Genipin derivatives, topical compositions comprising same, use as colorants

Abstract

The present application provides topical compositions comprising genipin derivatives of formula (I), # imgabs0, which are useful as colorants, for example, in semi-permanent tattoo.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority from European patent applications EP 23157133.2 and EP 23157132.4 filed on February 16, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to pigmented genipin derivatives that can adhere to the skin. Genipin derivatives can be used as colorants, for example, in semi-permanent tattoos. Background Art

[0004] Temporary or semi-permanent tattoos or body inks have been used to decorate the body throughout human history. Typically, temporary or semi-permanent tattoos are transferred to the skin by directly exposing the skin to a tattoo ink for a specified incubation period. The quality of the transferred image and its duration on the skin can depend on the ink distribution profile in the outer layer of the skin, known as the stratum corneum. Current manufacturing processes for prefabricated tattoo designs include the use of various forms of topical formulations, including flexographic or gravure inks, stencil printing, and inkjet printers.

[0005] Genipin is particularly advantageous for use in such semi-permanent tattoos because it chemically bonds to skin (mammalian, particularly human skin) in a durable manner and has an intense blue color. Figure 1 A model is shown in Figure 2, which represents the potential mechanism of chemical binding and color development on the skin. Figure 1 When chemically bound to the proteinaceous amino groups of the skin, genipin is believed to form a colored conjugated system, as seen in Figure 1. The color of genipin - when bound to the skin - is an intense dark blue.

[0006] However, it is also desirable to provide semi-permanent tattoos with other, but similarly intense, colors and / or other colors but with increased intensity. In practice, the design of genipin derivatives with specific colors can be challenging for a number of reasons: First, despite advances in calculating UV / visible absorption spectra, it is difficult to accurately predict the exact color performance and intensity of a given genipin derivative. Second, while the general principles of how conjugated systems and chemical moieties influence UV / vis absorption are well-established, designing genipin derivatives with desired color performance by trial and error is time-consuming and cumbersome. Designing a specific genipin color is further burdened by the fact that the genipin core provides the first chromophore when bound to the skin, while other moieties on the genipin derivative provide additional chromophore systems. The resulting color performance is determined by the combined absorption of all chromophore systems. Third, achieving the desired color depends not only on providing absorption at a given wavelength, but also on providing the appropriate amount of absorption at that wavelength. In practice, achieving both goals (absorption at a given wavelength and absorption intensity at that wavelength) with the same chemical chromophore can be challenging.

[0007] These challenges are further exacerbated when it comes to providing an intense yellow color: Due to eye sensitivity, the human eye typically perceives pure yellow—that is, without green or orange contributions—only within a very narrow wavelength range, between approximately 566 nm and approximately 589 nm. Therefore, absorption must be tailored around this wavelength region, more specifically within the visible range above approximately 589 nm and below approximately 566 nm. At the same time, yellow is an important color because it is a primary color and is useful in achieving many blended colors.

[0008] For these reasons, it would be desirable to have a genipin derivative that provides a suitable basis for convenient fine-tuning of color appearance and intensity, particularly for yellow derivatives. Summary of the Invention

[0009] In a first aspect, the present disclosure relates to a topical composition comprising a compound of formula (I),

[0010]

[0011] or a tautomer and / or a pharmaceutically acceptable salt thereof,

[0012] in:

[0013] R 1 represents an optionally substituted C1-C 30 part;

[0014] R 2 represents hydrogen or a protecting group capable of hydrolysis under physiological conditions after application of the topical composition to the skin;

[0015] R 3 represents an optionally substituted C1-C 30 part;

[0016] R 4 represents hydrogen or an optionally substituted C1-C 30 part;

[0017] in represents a single bond, and the two R 5 independently of one another represent hydrogen or an optionally substituted C1-C 30 part, or part of represents a double bond, and R 5 One of the does not exist, and R 5 The other represents hydrogen or an optionally substituted C1-C 30 part; and

[0018] Excipients suitable for topical administration.

[0019] In some embodiments, R 1 The optionally substituted C1-C 30 The following sections are included: C1-C 30 moieties: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

[0020] In some embodiments, R 1 Indicates -COOH, R 6 or -C(=O)-R 6 , where R 6 represents an optionally substituted C1-C 12 -alkyl, C2-C 12 -alkenyl, C2-C 12 -alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C1-C 12 -alkyl, O-C2-C 12 -alkenyl, O-C2-C 12 -alkynyl, O-C6-C 16 -aryl or O-C3-C 12 -heteroaryl.

[0021] In some embodiments, R 1Represents COOH, C(=O)-O-C1-C 12 -alkyl or C(=O)-O-C6-C 16 - aryl, and in particular COOH or C(═O)—O—C 1 -C 4 -alkyl.

[0022] In some embodiments, the compound of formula (I) is a compound of formula (II),

[0023]

[0024] or a tautomer and / or a pharmaceutically acceptable salt thereof,

[0025] where R 6 represents a hydroxyl group or an optionally substituted C1-C 30 part; and wherein R 2 、R 3 、R 4 、R 5 and are defined as indicated above for formula (I).

[0026] In some embodiments, R 2 represents hydrogen or a C1-C6 acyl group, and in particular hydrogen.

[0027] In some embodiments, R 3 represents an optionally substituted C1-C 12 -alkyl, optionally substituted C2-C 12 -alkenyl, optionally substituted C2-C 12 -alkynyl, optionally substituted C6-C 16 -aryl or optionally substituted C3-C 12 -heteroaryl.

[0028] In some embodiments, R 3 express:

[0029] a) optionally substituted C1-C 12 -alkyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms;

[0030] b) optionally substituted C1-C 12-alkenyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms;

[0031] c) optionally substituted C1-C 12 -alkynyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms;

[0032] d) optionally substituted C6-C 16 - aryl, with the proviso that the optional substituents contain in total between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms; or

[0033] e) a C3-C ... 12 -heteroaryl, wherein the C3-C 12 - heteroaryl is optionally substituted, provided that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms;

[0034] and 0 to 10, more specifically 0 to 8 and especially 0 to 6 halogen atoms.

[0035] In some embodiments, R 3 Indicates C6-C 16 -aryl, the C6-C 16- aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of:

[0036] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0037] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0038] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0039] O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl;

[0040] (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl;

[0041] O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl;

[0042] halogen, more particularly chlorine or fluorine, and especially fluorine;

[0043] Nitro;

[0044] NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl;

[0045] NH(CO)R 6 , wherein R6 represents C1-C6 alkyl or C6-C 12 aryl;

[0046] (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and

[0047] S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

[0048] In some embodiments, R 3 Indicates C6-C 16 -aryl, the C6-C 16- aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of:

[0049] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0050] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0051] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0052] halogen, more particularly chlorine or fluorine, and especially fluorine; and

[0053] Nitro.

[0054] In some embodiments, R 3 represents a phenyl group substituted by 1, 2 or 3 substituents, wherein each of said substituents is independently selected from the group consisting of:

[0055] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0056] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0057] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0058] halogen, more particularly chlorine or fluorine, and especially fluorine; and

[0059] Nitro.

[0060] In some embodiments, R 3 represents a phenyl group substituted by 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF3 groups, more particularly wherein R 3 It represents a phenyl group which is substituted in the para position by one fluorine atom or one CF3 group, in particular by one fluorine atom, or in the meta position by two fluorine atoms or two CF3 groups, in particular by two fluorine atoms or by two CF3 groups.

[0061] In some embodiments, R 3 represents a phenyl group which is monosubstituted in the ortho-, meta- and / or para-position by fluorine, a CF3 group or an O-C1-C4-alkyl group, in particular in the para-position by fluorine or a CF3 group, in particular fluorine.

