Genipin derivatives, topical compositions containing same, and use as semi-permanent coloring agents

Abstract

The present application provides topical compositions comprising genipin derivatives of formula (I), which are useful, for example, as coloring agents in semi-permanent tattoos. [Formula 1] JPEG2026505979000079.jpg25169

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to European Patent Application Publication Nos. 23157133.2 and 23157132.4, filed February 16, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to colored genipin derivatives that are adherent to skin and are useful, for example, as coloring agents in semi-permanent tattoos. [Background technology]

[0003] Temporary or semi-permanent tattoos or body inks have been used throughout human history to decorate the body. Generally, temporary or semi-permanent tattoos are transferred to the skin by directly exposing the skin to the tattoo ink for a specified latency period. The quality of the transferred image and its duration on the skin may depend on the ink distribution profile in the outer layer of the skin, called the stratum corneum. Currently used manufacturing methods for pre-made tattoo designs include the use of topical formulations in many forms, including flexographic or gravure inks, stencils, and inkjet printers.

[0004] Genipin is particularly beneficial for use in such semi-permanent tattoos because it chemically binds to skin (in mammals, particularly humans) in a long-lasting manner and produces an intense blue color. One model illustrating the possible mechanism of chemical binding and color development on skin is shown in Figure 1. As seen in Figure 1, genipin is believed to form a colored conjugated system upon chemical binding to amino groups on skin proteins. The color of genipin when bound to skin is an intense dark blue.

[0005] However, it is also desirable to provide semi-permanent tattoos in other colors of comparable intensity and / or improved intensity. In practice, designing genipin derivatives with specific colors can be challenging for several reasons. First, despite advances in calculating UV / vis absorption spectra, it is extremely difficult to precisely predict the exact color impression and intensity of a given genipin derivative. Second, while the general principles of how conjugated systems and chemical moieties affect UV / vis absorption are well established, designing genipin derivatives with the desired color impression using a trial-and-error approach can be time-consuming and laborious. Designing a specific genipin color is further burdened by the fact that the genipin core, upon binding to skin, provides the first chromophore, while other moieties on the genipin derivative provide additional chromophore systems. The resulting color impression is determined by the combined absorption of all chromophore systems. Second, 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 these two goals (absorption at a given wavelength and intensity of absorption at that wavelength) using the same chemical chromophore can be difficult.

[0006] For these reasons, it would be desirable to have a genipin derivative that provides a suitable platform for conveniently fine-tuning the color impression. Summary of the Invention

[0007] In a first aspect, the present disclosure provides a compound of formula (I): [ka] or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein: R 1 optionally substituted C1-C 30 represents a part, R 2 represents hydrogen or a protecting group that is hydrolyzable under physiological conditions after application of the topical composition to the skin, R 3represents an aromatic or heteroaromatic moiety substituted with one or more fluorine atoms and / or fluorine-containing groups, in particular CF3, R 4 is hydrogen or optionally substituted C-C 30 represents a part, [ka] represents a single bond, and both R 5 are, independently of each other, hydrogen or optionally substituted C-C 30 Represents a part, or [ka] represents a double bond, and R 5 does not exist and R 5 the other is hydrogen or an optionally substituted C-C 30 represents a part, The present invention relates to a topical composition comprising a compound, or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein L represents a bond or a spacer group containing 1 to 12 carbon atoms, more particularly containing 1 to 6 carbon atoms, and an excipient suitable for topical administration.

[0008] In some embodiments, R 1 Optionally substituted C1-C represented by 30 7. The topical composition of any one of claims 1 to 6, wherein the moiety comprises 1 to 30, more particularly 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and especially 0 to 6 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.

[0009] In some embodiments, R 1 is -COOH, R 6 , or -C(=O)-R 6 wherein R 6 is an optionally substituted C1-C 12 -Alkyl, C2-C12 -Alkenyl, C2-C 12 -Alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -heteroaryl.

[0010] In some embodiments, R 1 COOH, C(=O)-O-C1-C 12 -Alkyl, or C(=O)-O-C6-C 16 -aryl, in particular COOH or C(=O)-O-C1-C4-alkyl.

[0011] In some embodiments, R 2 represents hydrogen or C1-C6 acyl, especially hydrogen.

[0012] In some embodiments, L represents a linker group comprising 1-12 carbon atoms, 0-6 oxygen atoms, 0-4 nitrogen atoms, 0-3 sulfur atoms, and 0-6 halogen atoms.

[0013] In some embodiments, L represents an aliphatic linker group, L, containing 1-8 carbon atoms, 0-4 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulfur atoms, and 0-6 halogen atoms.

[0014] In some embodiments, L is (CH2) where n is an integer from 1 to 6. n , CH(OH)-, CH(OH)-(CH2) where m is an integer of 1 to 5 m -; C(=O)- or C(=O)-(CH2) where o is an integer of 1 to 5 o n is an integer from 1 to 5, and R x represents a C1-C6 acyl group, CH(OR x )-, CH(OR x )-(CH2)n - represents.

[0015] In some embodiments, R 3 represents: a) optionally further substituted C-C 16 -aryl, wherein the optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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 other than fluorine atoms; or b) C3-C containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S 12 -heteroaryl, C3-C 12 -heteroaryl is optionally further substituted, wherein the optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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 other than fluorine atoms.

[0016] In some embodiments, R 3 is a C-C optionally further substituted by 1 to 5, more particularly 1, 2, or 3, substituent(s), especially 1, 16 -aryl, each of the above substituents independently represents: C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, H, C-C alkyl, or C-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and It is selected from the group consisting of S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio.

[0017] In some embodiments, R 3 is a C-C optionally further substituted by 1 to 5, more particularly 1, 2, or 3, substituent(s), especially 1, 16 -aryl, each of the above substituents independently represents: C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and nitro.

[0018] In some embodiments, R 3 represents phenyl optionally further substituted with 1, 2, or 3 substituent(s), each of said substituents being, independently of one another, C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and nitro.

[0019] In some embodiments, R 3 is substituted with 1, 2, 3, 4, or 5 fluorine atoms and / or fluorine-containing groups, particularly CF3.

[0020] In some embodiments, R 3 represents phenyl, naphthenyl, anthracenyl, pyrenyl, indenyl, thiophenyl, furanyl, benzoxazolyl, or indolyl substituted with 1, 2, 3, 4, or 5 fluorine atoms and / or fluorine-containing groups, in particular CF3.

[0021] In some embodiments, R 3 represents phenyl substituted with 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF groups, more particularly R 3 represents phenyl substituted with one fluorine atom or one CF3 group, in particular one fluorine atom, in the para position, or phenyl substituted with two fluorine atoms or two CF3 groups, in particular two fluorine atoms or two CF3 groups, in the meta position.

[0022] In some embodiments, R 3 The following part: [ka] represents one of the following:

[0023] In some embodiments, R 4 Optionally substituted C1-C represented by 30 The part is C1-C 30 a moiety comprising 1 to 30, more particularly 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and especially 0 to 6 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.

[0024] In some embodiments, R 4 is hydrogen, C1-C6 alkyl or C6-C 16 It represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0025] In some embodiments, in formula (I): [ka] represents a single bond, and both R 5 are each independently hydrogen, C1-C6 alkyl, or C6-C 16 It represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0026] In some embodiments, in formula (I): [ka] represents a double bond, and one R 5 does not exist, and the other R 5 is hydrogen, C1-C6 alkyl, or C6-C 16It represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0027] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] where R 2 , R 3 , R 4 , and R 5 is as defined above in formula (I), [ka] is as defined above in formula (I), and R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -represents heteroaryl.

