the textbook Prodrug Design Perspectives, Approaches and Applications in Medicinal Chemistry, 1st Edition, 2015, ISBN:9780128035191, which is incorporated herein by reference (for the foregoing purposes and in its entirety).

[0208] In some implementations, A1 may represent C1-C of group b). 60 Partial or polymeric portion. Additionally or alternatively, A2 may represent C1-C of group b). 60 Partial or polymeric portion. Additionally or alternatively, A3 may represent C1-C of group b). 60 Partial or polymeric portion. Additionally or alternatively, the remaining portions of A1, A2, and A3 may represent substituents of group a), more specifically C1-C 30 Partial, H, hydroxyl, amino, or halogen.

[0209] In some embodiments, L1 is present and represents an optionally substituted hydrocarbon moiety comprising 1 to 8 carbon atoms in combination with its optional substituents; alternatively or additionally, in some embodiments, L2 may be present and represents an optionally substituted hydrocarbon moiety comprising 1 to 8 carbon atoms in combination with its optional substituents; alternatively or additionally, in some embodiments, L3 may be present and represents an optionally substituted hydrocarbon moiety comprising 1 to 8 carbon atoms in combination with its optional substituents.

[0210] In some embodiments, L1 may be present and represent an optionally substituted hydrocarbon moiety comprising 1 to 8 carbon atoms in combination with its optional substituents, and a functional group may be attached to L1. Alternatively or additionally, in some embodiments, L2 may be present and represent an optionally substituted hydrocarbon moiety comprising 1 to 8 carbon atoms in combination with its optional substituents, and a functional group may be attached to L2. Alternatively or additionally, in some embodiments, L3 may be present and represent an optionally substituted hydrocarbon moiety comprising 1 to 8 carbon atoms in combination with its optional substituents, and a functional group may be attached to L3. In some embodiments, when any one of L1 to L3 is optionally substituted with a heteroatom, the corresponding linking group may contain 1 to 8, more specifically 1 to 6, and particularly 1 to 4 oxygen atoms; 1 to 8, more specifically 1 to 6, and particularly 1 to 4 nitrogen atoms; 1 to 6, more specifically 1 to 4, and particularly 1 to 3 sulfur atoms; 1 to 6, more specifically 1 to 4, and particularly 1 to 3 phosphorus atoms; and 1 to 10, more specifically 1 to 8, and particularly 1 to 6 halogen atoms. In some embodiments, the corresponding linking group does not contain any other atomic species besides carbon, (optionally) the aforementioned atomic species, and hydrogen.

[0211] In some embodiments, L1 and L2 may be present and form an optionally substituted 5- or 6-membered ring, particularly cyclopentyl or cyclohexyl, and A1 and A2 may optionally be attached to the ring via groups selected from: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 - or combinations thereof. It should be understood that the aforementioned specific group can be part of a larger functional group, hence the mention of "combinations thereof". As an example, urethane esters can be considered as -O and -C(O)-NH or combinations thereof.

[0212] In some embodiments, L1 and L2 may be present and form a cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl ring, and A1 and A2 may optionally be attached to the ring via a group selected from: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4- or combinations thereof. It should be understood that the aforementioned specific group can be part of a larger functional group, hence the mention of "combinations thereof". As an example, urethane esters can be considered as -O and -C(O)-NH or combinations thereof.

[0213] In some implementations, A1 can be C1-C of group b). 60 Partial or polymeric portion. In some embodiments, A3 may be C1-C of group b). 60 Partial or polymeric portion. In some embodiments, particularly in the two embodiments described above, A2 may represent a substituent of group a), more specifically C1-C 30 Partial, H, hydroxyl, amino or halogen, especially hydrogen.

[0214] In some implementations, A1 can be C1-C of group b). 60 Partial or polymeric portion. In some embodiments, A2 and A3 may represent substituents of group a), more specifically, independently of each other, C1-C 30 Partial, H, hydroxyl, amino or halogen, and especially hydrogen.

[0215] In some implementations, A1 can be C1-C of group b). 60 Partial or polymeric moieties, and A2 and A3 can represent substituents of group a), more specifically, independently of each other, C1-C. 30 Partial, H, hydroxyl, amino or halogen, and especially hydrogen.

[0216] In some implementations, group a) of C1-C 30 A portion may contain 1 to 30, more specifically 1 to 16, and particularly 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 phosphorus atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms.

[0217] In some implementations, C1-C 30The portion may be selected from saturated or unsaturated cyclic or acyclic (hetero)alkyl groups comprising 1 to 30, more specifically 1 to 16, and particularly 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms; and / or C1-C 30 Some can be combined with L1, L2 and L3 respectively via carbon atoms, oxygen atoms, nitrogen atoms or sulfur atoms.

[0218] In some implementations, A3 may represent C1-C of group a). 30 Part, more specifically, selected from C1-C of saturated or unsaturated cyclic or acyclic (hetero)alkyl groups. 16 Part of the saturated or unsaturated cyclic or acyclic (hetero)alkyl group comprises 1 to 16, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and particularly 0 to 3 halogen atoms.

[0219] In some implementations, A3 may represent C1-C selected from the following: 16 Part: carboxylic acid or its salt; carboxylic acid ester; or ketone.

[0220] In some implementations, A3 may represent C1-C selected from the following: 16 Partial: Carboxylic acid or its salt; (C1-C4-alkyl)carboxylic acid ester; or C1-C4-alkyl carbonyl.

[0221] In some implementations, L1 and OR 1 Together with the carbon atoms to which they are attached, they can form 5- or 6-membered lactones.

[0222] In some implementations, R1 can represent hydrogen, C 1-6 Acyl or C 1-6 Alkyl group. In some embodiments, it may be particularly advantageous that R1 represents H. In some embodiments, it may be particularly advantageous that R1 does not represent glucoside.

[0223] In some implementations, at least one of A1, A2, and A3 can represent C1-C of group b1). 60Partial. In some embodiments, at least one of A1 and A2 can represent C1-C of group b1). 60 part.

[0224] In some implementations, at least one of A1, A2, and A3 can represent C1-C of group b2). 60 Partial or polymeric portion. In some embodiments, at least one of A1 and A2 may represent C1-C of group b2). 60 Partial or polymeric portion.

[0225] In some embodiments, the compound capable of covalently binding to the skin is a compound of formula (II) or its tautomers and / or a pharmaceutically acceptable salt.

[0226] (II);

[0227] in

[0228] R 1 L3, A1, and A3 are as defined in any of the foregoing embodiments;

[0229] (R 2 ) n Each of the n moieties is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, amino, or halogen.

[0230] n is an integer chosen from 1 and 2; and

[0231] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof; and

[0232] R 4 Selected from H or C1-C4-alkyl.

[0233] In some embodiments of formula (II), at least one of A1 and A3 can represent C1-C of group b). 60 Partial or polymeric portion. In some embodiments of formula (II), at least A1 may represent C1-C of group b). 60 Partial or polymeric portion. In some embodiments of formula (II), A3 may represent C1-C of group a). 30Part, more specifically, selected from C1-C of saturated or unsaturated cyclic or acyclic (hetero)alkyl groups. 16 Part of the saturated or unsaturated cyclic or acyclic (hetero)alkyl group comprises 1 to 16, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and particularly 0 to 3 halogen atoms.

[0234] In some embodiments, the compound capable of covalently binding to the skin is a compound of formula (III) or its tautomers and / or a pharmaceutically acceptable salt.

[0235] (III);

[0236] in

[0237] R 1 L3, A1, and A3 are as defined in any of the foregoing embodiments; and

[0238] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof; and

[0239] R 4 Selected from H or C1-C4-alkyl.

[0240] In some embodiments of formula (III), at least one of A1 and A3 can represent C1-C of group b). 60 Partial or polymeric portion. In some embodiments of formula (III), at least A1 may represent C1-C of group b). 60 Partial or polymeric portion. In some embodiments of formula (III), A3 may represent C1-C of group a). 30 Part, more specifically, selected from C1-C of saturated or unsaturated cyclic or acyclic (hetero)alkyl groups. 16Part of the saturated or unsaturated cyclic or acyclic (hetero)alkyl group comprises 1 to 16, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and particularly 0 to 3 halogen atoms.

[0241] In some embodiments of formula (III), L3 represents -C(O)-, -C(O)-O-, -C(O)-NH- or -C(O)-N(C1-C4-alkyl)-.

[0242] In some implementations of formula (III), A3 represents R 3 Group, wherein R 3 Indicates C1-C 14 The C1-C14 portion comprises 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl, C containing 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or 1 to 2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0243] In some implementations, the compound capable of covalently binding to the skin is a compound of formula (IV) or its tautomers and / or a pharmaceutically acceptable salt.

[0244] (IV);

[0245] in

[0246] R 1 A1 is as defined in any of the foregoing embodiments;

[0247] (R 2 ) n Each of the n moieties is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, amino, or halogen.

[0248] n is an integer chosen from 1 and 2;

[0249] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof;

[0250] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0251] R 4 It can be selected from H or C1-C4-alkyl.

[0252] In some implementations of formula (IV), A1 may represent C1-C of group b). 60 Partial or polymeric portion. In some embodiments of formula (IV), A1 may represent C1-C of group b). 60 part.

[0253] In some implementations of formula (IV), R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl, C containing 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or 1 to 2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0254] In some implementations of formula (IV), R 3 It can represent C1-C4 alkyl moieties or phenyl groups.

[0255] In some implementations, the compound capable of covalently binding to the skin is a compound of formula (V) or its tautomers and / or a pharmaceutically acceptable salt.

[0256] (V);

[0257] in

[0258] R 1 A1 is as defined in any of the foregoing embodiments;

[0259] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 -or combinations thereof;

[0260] R 3 Indicates C1-C4 alkyl moiety or phenyl, or R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0261] R 4 Selected from H or C1-C4-alkyl.

[0262] In some implementations of equation (V), A1 can represent C1-C of group b). 60 Partial or polymeric portion. In some embodiments of formula (V), A1 may represent C1-C of group b). 60 part.

[0263] In some implementations of formula (V), R 3Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0264] In the following discussion, the active component connected to the remainder of the compound according to the invention will be discussed. For the sake of brevity, the active component will be referred to as if it were a separate compound rather than a part attached to the remainder of the compound. It should be understood that this should be interpreted as referring to the part attached to the remainder of the compound, for example, by removing hydrogen atoms from the active component.

[0265] It should also be understood that the disclosures regarding the active components mentioned below can be freely combined with the disclosures above regarding compounds according to formulas (I) to (V). In fact, these combinations represent preferred embodiments of this disclosure, but it should be understood that this disclosure is not limited thereto.

[0266] Compounds that act as skin moisturizers

[0267] In some implementations, at least one of A1, A2, and A3 can be C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a skin moisturizer, and / or the portion is configured to act as a skin moisturizer after cleavage from the 3,4-dihydro-2H-pyran portion.

[0268] In some implementations, C1-C 60 The partial or polymeric portion may contain multiple hydrogen-bonded groups selected from the group consisting of hydroxyl, ether, carboxylic acid, amine, and amide; and their salts.

[0269] In some embodiments, the plurality of hydrogen-bonded groups may comprise three or more, more specifically four or more, and particularly six or more hydrogen-bonded groups.

[0270] In some implementations, C1-C 60 The ratio of C atoms to the total number of hydrogen-bonded groups contained in a portion can be from about 4:1 to 1:1, more specifically from about 3:1 to about 1:1, and particularly from about 2:1 to about 1:1.

[0271] In some implementations, C1-C 60 The portion may have a molecular weight of at least 60 g / mol, more specifically at least 90 g / mol, and particularly at least 120 g / mol.

[0272] In some embodiments, the polymer portion may have a molecular weight in the range of 200 g / mol to 50,000 g / mol.

[0273] In some implementations, C1-C 60The ratio of C atoms to the total number of heteroatoms contained in the portion may be from about 4:1 to 1:2, more specifically from about 3:1 to about 1:1.5, and particularly from about 2:1 to about 1:1, wherein the heteroatoms are selected from nitrogen and oxygen.

[0274] In some implementations, C1-C 60 Partial or polymeric portions may include:

[0275] Polyols, more specifically, polyols having n hydroxyl groups, where n is 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;

[0276] Mono- or polycarboxylic acids containing one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid;

[0277] Sugars, more specifically trisaccharides, tetrasaccharides, pentoses, hexoses, monosaccharides, disaccharides, trisaccharides, oligosaccharides or polysaccharides, especially glucose, mannose, galactose, glucosamine, N-acetyl-D-glucosamine, inositol, rhamnose, lythose, fucose, allose, ribose, arabinose, hyaluronic acid, especially hyaluronic acid with a molecular weight of less than 50,000 Daltons;

[0278] Sugar alcohols, more specifically sugar alcohols containing 2 to 24 carbon atoms, particularly ethylene glycol, propylene glycol, glycerol, erythritol, threitol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, idotitol, inositol, heptaheptaol, isomaltitol, maltitol, lactitol, malttriol, or maltitol; or

[0279] Sugar acids, more specifically aldonic acids, ketonic acids, uronic acids or aldonic diacids; or their salts; or their esters, especially their C1-C4-alkyl esters; or their amides.

[0280] In some implementations, C1-C 60 Some may contain urea derivatives; panthenol; or diuretics, especially allantoin.

[0281] In some implementations, C1-C 60 The partial or polymeric portion may contain amino acids or amino acid derivatives, more specifically serine, glycine, alanine, histidine, ornithine, arginine, or pyroglutamic acid. In some embodiments, the amino acid may be present as its L-enantiomer. In some embodiments, C1-C 60 The partial or polymeric portion may contain multiple amino acids or amino acid derivatives.

[0282] In some implementations, C1-C 60Some may have a molecular weight of 60 g / mol to 2000 g / mol, more specifically 90 g / mol to 1600 g / mol, and particularly 120 g / mol to 1200 g / mol.

[0283] In some implementations, group b) of C1-C 60 Partial or polymeric portions may contain aliphatic C 10 -C 60 Part, more specifically C 15 -C 60 The aliphatic portion, and especially C 20 -C 60 Aliphatic portion; or oligomeric or polysiloxane, especially poly(di-C1-C4-alkyl)siloxane.

[0284] In some embodiments, the polymer portion is an oligomer or polysiloxane, particularly a poly(di-C1-C4-alkyl)siloxane. In some embodiments, the poly(di-C1-C4-alkyl)siloxane may have 20 to 200 repeating units. In some embodiments, the poly(di-C1-C4-alkyl)siloxane is polydimethylsiloxane (dimethylpolysiloxane).

[0285] In some embodiments, the polymer portion is a polyether, particularly a polyether comprising ethylene oxide repeating units, propylene oxide repeating units, or mixtures thereof. Examples include polyethylene glycol (PEG) and polypropylene glycol (PPG).

[0286] In some embodiments, the polymer portion is a polyamine or a polymer containing a polyamine, such as PEG-15 tallow amine.

[0287] In some embodiments, the polymer portion is a polyquaternium salt, particularly polyquaternium salt-16, polyquaternium salt-46, polyquaternium salt-11, polyquaternium salt-28, polyquaternium salt-6, polyquaternium salt-7, polyquaternium salt-22, polyquaternium salt-39, polyquaternium salt-2, polyquaternium salt-17, or polyquaternium salt-18.

[0288] In some implementations, C1-C 60 Some may have a molecular weight of 140 g / mol to 2000 g / mol, more specifically 160 g / mol to 1600 g / mol, and especially 180 g / mol to 1200 g / mol.

[0289] In some implementations, C1-C 60 Some can have more than 30 carbon atoms.

[0290] In some implementations, C1-C 60 Some may contain saturated or unsaturated C 10-C 60 The aliphatic portion, more specifically C 15 -C 60 The aliphatic portion, and especially C 20 -C 60 Aliphatic portion.

[0291] In some implementations, C1-C 60 The ratio of C atoms to the total number of heteroatoms contained in the portion may be from about 60:1 to 5:1, more specifically from about 50:1 to about 10:1, and particularly from about 40:1 to about 20:1, wherein the heteroatoms are selected from nitrogen and oxygen.

[0292] In some implementations, C1-C 60 It can be fatty acids, fatty alcohols or their derivatives, more specifically saturated or unsaturated fatty acids, fatty alcohols or their derivatives, and in particular caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, linoleic acid, decanol, dodecyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol or fatty acid monoglycerides, diglycerides or triglycerides, especially caprylic acid glyceride, caprylic acid glyceride or stearic acid glyceride.

[0293] In some implementations, C1-C 60 Part of it may be sphingosine or its derivatives, especially ceramides or sphingomyelin.

[0294] In some implementations, group b) of C1-C 60 Some or polymeric components can be configured to act as skin moisturizers.

[0295] In some implementations, group b) of C1-C 60 The partial or polymeric portion can be configured to act as a skin moisturizer after cleavage from the 3,4-dihydro-2H-pyran portion.

[0296] C1-C in group b) 60 In some embodiments where a portion or polymer portion is configured to act as a skin moisturizer and / or is configured to act as a skin moisturizer after partial or complete cleavage from the 3,4-dihydro-2H-pyran moiety, it may be particularly advantageous that the compound of formula (I) is a compound of any one of formulas (II), (III), (IV), or (V) as defined above. It may also be particularly advantageous that R... 1 H represents H.

[0297] Compounds that act as pesticides

[0298] In some implementations, at least one of A1, A2, and A3 can be C1-C 60Part of which is configured to act as an insecticide, and / or part of which is configured to act as an insecticide after partial cleavage from 3,4-dihydro-2H-pyran.