[0062] In some embodiments, R 3 Represents one of the following:

[0063]

[0064] In some embodiments, R 4 The optionally substituted C1-C 30 The following sections are included: C1-C 30 moieties: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

[0065] In some embodiments, R 4 represents hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0066] In some embodiments, in Formula (I) or (II), represents a single bond, and the two R 5 independently represent hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0067] In some embodiments, in Formula (I) or (II), represents a double bond, and an R 5 does not exist, and another R 5 represents hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0068] In some embodiments, the compound of formula (I) is a compound of formula (III),

[0069]

[0070] where R 2 、R 4 、R 5 and R 6 As defined for formula (I), wherein As defined for formula (I), and wherein R n 7 represents n substituents R 7 ,

[0071] wherein n is an integer between 0 and 5, more particularly an integer between 0 and 3, and especially 1, and wherein n is 0 means that R 7 does not exist,

[0072] where R 7 independently of one another represent a moiety selected from the group consisting of:

[0073] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0074] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0075] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0076] O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl;

[0077] (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl;

[0078] O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl;

[0079] halogen, more particularly chlorine or fluorine, and especially fluorine;

[0080] Nitro;

[0081] NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl;

[0082] NH(CO)R 6 , where R 6 Represents C1-C6 alkyl or C6-C 12 aryl;

[0083] (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and

[0084] S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

[0085] In some embodiments, in Formula (III), n is 1, 2, or 3, and R 7 The substituents are in the ortho and / or para positions. In some embodiments, n is 1 and R 7 In the ortho or para position.

[0086] In some embodiments, in Formula (III), R 7 Each occurrence of represents, independently of one another, a moiety chosen from the group consisting of: O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; halogen, more particularly chlorine or fluorine, and especially fluorine; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; and nitro.

[0087] In some embodiments, the compound of formula (I) is a compound of formula (IV),

[0088]

[0089] where R 2 and R 6 As defined for formula (I), wherein As defined for formula (I), and wherein R n 7 As defined above for formula (III).

[0090] In some embodiments, the compound of formula (I) is a compound of formula (V),

[0091]

[0092] where R 2 and R 6 As defined for formula (I).

[0093] In some embodiments, the composition is in the form of a solid, liquid, ink, gel, a patch for transferring the composition to the skin, or a base carrier containing the topical composition.

[0094] In some embodiments, excipients suitable for topical administration include one or more excipients selected from the group consisting of water, ethanol, isopropyl alcohol, n-propyl alcohol, ethylene glycol, diethylene glycol, propylene glycol, glycerol, and mixtures thereof.

[0095] In some embodiments, the composition comprises a thickener and / or a film former.

[0096] In some embodiments, the compound of formula (I) after conversion with lysine to the corresponding compound of formula (VI)

[0097]

[0098] where R 3 、R 4 、R 5 and R 6 As defined for formula (I), and wherein As defined for formula (I),

[0099] absorbs light having wavelengths between about 380 nm and about 565 nm, more specifically between about 380 nm and about 568 nm, and particularly between about 380 nm and about 570 nm;

[0100] wherein the corresponding compound of formula (VI) optionally also absorbs light at a wavelength between about 590 nm and about 750 nm, more specifically between about 587 nm and about 750 nm, and especially between about 585 nm and about 750 nm; and

[0101] wherein the corresponding compound of formula (VI) optionally does not absorb light having a wavelength between about 566 nm and about 589 nm, more specifically between about 569 nm and about 586 nm, and especially between about 571 nm and about 584 nm.

[0102] In some embodiments, the composition further comprises genipin or a genipin derivative, more specifically, in a relative molar amount of 0.05 to 20 relative to the amount of the compound of formula (I).

[0103] In some embodiments, the composition further comprises an antioxidant.

[0104] In a second aspect, the present disclosure relates to a storage unit comprising a topical composition according to any embodiment of the first aspect, wherein the storage unit is protected from the ingress of oxygen or contains an oxygen scavenger.

[0105] In a third aspect, the present disclosure relates to a process for the preparation of a topical composition according to any embodiment of the first aspect, the process comprising admixing a compound of formula (I) as defined above with an excipient suitable for topical administration.

[0106] In a fourth aspect, the present disclosure relates to a method of mixing a compound of formula (I) as defined above with genipin or a genipin derivative. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] Figure 1 One potential binding mechanism of genipin to skin is shown, in this case to amino groups of skin macromolecules such as collagen or keratin.

[0108] Figure 2Shown is a comparison of the UV / vis spectra of the compound of Example 1 before and after conversion to its lysine conjugate. DETAILED DESCRIPTION

[0109] Provided herein are topical compositions comprising semi-permanent colorants and / or semi-permanent colorant precursors, which include derivatives of genipin. As used herein, a "topical composition" means a composition suitable for (i.e., cosmetically suitable for) application to the skin, more specifically to mammalian skin, particularly human skin. As used herein, a "semi-permanent colorant" refers to a colorant that penetrates one or more layers of the skin and cannot be removed from the skin without physical damage or natural desquamation of the skin. In some embodiments, the semi-permanent colorant may include a colorant precursor of a genipin derivative that exhibits color when reacting with, for example, one or more other molecules on the skin. In some embodiments, the semi-permanent colorant can penetrate the stratum corneum and react with other molecules present in the stratum corneum so that the semi-permanent colorant is fixed in the stratum corneum. For example, the semi-permanent colorant can react, for example, with collagen or keratin present in the stratum corneum. The semi-permanent colorant can penetrate the stratum corneum, and the colorant residence time can be determined by the natural skin desquamation process. In some embodiments, the semi-permanent colorant cannot be washed off by, for example, water, soap, and / or isopropyl alcohol.

[0110] In a first aspect, the present disclosure relates to a topical composition comprising a compound of formula (I),

[0111]

[0112] or a tautomer and / or a pharmaceutically acceptable salt thereof,

[0113] in:

[0114] R 1 represents an optionally substituted C1-C 30 part;

[0115] R 2 represents hydrogen or a protecting group capable of hydrolysis under physiological conditions after application of the topical composition to the skin;

[0116] R 3 represents an optionally substituted C1-C 30 part;

[0117] R 4 represents hydrogen or an optionally substituted C1-C 30 part;

[0118] in represents a single bond, and the two R 5independently of one another represent hydrogen or an optionally substituted C1-C 30 part, or part of represents a double bond, and R 5 One of the does not exist, and R 5 The other represents hydrogen or an optionally substituted C1-C 30 part; and

[0119] Excipients suitable for topical administration.

[0120] The present inventors have surprisingly discovered that providing a carbonyl-based substituent to the conjugated core system of a genipin derivative (when combined with an amino group present on the skin) provides a distinct and intense color performance to the chromophoric system of the genipin derivative. As will be described in the experimental section, the color performance is significantly brighter (an intense, bright yellow color compared to a pale yellow color) than a genipin derivative carrying an aldehyde-based substituent instead of a carbonyl-based substituent. Furthermore, while both aldehyde-based and carbonyl-based substituents can provide similar color performance, it is believed that the carbonyl-based genipin derivative will be more stable and potentially longer-lasting (when applied to the skin) than the corresponding aldehyde analogs.

[0121] In the present disclosure, the term "excipient" is to be understood as established in the pharmaceutical art, for example in the European Pharmacopoeia. In particular, the so-called "excipient" is intended to mean a pharmaceutically or metabolically inactive substance which acts as a vehicle or medium for the compound of formula (I).

[0122] When mentioning R 1 is an optionally substituted C1-C 30 When an optionally substituted C1-C 30 The moiety may be an (optionally substituted) C1-C 18 Part or (optionally substituted) C1-C 12 part.

