WO2024250111A1 - Dérivés de génipine hydrogénés pouvant être fixés à des tissus kératiniques - Google Patents

Dérivés de génipine hydrogénés pouvant être fixés à des tissus kératiniques Download PDF

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WO2024250111A1
WO2024250111A1 PCT/CA2024/050763 CA2024050763W WO2024250111A1 WO 2024250111 A1 WO2024250111 A1 WO 2024250111A1 CA 2024050763 W CA2024050763 W CA 2024050763W WO 2024250111 A1 WO2024250111 A1 WO 2024250111A1
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moiety
skin
group
compound
alkyl
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Christopher Caputo
Sanjay MANHAS
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BIC Inc
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BIC Inc
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Priority to IL324869A priority Critical patent/IL324869A/en
Priority to EP24818187.7A priority patent/EP4724432A1/fr
Priority to CN202480037001.5A priority patent/CN121646583A/zh
Priority to AU2024285582A priority patent/AU2024285582A1/en
Priority to KR1020257043002A priority patent/KR20260020125A/ko
Publication of WO2024250111A1 publication Critical patent/WO2024250111A1/fr
Priority to MX2025014469A priority patent/MX2025014469A/es
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/006—Antidandruff preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/10—Preparations for permanently dyeing the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/94—Involves covalent bonding to the substrate

Definitions

  • This disclosure relates to compounds which can be reliably and efficiently grafted onto keratinous tissues such as skin. More specifically, the present disclosure relates to conjugated molecules comprising an active component and specifically selected anchoring moieties which cannot form extensive conjugated 7t-systems once attached to the keratinous tissue. Therefore, the coupled anchoring moiety does not impart color and allows the compounds of the present disclosure to remain visually unobtrusive after being coupled onto the tissue. The disclosure also relates to topical compositions comprising these compounds and various methods and applications for these compounds.
  • Genipin is the naturally occurring compound methyl (lR,4aS,7aS)-l-hydroxy-7- (hydroxymethyl)-l,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (CAS RN. 6902- 77-8) and has the following structure: Genipin can be irreversibly coupled to keratinous tissues. For instance, keratin in skin comprises lysines having aliphatic amino side chains. These amino side chains react with the cyclic hemiacetal structure of genipin according to the below representative reaction scheme:
  • the finally resulting coupled genipin derivative is colored intensely blue. Due to the dark blue color, genipin is commercially used a tattooing dye in semi-permanent tattoos.
  • This skin-coupling property makes genipin an interesting candidate to couple various active components such as moisturizers, pesticides, in particular insect repellants, skin whitening agents, fragrance precursors and pharmaceuticals to skin.
  • active components such as moisturizers, pesticides, in particular insect repellants, skin whitening agents, fragrance precursors and pharmaceuticals
  • the dark blue color is aesthetically not pleasing to many, in particular if it is applied to facial or larger areas of skin. Therefore, while genipin carries a number of functional groups which can be readily utilized to attach active components, it was heretofore not seriously contemplated as a means for attaching an active component to skin.
  • the colorless (or nearly colorless and, thus, not visually perceivable on the skin) state of skin-coupled hydrogenated genipin derivative can be explained by the fact that the 1,4- dihydropyridine moiety formed with lysine is not endowed with a conjugated 7t-electron system with the double bond that is present in the cyclopentene-moiety of genipin (and absent in hydrogenated genipin).
  • 3,4-dihydro- 2H-pyran derivatives will unobtrusively bind to e.g. skin as long as the 3,4-dihydro-2H- pyran derivatives are selected such that formation of a conjugated 7t-electron system to the skin-bound 1,4-dihydropyridine moiety is avoided.
  • 3,4-Dihydro-2H-pyran derivatives meeting this requirement are, thus, particularly useful as a visually non-perceivable anchoring moieties to efficiently, irreversibly and unobtrusively couple active ingredients to keratinous tissues such as skin.
  • the active ingredient may be stably bound to the 3,4-dihydro-2H-pyran derivative or it may be bound to the 3,4-dihydro-2H-pyran derivative such that it is released over time, e.g. by hydrolysis or enzymatic cleavage of a functional group linking the active ingredient to the 3,4-dihydro-2H-pyran derivative.
  • Suitable functional groups providing sustained release properties are well-known in the art and readily available to the skilled person, see for instance V. Redasani, and S. Bariwidely, Prodrug Design - Perspectives, Approaches and Applications in Medicinal Chemistry, 1 st ed., 2015, ISBN: 9780128035191, which is incorporated herein in its entirety by reference thereto.
  • the present disclosure relates to a topical composition
  • a topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin is a compound of formula (I),
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin.
  • Li, L2 and L3 independently from each other represent a linker group or are absent.
  • Ai, A2 and A3 independently from each other represent a moiety of: group a): a C1-C30 moiety, H, hydroxyl, amino, or a halogen; or group b): a Ci-Ceo moiety or a polymeric moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b) is carrying the active ingredient/component. Accordingly, at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b).
  • Ci-Ceo moiety or polymeric moiety of group b) is subdivided into two sub-groups bl) and b2).
  • the Ci-Ceo moiety or polymeric moiety of group bl) is configured to act as a skin moisturizer, a pesticide, a skin whitening agent, or a pharmaceutical.
  • Ci-Ceo moiety or polymeric moiety of group bl is a skin moisturizing moiety, a moiety providing pesticidal activity, a skin-whitening moiety or a pharmaceutically active moiety while being attached to the remainder of the 3,4-dihydro-2H-pyran moiety.
  • Ci-Ceo moiety or polymeric moiety of group bl is a skin moisturizer, a pesticide, a skin-whitening agent or a pharmaceutical.
  • the Ci-Ceo moiety or polymeric moiety of group bl is a skin moisturizer, a pesticide, a skin whitening agent, or a pharmaceutical which is attached to the remainder of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b2) is configured to act as a skin moisturizer, a pesticide, a skin whitening agent, a fragrance or a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b2) is a skin moisturizer, a pesticide, a skin whitening agent, a fragrance or a pharmaceutical after being cleaved off or released from the remainder of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b2) is a skin moisturizer, a pesticide, a skin whitening agent, a fragrance or a pharmaceutical which can be cleaved off or released from the remainder of the 3,4-dihydro-2H-pyran moiety after the compound has covalently bound to the skin.
  • a polyol humectant may provide its activity while being attached to the 3,4-dihydro-2H-pyran moiety but also when it is released from the 3,4-dihydro-2H- pyran moiety.
  • the 3,4-dihydro-2H-pyran derivatives of the present disclosure are selected such that formation of a conjugated 7t-electron system to the skin-bound 1,4- dihydropyridine moiety is essentially avoided. Accordingly, the compounds of the present disclosure are restricted such that L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively.
  • the compound of the above formula may also be present as its tautomer and/or as a pharmaceutically acceptable salt.
  • the present disclosure relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pharmaceutical; and/or b2) configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; for use in medicine.
  • the present disclosure relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pharmaceutical; and/or b2) configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; for use in treating a skin-associated disease, an allergic condition, pain, or inflammation.
  • the present disclosure relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; for use in medicine, in particular a skin-associated disease, an allergic condition, pain, or inflammation, wherein the pharmaceutical is released over a plurality of hours or days.
  • the present disclosure relates to a use of a topical composition according to the first aspect as a skin moisturizer, pesticide, in particular an insect repellant, a skin whitening agent or a fragrance.
  • the present disclosure relates to a method of using a topical composition
  • a topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin may be a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a skin moisturizer, a pesticide or a skin whitening agent; and/or b2) configured to act as a skin moisturizer, a pesticide, a skin whitening agent or a fragrance after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; the method comprising applying the topical composition to skin.
  • the present 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 domestic or farm animals, wherein the topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin may be a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pesticide; and/or b2) configured to act as a pesticide after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively.
  • the present disclosure specifically relates to the compounds of the present disclosure per se, i.e. independent from the topical composition.
  • Fig. 1 shows a reaction scheme for the synthesis of a compound of the present disclosure comprising erythritol as active component.
  • Fig. 2 shows a reaction scheme for the synthesis of a compound of the present disclosure comprising p-methane-3,8-diol as active component.
  • Fig. 3 shows a reaction scheme for the synthesis of a compound of the present disclosure comprising minoxidil as active component.
  • Fig. 4 shows a reaction scheme for the synthesis of a compound of the present disclosure comprising desloratadine as active component.
  • Figs 5 to 9 and 11 show UV spectra of compounds comprising a 3,4-dihydro-2H-pyran moiety (some of which being compounds according to the present disclosure) and the UV spectra of their corresponding lysine conjugates.
  • Fig.s 10 and 12 show the attachment of compounds of the present disclosure to pig skin.
  • the present disclosure relates to a compound capable of covalently binding to skin, in particular to said compound being comprised in a topical composition further comprising an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin is a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • a compound capable of covalently binding to skin is applied its common meaning in the art and in particular refers to a compound which can undergo a chemical reaction which covalently binds it to amino sidechains of amino acids such as lysine. Additionally or alternatively, a compound is “capable of covalently binding to skin” if the compound (or a topical composition containing the compound) cannot be comprehensively washed off from (explanted) porcine skin by water, soap, and/or isopropanol after incubating the compound (or the topical composition comprising the compound) on the porcine skin at 37°C for 24 hours.
  • a compound is “capable of covalently binding to skin” if, when placing 0.1 mol/L of the compound in an aqueous solution having a pH of about 5 and further containing 0.1 mol/L lysine at 37°C for 24 hours, the compound is converted by more than 10 mol% to its corresponding 1,4-dihydropyridine derivative.
  • skin appendages are epidermal and dermal-derived components of the skin and include hair, nails, sweat glands, and sebaceous glands.
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin.
  • physiological conditions it should be understood that this in particular refers to the pH conditions encountered at the locus where the compound of formula (I) is supposed to bind to in the subject to be treated (skin or skin appendages).
  • the term “protective groups hydrolysable under physiological conditions after application of the topical composition” refers to a group which is hydrolysed when placing 0.1 mol/L of the compound of formula (I) in an aqueous solution having a pH of about 5 for 24 hours, wherein the group in question qualifies as “protective group hydrolysable under physiological conditions after application of the topical composition” if more than 10 mol% is converted to its corresponding hemiacetal.
  • Ai, A2 and A3 independently from each other represent a moiety of: group a): a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or group b): a Ci-Ceo moiety or a polymeric moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b) is carrying the active ingredient/component. Accordingly, at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety of group b).
  • the Ci-Ceo moiety or polymeric moiety of group b) is subdivided into two sub-groups bl) and b2).
  • the Ci-Ceo moiety or polymeric moiety of group bl) is configured to act as a skin moisturizer, a pesticide, a skin whitening agent, or a pharmaceutical.
  • the active ingredient/component is capable of providing its activity while being attached to the remainder of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b2) is configured to act as a skin moisturizer, a pesticide, a skin whitening agent, a fragrance or a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the active ingredient/component is capable of providing its activity after being released from the remainder of the 3,4-dihydro-2H-pyran moiety.
  • the two subgroups bl) and b2) are not necessarily mutually exclusive.
  • a polyol humectant may provide its moisturizing activity while being attached to the 3,4-dihydro-2H-pyran moiety but also when it is released from the 3,4-dihydro-2H- pyran moiety.
  • Ci-Ceo moiety or polymeric moiety of group b2) being cleaved off of (or released from) the 3,4-dihydro-2H-pyran moiety
  • this refers to the 3,4-dihydro-2H-pyran moiety which includes (or at least partially includes) Li, L2 and/or L3 (if present) as well as any remaining Ai to A3 moieties.
  • this refers to a cleavage (or release) under physiological conditions encountered by the compound after application of the topical composition onto skin (or skin appendages).
  • physiological conditions it should be understood that this in particular refers to the ambient conditions, in particular pH, enzymatic, and temperature conditions, encountered at the locus where the compound of formula (I) is supposed to bind to keratinous tissues in e.g. the stratum corneum and/or the epidermis of the (mammalian, in particular human) subject to be treated. Additionally or alternatively, the ability of a Ci-Ceo moiety or polymeric moiety of group b2) to be cleaved off of the 3,4-dihydro-2H-pyran moiety may be assessed on an ex-vivo porcine skin model at 37°C.
  • the 3,4-dihydro-2H-pyran derivatives of the present disclosure are selected such that the formation of a conjugated 7t-electron system to the skin-bound 1,4- dihydropyridine moiety is essentially avoided. Accordingly, the compounds of the present disclosure are restricted such that L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively.
  • Ai, A2 and A3 may independently from each other represent a C1-C30 moiety, i.e. be a moiety according to group a).
  • the term is not particularly limited beyond its common understanding in the art and refers to any moiety comprising between 1 and 30 carbon atoms.
  • the presence of further heteroatoms, i.e. atoms not being C, is not excluded, i.e. atoms such a H, O, and N may be contained in the moiety.
  • Ci-Ceo moiety may independently from each other represent a Ci-Ceo moiety or polymeric moiety of group bl) and/or b2).
  • Ci-Ceo moiety is not particularly limited beyond its common understanding in the art and refers to any moiety comprising between 1 and 60 carbon atoms.
  • polymeric moiety is not particularly limited beyond its common understanding in the art and refers to any oligomeric (herein defined as more than 3 and up to 8 repeat units) or polymeric moiety (herein defined as having more than 8 repeat units).
  • the polymeric moiety, i.e. polymer will typically comprise carbon and/or silicon, but the presence of further heteroatoms, i.e. atoms not being C or Si, is not excluded, i.e. atoms such a H, O, N and others may be contained in the polymeric moiety.
  • Ai, A2 and A3 may independently from each other represent a Ci-Ceo moiety or a polymeric moiety of group bl) which is configured to act as a skin moisturizer, a pesticide, a skin whitening agent, or a pharmaceutical.