[0299] In some embodiments, the insecticide may be an insect repellent. For the purposes of this disclosure, an insect repellent is a chemical used to control insects without killing or disabling them, particularly by making the host (i.e., the subject to whom the insect repellent is applied) less attractive to insects.

[0300] In some embodiments, the pesticide may be an insecticide. For the purposes of this disclosure, an insecticide is a chemical used to control insects by killing or incapacitating them.

[0301] In some implementations, the insect repellent or insecticide can act on ectoparasites and / or blood-sucking insects, particularly blood-sucking insects selected from the group consisting of mosquitoes, ticks, mites, midges, fleas, chiggers, leeches, and bedbugs. Ectoparasites are organisms that live on the host's skin and obtain nutrients from it.

[0302] In some implementations, the insecticide may be an insect repellent selected from isoprene, tertiary amide, and phenylpropionic acid derivatives.

[0303] In some embodiments, the insect repellent may be an isoprene, more specifically a monoterpene, diterpene, or triterpene, and particularly terpineol or its derivatives, monoterpene aldehydes or their derivatives, limonin compounds or their derivatives; or pyrethroids or their derivatives. In some embodiments, the isoprene may be selected from citronellal, hydroxycitronellal, citronellol, citral A, citral B or their derivatives; necrodane, particularly α-necrodol, or its derivatives; limonin compounds, particularly azadirachtin, or their derivatives; and pyrethroids, particularly jasmine ester, cinnamyl ester, or their derivatives.

[0304] In some embodiments, the insect repellent may comprise a tertiary amide. In some embodiments, the tertiary amide may be selected from picaridin, N,N-di(C1-C6 alkyl)-toluamide, particularly N,N-diethyl-m-methylbenzamide, ethyl 3-(N-butylacetamido)propionate; and derivatives thereof.

[0305] In some embodiments, the insect repellent may be selected from one of the following compounds and their fractions / derivatives: N,N-diethyl-m-methylbenzamide, diethylphenylacetamide, N-butylacetanilide, ethylbutylacetylaminopropionate, picaridin, N-(2-methylpiperidin-1-yl)cyclohex-3-en-1-carboxamide, and 1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine or 1-[3-cyclohexen-1-ylcarbonyl]piperidine.

[0306] In some implementations, the insect repellent may be a phenylpropionic acid, particularly eugenol or its derivatives.

[0307] In some embodiments, at least one of A1, A2, or A3 may be selected from a portion of formula (VIa) or formula (VIb).

[0308] (VIa) (VIb).

[0309] C1-C in group b) 60 In some embodiments where a portion or polymer portion is configured to act as an insecticide and / or is configured to act as an insecticide after partial cleavage from the 3,4-dihydro-2H-pyran moiety, it may be particularly advantageous that the compound of formula (I) is a compound of any of formulas (II), (III), (IV), or (V) as defined above. It may also be particularly advantageous that R... 1 H represents H.

[0310] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (VII) or its tautomers and / or pharmaceutically acceptable salts.

[0311] (VII),

[0312] in

[0313] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0314] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0315] L5 may be absent or may be a group selected from the following: -C(O)-, -C(O)-O-, -C(O)-O-(CH2). 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -, -S(O)2-, -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -or combinations thereof; and

[0316] R 4 It can be selected from H or C1-C4-alkyl.

[0317] In some implementation schemes, R3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0318] In some implementation schemes, it may be particularly advantageous that R 1 H is indicated. In some embodiments, it may also be particularly advantageous that L5 is present and selected from -C(O)-, -C(O)-O-, -C(O)-NHC(O)- or -C(O)-NHC(O)-O-.

[0319] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (VIII) or its tautomers and / or pharmaceutically acceptable salts.

[0320] (VIII),

[0321] in

[0322] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; and

[0323] R 3 This indicates a hydrocarbon moiety containing hydrogen or an optional substituent, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0324] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0325] In some implementation schemes, R 3 It can represent H or methyl, and R 1 It can represent H.

[0326] In some embodiments, the compounds disclosed herein are derived from picaridin, specifically:

[0327] In some implementations, one of A1, A2, or A3 may be a part of formula (IX).

[0328] (IX).

[0329] In some implementations, one of A1, A2, or A3 may be a part of formula (X).

[0330] (X).

[0331] In some embodiments, the compound capable of covalently binding to the skin can be a compound of formula (XI) or its tautomers and / or pharmaceutically acceptable salts.

[0332] (XI),

[0333] in

[0334] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0335] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0336] L6 may be absent or may be a group selected from the following: -(CH2) 1-4 -, -C(O)-, -C(O)-O-, -C(O)-O-(CH2) 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -, -S(O)2-, -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -or combinations thereof; and

[0337] R 4 It can be selected from H or C1-C4-alkyl.

[0338] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0339] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (XII) or its tautomers and / or pharmaceutically acceptable salts.

[0340] (XII),

[0341] in

[0342] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; and

[0343] R 3 This indicates a hydrocarbon moiety containing hydrogen or an optional substituent, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0344] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0345] In some implementation schemes, R3 It can represent H or methyl, and R 1 It can represent H.

[0346] In some implementations, the insecticide may be an insecticide, particularly an insecticide selected from or derived from the following: permethrin; cypermethrin; deltamethrin; ivermectin; amitraz, especially amitraz; imidacloprid; malathion; carbaryl; diazinon; dichlorodiphenyltrichloroethane (DDT); fenthion; fipronil; imidacloprid; acetamiprid; and propoxur.

[0347] In some implementations, C1-C 60 Some can be formulated to act as insecticides, especially insect repellents.

[0348] In some implementations, C1-C 60 Some of it can be formulated into insecticides, especially insect repellents, after partial cleavage from 3,4-dihydro-2H-pyran.

[0349] Compounds that act as skin whitening agents

[0350] In some implementations, at least one of A1, A2, and A3 can be C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a skin whitening agent, and / or the portion is configured to act as a skin whitening agent after being partially cleaved from 3,4-dihydro-2H-pyran.

[0351] In some implementations, skin whitening agents can whiten the skin chemically or metabolically, particularly by providing a bleaching effect or reducing melanin production.

[0352] In some implementations, the skin whitening agent may be selected from corticosteroids, particularly clobetasol derivatives, fluocinolone acetonide derivatives, or betamethasone; vitamin A derivatives, particularly retinoic acid, isotretinoin, acitretin, retinol, or retinaldehyde; hydroxyphenol derivatives, particularly hydroquinone; aliphatic dicarboxylic acids, particularly azelaic acid; α-hydroxy acids, particularly lactic acid and glycolic acid; and vitamin C and its derivatives.

[0353] In some implementations, group b) of C1-C 60 Some or polymeric components can be formulated to act as skin whitening agents.

[0354] In some implementations, group b) of C1-C 60 Some or polymeric portions can be formulated as skin whitening agents after being cleaved from the 3,4-dihydro-2H-pyran moiety.

[0355] C1-C in group b) 60In some embodiments where a portion or polymer portion is configured to act as a skin whitening agent and / or is configured to act as a skin whitening agent after partial cleavage from the 3,4-dihydro-2H-pyran moiety, it may be particularly advantageous that the compound of formula (I) is a compound of any of formulas (II), (III), (IV) or (V) as defined above. It may also be particularly advantageous that R... 1 H represents H.

[0356] Compounds that act as fragrances

[0357] In some implementations, at least one of A1, A2, and A3 can be C1-C of group b). 60 This portion is configured to act as an aromatizer after partial cleavage from 3,4-dihydro-2H-pyran.

[0358] In some implementations, C1-C 60 Parts may include C1-C 60 A functional group coupled to the corresponding L1, L2, or L3 moiety, or, if the corresponding L1, L2, or L3 moiety is absent, a functional group coupled to the 3,4-dihydro-2H-pyran moiety. In some embodiments, the functional group is configured to cleave into an aldehyde, ketone, thiol, hydroxyl group, or amine.

[0359] In some embodiments, the functional group may be an imine, acetal, 1,1-diester, enol ether, ester, amide, thioester, or thioacetal.

[0360] In some implementations, C1-C 60 Some of them, after cleavage, can have a molecular weight of less than 400 g / mol, more specifically less than 300 g / mol, and especially less than 200 g / mol.

[0361] In some implementations, the fragrance is selected from the group consisting of esters, aldehydes, ketones, thiols, lactones, alcohols, straight-chain terpenes, cyclic terpenes, aromatic compounds, and amines.

[0362] In some implementations, the fragrance agent is not benzyl alcohol or hexanol.

[0363] In group b), C1-C 60 In some embodiments where the compound is configured to act as an aromatizer after partial cleavage from 3,4-dihydro-2H-pyran, it may be particularly advantageous that the compound of formula (I) is a compound of any of formulas (II), (III), (IV), or (V) as defined above. It may also be particularly advantageous that R... 1 H represents H.

[0364] Compounds that act as drugs

[0365] In some implementations, at least one of A1, A2, and A3 can be C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a drug, and / or the portion is configured to act as a drug after being cleaved from the 3,4-dihydro-2H-pyran portion.

[0366] In some implementations, the drug may be suitable for treating skin-related diseases. In some implementations, skin-related diseases may be selected from acne-like rashes, autoinflammatory syndromes, chronic bullous diseases, mucosal diseases, skin appendage diseases, subcutaneous fat diseases, congenital abnormalities, connective tissue diseases, dermal fiber and elastic tissue abnormalities, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, pigmentary disorders, endocrine-related skin diseases, eosinophilic skin diseases, skin lesions, skin cancer, erythema, hereditary skin diseases, infection-related skin diseases, lichenification, lymphatic-related skin diseases, melanocytic nevi and growths, mononuclear and macrophage-related skin diseases, mucin storage diseases, neurodermal diseases, non-infectious immunodeficiency-related skin diseases, nutritional-related skin diseases, papulosquamous keratosis, palmoplantar keratosis, pruritus, psoriasis, reactive neutrophilic skin diseases, skin diseases caused by metabolic errors, skin diseases caused by physical factors, urticaria, dandruff, desquamation disorders, and vascular-related skin diseases.

[0367] In some implementations, the drug may be suitable for treating allergic conditions. In some implementations, the drug may be an antihistamine.

[0368] In some implementations, the drug (partially) may not be a compound (partially) used to prevent sunburn, skin cancer, and / or other skin diseases associated with UV-A / UV-B exposure.

[0369] In some implementations, at least one of A1 and A2 can be C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a drug, and / or the portion is configured to act as a drug after being cleaved from the 3,4-dihydro-2H-pyran portion.

[0370] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (XIII) or its tautomers and / or pharmaceutically acceptable salts.

[0371] (XIII),

[0372] in

[0373] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0374] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0375] L7 is selected from -C(O)- and -C(O)-(CH2). 1-4 -、-C(O)-O-、-C(O)-O-(CH2) 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -or-S(O)2-O-, -S(O)2-O-(CH2) 1-4 - groups; and

[0376] R 4 Selected from H or C1-C4-alkyl.

[0377] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0378] In some implementation schemes, R 3 It can represent H or methyl, and R 1 It can represent H.

[0379] In some implementations, it may also be particularly advantageous that L7 is selected from -C(O)- or -C(O)-O-(CH2). 1-4 -or -C(O)-NHC(O)-C(O)-O-(CH2) 1-4 -

[0380] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (XIV) or its tautomers and / or pharmaceutically acceptable salts.

[0381] (XIV),

[0382] in

[0383] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; and

[0384] R 3 This indicates a hydrocarbon moiety containing hydrogen or an optional substituent, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0385] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0386] In some implementation schemes, R 3 It can represent H or methyl, and R 1 It can represent H.

[0387] In some implementations, the medication may be suitable for treating hair loss.

[0388] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (XV) or its tautomers and / or pharmaceutically acceptable salts.

[0389] (XV),

[0390] in

[0391] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0392] R 3 This indicates a hydrocarbon moiety with hydrogen or optional substitution, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms;

[0393] R 5 It represents H, OH, C1-C4-alkyl, NH2, N(C1-C4-alkyl)2, N-morpholino-1-yl or piperidin-1-yl;

[0394] L8 is selected from -C(O)- and -C(O)-(CH2). 1-4 -、-C(O)-O-、-C(O)-O-(CH2) 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -or-S(O)2-O-, -S(O)2-O-(CH2) 1-4 - groups; and

[0395] R 4 Selected from H or C1-C4-alkyl.

[0396] In some implementation schemes, R 3 It can represent H or methyl, and R 1 It can represent H.

[0397] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0398] In some implementations, it may also be particularly advantageous that L8 is selected from -C(O)- or -C(O)-O-(CH2). 1-4 -or -C(O)-NHC(O)-C(O)-O-(CH2) 1-4 -

[0399] In some implementation schemes, R 5 It can be represented by H (i.e., kopexil) or piperidine-1-yl (i.e., minoxidil).

[0400] In some embodiments, the compound capable of covalently binding to the skin may be a compound of formula (XVI) or its tautomers and / or a pharmaceutically acceptable salt.

[0401] (XVI),

[0402] in

[0403] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0404] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0405] R 5 It represents H, OH, C1-C4-alkyl, NH2, N(C1-C4-alkyl)2, N-morpholino-1-yl or piperidin-1-yl.

[0406] In some implementation schemes, R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. It may be particularly advantageous that R... 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14aryl group, C containing 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-2 sulfur atoms 4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements. It may also be advantageous that R... 3 This indicates an optionally substituted phenyl group. It may be particularly advantageous that R... 3 The phenyl group represents an optionally substituted phenyl group, particularly wherein the optionally substituted phenyl group comprises 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms. In some embodiments of these embodiments, R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

[0407] In some implementation schemes, R 3 It can represent H or methyl, and R 1 It can represent H.

[0408] In some implementation schemes, R 5 It can be represented by H (i.e., kopexil) or piperidine-1-yl (i.e., minoxidil).

[0409] In some embodiments, the drug may be suitable for treating pain or inflammation. In some embodiments, the drug may be an analgesic or a corticosteroid. In some embodiments, the analgesic is acetaminophen (INN acetaminophen). In some embodiments, the analgesic is acetaminophen coupled to the remainder of the compound via its hydroxyl group.

[0410] In some embodiments, the drug may be used to induce a sensation of heat or cold on the skin. In some embodiments, the agent may be menthol, camphor, or derivatives thereof. In some embodiments, the agent may be an alkaloid, more specifically a capsaicinoid, particularly capsaicin, or a derivative thereof.

[0411] In some embodiments, the agent may be selected from nicotinamide and its derivatives or undecenoic acid and its derivatives.

[0412] In some implementations, C1-C 60 Part of it can be an agonist of retinoid receptors, more specifically retinoic acid receptors, retinoid X receptors, and / or RAR-associated orphan receptors.

[0413] In some implementations, C1-C 60 Some may contain vitamin A isotopes, more specifically selected from retinol, retinoic acid, isotretinoin, retinoic acid, etratiate, retinoic acid, adapalene and / or bexarotine isotopes, especially retinol, retinaldehyde and / or adapalene.

[0414] In some implementations, group b) of C1-C 60 Some or polymeric components may be configured to act as drugs.

[0415] In some implementations, group b) of C1-C 60 The partial or polymeric portion can be configured to act as a drug after cleavage from the 3,4-dihydro-2H-pyran portion.

[0416] In some implementations, group b) of C1-C 60 The component may be absent or derived from salicylic acid and its derivatives. In some embodiments, the compound and / or topical composition according to formula (I) does not contain an ester of salicylic acid. This includes both esters formed with the hydroxyl group of salicylic acid and esters formed from the carboxylic acid of salicylic acid.

[0417] In some implementations, at least one of A1, A2, and A3 can be C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a drug, and / or the portion is configured to act as a drug after being cleaved from the 3,4-dihydro-2H-pyran portion.

[0418] In some implementations, at least one of A1 and A2 can be C1-C of group b). 60 A partial or polymeric portion, configured to act as a drug, and / or configured to act as a drug after cleavage from the 3,4-dihydro-2H-pyran moiety. In some embodiments, at least one of A1 and A2 may be C1-C of group b). 60 A1 may be a partial or polymeric portion configured to act as a drug, and / or the portion may be configured to act as a drug after cleavage from the 3,4-dihydro-2H-pyran moiety, and A3 may be a portion of group a). In some embodiments, A1 may be C1-C of group b). 60 A portion or polymer portion configured to act as a drug, and / or a portion configured to act as a drug after cleavage from the 3,4-dihydro-2H-pyran portion, wherein A2 and A3 may be portions of group a).

[0419] In some implementations, group b) of C1-C 60 The portion and / or polymer portion is not a colored portion, especially not a colored portion having at least one absorption peak in the wavelength range of 380 nm to 790 nm.

[0420] In some implementations, group b) of C1-C 60 The portion and / or polymer portion is not a UV absorbing portion, especially not a UVA and / or UVB absorbing portion, and especially not a UVA and / or UVB absorbing portion having at least one absorption peak in the wavelength range of 280 nm to 379 nm.

[0421] In some embodiments, the compound of any of formulas (I) to (V) is not a compound disclosed in International Application WO 2023 / 102652 A1, the contents of which are incorporated herein by reference for this purpose. Specifically, in some embodiments, the compound of any of formulas (I) to (V) is not a compound comprising portions A1, A2, and / or A3, which is R in formula (IX) of WO 2023 / 102652 A1. 3 .

[0422] In some embodiments, the compound of any of formulas (I) to (V) is not a compound disclosed in International Application WO 2014 / 155016 A1, and in particular not a compound disclosed in formula (II), wherein R”1, R”2 and R”4 are as defined in the table below the formula, and R”3 represents C 12 H 25 The contents of S-WO 2014 / 155016 A1 are incorporated herein by reference for this purpose.