[0123] When in R 2 In the context of , when referring to protective groups that are capable of hydrolysis under physiological conditions after application of the topical composition to the skin: such groups are readily known to the skilled person and include in particular acyl moieties, such as optionally substituted acyl moieties, comprising 1 to 30, more particularly 1 to 16, and in particular 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and in particular 0 to 6 oxygen atoms; 0 to 8, more particularly 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, and in particular 0 to 6 halogen atoms. Specific examples include C1-C18 Acyl moieties, more specifically C1-C 12 Acyl moieties, and in particular C1-C4 acyl moieties. When reference is made to "physiological conditions" in this context, it is understood that this refers in particular to the pH conditions encountered at the site where the compound of formula (I) is assumed to bind to proteins, for example, in the stratum corneum and / or epidermis of the subject to be treated (a mammal, in particular a human). Additionally or alternatively, the term "protective group capable of hydrolyzing under physiological conditions after application of the topical composition" refers to a group that hydrolyzes when 0.1 mol / l of the compound of formula (I) is placed in an aqueous solution having a pH of about 5 and also containing 0.1 mol / l lysine at 37° C. for 2 hours, wherein the group in question qualifies as a "protective group capable of hydrolyzing under physiological conditions after application of the topical composition" if a significant amount of a 1,4-dihydropyridine derivative is formed (e.g., a conversion yield of greater than 10 mol %). Additionally or alternatively, a compound of formula (I) (or a topical composition comprising the compound) contains a "protecting group that is hydrolyzable under physiological conditions following application of the topical composition" if the compound (or a topical composition comprising the compound) cannot be completely washed off the (explanted) pig skin with water, soap and / or isopropyl alcohol after incubation of the compound on the pig skin at, for example, 37°C for, for example, 2 hours.

[0124] In some embodiments, R 1 The optionally substituted C1-C 30 The moiety is a moiety comprising: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms. The aforementioned numbers refer to the total number of carbon, oxygen, nitrogen, sulfur and halogen, respectively. It should be understood that the optionally substituted C1-C 30 The moiety may optionally contain other atoms and optional other substituents, but even in the presence of such optional other substituents, the aforementioned numbers of carbon, oxygen, nitrogen, sulfur and halogen cannot be exceeded. It should also be understood that halogen refers specifically to fluorine, chlorine and bromine.

[0125] In some embodiments, R 1 Indicates -COOH, R 6 or -C(=O)-R 6 , where R 6 represents an optionally substituted C1-C 12 -alkyl, C2-C 12 -alkenyl, C2-C 12-alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C1-C 12 -alkyl, O-C2-C 12 -alkenyl, O-C2-C 12 -alkynyl, O-C6-C 16 -aryl or O-C3-C 12 -heteroaryl.

[0126] In some embodiments, R 1 Represents COOH, C(=O)-O-C1-C 12 -alkyl or C(=O)-O-C6-C 16 - aryl, and in particular COOH or C(═O)—O—C 1 -C 4 -alkyl.

[0127] In some embodiments, the compound of formula (I) is a compound of formula (II),

[0128]

[0129] or a tautomer and / or a pharmaceutically acceptable salt thereof,

[0130] where R 6 represents a hydroxyl group or an optionally substituted C1-C 30 part; and wherein R 2 、R 3 、R 4 、R 5 and are defined as indicated above for formula (I).

[0131] In some embodiments, R 2 represents hydrogen or a C1-C6 acyl group, and in particular hydrogen.

[0132] In some embodiments, R 3 represents an optionally substituted C1-C 12 -alkyl, optionally substituted C2-C 12 -alkenyl, optionally substituted C2-C 12 -alkynyl, optionally substituted C6-C 16 -aryl or optionally substituted C3-C 12 -heteroaryl.

[0133] In some embodiments, R 3 express:

[0134] a) optionally substituted C1-C 12-alkyl, with the proviso that the optional substituents contain in total between 0 and 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more particularly 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more particularly 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, and especially 0 to 6 halogen atoms, more particularly fluorine, chlorine or bromine, and especially fluorine;

[0135] b) optionally substituted C1-C 12 -alkenyl, with the proviso that the optional substituents contain in total between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms, more specifically fluorine, chlorine or bromine, and especially fluorine;

[0136] c) optionally substituted C1-C 12 -alkynyl, with the proviso that the optional substituents contain in total between 0 and 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more particularly 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more particularly 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, and especially 0 to 6 halogen atoms, more particularly fluorine, chlorine or bromine, and especially fluorine;

[0137] d) optionally substituted C6-C 16 - aryl, with the proviso that the optional substituents contain in total between 0 and 12, more particularly 0 to 8, and in particular 0 to 6 carbon atoms; between 0 to 8, more particularly 0 to 6, and in particular 0 to 4 oxygen atoms; 0 to 8, more particularly 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, and in particular 0 to 6 halogen atoms, more particularly fluorine, chlorine or bromine, and in particular fluorine; or

[0138] e) a C3-C ... 12 -heteroaryl, wherein the C3-C 12- Heteroaryl is optionally substituted, provided that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms, more specifically fluorine, chlorine or bromine, and especially fluorine.

[0139] In some embodiments, it may be particularly advantageous for R 3 represents an optionally further substituted C6-C 16 - aryl, with the proviso that the optional substituents contain a total of between 0 and 12, more particularly 0 to 8, and in particular 0 to 6 carbon atoms; between 0 to 8, more particularly 0 to 6, and in particular 0 to 4 oxygen atoms; 0 to 8, more particularly 0 to 6, and in particular 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, and in particular 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, and in particular 0 to 6 halogen atoms, wherein these halogen atoms are more particularly fluorine, chlorine or bromine, and in particular fluorine.

[0140] In some embodiments, it may be particularly advantageous for R 3 represents a C3-C ... 12 -heteroaryl, wherein the C3-C 12- Heteroaryl is optionally further substituted, provided that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms, more specifically fluorine, chlorine or bromine, and especially fluorine. The term "heteroaryl" as used herein refers to a stable heterocyclic or polyheterocyclic aromatic moiety having 3 to 12 carbon ring atoms. As indicated above, the heteroaryl group may be substituted or unsubstituted within the aforementioned range. The heteroaryl group may contain one or more rings. Examples of typical heteroaryl rings include 5-membered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, etc.; 6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; and polycyclic heterocyclic groups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, etc. phenyl, benzothiazole, benzoimidazole, tetrahydroquinolinolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, phenoxazinyl, and the like (see, e.g., Katritzky, Handbook of Heterocyclic Chemistry, 3rd ed. 2010). Further specific examples of heteroaryl rings include 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl or benzisoxazolyl. Heteroaryl groups also include groups in which a heteroaromatic ring is fused to one or more aromatic or non-aromatic rings, wherein the linking group or point of attachment is on the heteroaromatic ring.Examples include tetrahydroquinoline, tetrahydroisoquinoline, and pyrido[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-c]pyrimidinyl, pyrazolo[1,5-a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl, pyrazolo[1,5-b][1,2,4]triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidinyl, triazolopyrimidinyl, pyridopyrazinyl.

[0141] In some embodiments, it may be particularly advantageous if R 3 Indicates C6-C 16 -aryl, the C6-C 16 - aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of:

[0142] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0143] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0144] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0145] O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl;

[0146] (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl;

[0147] O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl;

[0148] halogen, more particularly chlorine or fluorine, and especially fluorine;

[0149] Nitro;

[0150] NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl;

[0151] NH(CO)R 6 , where R6 Represents C1-C6 alkyl or C6-C 12 aryl;

[0152] (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and

[0153] S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

[0154] In some embodiments, it may be particularly advantageous if R 3 Indicates C6-C 12 -aryl, the C6-C 16 - aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of:

[0155] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0156] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0157] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0158] halogen, more particularly chlorine or fluorine, and especially fluorine; and

[0159] Nitro.

[0160] In some embodiments, it may be particularly advantageous if R 3 represents a phenyl group substituted by 1, 2 or 3 substituents, wherein each of said substituents is independently selected from the group consisting of:

[0161] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0162] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0163] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0164] halogen, more particularly chlorine or fluorine, and especially fluorine; and

[0165] Nitro.

[0166] In some embodiments, R 3 Substituted by 1, 2, 3, 4 or 5 fluorine atoms and / or fluorine-containing groups, in particular CF3.

[0167] In some embodiments, R 3 represents phenyl, naphthyl, anthracenyl, pyrenyl, indenyl, thienyl, furyl, benzoxazolyl or indolyl substituted by 1, 2, 3, 4 or 5 fluorine atoms and / or fluorine-containing groups, in particular CF3.