  • Said functional language is meant to imply that the Ci-Ceo moiety or the polymeric moiety (or more specifically the compound in its entirety after being covalently bound to keratinous material such as skin) is capable of providing the referenced effect (a skin moisturizing effect, a pesticidal effect, a skin whitening effect, or a pharmacological effect).
  • Ai, A2 and A3 may independently from each other also represent a Ci-Ceo moiety or a polymeric moiety of group b2) which is configured to act as a skin moisturizer, a pesticide, a skin whitening agent, a fragrance or a pharmaceutical after being cleaved off of the 3,4- dihydro-2H-pyran moiety.
  • the compound released from the Ci-Ceo moiety or from the polymeric moiety is capable of providing the referenced effect (a skin moisturizing effect, a pesticidal effect, a skin whitening effect, an olfactory effect, or a pharmacological effect).
  • Ai, A2 and A3 may independently from each other represent a polymeric moiety of group bl) or b2) which is configured to act as a skin moisturizer.
  • Said functional language is meant to imply that the polymeric moiety (or more specifically the compound in its entirety after being covalently bound to keratinous material such as skin) is capable of providing the skin moisturizing effect.
  • skin moisturizer refers to a compound/moiety which is capable of directly binding water (via hydrogen bonding) in the skin or of reducing evaporation of water from the skin. Accordingly, the term encompasses moisturizes, emollients and occlusives as these terms are used and understood in the art.
  • a pesticide refers to its common meaning in the art and in particular refers compounds capable of killing, incapacitating, repelling or in any other way ameliorating a risk to mammalian (human) health, comfort or well-being posed by invertebrates, in particular insects.
  • a skin whitening agent refers to the common meaning in the art and in particular refers to a compound which is chemically and/or metabolically able to lighten the color tone of skin.
  • a skin whitening agent does not refer to pigments or dyes or optical brighteners.
  • fragment refers to the common meaning in the art and in particular refers to a volatile compound which is capable of providing an olfactory impression, in particular an olfactory impression comprising one or more of the seven fundamental odors (floral, fruity, minty, nutty, pungent, sweet, and woody).
  • pharmaceutical refers to the common meaning in the art and in particular refers to a compound capable/intended for use in the diagnosis, cure, mitigation, treatment, therapy, or prevention of disease in mammals, in particular humans and domestic and farm animals.
  • Li, L2 and L3 independently from each other represent a linker group or are absent.
  • linker group is not particularly limited and refers to any chemical group which covalently connects the 3,4-dihydro-2H-pyran moiety to the corresponding moiety Ai, A2 and A3 moiety, respectively.
  • Li and L2 connect to the 3,4-dihydro-2H-pyran moiety by a single bond, i.e. ring positions marked with “a” and “b” represent methines (“CHR3”).
  • Li, L2 and L3 may, if present and independently from each other, represent optionally substituted hydrocarbon moieties each comprising, in combination with their optional substituents, 1 to 14 carbon atoms. In some embodiments, Li and L2 may, if present and independently from each other, represent optionally substituted hydrocarbon moieties each comprising, in combination with their optional substituents, 1 to 14 carbon atoms. In some embodiments, Li, L2 and L3 may also form optionally substituted cyclic structures.
  • Li and L2 are present and form a 5-, 6-, 7- or 8-membered ring, in particular a cyclopentyl, a cyclohexyl, a pyrrolidinyl, a piperidinyl, a tetrahydrofuranyl or a tetrahydropyranyl.
  • Li and L2 form an optionally substituted 5- or 6-membered ring and comprise, together with their substituents, 2 to 14 carbon atoms, more specifically 3 to 12, and in particular 4 to 8 carbon atoms.
  • substituents 2 to 14 carbon atoms, more specifically 3 to 12, and in particular 4 to 8 carbon atoms.
  • two of the ring carbons stem from the 3,4- dihydro-2H-pyran moiety and are therefore not counted toward the total carbon number of Li and L2.
  • the number of carbon atoms is 2.
  • Li and L2 form a cyclopentyl which is monosubstituted with a -CH2- OH group, the number of carbon atoms is 4.
  • Li and L2 are present and form an optionally substituted 5-or 6-membered ring, in particular cyclopentyl or cyclohexyl, to which Ai and A2 are attached, optionally via a group selected from: -O-, - S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O- and -O- (CH 2 )I- 4 -, or combinations thereof.
  • Li and L2 are present and form a cyclopentyl, a cyclopentenyl, a cyclohexyl, or a cyclohexenyl ring to which Ai and A2 are attached, optionally via a group selected from: - O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O- and - O-(CH2)I- 4 - or combinations thereof.
  • the compound capable for covalently binding to skin is a compound of formula (II), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 , L3, Ai and A3 are as defined for the compound of formula (I); wherein (R 2 ) n represents, independently from each other, n moieties selected from H, Ci- C4 alkyl, C1-C4 alkoxyl, hydroxyl, amino, or halogen; wherein n is an integer selected from 1 and 2; and wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O-, -O-(CH 2 )I- 4 - or combinations thereof; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • the compound capable for covalently binding to skin is a compound of formula (III), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 , L3, Ai and A3 are as defined for the compound of formula (I); and wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O-, -O-(CH 2 )I- 4 - or combinations thereof; and wherein R 4 is selected from H or Ci-C 4 -alkyl.
  • the compound capable for covalently binding to skin is a compound of formula (IV), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 and Ai are as for the compound of formula (I); wherein (R 2 ) n represents, independently from each other, n moieties selected from H, Ci- C 4 alkyl, Ci-C 4 alkoxyl, hydroxyl, amino, or halogen; wherein n is an integer selected from 1 and 2; wherein L 4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO 2 -, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I.
  • R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms; and wherein R 4 is selected from H or Ci-C 4 -alkyl.
  • the compound capable for covalently binding to skin is a compound of formula (V), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 and Ai are as defined for the compound of formula (I); wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O-, -O-(CH 2 )I- 4 - or combinations thereof; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • the first example concerns a compound intended to provide a moisturizing effect.
  • Skin moisturizers are well-established in cosmetics and include a large variety of compounds capable of binding water in the stratum corneum. Examples include polyols such as glycerol, pentaerythritol and sorbitol but also other hydrogen-bonding compounds such as urea.
  • a compound according to the present disclosure carrying a pentaerythritol as the Ci- Ceo moiety of group b) is shown below:
  • Genipin derivatives are well-known to bind to the stratum corneum. Due to the large number of hydroxyl groups, the above compound according to the present disclosure can be expected to provide a long-lasting moisturizing effect to the skin. The moisturizing effect will be given even if the pentaerythritol moiety is still attached to the skin via the 3,4-dihydro-2H-pyran moiety. As such, the moiety is an example of group bl).
  • the ester group linking the pentaerythritol moiety to the remainder of the compound is cleavable by esterases which are abundantly found on the skin. Therefore, it is also an example of a moiety which at the same time belongs to group b2). If it is desirable that the pentaerythritol moiety belongs to only group bl) another functional group may be selected. For instance, replacing the ester linkage by an ether linkage may be contemplated.
  • Fig. 1 An outline of the chemical synthesis of the above compound is shown in Fig. 1.
  • the synthesis of compounds (1) and (2) is disclosed in the co-pending international application WO 2023/102652 Al. (2) can be converted to the corresponding acylchloride by thionyl chloride which then can be coupled with pentaerythritol to yield ester (3). Ester (3) can be hydrolysed in an acidic aqueous solution with mild heating to yield the target compound (4).
  • the humectant glycerol and the emollient decanol can be linked to hydrogenated genipin derivatives and that the resulting conjugates can be conjugated to skin.
  • the following compounds were synthesized and conjugated to skin.
  • the second example concerns a compound intended to provide a pesticidal effect, more specifically an insect repellant effect.
  • para-Menthane-3,8-diol is an insect repellent which can be used directly on skin or clothing. It has broad efficacy against various arthropods such as mosquitos, ticks, gnats, flies and fleas, and is colorless.
  • the chemical structure of PMD is reproduced below:
  • PMD insect repelling potency rivals that of N,N-diethyl-m-methylbenzamide (DEET). However, like DEET, it provides only a briefly lasting effect of up to 6-8 hours. This is mostly due to the relatively high volatility of PMD.
  • DEET N,N-diethyl-m-methylbenzamide
  • Fig. 2 An outline of the chemical synthesis of the above compound is shown in Fig. 2.
  • the synthesis of compounds (1) and (2) is disclosed in the co-pending international application WO 2023/102652 Al. (2) can be converted to the corresponding acylchloride by e.g. thionyl chloride which then can be coupled with PMD to yield ester (3). Ester (3) can be hydrolysed in an acidic aqueous solution with mild heating to yield the target compound (4).
  • the ester group linking PMD to the remainder of the compound can be expected to be cleaved by esterases of the skin and PMD is released over time to the stratum corneum to provide its insect repellent effect.
  • insect repellant picaridin can be linked to a hydrogenated genipin derivative and that the resulting conjugate can be conjugated to skin.
  • the following compound was synthesized and conjugated to skin.
  • the third example concerns a compound intended to provide a pharmaceutical effect, more specifically the treatment/prevention of alopecia.
  • Minoxidil and its derivatives are topically applied to treat alopecia.
  • Minoxidil is typically applied twice per day to the scalp in an alcoholic solution (ethanol and propylene glycol).
  • alcoholic solution ethanol and propylene glycol
  • the compound is generally well tolerated, but common side effects include dandruff and contact dermatitis which are caused by the frequent exposure to ethanol and propylene glycol which dry the scalp.
  • a topical delivery system which requires less frequent application of minoxidil would be desirable.
  • Minoxidil has the following chemical structure:
  • Fig. 3 An outline of the chemical synthesis of the above compound is shown in Fig. 3.
  • the synthesis of compound (3) is disclosed in the co-pending international application WO 2023/102652 Al.
  • Minoxidil (1) is activated by CDI to compound (2) which is then reacted with (3) to yield the carbamate (4).
  • (4) is hydrolysed in an acidic aqueous solution with mild heating to yield the target compound (5) which couples minoxidil to the remainder of the compound via a monosubstituted carbamate group.
  • 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).
  • esterases see review by Gosh et al., J. Med. Chem., 2015, 58, 7, 2895-2940.
  • the above compound is a promising candidate to provide sustained release of minoxidil to the skin.
  • the fourth example also concerns a compound intended to provide a pharmaceutical effect, more specifically the treatment of an allergic condition.
  • Desloratadine the metabolically active form of loratadine, is a very potent antihistamine that is administered orally once per day at a dosage of 5 mg.
  • Topical formulations of desloratadine are currently investigated.
  • Mohamed et al., Pharmaceuticals 2023, 16(4), 578 describe desloratadine as having good permeation through the skin when applied as a transdermal gel formulation. They found that the gel formulation had higher bioavailability, and eliminated slowly compared to the tablet formulation. The bioavailability of the gel formulation was 2.4-3.2 fold of the tablet formulation.
  • Desloratadine has the following chemical structure:
  • Fig. 4 An outline of the chemical synthesis of the above compound is shown in Fig. 4.
  • the synthesis of compound (2) is disclosed in the co-pending international application WO 2023/102652 Al.
  • Desloratadine (1) is coupled with CDI to compound (2) to yield the carbamate (3).
  • Compound (3) is hydrolysed in an acidic aqueous solution with mild heating to yield the target compound (4) which couples desloratadine to the remainder of the compound via a N,N-disubstituted carbamate group.
  • This synthetical pathway allows easy access to the following compound of the present disclosure:
  • N,N-disubstituted carbamate groups as utilized in the above compound are frequently used in prodrugs (e.g. in bambuterol) and can be cleaved by esterases with a relatively long sustained release (see review by Gosh et al., J. Med. Chem., 2015, 58, 7, 2895-2940).
  • the above compound is a promising candidate to provide a long-term release of desloratadine to the skin.
  • a long-lasting depot effect can be expected, possibly allowing less frequent administration, in particular such as a once weekly administration. In practice, this may be done by applying a transdermal patch overnight which transfers and anchors the desloratadine-containing compound to the skin. From there it is released by the skin’s enzymatic activity over the period of e.g. one week.
  • the compounds of the present disclosure provide broad utility and versatility in topically applying active ingredients to keratinous tissue.
  • the Ci-Ceo moiety or polymeric moiety of group b) may comprise a functional group which couples the Ci-Ceo moiety or the polymeric moiety to the corresponding Li, L2 or L3 moiety or, if the corresponding Li, L2 or L3 moiety is absent, to the 3,4-dihydro-2H-pyran moiety.
  • the functional group may comprise 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 in particular a carbon atom and/or an oxygen atom.
  • the functional group may comprise one or more of, two or more of, three or more of, four or more of, or all of between 1 and 12 carbon atoms, more specifically between 1 and 6 carbon atoms, and in particular between 1 and 3 carbon atoms; between 1 and 12 oxygen atoms, more specifically between 1 and 6 oxygen atoms, and in particular between 1 and 3 oxygen atoms; between 1 and 4 nitrogen atoms, more specifically between 1 and 3 nitrogen atoms, and in particular between 1 and 2 nitrogen atoms; between 1 and 3 sulfur atoms, more specifically between 1 and 2 sulfur atoms, and in particular 1 sulfur atom; between 1 and 3 phosphorus atoms, more specifically between 1 and 2 phosphorus atoms, and in particular 1 phosphorus atom.
  • the functional group may be cleavable under physiological conditions after application of the topical composition onto skin.
  • physiological conditions it should be understood that this in particular refers to the pH conditions encountered at the locus where the compound of formula (I) is supposed to bind to keratinous tissues in e.g. the stratum corneum and/or the epidermis of the (mammalian, in particular human) subject to be treated.