[0423] In some embodiments, if A3 represents C1-C of group b2) configured to act as an aromatizer after partial cleavage of 3,4-dihydro-2H-pyran. 60 If it is a partial or polymeric part, then A3 does not represent a benzyloxy or alkoxy moiety, especially a hexyloxy moiety.

[0424] In some embodiments, the compounds of formulas (I) and (II) are not compounds in which L1-A1 represents a portion containing a hydroxyl group attached to the carbon atom at the α-position of the carbon atom labeled "a" in formula (I).

[0425] In some embodiments, the compounds of any of formulas (I) through (V) are not compounds disclosed in U.S. Patent 6,022,888, the contents of which are incorporated herein by reference for this purpose.

[0426] In some embodiments, the compounds disclosed herein do not contain epoxy groups.

[0427] Although specific embodiments of this disclosure are generally discussed with respect to hydrogenated genipin derivatives, it should be understood that this disclosure is not limited to these derivatives. Instead, many alternative 3,4-dihydro-2H-pyran derivatives are available to those skilled in the art and are equally applicable to and covered by this disclosure. Alternative examples based on deglycosylated oleuropein in its hydrogenated form are described below.

[0428] Therefore, in some embodiments, the compound of formula (I) capable of covalently binding to the skin is a compound of formula (XVII) or its tautomer and / or a pharmaceutically acceptable salt.

[0429] (XVII);

[0430] in

[0431] R 1 L1, L3, A1, A2 and A3 are as defined in any of the foregoing embodiments, and wherein L1 is specifically selected from the group consisting of: -CH2-, -C(O)-, C(O)-O-, -C(O)-NH-, -C(O)-N(C1-C4-alkyl)- and combinations thereof.

[0432] preparation

[0433] Topical compositions are not particularly limited and include any such compositions intended for topical application. Topical application in the sense of this disclosure means any local (i.e., non-systemic) application of the compounds or compositions of this disclosure, whether by ointment, gel, cream, lotion or other similar formulation, including direct application to the epidermis or dermis of a subject, including application to skin appendages such as hair, but excluding oral, rectal, intrapulmonary and intranasal administration.

[0434] This disclosure is one form of a topical composition, and in some embodiments also relates to compounds or compositions of this disclosure used as cosmetics. In this application, "cosmetic" or "cosmetic use" means that the composition is suitable for external use (i.e., external application, e.g., not ingested) and is particularly suitable for application to the skin or hair.

[0435] Typically, the aforementioned compositions can be formulated in any form known in the art for cosmetic (topical) application. Therefore, the compositions can be applied in any topical form, such as aerosol sprays, creams, emulsions, solids, liquids, dispersions, foams, oils, gels, hydrogels, lotions, mousses, ointments, powders, patches, hair oils, solutions, pump sprays, sticks, towels, soaps, or other forms commonly used in the fields of topical application and / or cosmetic / sunscreen and skincare formulations. The compositions can also be water-resistant (e.g., waterproof).

[0436] Topical compositions can also be present in the form of patches or carriers containing the topical composition. Examples of patches include adhesive labels or foils on which the composition is coated or printed. Examples of carriers include nonwoven materials or hydrogels in which the composition is impregnated.

[0437] The compositions disclosed herein may contain any of the compounds described herein in the range of 0.005% to 99% by weight, with the balance consisting of suitable excipients. The compositions of consideration may contain 0.01% to 99% by weight, 0.1% to 95% by weight in one embodiment, 75% to 85% by weight in another embodiment, and 20% to 80% by weight in yet another embodiment of any of the compounds provided herein, wherein the balance may consist of any excipients described herein or any combination of such excipients.

[0438] The topical compositions according to this disclosure also include excipients suitable for topical application. The excipients are not particularly limited. In some embodiments, the excipients suitable for topical application include one or more selected from water, ethanol, isopropanol, n-propanol, ethylene glycol, diethylene glycol, propylene glycol, diethylene glycol monoethyl ether, DMSO, and glycerin.

[0439] In some embodiments, the topical composition may also be a pre-dispersed composition comprising the compounds of this disclosure and a liquid carrier. These compositions may be solutions (e.g., free of any undissolved solid particles), dispersions (e.g., containing a liquid phase and a solid precipitant phase), or emulsions.

[0440] In some embodiments, the topical composition may contain water and / or an organic solvent as a suitable carrier and excipient. In one example, the liquid composition may be sterile and / or prepared from a sterile aqueous solution for infusion.

[0441] In some embodiments, the composition may also comprise a surfactant, such as an alkylbenzene sulfonate, alkyl sulfate, alkyl ether sulfate, soap, ethoxylate, alkyl alcohol, lignin sulfonate, or triglyceride. The composition may also comprise a solid matrix. Suitable examples of matrix components include sugars, sugar alcohols (e.g., sorbitol, mannitol, xylitol, isomaltitol, hydrogenated starch hydrolysate), polymers, or combinations of two or more of these.

[0442] In some embodiments, the composition may also comprise a skin penetration enhancer. As used herein, a "skin penetration enhancer" refers to a substance that penetrates into the skin (the penetrant) to reversibly reduce its barrier resistance. In some embodiments, the skin penetration enhancer may 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 skin penetration enhancers include alcohols, amides, esters, ether alcohols, fatty acids, glycols, pyrrolidones, sulfoxides, surfactants, and terpenes.

[0443] In some embodiments, the composition may further comprise preservatives, thickeners, film-forming agents, and / or wetting agents. Non-limiting examples of thickeners include starch, gums (e.g., natural and synthetic gums), cellulose, and arabinogalactan. Non-limiting examples of wetting agents include polyols such as polyalkylene glycols (e.g., alkylene polyols and their derivatives), alpha-hydroxy acids, sugars, aloe vera gel, vegetable oils, lithium chloride, allantoin, urea, and dicyandiamide. Non-limiting examples of film-forming agents include volatile silicone resins, polyvinylpyrrolidone, acrylates, acrylamide, copolymers, and isododecane resins.

[0444] The composition can be applied to the subject's skin directly onto a skin transfer substrate, such as a patch, using inkjet printing. In this case, a printer nozzle is used to apply the composition to the transfer substrate. In some embodiments, the composition may also be contained in a pen applicator, as this allows for more selective local delivery.

[0445] In some embodiments, the topical formulation comprising compound (I) is stored stably (i.e., the compound (I) retains its original chemical structure at a concentration greater than 95 mol%) for a period of more than one month, more specifically more than three months, and particularly more than six months when stored at 21°C and 25% RH. In some embodiments, the water solubility of compound (I) is about 1 g / L to about 100 g / L, about 5 g / L to about 50 g / L, or about 10 g / L to about 100 g / L.

[0446] In some embodiments, it may be particularly advantageous that the topical composition is not too "flowable" in order to promote local retention of the topical formulation on the skin at the application site. Therefore, it may be particularly advantageous that the dynamic viscosity of the topical composition, measured at 37°C, is greater than 2 mPa·s, more specifically greater than 10 mPa·s, and especially greater than 50 mPa·s, for example 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 especially in the range of 50 mPa·s to 10,000 mPa·s. Suitable measurement methods are well known in the art and include using ASTM D-2196-20 of Test Method A at 30 rpm on a rotational viscometer (e.g., ViscoQC 100, optionally equipped with a PTD 100 cone plate for smaller sample sizes, available from Anton Paar GmbH, Germany), or DIN EN ISO 2555:2018-09 at 30 rpm.

[0447] In some embodiments, the hair care preparation is packaged in a container. In some embodiments, the container is sealed and / or releasable upon opening. In some embodiments, the container includes a label and / or is provided with packaging.

[0448] Other uses and methods

[0449] In a second aspect, this disclosure relates to compounds of formula (I) or their tautomers and / or pharmaceutically acceptable salts.

[0450] (I);

[0451] in

[0452] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0453] L1, L2, and L3 represent the linking group independently or not at all.

[0454] A1, A2, and A3 represent each other independently.

[0455] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0456] b)C1-C 60 Partial or polymeric components;

[0457] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0458] Group b) C1-C 60 Partial or polymeric portion

[0459] b1) is configured to act as a drug; and / or

[0460] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0461] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0462] Used in medicine.

[0463] Any specific compound disclosed in connection with the first aspect of this disclosure and relating to the pharmaceutical portion also represents a specific embodiment of that aspect of this disclosure.

[0464] In a third aspect, this disclosure relates to compounds of formula (I) or their tautomers and / or pharmaceutically acceptable salts.

[0465] (I);

[0466] in

[0467] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0468] L1, L2, and L3 represent the linking group independently or not at all.

[0469] A1, A2, and A3 represent each other independently.

[0470] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0471] b)C1-C 60 Partial or polymeric components;

[0472] At least one of A1, A2, and A3 is C1-C of group b). 60Partial or polymeric components;

[0473] Group b) C1-C 60 Partial or polymeric portion

[0474] b1) is configured to act as a drug; and / or

[0475] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0476] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0477] Used to treat skin-related diseases, allergic conditions, pain, or inflammation.

[0478] In some implementations, skin-related diseases may be selected from acne-like rashes, autoinflammatory syndromes, chronic bullae, mucosal diseases, skin appendage diseases, subcutaneous fat diseases, congenital abnormalities, connective tissue diseases, dermal fiber and elastic tissue abnormalities, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, pigmentary disorders, endocrine-related skin diseases, eosinophilic skin diseases, skin lesions, skin cancer, erythema, hereditary skin diseases, infection-related skin diseases, lichenification, lymphatic-related skin diseases, melanocytic nevi and growths, monocyte and macrophage-related skin diseases, mucin storage diseases, neurodermal diseases, non-infectious immunodeficiency-related skin diseases, nutrition-related skin diseases, papulosquamous keratosis, palmoplantar keratosis, pruritus, psoriasis, reactive neutrophilic skin diseases, skin diseases caused by metabolic errors, skin diseases caused by physical factors, urticaria, dandruff, desquamation disorders, and vascular-related skin diseases.

[0479] In some implementations, skin-related diseases are selected from hair loss, psoriasis, desquamation disorders, and seborrheic dermatitis.

[0480] Any specific compound disclosed in connection with the first aspect of this disclosure and relating to the pharmaceutical portion also represents a specific embodiment of that aspect of this disclosure.

[0481] In a fourth aspect, this disclosure relates to compounds of formula (I) or their tautomers and / or pharmaceutically acceptable salts.

[0482] (I);

[0483] in:

[0484] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0485] L1, L2, and L3 represent the linking group independently or not at all.

[0486] A1, A2, and A3 represent each other independently.

[0487] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0488] b)C1-C 60 Partial or polymeric components;

[0489] At least one of A1, A2, and A3 is a C1-C group configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran. 60 Partial or polymeric portion; and

[0490] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0491] Used in medicine, particularly for skin-related diseases, allergic conditions, pain, or inflammation, in which the drug is released within hours or days.

[0492] In some implementations, "several hours" refers to 8 hours or longer, more specifically 12 hours or longer, and especially 24 hours or longer.

[0493] In some implementations, "several days" means two days or longer, more specifically three days or longer, and especially seven days or longer.

[0494] Any specific compound disclosed in connection with the first aspect of this disclosure and relating to the pharmaceutical portion also represents a specific embodiment of that aspect of this disclosure.

[0495] In a fifth aspect, this disclosure relates to the use of the topical composition according to the first aspect as a skin moisturizer, insecticide, particularly an insect repellent, skin brightener, or fragrance.

[0496] Any particular compound disclosed in connection with the first aspect of this disclosure and relating to one or more parts of a skin moisturizer, insecticide, particularly an insect repellent, skin brightener, or fragrance also represents a particular embodiment of that aspect of this disclosure.

[0497] In a sixth aspect, this disclosure relates to a method of using a topical composition comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin may be a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0498] (I);

[0499] in:

[0500] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0501] L1, L2, and L3 represent the linking group independently or not at all.

[0502] A1, A2, and A3 represent each other independently.

[0503] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0504] b)C1-C 60 Partial or polymeric components;

[0505] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0506] Group b) C1-C 60 Partial or polymeric portion

[0507] b1) is configured to act as a skin moisturizer, insecticide, or skin brightener; and / or

[0508] b2) is configured to act as a skin moisturizer, insecticide, skin brightener, or fragrance after partial cleavage from 3,4-dihydro-2H-pyran; and

[0509] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0510] The method involves applying a topical composition to the skin.

[0511] In some embodiments, the method may include leaving the topical composition on the skin for at least 30 minutes.

[0512] In some embodiments, the method may include chemically peeling the skin before applying the topical composition to the skin.

[0513] Any particular compound disclosed in connection with the first aspect of this disclosure and relating to the portion intended for use as a skin moisturizer, insecticide, skin whitening agent, or fragrance also represents a particular embodiment of that aspect of this disclosure.

[0514] In a seventh aspect, this disclosure relates to a method of treating domestic or farm animals, the method comprising applying a topical composition to the skin and / or fur of the domestic or farm animal, wherein the topical composition comprises a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin may be a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0515] (I);

[0516] in:

[0517] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0518] L1, L2, and L3 represent the linking group independently or not at all.

[0519] A1, A2, and A3 represent each other independently.

[0520] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0521] b)C1-C 60 Partial or polymeric components;

[0522] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0523] Group b) C1-C 60 Partial or polymeric portion

[0524] b1) is configured to act as an insecticide; and / or

[0525] b2) is configured to act as an insecticide after partial cleavage from 3,4-dihydro-2H-pyran; and

[0526] L1-A1 and L2-A2 do not indicate portions containing unsaturated CC or CN bonds at the α positions of carbon atoms labeled "a" and "b" respectively.

[0527] Any particular compound disclosed in connection with the first aspect of this disclosure and relating to use as one or more parts of an insecticide also represents a particular embodiment of that aspect of this disclosure.

[0528] In the eighth aspect, this disclosure specifically relates to the compounds of this disclosure themselves, i.e., independent of topical compositions.

[0529] Any compound disclosed in relation to the first aspect of this disclosure also represents a specific embodiment of that aspect of this disclosure.

[0530] definition

[0531] As used in this article, the term "hair" refers to hair and other fibrous keratinous materials, such as eyebrows and eyelashes.

[0532] As used herein, the term “about” means “approximately” (e.g., about 10% of the indicated value, plus or minus). For example, “about 20” means or contains a quantity of 18 to 22, including 22.

[0533] Substituents of the compounds of the present invention are disclosed in various places in this specification by group or range. The present invention is particularly intended to include each and every individual subcombination of members of such groups and ranges. For example, the term "C" 1-6 The term "alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0534] As used in this article, the term "carboxyl group" refers to the -C(O)OH group.

[0535] Throughout the definition, the term "C" n-m The instruction includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-4 C 1-6 wait.

[0536] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkyl" refers to a saturated hydrocarbon group having n to m carbon atoms, which can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, more specifically 1 to 4 carbon atoms, even more specifically 1 to 3 carbon atoms, and particularly 1 to 2 carbon atoms.

[0537] As used herein, the term "C" is used alone or in combination with other terms. n-m An acyl group is a saturated hydrocarbon group that has n to m carbon atoms and can be either straight-chain or branched.

[0538] As used herein, the term "C" is used alone or in combination with other terms. n-m"Halogenated alkyl" refers to an alkyl group having one to 2s+1 halogen atoms that may be the same or different, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the halogenated alkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0539] As used in this article, "C" n-m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0540] As used in this article, "C" n-m "Alynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0541] As used herein, the term "C" is used alone or in combination with other terms. n-m "alkylene" refers to a divalent alkyl linking group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethyl-1,1-diyl, ethyl-1,2-diyl, propyl-1,1-diyl, propyl-1,3-diyl, propyl-1,2-diyl, but-1,4-diyl, but-1,3-diyl, but-1,2-diyl, 2-methyl-propyl-1,3-diyl, etc. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0542] As used herein, the term "amino" refers to a group of the formula -NH2.

[0543] As used herein, the term "fatty acid" in, for example, fatty acids or fatty alcohols, refers to a straight-chain or branched saturated, monounsaturated, or polyunsaturated hydrocarbon moiety having 8 to 34 carbon atoms. Examples of fatty acids include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, docosanoic acid, tetracosanoic acid, icosanoic acid; linolenic acid, arachidonic acid, oleic acid, and eicosatrienoic acid. Examples of fatty alcohols include decanol, undecanoic acid, cetyl alcohol, stearyl alcohol, oleyl alcohol, beeswax alcohol, and erythritol.

[0544] As used in this article, the term "halogen" specifically refers to F, Cl, Br, and I.

[0545] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein as a particular tautomer by name or structure are intended to include other tautomers.

[0546] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from non-optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, N=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are considered in this invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separate isomers. In some embodiments, the compounds have an (R)-configuration. In some embodiments, the compounds have an (S)-configuration.