[0168] In some embodiments, R 3 represents a phenyl group substituted by 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF3 groups, more particularly wherein R 3 It represents a phenyl group which is substituted in the para position by one fluorine atom or one CF3 group, in particular by one fluorine atom, or in the meta position by two fluorine atoms or two CF3 groups, in particular by two fluorine atoms or by two CF3 groups.

[0169] In some embodiments, R 3 represents a phenyl group which is monosubstituted in the ortho-, meta- and / or para-position by fluorine or a CF3 group or an O-C1-C4-alkyl group, in particular in the para-position by fluorine or a CF3 group, in particular fluorine.

[0170] In some embodiments, R 3 Represents one of the following:

[0171]

[0172] In some embodiments, R 3 Represents one of the following:

[0173]

[0174] The fluoro substituents in the aforementioned embodiments can provide a strong color effect (i.e., increased absorption) without causing a significant red shift or blue shift. For these reasons, the genipin derivatives of the present disclosure carrying such substituents are particularly interesting in providing genipin derivatives with strong colors and in facilitating the design of genipin derivatives with desired colors, because R 3 The absorbance of some components can be decoupled from the absorption wavelength to a certain extent.

[0175] In some embodiments, R 4 The optionally substituted C1-C 30 The following sections are included: C1-C 30moieties: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms. In some embodiments, the optionally substituted C1-C 30 The moiety may be an (optionally substituted) C1-C 18 Part or (optionally substituted) C1-C 12 part.

[0176] In some embodiments, R 4 The optionally substituted C1-C 30 The moiety is a moiety comprising: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms. The aforementioned numbers refer to the total number of carbon, oxygen, nitrogen, sulfur and halogen, respectively. It should be understood that the optionally substituted C1-C 30 The moiety may optionally contain other atoms and optional other substituents, but even in the presence of such optional other substituents, the aforementioned numbers of carbon, oxygen, nitrogen, sulfur and halogen cannot be exceeded. It should also be understood that halogen refers specifically to fluorine, chlorine and bromine.

[0177] In some embodiments, R 4 represents hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0178] In some embodiments, R 5 Each case of represents an optionally substituted C1-C 30 The moiety is a moiety comprising (independently of each other) 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms. The aforementioned numbers refer to the total number of carbon, oxygen, nitrogen, sulfur and halogen, respectively. It should be understood that the optionally substituted C1-C 30The moiety may optionally contain other atoms and optional other substituents, but even in the presence of such optional other substituents, the aforementioned numbers of carbon, oxygen, nitrogen, sulfur and halogen cannot be exceeded. It should also be understood that halogen refers specifically to fluorine, chlorine and bromine.

[0179] In some embodiments, in Formula (I), represents a single bond, and the two R 5 independently represent hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0180] In some embodiments, in Formula (I), represents a double bond, and an R 5 does not exist, and another R 5 represents hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0181] In some embodiments, the compound of formula (I) is a compound of formula (III),

[0182]

[0183] where R 2 、R 4 、R 5 and R 6 As defined for formula (I), more specifically wherein R 2 、R 4 and R 5 represents hydrogen, and R 6 represents a methoxy group, wherein As defined for formula (I), and wherein R n 7 represents n substituents R 7 ,

[0184] wherein n is an integer between 0 and 5, more particularly an integer between 0 and 3, and especially 1, and wherein n is 0 means that R 7 does not exist,

[0185] where R 7 independently of one another represent a moiety selected from the group consisting of:

[0186] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0187] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0188] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0189] O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl;

[0190] (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl;

[0191] O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl;

[0192] halogen, more particularly chlorine or fluorine, and especially fluorine;

[0193] Nitro;

[0194] NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl;

[0195] NH(CO)R 6 , where R 6 Represents C1-C6 alkyl or C6-C 12 aryl;

[0196] (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and

[0197] S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio, more particularly where n represents 1 and R 7 represents fluorine or CF3, more particularly fluorine, more particularly wherein R 7 In counterpoint.

[0198] In some embodiments, in Formula (III), n is 1, 2, or 3, and R 7 The substituents are in the ortho and / or para positions. In some embodiments, n is 1 and R 7 In the ortho or para position.

[0199] In some embodiments, in Formula (III), R 7Each occurrence of represents, independently of one another, a moiety chosen from the group consisting of: O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; halogen, more particularly chlorine or fluorine, and especially fluorine; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; and nitro.

[0200] In some preferred embodiments, in formula (III), R 2 represents hydrogen, R 6 represents a methoxy group, n represents 1, is a single bond, and R 7 represents fluorine, more specifically R 7 In an even more preferred embodiment, R 4 and R 5 Represents hydrogen.

[0201] In some embodiments, the compound of formula (I) is a compound of formula (IV),

[0202]

[0203] where R 2 and R 6 As defined for formula (I), wherein As defined for formula (I), more specifically, wherein R 2 represents hydrogen, and R 6 represents a methoxy group, and wherein R n 7 As defined above for formula (III), more specifically, wherein n represents 1, and R 7 represents fluorine or CF3, more particularly fluorine, more particularly wherein R 7 In counterpoint.

[0204] In some preferred embodiments, in formula (IV), R 2 represents hydrogen, R 6 represents a methoxy group, n represents 1, is a single bond, and R 7 represents fluorine, more specifically R 7 In position.

[0205] In some embodiments, the compound of formula (I) is a compound of formula (V),

[0206]

[0207] where R 2 and R 6 As defined for formula (I).

[0208] In some preferred embodiments, in Formula (V), R 2 represents hydrogen, and R 6 represents a methoxy group.

[0209] In some preferred embodiments, the compound of formula (III) or formula (IV) or formula (V) is the following compound:

[0210]

[0211] Typically, the aforementioned compositions can be formulated in any form known in the art for topical or cosmetic applications. Thus, the compositions can be applied in any topical form, such as in the form of an 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 used in the field of topical application and / or cosmetics / sunscreens and skin care formulations. The compositions can also be water-resistant (e.g., waterproof).

[0212] In some embodiments, the composition is in the form of a solid, liquid, ink, gel, a patch for transferring the composition to the skin, or a base carrier containing the topical composition.

[0213] The composition of the present disclosure can contain any one of the compounds described herein in the range of 0.005 weight % to 99 weight %, and the balance is made up of a suitable excipient. The composition of the present disclosure can contain any one of the compounds provided herein in the range of 0.005 weight % to 99 weight %, in one embodiment 0.1 weight % to 95 weight %, in another embodiment 75 weight % to 85 weight %, in another embodiment 20 weight % to 80 weight % of the compounds provided herein, wherein the balance can be made up of any excipient as described herein or any combination of these excipients. In some preferred embodiments, the topical composition can contain any one of the compounds provided herein in the range of 0.05 weight % to 15 weight %, even more specifically 0.05 weight % to 10 weight %, more specifically 0.08 weight % to 5 weight %, and particularly 0.1 weight % to 3 weight % relative to the total weight of the composition.

[0214] In some embodiments, the topical composition comprises one or more additional ingredients, carriers or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (humectants), emulsifiers, film formers / preservatives, fragrances, leave-on exfoliants, prescription medications, preservatives, scrubs, silicones, skin-like / healing agents, slip agents, additional conventional sunscreen actives (non-limiting examples of such sunscreens include titanium oxide and zinc oxide), surfactants / detergents, penetration enhancers and thickeners. Specifically, the composition may contain any acceptable excipient approved by the FDA or EMA for such use. Examples of acceptable inactive excipients include retinyl palmitate, parabens, PEG, fragrances, BHT, phthalates, phenoxyethanol, coconut oil, aloe vera, sunflower oil, calendula, almond oil, starch, gelatin, hemicellulose, arabinogalactan, agar, glycerin, lactic acid, propylene glycol, polyethylene glycol, polyvinyl pyrrolidone, acrylates, acrylamide, copolymers of the foregoing, amino acids (such as arginine, alanine or asparagine), ascorbic acid, citric acid, and mixtures thereof.