[0028] In some embodiments, the compound of formula (I) is a compound of formula (III): [ka] where R 2 , R 4 , and R 5 is as defined above for formula (I), [ka] is as defined above for formula (I), and R 6 is an optionally substituted C1-C 12 -Alkyl, C2-C12 -Alkenyl, C2-C 12 -Alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -heteroaryl, L is as defined above for formula (I), n is an integer from 1 to 5, and R 7 are independent of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, However, R 7 At least one of represents fluorine or CF3.

[0029] In some embodiments, the compound of formula (I) is a compound of formula (IV): [ka] where R 2 , R 4 , and R 5 is as defined above for formula (I), [ka] is as defined above for formula (I), R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 represents heteroaryl, n is an integer from 1 to 5, R 7 are independent of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, However, R 7 At least one of represents fluorine or CF3.

[0030] In some embodiments, the compound of formula (I) is a compound of formula (V): [ka] where R 2 , R 4 , and R 5 is as defined for formula (I) above, [ka] is as defined above for formula (I), R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 represents heteroaryl, n is an integer from 1 to 5, R 7 are independent of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, R 8 is hydrogen or C1-C 12 represents an acyl group, However, R 7 At least one of represents fluorine or CF3.

[0031] In some embodiments of any one of formulas (II)-(IV), n is 1, 2, or 3; and R 7 represents fluorine or CF3, more specifically fluorine.

[0032] In some embodiments of any one of formulas (II)-(IV), n is 1 and R 7 is in the para position, or n is 2 and both R 7 is in meta position.

[0033] In some embodiments of any one of formulas (II)-(IV), n is greater than 1 and R 7 At least one of represents a moiety selected from the group consisting of O-C-C-alkyl, more particularly O-C-C-alkyl, in particular methoxy or ethoxy; and halogen or C-C-haloalkyl, more particularly C-C-fluoroalkyl, in particular trifluoromethyl.

[0034] In some embodiments, the composition is in the form of a substrate carrier, including a solid, liquid, ink, gel, patch for transferring the composition onto the skin, or topical composition.

[0035] In some embodiments, excipients suitable for topical administration include one or more excipients selected from water, ethanol, isopropanol, n-propanol, ethylene glycol, diethylene glycol, propylene glycol, and glycerol, or mixtures thereof.

[0036] In some embodiments, the composition comprises a thickening agent and / or a film-forming agent.

[0037] In some embodiments, the composition further comprises an antioxidant.

[0038] In a further aspect, the present invention relates to a storage unit comprising a topical composition according to any of the foregoing embodiments of the first aspect, wherein the storage unit is protected from oxygen ingress or comprises an oxygen scavenger.

[0039] In a further aspect, the present invention relates to a method for preparing a topical composition according to any of the preceding embodiments of the first aspect, comprising mixing a compound of formula (I) with excipients suitable for topical administration. [Brief explanation of the drawings]

[0040] [Figure 1] One possible mechanism of binding of genipin to skin, in this case to amino groups of skin macromolecules such as collagen or keratin, is shown. [Figure 2] 1 shows a comparison of UV / vis spectra of genipin, Example 1, and Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0041] Provided herein are topical compositions comprising a semi-permanent colorant and / or a semi-permanent colorant precursor, including a genipin derivative. As used herein, "topical composition" refers to a composition suitable for application to skin, more specifically mammalian skin, particularly human skin (i.e., suitable for cosmetic use). As used herein, "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 disruption or natural desquamation of the skin. In some embodiments, the semi-permanent colorant may include, for example, genipin, a genipin derivative colorant precursor, which develops color upon reaction with one or more other molecules on the skin. In some embodiments, the semi-permanent colorant may penetrate the stratum corneum and react with other molecules present in the stratum corneum, thereby immobilizing the semi-permanent colorant within the stratum corneum. For example, the semi-permanent colorant may react with, for example, collagen or keratin found in the stratum corneum. The semi-permanent colorant penetrates the stratum corneum, and the residence time of the colorant may depend on the natural skin exfoliation process. In some embodiments, the semi-permanent colorant cannot be washed off, for example, by water, soap, and / or isopropanol.

[0042] In a first aspect, the present disclosure provides a compound of formula (I): [ka] or a tautomer and / or a pharmaceutically acceptable salt thereof, wherein: R 1 optionally substituted C1-C 30 represents a part, R 2 represents hydrogen or a protecting group that is hydrolyzable under physiological conditions after application of the topical composition to the skin, R 3 represents an aromatic or heteroaromatic moiety substituted with one or more fluorine atoms and / or fluorine-containing groups, in particular CF3, R 4 is hydrogen or optionally substituted C-C 30 represents a part, [ka] represents a single bond, and both R 5 are, independently of each other, hydrogen or optionally substituted C-C 30 Represents a part, or [ka] represents a double bond, and R 5 does not exist and R 5 the other is hydrogen or an optionally substituted C-C 30 represents a part, L represents a bond or a spacer group containing 1 to 12 carbon atoms, in particular 1 to 6 carbon atoms, or a tautomer and / or a pharmaceutically acceptable salt thereof; and an excipient suitable for topical administration.

[0043] The present inventors have surprisingly found that providing a fluoro-based substituent on the (hetero)aromatic moiety of a genipin derivative allows for fine tuning of the absorbance of the moiety without excessively shifting the absorption wavelength of the moiety. The fluoro-based substituent appears to provide a hyperchromic effect (i.e., increased absorption) without causing a significant bathochromic or hypsochromic shift. For these reasons, the genipin derivatives of the present disclosure are particularly interesting in providing genipin derivatives with strong colors and facilitating the design of genipin derivatives with desired colors, since the absorbance of the (hetero)aromatic moiety can be decoupled to some extent from the absorption wavelength.

[0044] In the present disclosure, the term "excipient" is understood as established in the pharmaceutical field, for example as established in the European Pharmacopoeia. In particular, "excipient" means a pharmaceutically or metabolically inactive substance that serves as a vehicle or medium for a compound of formula (I).

[0045] R 1 optionally substituted C1-C 30When referring to a moiety, it should be understood that the moiety may optionally contain other atoms, but the optional substituents do not bring the total carbon number of the moiety beyond 30. In some embodiments, an optionally substituted C-C 30 The moiety is (optionally substituted) C-C 18 Moiety or (optionally substituted) C1-C 12 It can be a part.

[0046] R 2 In this context, when referring to protecting groups that are hydrolyzable under physiological conditions after application of the topical composition to the skin, the following applies: such groups will be readily apparent to those skilled in the art and include, in particular, acyl moieties, such as optionally substituted acyl moieties containing 1 to 30, more particularly 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and especially 0 to 6 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. Specific examples include C1-C 18 The acyl moiety, more specifically C1-C 12 Acyl moieties, particularly C1-C4 acyl moieties, are included.

[0047] When referring to "physiological conditions" in this context, it should be understood that this refers in particular to the pH conditions encountered at the site where the compound of formula (I) is expected to bind to proteins, for example, in the stratum corneum and / or epidermis of a treated (mammalian, particularly human) subject. Additionally or alternatively, the term "protecting group hydrolyzable under physiological conditions after application of a topical composition" refers to a group that is hydrolyzed when 0.1 mol / L of the compound of formula (I) is placed in an aqueous solution having a pH of about 5 and further containing 0.1 mol / L of lysine at 37°C for 2 hours, and the group in question qualifies as a "protecting group hydrolyzable under physiological conditions after application of a topical composition" if a significant amount of a 1,4-dihydropyridine derivative (e.g., a conversion yield of more than 10 mol%) is formed. Additionally or alternatively, a compound of formula (I) contains a "protecting group hydrolyzable under physiological conditions after application of a topical composition" if the compound (or a topical composition containing the compound) cannot be comprehensively washed off the (explanted) pig skin with water, soap, and / or isopropanol after incubating the compound (or a topical composition containing the compound) on the pig skin, e.g., at 37°C for, e.g., 2 hours.