[0547] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton-mutant tautomers, which are isomeric protonated states having the same empirical formula and total charge. Exemplary proton-mutant tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

[0548] As used herein, a “salt” or “pharmaceutically acceptable salt” of a compound of any of the chemical formulas disclosed herein is formed between an acid and a basic group (such as an amino functional group) of the compound, or between a base and an acidic group (such as a carboxyl functional group) of the compound. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly used to form pharmaceutically acceptable salts of compounds of any of the chemical formulas include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-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, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as associated inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this type include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprates, acrylates, formates, isobutyrates, caprates, heptanoates, propynates, oxalates, malonates, succinates, caprylates, sebates, and fumarates. Maleates, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and particularly those formed with organic acids such as maleic acid.In some embodiments, the base commonly used to form pharmaceutically acceptable salts of compounds of any of the chemical formulas disclosed herein includes 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 hydroxylated monoalkylamines, dialkylamines, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methylamine; N-ethylamine; diethylamine; triethylamine; mono-(2-OH-(C1-C6)-alkylamines), bis-(2-OH-(C1-C6)-alkylamines), or tri-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucosamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, etc. In some embodiments, the compounds of any of the chemical formulas disclosed herein, or their salts, are substantially isolated.

[0549] As used herein, the terms “individual” or “subject” are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0550] The terms “protecting group” and “protective group” refer to the portion of a functional group that is reversibly chemically modified to obtain chemoselectivity or reduce degradation in one or more subsequent chemical reactions. Suitable protecting groups are well known in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., JohnWiley & Sons, New York, NY, 1999, the full text of which is incorporated herein by reference).

[0551] As used in this article, “color” refers to the wavelength of electromagnetic radiation visible to the human eye, and “colorless” means that there is no electromagnetic radiation wavelength visible to the human eye.

[0552] Example

[0553] All starting materials / reagents / solvents were purchased from Sigma Aldrich, Thermo Fisher, VWR, TCIC Chemicals, or Oakwood Chemicals and were ready to use without purification. Genipin was provided by Herb-Sun Biotechnology.

[0554] The following examples describe the synthesis of hydrogenated genipin derivatives and demonstrate the flexibility and robustness of the 3,4-dihydro-2H-pyran moiety in conjugation with keratinocytes in in vitro tests utilizing lysine. These examples also demonstrate that the lysine conjugates are colorless. Some examples are not according to this disclosure because they do not carry the moiety of group b). These examples serve to demonstrate that the 3,4-dihydro-2H-pyran moiety can be widely substituted while retaining the effects described (the ability to bind to the skin and colorlessness in the bound state).

[0555] Example 1 - Genipin derivative compound 1-hydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopentadiene [c] Preparation of methyl pyran-4-carboxylate (compound 1)

[0556] (1)

[0557] Genipin (methyl 1-hydroxy-7-(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopentadieno[c]pyran-4-carboxylate) (1 equivalent) was added to a Schlenk flask along with 10% Pd / C (10 wt%). The flask was circulated three times between vacuum and nitrogen. In a separate flask, nitrogen was bubbled into methanol for 15 minutes. Once complete, methanol (0.05 M) was slowly added to the Schlenk flask under a nitrogen stream. The Schlenk flask was placed under vacuum and backfilled with H2 via a balloon. The reaction mixture was heated to 50 °C and monitored by TLC until the starting material was completely converted. The crude reaction mixture was filtered through a diatomaceous earth pad and washed with dichloromethane. The filtered solution was concentrated and separated into diastereomeric mixtures by rapid column chromatography.

[0558] 1 H NMR (300MHz, CDCl3) δ 7.42 (d, J = 1.3Hz, 1H), 4.91 (t, J = 6.3Hz,1H), 3.71 (s, 3H), 2.89 (m, 1H), 2.35–2.14 (m, 1H), 2.11–1.94 (m, 1H), 1.94 –1.78 (m, 1H), 1.64 (m, 1H), 1.35–1.15 (m, 2H), 1.11 (d, J = 6.7Hz, 3H). HRMS (DART+): C 11 H 17 Calculated value of O4 [M+H+]: 213.1121 m / z, measured value: 213.1124 m / z.

[0559] Example 2 - Hydrogenated genipin derivative compound 1-hydroxy-7-(hydroxymethyl)-1,4a,5,6,7,7a-hexahydro Preparation of methyl cyclopentadieno[c]pyran-4-carboxylate (compound 2)

[0560] (2)

[0561] Step 1 - 1-((tert-butyldimethylsilyl)oxy)-7-(((tert-butyldimethylsilyl)oxy) Synthesis of methyl 1,4a,5,7a-tetrahydrocyclopentadienyl[c]pyran-4-carboxylate

[0562]

[0563] Genipin (1 equivalent) was added together with tert-butyldimethylsilyl chloride (2.4 equivalents) and imidazole (5 equivalents) to an oven-dried round-bottom flask. The reagents were then dissolved in dimethylformamide (0.3 M) and stirred at room temperature for 4 days. After completion, the crude reaction mixture was added to a separatory funnel along with ethyl acetate and brine. The organic phase was washed three times with brine. The combined aqueous layers were extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated using a rotary evaporator. The title compound was separated by rapid column chromatography using a gradient of ethyl acetate and hexane.

[0564] Step 2 - 1-((tert-butyldimethylsilyl)oxy)-7-(((tert-butyldimethylsilyl)oxy) Synthesis of methyl 1,4a,5,6,7,7a-hexahydrocyclopentadienyl[c]pyran-4-carboxylate

[0565]

[0566] The product from step 1 (1 equivalent) was added to a Schlenk flask along with 10% Pd / C (10 wt%). The flask was circulated three times between vacuum and nitrogen. In a separate flask, nitrogen was bubbled into methanol for 15 minutes. Once complete, methanol (0.05 M) was slowly added to the Schlenk flask under a nitrogen stream. The Schlenk flask was placed under vacuum and backfilled with H2 via a balloon. The reaction mixture was heated to 50 °C and monitored by TLC until the starting material was completely converted. The crude reaction mixture was filtered through a diatomaceous earth pad and washed with dichloromethane. The filtered solution was concentrated and separated into diastereomeric mixtures by rapid column chromatography.

[0567] Step 3 - 1-Hydroxy-7-(hydroxymethyl)-1,4a,5,6,7,7a-hexahydrocyclopentadien[c]pyran-4-carboxylic acid Synthesis of methyl ester

[0568] The product from step 2 (1 equivalent) was added to an oven-dried flask and dissolved in THF (0.04 M). TBAF (1 equivalent of 1 M THF solution) was added, and the reaction mixture was stirred for 1 hour. The crude reaction mixture was concentrated, and the desired compound (3) was separated by rapid column chromatography.

[0569] 1H NMR (400MHz, MeOD) δ 7.48 (s, 1H), 3.70 (s, 3H), 3.64–3.56 (m,1H), 3.51 (m, 1H), 2.80–2.70 (m, 1H), 2.27–2.07 (m, 2H), 2.00–1.64 (m, 3H),1.50–1.19 (m, 3H). HRMS (DART+): C 11 H 17 Calculated value of O5 [M+H+]: 229.1070 m / z, measured value: 229.1066 m / z.

[0570] Example 3 - Genipin derivative compound 7-formyl-1-hydroxy-1,4a,5,6,7,7a-hexahydrocyclopentadiene [c]methyl pyran-4-carboxylate (compound 6) and genipin derivative compound 3-hydroxy-1,2a,2a1,3,4a,7a-hexadecanoate Preparation of methyl hydrogen-2H-4,5-dioxacyclopentadien[cd]indene-7-carboxylate (compound 7)

[0571]

[0572] Step 1 - 7-(hydroxymethyl)-1-methoxy-1,4a,5,7a-tetrahydrocyclopentadien[c]pyran-4-carboxylic acid ester

[0573]

[0574] Genipin (1 equivalent) was added to a round-bottom flask and dissolved in methanol (0.05 M). p-Toluenesulfonic acid (0.3 equivalent) was added to the stirred solution of genipin and allowed to react at room temperature until the starting material was completely converted. Once complete, the crude material was concentrated using rotary evaporation and filtered through a silica stopper. The crude material was washed with dichloromethane and concentrated. The title compound was separated by rapid column chromatography.

[0575] Step 2 - Methyl 7-formyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopentadien[c]pyran-4-carboxylate

[0576]

[0577] Add Dess-Martin periodide (DMP) (1.2 equivalents) to a stirred solution of the product from step 1 (1 equivalent) in dichloromethane. Stir the reaction mixture for 24 hours. Once complete, add saturated solutions of NaHCO3 and Na2S2O3 sequentially to the reaction mixture and stir for 30 minutes. Add the two-phase mixture to a separatory funnel and extract with dichloromethane / water (3×), followed by extraction with brine. Dry the combined organic layers with MgSO4 and concentrate under reduced pressure. Dry-load the crude material onto silica and purify by rapid chromatography (hexane:ethyl acetate) to give the title compound.

[0578] Step 3 - 7-Formyl-1-methoxy-1,4a,5,6,7,7a-hexahydrocyclopentadien[c]pyran-4-carboxylic acid Methyl ester

[0579]

[0580] The product from step 2 (1 equivalent) was added to a Schlenk flask along with 10% Pd / C (10 wt%). The flask was circulated three times between vacuum and nitrogen. In a separate flask, nitrogen was bubbled into methanol for 15 minutes. Once complete, methanol (0.05 M) was slowly added to the Schlenk flask under a nitrogen stream. The Schlenk flask was placed under vacuum and backfilled with H2 via a balloon. The reaction mixture was heated to 50 °C and monitored by TLC until the starting material was completely converted. The crude reaction mixture was filtered through a diatomaceous earth pad and washed with dichloromethane. The filtered solution was concentrated and separated into a mixture of diastereomers (title compounds) by rapid column chromatography.

[0581] Step 4 - Synthesis of compounds 6 and 7

[0582] The product from step 3 was dissolved in acetic acid / 1M HCl / THF at a ratio of 3:2:5, to a total concentration of 0.07M. The solution was stirred overnight at 60°C. Once complete, the solution was poured into a separatory funnel along with water and ethyl acetate. The combined ethyl acetate extract was dried over sodium sulfate and concentrated under reduced pressure. The desired compound (as a 15:85 mixture of aldehyde 6 and acetal 7) was separated by rapid column chromatography (hexane:ethyl acetate).

[0583] 1H NMR (400MHz, CDCl3) δ 9.79 (s, 0.05 H), 9.97 (s, 0.11 H) 7.56–7.44 (m, 1H), 6.07 (d, J = 5.9Hz, 0.05 H), 5.90–5.82 (m, 0.55 H), 5.74 (d, J =5.0Hz, 0.11 H), 5.36 (d, J = 4.9Hz, 0.05 H), 5.11 (d, J = 1.6Hz, 0.55 H), 5.03 (d, J = 1.5Hz, 0.11 H), 4.91 (d, J = 7.5Hz, 0.15 H), 3.74 (m, 3H), 3.61–3.55 (m, 0.05 H), 3.38 (t, J = 7.4Hz, 0.05 H), 3.02 (m, 0.75 H), 2.94–2.78 (m, 1H), 2.76–2.58 (m, 1.4 H), 2.56–2.43 (m, 0.20 H), 2.39–2.22 (m, 1H), 2.06 (m, 0.25 H), 1.93–1.80 (m, 1H), 1.72 (m, 1H), 1.44 (m, 0.11 H), 1.15 (m, 0.8H). HRMS (DART+): C 11 H 15 Calculated value of O5 [M+H+]: 227.0914 m / z, measured value: 227.0913 m / z.

[0584] Example 4 - 1-Hydroxy-4-(methoxycarbonyl)-1,4a,5,6,7,7a-hexahydrocyclopentadien[c]pyran- 7-Formic acid (compound 8) and 3-oxo-1,2a,2a1,3,4a,7a-hexahydro-2H-4,5-dioxacyclopentadien[cd]indene- Synthesis of methyl 7-carboxylate (compound 9)

[0585]

[0586] Step 1 - 1-Methoxy-4-(methoxycarbonyl)-1,4a,5,6,7,7a-hexahydrocyclopentadien[c]pyran- Synthesis of 7-formic acid

[0587]

[0588] The product from step 3 of Example 3 was dissolved in dimethylformamide (0.2 M) and stirred with 4 equivalents of potassium persulfate for 48 hours. The crude material was added to a separatory funnel along with ethyl acetate and brine. The combined ethyl acetate was dried over sodium sulfate and concentrated, then separated by rapid column chromatography to give the title compound.

[0589] Step 2 - Synthesis of Compounds 8 and 9

[0590] The product from step 1 was dissolved in acetic acid / 1M HCl / THF at a ratio of 3:2:5, to a total concentration of 0.07M. The solution was stirred overnight at 60°C. Once complete, the solution was poured into a separatory funnel along with water and ethyl acetate. The combined ethyl acetate extract was dried over sodium sulfate and concentrated. The title compound was separated by rapid column chromatography (hexane:ethyl acetate) to give the desired compound described below.

[0591] 1 H NMR (400MHz, CDCl3) δ 7.47 (d, J = 1.2Hz, 1H), 6.05 (d, J = 5.9Hz,1H), 3.75 (s, 3H), 3.41 – 3.32 (m, 1H), 2.97 (ddd, J = 10.6, 7.7, 5.9Hz, 1H), 2.93 – 2.81 (m, 1H), 2.54 – 2.43 (m, 1H), 2.26 (dd, J = 12.9, 6.0Hz, 1H), 1.76 (tdd, J = 13.2, 7.1, 6.2Hz, 1H), 1.10 (tdd, J = 13.2, 11.4, 6.0Hz, 1H).

[0592] 13 C NMR (101MHz, CDCl3) δ 175.9, 167.1, 148.5, 110.0, 96.9, 51.7, 48.8, 37.5, 33.4, 31.7, 29.0.

[0593] HRMS (DART+): C 11 H 13 The calculated value of O5 [M+H+] is 225.0758 m / z, and the measured value is 225.0751 m / z.

[0594] Example 5 - (E)-1-hydroxy-7-(((4-(phenyldiazeninyl)benzoyl)oxy)methyl)-1,4a,5, Synthesis of methyl 6,7,7a-hexahydrocyclopentadien[c]pyran-4-carboxylate (compound 10)

[0595] (10)

[0596] Step 1 - 7-(hydroxymethyl)-1-methoxy-1,4a,5,6,7,7a-hexahydrocyclopentadien[c]pyran-4-methyl Synthesis of methyl ester

[0597]

[0598] The compound obtained in step 3 of Example 3 (1 equivalent) was dissolved in methanol (0.27 M) and stirred at 0 °C. Sodium borohydride (1.5 equivalent) was added. The reaction mixture was stirred for 30 minutes while being heated to room temperature. Once complete, the crude reaction mixture was diluted with saturated NH4Cl and extracted with ethyl acetate (3×) in a separatory funnel. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The title compound was separated by rapid column chromatography.

[0599] Step 2 - (E)-1-methoxy-7-(((4-(phenyldiazeninyl)benzoyl)oxy)methyl)-1,4a,5, Synthesis of methyl 6,7,7a-hexahydrocyclopentadien[c]pyran-4-carboxylate

[0600]

[0601] The compound obtained in step 1 (1 equivalent) was dissolved in dichloromethane / pyridine (1:1 v / v) (0.2 M) and cooled to 0 °C. 4-(phenylazo)benzoyl chloride (1.2 equivalent) was added dropwise at 0 °C and allowed to react overnight while simultaneously warming to room temperature. The crude reaction mixture was quenched with saturated sodium bicarbonate and extracted with dichloromethane and water in a separatory funnel. The combined DCM layers were dried over sodium sulfate, concentrated under reduced pressure, and separated by rapid column chromatography to give the title compound.

[0602] Step 3 - Synthesis of the title compound in this embodiment

[0603] The product from step 2 was dissolved in acetic acid / 1M HCl / THF at a ratio of 3:2:5, resulting in a total concentration of 0.07M. The solution was stirred overnight at 60°C. Once complete, the solution was poured into a separatory funnel along with water and ethyl acetate. The combined ethyl acetate extract was dried over sodium sulfate and concentrated under reduced pressure. The title compound was separated by rapid column chromatography (hexane:ethyl acetate) to give the desired compound (10).

[0604] 1H NMR (300MHz, CDCl3) δ 8.22–8.15 (m, 2H), 7.99–7.91 (m, 4H), 7.59–7.50 (m, 3H), 7.45 (m, 1H), 5.66 (t, J = 3.7Hz, 0.3 H), 5.19–5.09 (m, 0.65H), 4.69 (dd, J = 11.2, 7.3Hz, 0.65 H), 4.56 (d, J = 8.0Hz, 0.6 H), 4.46 (dd,J = 11.3, 7.4Hz, 0.6 H), 3.74 (s, 3H), 3.69 (m, 1H), 3.63–3.55 (m, 2H), 3.08(m, 0.3 H), 2.98 (m, 0.7 H), 2.79 (m, 1H), 2.45–2.18 (m, 2H), 2.12–2.03 (m,0.6 H), 1.95–1.81 (m, 2H), 1.79–1.59 (m, 3H), 1.55–1.41 (m, 0.6 H). HRMS (DART+): C 24 H 25 Calculated value of N2O6 [M+H+]: 437.1707 m / z, measured value: 437.1714 m / z.

[0605] Example 6 - Color properties of conjugation with lysine and hydrogenated genipin

[0606] The hydrogenated genipin derivative (compound 1) was conjugated with lysine to obtain compound 1-lysine conjugate:

[0607]

[0608] like Figure 5 As shown, reacting anchoring compound 1 with amino acids to mimic skin binding resulted in a slight shift in the compound's strong UV absorption (absorption at wavelengths below 410 nm), but no visible color (no absorption at wavelengths above 410 nm).

[0609] Figure 6A The results showed that reacting anchoring compound 2 with lysine to mimic skin binding resulted in strong UV light absorption and no visible color.

[0610] Figure 6B The results showed that reacting the anchoring compound 6 / 7 with lysine to mimic skin binding resulted in UV light absorption and no visible color.