  • the functional group may be hydrolysable at the physiological pH of mammal skin, more specifically of human skin, and in particular at a pH of between about 5 to about 6.
  • a suitable in-vitro test is placing 0.1 mol/L of the compound of formula (I) in aqueous solution having a pH of about 5 at 37°C for 24 hours, wherein the group in question qualifies as hydrolysable if a notable amount of the group is hydrolysed (e.g. more than 5 mol%, or more than 10 mol%).
  • the functional group may be enzymatically cleavable under physiological conditions after application of the topical composition onto skin, in particular enzymatically cleavable by enzymes present in the human skin.
  • physiological conditions it should be understood that this in particular refers to the conditions encountered at the locus where the compound of formula (I) is supposed to bind to keratinous tissues in e.g. the stratum corneum and/or the epidermis of the (mammalian, in particular human) subject to be treated.
  • a suitable in-vitro test is placing 0.1 mol/L of the compound of formula (I) in aqueous solution having a pH of about 5 at 37°C for 24 hours and further containing 50 U of esterase activity, wherein the group in question qualifies as enzymatically cleavable if a notable amount of the group is cleaved (e.g. more than 5 mol-%, or more than 10 mol-%).
  • the functional group may be configured to be cleaved to a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefin or an oxime; or salts thereof.
  • the functional group may be configured to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefin, or an oxime; or salts thereof; on the corresponding Li, L2 or L3 moiety which is attached to the Ci-Ceo moiety or polymeric moiety of group b) or, if the corresponding Li, L2 or L3 moiety is absent, on the 3,4-dihydro-2H-pyran moiety after cleaving.
  • the functional group may be configured to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefin, or an oxime; or salts thereof; on the Ci-Ceo moiety or polymeric moiety of group b) after cleaving.
  • the functional group may comprise a carbon ester, in particular a monoester, 1,1 -diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; an carbon amide, in particular a peptide or a N-Mannich base; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amid; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; or a phosphonic acid amide.
  • a carbon ester in particular a monoester, 1,1 -diester, a carbonate, or a carbamate
  • an ether or thioether in particular an acetal, a hemi-acetal, a glycosidic
  • the functional group may be a functional group mentioned in chapter 6 of the textbook Prodrug Design Perspectives, Approaches and Applications in Medicinal Chemistry, 1 st ed., 2015, ISBN: 9780128035191, which is incorporated herein (for the aforementioned purpose and in its entirety) by reference thereto.
  • Ai may represent the Ci-Ceo moiety or polymeric moiety of group b). Additionally or alternatively, A2 may represent a Ci-Ceo moiety or polymeric moiety of group b). Additionally or alternatively, A3 may represent a Ci-Ceo moiety or polymeric moiety of group b). Additionally or alternatively, the remainder of Ai, A2 and A3 may represent a substituent of group a), more specifically a C1-C30 moiety, H, hydroxyl, amino, or a halogen.
  • Li are present and represent an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms.
  • L2 may be present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms.
  • L3 may be present and represent an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms.
  • Li may be present and represent an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms and the functional group may be attached to Li.
  • L2 may be present and represent an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms and the functional group may be attached to L2.
  • L3 may be present and represent an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms and the functional group may be attached to L3.
  • the respective linker group may comprise 1 to 8, more specifically 1 to 6, and in particular 1 to 4 oxygen atoms; 1 to 8, more specifically 1 to 6, and in particular 1 to 4 nitrogen atoms; 1 to 6, more specifically 1 to 4, and in particular 1 to 3 sulfur atoms; 1 to 6, more specifically 1 to 4, and in particular 1 to 3 phosphor atoms, and 1 to 10, more specifically 1 to 8, and in particular 1 to 6 halogen atoms.
  • said respective linker group does not contain any further atom species besides carbon, the (optional) aforementioned atom species and hydrogen.
  • Li and L2 may be present and form an optionally substituted 5-or 6-membered ring, in particular cyclopentyl or cyclohexyl, to which Ai and A2 may be attached, optionally via a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH- C(O)-, -C(O)-NH-, -(CH2)i-4-, -(CH2)I-4-O- and -O-(CH2)i-4-, or combinations thereof.
  • the aforementioned specific groups may be part of a larger functional group, hence the reference to “combinations thereof’.
  • a carbamate may be considered as both -O- and -C(O)-NH- or a combination thereof.
  • Li and L2 may be present and form a cyclopentyl, a cyclopentenyl, a cyclohexyl, or a cyclohexenyl ring to which Ai and A2 may be attached, optionally via a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NH-C(O)-, -C(O)-NH-, -(CH 2 )I- 4-, -(CH2)I-4-O- and -O-(CH2)I-4-, or combinations thereof.
  • a carbamate may be considered as both -O- and -C(O)-NH- or a combination thereof.
  • Ai may be a Ci-Ceo moiety or polymeric moiety of group b).
  • A3 may be a Ci-Ceo moiety or polymeric moiety of group b).
  • A2 may represent the substituent of group a), more specifically a C1-C30 moiety, H, hydroxyl, amino, or a halogen, in particular hydrogen.
  • Ai may be a Ci-Ceo moiety or polymeric moiety of group b).
  • A2 and A3 may represent substituents of group a), more specifically independently from each other a C1-C30 moiety, H, hydroxyl, amino, or a halogen, and in particular hydrogen.
  • Ai may be a Ci-Ceo moiety or polymeric moiety of group b) and A2 and A3 may represent substituents of group a), more specifically independently from each other a C1-C30 moiety, H, hydroxyl, amino, or a halogen, and in particular hydrogen.
  • the C1-C30 moiety of group a) may comprise 1 to 30, more specifically 1 to 16, and in particular 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 phosphor atoms, and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the C1-C30 moiety may be selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 30, more specifically 1 to 16, and in particular 1 to 12, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms; and/or the C1-C30 moiety may be bound to Li, L2 and L3, respectively, via a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom.
  • a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 30, more specifically 1 to 16, and in particular 1 to 12, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular
  • A3 may represent a C1-C30 moiety of group a), more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and in particular 0 to 3 halogen atoms.
  • group a more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 6,
  • A3 may represent a C1-C16 moiety selected from a carboxylic acid or a salt thereof; a carboxylic ester; or a ketone.
  • A3 may represent a C1-C16 moiety selected from a carboxylic acid or a salt thereof; a (Ci-C4-alkyl)carboxylic ester; or a Ci-C4-alkylcarbonyl.
  • Li and OR 1 together with the carbon atoms to which they are attached, may form a 5- or 6-membered lactone.
  • Ri may represent hydrogen, C1-6 acyl, or C1-6 alkyl. In some embodiments, it may be particularly advantageous that Ri represents H. In some embodiments, it may be particularly advantageous that Ri does not represent a glucoside.
  • At least one of Ai, A2 and A3 may represent a Ci-Ceo moiety of group bl). In some embodiments, at least one of Ai and A2 may represent a Ci-Ceo moiety of group bl).
  • At least one of Ai, A2 and A3 may represent a Ci-Ceo moiety or a polymeric moiety of group b2). In some embodiments, at least one of Ai and A2 may represent a Ci-Ceo moiety or polymeric moiety of group b2).
  • the compound capable of covalently binding to skin is a compound of formula (II), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 , L3, Ai and A3 are as defined as in any preceding embodiment
  • (R 2 ) n represents, independently from each other, n moieties selected from H, C1-C4 alkyl, C1-C4 alkoxyl, hydroxyl, amino, or halogen; n is an integer selected from 1 and 2; and
  • L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NR 4 -, - NR 4 -C(O)-, -C(O)-NR 4 -, -(CH2)I-4-, -(CH2)I-4-O-, -O-(CH2)I-4-, or combinations thereof;
  • R 4 is selected from H or Ci-C4-alkyl.
  • At least one of Ai and A3 may represent a Ci-Ceo moiety or a polymeric moiety of group b). In some embodiments of formula (II), at least Ai may represent a Ci-Ceo moiety or a polymeric moiety of group b).
  • A3 may represent a C1-C30 moiety of group a), more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and in particular 0 to 3 halogen atoms.
  • the compound capable of covalently binding to skin is a compound of formula (III), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 , L3, Ai and A3 are as defined in any preceding embodiment.
  • L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, -NR 4 -, - NR 4 -C(O)-, -C(O)-NR 4 -, -(CH2)I-4-, -(CH2)I-4-O-, -O-(CH )I-4-, or combinations thereof; and
  • R 4 is selected from H or Ci-C4-alkyl.
  • At least one of Ai and A3 may represent a Ci-Ceo moiety or a polymeric moiety of group b). In some embodiments of formula (III), at least Ai may represent a Ci-Ceo moiety or a polymeric moiety of group b).
  • A3 may represent a C1-C30 moiety of group a), more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and in particular 0 to 3 halogen atoms.
  • group a more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 6,
  • L3 represents -C(O)-, -C(O)-O-, -C(O)-NH-, or - C(O)-N(Ci-C 4 -alkyl)-.
  • A3 represents an R 3 group with R 3 representing a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and/or 1 to 2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of: -C1-4 alkyl, -O-C1-4 alkyl, -S-C1-4 alkyl, - NH-C1-4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO2C1-4 alkyl, -O2C-C1-4 alkyl, -C(O)NH- C1-4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, -N(CI- 4 alkyl)-C(O)Ci- 4 alkyl, -SO3H, -NO2, -NH2, -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of: -C1-4 alkyl,
  • the compound capable of covalently binding to skin is a compound of formula (IV), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 and Ai are as defined in any preceding embodiment
  • (R 2 ) n represents, independently from each other, n moieties selected from H, C1-C4 alkyl, C1-C4 alkoxyl, hydroxyl, amino, or halogen; n is an integer selected from 1 and 2;
  • R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms;
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and/or 1 to 2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • the compound capable of covalently binding to skin is a compound of formula (V), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 and Ai are as defined in any preceding embodiment
  • R 4 is selected from H or Ci-C4-alkyl.
  • Ai may represent a Ci-Ceo moiety or a polymeric moiety of group b). In some embodiments of formula (V), Ai may represent a Ci-Ceo moiety of group b). In some embodiments of formula (V), R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of: -C1-4 alkyl, -O-C1-4 alkyl, -S-C1-4 alkyl, -NH-C1-4 alkyl, -N(CI-4 alkyl)2, - C(O)Ci- 4 alkyl, -CO2C1-4 alkyl, -O2C-C1-4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, -N(CI- 4 alkyl)-C(O)Ci- 4 alkyl, -SO3H, -NO 2 , -NH 2 , -OH, -SH, - COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of: -C1-4 alkyl,
  • the active components linked to the remainder of the compounds according to the invention will be discussed.
  • reference to the active ingredient will be made as if the active ingredient is an individual compound instead of a moiety attached to the remainder of the compound. It should be understood that this is to be interpretated as a reference to a moiety that is attached to the remainder of the compound, by e.g. elimination of a hydrogen atom from the active ingredient.
  • the below mentioned disclosure regarding the active components is freely combinable with the above disclosure relating to the compounds according to formulae (I) to (V). Indeed, these combinations represent preferred embodiments of the present disclosure, although it should be understood that the present disclosure is not limited thereto.
  • At least one of Ai, A2 and A3 may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a skin moisturizer, and/or which is configured to act as a skin moisturizer, after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the plurality of hydrogen bonding groups may comprise three or more, more specifically 4 or more, and in particular 6 or more hydrogen bonding groups.
  • the ratio of C-atoms to the sum of hydrogen bonding groups comprised in the Ci-Ceo moiety may be between about 4: 1 to 1 : 1, more specifically between about 3 : 1 to about 1 : 1 and in particular between about 2: 1 to about 1 : 1.
  • the Ci-Ceo moiety may have a molecular weight of at least 60 g/mol, more specifically at least 90 g/mol, and in particular at least 120 g/mol.
  • the polymeric moiety may have a molecular weight ranging from 200 to 50000 g/mol.
  • the ratio of C-atoms to the sum of heteroatoms comprised in the Ci- Ceo moiety may be between about 4: 1 to 1 :2, more specifically between about 3 : 1 to about 1 : 1.5, and in particular between about 2: 1 to about 1 : 1, wherein the heteroatoms are selected from nitrogen and oxygen.
  • the Ci-Ceo moiety or polymeric moiety may comprise: a polyol, more specifically a polyol having n hydroxyl groups with n being 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 8 or more, 10 or more, 12 or more, or 16 or more; a mono- or polyvalent carboxylic acid comprising one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; a sugar, more specifically a triose, a tetrose, a pentose a hexose, a monosaccharide, a disaccharide, a tri saccharide, an oligosaccharide, or a polysaccharide, in particular glucose, mannose, galactose, glucosamine, N-acetyl-D-glucosamine, myo-Inositol, rhamnose, lyxose,
  • the Ci-Ceo moiety may comprise a urea derivative; panthenol; or a diuride, in particular allantoin.
  • the Ci-Ceo moiety or polymeric moiety may comprise an amino acid or amino acid derivative, more specifically serine, glycine, alanine, histidine, ornithine, arginine, or pyroglutamic acid.
  • the amino acid may be present in its L-enantiomer.
  • the Ci-Ceo moiety or the polymeric moiety may comprise a plurality of amino acids or amino acid derivatives.
  • the Ci-Ceo moiety may have a molecular weight of 60 g/mol to 2000 g/mol, more specifically 90 g/mol to 1600 g/mol, and in particular 120 g/mol to 1200 g/mol.
  • the Ci-Ceo moiety or polymeric moiety of group b) may comprise an aliphatic Cio-Ceo moiety, more specifically a Cis-Ceo aliphatic moiety and in particular C20-C60 aliphatic moiety; or an oligo- or polysiloxane, in particular a poly(di-Ci-C4- alkyl)siloxane.