[0048] When referring to a spacer group, L, it should be understood that this term refers to any group having the requisite number of carbon atoms. L serves to covalently link each adjacent group to each other. For this reason, in this disclosure, the term linker group is used interchangeably with the term spacer group.

[0049] In some embodiments, R 1 Optionally substituted C1-C represented by 30The moiety is a moiety containing 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 above numbers refer to the total number of carbon, oxygen, nitrogen, sulfur, and halogen atoms, respectively. The above optionally substituted C1-C 30 It is to be understood that the moiety may optionally include other atoms and optionally further substituents, but that even in the presence of such optional further substituents the number of carbon, oxygen, nitrogen, sulfur, and halogen mentioned above may not be exceeded. It is also to be understood that halogen refers specifically to fluoro, chloro, and bromo.

[0050] In some embodiments, R 1 is -COOH, R 6 , or -C(=O)-R 6 wherein R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -heteroaryl.

[0051] In some embodiments, R 1 COOH, C(=O)-O-C1-C 12 -Alkyl, or C(=O)-O-C6-C 16 -aryl, in particular COOH or C(=O)-O-C1-C4-alkyl.

[0052] In some embodiments, R 2represents hydrogen or C1-C6 acyl, especially hydrogen.

[0053] In some embodiments, L represents a linker group comprising 1-12 carbon atoms, 0-6 oxygen atoms, 0-4 nitrogen atoms, 0-3 sulfur atoms, and 0-6 halogen atoms. In some embodiments, L represents an aliphatic linker group L comprising 1-8 carbon atoms, 0-4 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulfur atoms, and 0-6 halogen atoms. In some embodiments, L represents a linker group comprising 1-6 carbon atoms, 0-6 oxygen atoms, 0-4 nitrogen atoms, 0-3 sulfur atoms, and 0-6 halogen atoms. In some embodiments, L represents an aliphatic linker group L comprising 1-4 carbon atoms, 0-4 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulfur atoms, and 0-6 halogen atoms.

[0054] In some embodiments, L is (CH2) where n is an integer from 1 to 6. n , CH(OH)-, CH(OH)-(CH2) where m is an integer of 1 to 5 m -; C(=O)-; C(=O)-(CH2) where o is an integer from 1 to 5 o -, or n is an integer from 1 to 5, and R x represents a C1-C6 acyl group, CH(OR x )-, CH(OR x )-(CH2) n - represents.

[0055] In some embodiments, R 3 is an optionally further substituted C-C 16 -aryl, wherein the optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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, which are not fluorine atoms (e.g., bromo or chloro).

[0056] In some embodiments, R 3 is a C3-C aryl group containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S; 12 -heteroaryl, C3-C 12 Heteroaryl is optionally further substituted, provided that the optional substituents contain, in total, 0 to 12, more specifically 0 to 8, and particularly 0 to 6 carbon atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 oxygen atoms; 0 to 8, more specifically 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more specifically 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more specifically 0 to 8, and particularly 0 to 6 halogen atoms, where the halogen atoms are not fluorine atoms (e.g., bromo or chloro). As used herein, the term "heteroaryl" refers to a stable heterocyclic or polyheterocyclic aromatic moiety having 3 to 12 carbon ring atoms. As described above, heteroaryl groups can be substituted or unsubstituted within the above ranges. Heteroaryl can contain one or more rings. Typical examples of heteroaryl rings include 5-membered monocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, and thiazolyl; 6-membered monocyclic ring groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; and polycyclic heterocyclic ring groups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, and isoindo. Examples of aryl include indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, benzothiazole, benzimidazole, tetrahydroquinoline, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl (see, for example, Katritzky, Handbook of Heterocyclic Chemistry, 3 rded. 2010). Further specific examples of heteroaryl rings include 2-furanyl, 3-furanyl, 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-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2 ... -pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinoiinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. Heteroaryl groups also include groups in which the heteroaromatic ring is fused to one or more aromatic or non-aromatic rings, where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinoline, tetrahydroisoquinoline, and pyrido[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyiridinyl, imidazo[1,2-c]pyrimidyl, pyrazolo[1,5-a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidyl, pyrazolo[1,5-b][1,2,4]triazine, quinolyl, isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl, triazolopyrimidyl, and pyridopyrazinyl.

[0057] In some embodiments, R 3 is a C-C optionally further substituted by 1 to 5, more particularly 1, 2, or 3, substituent(s), especially 1, 16 -aryl, each of the above substituents independently represents: C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, H, C-C alkyl, or C-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and It is selected from the group consisting of S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio.

[0058] In some embodiments, R 3 is a C-C optionally further substituted by 1 to 5, more particularly 1, 2, or 3, substituent(s), especially 1, 16 -aryl, each of the above substituents independently represents: C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and nitro.

[0059] In some embodiments, R 3 represents phenyl optionally further substituted with 1, 2, or 3 substituent(s), each of said substituents being, independently of one another, C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and nitro.

[0060] In some embodiments, R 3 is substituted with 1, 2, 3, 4, or 5 fluorine atoms and / or fluorine-containing groups, particularly CF3.

[0061] In some embodiments, R 3 represents phenyl, naphthenyl, anthracenyl, pyrenyl, indenyl, thiophenyl, furanyl, benzoxazolyl, or indolyl substituted with 1, 2, 3, 4, or 5 fluorine atoms and / or fluorine-containing groups, in particular CF3.

[0062] In some embodiments, R 3represents phenyl substituted with 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF groups, more particularly R 3 represents phenyl substituted with one fluorine atom or one CF3 group, in particular one fluorine atom, in the para position, or phenyl substituted with two fluorine atoms or two CF3 groups, in particular two fluorine atoms or two CF3 groups, in the meta position.

[0063] In some embodiments, R 3 The following part: [ka] represents one of the following:

[0064] In some embodiments, R 4 Optionally substituted C1-C represented by 30 The part is C1-C 30 and 0 to 10, more particularly 0 to 8, particularly 0 to 6 halogen atoms. In some embodiments, an optionally substituted C1-C 30 The moiety is (optionally substituted) C-C 18 Moiety or (optionally substituted) C1-C 12 It can be a part.

[0065] In some embodiments, R 4 Optionally substituted C1-C represented by 30The moiety is a moiety containing 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 above numbers refer to the total number of carbon, oxygen, nitrogen, sulfur, and halogen atoms, respectively. The above optionally substituted C1-C 30 It is to be understood that the moiety may optionally include other atoms and optionally further substituents, but that even in the presence of such optional further substituents the number of carbon, oxygen, nitrogen, sulfur, and halogen mentioned above may not be exceeded. It is also to be understood that halogen refers specifically to fluoro, chloro, and bromo.

[0066] In some embodiments, R 4 is hydrogen, C1-C6 alkyl or C6-C 16 It represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0067] In some embodiments, R 5 Optionally substituted C1-C represented by each example of 30 The moieties are those containing (independently of each other) 1 to 30, more particularly 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and especially 0 to 6 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. The above numbers refer to the total number of carbon, oxygen, nitrogen, sulfur, and halogen atoms, respectively. The above optionally substituted C1-C 30 It is to be understood that the moiety may optionally include other atoms and optionally further substituents, but that even in the presence of such optional further substituents the number of carbon, oxygen, nitrogen, sulfur, and halogen mentioned above may not be exceeded. It is also to be understood that halogen refers specifically to fluoro, chloro, and bromo.