[0611] Figure 6CThe results showed that reacting anchoring compound 8 / 9 with lysine to mimic skin binding resulted in UV light absorption and no visible color.

[0612] The azo dye compound (compound 10) from Example 5 was conjugated with lysine to obtain a conjugate:

[0613]

[0614] like Figure 6D As shown, the dye conjugate of the anchoring compound reacts with an amino acid to mimic skin binding, producing color due to the presence of the azo dye moiety. However, the conjugation process does not alter the absorbance properties of the compound prior to conjugation with lysine.

[0615] Due to the lack of C1-C in group b), 60 In part, all of the above embodiments are not based on this disclosure.

[0616] Example 7 - 1-Hydroxy-7-(((2-hydroxybenzoyl)oxy)methyl)-1,4a,5,6,7,7a-hexahydrocyclohexane methyl pentadieno[c]pyran-4-carboxylate

[0617]

[0618] Step 1 - 7-(hydroxymethyl)-1-methoxy-1,4a,5,6,7,7a-hexahydrocyclopentadien[c]pyran-4-methyl Synthesis of methyl ester

[0619]

[0620] The compound obtained in step 3 of Example 3 (1 equivalent) was dissolved in methanol (0.27 M) and stirred at 0 °C. Sodium borohydride (1.5 equivalent) was added. The reaction mixture was stirred for 30 minutes while being heated to room temperature. Once complete, the crude reaction mixture was diluted with saturated NH4Cl and extracted with ethyl acetate (3×) in a separatory funnel. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The title compound was separated by rapid column chromatography.

[0621] Step 2 - 7-(((2-acetoxybenzoyl)oxy)methyl)-1-methoxy-1,4a,5,6,7,7a-hexadecyl Synthesis of methyl hydrocyclopentadieno[c]pyran-4-carboxylate

[0622]

[0623] The product from step 1 (1 equivalent) was dissolved in dichloromethane / pyridine (1:1 v / v) (0.2 M) and cooled to 0 °C. O-acetyl salicyl chloride (1.2 equivalent) was added dropwise at 0 °C and allowed to react overnight while simultaneously warming to room temperature. The crude reaction mixture was quenched with saturated sodium bicarbonate and extracted with dichloromethane and water in a separatory funnel. The combined DCM layers were dried over sodium sulfate, concentrated under reduced pressure, and separated by rapid column chromatography to give the title compound.

[0624] Step 3 - Synthesis of the title compound in this embodiment

[0625] The product from step 2 was dissolved in acetic acid / 1M HCl / THF at a ratio of 3:2:5, to a total concentration of 0.07M. The solution was stirred overnight at 60°C. Once complete, the solution was poured into a separatory funnel along with water and ethyl acetate. The combined ethyl acetate extract was dried over sodium sulfate and concentrated under reduced pressure. The title compound was separated by rapid column chromatography (hexane:ethyl acetate) to obtain the desired compound.

[0626] 1 H NMR (400MHz, CDCl3) δ 10.79 (s, 0.25 H), 10.77 (s, 0.6 H), 7.84 (m,1H), 7.49–7.45 (m, 2H), 7.01 (m, 1H), 6.91 (m, 1H), 5.65 (t, J = 3.6Hz, 0.25H), 5.15 (dd, J = 8.5, 6.5Hz, 0.7 H), 4.67 (dd, J = 11.1, 7.2Hz, 0.7 H), 4.58 (d, J = 8.2Hz, 0.5 H), 4.48 (dd, J = 11.2, 7.6Hz, 0.7 H), 3.76 (m, 3H), 3.34(m, 0.7 H), 3.00 (m, 1H), 2.95–2.68 (m, 1H), 2.46–2.30 (m, 1H), 2.26 (m, 0.7H), 2.18–1.89 (m, 1H), 1.83–1.43 (m, 2H).

[0627] HRMS (DART+): C 18 H 24 The calculated value of NO7 [M+NH+] is 366.1547 m / z, and the measured value is 366.1550 m / z.

[0628] Example 8 - Conjugation with lysine

[0629] The compound from Example 7 was conjugated with lysine to obtain a lysine conjugate:

[0630]

[0631] like Figure 7 As shown, the compound of Example 7 (i.e., hydrogenated genipin salicylate) was subjected to... Figure 7 (referred to as "genipin salicylate" in Chinese) and the amino acid lysine (in... Figure 7The reaction, referred to as "amine" in Chinese, mimics skin binding, resulting in a slight shift in the UV absorption peak (without producing visible color).

[0632] Example 9 - Preparation and conjugation with lysine

[0633]

[0634] Weigh the aldehyde, which can be obtained as described in WO 2022 / 036113 A1, and transfer it to a round-bottom flask. Add MeOH (0.2M) and stir until completely dissolved. First wash DOWEX with methanol. ® 50W x 8, and dry under vacuum. Once dry, apply DOWEX. ® 50 W x 8 (H+ form) was added to the stirred aldehyde solution. The reaction mixture was heated at 40 °C for 65 hours. Once complete, methanol was removed by rotary evaporation, and the product was precipitated using diethyl ether / hexane to give a white powder.

[0635]

[0636] Add the obtained aldehyde to Oxone ® A solution of potassium persulfate (4 equivalents) in DMF (0.2 M) was prepared, and the reaction mixture was stirred at room temperature for four days. The crude mixture was added to a separatory funnel along with ethyl acetate and brine. The aqueous layer was thoroughly washed with ethyl acetate. The combined ethyl acetate layers (3x) were then extracted with saturated NH3. The combined alkaline aqueous layers were acidified again with concentrated HCl until the pH was below 7. The acidified solution was then extracted with ethyl acetate (3x). The combined ethyl acetate layers were dried over Na2SO4 and concentrated.

[0637]

[0638] 1-Chloro-N,N-2-trimethyl-1-propenylamine was added to a solution of carboxylic acid in MeCN (0.25 M) at 0 °C for 1 h. Once the starting material was consumed (verified by TLC), the mixture was concentrated to an oil under vacuum. Once concentrated, dichloromethane (0.2 M) was added to the reaction mixture and stirred at 0 °C. 1-Decanol was added, followed by pyridine (equal volume to dichloromethane). The ice bath was removed, and the mixture was heated to room temperature for 1 h. Once complete, the reaction mixture was diluted with DCM and transferred to a separatory funnel. The mixture was washed with 1 M HCl (2X) to remove pyridine. It was washed with saturated NaHCO3 (1X) to remove unreacted acyl chloride. The mixture was dried over sodium sulfate and concentrated to dryness. The resulting material was purified by rapid column chromatography using a gradient of ethyl acetate and hexane.

[0639]

[0640] Weigh 10% carbon-supported palladium (10 wt%) into an oven-dried Schlenk flask. Circulate the flask between argon and vacuum three times. Add toluene equipped with a stir bar to a separate conical flask. Immerse a needle connected to the argon line in the toluene and bubble through the solvent for 15 minutes. Meanwhile, weigh the ester material into a vial. Once toluene aeration is complete, dissolve the ester starting material in degassed toluene. Carefully add this solution to the Schlenk flask under an argon flow. Once complete, place a rubber diaphragm on the Schlenk flask and evacuate under vacuum, then place under static vacuum. Fill a balloon with H2 and equip it with an 18G needle. Add the balloon to the reaction flask, heat to 50°C, and allow it to react for 24 hours. The crude reaction proceeds to the next step without further purification.

[0641]

[0642] The reduced ester starting material was deprotected using a mixture of HCl / acetic acid in tetrahydrofuran with prolonged heating. The crude reaction mixture was added to a separatory funnel and carefully quenched with a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude material was separated by rapid column chromatography using a gradient of ethyl acetate and hexane.

[0643] HRMS (DART+): C 21 H 35 O6 [M+H] + Calculated value: 383.2428 m / z, measured value: 383.2420 m / z

[0644] 1 ¹H NMR (400MHz, CDCl₃) diastereomer mixture δ 7.45 (m, 1H – mixture integral is 1), 5.51 (d, J = 8.0Hz, 0.33H), 5.34–4.72 (m, 1H), 4.18–4.00 (m, 2H), 3.71 (s, 3H), 3.12 (m 0.36H), 3.07–2.87 (m, 1H), 2.80 (m, 1H), 2.69–2.39 (m, 1H), 2.32 (m, 1H), 2.10–1.92 (m, 2H), 1.92–1.76 (m, 1H), 1.63 (m 2H), 1.48–1.18 (m, 15H). 0.94–0.82 (m, 3H).

[0645]

[0646] The deprotected substance from the previous step was reacted with L-lysine (2 molar equivalents) in MeOH (0.05M) with a few drops of water and stirred at 35°C for 18 hours.

[0647] HRMS (DART+): C 27 H 45 N2O6 [M+H + Calculated value: 493.3272 m / z, measured value: 493.3267 m / z

[0648] like Figure 8 As shown, the obtained lysine conjugate (B) is almost colorless (very pale yellow).

[0649] Example 10 - Preparation of hydrogenated genipin derivatives linked to glycerol and their conjugation with lysine

[0650] Starting material synthesis :

[0651]

[0652] An equimolar amount of phenylboronic acid was added to a stirred toluene solution (0.5 M) of glycerol. The mixture was heated to reflux for 5 hours, and then the reaction mixture was concentrated by rotary evaporation. Fresh toluene was added three times, and the mixture was evaporated to remove excess water. The resulting glycerol borate ester was a mixture of isomers and was carried over to the next step.

[0653]

[0654] Step 1: O-benzyl protection of genipin 7-(hydroxymethyl)-1-methoxy-1,4a,5,7a-tetrahydrocyclopentadien[c]pyran-4-carboxylic acid benzyl ester

[0655] Add genipin (1 equivalent) to a round-bottom flask and dissolve it in benzyl alcohol / dichloromethane (1 / 1 volume / volume) (0.5 M). Add Dowex... ® 50 W x 8 (20 wt%) was added to the stirred solution of genipin and allowed to react at 40°C until the starting material was completely converted. Once complete, the coarse material was filtered to remove Dowex. ® The resin was then concentrated by rotary evaporation. The title compound was separated by rapid column chromatography.

[0656] Step 2: Oxidation of o-benzyl-protected genipin 7-Formyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopentadienyl[c]pyran-4-carboxylic acid benzyl ester

[0657] Add 20 mol% CuBr, 2,2'-bipyridine, and TEMPO catalyst to a stirred acetonitrile solution (0.5 M) of benzyl-protected genipin. Stir the contents vigorously in an open flask until the starting material is completely converted. Separate the title compound by rapid column chromatography.

[0658] Step 3: Oxidation to carboxylic acid

[0659] The product from step 2 was dissolved in dimethylformamide (0.2 M) and stirred with 4 equivalents of potassium persulfate for 48 hours. The crude material was added together with ethyl acetate into a separatory funnel and washed with brine (3x). The aqueous phase was then back-extracted with ethyl acetate (3x). The combined ethyl acetate was dried over sodium sulfate and concentrated, and then separated by rapid column chromatography to give the title compound.

[0660]

[0661] Step 1: Acylation of genipin carboxylic acid ester derivatives

[0662] 1-Chloro-N,N-2-trimethyl-1-propenylamine (1.2 equivalents) was added to a solution of carboxylic acid in anhydrous MeCN (0.25 M) at 0 °C and stirred for 1 h while warming to room temperature. Once the starting material was consumed (verified by TLC), the mixture was concentrated to an oil under vacuum. Once concentrated, anhydrous dichloromethane (0.2 M) was added to the reaction mixture and stirred at 0 °C. Glyceryl-phenylboronic acid ester was added, followed by pyridine (equal volume to dichloromethane). The ice bath was removed and the mixture was warmed to room temperature for 1 h. Once complete, the reaction mixture was diluted with DCM and transferred to a separatory funnel. The mixture was washed with 1 M HCl (2X) to remove pyridine. The DCM was concentrated and resuspended in ethyl acetate, then washed with 1 M D-sorbitol / 1 M Na2CO3 (3X) to cleave the borate ester and remove phenylboronic acid. The combined aqueous phases were back-extracted with ethyl acetate, dried over sodium sulfate, and concentrated to dryness. The crude material was purified by rapid column chromatography using a gradient of ethyl acetate and pentane.

[0663] Step 2: Reduction and deprotection of acylated genipin derivatives

[0664] Weigh 10% carbon-supported palladium (10 wt%) into an oven-dried Schlenk flask. Circulate the flask between argon and vacuum three times. Add methanol equipped with a stir bar to a separate conical flask. Immerse a needle connected to the argon line in the methanol and bubble through the solvent for 15 minutes. Meanwhile, weigh the ester material into a vial. Once methanol aeration is complete, dissolve the ester starting material in degassed methanol. Carefully add this solution to the Schlenk flask under an argon flow. Once complete, place a rubber diaphragm on the Schlenk flask and evacuate under vacuum, then place under static vacuum. Pack a balloon with H2 and equip it with an 18G needle. Add the balloon to the reaction flask, heat to 50°C, and allow it to react for 24 hours. Purify the crude reaction by rapid column chromatography using a gradient of dichloromethane and methanol.

[0665]

[0666] ¹H NMR (400 MHz, MeOD) major diastereomers δ 7.48 (s, ¹H), 4.89 (d, J = 7.8 Hz, ¹H), 4.23–4.06 (m, 2H), 3.84 (m, ¹H), 3.70 (s, 3H), 3.69–3.62 (m, ¹H), 3.56 (dd, J = 5.5, 2.1 Hz, 2H), 2.89 (m, 2H), 2.38 (m, 1H), 2.32–2.18 (m, 1H), 2.05 (m, 1H), 1.84 (m, 1H), 1.41 (m, 1H).

[0667] 13 C NMR (101MHz, MeOD) major diastereomers δ 177.0, 169.6, 154.2, 110.9, 96.2, 71.1, 66.8, 64.0, 51.7, 46.8, 46.6, 36.9, 33.9, 29.4.

[0668] HRMS (DART+): C 14 H 24 Calculated value of NO8 [M+NH4+]: 334.1496 m / z, measured value: 334.1503 m / z.

[0669]

[0670] The deprotected substance from the previous step was reacted with L-lysine (2 molar equivalents) in MeOH (0.05M) with a few drops of water and stirred at 35°C for 18 hours.

[0671] HRMS (ESI+): C 20 H 31 N₂O₈ [M+H+]: 427.2075 m / z

[0672] like Figure 9 As shown, the obtained lysine conjugate is almost colorless (very pale yellow).

[0673] The conjugation of compounds from Examples 11-10 with skin

[0674] A 100 mM methanol solution of the hydrogenated genipin derivatives obtained in Examples 9 and 10 was prepared, and 200 μl of each solution was drop-applied to the explanted pig skin. Methanol was applied at a third point as a control. The hydrogenated genipin derivatives were allowed to bind to the skin in a hydration chamber for 2 hours. The pig skin was then removed from the chamber and thoroughly washed with water to remove any residual unreacted genipin derivatives.

[0675] like Figure 10 As shown, pigskin showed no visual changes under normal sunlight, but exposure to UV light indicated that the hydrogenated genipin derivative had been coupled to the skin.

[0676] Example 12 - Preparation of hydrogenated genipin derivatives linked to picaridin and their conjugation with lysine

[0677]

[0678] Step 1: Acylation of genipin carboxylic acid ester derivatives

[0679] 1-Chloro-N,N-2-trimethyl-1-propenylamine (1.2 equivalents) was added to a solution of carboxylic acid in anhydrous MeCN (0.25 M) at 0 °C for 1 h. Once the starting material was consumed (verified by TLC), the mixture was concentrated to an oil under vacuum. Once concentrated, anhydrous dichloromethane (0.2 M) was added to the reaction mixture and stirred at 0 °C. Icaridin was added, followed by pyridine (equal volume to dichloromethane). The ice bath was removed, and the mixture was heated to room temperature for 1 h. Once complete, the reaction mixture was diluted with DCM and transferred to a separatory funnel. The mixture was washed with 1 M HCl (2X) to remove pyridine. It was washed with saturated NaHCO3 (1X) to remove unreacted acyl chloride. The mixture was dried over sodium sulfate and concentrated to dryness. The resulting material was purified by rapid column chromatography using a gradient of ethyl acetate and pentane.

[0680] Step 2: Reduction and deprotection of acylated genipin derivatives

[0681] Weigh 10% carbon-supported palladium (10 wt%) into an oven-dried Schlenk flask. Circulate the flask between argon and vacuum three times. Add methanol equipped with a stir bar to a separate conical flask. Immerse a needle connected to the argon line in the methanol and bubble through the solvent for 15 minutes. Meanwhile, weigh the ester material into a vial. Once methanol aeration is complete, dissolve the ester starting material in degassed methanol. Carefully add this solution to the Schlenk flask under an argon flow. Once complete, place a rubber diaphragm on the Schlenk flask and evacuate under vacuum, then place under static vacuum. Pack a balloon with H2 and equip it with an 18G needle. Add the balloon to the reaction flask, heat to 50°C, and allow it to react for 24 hours. Purify the crude reaction by rapid column chromatography using a gradient of ethyl acetate and pentane.

[0682]

[0683] 1 ¹H NMR (400MHz, DMSO) diastereomer mixture δ 7.50–7.30 (m, 2H), 5.39–4.79 (m, 1H), 4.59 (m, 1H), 4.28 (br s, 1H), 3.98 (m, 2H), 3.86 (d, J = 13.8Hz, 1H), 3.62 (s, 3H), 2.87–2.65 (m, 3H), 2.25 (m, 1H), 2.16–1.83 (m, 3H), 1.80–1.65 (m, 2H), 1.63–1.42 (m, 7H), 1.42–1.18 (m, 2H), 1.17–1.04 (m, 3H), 0.83 (m, 3H).