[0215] In some embodiments, excipients suitable for topical administration include one or more excipients selected from the group consisting of water, ethanol, isopropyl alcohol, n-propyl alcohol, ethylene glycol, diethylene glycol, propylene glycol, glycerol, and mixtures thereof.

[0216] In some preferred embodiments, excipients suitable for topical administration include water, monohydric or polyhydric alcohols, or mixtures thereof.

[0217] In some preferred embodiments, the excipients include water, C1-C4 alkyl alcohol, C1-C4 alkoxydiglycol, C2-C8 alkanediol, glycerol, C1-C 12 Alkylglycerol, di(C1-C6 alkyl)glycerol, sugar, disaccharide, polysaccharide, phenoxyethanol, oil, terpenoid, phenylpropionic acid compound, amino acid, protein, water-soluble polymer or mixtures thereof.

[0218] In some embodiments, it may be particularly preferred that the pH of the topical composition is between 2.5 and 9, more particularly between 3 and 8, and especially between 4 and 7.

[0219] In some embodiments, the composition comprises a thickener and / or a film former.

[0220] In some embodiments, the composition further comprises an antioxidant.

[0221] In some embodiments, the topical composition is contained in a container and optionally also provided with a package surrounding the container. The term packaging should be understood to refer to its conventional meaning in the art, and in particular refers to the closure or protection of a container for distribution, storage, sale and / or use.

[0222] In some embodiments, the compound of formula (I) after conversion with lysine to the corresponding compound of formula (VI)

[0223]

[0224] where R 3 、R 4 、R 5 and R 6 As defined for formula (I), and wherein As defined for formula (I),

[0225] absorbs light having wavelengths between about 380 nm and about 565 nm, more specifically between about 380 nm and about 568 nm, and particularly between about 380 nm and about 570 nm;

[0226] wherein the corresponding compound of formula (VI) optionally also absorbs light at a wavelength between about 590 nm and about 750 nm, more specifically between about 587 nm and about 750 nm, and especially between about 585 nm and about 750 nm; and

[0227] wherein the corresponding compound of formula (VI) optionally does not absorb light having a wavelength between about 566 nm and about 589 nm, more specifically between about 569 nm and about 586 nm, and especially between about 571 nm and about 584 nm.

[0228] With respect to the aforementioned absorption characteristics, it should be noted that the human eye is most sensitive to green light, and therefore, absorption of light having wavelengths between approximately 380 nm and approximately 565 nm, more specifically between approximately 380 nm and approximately 568 nm, and especially between approximately 380 nm and approximately 570 nm, specifically removes from the visible spectrum those portions that would provide a green hue to the color and that are most readily accepted by the human eye.

[0229] Optionally, the aforementioned corresponding compound of formula (VI) does not absorb light having wavelengths between about 566 nm and about 589 nm, more specifically between about 569 nm and about 586 nm, and in particular between about 571 nm and about 584 nm, which correspond to wavelengths perceived by the human eye as red or reddish. Since the human eye is substantially less sensitive to these wavelengths than to "green" wavelengths, lower (relative) absorption is generally better tolerated in this wavelength region than in the "green" wavelength region.

[0230] In addition, the aforementioned corresponding compound of formula (VI) optionally absorbs light having a wavelength between about 590 nm and about 750 nm, more specifically between about 587 nm and about 750 nm, and especially between about 585 nm and about 750 nm. This wavelength region is typically perceived as yellow by the human eye, and the narrow wavelength bandwidth reflected by this feature is a measure of the brightness of the color (a narrower wavelength distribution is perceived as brighter by the human eye).

[0231] The measurement conditions for determining the absorption (or lack of absorption) of the aforementioned corresponding compound of formula (VI) are not particularly limited. Exemplary conditions are typical conditions for UV / visible spectroscopy, such as about 1-5×10 -5 M solution. A person skilled in the art is generally able to interpret UV / visible spectra and determine whether there is absorption in a specific wavelength region. However, in the case where quantitative measurements are required, if the (normalized) absorption coefficient is not higher than 0.4, specifically not higher than 0.2, and in particular not higher than 0.1 in the wavelength region in question, the corresponding compound of formula (VI) can be considered invalid.

[0232] In some embodiments, the composition further comprises an antioxidant.

[0233] In a second aspect, the present disclosure relates to a storage unit comprising a topical composition according to any embodiment of the first aspect, wherein the storage unit is protected from the ingress of oxygen or contains an oxygen scavenger. In some embodiments, the storage unit is further provided with a packaging surrounding the storage unit.

[0234] In a third aspect, the present disclosure relates to a process for the preparation of a topical composition according to any embodiment of the first aspect, the process comprising admixing a compound of formula (I) as defined above with an excipient suitable for topical administration.

[0235] In a fourth aspect, the present disclosure relates to a method of mixing a compound of formula (I) as defined above with genipin or a genipin derivative.

[0236] The term "genipin derivative" includes any derivative of genipin, in particular any compound comprising a substituted chemical moiety of formula (VII) below,

[0237]

[0238] wherein R independently of one another represents H or a substituent, and wherein Represents a single bond and is attached to The two R's independently represent hydrogen or a substituent, or wherein represents a double bond and is attached to One of the R's does not exist and is attached to The other of R represents hydrogen or a substituent. In some embodiments, the genipin derivative is a compound of formula (I), and more specifically, the genipin derivative is a compound of formula (II), (III), (IV) and / or (V).

[0239] In another aspect, the present disclosure relates to mixtures of a compound of formula (I) as defined above with a dye, pigment and / or genipin or a genipin derivative as defined above.

[0240] For the sake of clarity, the present disclosure also relates to compounds of formula (I), and more particularly compounds of formula (II), (III), (IV) and (V) per se.

[0241] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (I), and more specifically a compound of formula (II), (III), (IV), or (V).

[0242] In yet another aspect, the disclosure relates to the use of a compound of formula (I), and more particularly a compound of formula (II), (III), (IV) or (V), for coloring the skin or artificial or natural fibers, and in particular for coloring the skin or hair.

[0243] In some embodiments, the use comprises applying the compound to skin, particularly mammalian skin; and / or the surface, epidermis, or dermis of the skin; and / or skin appendages, such as nails. In some embodiments, the use comprises applying the compound to artificial and natural fibers. In some embodiments, the use comprises applying the compound to hair, particularly mammalian hair, and particularly hair that is still attached to the skin.

[0244] In yet another aspect, the present disclosure relates to a method of coloring skin or artificial or natural fibers using a compound of formula (I), and more specifically a compound of formula (II), (III), (IV) or (V); and in particular, coloring skin or hair. In some preferred embodiments, the method is a tattoo.

[0245] Compounds provided herein also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton-isotropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Example proton-isotropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially locked into a form by appropriate substitution.

[0246] As used herein, a "salt" or "pharmaceutically acceptable salt" of a compound of any of the formulae disclosed herein is formed between an acid and a basic group (such as an amino functional group) of the compound, or between a base and an acidic group (such as a carboxyl functional group) of the compound. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly used to form pharmaceutically acceptable salts of compounds of any of the formulae include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, Pharmaceutically acceptable acid addition salts include, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and in particular those formed with organic acids such as maleic acid.In some embodiments, bases commonly used to form pharmaceutically acceptable salts of compounds of any of the formulae disclosed herein include alkali metal hydroxides, including sodium, potassium, and lithium; alkaline earth metal hydroxides, such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributylamine; pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine; mono-(2-OH-(C1-C6)-alkylamine), bis-(2-OH-(C1-C6)-alkylamine), or tri-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids, such as arginine, lysine, and the like. In some embodiments, the compound of any of the formulae disclosed herein, or a salt thereof, is substantially isolated.

[0247] The compounds of the present disclosure can be prepared using conventional synthetic routes known in the art or by the following reaction schemes.

[0248] Examples and Comparative Examples

[0249] All starting materials / reagents / solvents were purchased from Sigma Aldrich, Thermo Fisher, VWR, TCI Chemicals or Oakwood chemicals and used without purification. Genipin was provided by Herb-Sun Biotechnology.