[0068] In some embodiments, in formula (I): [ka] represents a single bond, and both R 5 are each independently hydrogen, C1-C6 alkyl, or C6-C 16 It represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0069] In some embodiments, in formula (I): [ka] represents a double bond, and one R 5 does not exist, and the other R 5 is hydrogen, C1-C6 alkyl, or C6-C 16 It represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0070] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] where R 2 , R 3 , R 4 , and R 5 is as defined above in formula (I), [ka] is as defined above in formula (I), and R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12-Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -represents heteroaryl.

[0071] In some embodiments, the compound of formula (I) is a compound of formula (III): [ka] where R 2 , R 4 , and R 5 is as defined above for formula (I), more specifically, in which R 2 , R 4 , and R 5 represents hydrogen, [ka] is as defined above for formula (I), and R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -heteroaryl, more specifically R 6 is O-C1-C 12 -alkyl, more particularly a methoxy group, L is as defined above for formula (I), more particularly L represents CH(OH)-; n is an integer of 1 to 5, and more specifically, n is 1; R 7 are independent of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, However, R 7 at least one of represents fluorine or CF3, In particular, n represents 1 and R 7 represents fluorine or CF, more particularly fluorine, and more particularly R 7 is in para position.

[0072] In some preferred embodiments, in formula (III), R 2 represents hydrogen, and R 6represents a methoxy group, L represents CH(OH)—, and n represents 1; [ka] 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.

[0073] In some preferred embodiments, the compound of formula (III) is the following compound: [ka] is.

[0074] In some embodiments, the compound of formula (I) is a compound of formula (IV): [ka] where R 2 , R 4 , and R 5 is as defined above for formula (I), and more specifically, R 2 , R 4 , and R 5 represents hydrogen, [ka] is as defined above for formula (I), R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12-heteroaryl, more specifically R 6 is O-C1-C 12 - represents an alkyl, more specifically a methoxy group, n is an integer of 1 to 5, and more specifically, n is 1; R 7 are independent of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, However, R 7At least one of n represents fluorine or CF3, more specifically, n represents 1, and R 7 represents fluorine or CF, more particularly fluorine, and more particularly R 7 is in para position.

[0075] In some preferred embodiments, in formula (IV), R 2 represents hydrogen, and R 6 represents a methoxy group, and n represents 1. [ka] 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.

[0076] In some preferred embodiments, the compound of formula (IV) is the following compound: [ka] is.

[0077] In some embodiments, the compound of formula (I) is a compound of formula (V): [ka] where R 2 , R 4 , and R 5 is as defined for formula (I) above, more specifically, R 2 , R 4 , and R 5 represents hydrogen, [ka] is as defined above for formula (I) R 6 is 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-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -heteroaryl, more specifically R 6 is O-C1-C 12 - represents an alkyl, more specifically a methoxy group, n is an integer of 1 to 5, and more specifically, n is 1; R 7 are independent of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, R 8 is hydrogen or C1-C 12 represents an acyl group, However, R 7 at least one of represents fluorine or CF3, In particular, n represents 1 and R 7 represents fluorine or CF, more particularly fluorine, and more particularly R 7 is in para position.

[0078] In some embodiments of any one of formulas (II)-(IV), n is 1, 2, or 3; and R 7 represents fluorine or CF3, more specifically fluorine.

[0079] In some embodiments of any one of formulas (II)-(IV), n is 1 and R 7 is in the para position, or n is 2 and both R 7 is in meta position.

[0080] In some embodiments of any one of formulas (II)-(IV), n is greater than 1 and R 7 At least one of represents a moiety selected from the group consisting of O-C-C-alkyl, more particularly O-C-C-alkyl, in particular methoxy or ethoxy; and halogen or C-C-haloalkyl, more particularly C-C-fluoroalkyl, in particular trifluoromethyl.

[0081] In some preferred embodiments, in formula (V), R 2 represents hydrogen, and R 6 represents a methoxy group, and n represents 1. [ka] is a single bond, and R 7 represents fluorine, and R 8 represents hydrogen, and more specifically, R 7 In an even more preferred embodiment, R 4 and R 5 represents hydrogen.

[0082] In some preferred embodiments, the compound of formula (V) is the following compound: [ka] is.

[0083] Generally, the above-mentioned composition can be formulated into any form known in the art for topical or cosmetic administration.Therefore, the composition can be applied in any topical form, such as 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 topical administration and / or cosmetics / sunscreen and skin care formulation fields.The composition can be water-resistant (for example, waterproof).

[0084] In some embodiments, the composition is in the form of a substrate carrier, including a solid, liquid, ink, gel, patch for transferring the composition onto the skin, or topical composition.

[0085] The compositions of the present disclosure may contain 0.005% to 99% by weight of any one of the compounds described herein, with the remainder consisting of suitable excipients. Contemplated compositions may contain 0.001% to 99% by weight of any one of the compounds provided herein, in one embodiment 0.1 to 95% by weight, in another embodiment 75 to 85% by weight, and in a further embodiment 20 to 80% by weight, with the remainder consisting of any excipient described herein, or any combination of these excipients. In some preferred embodiments, the topical composition may contain 0.05% to 15% by weight, more specifically 0.05% to 10% by weight, even more specifically 0.08% to 5% by weight, and particularly 0.1% to 3% by weight, of any one of the compounds provided herein, based on the total weight of the composition.

[0086] 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 (moisturizers), emulsifiers, film-forming / retentive agents, fragrances, leave-on exfoliants, prescription medications, preservatives, exfoliants, silicones, skin-leveling / repairing agents, slip agents, additional conventional sunscreen actives (non-limiting examples of such sunscreens include titanium dioxide and zinc oxide), surfactants / detergents, penetration enhancers, and thickeners. In particular, 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 seed oil, calendula, almond oil, starch, gelatin, hemicellulose, arabinogalactan, agar, glycerol, lactic acid, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, acrylates, acrylamide, copolymers of the above, amino acids such as arginine, alanine, or asparagine, ascorbic acid, and citric acid, and mixtures thereof.

[0087] In some embodiments, excipients suitable for topical administration include one or more excipients selected from water, ethanol, isopropanol, n-propanol, ethylene glycol, diethylene glycol, propylene glycol, and glycerol, and / or mixtures thereof.

[0088] In some preferred embodiments, excipients suitable for topical administration include water, monohydric or polyhydric alcohols, or mixtures thereof.

[0089] In some preferred embodiments, the excipient is water, C1-C4 alkyl alcohol, C1-C4 alkyloxydiglycol, C2-C8 alkanediol, glycerol, C1-C 12 These include alkylglycerols, di(C1-C6 alkyl)glycerols, saccharides, disaccharides, polysaccharides, phenoxyethanol, oils, terpenoids, phenylpropanoids, amino acids, proteins, water-soluble polymers, or mixtures thereof.

[0090] In some embodiments, it may be particularly preferred for the topical composition to have a pH of 2.5-9, more particularly 3-8, and especially 4-7.

[0091] In some embodiments, the composition comprises a thickening agent and / or a film-forming agent.

[0092] In some embodiments, the composition further comprises an antioxidant.

[0093] In some embodiments, the topical composition is contained within a container, optionally further comprising packaging surrounding the container. The term packaging should be understood to refer to its conventional meaning in the art, particularly to the enclosure or protection by a container for distribution, storage, sale, and / or use.

[0094] In a further aspect, the present invention relates to a storage unit comprising a topical composition according to any of the preceding embodiments of the first aspect, wherein the storage unit is protected from oxygen ingress or comprises an oxygen scavenger. In some embodiments, the storage unit further comprises packaging surrounding the storage unit.