  • the polymeric moiety is an oligo- or polysiloxane, in particular a poly(di-Ci-C4-alkyl)siloxane.
  • the poly(di-Ci-C4-alkyl)siloxane may have between 20 and 200 repeat units.
  • the poly(di-Ci-C4- alkyl)siloxane is a polydimethysiloxane (dimethicone).
  • the polymeric moiety is a polyether, in particular a polyether comprising ethylene oxide repeat units, propylene oxide repeat unity or mixtures thereof.
  • examples include polyethylene glycol (PEG) and polypropylene glycol (PPG).
  • the polymeric moiety is a polyamine or polymers comprising a polyamine such as PEG- 15 tallow amine.
  • the polymeric moiety is a polyquaternium, in particular polyquaternium-16, polyquaternium-46, polyquaternium-11, polyquaternium-28, polyquaternium-6, polyquaternium-7, polyquaternium-22, polyquaternium-39, polyquaternium-2, polyquaternium- 17, or polyquaternium- 18.
  • the Ci-Ceo moiety may have a molecular weight of 140 g/mol to 2000 g/mol, more specifically 160 g/mol to 1600 g/mol, and in particular 180 g/mol to 1200 g/mol.
  • the Ci-Ceo moiety may have more than 30 carbon atoms. In some embodiments, the Ci-Ceo moiety may comprise a saturated or unsaturated Cio-Ceo aliphatic moiety, more specifically a Cis-Ceo aliphatic moiety and in particular a C20-C60 aliphatic moiety.
  • the ratio of C-atoms to the sum of heteroatoms comprised in the Ci- Ceo moiety may be between about 60: 1 to 5: 1, more specifically between about 50: 1 to about 10: 1 and in particular between about 40: 1 to about 20: 1, wherein the heteroatoms are selected from nitrogen and oxygen.
  • the Ci-Ceo may be a fatty acid, fatty alcohol or derivatives thereof, more specifically saturated or unsaturated fatty acids, fatty alcohols or derivatives thereof and in particular caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, linoleic acid, decyl alcohol, dodecyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol or a fatty acid mono-, di- or triglyceride, in particular caprylic glyceride, capric glyceride or glyceryl stearate.
  • the Ci-Ceo moiety or polymeric moiety of group b) may be configured to act as a skin moisturizer.
  • the Ci-Ceo moiety or polymeric moiety of group b) may be configured to act as a skin moisturizer after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b) is configured to act as a skin moisturizer, and/or is configured to act as a skin moisturizer, after being cleaved off of 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 formulae (II), (Ill), (IV) or (V) as defined above. It may also be particularly advantageous that R 1 represents H.
  • At least one of Ai, A2 and A3 may be a Ci-Ceo moiety which is configured to act as a pesticide, and/or which is configured to act as a pesticide after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the insect repellant or insecticide may act against an ectoparasite and/or a hematophagous insect, in particular a hematophagous insect selected from the group consisting of mosquitoes, ticks, mites, gnats, fleas, chiggers, leeches and bugs.
  • Ectoparasites are organisms that live on the skin of a host, from which they derive their sustenance.
  • the pesticide may be an insect repellant which may be selected from isoprenoids, tertiary amides, and phenylpropanoids.
  • the insect repellant may be an isoprenoid, more specifically a monoterpenoid, a diterpenoid or a triterpenoid, and in particular a terpineol or derivative thereof, a monoterpenoid aldehyde or a derivative thereof, a limonoid or a derivative thereof; or a pyrethrin or a derivative thereof.
  • the isoprenoid may be selected from citronellal, hydroxy citronellal, citronellol, citral A, citral B, or a derivative thereof; a necrodane, in particular a-necrodol, or a derivative thereof; a limonoid, in particular azadirachtine, or a derivative thereof; or a pyrethrin, in particular a jasmolin, a cinerin, or a derivative thereof.
  • the insect repellant may comprise a tertiary amide.
  • the tertiary amide may be selected from picaridine, an N,N-di(Ci-Ce-alkyl)- toluamide, in particular N,N-diethyl-meta-toluamide, ethyl 3-(N- butylacetamido)propanoate; and derivatives thereof.
  • the insect repellant may be a phenylpropanoid, in particular eugenol or a derivative thereof.
  • At least one of Ai, A2 or A3 may be selected from a moiety of formula (Via) or formula (VIb), (VIb).
  • the compound capable of covalently binding to skin may be a compound of formula (VII), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • L5 may be either absent or a group selected from -C(O)-, -C(O)-O-, -C(O)-O-(CH2)I-4-, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I- 4 -, -S(O) 2 -, -S(O) 2 -O-, -S(O) 2 -O-(CH 2 )I. 4 - or combinations thereof; and
  • R 4 may be selected from H or Ci-C4-alkyl.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of: -C1-4 alkyl, -O-C1-4 alkyl, -S-C1-4 alkyl, -NH-C1-4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO2C1- 4 alkyl, -O2C-C1-4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, - N(CI- 4 alkyl)-C(O)Ci- 4 alkyl, -SO3H, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of: -C
  • R 1 represents H.
  • L5 is present and selected from -C(O)-, -C(O)-O-, -C(O)-NHC(O)- or -C(O)-NHC(O)-O-.
  • the compound capable of covalently binding to skin may be a compound of formula (VIII), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of: -C1-4 alkyl, -O-C1-4 alkyl, -S-C1-4 alkyl, -NH-C1-4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO2C1- 4 alkyl, -O2C-C1-4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, - N(CI-4 alkyl)-C(O)Ci-4 alkyl, -SO3H, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of: -C1-4 al
  • R 3 may represent H or methyl and R 1 may represent H.
  • the compound of the present disclosure is derived from picaridine, in particular:
  • one of Ai, A2 or A3 may be the moiety of formula (IX),
  • one of Ai, A 2 or A3 may be the moiety of formula (X),
  • the compound capable of covalently binding to skin may be a compound of formula (XI), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms;
  • Le may be either absent or a group selected from -(CH2)I-4-, -C(O)-, -C(O)-O-, -C(O)-O- (CH 2 )I- 4 -, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I- 4 -, -S(O) 2 -, -S(O) 2 -O-, -S(O) 2 -O- (CH 2 )I-4-, or combinations thereof; and
  • R 4 may be selected from H or Ci-C4-alkyl.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of -Ci-4 alkyl, -O-Ci-4 alkyl, -S-C1-4 alkyl, -NH-CI-4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO2C1- 4 alkyl, -O2C-C1-4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, - N(CI-4 alkyl)-C(O)Ci-4 alkyl, -SO3H, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of -Ci-4
  • the compound capable of covalently binding to skin may be a compound of formula (XII), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • the pesticide may be an insecticide, in particular an insecticide selected or derived from permethrine; cypermethrin; deltamethrin; ivermectin; amidines, in particular amitraz; bendiocarb; malathion; carbaryl; diazinon; dichlorodiphenyltrichloroethane (DDT); fenthion; fipronil; imidacloprid; nitenpyram; and propoxur.
  • the Ci-Ceo moiety may be configured to act as a pesticide, in particular an insect repellant.
  • the Ci-Ceo moiety may be configured as a pesticide, in particular an insect repellant, after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • At least one of Ai, A2 and A3 may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a skin whitening agent, and/or which is configured to act as a skin whitening agent after being cleaved off of the 3,4-dihydro-2H- pyran moiety.
  • the skin whitening agent may act by chemically or metabolically whitening the skin, in particular by providing a bleaching effect or decreasing melanin production.
  • the skin whitening agent may be selected from corticosteroids, in particular clobetasol derivatives, fluocinolone derivative, or betamethasone; a vitamin A derivative, in particular tretinoin, isotretinoin, alitretinoin, retinol or retinal; a hydroxyphenol derivative, in particular hydroquinone; an aliphatic dicarboxylic acid, in particularvestic acid; alpha-hydroxy-acids, in particular lactic and glycolic acid; and vitamin C and its derivatives.
  • corticosteroids in particular clobetasol derivatives, fluocinolone derivative, or betamethasone
  • a vitamin A derivative in particular tretinoin, isotretinoin, alitretinoin, retinol or retinal
  • a hydroxyphenol derivative in particular hydroquinone
  • an aliphatic dicarboxylic acid in particularvestic acid
  • alpha-hydroxy-acids in particular lactic and glycolic acid
  • the Ci-Ceo moiety or polymeric moiety of group b) may be configured to act as a skin whitening agent.
  • the Ci-Ceo moiety or polymeric moiety of group b) may be configured as a skin whitening agent, after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety or polymeric moiety of group b) is configured to act as a skin whitening agent, and/or is configured to act as a skin whitening agent after being cleaved off of the 3,4-dihydro-2H-pyran moiety
  • the compound of formula (I) is a compound of any one of formulae (II), (III), (IV) or (V) as defined above. It may also be particularly advantageous that R 1 represents H.
  • At least one of Ai, A2 and A3 may be a Ci-Ceo moiety of group b) which is configured to act as a fragrance after being cleaved off of the 3,4-dihydro-2H- pyran moiety.
  • the Ci-Ceo moiety may comprise a functional group which couples the Ci-Ceo moiety to the corresponding Li, L2 or L3 moiety or, if the corresponding Li, L2 or L3 moiety is absent, to the 3,4-dihydro-2H-pyran moiety.
  • said functional group is configured to be cleaved to an aldehyde, a ketone, a thiol, a hydroxyl or an amine.
  • the functional group may be an imine, an acetal, a 1,1-diester, an enol ether, an ester, an amide, a thioester, or a thioacetal.
  • the Ci-Ceo moiety may have a molecular mass after being cleaved off of less than 400 g/mol, more specifically less than 300 g/mol, and in particular less than 200 g/mol.
  • the pharmaceutical may be suitable for treating a skin-associated disease.
  • the skin-associated disease may be selected from acneiform eruptions, autoinflammatory syndromes, chronic blistering, conditions of the mucus membranes, conditions of the skin appendages, conditions of the subcutaneous fat, congenital anomalies, connective tissue diseases, abnormalities of dermal fibrous and elastic tissue, dermal and subcutaneous growths, dermatitis, eczema, seborrheic dermatitis, disturbances of pigmentation, endocrine-related skin conditions, eosinophilic cutaneous conditions, skin lesions, skin cancer, erythemas, genodermatoses, infection-related cutaneous conditions, lichenoid eruptions, lymphoid-related cutaneous condition, melanocytic nevi and neoplasms, monocyte- and macrophage-related cutaneous conditions, mucinoses, neurocutaneous conditions, noninfectious immunodeficiency- related cutaneous conditions, nutrition-related cutaneous conditions, papul
  • the pharmaceutical (moiety) may not be a compound (moiety) for the prevention of sunburn, skin cancer and/or other skin diseases associated with UV- A/UV-B exposure.
  • At least one of Ai and A2 may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a pharmaceutical, and/or which is configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the compound capable of covalently binding to skin may be a compound of formula (XIII), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms; and L 7 is a group selected from -C(O)-, -C(O)-(CH 2 )I- 4 -, -C(O)-O-, -C(O)-O-(CH 2 )I- 4 -, -C(O)- NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I. 4 -, or -S(O) 2 -O-, -S(O) 2 -O-(CH 2 )I- 4 -; and
  • R 3 represents a Ci-Ci 4 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents Ci-i 4 alkyl, C 2 -i 4 alkenylene, C 2 -i 4 alkynylene, Ce-i 4 aryl, C 4 -i 4 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of: -Ci- 4 alkyl, -O-Ci- 4 alkyl, -S-Ci- 4 alkyl, -NH-CI- 4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO 2 Ci- 4 alkyl, -O 2 C-Ci- 4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, - N(CI- 4 alkyl)-C(O)Ci- 4 alkyl, -SO 3 H, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the
  • R 3 may represent H or methyl and R 1 may represent H.
  • L7 is selected from -C(O)-, -C(O)-O-(CH 2 )I. 4 -, or -C(O)-NHC(O)-C(O)-O-(CH 2 )I- 4 -.
  • the compound capable of covalently binding to skin may be a compound of formula (XIV), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • the compound capable of covalently binding to skin may be a compound of formula (XV), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 5 represents H, OH, Ci-C4-alkyl, NH2, N(Ci-C4-alkyl)2, N-morpholino-l-yl, or piperidin- i-yi;
  • L 8 is a group selected from -C(O)-, -C(O)-(CH 2 )I- 4 -, -C(O)-O-, -C(O)-O-(CH 2 )I- 4 -, -C(O)- NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I- 4 -, or -S(O) 2 -O-, -S(O) 2 -O-(CH 2 )I-4-; and
  • R 4 is selected from H or Ci-C4-alkyl.
  • R 3 may represent H or methyl and R 1 may represent H.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of: -C1-4 alkyl, -O-C1-4 alkyl, -S-C1-4 alkyl, -NH-C1-4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO2C1- 4 alkyl, -O2C-C1-4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, - N(CI-4 alkyl)-C(O)Ci-4 alkyl, -SO3H, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of: -C1-4 al
  • Ls is selected from -C(O)-, -C(O)-O-(CH 2 )I- 4 -, or -C(O)-NHC(O)-C(O)-O-(CH 2 )I- 4 -.
  • R 5 may represent H (i.e. kopexil) or piperidin-l-yl (i.e. minoxidil).
  • the compound capable of covalently binding to skin may be a compound of formula (XVI), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms;
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded. It may also be advantageous that R 3 represents an optionally substituted phenyl.