[0250] Comparative Example 1, i.e., methyl (4aS,7aS)-7-formyl-1-hydroxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate, was prepared as follows:

[0251]

[0252] To a stirred solution of genipin (50 mmol, 1 eq) in dichloromethane was added Dess-Martin periodinane (DMP) (55 mmol, 1.2 eq) and the mixture was stirred overnight. Saturated solutions of NaHCO3 and Na2S2O3 were added to the reaction mixture in sequence. The resulting mixture was added to a separatory funnel and extracted with dichloromethane / water (3 times) followed by brine. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting crude material had 10%-15% hydration product. The crude mixture was then dissolved in methanol and a spatula tip was added to it. IRA-400 resin (hydroxide form). The combination was stirred at room temperature for 15 minutes. The resin was filtered, and the crude material was dry-loaded onto silica and purified by flash chromatography (hexane:ethyl acetate 60:40). NMR data were consistent with previous reports (see Tetrahedron, 1993, 49, 10555-10576, Tetrahedron Letters, 1993, 34, 2621-2624).

[0253] 1 H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 9.69 (s, 1H), 7.59-7.54 (m, 1H), 7.50 (s, 1H), 7.23 ( m, 1H), 7.16 (m, 1H), 6.71 (d, J=10.9Hz, 1H), 5.24 (dd, J=10.9, 2.1Hz, 1H), 4.79 (dd, J= 8.4, 5.9Hz, 1H), 4.57 (d, J=6.2Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.50 (m, 2H), 3.36-3 .18 (m, 2H), 3.02-2.87 (m, 2H), 2.72 (dtd, J=19.8, 2.8, 1.7Hz, 1H), 2.49-2.33 (m, 1H).

[0254] 13 C NMR (100MHz, CDCl3) δ191.8, 191.0, 167.6, 167.4, 161.8, 156.0, 154.7, 153.3, 144. 9, 144.6, 109.9, 109.6, 95.6, 95.1, 51.5, 51.4, 48.3, 45.8, 40.8, 39.6, 37.3, 36.0;

[0255] HRMS(DART+):C 11 H 13 O5[M+H] + Calculated value: 225.07575 m / z, found: 225.07637 m / z.

[0256] Example 1 was prepared from Comparative Example 1 using the following overall reaction scheme:

[0257] Overall reaction scheme :

[0258]

[0259] Step 1:

[0260]

[0261] Genipine aldehyde (1 equivalent) is added to a round-bottom flask and dissolved in anhydrous methanol (0.2M). To this is added p-toluenesulfonic acid monohydrate (0.3eq), and the reaction is stirred for 68 hours, or until complete conversion is observed by TLC. Methanol is removed in vacuo, and the residue is redissolved in dichloromethane. The solution is passed through a silica plug and rinsed with dichloromethane to remove the acid catalyst. Dichloromethane is removed via rotary evaporation, and then diethyl ether / hexane is added to the residue to obtain a white precipitate. The precipitate is filtered through a Buchner funnel and washed with cold ether / hexane.

[0262] Step 2:

[0263]

[0264] The crude aldehyde from step 1 was transferred to a 1 L Schlenk flask. THF (0.05 M) and a magnetic stirring bar were added thereto. The flask was cooled to 0 ° C, and then Grignard reagent (0.99 equivalents) was added dropwise at 0 ° C and warmed to room temperature. The reaction was monitored by TLC and completed after 90 minutes. Once completed, the reaction was cooled to 0 ° C and quenched with 1 M HCl. The quenched solution was stirred for 30 minutes. THF / 1 M HCl solution was poured into a separatory funnel with ethyl acetate and water. The aqueous phase was washed 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated via rotary evaporation. The crude reaction mixture was dry loaded onto silica and purified via flash column chromatography (EtOAc / hexane: 0: 100 → 25: 75). The resulting purified material can still be a mixture of diastereomers. The two diastereomers can be separated by a second column with diethyl ether / hexane (20: 80 → 40: 60).

[0265] Step 3:

[0266]

[0267] To a stirred solution of alcohol (1 equivalent) in dichloromethane (0.25 M) was added DMP (1.1 equivalents) at room temperature. The reaction was monitored by TLC for 60 minutes. Once complete, the solvent was evaporated under reduced pressure and the residue was washed with saturated sodium bicarbonate and sodium thiosulfate (Na2S2O3) in a separatory funnel with diethyl ether. The organic phase was dried over sodium sulfate, concentrated, and separated by flash column chromatography.

[0268] Step 4:

[0269]

[0270] The separated material from step 3 was dissolved in a mixture of acetic acid, THF and 3M HCl at a total concentration of 0.07M. The respective ratios were 30% AcOH, 50% THF and 20% 3M HCl. The mixture was heated to 50°C for 5 days. Once complete, the mixture was quenched with a saturated sodium bicarbonate solution and checked with pH paper until neutral / alkaline. The mixture was then distributed between ethyl acetate and water in a separatory funnel. The organic phase was collected, dried over sodium sulfate and concentrated in vacuo. The crude material was separated by flash column chromatography.

[0271] Characterization of major diastereomers

[0272] 1 H NMR (400 MHz, CDCl3) δ 7.88-7.82 (m, 2H, arylCH), 7.64 (1H), 7.23-7.16 (m, 2H, arylCH), 6.89 (broad t, J = 2.7 Hz, 1H), 6.43 (d, J = 4.0 Hz, 1H, OH), 4.92 (broad dd, J = 8.5, 4.0 Hz, 1H), 3.78 (s, 3H), 3.39 (m, 1H), 3.29 (ddd, J = 19.0, 8.3, 3.2 Hz, 1H), 3.04 (m, 1H), 2.44 (ddt, J = 19.0, 9.5, 2.1 Hz, 1H).

[0273] 13 C NMR (101MHz, CDCl3) δ194.7, 167.7, 167.3, 164.7, 153.4, 152.0, 141.6, 132.3, 132.2, 116.1, 115.8, 109.7, 95.9, 51.5, 48.3, 41.4, 36.3.

[0274] Genipin and the compounds of Example 1 and Comparative Example 1 were converted into their corresponding lysine conjugates according to the following procedure:

[0275] Prepare the solution of 0.05M reactive dye precursor in MeOH, and make it of short duration stirring in the bottle that is equipped with stirring bar.Add two equivalents of L-lysine, and reaction mixture is capped loosely and at room temperature stirred 24 hours.In case finish, remove solvent in vacuum, and use high vacuum further drying.

[0276] Example 1 provides an intense and bright yellow color, while Comparative Example 1 is yellow, but pale in comparison.

[0277] In addition, the UV / visible spectra obtained for the compound of Example 1 and its conjugate with lysine showed Figure 2 middle.

[0278] As from Figure 2 As is evident from the Figure 3, the conjugate of the compound of Example 1 with lysine is characterized by two absorption peaks centered at approximately 350 nm and 450 nm. These peaks were absent from the compound of Example 1 before it was converted into the lysine conjugate.

[0279] List of implementation plans

[0280] The following further embodiments also belong to the present disclosure:

[0281] 1. A topical composition comprising a compound of formula (I),

[0282]

[0283] or a tautomer and / or a pharmaceutically acceptable salt thereof,

[0284] in:

[0285] R 1 represents an optionally substituted C1-C 30 part;

[0286] R 2 represents hydrogen or a protecting group capable of hydrolysis under physiological conditions after application of the topical composition to the skin;

[0287] R 3 represents an optionally substituted C1-C 30 part;

[0288] R 4 represents hydrogen or an optionally substituted C1-C 30 part;

[0289] in represents a single bond, and the two R 5 independently of one another represent hydrogen or an optionally substituted C1-C 30 part, or part of represents a double bond, and R 5 One of the does not exist, and R 5 The other represents hydrogen or an optionally substituted C1-C 30 part;

[0290] as well as

[0291] Excipients suitable for topical administration.