[0095] In a still further aspect, the present invention relates to a method for preparing a topical composition according to any of the preceding embodiments of the first aspect, comprising mixing a compound of formula (I) with excipients suitable for topical administration.

[0096] In a further aspect, the present disclosure relates to a method of combining a compound of formula (I) as defined above with a dye, pigment, genipin and / or a genipin derivative.

[0097] The term "genipin derivative" refers to any derivative of genipin, in particular the following substituted chemical moiety of formula (VI): [ka] wherein R independently represent H or a substituent; [ka] represent a single bond, and each independently [ka] both R's attached to represent hydrogen or substituents, or [ka] represents a double bond, and [ka] One of the Rs bonded to is absent, [ka] The other R bonded to represents hydrogen or a substituent. In some embodiments, the genipin derivative is a compound of formula (I), more specifically, the genipin derivative is a compound of formula (II), (III), (IV), and / or (V), particularly a compound selected from formula (IV) and / or (V).

[0098] In a further aspect, the present disclosure relates to a mixture of a compound of formula (I) as defined above with a dye, pigment, and / or genipin or a genipin derivative as defined above.

[0099] For clarity, the present disclosure also relates to compounds of formula (I), and more specifically to compounds of formulas (II), (III), (IV), and (V) per se.

[0100] In a still further aspect, the present disclosure relates to methods for preparing compounds of formula (I), and more particularly, compounds of formula (II), (III), (IV), or (V).

[0101] In a still further aspect, the present disclosure relates to the use of a compound of formula (I), more particularly a compound of formula (II), (III), (IV) or (V), for coloring the skin or artificial or natural fibers, in particular for coloring the skin or hair.

[0102] In some embodiments, the use comprises administering the compound to skin, particularly mammalian skin, and / or to the surface, epidermis or dermis of the skin, and / or to 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 administering the compound to hair, particularly mammalian hair, especially hair still attached to the skin.

[0103] In still further aspects, the present disclosure relates to methods of coloring skin or artificial or natural fibers, particularly for skin or hair coloration using compounds of formula (I), more particularly compounds of formula (II), (III), (IV), or (V), hi some preferred embodiments, the method is a tattooing method.

[0104] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in 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 can be sterically fixed into one form by appropriate substitution.

[0105] As used herein, a "salt" or "pharmaceutically acceptable salt" of a compound of any one of the formulas disclosed herein is formed between an acidic group of the compound, such as an amino functional group, and a basic group, or between a basic group of the compound, such as a carboxy functional group, and an acidic group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly utilized to form pharmaceutically acceptable salts of a compound of any one of the formulas include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6- Included are dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, 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 mineral acids such as hydrochloric acid, hydrobromic acid, and especially those formed with organic acids such as maleic acid.In some embodiments, bases commonly utilized to form pharmaceutically acceptable salts of a compound of any one of the formulas include hydroxides of alkali metals including sodium, potassium, and lithium, hydroxides of alkaline earth metals such as calcium and magnesium, hydroxides of other metals such as aluminum and zinc, ammonia, unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, organic amines such as dicyclohexylamine, tributylamine, pyridine, N-methyl, N-ethylamine, diethylamine, triethylamine, mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamines) such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, and amino acids such as arginine and lysine. In some embodiments, a compound of any one of the formulas disclosed herein or a salt thereof is substantially isolated.

[0106] The compounds of the present disclosure can be prepared using conventional synthetic routes known in the art or by following the reaction schemes below.

[0107] Examples and Comparative Examples All starting materials / reagents / solvents were obtained from Sigma Aldrich, Thermo Fisher, VWR, TCI Chemicals, or Oakwood chemicals and used without further purification. Genipin was supplied by Herb-Sun Biotechnology.

[0108] Compound (1), methyl (4aS,7aS)-7-formyl-1-hydroxy-1,4a,5,7a-tetrahydrocyclopenta[c]-pyran-4-carboxylate, was prepared as follows. [ka]

[0109] To a stirred solution of genipin (50 mmol, 1 equiv.) in dichloromethane was added Dess-Martin periodinane (DMP) (55 mmol, 1.2 equiv.), and the mixture was stirred overnight. Saturated solutions of NaHCO3 and Na2SO3 were added sequentially to the reaction mixture. The resulting mixture was added to a separatory funnel and extracted with dichloromethane / water (three times), followed by brine. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting crude material was 10-15% hydrated. The crude mixture was then dissolved in methanol, to which a spatula tip of Amberlite® IRA-400 resin (hydroxide form) was added. The combination was stirred at room temperature for 15 minutes. The resin was filtered, and the crude material was dry-loaded onto silica gel and purified by flash chromatography (hexane:ethyl acetate = 60:40). The NMR data were consistent with previous reports (see Tetrahedron, 1993, 49, 10555-10576; Tetrahedron Letters, 1993, 34, 2621-2624).

[0110] 1 H NMR(400MHz,CDCl3)δ 9.80(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).

[0111] 13C NMR(100MHz,CDCl3)δ 191.8,191.0,167.6,167.4,161.8,156.0,154.7,153.3,144.9,144.6,109 .9,109.6,95.6,95.1,51.5,51.4,48.3,45.8,40.8,39.6,37.3,36.0;(M+H) + 225.07637 m / z.

[0112] HRMS(DART+):C 11 H 13 O5 [M+H] + Calculated value: 225.07575 m / z, Measured value: 225.07637 m / z

[0113] Example 1 was prepared from compound (1) using the following general reaction scheme. [ka] [ka]

[0114] Compound (1) (22.3 mmol, 5.0 g) was dissolved in 19 mL of AcO and 19 mL of pyridine. The reaction was stirred at room temperature for 68 hours. The resulting crude product was concentrated by rotary evaporation or with a steady stream of air in a fume hood. The crude oil was then dissolved in dichloromethane and transferred to a 1 L separatory funnel. To this was added 1 M HCl / brine / water and shaken. The DCM layer was removed and fresh DCM was added two more times. The combined DCM phases were returned to the separatory funnel and washed with fresh 1 M HCl / brine / water to remove residual pyridine. The combined DCM layers were dried over sodium sulfate and concentrated. The crude material appeared as a thick, dark oil with a purity of approximately 95% by NMR. This material was used in the next step without further purification. [ka]

[0115] The crude aldehyde obtained in step 1 was transferred to a 1 L Schlenk flask. To this was added THF (0.05 M) and a magnetic stir bar. The flask was cooled to 0 °C, and then the Grignard reagent (0.99 equiv.) was added dropwise at 0 °C and allowed to warm to room temperature. The reaction was monitored by TLC and was complete after 90 min. Upon completion, the reaction was cooled to 0 °C and quenched with 1 M HCl. The quenched solution was stirred for 30 min. The THF / 1 M HCl solution was poured into a separatory funnel containing ethyl acetate and water. The aqueous phase was washed three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated by rotary evaporation. The crude reaction mixture was dry-loaded onto silica and purified by flash column chromatography (EtOAc / hexane: 0:100 to 25:75). The resulting purified material may still be a mixture of diastereomers. The two diastereomers can be separated on a second column with diethyl ether / hexane (20:80→40:60). [ka]

[0116] The material isolated from step 2 was dissolved in a mixture of acetic acid, THF, and 1M HCl at a total concentration of 0.07M. The respective proportions were 30% AcOH, 50% THF, and 20% 1M HCl. The mixture was heated to 40°C for 46 hours. Upon completion, the mixture was quenched with saturated sodium bicarbonate solution and checked with pH paper until neutral / basic. The mixture was then partitioned 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 isolated by flash column chromatography.