  • R 3 represents optionally substituted phenyl, in particular wherein the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • the optionally substituted phenyl comprises 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen
  • R 3 is substituted with one or more moieties selected from the group consisting of -C1-4 alkyl, -O-C1-4 alkyl, -S-C1-4 alkyl, -NH-C1-4 alkyl, -N(CI- 4 alkyl) 2 , -C(O)Ci- 4 alkyl, -CO2C1- 4 alkyl, -O2C-C1-4 alkyl, -C(O)NH-CI- 4 alkyl, -C(O)N(CI- 4 alkyl) 2 , -NH-C(O)CI- 4 alkyl, - N(CI- 4 alkyl)-C(O)Ci- 4 alkyl, -SO3H, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(O)H, halogen, in particular Cl, Br or F; and -CF3.
  • moieties selected from the group consisting of -C1-4 al
  • R 3 may represent H or methyl and R 1 may represent H.
  • R 5 may represent H (i.e. kopexil) or piperidin-l-yl (i.e. minoxidil).
  • the pharmaceutical may be suitable for treating pain or inflammation.
  • the pharmaceutical may be an analgesic or a corticosteroid.
  • the analgesic is acetaminophen (INN paracetamol).
  • the analgesic is acetaminophen which is coupled via its hydroxyl group to the remainder of the compound.
  • the pharmaceutical may be suitable to induce a hot or cold skin sensation.
  • the pharmaceutical agent may be menthol, camphor; or a derivative thereof.
  • the pharmaceutical agent may be an alkaloid, more specifically a capsaicinoid, in particular capsaicin, or a derivative thereof.
  • the pharmaceutical agent may be selected from nicotinamide and its derivatives or undecylenic acid and its derivatives.
  • the Ci-Ceo moiety may be an agonist of a retinoid receptor, more specifically a retinoic acid receptor, a retinoid X receptor and/or a RAR-related orphan receptor.
  • the Ci-Ceo moiety may comprise a vitamin A vitamer, more specifically a vitamer selected from the group of retinol, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene and/or bexarotene, in particular retinol, retinal and/or adapalene.
  • a vitamin A vitamer more specifically a vitamer selected from the group of retinol, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene and/or bexarotene, in particular retinol, retinal and/or adapalene.
  • the Ci-Ceo moiety or polymeric moiety of group b) may be configured to act as a skin pharmaceutical.
  • the Ci-Ceo moiety or polymeric moiety of group b) may be configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • the Ci-Ceo moiety of group b) may not comprise or be derived from salicylic acid and its derivatives.
  • the compound and/or topical composition according to formula (I) does not comprise an ester of salicylic acid. This includes both esters formed with the hydroxy group of salicylic acid and esters formed by the carboxylic acid of salicylic acid.
  • At least one of Ai, A2 and A3 may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a pharmaceutical, and/or which is configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • At least one of Ai and A2 may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a pharmaceutical, and/or which is configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • at least one of Ai and A2 may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a pharmaceutical, and/or which is configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety and A3 may be a moiety of group a).
  • Ai may be a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a pharmaceutical, and/or which is configured to act as a pharmaceutical after being cleaved off of the 3,4- dihydro-2H-pyran moiety
  • A2 and A3 may be a moiety of group a).
  • the Ci-Ceo moiety and/or the polymeric moiety of group b) is not a color-imparting moiety, in particular not a color-imparting moiety having at least one absorption peak within the wavelength range of 380 to 790 nm.
  • the Ci-Ceo moiety and/or the polymeric moiety of group b) is not a UV-absorbing moiety, in particular not a UVA- and/or UVB-absorbing moiety, in particular not a UVA- and/or UVB-absorbing moiety having at least one absorption peak within the wavelength range of 280 to 379 nm.
  • the compound of any of formulae (I) to (V) is not a compound disclosed in the international application WO 2023/102652 Al, the contents of which are incorporated herein for this purpose by the reference thereto. Specifically, in some embodiments, the compound of any of formulae (I) to (V) is not a compound comprising a moiety Ai, A2 and/or A3 which is R 3 in formula (IX) of WO 2023/102652 Al.
  • the compound of any of formulae (I) to (V) is not a compound disclosed in the international application WO 2014/155016 Al, and in particular not a compound disclosed in formulae (II) with R”i, R”2 and R”4 being as defined in the table beneath said formula and R”s representing C12H25S-.
  • the contents of WO 2014/155016 Al are incorporated herein for this purpose by the reference thereto.
  • A3 in case of A3 representing a Ci-Ceo moiety or polymeric moiety according to group b2) which is configured to act as a fragrance after being cleaved off of the 3,4-dihydro-2H-pyran moiety, A3 does not represent a benzyloxy moiety or an alkoxy moiety, in particular hexyloxy.
  • the compound of formulae (I) and (II) is not a compound in which L1-A1 represents a moiety comprising a hydroxyl group attached to a carbon atom in alphaposition to the carbon atom marked “a” in formula (I).
  • the compound of any of formulae (I) to (V) is not a compound disclosed in the US patent US 6,022,888, the contents of which are incorporated herein for this purpose by the reference thereto.
  • the compounds of the present disclosure do not comprise an epoxy group.
  • the compound of formula (I) capable of covalently binding to skin is a compound of formula (XVII), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 , Li, L3, Ai , A2 and A3 are as defined in any preceding embodiment, and wherein Li is in particular selected from the group consisting of -CH2-, -C(O)-, C(O)-O-, -C(O)-NH-, - C(O)-N(Ci-C4-alkyl)-, and combinations thereof.
  • Topical administration in the sense of the present disclosure refers to any local (i.e. not systemic) administration, whether through ointments, gels, creams, lotions, or other similar formulations, of the compounds or compositions of the present disclosure, including administration directly to the external epidermis or dermis a subject, including administration to skin appendages such as hair but excluding oral, rectal, intrapulmonary and intranasal administration.
  • the present disclosure further pertains in some embodiments to the compounds or compositions of the present disclosure for use as a cosmetic.
  • a cosmetic or a cosmetic use means that the composition is suitable for external use (i.e. extracorporal use, e.g. not ingested) and is in particular suitable for application to the skin or hair.
  • the aforementioned compositions can be formulated in any form known in the art for cosmetic (topical) administration.
  • the composition can be applied in any topical form, such as in the form of aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic/sunscreen and skin care formulation.
  • the composition can also be water-resistant (e.g., waterproof).
  • the topical composition may also be present in the form of patch or carrier comprising the topical composition.
  • a patch include an adhesive label or thin foil on which the composition is coated or printed.
  • a carrier includes a non-woven material or a hydrogel in which the composition is impregnated.
  • the topical composition according to the present disclosure further comprises an excipient suitable for topical administration.
  • the excipient is not particularly limited.
  • the excipient suitable for topical administration comprises one or more excipients selected from water, ethanol, isopropanol, n-propanol, ethylene glycol, diethylene glycol, a propylene glycol, diethylene glycol monoethyl ether, DMSO, and glycerol.
  • the topical composition can also be a pre-dispersed composition comprising the compound of this disclosure and a liquid carrier.
  • a pre-dispersed composition comprising the compound of this disclosure and a liquid carrier.
  • These compositions can be a solution (e.g., free of any undissolved solid particles), a dispersion (e.g., containing a liquid phase and a solid precipitant phase), or an emulsion.
  • the topical composition may contain water and/or organic solvents as suitable carriers and excipients.
  • the liquid composition can be sterile and/or prepared from a sterile aqueous solution for infusion.
  • the composition may also include a surface-active agents, such as an alkylbenzene sulfonate, an alkyl sulfate, an alkyl ether sulfate, a soap, an ethoxylate, an alkyl alcohol, a lignosulfonate, or a triglyceride.
  • the composition may also include a solid matrix. Suitable examples of a matrix component include a sugar, a sugar alcohol (e.g., sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydrolysates), a polymer, or a combination of two or more thereof.
  • the composition may also include a skin penetration enhancer.
  • skin penetration enhancer refers to a substance that penetrates into skin (penetrant) to reversibly decrease its barrier resistance.
  • a skin penetration enhancer can also enhance the solubility of the penetrant to increase loading, which may, for example, enhance the flux of the penetrant across the skin.
  • Non-limiting examples of a skin penetration enhancer include an alcohol, an amide, an ester, an ether alcohol, a fatty acid, a glycol, a pyrrolidone, a sulphoxide, a surfactant, and a terpene.
  • the composition may also include a preservative, a thickening agent, a film-forming agent and/or a humectant.
  • thickening agents include starches, gums (e.g., natural and synthetic gums), cellulosics, and arabinogalactan.
  • humectants include polyhydric alcohols, for example, polyalkylene glycols (e.g., alkylene polyols and their derivatives), alpha hydroxy acids, sugars, Aloe vera gel, vegetable oil, lithium chloride, allantoin, urea, and dicyanamide.
  • Non-limiting examples of film-forming agents include volatile silicone resins, polyvinylpyrrolidone, acrylates, acrylamides, copolymers, and isododecane resins.
  • the compositions can be applied to the skin of the subject using inkjet printing directly onto a skin transfer substrate such as a patch.
  • the composition in this case is applied to the transfer substrate using printer nozzles.
  • the composition may also be contained in a pen-like applicator since this may allow more selective localized delivery.
  • the topical formulation comprising the compound of formula (I) is storage stable (i.e., the compound of formula (I) retains its original chemical structure at greater than 95 mol.-%) for a period of time from greater than 1 month, more specifically greater than 3 months, and in particular greater than 6 months, when stored at 21 °C and 25% RH.
  • aqueous solubility of the compound of formula (I) is from about 1 g/L to about 100 g/L, from about 5 g/L to about 50 g/L, or from about 10 g/L to about 100 g/L.
  • the topical composition is not too “runny” in order to facilitate that the topical formulation is retained locally on the skin at the site of administration. Accordingly, it may be particularly advantageous that the topical composition is having a dynamic viscosity, measured at 37°C, of more than 2 mPa s, more specifically more than 10 mPa s, and in particular more than 50 mPa s, for instance, in the range of 2 mPa s to 50,000 mPa s, more specifically in the range of 10 mPa- s to 20,000 mPa- s, and in particular in the range of 50 mPa- s to 10,000 mPa- s.
  • a dynamic viscosity measured at 37°C
  • the hair care formulation is enclosed in a container.
  • the container is sealed and/or releasable after opening.
  • the container comprises a label and/or is provided with a packaging.
  • the present disclosure relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pharmaceutical; and/or b2) configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro- 2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; for use in medicine.
  • the present disclosure relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • the skin-associated disease is selected from alopecia, psoriasis, desquamation disorders, and seborrheic dermatitis.
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety configured to act as a pharmaceutical after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; for use in medicine, in particular a skin-associated disease, an allergic condition, pain, or inflammation, wherein the pharmaceutical is released over a plurality of hours or days.
  • the plurality of days is 2 days or more, more specifically 3 days or more, and in particular 7 days or more.
  • the present disclosure relates to the use of a topical composition according to the first aspect as a skin moisturizer, pesticide, in particular an insect repellant, a skin whitening agent or a fragrance.
  • any of the specific compounds which are disclosed for the first aspect of the present disclosure and which are directed to a moiety (or moieties) to be used as skin moisturizer, pesticide, in particular an insect repellant, skin whitening agent or fragrance also represent specific embodiments according to this aspect of the present disclosure.
  • the present disclosure relates to a method of using a topical composition
  • a topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin may be a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a skin moisturizer, a pesticide or a skin whitening agent; and/or b2) configured to act as a skin moisturizer, a pesticide, a skin whitening agent or a fragrance after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively; the method comprising applying the topical composition to skin.
  • the method may include leaving the topical composition on the skin for at least 30 minutes.
  • the method may include chemically peeling the skin prior to applying the topical composition onto the skin.
  • any of the specific compounds which are disclosed for the first aspect of the present disclosure and which are directed to a moieties to be used as skin moisturizer, pesticide, skin whitening agent or fragrance also represent specific embodiments according to this aspect of the present disclosure.
  • the present 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 domestic or farm animals, wherein the topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin may be a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • Li, L2 and L3 independently from each other represent a linker group or is absent
  • Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety of group b); the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pesticide; and/or b2) configured to act as a pesticide after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and
  • L1-A1 and L2-A2 do not represent a moiety comprising an unsaturated C-C or C-N bond in alpha-position to the carbon atom marked “a” and “b”, respectively.
  • Any of the specific compounds which are disclosed for the first aspect of the present disclosure and which are directed to a moiety (or moieties) to be used as pesticide also represent specific embodiments according to this aspect of the present disclosure.
  • the present disclosure specifically relates to the compounds of the present disclosure per se, i.e. independent from the topical composition.
  • hair refers to hair and other fibrous keratinous materials such as eyebrows and eye lashes.
  • the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
  • “about 20” means or includes amounts from 18 to and including 22.
  • carboxy refers to a -C(O)OH group.
  • C n -m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.
  • C n -m alkyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched, having n to m carbons.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, //-butyl, Zc/7-butyl, isobutyl, ec-butyl; higher homologs such as 2-methyl-l -butyl, //-pentyl, 3-pentyl, //-hexyl, 1,2,2-trimethylpropyl, and the like.
  • the alkyl group contains from 1 to 6 carbon atoms, more specifically from 1 to 4 carbon atoms, even more specifically from 1 to 3 carbon atoms, and in particular 1 to 2 carbon atoms.
  • C n -m acyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched, having n to m carbons.
  • C n -m alkynyl refers to an alkyl group having one or more triple carboncarbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • C n -m alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons.
  • fatty in e.g. fatty acids or fatty alcohols, refers to linear-chain or branched-chain saturated, monounsaturated or polyunsaturated hydrocarbon moieties having between 8 and 34 carbon atoms.
  • fatty acids include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid; linolenic acid, arachidonic acid, oleic acid and mead acid.
