Compositions for sebum control

Abstract

The present invention provides compositions comprising a combination of a plant or fungal extract and a phenolic compound. Such compositions are useful for reducing lipid levels in sebocytes, and the compositions can be used to treat acne vulgaris and rosacea. The compositions can comprise: (a) a phenolic compound according to Formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and (b) a plant or fungal extract selected from the group consisting of extracts of plants belonging to the genera Arctostaphylos, Fragaria, Garcinia, Hedera, Ilex, and Rubus, and extracts of the fungal genus Poria, wherein R 1 to R 5 and -L- are each as described herein.

Description

Technical Field

[0001] This invention relates to compositions comprising a combination of plant or fungal extracts and phenolic compounds, and the use of the composition in methods for reducing lipid production in sebocytes. It also provides the use of the composition in cosmetic methods for reducing lipid production in individual skin, and in methods for treating skin diseases or disorders associated with increased lipid production in sebocytes. Background Technology

[0002] Sebum is an oily substance secreted by sebaceous glands in the human body. Sebum is produced by sebaceous gland cells, which are highly specialized epithelial cells typically found in the skin and associated with hair follicles, although there are also sebaceous glands unrelated to hair follicles.

[0003] Adult sebum typically contains triglycerides (~41%), monoceryl esters (~25%), free fatty acids (~16%), and squalene (~12%) (Cheng et al., 2004). Other components, such as keratin and cellular material, may also be present.

[0004] Sebum forms part of the epidermal barrier and the skin's immune system. It is a natural moisturizer for the epidermis, helping to maintain its integrity. Sebum is important in maintaining the pH of the skin surface, playing a role in protecting the skin from exogenous (pathogenic) microorganisms and promoting the growth of endogenous (resident) microbial communities. Sebum secretions, combined with apocrine (sweat) glands, are also believed to play an important role in thermoregulation.

[0005] Sebaceous gland cell formation is controlled by multiple molecular pathways (such as Blimp1, Wnt, C-myc, and Hedgehog), and sebum synthesis is strongly regulated by hormones, especially androgens such as testosterone.

[0006] Sebum is produced during the entire secretory process, in which sebaceous gland cells rupture and disintegrate as they release sebum and cellular residues. During the terminal differentiation of sebaceous gland cells, metabolic activity focuses on lipid biosynthesis (lipogenesis), particularly on the new synthesis of fatty acids and squalene.

[0007] The level of sebum production varies from person to person and is affected by gender, age, physical activity, stress, some medications, and diseases. Due to hormonal changes that occur throughout puberty, oily skin is usually observed during adolescence.

[0008] Excessive sebum production is associated with cosmetic problems such as oily or shiny skin and poor makeup retention, as well as medical issues. Excessive sebum production is seen in acne vulgaris (one of the most common skin conditions). Hyperseborrhea is a scalp problem caused by excessive sebum production. Direct symptoms of hyperseborrhea include itchy and painful scalp, although hair loss is a later symptom. Individuals with seborrheic dermatitis typically exhibit sebum production greater than 200 μg / cm² on the forehead. -2 The level of sebum (as discussed, for example, in WO 2020 / 263188). Dysregulated sebaceous gland cell differentiation is also a feature of some rare benign and malignant tumors.

[0009] Cosmetic treatments for excess sebum production generally do not address the underlying cause. Instead, they typically provide relief for immediate symptoms such as oiliness, enlarged pores, acne-prone skin, and irregular skin texture. For example, a common approach to treating oily or shiny skin is to use powders that provide an immediate masking effect by absorbing excess sebum from the skin's surface. Alternatively, astringents and cleansers may be used.

[0010] Known methods for reducing lipids on the skin surface are limited and produce few sustainable, visible results over extended periods. Prolonged use of astringents and cleansers may exacerbate the condition.

[0011] Therefore, there is a need to develop compositions and methods for reducing lipid production in an individual's sebaceous gland cells and skin. Summary of the Invention

[0012] Most generally, the present invention relates to compositions comprising a combination of plant or fungal extracts and phenolic compounds. The inventors have discovered that such compositions provide excellent lipid-lowering effects in sebaceous gland cells.

[0013] Phenols can be stilbene compounds, such as pterostilbene or piceatannol; meroterpenes, such as bakuchiol or δ-3,2-hydroxypsoralen; or abietane diterpenoids, such as ferruginol, sugiol, or podocarpic acid.

[0014] Therefore, in a first aspect of the invention, a composition is provided comprising:

[0015] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0016] (b) Extracts from plants or fungi belonging to the genera Arctostaphylos, Fragaria, Garcinia, Hedera, Ilex, and Rubus, and extracts from the fungus Wolfiporia.

[0017]

[0018] in:

[0019] R 1 R 2 R 3 and R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl;

[0020] L represents -CH=CH-, -CH2-CH2-, or -C(=O)CH2-;

[0021] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0022] R 6 R 7 R 8 R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl and C 1-4Halogenated alkyl groups.

[0023] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, are set forth below.

[0024] The inventors have discovered that the composition of the first aspect reduces the production of lipids in sebaceous gland cells.