[0684] 13 The major diastereomeric δ values ​​shown by C NMR (101 MHz, DMSO) are 174.6, 166.9, 154.5, 152.6, 108.9, 94.6, 72.1, 61.9, 50.9, 44.9, 44.7, 38.4, 35.1, 32.2, 28.5, 28.4, 28.1, 27.9, 25.1, 19.5, 19.5, 18.5, and 9.5.

[0685] HRMS (DART+): C 23 H 36 The calculated value of NO8 [M+H+] is 454.2435 m / z, and the measured value is 454.2445 m / z.

[0686] The deprotected substance from the previous step was reacted with L-lysine (2 molar equivalents) in MeOH (0.05M) with a few drops of water and stirred at 35°C for 18 hours.

[0687]

[0688] HRMS (ESI+): C 29 H 46 Calculated value of N3O8 [M+H+]: 564.3279 m / z, measured value: 564.3290 m / z

[0689] like Figure 11 As shown, the obtained lysine conjugate is almost colorless (very pale yellow).

[0690] The conjugation of compounds from Examples 13-12 with skin

[0691] A 50 mM methanol solution of the hydrogenated genipin derivative of Example 11 was prepared, and 100 μl of the solution (containing 2.2 mg of the genipin derivative) was drop-applied to explanted porcine skin. The hydrogenated genipin derivative was allowed to bind to the skin under ambient conditions for 2 hours. The porcine skin was then cleaned with a damp paper towel by wiping and scrubbing to remove any residual unreacted genipin derivative. The binding of the compound to the porcine skin was confirmed by UV light. After 24 hours, the porcine skin was immersed in water, then removed, dried, and scrubbed again. Exposure to UV light further confirmed the stable binding of the hydrogenated genipin derivative of Example 11 to the skin.

[0692] like Figure 12 As shown, pigskin showed no visual changes under normal sunlight, but exposure to UV light indicated that the hydrogenated genipin derivative had been coupled to the skin at the aforementioned 2-hour and 24-hour intervals.

[0693] Example 14 - Preparation of hydrogenated genipin derivatives linked to D-glucose using ethylene glycol linkers and their relationship with lysine amino acid conjugation

[0694]

[0695] Steps 1 and 2: Acylation of genipin carboxylic acid ester derivatives :

[0696] 1-Chloro-N,N-2-trimethyl-1-propenylamine (1.2 equivalents) was added to a solution of carboxylic acid in anhydrous MeCN (0.25 M) at 0 °C for 1 h. Once the starting material was consumed (verified by TLC), the mixture was concentrated to an oil under vacuum. Once concentrated, anhydrous dichloromethane (0.2 M) was added to the reaction mixture and stirred at 0 °C. A glucose derivative (as shown above) was added, followed by pyridine (equal volume to dichloromethane) (0.2 M). The ice bath was removed, and the mixture was heated to room temperature for 1 h. Once complete, the reaction mixture was diluted with DCM and transferred to a separatory funnel. The mixture was washed with 1 M HCl (2X) to remove pyridine. It was washed with saturated NaHCO3 (1X) to remove unreacted acyl chloride. The mixture was dried over sodium sulfate and concentrated to dryness. The resulting material was purified by rapid column chromatography using a gradient of ethyl acetate and pentane.

[0697] Step 3: Selective deprotection of the acetyl protecting group

[0698] The acetyl-protected product from step 2 was selectively deprotected by dissolving it in methanol (0.2 M), then adding 4.1 equivalents of n-hexylamine, and stirring at 50 °C for 2 hours. The deprotected product was then separated by a gradient of methanol and dichloromethane using rapid column chromatography.

[0699] Step 4: Reduction and deprotection of acylated genipin derivatives

[0700] Weigh 10% carbon-supported palladium (10 wt%) into an oven-dried Schlenk flask. Circulate the flask between argon and vacuum three times. Add methanol equipped with a stir bar to a separate conical flask. Immerse a needle connected to the argon line in the methanol and bubble through the solvent for 15 minutes. Meanwhile, weigh the ester material into a vial. Once methanol aeration is complete, dissolve the ester starting material in degassed methanol. Carefully add this solution to the Schlenk flask under an argon flow. Once complete, place a rubber diaphragm on the Schlenk flask and evacuate under vacuum, then place under static vacuum. Pack a balloon with H2 and equip it with an 18G needle. Add the balloon to the reaction flask, heat to 50°C, and allow it to react for 24 hours. Purify the crude reaction by rapid column chromatography using a gradient of methanol and dichloromethane.

[0701]

[0702] HRMS (ESI+): C 19 H 28 O 12 Calculated value of Na[M+Na+]: 471.1473 m / z, measured value: 471.1470 m / z

[0703]

[0704] The deprotected substance from the previous step was reacted with L-lysine (2 molar equivalents) in MeOH (0.05M) with a few drops of water and stirred at 35°C for 18 hours.

[0705] HRMS (DART+): C 25 H 38 N2O 12 Calculated value of [M+H+]: 559.2498 m / z, measured value: 559.2508 m / z

[0706] The obtained lysine conjugate is almost colorless (very pale yellow).

[0707] Other implementation plans

[0708] It should be understood that although this application has been described in conjunction with specific embodiments thereof, the specification is intended to illustrate and not limit the scope of the application, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0709] This disclosure also relates to the following embodiments, which supplement the above description and can be freely combined with it:

[0710] 1. A topical composition comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound suitable for covalently binding to the skin is a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt.

[0711] (I);

[0712] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0713] Where L1, L2, and L3 represent the linking group independently or are absent.

[0714] A1, A2, and A3 represent each other independently.

[0715] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0716] b)C1-C 60 Partial or polymeric components;

[0717] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0718] Among them, group b) C1-C 60 Partial or polymeric components:

[0719] b1) is configured to act as a skin moisturizer, insecticide, skin brightener, or medicine; and / or

[0720] b2) is configured to act as a skin moisturizer, insecticide, skin brightener, fragrance, or medicine after partial cleavage from 3,4-dihydro-2H-pyran; and

[0721] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0722] 2. The topical composition according to embodiment 1, wherein C1-C of group b) 60 Partial or polymeric portions contain C1-C 60 Functional groups that are partially coupled to the corresponding L1, L2 or L3 moieties, or functional groups that are coupled to the 3,4-dihydro-2H-pyran moieties if the corresponding L1, L2 or L3 moieties are not present.

[0723] 3. The topical composition according to embodiment 2, wherein the functional group comprises carbon atom, oxygen atom, nitrogen atom, sulfur atom, phosphorus atom or a combination thereof; more specifically, carbon atom, oxygen atom, nitrogen atom or a combination thereof; and particularly carbon atom and / or oxygen atom.

[0724] 4. The topical composition according to embodiment 3, wherein the functional group comprises one or more, two or more, three or more, four or more, or all of the following:

[0725] 1 to 12 carbon atoms, more specifically 1 to 6 carbon atoms, and especially 1 to 3 carbon atoms;

[0726] 1 to 12 oxygen atoms, more specifically 1 to 6 oxygen atoms, and especially 1 to 3 oxygen atoms;

[0727] One to four nitrogen atoms, more specifically one to three nitrogen atoms, and especially one to two nitrogen atoms;

[0728] One to three sulfur atoms, more specifically one to two sulfur atoms, and especially one sulfur atom;

[0729] One to three phosphorus atoms, more specifically one to two phosphorus atoms, and especially one phosphorus atom.

[0730] 5. The topical composition according to any one of embodiments 2 to 4, wherein the functional group is capable of cleavage under physiological conditions after the topical composition is applied to the skin.

[0731] 6. The topical composition according to any one of embodiments 2 to 5, wherein the functional group is hydrolyzable at the physiological pH of mammalian skin, more specifically human skin, and particularly at a pH of about 5 to about 6.

[0732] 7. The topical composition according to any one of embodiments 2 to 6, wherein the functional group is capable of enzymatic cleavage under physiological conditions after the topical composition is applied to the skin, particularly by enzymes present in human skin.

[0733] 8. The topical composition according to any one of embodiments 2 to 7, wherein the functional group is configured to cleave into a hydroxyl, primary or secondary amine group, carboxylic acid, thiol, aldehyde, ketone, thiocarbonate, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, olefin, alkene or oxime; or salts thereof.

[0734] 9. The topical composition according to any one of embodiments 2 to 8, wherein the functional group is configured to, upon cleavage, provide a hydroxyl, primary or secondary amine group, carboxylic acid, thiol, aldehyde, ketone, thiocarbonate, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, olefin, alkene or oxime; or salts thereof; to the C1-C of group b). 60 Provided on the corresponding L1, L2, or L3 portion of the partial or polymeric portion, or on the 3,4-dihydro-2H-pyran portion if the corresponding L1, L2, or L3 portion does not exist.

[0735] 10. The topical composition according to any one of embodiments 2 to 8, wherein the functional group is configured to, upon cleavage, provide a hydroxyl, primary or secondary amine group, carboxylic acid, thiol, aldehyde, ketone, thiocarbonate, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, alkene or oxime; or salts thereof; to the C1-C of group b). 60 On a portion or polymer portion.

[0736] 11. The topical composition according to any one of embodiments 2 to 10, wherein the functional group comprises a carbon ester, particularly a monoester, 1,1-diester, carbonate or carbamate; an ether or thioether, particularly an acetal, hemiacetal, glycosidic group or thioacetal; a carbamide, particularly a peptide or N-Mannich base; an enol; an enamine; an imine; an oxime; a sulfate; a sulfonate; a sulfonamide; a phosphate; a phosphonate; a phosphoramide; or a phosphonamide.

[0737] 12. The topical composition according to any one of embodiments 1 to 11, wherein A1 represents C1-C of group b).60 Partial or polymeric portion.

[0738] 13. The topical composition according to any one of embodiments 1 to 12, wherein A2 represents C1-C of group b). 60 Partial or polymeric portion.

[0739] 14. The topical composition according to any one of embodiments 1 to 13, wherein A3 represents C1-C of group b). 60 Partial or polymeric portion.

[0740] 15. The topical composition according to any one of embodiments 12 to 14, wherein the remaining portions of A1, A2, and A3 represent C1-C 30 Partial, H, hydroxyl, amino, or halogen.

[0741] 16. The topical composition according to any one of embodiments 1 to 15, wherein:

[0742] L1 is present and represents an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 8 carbon atoms; and / or

[0743] L2 is present and represents an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 8 carbon atoms; and / or

[0744] L3 exists and represents an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, contains 1 to 8 carbon atoms.

[0745] 17. The topical composition according to any one of embodiments 2 to 15, wherein:

[0746] L1 is present and represents an optionally substituted hydrocarbon moiety, which, together with its optionally substituents, comprises 1 to 8 carbon atoms, wherein a functional group is attached to L1; and / or

[0747] L2 is present and represents an optionally substituted hydrocarbon moiety, which, together with its optionally substituents, comprises 1 to 8 carbon atoms, wherein a functional group is attached to L2; and / or

[0748] L3 exists and represents an optionally substituted hydrocarbon moiety, which, together with its optionally substituents, comprises 1 to 8 carbon atoms, wherein a functional group is attached to L3.

[0749] 18. The topical composition according to any one of embodiments 1 to 17, wherein L1 and L2 are present and form a 5-membered, 6-membered, 7-membered or 8-membered ring, particularly cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl.

[0750] 19. The topical composition according to embodiment 18, wherein L1 and L2 are present and form an optionally substituted 5- or 6-membered ring, particularly cyclopentyl or cyclohexyl, and A1 and A2 are optionally attached to the ring via groups selected from: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 - or a combination thereof.

[0751] 20. The topical composition according to embodiment 18, wherein L1 and L2 are present and form a cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl ring, and A1 and A2 are optionally attached to the ring via a group selected from: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 - or a combination thereof.

[0752] 21. The topical composition according to embodiment 20, wherein A1 is C1-C of group b). 60 Partial or polymeric portion.

[0753] 22. The topical composition according to embodiment 20 or embodiment 21, wherein A3 is C1-C of group b). 60 part.

[0754] 23. The topical composition according to embodiment 21 or embodiment 22, wherein A2 represents C1-C 30 Partial, H, hydroxyl, amino or halogen, especially hydrogen.

[0755] 24. The topical composition according to any one of embodiments 1 to 23, wherein C1-C of group a) 30 The portion contains 1 to 30, more specifically 1 to 16, and particularly 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 phosphorus atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms.

[0756] 25. The topical composition according to embodiment 24, wherein C1-C30 The alkyl group is partially selected from saturated or unsaturated cyclic or acyclic (hetero)alkyl groups comprising 1 to 30, more specifically 1 to 16, and particularly 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms; and / or wherein the C1-C 30 Some of them are bonded to L1, L2 and L3 respectively via carbon atoms, oxygen atoms, nitrogen atoms or sulfur atoms.

[0757] 26. The topical composition according to any of the foregoing embodiments, wherein A3 represents C1-C of group a). 30 Part, more specifically, selected from C1-C of saturated or unsaturated cyclic or acyclic (hetero)alkyl groups. 16 Part of the saturated or unsaturated cyclic or acyclic (hetero)alkyl group comprises 1 to 16, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and particularly 0 to 3 halogen atoms.

[0758] 27. The topical composition according to embodiment 26, wherein A3 represents C1-C selected from the following: 16 Part: carboxylic acid or its salt; carboxylic acid ester; or ketone.

[0759] 28. The topical composition according to embodiment 26, wherein A3 represents C1-C selected from the following: 16 Partial: Carboxylic acid or its salt; (C1-C4-alkyl)carboxylic acid ester; or C1-C4-alkyl carbonyl.

[0760] 29. The topical composition according to any of the foregoing embodiments, wherein L1 and OR 1 Together with the carbon atoms to which they are attached, they form 5- or 6-membered lactones.

[0761] 30. The topical composition according to any of the foregoing embodiments, wherein R 1 Indicates hydrogen, C 1-6 Acyl or C 1-6 Alkyl groups; and especially hydrogen.

[0762] 31. The topical composition according to any one of embodiments 1 to 30, wherein at least one of A1, A2 and A3 represents C1-C of group b1). 60 Partial or polymeric portion.

[0763] 32. The topical composition according to any one of embodiments 1 to 31, wherein at least one of A1, A2 and A3 represents C1-C of group b2). 60 Partial or polymeric portion.

[0764] 33. The topical composition according to any one of embodiments 1 to 32, wherein the compound capable of covalently binding to the skin is a compound of formula (II) or a tautomer thereof and / or a pharmaceutically acceptable salt.

[0765] (II);

[0766] Where R 1 L3, A1, and A3 are as described in any one of embodiments 1 to 32.

[0767] Among them (R) 2 ) n Each of the n moieties is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, amino, or halogen.

[0768] Where n is an integer selected from 1 and 2; and

[0769] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 -;and

[0770] Where R 4 Selected from H or C1-C4-alkyl.

[0771] 34. The topical composition according to any one of embodiments 1 to 33, wherein the compound capable of covalently binding to the skin is a compound of formula (III) or a tautomer thereof and / or a pharmaceutically acceptable salt.

[0772] (III);

[0773] Where R 1 L3, A1, and A3 are as described in any one of embodiments 1 to 32, and

[0774] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 -;and

[0775] Where R 4 Selected from H or C1-C4-alkyl.

[0776] 35. The topical composition according to any one of embodiments 1 to 33, wherein the compound capable of covalently binding to the skin is a compound of formula (IV) or its tautomer and / or a pharmaceutically acceptable salt.

[0777] (IV);

[0778] Where R 1 And A1 as described in any one of embodiments 1 to 32.

[0779] Among them (R) 2 ) n Each of the n moieties is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, amino, or halogen.

[0780] Where n is an integer selected from 1 and 2;

[0781] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 -;

[0782] Where R 3 The term represents a hydrocarbon moiety with hydrogen or optional substitution, said hydrocarbon moiety and its optional substituents comprising 1 to 14 carbon atoms; and

[0783] Where R 4 Selected from H or C1-C4-alkyl.

[0784] 36. The topical composition according to embodiment 35, wherein R3 It indicates a C1-C4 alkyl moiety or a phenyl group.

[0785] 37. The topical composition according to any one of embodiments 1 to 34, wherein the compound capable of covalently binding to the skin is a compound of formula (V) or a tautomer thereof and / or a pharmaceutically acceptable salt.

[0786] (V);

[0787] Where R 1 And A1 as described in any one of embodiments 1 to 32.

[0788] L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O- and -O-(CH2) 1-4 -;

[0789] Where R 3 As described in implementation scheme 35 or implementation scheme 36; and

[0790] Where R 4 Selected from H or C1-C4-alkyl.

[0791] 38. The topical composition according to any one of embodiments 1 to 37, wherein at least one of A1, A2 and A3 is C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a skin moisturizer, and / or the portion is configured to act as a skin moisturizer after cleavage from the 3,4-dihydro-2H-pyran portion.

[0792] 39. The topical composition according to embodiment 38, wherein C1-C 60 The partial or polymeric portion contains multiple hydrogen-bonded groups selected from the group consisting of hydroxyl, ether, carboxylic acid, amine, and amide; and their salts.

[0793] 40. The topical composition according to embodiment 39, wherein the plurality of hydrogen-bonded groups comprises three or more, more specifically four or more, and particularly six or more hydrogen-bonded groups.