  • fatty alcohols include decanol, undecanol, cetylalcohol, stearyl alcohol, oleyl alcohol, myricyl alcohol, and geddyl alcohol.
  • halogen refers in particular to F, Cl, Br and I.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • the compound has the ⁇ -configuration. In some embodiments, the compound has the ( ⁇ -configuration.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4- triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • a “salt” or “pharmaceutically acceptable salt” of a compound of any one of the formulae disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • acids commonly employed to form pharmaceutically acceptable salts of the compounds of any one of the formulae include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenyl
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • bases commonly employed to form pharmaceutically acceptable salts of the compounds of any one of the formulae disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N- dimethyl-N-(2-hydroxyethyl)amine or tri-(
  • the terms “individual” or “subject” are used interchangeably, and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • protecting group and “protective group” refer to a moiety that reversibly chemically modifies a functional group in order to obtain chemoselectivity or in order to reduce degradation in one or more subsequent chemical reactions.
  • Suitable protecting groups are well known in the art (see, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety).
  • color refers to wavelengths of electromagnetic radiation visible to the human eye and “colorless” refers to the absence of wavelengths of electromagnetic radiation visible to the human eye.
  • the following examples describe the synthesis of hydrogenated genipin derivatives and show the versatility and robustness of the 3,4-dihydro-2H-pyran moiety in coupling to keratinous tissues in in-vitro tests utilizing lysine.
  • the examples also demonstrate that the lysine conjugates are colorless. Some of the examples are not according to the present disclosure since they do not carry a moiety of group b). These examples serve to demonstrate that the 3,4-dihydro-2H-pyran moiety can be broadly substituted while retaining the described effects (capability to bind to skin and colorless in the bound state).
  • Genipin (methyl l-hydroxy-7-(hydroxymethyl)-l,4a,5,7a-tetrahydrocyclopenta[c]pyran- 4-carboxylate) (1 equivalent) was added to a Schlenk flask along with 10% Pd/C (10 wt. %). The flask was cycled between vacuum and nitrogen gas three times. In a separate flask, nitrogen was bubbled into methanol for 15 minutes. Once complete, methanol was added slowly (0.05 M) to the Schlenk flask under flow of nitrogen. The Schlenk flask was put under vacuum and backfilled with H2 via a balloon. The reaction was warmed to 50 °C and monitored by TLC until complete conversion of starting material. The crude reaction mixture was filtered through a pad of celite and flushed with dichloromethane. The filtered solution was concentrated and isolated by flash column chromatography as a mixture of diastereomers.
  • Step 1 synthesis of methyl l-((tert-butyldimethylsilyl)oxy)-7-(((tert-)
  • Genipin (1 equivalent) was added to an oven-dried round bottom flask along with tertbutyldimethylsilyl chloride (2.4 equivalents) and imidazole (5 equivalents). 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 with ethyl acetate and brine. Organic phase was washed with brine three times. The combined aqueous layer was extracted with ethyl acetate two times. The combined organic phase was dried with magnesium sulfate and concentrated using a rotary evaporator. The title compound was isolated via flash column chromatography using a gradient of ethyl acetate and hexane.
  • Step 2 synthesis of methyl l-((tert-butyldimethylsilyl)oxy)-7-(((tert- butyldimethylsilyl)oxy)methyl)-l, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[c]pyran-4- carboxylate
  • step 1 The product of step 1 (1 equivalent) was added to a Schlenk flask along with 10% Pd/C (10 wt. %). The flask was cycled between vacuum and nitrogen gas three times. In a separate flask, nitrogen was bubbled into methanol for 15 minutes. Once complete, methanol was added slowly (0.05 M) to the Schlenk flask under flow of nitrogen. The Schlenk flask was put under vacuum and backfilled with H2 via balloon. The reaction was warmed to 50 °C and monitored by TLC until complete conversion of starting material. The crude reaction mixture was filtered through a pad of celite and flushed with dichloromethane. The filtered solution was concentrated and isolated by flash column chromatography as a mixture of diastereomers.
  • step 2 The product of step 2 (1 equivalent) was added to an oven-dried flask and dissolved in THF (0.04 M). To this was added TBAF (1 equivalent from a 1 M solution in THF), and the reaction was stirred for 1 hour. The crude reaction mixture was concentrated, and the desired compound (3) was isolated via flash column chromatography.
  • 'H NMR 400 MHz, MeOD 6 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).
  • Example 3 preparation of genipin derivative compound methyl 7-formyl-l- hydroxy-l,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-4-carboxylate (compound 6) and genipin derivative compound methyl 3-hydroxy-l,2a,2al,3,4a,7a-hexahydro-2H- 4,5-dioxacyclopenta[cd]indene-7-carboxylate (compound 7)
  • Step 1 methyl 7 -(hydroxymethyl) -1 -methoxy- 1, 4a, 5, 7a-tetrahydrocyclo- penta [ c ]pyran-4-carboxylate
  • Genipin (1 equivalent) was added to a round bottom flask and dissolved with methanol (0.05 M). Para-toluenesulfonic acid (0.3 equivalent) was added to the stirring solution of genipin and allowed to react at room temperature until complete conversion of starting material. Once complete, the crude material was concentrated using rotary evaporation and filtered through a plug of silica. The crude material was flushed with dichloromethane and concentrated. The title compound was isolated via flash column chromatography.
  • Step 2 methyl 7 -formyl- 1 -methoxy- 1,4a, 5, 7 a-tetr ahydrocyclopenta [c]pyran-4- carboxylate
  • step 2 Product of step 2 (1 equivalent) was added to a Schlenk flask along with 10% Pd/C (10 wt. %). The flask was cycled between vacuum and nitrogen gas three times. In a separate flask, nitrogen was bubbled into methanol for 15 minutes. Once complete, methanol was added slowly (0.05 M) to the Schlenk flask under flow of nitrogen. The Schlenk flask was put under vacuum and backfilled with H2 via balloon. The reaction was warmed to 50 °C and monitored by TLC until complete conversion of starting material. The crude reaction mixture was filtered through a pad of celite and flushed with dichloromethane. The filtered solution was concentrated and isolated by flash column chromatography as a mixture of diastereomers (the title compound).
  • step 3 Product of step 3 was dissolved in acetic acid/1 M HC1/THF in a 3:2:5 ratio at an overall concentration of 0.07 M. The solution was stirred overnight at 60 °C. Once complete, the solution was poured into a separatory funnel with water and ethyl acetate. The combined ethyl acetate extract was dried with sodium sulfate and concentrated under reduced pressure. The desired compound (as a 15:85 mixture of aldehyde compound 6/acetal compound 7) was isolated via flash column chromatography (hexane:ethyl acetate).
  • step 3 of example 3 was dissolved in dimethylformamide (0.2 M) and stirred with 4 equivalents of potassium peroxymonosulfate for 48 hours.
  • the crude material was added to a separatory funnel with ethyl acetate and brine.
  • the combined ethyl acetate was dried with sodium sulfate and concentrated before isolation via flash column chromatography to give the title compound.
  • step 1 The product of step 1 was dissolved in acetic acid/1 M HC1/THF in a 3:2:5 ratio at an overall concentration of 0.07 M. The solution was stirred overnight at 60 °C. Once complete, the solution was poured into a separatory funnel with water and ethyl acetate. The combined ethyl acetate extract was dried with sodium sulfate and concentrated. The title compound was isolated via flash column chromatography (hexane : ethyl acetate) to give the desired compound below.
  • Step 1 synthesis of methyl 7-(hydroxymethyl)-l-methoxy-l,4a,5,6, 7, 7a-
  • step 3 of example 3 The compound obtained in step 3 of example 3 (1 equivalent) was dissolved in methanol (0.27 M) and stirred at 0 °C. To this, was added sodium borohydride (1.5 equivalents). The reaction was stirred for 30 minutes as it warmed to room temperature. Once complete, the crude reaction mixture was diluted with saturated NH4CI and extracted with ethyl acetate (3X) in a separatory funnel. The combined organic phase was dried with sodium sulfate and concentrated under reduced pressure. Title compound was isolated via flash column chromatography.
  • step 1 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 equivalents) was added dropwise at 0 °C and allowed to react overnight while warming to room temperature. The crude reaction mixture was quenched with saturated sodium bicarbonate and extracted in a separatory funnel with dichloromethane and water. The combined DCM layer was dried with sodium sulfate, concentrated under reduced pressure and isolated via flash column chromatography to give the title compound.
  • step 2 The product of step 2 was dissolved in acetic acid/lM HC1/THF in a 3 :2:5 ratio at an overall concentration of 0.07 M. The solution was stirred overnight at 60 °C. Once complete, the solution was poured into a separatory funnel with water and ethyl acetate. The combined ethyl acetate extract was dried with sodium sulfate and concentrated under reduced pressure. The title compound was isolated via flash column chromatography (hexane:ethyl acetate) to give the desired compound (10).
  • a hydrogenated genipin derivative (compound 1) was conjugated with lysine to obtain compound 1 -lysine conjugate:
  • Figure 6A shows that reacting the anchor compound 2 with lysine to mimic skin binding results in strong UV-light absorption and no visible color.
  • Figure 6B shows that reacting the anchor compound 6/7 with lysine to mimic skin binding results in UV-light absorption and no visible color.
  • Figure 6C shows that reacting the anchor compound 8/9 with lysine to mimic skin binding results in UV-light absorption and no visible color.
  • Example 7 methyl l-hydroxy-7-(((2-hydroxybenzoyl)oxy)methyl)-l, 4a, 5,6,7,7a- hexahydrocyclopenta [c] pyran-4-carboxylate
  • Step 1 synthesis of methyl 7-(hydroxymethyl)-l-methoxy-l,4a,5,6, 7, 7a-
  • methanol 0.27 M
  • sodium borohydride 1.5 equivalents
  • step 1 The product of step 1 (1 equivalent) was dissolved in dichloromethane/pyridine (1 : 1 v/v) (0.2 M) and cooled to 0 °C. O-acetylsalicyloyl chloride (1.2 equivalents) was added dropwise at 0 °C and allowed to react overnight while warming to room temperature. The crude reaction mixture was quenched with saturated sodium bicarbonate and extracted in a separatory funnel with dichloromethane and water. The combined DCM layer was dried with sodium sulfate, concentrated under reduced pressure and isolated via flash column chromatography to give the title compound.
  • step 2 The product of step 2 was dissolved in acetic acid/1 M HC1/THF in a 3:2:5 ratio at an overall concentration of 0.07 M. The solution was stirred overnight at 60 °C. Once complete, the solution was poured into a separatory funnel with water and ethyl acetate. The combined ethyl acetate extract was dried with sodium sulfate and concentrated under reduced pressure. The title compound was isolated via flash column chromatography (hexane:ethyl acetate) to give the desired compound.
  • Example 7 The compound of Example 7 was conjugated with lysine to obtain the lysine conjugate:
  • Example 7 As shown in Figure 7, reacting the compound of Example 7 (i.e. a hydrogenated genipin salicylate, called “genipin salicylate” in Fig. 7) with the amino acid lysine (called “amine” in Fig. 7) to mimic skin binding results in small shift in UV absorbance peak (no visible color is produced).
  • genipin salicylate a hydrogenated genipin salicylate
  • amine amino acid lysine
  • the aldehyde obtainable as described in WO 2022/036113 Al, was weighed and transferred to a round bottom flask. To this, was added MeOH (0.2 M) and stirred until fully solubilized. DOWEX® 50WX8 was first washed with methanol and dried under vacuum. Once dry, the DOWEX® 50WX8 (H+ form) was added to the stirred solution of aldehyde. The reaction mixture was heated at 40 °C for 65 hours. Once complete, the methanol was removed via rotary evaporation and the product was precipitated using ether/hexane to obtain a white powder.
  • the obtained aldehyde was added to a suspension of Oxone® (potassium peroxymonosulfate; 4 equivalents) in DMF (0.2 M), and the reaction mixture was stirred at room temperature for four days.
  • the crude mixture was added to a separatory funnel with ethyl acetate and brine.
  • the aqueous layer was washed thoroughly with ethyl acetate.
  • the combined ethyl acetate layers were subsequently extracted (3x) with saturated NHCO3.
  • the combined aqueous basic layer was re-acidified with concentrated HC1 until the pH was below 7.
  • the acidified solution was then extracted with ethyl acetate (3x).
  • the combined ethyl acetate layer was dried with Na2SO4 and concentrated.
  • a rubber septum was placed on the Schlenk flask and evacuated under vacuum, then left under static vacuum.
  • a balloon was filled with H2 and equipped with an 18 G needle. The balloon was added to the reaction flask, warmed to 50 °C, and allowed to react for 24 hours. The crude reaction was carried forward to the next step without further purification.
  • the reduced ester starting material was deprotected using a mixture of HCl/acetic acid in tetrahydrofuran while heating for prolonged periods.
  • the crude reaction mixture was added to a separatory funnel and carefully quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate.
  • the combined organic phases were dried with sodium sulfate and concentrated in vacuo.
  • the crude material was isolated via flash column chromatography using a gradient of ethyl acetate and hexanes.
  • glycerol boronic esters are a mixture of isomers and carried to the next step.
  • Step J O -benzyl protection of genipin'. benzyl 7 -(hydroxymethyl) -1-methoxy- 1, 4a, 5, 7a-tetrahydrocyclo-penta[ c ]pyran-4-carboxylate
  • Genipin (1 equivalent) was added to a round bottom flask and dissolved with benzyl alcohol/dichloromethane (1/1 v/v) (0.5 M).
  • Dowex® 50WX8 (20 wt %) was added to the stirring solution of genipin and allowed to react at 40 °C until complete conversion of starting material. Once complete, the crude material was filtered to remove the Dowex® resin and then concentrated via rotary evaporation. The title compound was isolated via flash column chromatography.