[0292] 2. The topical composition according to embodiment 1, wherein R 1 The optionally substituted C1-C 30 The following sections are included: C1-C 30moieties: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

[0293] 3. The topical composition according to embodiment 1 or embodiment 2, wherein R 1 Indicates -COOH, R 6 or -C(=O)-R 6 , where R 6 represents an optionally substituted C1-C 12 -alkyl, C2-C 12 -alkenyl, C2-C 12 -alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C1-C 12 -alkyl, O-C2-C 12 -alkenyl, O-C2-C 12 -alkynyl, O-C6-C 16 -aryl or O-C3-C 12 -heteroaryl.

[0294] 4. A topical composition according to any preceding embodiment, wherein R 1 Represents COOH, C(=O)-O-C1-C 12 -alkyl or C(=O)-O-C6-C 12 - aryl, and in particular COOH or C(═O)—O—C 1 -C 4 -alkyl.

[0295] 5. The topical composition according to any preceding embodiment, wherein the compound of formula (I) is a compound of formula (II),

[0296]

[0297] or a tautomer and / or a pharmaceutically acceptable salt thereof,

[0298] where R 6 represents a hydroxyl group or an optionally substituted C1-C 30 part; and wherein R 2 、R 3 、R 4 、R 5 and Defined as indicated in embodiment 1.

[0299] 6. A topical composition according to any preceding embodiment, wherein R 2 represents hydrogen or a C1-C6 acyl group, and in particular hydrogen.

[0300] 7. A topical composition according to any preceding embodiment, wherein R 3 represents an optionally substituted C1-C 12 -alkyl, optionally substituted C2-C 12 -alkenyl, optionally substituted C2-C 12 -alkynyl, optionally substituted C6-C 16 -aryl or optionally substituted C3-C 12 -heteroaryl.

[0301] 8. A topical composition according to any preceding embodiment, wherein R 3 express:

[0302] a) optionally substituted C1-C 12 -alkyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms;

[0303] b) optionally substituted C1-C 12 -alkenyl, with the proviso that the optional substituents contain between 0 and 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms in total;

[0304] between 0 and 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms;

[0305] c) optionally substituted C1-C 12 -alkynyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms;

[0306] d) optionally substituted C6-C 16 - aryl, with the proviso that the optional substituents contain in total between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms; or

[0307] e) a C3-C ... 12 -heteroaryl, wherein C3-C 12 - Heteroaryl is optionally substituted, provided that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

[0308] 9. A topical composition according to any preceding embodiment, wherein R3 represents C6-C 16 -aryl, the C6-C 16 - aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of:

[0309] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0310] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0311] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0312] O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl;

[0313] (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl;

[0314] O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl;

[0315] halogen, more particularly chlorine or fluorine, and especially fluorine;

[0316] Nitro;

[0317] NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl;

[0318] NH(CO)R 6 , where R 6 Represents C1-C6 alkyl or C6-C 12 aryl;

[0319] (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and

[0320] S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

[0321] 10. A topical composition according to any preceding embodiment, wherein R3 represents C6-C 16 -aryl, the C6-C 16 - aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of:

[0322] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0323] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0324] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0325] halogen, more particularly chlorine or fluorine, and especially fluorine; and

[0326] Nitro.

[0327] 11. The topical composition according to any preceding embodiment, wherein R3 represents phenyl substituted with 1, 2 or 3 substituents, wherein each of said substituents is independently selected from the group consisting of:

[0328] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0329] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0330] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0331] halogen, more particularly chlorine or fluorine, and especially fluorine; and

[0332] Nitro.

[0333] 12. A topical composition according to any preceding embodiment, wherein R3 represents a phenyl group substituted by 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF3 groups, more particularly wherein R 3 It represents a phenyl group which is substituted in the para position by one fluorine atom or one CF3 group, in particular by one fluorine atom, or in the meta position by two fluorine atoms or two CF3 groups, in particular by two fluorine atoms or by two CF3 groups.

[0334] 13. A topical composition according to any preceding embodiment, wherein R 3 Represents one of the following:

[0335]

[0336] 14. A topical composition according to any preceding embodiment, wherein R 4 The optionally substituted C1-C 30 The following sections are included: C1-C 30 moieties: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

[0337] 15. The topical composition according to any preceding embodiment, wherein R 4 represents hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0338] 16. A topical composition according to any preceding embodiment, wherein represents a single bond, and the two R 5 independently represent hydrogen, C1-C6 alkyl or C6-C 12 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0339] 17. A topical composition according to any preceding embodiment, wherein represents a double bond, and an R 5 does not exist and another R 5 represents hydrogen, C1-C6 alkyl or C6-C 16 Aryl; more particularly hydrogen or C1-C4 alkyl; and especially hydrogen.

[0340] 18. The topical composition according to any preceding embodiment, wherein the compound of formula (I) is a compound of formula (III),

[0341]

[0342] where R 2 、R 4 、R 5 and R 6 According to any one of embodiments 1 to 17, wherein According to embodiment 1, wherein R n 7 represents n substituents R 7 , wherein n is an integer between 0 and 5, more particularly an integer between 0 and 3, and especially 1, and wherein n is 0 means that R 7 does not exist,

[0343] where R 7 independently of one another represent a moiety selected from the group consisting of:

[0344] C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl;

[0345] C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl;

[0346] O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy;

[0347] O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl;

[0348] (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl;

[0349] O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl;

[0350] halogen, more particularly chlorine or fluorine, and especially fluorine;

[0351] Nitro;

[0352] NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl;

[0353] NH(CO)R 6 , where R 6 Represents C1-C6 alkyl or C6-C 12 aryl;

[0354] (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and

[0355] S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

[0356] 19. The topical composition of embodiment 18, wherein n is 1, 2 or 3, and wherein the R 7 The substituents are in the ortho and / or para positions; in particular, where n is 1 and R 7 In the ortho or para position.

[0357] 20. The topical composition of any one of embodiments 18 to 19, wherein R 7 independently of one another represent a moiety chosen from the group consisting of O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; halogen, more particularly chlorine or fluorine, and especially fluorine; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; and nitro.

[0358] 21. The topical composition according to any preceding embodiment, wherein the compound of formula (I) is a compound of formula (IV),

[0359]

[0360] where R 2 and R 6 According to any one of embodiments 1 to 17, wherein According to embodiment 1, wherein R n 7 According to any one of embodiments 18 to 20.

[0361] 22. The topical composition according to any preceding embodiment, wherein the compound of formula (I) is a compound of formula (V),

[0362]

[0363] where R 2 and R 6 According to any one of embodiments 1 to 17.

[0364] 23. The topical composition according to any preceding embodiment, wherein the composition is in the form of a solid, a liquid, an ink, a gel, a patch for transferring the composition to the skin, or a substrate carrier comprising the topical composition.

[0365] 24. The topical composition according to any preceding embodiment, wherein the excipients suitable for topical administration comprise one or more excipients selected from the group consisting of water, ethanol, isopropyl alcohol, n-propyl alcohol, ethylene glycol, diethylene glycol, propylene glycol, glycerol, and mixtures thereof.

[0366] 25. The topical composition according to any preceding embodiment, wherein the composition comprises a thickener and / or a film former.

[0367] 26. The topical composition according to any preceding embodiment, wherein the compound of formula (I) after conversion with lysine to the corresponding compound of formula (VI)

[0368]

[0369] where R 3 、R 4 、R 5 and R 6 According to any one of embodiments 1 to 17, and wherein According to embodiment 1,

[0370] absorbs light at wavelengths between about 380 nm and about 565 nm, more specifically between about 380 nm and about 568 nm, and in particular between about 380 nm and about 570 nm; wherein the corresponding compound of formula (VI) optionally also absorbs light at wavelengths between about 590 nm and about 750 nm, more specifically between about 587 nm and about 750 nm, and in particular between about 585 nm and about 750 nm; and

[0371] wherein the corresponding compound of formula (VI) optionally does not absorb light having a wavelength between about 566 nm and about 589 nm, more specifically between about 569 nm and about 586 nm, and especially between about 571 nm and about 584 nm.