[0117] Characterization of the major diastereomer 1H NMR(400MHz,CDCl3)δ7.48-7.46(m,1H),7.38(m,2H),7.06-6.99(m,2H),6.55-6.51(m,1H),5.98(m,1H),4.90(dd,J=8.7,5.4Hz,1H),4.0 6(d,J=5.4Hz,1H),3.71(s,3H),3.14-3.04(m,1H),2.95(dddd,J=16.5,8.6,3.1,1.2Hz,1H),2.18-2.13(m,1H),2.10(s,3H),2.07(m,1H).

[0118] 13C NMR(101MHz,CDCl3)δ170.4,167.8,164.1,161.7,152.4,142.3,130.3,13 0.2,127.2,115.8,115.6,110.7,96.6,74.4,51.5,47.1,39.1,36.4,21.4.

[0119] HRMS(DART+):C 19 H 23 NO6F[M+NH4] + Calculated value: 380.1503 m / z, Measured value: 380.1512 m / z

[0120] Following the same reaction scheme, Comparative Example 1 was prepared, which had the following structure (shown with and without the acetyl protecting group, with the deacetylated compound representing Comparative Example 1): [ka]

[0121] Genipin and the compounds of Example 1 and Comparative Example 1 were converted to their corresponding lysine conjugates according to the following procedure.

[0122] A 0.05M solution of the reactive dye precursor in MeOH was prepared and briefly stirred in a small vial equipped with a stir bar. Two equivalents of L-lysine were added, and the reaction mixture was loosely capped and stirred at room temperature for 24 hours. Upon completion, the solvent was removed under vacuum and further dried using high vacuum. During this reaction, the acetyl protecting group was also cleaved to yield the respective target compounds. [ka]

[0123] The UV / Vis spectra obtained for the three complexes are shown in Figure 2.

[0124] As can be seen from Figure 2, both the genipin conjugate and the conjugate of Comparative Example 1 are characterized by an absorption peak at approximately 580 nm. Substitution of the phenyl ring with a fluoro substituent can substantially increase this absorption at approximately 580 nm without causing a substantial bathochromic or hypsochromic shift.

[0125] Direct visual comparison of the composites confirms the results: the composite of Comparative Example 1 is characterized by a pale bluish-green color, whereas Example 1 has the same hue but a much stronger coloration. Thus, the observed hyperchromic effect of the fluorine substituents improves color intensity without significantly changing the color of the composite.

[0126] List of Embodiments The following further embodiments are also relevant to the present disclosure:

[0127] 1. A compound of formula (I), [ka] or a tautomer and / or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 optionally substituted C1-C 30 represents a part, R 2represents hydrogen or a protecting group that is hydrolyzable under physiological conditions after application of the topical composition to the skin, R 3 represents an aromatic or heteroaromatic moiety substituted with one or more fluorine atoms and / or fluorine-containing groups, in particular CF3, R 4 is hydrogen or optionally substituted C-C 30 represents a part, [ka] represents a single bond, and both R 5 are, independently of each other, hydrogen or optionally substituted C-C 30 Represents a part, or [ka] represents a double bond, and R 5 does not exist and R 5 the other is hydrogen or an optionally substituted C-C 30 represents a part, L represents a bond or a spacer group containing 1 to 12 carbon atoms, or a tautomer and / or a pharmaceutically acceptable salt thereof; and an excipient suitable for topical administration.

[0128] 2. R 1 Optionally substituted C1-C represented by 30 The part is C1-C 30 10, more particularly 0 to 8, particularly 0 to 6 halogen atoms; 0 to 12, more particularly 0 to 8, particularly 0 to 6 oxygen atoms; 0 to 8, more particularly 0 to 6, particularly 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, particularly 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, particularly 0 to 6 halogen atoms.

[0129] 3. R 1 -COOH, R 6 , or -C(=O)-R 6wherein R 6 optionally substituted C1-C 12 -Alkyl, C2-C 12 -Alkenyl, C2-C 12 -Alkynyl, C6-C 16 -aryl or C3-C 12 -heteroaryl, O-C-C 12 -Alkyl, O-C2-C 12 -Alkenyl, O-C2-C 12 -Alkynyl, O-C-C 16 -aryl or O-C3-C 12 -heteroaryl.

[0130] 4. R 1 COOH, C(=O)-O-C1-C 12 -Alkyl or C(=O)-O-C6-C 16 -aryl, in particular COOH or C(=O)-O-C1-C4-alkyl.

[0131] 5. R 2 represents hydrogen or C1-C6 acyl, in particular hydrogen.

[0132] 6. The topical composition of any one of embodiments 1-5, wherein L represents a linker group comprising 1-12 carbon atoms, 0-6 oxygen atoms, 0-4 nitrogen atoms, 0-3 sulfur atoms, and 0-6 halogen atoms.

[0133] 7. The topical composition of any one of embodiments 1-6, wherein L represents an aliphatic linker group L comprising 1-8 carbon atoms, 0-4 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulfur atoms, and 0-6 halogen atoms.

[0134] 8. L is (CH2) where n is an integer from 1 to 6. n -, CH(OH)-, CH(OH)-(CH2) where m is an integer from 1 to 5 m-; C(=O)-, C(=O)-(CH2) where o is an integer from 1 to 5 o -, or n is an integer from 1 to 5, and R x represents a C1-C6 acyl group, CH(OR x )-, CH(OR x )-(CH2) n 8. The topical composition of any one of embodiments 1 to 7, wherein

[0135] 9. R 3 But the following: a) optionally further substituted C-C 16 -aryl, wherein the optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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 other than fluorine atoms; or b) C3-C containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S 12 -heteroaryl, C3-C 12 heteroaryl is optionally further substituted, provided that the optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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 other than fluorine atoms. 9. The topical composition of any one of embodiments 1 to 8, wherein

[0136] 10. R 3 is optionally further substituted by 1 to 5, more particularly 1, 2, or 3, substituent(s), especially 1, 16 -aryl, wherein each of the above substituents, independently of one another, is C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, H, C-C alkyl, or C-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and 10. The topical composition according to any one of embodiments 1 to 9, wherein the alkyl group is selected from the group consisting of S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio.

[0137] 11. R 3 is optionally further substituted by 1 to 5, more particularly 1, 2, or 3, substituent(s), especially 1, 16 -aryl, wherein each of the above substituents, independently of one another, is C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and 11. The topical composition of any one of embodiments 1-10, wherein the compound is selected from the group consisting of nitro.

[0138] 12. R 3 represents phenyl optionally further substituted with 1, 2 or 3 substituent(s), each of said substituents being, independently of one another, C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and 12. The topical composition of any one of embodiments 1-11, wherein the compound is selected from the group consisting of nitro.

[0139] 13. R 3 is substituted with 1, 2, 3, 4, or 5 fluorine atoms and / or fluorine-containing groups, particularly CF.

[0140] 14. R 3 represents phenyl, naphthenyl, anthracenyl, pyrenyl, indenyl, thiophenyl, furanyl, benzoxazolyl, or indolyl substituted with 1, 2, 3, 4, or 5 fluorine atoms and / or fluorine-containing groups, in particular CF.

[0141] 15. R 3 represents phenyl substituted with 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF groups, more particularly R 3 represents phenyl substituted with one fluorine atom or one CF3 group, particularly one fluorine atom, in the para position, or phenyl substituted with two fluorine atoms or two CF3 groups, particularly two fluorine atoms or two CF3 groups, in the meta position.