[0794] 41. The topical composition according to embodiment 39 or embodiment 40, wherein C1-C 60The ratio of C atoms to the total number of hydrogen-bonded groups contained in the portion is about 4:1 to 1:1, more specifically about 3:1 to about 1:1, and particularly about 2:1 to about 1:1.

[0795] 42. The topical composition according to any one of embodiments 38 to 41, wherein C1-C 60 The portion has a molecular weight of at least 60 g / mol, more specifically at least 90 g / mol, and particularly at least 120 g / mol.

[0796] 43. The topical composition according to any one of embodiments 38 to 42, wherein C1-C 60 The ratio of C atoms to the total number of heteroatoms contained in the portion is about 4:1 to 1:2, more specifically about 3:1 to about 1:1.5, and particularly about 2:1 to about 1:1, wherein the heteroatoms are selected from nitrogen and oxygen.

[0797] 44. The topical composition according to any one of embodiments 38 to 43, wherein C1-C 60 Partially includes:

[0798] Polyols, more specifically, polyols having n hydroxyl groups, where n is 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;

[0799] Mono- or polycarboxylic acids containing one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid;

[0800] Sugars, more specifically trioses, tetraoses, pentoses, hexoses, monosaccharides, disaccharides, trisaccharides, or oligosaccharides;

[0801] Sugar alcohols, more specifically sugar alcohols containing 2 to 24 carbon atoms, particularly ethylene glycol, glycerol, erythritol, threitol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, idotitol, inositol, heptacaphexyl alcohol, isomaltitol, maltitol, lactitol, malttriol, or maltitol; or

[0802] Sugar acids, more specifically aldonic acids, ketonic acids, uronic acids or aldonic diacids; or their salts; or their esters, especially their C1-C4-alkyl esters; or their amides.

[0803] 45. The topical composition according to embodiment 44, wherein C1-C 60 Some have molecular weights ranging from 60 g / mol to 2000 g / mol, more specifically from 90 g / mol to 1600 g / mol, and particularly from 120 g / mol to 1200 g / mol.

[0804] 46. ​​The topical composition according to any one of embodiments 38 to 45, wherein C1-C of group b) 60 Some or polymeric components are configured to act as skin moisturizers.

[0805] 47. The topical composition according to any one of embodiments 38 to 45, wherein C1-C of group b) 60 Some or polymeric portions are configured to act as skin moisturizers after cleavage from the 3,4-dihydro-2H-pyran portion.

[0806] 48. The topical composition according to embodiment 38, wherein C1-C of group b) 60 The partial or polymeric portion includes:

[0807] C 10 -C 60 Part, more specifically C 15 -C 60 The aliphatic portion, and especially C 20 -C 60 aliphatic portion; or

[0808] Oligomeric or polysiloxanes, especially poly(di-C1-C4-alkyl)siloxanes.

[0809] 49. The topical composition according to embodiment 48, wherein C1-C 60 Some have molecular weights ranging from 140 g / mol to 2000 g / mol, more specifically from 160 g / mol to 1600 g / mol, and especially from 180 g / mol to 1200 g / mol.

[0810] 50. The topical composition according to embodiment 48 or embodiment 49, wherein C1-C 60 Some have more than 30 carbon atoms.

[0811] 51. The topical composition according to any one of embodiments 48 to 50, wherein C1-C 60 Some contain saturated or unsaturated C 10 -C 60 The aliphatic portion, more specifically C 15 -C 60 The aliphatic portion, and especially C 20 -C 60 Aliphatic portion.

[0812] 52. The topical composition according to any one of embodiments 48 to 51, wherein C1-C 60The ratio of C atoms to the total number of heteroatoms contained in the portion is from about 60:1 to 5:1, more specifically from about 50:1 to about 10:1, and particularly from about 40:1 to about 20:1, wherein the heteroatoms are selected from nitrogen and oxygen.

[0813] 53. The topical composition according to any one of embodiments 48 to 52, wherein C1-C 60 Part of it is sphingosine or its derivatives, especially ceramides or sphingomyelin.

[0814] 54. The topical composition according to any one of embodiments 48 to 53, wherein C1-C 60 Some are formulated to act as skin moisturizers, more specifically as emollients or occlusives.

[0815] 55. The topical composition according to any one of embodiments 1 to 37, wherein at least one of A1, A2 and A3 is C1-C 60 Part of which is configured to act as an insecticide, and / or part of which is configured to act as an insecticide after partial cleavage from 3,4-dihydro-2H-pyran.

[0816] 56. The topical composition according to embodiment 55, wherein the insecticide is an insect repellent.

[0817] 57. The topical composition according to embodiment 55, wherein the insecticide is an insecticide.

[0818] 58. The topical composition according to embodiment 56 or embodiment 57, wherein the insect repellent or insecticide acts on ectoparasites and / or blood-sucking insects, particularly blood-sucking insects selected from the group consisting of mosquitoes, ticks, mites, midges, fleas, chiggers, leeches and bedbugs.

[0819] 59. The topical composition according to embodiment 56 or embodiment 58, wherein the insecticide is an insect repellent selected from isoprene, tertiary amide and phenylpropionic acid derivatives.

[0820] 60. The topical composition according to embodiment 59, wherein the insect repellent is an isoprene, more specifically a monoterpene, diterpene, or triterpene, and particularly terpineol or a derivative thereof, a monoterpene aldehyde or a derivative thereof, a limonene compound or a derivative thereof; or a pyrethroid or a derivative thereof.

[0821] 61. The topical composition according to embodiment 60, wherein the isoprene is selected from citronellol, hydroxycitronellol, citronellol, citral A, citral B or derivatives thereof; necrodane, especially α-necrodine or derivatives thereof; limonene compounds, especially azadirachtin or derivatives thereof; pyrethroids, especially jasminoids, cinnamyl esters or derivatives thereof.

[0822] 62. The topical composition according to embodiment 60, wherein one of A1, A2, or A3 is selected from a portion of formula (VIa) or formula (VIb).

[0823] (VIa) (VIb).

[0824] 63. The topical composition according to embodiment 60, wherein the compound capable of covalently binding to the skin is a compound of formula (VII) or its tautomer and / or a pharmaceutically acceptable salt.

[0825] (VII),

[0826] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0827] Where R 3 The term represents a hydrocarbon moiety with hydrogen or optional substitution, said hydrocarbon moiety and its optional substituents comprising 1 to 14 carbon atoms; and

[0828] L5 is absent or is a group selected from the following: -C(O)-, -C(O)-O-, -C(O)-O-(CH2). 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -, -S(O)2-, -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -;and

[0829] Where R 4 Selected from H or C1-C4-alkyl.

[0830] 64. The topical composition according to embodiment 63, wherein the compound capable of covalently binding to the skin is a compound of formula (VIII) or its tautomer and / or a pharmaceutically acceptable salt.

[0831] (VIII),

[0832] Where R1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; and

[0833] Where R 3 This indicates a hydrocarbon moiety containing hydrogen or an optional substituent, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0834] 65. The topical composition according to embodiment 63 or embodiment 64, wherein R 3 It represents H or methyl, and R is where 1 H represents H.

[0835] 66. The topical composition according to embodiment 59, wherein the insect repellent is a phenylpropionic acid, particularly eugenol or a derivative thereof.

[0836] 67. The topical composition according to embodiment 59, wherein the insect repellent comprises a tert-amide.

[0837] 68. The topical composition according to embodiment 67, wherein the tertiary amide is selected from picaridin, N,N-di(C1-C6-alkyl)-toluamide, particularly N,N-diethyl-m-methylbenzamide, p-menthane-3,8-diol, ethyl 3-(N-butylacetamido)propionate; and derivatives thereof.

[0838] 69. The topical composition according to embodiment 67, wherein the insect repellent is selected from one of the following compounds and their portions / derivatives: N,N-diethyl-m-methylbenzamide, diethylphenylacetamide, N-butylacetanilide, ethylbutylacetylaminopropionate, picaridin, N-(2-methylpiperidin-1-yl)cyclohex-3-en-1-carboxamide and 1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine or 1-[3-cyclohexen-1-ylcarbonyl]piperidine.

[0839] 70. The topical composition according to embodiment 67, wherein one of A1, A2, or A3 is a part of formula (IX),

[0840] (IX).

[0841] 71. The topical composition according to embodiment 67, wherein one of A1, A2, or A3 is a part of formula (X),

[0842] (X).

[0843] 72. The topical composition according to embodiment 67, wherein the compound capable of covalently binding to the skin is a compound of formula (XI) or its tautomer and / or a pharmaceutically acceptable salt.

[0844] (XI),

[0845] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0846] Where R 3 The term represents a hydrocarbon moiety with hydrogen or optional substitution, said hydrocarbon moiety and its optional substituents comprising 1 to 14 carbon atoms; and

[0847] L6 is absent or is selected from the following groups: -(CH2) 1-4 -, -C(O)-, -C(O)-O-, -C(O)-O-(CH2) 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -, -S(O)2-, -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -;and

[0848] Where R 4 Selected from H or C1-C4-alkyl.

[0849] 73. The topical composition according to embodiment 67, wherein the compound capable of covalently binding to the skin is a compound of formula (XII) or its tautomer and / or a pharmaceutically acceptable salt.

[0850] (XII),

[0851] Where R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; and

[0852] Where R 3 This indicates a hydrocarbon moiety containing hydrogen or an optional substituent, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0853] 74. The topical composition according to embodiment 72 or embodiment 73, wherein R 3 It represents H or methyl, and R is where 1 H represents H.

[0854] 75. The topical composition according to embodiment 57, wherein the insecticide is a topical insecticide, particularly a topical insecticide selected from the following: permethrin; cypermethrin; deltamethrin; ivermectin; amitraz, especially amitraz; imidacloprid; malathion; carbaryl; diazinon; DDT; fenthion; fipronil; imidacloprid; acetamiprid; and propoxur.

[0855] 76. The topical composition according to any one of embodiments 55 to 75, wherein C1-C 60 Some are formulated to act as insecticides, especially insect repellents.

[0856] 77. The topical composition according to any one of embodiments 55 to 75, wherein C1-C 60 Some of it is formulated into insecticides, particularly anthelmintics, after partial cleavage from 3,4-dihydro-2H-pyran.

[0857] 78. The topical composition according to any one of embodiments 1 to 37, wherein at least one of A1, A2 and A3 is C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a skin whitening agent, and / or the portion is configured to act as a skin whitening agent after being partially cleaved from 3,4-dihydro-2H-pyran.

[0858] 79. The topical composition according to embodiment 78, wherein the skin whitening agent works by chemically or metabolically whitening the skin, particularly by providing a bleaching effect or reducing melanin production.

[0859] 80. The topical composition according to embodiment 78 or embodiment 79, wherein the skin whitening agent is selected from corticosteroids, particularly clobetasol derivatives, fluocinolone acetonide derivatives or betamethasone; vitamin A derivatives, particularly retinoic acid, isotretinoin, acitretin, retinol or retinaldehyde; hydroxyphenol derivatives, particularly hydroquinone; aliphatic dicarboxylic acids, particularly azelaic acid; α-hydroxy acids, particularly lactic acid and glycolic acid; and vitamin C.

[0860] 81. The topical composition according to any one of embodiments 78 to 80, wherein C1-C of group b) 60 Some or polymeric components are formulated to act as skin whitening agents.

[0861] 82. The topical composition according to any one of embodiments 78 to 80, wherein C1-C of group b) 60 Some or polymeric portions are formulated as skin whitening agents after being cleaved from the 3,4-dihydro-2H-pyran portion.

[0862] 83. The topical composition according to any one of embodiments 1 to 37, wherein at least one of A1, A2 and A3 is C1-C of group b). 60 This portion is configured to act as an aromatizer after partial cleavage from 3,4-dihydro-2H-pyran.

[0863] 84. The topical composition according to embodiment 83, wherein C1-C 60 Partially includes C1-C 60 A functional group coupled to the corresponding L1, L2 or L3 moiety, or, if the corresponding L1, L2 or L3 moiety is not present, a functional group coupled to the 3,4-dihydro-2H-pyran moiety, and the moiety is configured to cleave into an aldehyde, ketone, thiol, hydroxyl or amine.

[0864] 85. The topical composition according to embodiment 84, wherein the functional group is an imine, acetal, 1,1-diester, enol ether, ester, amide, thioester, or thioacetal.

[0865] 86. The topical composition according to embodiment 84, wherein C1-C 60 Some of them, after cleavage, have a molecular weight of less than 400 g / mol, more specifically less than 300 g / mol, and especially less than 200 g / mol.

[0866] 87. The topical composition according to any one of embodiments 1 to 37, wherein at least one of A1, A2 and A3 is C1-C of group b). 60 A partial or polymeric portion, which is configured to act as a drug, and / or the portion is configured to act as a drug after being cleaved from the 3,4-dihydro-2H-pyran portion.

[0867] 88. The topical composition according to embodiment 87, wherein the drug is suitable for treating skin-related diseases.

[0868] 89. The topical composition according to embodiment 88, wherein the skin-related diseases are selected from acne-like rashes, autoinflammatory syndromes, chronic bullae, mucosal diseases, skin appendage diseases, subcutaneous fat diseases, congenital abnormalities, connective tissue diseases, dermal fiber and elastic tissue abnormalities, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, pigmentary disorders, endocrine-related skin diseases, eosinophilic skin diseases, skin lesions, skin cancer, erythema, hereditary skin diseases, infection-related skin diseases, lichenification, lymphatic-related skin diseases, melanocytic nevi and growths, monocyte and macrophage-related skin diseases, mucin storage diseases, neurodermal diseases, non-infectious immunodeficiency-related skin diseases, nutrition-related skin diseases, papulosquamous keratosis, palmoplantar keratosis, pruritus, psoriasis, reactive neutrophilic skin diseases, skin diseases caused by metabolic errors, skin diseases caused by physical factors, urticaria, dandruff, desquamation disorders, and vascular-related skin diseases.

[0869] 90. The topical composition according to any one of embodiments 87 to 89, wherein C1-C 60 Part of it is an agonist of retinoid receptors, more specifically retinoic acid receptors, retinoid X receptors, and / or RAR-associated orphan receptors.

[0870] 91. The topical composition according to any one of embodiments 87 to 89, wherein C1-C 60 Some contain vitamin A isotopes, more specifically selected from retinol, retinoic acid, isotretinoin, tretinoin, etratiate, tretinoin, adapalene and / or bexarotine isotopes, especially retinol, retinaldehyde and / or adapalene.

[0871] 92. The topical composition according to any one of embodiments 87 to 92, wherein C1-C of group b) 60 Some or polymeric portions are configured to act as drugs.

[0872] 93. The topical composition according to any one of embodiments 87 to 92, wherein C1-C of group b) 60 The partial or polymeric portion is formulated into a drug after being cleaved from the 3,4-dihydro-2H-pyran portion.

[0873] 94. A compound of formula (I) or its tautomers and / or pharmaceutically acceptable salts,

[0874] (I);

[0875] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0876] Where L1, L2, and L3 represent the linking group independently or are absent.

[0877] A1, A2, and A3 represent each other independently.

[0878] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0879] b)C1-C 60 Partial or polymeric components;

[0880] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0881] Among them, group b) C1-C 60 Partial or polymeric components:

[0882] b1) is configured to act as a drug; and / or

[0883] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0884] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0885] Used in medicine.

[0886] 95. A compound of formula (I) or its tautomers and / or a pharmaceutically acceptable salt,

[0887] (I);

[0888] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0889] Where L1, L2, and L3 represent the linking group independently or are absent.

[0890] A1, A2, and A3 represent each other independently.

[0891] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0892] b)C1-C 60 Partial or polymeric components;

[0893] At least one of A1, A2, and A3 is C1-C of group b). 60Partial or polymeric components;

[0894] Among them, group b) C1-C 60 Partial or polymeric components:

[0895] b1) is configured to act as a drug; and / or

[0896] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0897] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0898] Used to treat skin-related diseases, allergic conditions, pain, or inflammation.

[0899] 96. A compound of formula (I) or its tautomers and / or pharmaceutically acceptable salts,

[0900] (I);

[0901] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0902] Where L1, L2, and L3 represent the linking group independently or are absent.

[0903] A1, A2, and A3 represent each other independently.

[0904] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0905] b)C1-C 60 part;

[0906] At least one of A1, A2, and A3 is a C1-C group configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran. 60 Partial; and

[0907] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0908] Used in medicine, where the drug is released over hours or days.

[0909] 97. A compound of formula (I) or its tautomers and / or pharmaceutically acceptable salts,

[0910] (I);

[0911] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0912] Where L1, L2, and L3 represent the linking group independently or are absent.

[0913] A1, A2, and A3 represent each other independently.

[0914] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0915] b)C1-C 60 Partial or polymeric components;

[0916] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0917] Among them, group b) C1-C 60 Partial or polymeric components:

[0918] b1) is configured to act as a drug; and / or

[0919] b2) is configured to act as a drug after partial cleavage from 3,4-dihydro-2H-pyran; and

[0920] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0921] It is used to treat acne-like rashes, autoinflammatory syndromes, chronic bullous lesions, mucosal diseases, skin appendage diseases, subcutaneous fat diseases, congenital abnormalities, connective tissue diseases, dermal fiber and elastic tissue abnormalities, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, pigmentary disorders, endocrine-related skin diseases, eosinophilic skin diseases, skin lesions, skin cancer, erythema, hereditary skin diseases, infection-related skin diseases, lichenification, lymphatic-related skin diseases, melanocytic nevi and growths, monocyte and macrophage-related skin diseases, mucin storage diseases, neurodermal diseases, non-infectious immunodeficiency-related skin diseases, nutrition-related skin diseases, papulosquamous keratosis, palmoplantar keratosis, pruritus, psoriasis, reactive neutrophilic skin diseases, skin diseases caused by metabolic errors, skin diseases caused by physical factors, urticaria, dandruff, desquamation disorders, or vascular-related skin diseases.