  • Step 2 Oxidation of o-benzyl protected genipin: benzyl 7 -formyl- 1-methoxy- 1, 4a, 5, 7a-tetrahydrocyclopenta[ c ]pyran-4-carboxylate
  • step 2 The product of step 2 was dissolved in dimethylformamide (0.2 M) and stirred with 4 equivalents of potassium peroxymonosulfate for 48 hours.
  • the crude material was added to a separatory funnel with ethyl acetate and washed with brine (3x). The aqueous phase was then back-extracted with ethyl acetate (3x). The combined ethyl acetate was dried with sodium sulfate and concentrated before isolation via flash column chromatography to give the title compound.
  • Step 1 Acylation of genipin carboxylate derivative
  • reaction was diluted with DCM and transferred to a separatory funnel. Wash with 1 M HC1 (2X) to remove pyridine.
  • the DCM was concentrated and resuspended in ethyl acetate before being washed with 1 M D-sorbitol/lM Na2CO3 (3X) to cleave the boronic ester and remove phenylboronic acid.
  • the combined aqueous phases were back- extracted with ethyl acetate, dried with sodium sulfate and concentrated to dryness.
  • the resultant crude material was purified via flash column chromatography using a gradient of ethyl acetate and pentane.
  • Step 2 Reduction and deprotection of acylated genipin derivative 10 % Palladium on carbon (10 wt %) was weighed into an oven dried Schlenk flask. The flask was cycled between argon and vacuum 3 times. In a separate Erlenmeyer flask was added methanol equipped with a stir bar. A needle connected to a hose on the argon line was submerged into the methanol and bubbled through the solvent for 15 minutes. Meanwhile, the ester material was weighed into a vial. Once the methanol sparge was complete, the ester starting material was dissolved in degassed methanol. This solution is carefully added to the Schlenk flask under a flow of argon.
  • Example 11 Conjugation of the Compound of Example 10 to skin
  • the pig skin was visually unchanged in normal daylight, but exposure to UV light revealed that the hydrogenated genipin derivatives had coupled to the skin.
  • a balloon was filled with H2 and equipped with an 18 G needle. The balloon was added to the reaction flask, warmed to 50 °C, and allowed to react for 24 hours. The crude reaction was purified via flash column chromatography using a gradient of ethyl acetate and pentane.
  • the obtained lysine conjugate was nearly colorless (very pale yellow).
  • Example 13 Conjugation of the Compound of Example 12 to skin
  • a 50 mM methanolic solution of the hydrogenated genipin derivative of Example 11 was prepared and 100 pl of the solution (containing 2.2 mg of the genipin derivative) was drop- casted onto explanted pig skin.
  • the hydrogenated genipin derivative was allowed to bind to the skin for 2 hours at ambient conditions.
  • the piece of pig skin was then cleaned with a wet paper towel by wiping and scrubbing to remove any residual unreacted genipin derivative. Binding of the compound to the pig skin was confirmed by UV light. After 24 hrs, the pig skin was submerged in water and then removed, dried and scrubbed again. Exposure to UV light reconfirmed that the hydrogenated genipin derivative of Example 11 was stably bound to the skin.
  • the pig skin was visually unchanged in normal daylight, but exposure to UV light revealed that the hydrogenated genipin derivatives had coupled to the skin at the aforementioned 2 hrs- and 24 hrs-intervalls.
  • Example 14 Preparation of a hydrogenated genipin derivative linked to D-glucose with an ethylene glycol linker and its conjugation to lysine
  • Steps 1 and 2 Acylation of genipin carboxylate derivative:
  • Step 3 Selective deprotection of acetyl protecting groups
  • the acetyl -protected product from Step 2 was selectively deprotected by dissolving in methanol (0.2 M), and then adding 4.1 equivalents of n-hexylamine stirring for 2 h at 50 °C.
  • the resulting deprotected product was isolated via flash column chromatography using a gradient of methanol and dichloromethane.
  • Step 4 Reduction and deprotection of acylated genipin derivative
  • a balloon was filled with H2 and equipped with an 18 G needle. The balloon was added to the reaction flask, warmed to 50 °C, and allowed to react for 24 hours. The crude reaction was purified via flash column chromatography using a gradient of methanol and di chi or om ethane .
  • the obtained lysine conjugate was nearly colorless (very pale yellow).
  • a topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound suitable for covalently binding to skin is a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or a polymeric moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or a polymeric moiety of group b); wherein the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a skin moisturizer,
  • composition according to embodiment 2, wherein the functional group comprises a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorous atom, or a combination thereof; more specifically a carbon atom, an oxygen atom, a nitrogen atom, or a combination thereof; and in particular a carbon atom and/or an oxygen atom.
  • composition according to embodiment 3, wherein the functional group comprises one or more of, two or more of, three or more of, four or more of, or all of:
  • 1 and 12 carbon atoms more specifically between 1 and 6 carbon atoms, and in particular between 1 and 3 carbon atoms;
  • oxygen atoms more specifically between 1 and 6 oxygen atoms, and in particular between 1 and 3 oxygen atoms;
  • 1 and 3 phosphorous atoms more specifically between 1 and 2 phosphorous atoms, and in particular 1 phosphorous atom.
  • composition according to any one of embodiments 2 to 5, wherein the functional group is hydrolysable at the physiological pH of mammal skin, more specifically of human skin, and in particular at a pH of between about 5 to about 6.
  • composition according to any one of embodiments 2 to 8, wherein the functional group is configured to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefin, an olefine, or an oxime; or salts thereof; on the corresponding Li, L2 or L3 moiety which is attached to the Ci-Ceo moiety or polymeric moiety of group b) or, if the corresponding Li, L2 or L3 moiety is absent, on the 3,4-dihydro-2H-pyran moiety after cleaving.
  • the functional group is configured to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ket
  • composition according to any one of embodiments 2 to 8, wherein the functional group is configured to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, or an oxime; or salts thereof; on the Ci-Ceo moiety or polymeric moiety of group b) after cleaving.
  • the functional group is configured to provide a hydroxyl group, a primary or secondary amine group, a carboxylic acid, a thiol, an aldehyde, a ketone, a thiocarbonic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a phosphonic acid, an olefine, or an oxime; or salts
  • the functional group comprises a carbon ester, in particular a monoester, 1,1-diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosidic group or a thioacetal; an carbon amide, in particular a peptide or a N- Mannich base; an enol; an enamine; an imine; an oxime; a sulfate ester; a sulfonic acid ester; a sulfonic acid amid; a phosphoric acid ester; a phosphonic acid ester; a phosphoric acid amide; or a phosphonic acid amide.
  • the functional group comprises a carbon ester, in particular a monoester, 1,1-diester, a carbonate, or a carbamate; an ether or thioether, in particular an acetal, a hemi-acetal, a glycosi
  • composition according to any one of embodiments 1 to 11, wherein Ai represents a Ci-Ceo moiety or a polymeric moiety of group b).
  • composition according to any one of embodiments 1 to 12, wherein A2 represents a Ci-Ceo moiety or a polymeric moiety of group b).
  • composition according to any one of embodiments 1 to 13, wherein A3 represents a Ci-Ceo moiety or a polymeric moiety of group b).
  • composition according to any one of embodiments 12 to 14, wherein the remainder of Ai, A2 and A3 represents a C1-C30 moiety, H, hydroxyl, amino, or a halogen.
  • Li is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms; and/or L2 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms; and/or
  • L3 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms.
  • Li is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms and wherein the functional group is attached to Li;
  • L2 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms and wherein the functional group is attached to L2;
  • L3 is present and represents an optionally substituted hydrocarbon moiety comprising, in combination with its optional substituents, 1 to 8 carbon atoms and wherein the functional group is attached to L3.
  • composition according to any one of embodiments 1 to 17, wherein Li and L2 are present and form a 5-, 6-, 7- or 8-membered ring, in particular a cyclopentyl, a cyclohexyl, a pyrrolidinyl, a piperidinyl, a tetrahydrofuranyl or a tetrahydropyranyl.
  • a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 30, more specifically 1 to 16, and in particular 1 to 12, carbon atoms; 0 to 12,
  • A3 represents a C1-C30 moiety of group a), more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 oxygen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 6, more specifically 0 to 4, and in particular 0 to 3 halogen atoms.
  • A3 represents a C1-C30 moiety of group a), more specifically a C1-C16 moiety selected from a saturated or unsaturated, cyclic or acylic (hetero)alkyl comprising 1 to 16, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 6, more specifically 0 to 4, and in particular
  • R 1 represents hydrogen, C1-6 acyl, or C1-6 alkyl; and in particular hydrogen.
  • composition according to any one of embodiments 1 to 30, wherein at least one of Ai, A2 and A3 represents a Ci-Ceo moiety or a polymeric moiety of group bl).
  • composition according to any one of embodiments 1 to 31, wherein at least one of Ai, A2 and A3 represents a Ci-Ceo moiety or a polymeric moiety of group b2).
  • composition according to any one of embodiments 1 to 32, wherein the compound capable for covalently binding to skin is a compound of formula (II), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 , L3, Ai and A3 are as defined in any of embodiments 1 to 32; wherein (R 2 ) n represents, independently from each other, n moieties selected from H, Ci- C4 alkyl, C1-C4 alkoxyl, hydroxyl, amino, or halogen; wherein n is an integer selected from 1 and 2; and wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O- and -O-(CH 2 )I- 4 -; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • composition according to any one of embodiments 1 to 33, wherein the compound capable for covalently binding to skin is a compound of formula (III), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein R 1 , L3, Ai and A3 are as defined in any of embodiments 1 to 32; and wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O- and -O-(CH 2 )I- 4 -; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • composition according to any one of embodiments 1 to 33, wherein the compound capable for covalently binding to skin is a compound of formula (IV), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 and Ai are as defined in any of embodiments 1 to 32; wherein (R 2 ) n represents, independently from each other, n moieties selected from H, Ci- C4 alkyl, C1-C4 alkoxyl, hydroxyl, amino, or halogen; wherein n is an integer selected from 1 and 2; wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O- and -O-(CH 2 )I- 4 -; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms; and wherein R 4 is selected from
  • R 1 and Ai are as defined in any of embodiments 1 to 32; wherein L4 is either absent or a group selected from: -O-, -S-, -C(O)-, -CO2-, -O-C(O)-, - NR 4 -, -NR 4 -C(O)-, -C(O)-NR 4 -, -(CH 2 )I- 4 -, -(CH 2 )I- 4 -O- and -O-(CH 2 )I- 4 -; wherein R 3 is as defined in embodiment 35 or embodiment 36; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • composition according to any of embodiments 1 to 37, wherein at least one of Ai, A 2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a skin moisturizer, and/or which is configured to act as a skin moisturizer, after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • Ci-Ceo moiety or polymeric moiety comprises a plurality of hydrogen bonding groups selected from the group consisting of hydroxyl groups, ether groups, carboxylic acids, amines and amides; and their salts.
  • the topical composition according to embodiment 39, wherein the plurality of hydrogen bonding groups comprises three or more, more specifically 4 or more, and in particular 6 or more hydrogen bonding groups.
  • the topical composition according to embodiment 39 or embodiment 40, wherein the ratio of C-atoms to the sum of hydrogen bonding groups comprised in the Ci-Ceo moiety is between about 4: 1 to 1 : 1, more specifically between about 3: 1 to about 1 : 1 and in particular between about 2: 1 to about 1 : 1.
  • composition according to any one of embodiments 38 to 41, wherein the Ci-Ceo moiety has a molecular weight of at least 60 g/mol, more specifically at least 90 g/mol, and in particular at least 120 g/mol.
  • the topical composition according to any one of embodiments 38 to 42, wherein the ratio of C-atoms to the sum of heteroatoms comprised in the Ci-Ceo moiety is between about 4: 1 to 1 :2, more specifically between about 3: 1 to about 1 : 1.5, and in particular between about 2: 1 to about 1 : 1, wherein the heteroatoms are selected from nitrogen and oxygen.
  • Ci-Ceo moiety comprises: a polyol, more specifically a polyol having n hydroxyl groups with n being 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 8 or more, 10 or more, 12 or more, or 16 or more; a mono- or polyvalent carboxylic acid comprising one or more hydroxyl groups, more specifically glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; a sugar, more specifically a triose, a tetrose, a pentose a hexose, a monosaccharide, a di saccharide, a tri saccharide, or an oligosaccharide; a sugar alcohol, more specifically a sugar alcohol comprising between 2 and 24 carbon atoms, in particular ethylene glycol, glycerol, erythritol, threitol, arabitol
  • the topical composition according to embodiment 44, wherein the Ci-Ceo moiety has a molecular weight of 60 g/mol to 2000 g/mol, more specifically 90 g/mol to 1600 g/mol, and in particular 120 g/mol to 1200 g/mol.
  • composition according to any one of embodiments 38 to 45, wherein the Ci-Ceo moiety or polymeric moiety of group b) is configured to act as a skin moisturizer.
  • the topical composition according to any one of embodiments 48 to 51, wherein the ratio of C-atoms to the sum of heteroatoms comprised in the Ci-Ceo moiety is between about 60: 1 to 5: 1, more specifically between about 50: 1 to about 10: 1 and in particular between about 40: 1 to about 20: 1, wherein the heteroatoms are selected from nitrogen and oxygen.
  • composition according to any one of embodiments 48 to 52, wherein the Ci-Ceo moiety is a sphingosine or a derivative thereof, in particular a ceramide or a sphingomyelin.
  • composition according to any one of embodiments 48 to 53, wherein the Ci-Ceo moiety is configured to act as a skin moisturizer, more specifically as an emollient or an occlusive.