[0142] 16. R 3 But the following part: [ka] 16. The topical composition of any one of embodiments 1-15, representing one of:

[0143] 17. R 4 Optionally substituted C1-C represented by 30 The part is C1-C 30 17. The topical composition of any one of embodiments 1-16, wherein the moiety comprises 1 to 30, more particularly 1 to 16, and particularly 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and particularly 0 to 6 oxygen atoms; 0 to 8, more particularly 0 to 6, and particularly 0 to 4 nitrogen atoms; 0 to 6, more particularly 0 to 4, and particularly 0 to 3 sulfur atoms; and 0 to 10, more particularly 0 to 8, and particularly 0 to 6 halogen atoms.

[0144] 18. R 4 is hydrogen, C1-C6 alkyl, or C6-C 16 18. The topical composition according to any one of embodiments 1 to 17, wherein R represents aryl; more particularly hydrogen or C1-C4 alkyl; in particular hydrogen.

[0145] 19. [ka] represents a single bond, and both R 5 are each independently hydrogen, C1-C6 alkyl, or C6-C 16 19. The topical composition according to any one of embodiments 1 to 18, wherein R represents aryl; more particularly hydrogen or C1-C4 alkyl; in particular hydrogen.

[0146] 20. [ka] represents a double bond, and one R 5 does not exist, and the other R 5 is hydrogen, C1-C6 alkyl or C6-C 16 20. The topical composition of any one of embodiments 1 to 19, wherein R represents aryl; more particularly hydrogen or C1-C4 alkyl; especially hydrogen.

[0147] 21. The compound of formula (I) is a compound of formula (II): [ka] where R 2 , R 3 , R 4 , and R 5 is as defined in any one of embodiments 1 to 20; [ka] is as defined in embodiment 1; R 6 is as defined in embodiment 3.

[0148] 22. The compound of formula (I) is a compound of formula (III): [ka] where R 2 , R 4 , and R 5 is as defined in any one of embodiments 1 to 20; [ka] is as defined in embodiment 1; R 6 is as defined in embodiment 3; L is as defined in embodiments 6 to 8; n is an integer from 1 to 5, R 7 But independently of each other, Fluorine; C1-C6-alkyl, more particularly C1-C4-alkyl, in particular methyl, ethyl and tert-butyl; C1-C4-haloalkyl, more particularly C1-C4-fluoroalkyl, in particular trifluoromethyl; O-C1-C6-alkyl, more particularly O-C1-C4-alkyl, in particular methoxy or ethoxy; O-C2-C 12 -alkenyl, more particularly O-C2-C7-alkenyl, in particular O-C2-C5-alkenyl; (C=O)-O-C1-C6-alkyl, more particularly (C=O)-O-C1-C4-alkyl; O—(C═O)—C1-C6-alkyl, more particularly O—(C═O)—C1-C4-alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 represents aryl); NH(CO)R 6 (In the formula, R 6 is C1-C6 alkyl or C6-C 12 represents aryl); (C=O)NR 6 2 (wherein, R 6 are each, independently of one another, hydrogen, C1-C6 alkyl, or C6-C 12 aryl); and S-C1-C6-alkyl, more particularly S-C1-C4-alkyl, in particular methylthio or ethylthio, However, R 7 22. The topical composition of any one of embodiments 1-21, wherein at least one of represents fluorine or CF3.

[0149] 23. The compound of formula (I) is a compound of formula (IV): [ka] where R 2 , R 4 , and R 5 is as defined in any one of embodiments 1 to 20; [ka] is as defined in embodiment 1; R 6 is as defined in embodiment 3; n is an integer from 1 to 5, R 7 is as defined in embodiment 22.

[0150] 24. The compound of formula (I) is a compound of formula (V): [ka] where R 2 , R 4 , and R 5 is as defined in any one of embodiments 1 to 20; [ka] is as defined in embodiment 1; R 6 is as defined in embodiment 3; n is an integer from 1 to 5, R 7is as defined in embodiment 22; R 8 is hydrogen or C1-C 12 24. The topical composition of any one of embodiments 1-23, wherein the compound represents an acyl group.

[0151] 25. n is 1, 2 or 3, and R 7 25. The topical composition of any one of embodiments 22-24, wherein represents fluorine or CF3, more specifically fluorine.

[0152] 26. n is 1 and R 7 is in the para position, or n is 2 and both R 7 Embodiment 26. The topical composition of embodiment 22 or embodiment 25, wherein is in the meta position.

[0153] 27. n is greater than 1 and R 7 represents a moiety selected from the group consisting of O-C-C-alkyl, more particularly O-C-C-alkyl, in particular methoxy or ethoxy; and halogen or C-C-haloalkyl, more particularly C-C-fluoroalkyl, in particular trifluoromethyl.

[0154] 28. The topical composition of embodiment 22, R 2 represents hydrogen, R 6 represents a methoxy group, L represents CH(OH)-; n represents 1, [ka] is a single bond, and R 7 represents fluorine, more specifically, R 7 is in para position, In particular, R 4 and R 5 represents hydrogen.

[0155] 29. The topical composition of embodiment 23, comprising: R 2 represents hydrogen, R 6 represents a methoxy group, N represents 1, [ka] is a single bond, and R 7 represents fluorine, more specifically, R 7 is in para position, In particular, R 4 and R 5 represents hydrogen.

[0156] 30. The topical composition of embodiment 24, R 2 represents hydrogen, R 6 represents a methoxy group, n represents 1, [ka] is a single bond, R 7 represents fluorine, more specifically, R 7 is in para position, R 8 represents hydrogen, In particular, R 4 and R 5 represents hydrogen.

[0157] 31. A topical composition described in any one of embodiments 1 to 30, wherein the composition is in the form of a solid, liquid, ink, gel, a patch for transferring the composition onto the skin, or a substrate carrier containing the topical composition.

[0158] 32. A topical composition described in any one of embodiments 1 to 31, wherein the excipient suitable for topical administration comprises one or more excipients selected from water, ethanol, isopropanol, n-propanol, ethylene glycol, diethylene glycol, propylene glycol, and glycerol, or mixtures thereof.

[0159] 33. A topical composition described in any one of embodiments 1 to 32, wherein the composition comprises a thickening agent and / or a film-forming agent.

[0160] 34. A topical composition described in any one of embodiments 1 to 33, wherein the composition further comprises an antioxidant.

[0161] 35. The topical composition of any one of embodiments 1-34, wherein L in formula (I), (II), and / or (III) is not 1,4-piperazinediyl.

[0162] 36. The compound of formula (I), (II), and / or (III) is the following compound: [ka] 36. The topical composition of any one of embodiments 1-35, wherein the topical composition is not

Claims

1. A compound of formula (I), 【Chemistry 1】 or a tautomer and / or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is optionally substituted C １ -C ３０ represents a part, R ２ represents hydrogen or a protecting group that is hydrolyzable under physiological conditions after application of the topical composition to the skin, R ３ is an aromatic or heteroaromatic moiety substituted with one or more fluorine atoms and / or fluorine-containing groups, in particular CF ３ represents R ４ is hydrogen or optionally substituted C １ -C ３０ represents a part, 【Chemistry 2】 represents a single bond, and both R ５ are each independently hydrogen or optionally substituted C １ -C ３０ Represents a part, or 【Transformation 3】 represents a double bond, and R ５ does not exist, and R ５ The other is hydrogen or an optionally substituted C １ -C ３０ represents a part, L represents a bond or a spacer group containing 1 to 12 carbon atoms, or a tautomer and / or a pharmaceutically acceptable salt thereof; and an excipient suitable for topical administration.

2. R １ The optionally substituted C １ -C ３０ The part is C １ -C ３０ 2. The topical composition of claim 1, which is a moiety comprising 1 to 30, more particularly 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and especially 0 to 6 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.