[0372] 27. The topical composition of embodiment 18, wherein:

[0373] R 2 represents hydrogen,

[0374] R 6 represents a methoxy group,

[0375] N represents 1, is a single bond, and

[0376] R 7 represents fluorine, more particularly wherein R 7 In position, and

[0377] Especially R 4 and R 5 Represents hydrogen.

[0378] 28. The topical composition of embodiment 21, wherein:

[0379] R 2 represents hydrogen,

[0380] R 6 represents a methoxy group,

[0381] n represents 1, is a single bond, and

[0382] R 7 represents fluorine, more particularly wherein R 7 In position.

[0383] 29. The topical composition of embodiment 22, wherein:

[0384] R 2 represents hydrogen, and

[0385] R 6 represents a methoxy group.

[0386] 30. The topical composition according to any preceding embodiment, wherein the composition further comprises genipin or a genipin derivative, more particularly in a relative molar amount of 0.05 to 20 relative to the amount of the compound of formula (I).

[0387] 31. The topical composition according to any preceding embodiment, wherein the composition further comprises an antioxidant.

[0388] 32. A storage unit comprising a topical composition according to any preceding embodiment, wherein the storage unit is protected from the ingress of oxygen or contains an oxygen scavenger.

[0389] 33. A process for the preparation of a topical composition according to any one of embodiments 1 to 31, which process comprises mixing a compound of formula (I) as defined in any one of embodiments 1 to 30 with an excipient suitable for topical administration.

[0390] 34. A method of mixing a compound of formula (I) according to any one of embodiments 1 to 31 with genipin or a genipin derivative.

Claims

1. A topical composition comprising a compound of formula (I), or a tautomer and / or a pharmaceutically acceptable salt thereof, in: R 1 represents an optionally substituted C1-C 30 part; R 2 represents hydrogen or a protecting group capable of hydrolysis under physiological conditions after application of the topical composition to the skin; R 3 represents an optionally substituted C1-C 30 part; R 4 represents hydrogen or an optionally substituted C1-C 30 part; in represents a single bond, and the two R 5 independently of one another represent hydrogen or an optionally substituted C1-C 30 part, or part of represents a double bond, and R 5 One of the does not exist, and R 5 The other represents hydrogen or an optionally substituted C1-C 30 portion; and excipients suitable for topical administration.

2. The topical composition according to claim 1, wherein R 1 The optionally substituted C1-C 30 The following sections are included: C1-C 30 moieties: 1 to 30, more specifically 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more specifically 0 to 8, and especially 0 to 6 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

3. The topical composition according to claim 1 or claim 2, wherein R 1 Indicates -COOH, R 6 or -C(=O)-R 6 , where R 6 represents an optionally substituted C1-C 12 -alkyl, C2-C 12 -alkenyl, C2-C 12 -alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C1-C 12 -alkyl, O-C2-C 12 -alkenyl, O-C2-C 12 -alkynyl, O-C6-C 16 -aryl or O-C3-C 12 -heteroaryl.

4. A topical composition according to any preceding claim, wherein the compound of formula (I) is a compound of formula (II), or a tautomer and / or a pharmaceutically acceptable salt thereof, where R 6 represents a hydroxyl group or an optionally substituted C1-C 30 part; and wherein R 2 、R 3 、R 4 、R 5 and As defined in claim 1.

5. A topical composition according to any preceding claim, wherein R 2 represents hydrogen or a C1-C6 acyl group, and in particular hydrogen.

6. A topical composition according to any preceding claim, wherein R 3 represents an optionally substituted C1-C 12 -alkyl, optionally substituted C2-C 12 -alkenyl, optionally substituted C2-C 12 -alkynyl, optionally substituted C6-C 16 -aryl or optionally substituted C3-C 12 -heteroaryl.

7. A topical composition according to any preceding claim, wherein R 3 express: a) optionally substituted C1-C 12 -alkyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms; b) optionally substituted C1-C 12 -alkenyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms; c) optionally substituted C1-C 12 -alkynyl, with the proviso that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms; d) optionally substituted C6-C 16 - aryl, with the proviso that the optional substituents contain in total between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms; or e) a C3-C ... 12 -heteroaryl, wherein the C3-C 12 - Heteroaryl is optionally substituted, provided that the optional substituents contain a total of between 0 and 12, more specifically 0 to 8, and especially 0 to 6 carbon atoms; between 0 to 8, more specifically 0 to 6, and especially 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and especially 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and especially 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and especially 0 to 6 halogen atoms.

8. A topical composition according to any preceding claim, wherein R 3 Indicates C6-C 16 -aryl, the C6-C 16 - aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of: C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl; O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl; halogen, more particularly chlorine or fluorine, and especially fluorine; Nitro; NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; NH(CO)R 6 , where R 6 Represents C1-C6 alkyl or C6-C 12 aryl; (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

9. A topical composition according to any preceding claim wherein R3 represents C6-C 16 -aryl, the C6-C 16 - aryl is optionally substituted by 1 to 5, more particularly 1, 2 or 3, substituents, and especially 1 substituent, wherein each of said substituents is independently selected from the group consisting of: C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; halogen, more particularly chlorine or fluorine, and especially fluorine; and Nitro.

10. A topical composition according to any preceding claim, wherein R 3 represents a phenyl group substituted by 1, 2 or 3 substituents, wherein each of said substituents is independently selected from the group consisting of: C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; halogen, more particularly chlorine or fluorine, and especially fluorine; and Nitro.

11. A topical composition according to any preceding claim, wherein the compound of formula (I) is a compound of formula (III), where R 2 、R 4 、R 5 and R 6 According to any one of claims 1 to 10, wherein According to claim 1, and wherein R n 7 represents n substituents R 7 , wherein n is an integer between 0 and 5, more particularly an integer between 0 and 3, and especially 1, and wherein n is 0 means that R 7 does not exist, where R 7 independently of one another represent a moiety selected from the group consisting of: C1-C6-alkyl, more particularly C1-C4-alkyl, and especially methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, and especially trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, and especially methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl and especially O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more specifically (C=O)-O-C1-C4-alkyl; O-(C=O)-C1-C6-alkyl, more particularly O-(C=O)-C1-C4-alkyl; halogen, more particularly chlorine or fluorine, and especially fluorine; Nitro; NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; NH(CO)R 6 , where R 6 Represents C1-C6 alkyl or C6-C 12 aryl; (C=O)NR 6 2, where each R 6 independently represent hydrogen, C1-C6 alkyl or C6-C 12 aryl; and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, and especially methylthio or ethylthio.

12. A topical composition according to any preceding claim, wherein the compound of formula (I) is a compound of formula (IV), where R 2 and R 6 According to any one of claims 1 to 10, wherein According to claim 1, and wherein R n 7 According to claim 11.

13. A topical composition according to any preceding claim, wherein the compound of formula (I) is a compound of formula (V), where R 2 and R 6 According to any one of claims 1 to 10.

14. A topical composition according to any preceding claim, wherein the compound of formula (I), after conversion with lysine to the corresponding compound of formula (VI), where R 3 、R 4 、R 5 and R 6 According to any one of claims 1 to 10, and wherein According to claim 1, absorbs light having wavelengths between about 380 nm and about 565 nm, more specifically between about 380 nm and about 568 nm, and particularly between about 380 nm and about 570 nm; wherein the corresponding compound of formula (VI) optionally also absorbs light at a wavelength between about 590 nm and about 750 nm, more specifically between about 587 nm and about 750 nm, and especially between about 585 nm and about 750 nm; and wherein the corresponding compound of formula (VI) optionally does not absorb light having a wavelength between about 566 nm and about 589 nm, more specifically between about 569 nm and about 586 nm, and especially between about 571 nm and about 584 nm.

15. A method of mixing a compound of formula (I) according to any one of claims 1 to 14 with genipin or a genipin derivative.

16. A compound of formula (VIII):

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