[0922] 98. The topical composition according to any one of embodiments 1 to 93 is used as a skin moisturizer, insecticide, and in particular as an insect repellent, skin whitening agent, or fragrance.

[0923] 99. A method of using a topical composition comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin is a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0924] (I);

[0925] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0926] Where L1, L2, and L3 represent the linking group independently or are absent.

[0927] A1, A2, and A3 represent each other independently.

[0928] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0929] b)C1-C 60 Partial or polymeric components;

[0930] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0931] Among them, group b) C1-C 60 Partial or polymeric components:

[0932] b1) is configured to act as a skin moisturizer, insecticide, or skin brightener; and / or

[0933] b2) is configured to act as a skin moisturizer, insecticide, skin brightener, or fragrance after partial cleavage from 3,4-dihydro-2H-pyran; and

[0934] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0935] The method involves applying a topical composition to the skin.

[0936] 100. The method according to embodiment 99, wherein the method comprises leaving the topical composition on the skin for at least 30 minutes.

[0937] 101. The method according to embodiment 100, wherein the method includes chemically peeling the skin prior to applying the topical composition to the skin.

[0938] 102. A method of treating domestic or farm animals, the method comprising applying a topical composition to the skin and / or fur of the domestic or farm animal, wherein the topical composition comprises a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin is a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0939] (I);

[0940] Where R 1 This refers to hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0941] Where L1, L2, and L3 represent the linking group independently or are absent.

[0942] A1, A2, and A3 represent each other independently.

[0943] a)C1-C 30 Partial, H, hydroxyl, amino or halogen, or

[0944] b)C1-C 60 Partial or polymeric components;

[0945] At least one of A1, A2, and A3 is C1-C of group b). 60 Partial or polymeric components;

[0946] Among them, group b) C1-C 60 Partial or polymeric components:

[0947] b1) is configured to act as an insecticide; and / or

[0948] b2) is configured to act as an insecticide after partial cleavage from 3,4-dihydro-2H-pyran; and

[0949] L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

[0950] 103. A compound disclosed according to any one of embodiments 1 to 102.

[0951] 104. A compound of formula (XIII) or its tautomers and / or pharmaceutically acceptable salts,

[0952] (XIII),

[0953] in:

[0954] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0955] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0956] L7 is selected from -C(O)- and -C(O)-(CH2). 1-4 -、-C(O)-O-、-C(O)-O-(CH2) 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -or-S(O)2-O-, -S(O)2-O-(CH2) 1-4 - groups; and

[0957] R 4 Selected from H or C1-C4-alkyl.

[0958] 105. The compound according to embodiment 104, wherein R 3 Represents H or methyl, and R 1 H represents H.

[0959] 106. The compound according to embodiment 104 or embodiment 105, wherein L7 is selected from -C(O)-, -C(O)-O-(CH2). 1-4 -or -C(O)-NHC(O)-C(O)-O-(CH2) 1-4 -

[0960] 107. A compound of formula (XIV) or its tautomers and / or pharmaceutically acceptable salts,

[0961] (XIV),

[0962] in:

[0963] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin; and

[0964] R 3 This indicates a hydrocarbon moiety containing hydrogen or an optional substituent, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms.

[0965] 108. The compound according to embodiment 107, wherein R 3 Represents H or methyl, and R 1 H represents H.

[0966] 109. A compound of formula (XV) or its tautomers and / or pharmaceutically acceptable salts,

[0967] (XV),

[0968] in:

[0969] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0970] R 3 This indicates a hydrocarbon moiety with hydrogen or optional substitution, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms;

[0971] R 5 It represents H, OH, C1-C4-alkyl, NH2, N(C1-C4-alkyl)2, N-morpholino-1-yl or piperidin-1-yl;

[0972] L8 is selected from -C(O)- and -C(O)-(CH2). 1-4 -、-C(O)-O-、-C(O)-O-(CH2) 1-4 -、-C(O)-NR 4 C(O)-、-C(O)-NR 4 C(O)-(CH2) 1-4 -or-S(O)2-O-, -S(O)2-O-(CH2) 1-4 - groups; and

[0973] R 4 Selected from H or C1-C4-alkyl.

[0974] 110. The compound according to embodiment 109, wherein R 3 Represents H or methyl, and R 1 H represents H.

[0975] 111. The compound according to embodiment 109 or embodiment 110, wherein L8 is selected from -C(O)-, -C(O)-O-(CH2). 1-4 -or -C(O)-NHC(O)-C(O)-O-(CH2) 1-4 -

[0976] 112. The compound according to any one of embodiments 109 to 111, wherein R5 It represents H or piperidin-1-yl.

[0977] 113. A compound of formula (XVI) or its tautomers and / or pharmaceutically acceptable salts,

[0978] (XVI),

[0979] in:

[0980] R 1 This indicates hydrogen or a protective group that can be hydrolyzed under physiological conditions after the topical composition is applied to the skin;

[0981] R 3 This indicates a hydrogen or optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, comprises 1 to 14 carbon atoms; and

[0982] R 5 It represents H, OH, C1-C4-alkyl, NH2, N(C1-C4-alkyl)2, N-morpholino-1-yl or piperidin-1-yl.

[0983] 114. The compound according to embodiment 113, wherein R 3 Represents H or methyl, and R 1 H represents H.

[0984] 115. The compound according to embodiment 113 or embodiment 114, wherein R 5 It represents H or piperidin-1-yl.

[0985] 116. The composition or compound according to any of the foregoing embodiments, wherein R 3 Indicates C1-C 14 Part of the C1-C 14 The portion contains 1 to 14, more specifically 1 to 12, and particularly 1 to 8 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms.

[0986] 117. The composition or compound according to any of the foregoing embodiments, wherein R 3 Indicate C 1-14 Alkyl, C 2-14 imidene group, C 2-14 Ethyne group, C 6-14 aryl, C containing 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or 1 to 2 sulfur atoms4-14 Heteroaryl, wherein any of the aforementioned groups may optionally be further substituted, provided that the substitution does not exceed the aforementioned for R 3 The sum of the elements.

[0987] 118. The composition or compound according to any of the foregoing embodiments, wherein R 3 The term represents an optionally substituted phenyl group, particularly an optionally substituted phenyl group, especially an optionally substituted phenyl group comprising: 6 to 14, more specifically 6 to 12, and particularly 6 to 10 carbon atoms; 0 to 12, more specifically 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms.

[0988] 119. The composition or compound according to any one of embodiments 116 to 118, wherein R 3 Replaced by a portion of one or more of the following selected items: -C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2、-C(O)C 1-4 Alkyl, -CO2C 1-4 Alkyl, -O2C-C 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2、-NH-C(O)C 1-4 Alkyl, -N(C) 1-4 alkyl)-C(O)C 1-4 Alkyl groups, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogens, especially Cl, Br or F; and -CF3.

Claims

1. A topical composition comprising a compound capable of covalently binding to the skin and an excipient suitable for topical application, wherein the compound capable of covalently binding to the skin is a compound of formula (I) or a tautomer thereof and / or a pharmaceutically acceptable salt. (I)； wherein R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; Where L1, L2, and L3 represent the linking group independently or are absent. A1, A2, and A3 represent each other independently. a) C1-C 30 C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4 b) C1-C 60 moieties; wherein at least one of A1, A2and A3is a C1-C 60 or a polymeric moiety; wherein said C1-C 60 moieties or polymer moieties: b1) is configured to act as a skin moisturizer, insecticide, skin brightener, or medicine; and / or b2) is configured to act as a skin moisturizer, insecticide, skin brightener, fragrance, or medicine after partial cleavage from 3,4-dihydro-2H-pyran; and L1-A1 and L2-A2 do not indicate that the carbon atoms labeled "a" and "b" contain unsaturated CC or CN bonds at the α position, respectively.

2. The topical composition according to claim 1, wherein the C1-C 60 moieties or polymeric moieties comprise a functional group that couples the C1-C 60 moieties to the corresponding L1, L2 or L3 moiety, or if the corresponding L1, L2 or L3 moiety is not present, to the 3,4-dihydro-2H-pyran moiety.

3. The topical composition according to claim 2, wherein the functional groups are capable of cleavage under physiological conditions after the topical composition is applied to the skin.

4. The topical composition according to claim 2 or claim 3, wherein the functional group is hydrolyzable at the physiological pH of mammalian skin, more specifically human skin, and particularly at a pH of about 5 to about 6; and / or wherein the functional group is enzymatically cleavable under physiological conditions after the topical composition is applied to the skin, particularly by enzymes present in the human skin.

5. The topical composition according to any one of claims 2 to 4, wherein the functional group comprises carbon esters, particularly monoesters, 1,1-diesters, carbonates or carbamates; ethers or thioethers, particularly acetals, hemiacetals, glycosidic groups or thioacetals; carbamates, particularly peptides or N-Mannich bases; enols; enamines; imines; oximes; sulfates; sulfonates; sulfonamides; phosphates; phosphonates; phosphatases; or phosphonamides.

6. The topical composition according to any one of claims 1 to 5, wherein A1represents the C1-C 60 moiety, and wherein A2and A3independently of one another represent a C1-C 30 moiety, H, hydroxyl, amino or halogen.

7. The topical composition according to any one of claims 1 to 6, wherein L1and L2are present and form an optionally substituted 5- or 6-membered ring, in particular a cyclopentyl or cyclohexyl group, A1and A2are optionally attached to the ring via a group selected from -0-, -S-, -C(O)-, -CO2-, -0-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH2) 1-4 - -(CH2) 1-4 -O- and -0-(CH2) 1-4 - or combinations thereof.

8. The topical composition according to any one of claims 1 to 7, wherein the compound capable of covalently binding to the skin is a compound of formula (II) or a tautomer thereof and / or a pharmaceutically acceptable salt. (I); and (II). wherein R 1 , L3, A1and A3are according to any one of claims 1 to 7; wherein (R 2 ) n independently of one another n moieties selected from H, C1-C4alkyl, C1-C4alkoxy, hydroxy, amino or halogen; Where n is an integer selected from 1 and 2; and wherein L4is absent or a group selected from -0-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NR 4 -C(O)-, -C(O)-NR 4 -C(O)-, -C(O)-NR 4 -CH2-, 1-4 -CH2-, 1-4 -O-, -O-(CH2) 1-4 or combinations thereof; and wherein R 4 is selected from H or C1-C4-alkyl.

9. The topical composition according to any one of claims 1 to 8, wherein the compound capable of covalently binding to the skin is a compound of formula (III) or a tautomer thereof and / or a pharmaceutically acceptable salt. (III); wherein R 1 L3, A1and A3are according to any one of claims 1 to 7; and L4 is absent or is a group selected from the following: -O-, -S-, -C(O)-, -CO2-, -OC(O)-, -NR 4 -、-NR 4 -C(O)-、-C(O)-NR 4 -、-(CH2) 1-4 -、-(CH2) 1-4 -O-, -O-(CH2) 1-4 -or combinations thereof; and wherein R 4 is selected from H or C1-C4-alkyl.

10. The topical composition according to any one of claims 1 to 9, wherein the compound capable of covalently binding to the skin is a compound of formula (IV) or a tautomer thereof and / or a pharmaceutically acceptable salt. (IV); wherein R 1 and A1is according to any one of claims 1 to 7; wherein (R 2 ) n independently of one another, n moieties selected from H, C1-C4alkyl, C1-C4alkoxy, hydroxy, amino or halogen; Where n is an integer selected from 1 and 2; wherein L4is absent or a group selected from -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NR 4 -C(O)-, -C(O)-NR 4 -C(O)-, -C(O)-NR 4 -CH2- and -O-(CH2) 1-4 -CH2- and -O-(CH2) 1-4 -CH2- and -O-(CH2) 1-4 -; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, contains 1 to 14 carbon atoms; and wherein R 4 is selected from H or C1-C4-alkyl.

11. The topical composition according to any one of claims 1 to 10, wherein the compound capable of covalently binding to the skin is a compound of formula (V) or a tautomer thereof and / or a pharmaceutically acceptable salt. (V)； wherein R 1 and A1is according to any one of claims 1 to 7; wherein L4is absent or a group selected from -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NR 4 -C(O)-, -C(O)-NR 4 -C(O)-, -C(O)-NR 4 -CH2-, 1-4 -CH2-, 1-4 -O- and -O-(CH2) 1-4 -; wherein R 3 According to claim 10; and wherein R 4 is selected from H or C1-C4-alkyl.

12. The topical composition according to any one of the preceding claims, wherein the C1-C 60 moieties are C1-C 60 moieties configured to act as a skin moisturizer, and comprise: Polyols, more specifically, polyols having n hydroxyl groups, where n is 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; Monobasic or polybasic carboxylic acids comprising one or more hydroxyl groups, more particularly glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; sugars, more particularly trioses, tetroses, pentoses, hexoses, monosaccharides, disaccharides, trisaccharides or oligosaccharides; sugar alcohols, more particularly sugar alcohols comprising 2 to 24 carbon atoms, in particular ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomaltitol, maltitol, lactitol, maltotriitol or maltotetraitol; or sugar acids, more particularly aldonic acids, ketonic acids, uronic acids or aldatic diacids; or their salts; or their esters, in particular their C1-C4-alkyl esters; or their amides.

13. A compound of formula (VII) or a tautomer and / or a pharmaceutically acceptable salt thereof, (VII), wherein R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, contains 1 to 14 carbon atoms; and wherein L5 is absent or a group selected from -C(O)-, -C(O)-O-, -C(O)-O-(CH2) 1-4 -; -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH2) 1-4 -; -S(O)2-, -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -; and wherein R 4 is selected from H or C1-C4-alkyl; or A compound of formula (XI) or a tautomer and / or a pharmaceutically acceptable salt thereof, (XI), wherein R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, contains 1 to 14 carbon atoms; and wherein L6 is absent or a group selected from -(CH2) 1-4 -, -C(O)-, -C(O)-O-, -C(O)-O-(CH2) 1-4 -, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH2) 1-4 -, -S(O)2-, -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -; and wherein R 4 is selected from H or C1-C4-alkyl; or A compound of formula (XIII) or a tautomer and / or a pharmaceutically acceptable salt thereof, (XIII), wherein: R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; R 3 represents hydrogen or an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, contains 1 to 14 carbon atoms; and L7is a radical selected from the group consisting of -C(O)-, -C(O)-(CH2) 1-4 -, -C(O)-O-, -C(O)-O-(CH2) 1-4 -, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH2) 1-4 - or -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -; and R 4 selected from H or C1-C4-alkyl; or A compound of formula (XV) or a tautomer and / or a pharmaceutically acceptable salt thereof, (XV), wherein: R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; R 3 represents hydrogen or an optionally substituted hydrocarbon moiety, which, in combination with its optional substituents, contains 1 to 14 carbon atoms; R 5 represents H, OH, C1-C4-alkyl, NH2, N(C1-C4-alkyl)2, N-morpholino-1-yl or piperidin-1-yl; L8is a radical selected from the group consisting of -C(O)-, -C(O)-(CH2) 1-4 -, -C(O)-O-, -C(O)-O-(CH2) 1-4 -, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH2) 1-4 - or -S(O)2-O-, -S(O)2-O-(CH2) 1-4 -; and R 4 is selected from H or C1-C4-alkyl.

14. A method of using a topical composition comprising a compound capable of covalent binding to skin and an excipient suitable for topical application, wherein the compound capable of covalent binding to skin is a compound of formula (I) or a tautomer and / or a pharmaceutically acceptable salt thereof, (I)； wherein R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; wherein L1, L2and L3independently of one another represent a linking group or are absent, wherein A1, A2and A3independently of one another represent a) C1-C 30 C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, halo, C1-C3haloalkyl, C b) C1-C 60 moieties; wherein at least one of A1, A2and A3is a C1-C 60 moieties; wherein said C1-C 60 moieties or polymeric moieties: b1) is configured to act as a skin moisturizer, insecticide or skin whitening agent; and / or b2) is configured to act as a skin moisturizer, insecticide, skin whitening agent or fragrance after cleavage from the 3,4-dihydro-2H-pyran moiety; and wherein L1-A1and L2-A2do not represent a moiety comprising an unsaturated C-C or C-N bond in the alpha position of the carbon atoms labeled "a" and "b", respectively; the method comprising applying the topical composition to the skin.

15. A compound of formula (I) or a tautomer and / or a pharmaceutically acceptable salt thereof, (I)； wherein R 1 represents hydrogen or a protecting group capable of being hydrolyzed under physiological conditions after application of the topical composition to the skin; wherein L1, L2and L3independently of one another represent a linking group or are absent, wherein A1, A2and A3independently of one another represent a) C1-C 30 C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, halo, C1-C3haloalkyl, C b) C1-C 60 moieties; wherein at least one of A1, A2and A3is a C1-C 60 moieties; wherein said C1-C 60 moieties or polymeric moieties: b1) is configured to act as a drug; and / or b2) is configured to act as a drug after cleavage from the 3,4-dihydro-2H-pyran moiety; and wherein L1-A1and L2-A2do not represent a moiety comprising an unsaturated C-C or C-N bond in the alpha position of the carbon atoms labeled "a" and "b", respectively; for use in medicine.

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