3. R １ But -COOH, R ６ , or -C(=O)-R ６ wherein R ６ is optionally substituted C １ -C １２ -Alkyl, C ２ -C １２ -alkenyl, C ２ -C １２ -alkynyl, C ６ -C １６ -aryl or C ３ -C １２ -heteroaryl, O—C １ -C １２ -alkyl, O—C ２ -C １２ -alkenyl, O—C ２ -C １２ -alkynyl, O—C ６ -C １６ -aryl or O-C ３ -C １２ 3. The topical composition of claim 1 or claim 2, wherein the aryl is -heteroaryl.

4. R ２ is hydrogen or C １ -C ６ The topical composition according to any one of claims 1 to 3, wherein acyl represents, in particular, hydrogen.

5. 5. The topical composition of any one of claims 1 to 4, wherein L represents a linker group comprising 1 to 12 carbon atoms, 0 to 6 oxygen atoms, 0 to 4 nitrogen atoms, 0 to 3 sulfur atoms, and 0 to 6 halogen atoms.

6. R ３ but the following: a) optionally further substituted C ６ -C １６ -aryl, provided that said optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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 other than fluorine atoms; or b) C containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S. ３ -C １２ -heteroaryl, wherein said C ３ -C １２ heteroaryl is optionally further substituted, with the proviso that said optional substituents comprise, in total, 0 to 12, more particularly 0 to 8, and especially 0 to 6 carbon atoms; 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 other than fluorine atoms. The topical composition according to any one of claims 1 to 5,

7. R ３ is optionally further substituted by 1 to 5, more particularly 1, 2 or 3 substituent(s), especially 1 substituent; ６ -C １６ -aryl, wherein each of the substituents is, independently of one another, C １ -C ６ - alkyl, more specifically C １ -C ４ - alkyl, in particular methyl, ethyl and tert-butyl; C １ -C ４ -haloalkyl, more specifically C １ -C ４ fluoroalkyl, in particular trifluoromethyl; O-C １ -C ６ -alkyl, more specifically O—C １ -C ４ alkyl, in particular methoxy or ethoxy; O-C ２ -C １２ -alkenyl, more specifically O—C ２ -C ７ -alkenyl, especially O—C ２ -C ５ -alkenyl; (C═O)—O—C １ -C ６ -alkyl, more specifically (C=O)-O-C １ -C ４ - alkyl; O-(C=O)-C １ -C ６ -alkyl, more specifically O—(C═O)—C １ -C ４ - alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR ６ ２ (In the formula, R ６ are each independently H, C １ -C ６ Alkyl, or C ６ -C １２ represents aryl); NH(CO)R ６ (In the formula, R ６ is C １ -C ６ Alkyl or C ６ -C １２ represents aryl); (C=O)NR ６ ２ (In the formula, R ６ are each independently hydrogen, C １ -C ６ Alkyl, or C ６ -C １２ aryl); and SC １ -C ６ -alkyl, more specifically S—C １ -C ４ The topical composition according to any one of claims 1 to 6, wherein the thiol group is selected from the group consisting of alkyl, in particular methylthio or ethylthio.

8. R ３ represents phenyl optionally further substituted with 1, 2 or 3 substituent(s), each of said substituents, independently of one another, being C １ -C ６ - alkyl, more specifically C １ -C ４ - alkyl, in particular methyl, ethyl and tert-butyl; C １ -C ４ -haloalkyl, more specifically C １ -C ４ fluoroalkyl, in particular trifluoromethyl; O-C １ -C ６ -alkyl, more specifically O—C １ -C ４ alkyl, in particular methoxy or ethoxy; Halogens other than fluorine, more particularly chloro or bromo; and 8. The topical composition of any one of claims 1 to 7, wherein the compound is selected from the group consisting of nitro.

9. R ３ contains 1, 2, 3, 4 or 5 fluorine atoms and / or fluorine-containing groups, in particular CF ３ 9. The topical composition according to claim 1, wherein R represents phenyl, naphthenyl, anthracenyl, pyrenyl, indenyl, thiophenyl, furanyl, benzoxazolyl, or indolyl substituted with R.

10. R ３ is 1, 2 or 3 fluorine atoms and / or 1, 2 or 3 CF ３ represents a phenyl substituted with a group, more specifically, R ３ is one fluorine atom or one CF in the para position ３ groups, in particular phenyl substituted with one fluorine atom, or two fluorine atoms or two CF in the meta position ３ groups, especially two fluorine atoms or two CF ３ 10. The topical composition according to any one of claims 1 to 9, wherein the phenyl group is substituted with a phenyl group.

11. R ３ But the following part: 【Chemistry 4】 The topical composition according to any one of claims 1 to 10, wherein the composition is one of

12. R ４ The optionally substituted C １ -C ３０ The part is C １ -C ３０ 12. The topical composition of any one of claims 1 to 11, which is a moiety comprising 1 to 30, more particularly 1 to 16, and especially 1 to 12 carbon atoms; 0 to 12, more particularly 0 to 8, and especially 0 to 6 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.

13. The compound of formula (I) is a compound of formula (III): 【Transformation 5】 wherein R ２ , R ４ , and R ５ is as defined in any one of claims 1 to 12, 【Transformation 6】 is as defined in claim 1, R ６ is as defined in claim 3, L is as defined in claim 5, n is an integer from 1 to 5, R ７ But independently of each other, Fluorine; C １ -C ６ - alkyl, more specifically C １ -C ４ - alkyl, in particular methyl, ethyl and tert-butyl; C １ -C ４ -haloalkyl, more specifically C １ -C ４ fluoroalkyl, in particular trifluoromethyl; O-C １ -C ６ -alkyl, more specifically O—C １ -C ４ alkyl, in particular methoxy or ethoxy; O-C ２ -C １２ -alkenyl, more specifically O—C ２ -C ７ -alkenyl, especially O—C ２ -C ５ -alkenyl; (C═O)—O—C １ -C ６ -alkyl, more specifically (C=O)-O-C １ -C ４ - alkyl; O-(C=O)-C １ -C ６ -alkyl, more specifically O—(C═O)—C １ -C ４ - alkyl; Halogens other than fluorine, more particularly chloro or bromo; Nitro; NR ６ ２ (In the formula, R ６ are each independently hydrogen, C １ -C ６ Alkyl, or C ６ -C １２ represents aryl); NH(CO)R ６ (In the formula, R ６ is C １ -C ６ Alkyl or C ６ -C １２ represents aryl); (C=O)NR ６ ２ (In the formula, R ６ are each independently hydrogen, C １ -C ６ Alkyl, or C ６ -C １２ aryl); and SC １ -C ６ -alkyl, more specifically S—C １ -C ４ - alkyl, in particular methylthio or ethylthio, However, R ７ At least one of the ３ The topical composition according to any one of claims 1 to 12, wherein

14. The compound of formula (I) is a compound of formula (IV): 【Transformation 7】 wherein R ２ , R ４ , and R ５ is as defined in any one of claims 1 to 12, 【Transformation 8】 is as defined in claim 1, R ６ is as defined in claim 3, n is an integer from 1 to 5, R ７ A topical composition according to any one of claims 1 to 13, wherein is as defined in claim 13.

15. The compound of formula (I) is a compound of formula (V): 【Chemistry 9】 wherein R ２ , R ４ , and R ５ is as defined in any one of claims 1 to 12, 【Chemistry 10】 is as defined in claim 1, R ６ is as defined in claim 3, n is an integer from 1 to 5, R ７ is as defined in claim 13, R ８ is hydrogen or C １ -C １２ The topical composition according to any one of claims 1 to 13, which exhibits an acyl group.

16. Formula (VII) or Formula (VIII), 【Chemistry 11】 【Chemistry 12】 Compound.

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