  • composition according to any of embodiments 1 to 37, wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety which is configured to act as a pesticide, and/or which is configured to act as a pesticide after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • composition according to embodiment 56 or embodiment 57 wherein the insect repellant or insecticide acts against an ectoparasite and/or a hematophagous insect, in particular a hematophagous insect selected from the group consisting of mosquitoes, ticks, mites, gnats, fleas, chiggers, leeches and bugs.
  • insect repellant or insecticide acts against an ectoparasite and/or a hematophagous insect, in particular a hematophagous insect selected from the group consisting of mosquitoes, ticks, mites, gnats, fleas, chiggers, leeches and bugs.
  • the insect repellant is an isoprenoid, more specifically a monoterpenoid, a diterpenoid or a triperpenoid, and in particular a terpineol or derivative thereof, a monoterpenoid aldehyde or a derivative thereof, a limonoid or a derivative thereof; or a pyrethrin or a derivative thereof.
  • the isoprenoid is selected from citronellal, hydroxy citronellal, citronellol, citral A, citral B, or a derivative thereof; a necrodane, in particular a-necrodol, or a derivative thereof; a limonoid, in particular azadirachtine, or a derivative thereof; or a pyrethrin, in particular a jasmolin, a cinerin, or a derivative thereof.
  • composition according to embodiment 60 wherein the compound capable for covalently binding to skin is a compound of formula (VII), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms; and wherein Ls is either absent or a group selected from -C(O)-, -C(O)-O-, -C(O)-O-(CH2)I-4-, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I- 4 -, -S(O) 2 -, -S(O) 2 -O-, -S(O) 2 -O-(CH 2 )I. 4 -; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • composition according to embodiment 63, wherein the compound capable for covalently binding to skin is a compound of formula (VIII), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; and wherein R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms.
  • tertiary amide is selected from picaridine, an N,N-di(Ci-C6-alkyl)-toluamide, in particular N,N-diethyl- meta-toluamide, p-menthane-3,8-diol, ethyl 3-(7V-butylacetamido)propanoate; and derivatives thereof.
  • insect repellant is selected from one of the following compounds and moieties/derivatives thereof: N,N- diethyl-meta-toluamide, diethyl phenyl acetamide, N-butylacetanilide, ethyl butylacetylaminopropionate, picaridine, N-(2-methylpiperidin- 1 -yl)cyclohex-3 -ene- 1 - carboxamide, and l-[3-cyclo-hexen-l-ylcarbonyl]-2-methylpiperi dine or l-[3-cyclohexen- 1-ylcarbonyl] piperidine.
  • composition according to embodiment 67 wherein the compound capable for covalently binding to skin is a compound of formula (XI), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms; and wherein Le is either absent or a group selected from -(CH2)I-4-, -C(O)-, -C(O)-O-, -C(O)- O-(CH 2 )I-4-, -C(O)-NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I-4-, -S(O) 2 -, -S(O) 2 -O-, -S(O) 2 -O- (CH 2 )I-4-; and wherein R 4 is selected from H or Ci-C4-alkyl.
  • the topical composition according to embodiment 67 wherein the compound capable for covalently binding to skin is a compound of formula (XII), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; and wherein R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms.
  • composition according to any one of embodiments 55 to 75, wherein the Ci-Ceo moiety is configured to act as a pesticide, in particular an insect repellant.
  • composition according to any of embodiments 1 to 37, wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b) which is configured to act as a skin whitening agent, and/or which is configured to act as a skin whitening agent after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • composition according to embodiment 78 wherein the skin whitening agent acts by chemically or metabolically whitening the skin, in particular by providing a bleaching effect or decreasing melanin production.
  • composition according to any one of embodiments 78 to 80, wherein the Ci-Ceo moiety or polymeric moiety of group b) is configured as a skin whitening agent, after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • composition according to any of embodiments 1 to 37, wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety of group b) which is configured to act as a fragrance after being cleaved off of the 3,4-dihydro-2H-pyran moiety.
  • composition according to embodiment 83 wherein the Ci-Ceo moiety comprises a functional group which couples the Ci-Ceo moiety to the corresponding Li, L2 or L3 moiety or, if the corresponding Li, L2 or L3 moiety is absent, to the 3,4-dihydro-2H- pyran moiety, and which is configured to be cleaved to an aldehyde, a ketone, a thiol, a hydroxy or an amine.
  • composition according to embodiment 84 wherein the functional group is an imine, an acetal, a 1 , 1 -diester, an enol ether, an ester, an amide, a thioester, or a thioacetal .
  • composition according to embodiment 84, wherein the Ci-Ceo moiety has a molecular mass after being cleaved off of less than 400 g/mol, more specifically less than 300 g/mol, and in particular less than 200 g/mol.
  • composition according to any of embodiments 87 to 89, wherein the Ci-Ceo moiety is an agonist of a retinoid receptor, more specifically a retinoic acid receptor, a retinoid X receptor and/or a RAR-related orphan receptor.
  • Ci-Ceo moiety comprises a vitamin A vitamer, more specifically a vitamer selected from the group of retinol, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene and/or bexarotene, in particular retinol, retinal and/or adapalene.
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or polymeric moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); wherein the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pharmaceutical; and/or b2) configured to act as a pharmaceutical after being cleaved off of 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
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or polymeric moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); wherein the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pharmaceutical; and/or b2) configured to act as a pharmaceutical after being cleaved off of 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
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety configured to act as a pharmaceutical after being cleaved off of 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 in alpha-position to the carbon atom marked “a” and “b”, respectively; for use in medicine, wherein the pharmaceutical is released over a plurality of hours or days.
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or polymeric moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); wherein the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a pharmaceutical; and/or b2) configured to act as a pharmaceutical after being cleaved off of 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
  • a topical composition according to any one of embodiments 1 to 93 as a skin moisturizer, a pesticide, in particular as an insect repellant, a skin whitening agent or a fragrance.
  • Method of using a topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin is a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or polymeric moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); wherein the Ci-Ceo moiety or polymeric moiety of group b) is bl) configured to act as a skin moisturizer, a pesticide or a skin whitening agent; and/or b2) configured to act as a skin moisturizer, a pesticide, a skin whitening agent or a fragrance after being cleaved off of the 3,4-dihydro-2H-pyran moiety; and wherein
  • Method of treating domestic or farm animals comprising applying a topical composition to the skin and/or fur of domestic or farm animals, wherein the topical composition comprising a compound capable of covalently binding to skin and an excipient suitable for topical administration, wherein the compound capable of covalently binding to skin is a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin; wherein Li, L2 and L3 independently from each other represent a linker group or are absent, wherein Ai, A2 and A3 independently from each other represent a) a C1-C30 moiety, H, hydroxyl, amino, or a halogen, or b) a Ci-Ceo moiety or polymeric moiety; wherein at least one of Ai, A2 and A3 is a Ci-Ceo moiety or polymeric moiety of group b); wherein the Ci-
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • R 3 represents hydrogen or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms;
  • L 7 is a group selected from -C(O)-, -C(O)-(CH 2 )I- 4 -, -C(O)-O-, -C(O)-O-(CH 2 )I- 4 -, -C(O)-
  • R 4 is selected from H or Ci-C 4 -alkyl.
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms.
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms;
  • R 5 represents H, OH, Ci-C4-alkyl, NH2, N(Ci-C4-alkyl)2, N-morpholino-l-yl, or piperidin- i-yi;
  • L 8 is a group selected from -C(O)-, -C(O)-(CH 2 )I- 4 -, -C(O)-O-, -C(O)-O-(CH 2 )I- 4 -, -C(O)- NR 4 C(O)-, -C(O)-NR 4 C(O)-(CH 2 )I- 4 -, or -S(O) 2 -O-, -S(O) 2 -O-(CH 2 )I-4-; and
  • R 1 represents hydrogen or a protective group hydrolysable under physiological conditions after application of the topical composition onto skin;
  • R 3 represents hydrogen, or an optionally substituted hydrocarbon moiety comprising, in combination with their optional substituents, 1 to 14 carbon atoms;
  • R 5 represents H, OH, Ci-C4-alkyl, NH2, N(Ci-C4-alkyl)2, N-morpholino-l-yl, or piperidin- 1-yl.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents a C1-C14 moiety comprising 1 to 14, more specifically 1 to 12, and in particular 1 to 8, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.
  • R 3 represents C1-14 alkyl, C2-14 alkenylene, C2-14 alkynylene, Ce-i4 aryl, C4-14 heteroaryl comprising 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and/or 1 to 2 sulfur atoms, wherein any of the aforementioned groups is optionally further substituted with the proviso that the aforementioned total sum of the elements recited for R 3 is not exceeded.
  • R 3 represents an optionally substituted phenyl, in particular an optionally substituted phenyl, in particular an optionally substituted phenyl comprising 6 to 14, more specifically 6 to 12, and in particular 6 to 10, carbon atoms; 0 to 12, more specifically 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and in particular 0 to 6 halogen atoms.

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Abstract

La présente demande concerne une composition topique comprenant un composé pouvant se lier de manière covalente à la peau et un excipient approprié en vue d'une administration topique, le composé pouvant se lier de manière covalente à la peau étant un composé de formule (I), ou un tautomère et/ou un sel pharmaceutiquement acceptable de celui-ci, R1 représentant l'hydrogène ou un groupe protecteur hydrolysable dans des conditions physiologiques après application de la composition topique sur la peau ; L1, L2 et L3 représentant indépendamment l'un de l'autre un groupe lieur ou sont absents, A1, A2 et A3 représentant indépendamment l'un de l'autre a) une fraction en C1-C30, H, hydroxyle, amino, ou halogène, ou b) une fraction en C1-C60 ou une fraction polymère ; au moins l'un de A1, A2 et A3 étant une fraction en C1-C60 ou une fraction polymère du groupe b) ; la fraction en C1-C60 ou la fraction polymère du groupe b) étant b1) conçue pour agir en tant qu'hydratant de la peau, pesticide, agent de blanchiment de la peau ou produit pharmaceutique ; et/ou b2) conçue pour agir en tant qu'hydratant de la peau, pesticide, agent de blanchiment de la peau, parfum ou produit pharmaceutique après clivage de la fraction 3,4-dihydro-2H-pyrane ; et L1-A1 et L2-A2 ne représentant pas une fraction comprenant une liaison C-C ou C-N insaturée en position alpha par rapport à l'atome de carbone marqué "a" et " b ", respectivement.
PCT/CA2024/050763 2023-06-07 2024-06-07 Dérivés de génipine hydrogénés pouvant être fixés à des tissus kératiniques Ceased WO2024250111A1 (fr)

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IL324869A IL324869A (en) 2023-06-07 2024-06-07 History of hydrogenated genipin that can be attached to keratinous tissues
EP24818187.7A EP4724432A1 (fr) 2023-06-07 2024-06-07 Dérivés de génipine hydrogénés pouvant être fixés à des tissus kératiniques
CN202480037001.5A CN121646583A (zh) 2023-06-07 2024-06-07 可附着到角质组织的氢化的京尼平衍生物
AU2024285582A AU2024285582A1 (en) 2023-06-07 2024-06-07 Hydrogenated genipin derivatives attachable to keratinous tissues
KR1020257043002A KR20260020125A (ko) 2023-06-07 2024-06-07 케라틴성 조직에 부착가능한 수소화된 제니핀 유도체
MX2025014469A MX2025014469A (es) 2023-06-07 2025-12-02 Derivados de genipina hidrogenada que pueden fijarse a tejidos queratinosos

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EP23178138.6 2023-06-07
EP23178139.4 2023-06-07
EP23178139 2023-06-07

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CN (2) CN121646583A (fr)
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KR960016192A (ko) * 1994-10-31 1996-05-22 표시부를 구비한 전자 장치용 방진 구조체
WO2014155016A1 (fr) * 2013-03-29 2014-10-02 L'oreal Composes derives d'iridoides proteges ou non, composition les comprenant, utilisation comme colorant des fibres keratiniques et dispositifs
US20190161465A1 (en) * 2016-06-17 2019-05-30 Keiko Izumida Red colorant composition derived from iridoid compounds and method for producing same
WO2023102652A1 (fr) * 2021-12-07 2023-06-15 Inkbox Ink Incorporated Composés pouvant se fixer sur la peau

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10500145B2 (en) * 2015-06-19 2019-12-10 inkbox ink Inc. Body ink compositions and applicators
WO2022045385A1 (fr) * 2020-08-25 2022-03-03 주식회사 엘지생활건강 Composition pour prévenir la chute des cheveux ou stimuler la repousse des cheveux

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR960016192A (ko) * 1994-10-31 1996-05-22 표시부를 구비한 전자 장치용 방진 구조체
WO2014155016A1 (fr) * 2013-03-29 2014-10-02 L'oreal Composes derives d'iridoides proteges ou non, composition les comprenant, utilisation comme colorant des fibres keratiniques et dispositifs
US20190161465A1 (en) * 2016-06-17 2019-05-30 Keiko Izumida Red colorant composition derived from iridoid compounds and method for producing same
WO2023102652A1 (fr) * 2021-12-07 2023-06-15 Inkbox Ink Incorporated Composés pouvant se fixer sur la peau

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EP4724432A1 (fr) 2026-04-15
MX2025014470A (es) 2026-01-07
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IL324870A (en) 2026-01-01
WO2024250112A1 (fr) 2024-12-12
KR20260020125A (ko) 2026-02-10
EP4724035A1 (fr) 2026-04-15
KR20260020958A (ko) 2026-02-12
IL324869A (en) 2026-01-01
CN121712483A (zh) 2026-03-20
AU2024283922A1 (en) 2025-12-18
AU2024285582A1 (en) 2025-12-18

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