[0025] Therefore, in a second aspect of the invention, a method for reducing lipid production in sebaceous gland cells is provided, the method comprising contacting the sebaceous gland cells with the composition of the first aspect. This method may be in vivo or ex vivo, for example, in vitro.

[0026] The inventors have discovered that the composition of the first aspect can reduce or improve cosmetic problems associated with excessive production of lipids in the skin, such as oily or shiny skin, oily hair, enlarged skin pores, undesirable body odor, and reduced retention of cosmetic products on the skin.

[0027] Therefore, in a third aspect of the invention, a cosmetic method for reducing lipid production in individual skin is provided, the method comprising contacting the skin with the composition of the first aspect.

[0028] The inventors have discovered that the composition of the first aspect can be used to treat or prevent medical problems related to excessive production of lipids in the skin, such as acne vulgaris and rosacea.

[0029] Therefore, in a fourth aspect of the invention, a composition of the first aspect is provided for use in a treatment method.

[0030] In another related aspect of the invention, a composition of the first aspect is provided for use in a method of treating skin diseases or conditions such as acne vulgaris and rosacea associated with excessive production of lipids in the skin.

[0031] These and other aspects and embodiments of the present invention are described in further detail below. Attached Figure Description

[0032] The invention is described with reference to the accompanying drawings listed below.

[0033] Figure 1The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), salicylic acid (SA, positive control), α-dextrin (AM), psoralen (B), oleanolic acid (OA), Hedera helix extract (HH), Ilexa quifolium extract (IA), Rubus idaeus extract (RI), α-dextrin (AM) and Rubus idaeus (Rubus) Combinations of idaeus extract (RI), combinations of psoralen (B) and raspberry extract (RI), combinations of oleanolic acid (OA) and raspberry extract (RI), combinations of ivy extract (HH) and raspberry extract (RI), combinations of holly extract (IA) and raspberry extract (RI), combinations of ivy extract (HH) and psoralen (B), and combinations of holly extract (IA) and psoralen (B).

[0034] In the figure, comparisons in one-way analysis of variance (ANOVA) are labeled as follows:

[0035] P-value: 0.0113 (Statistically significant compared to DMSO)

[0036] P-value: <0.0001 (Statistically significant compared to DMSO)

[0037] #P value: 0.0103 (Statistically significant compared with Rubus idaeus extract (RI))

[0038] ##P value: 0.0012–0.0081 (statistically significant compared with α-adipone (AM), bakuchiol (B), or oleanolic acid (OA))

[0039] ###P value: 0.0002 (Statistically significant compared to bakuchiol (B))

[0040] When one label is present, the asterisk indicates the p-value relative to DMSO. When two labels are present, the lower asterisk indicates the p-value relative to DMSO, and the upper asterisk indicates the p-value relative to oleanolic acid (OA), α-dextrin (AM), or psoralen (B).

[0041] Figure 2 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), psoralen (B), ferrictanol (F), pterostilbene (P), Garcinia mangostana pericarp extract (GMP), a combination of psoralen (B) and Garcinia mangostana pericarp extract (GMP), a combination of ferrictanol (F) and Garcinia mangostana pericarp extract (GMP), and a combination of pterostilbene (P) and Garcinia mangostana pericarp extract (GMP).

[0042] Figure 3 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), psoralen (B), ferrictanol (F), pterostilbene (P), ivy extract (HH), a combination of psoralen (B) and ivy extract (HH), a combination of ferrictanol (F) and ivy extract (HH), and a combination of pterostilbene (P) and ivy extract (HH).

[0043] Figure 4 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), psoralen (B), ferrictanol (F), pterostilbene (P), Ilex cornuta extract (IA), a combination of psoralen (B) and Ilex cornuta extract (IA), a combination of ferrictanol (F) and Ilex cornuta extract (IA), and a combination of pterostilbene (P) and Ilex cornuta extract (IA).

[0044] Figure 5The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), psoralen (B), ferrictanol (F), pterostilbene (P), wild strawberry extract (FV), a combination of psoralen (B) and wild strawberry extract (FV), a combination of ferrictanol (F) and wild strawberry extract (FV), and a combination of pterostilbene (P) and wild strawberry extract (FV).

[0045] Figure 6 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), psoralen (B), ferrictanol (F), pterostilbene (P), raspberry extract (RI), a combination of psoralen (B) and raspberry extract (RI), a combination of ferrictanol (F) and raspberry extract (RI), and a combination of pterostilbene (P) and raspberry extract (RI).

[0046] exist Figure 2-6 In this context, the following labels are used for comparisons in one-way ANOVA:

[0047] P-value: <0.05 (Statistically significant compared to DMSO)

[0048] P-value: <0.01 (Statistically significant compared to DMSO)

[0049] P-value: 0.001 (Statistically significant compared to DMSO)

[0050] P-value: <0.0001 (Statistically significant compared to DMSO)

[0051] #P-value: <0.05 (Statistically significant compared to psoralen, ferricyanide, or pterostilbene)

[0052] ##P-value: <0.01 (Statistically significant compared to psoralen, ferricyanide, or pterostilbene)

[0053] ###P-value: <0.001 (Statistically significant compared to psoralen, ferricyanide, or pterostilbene)

[0054] Figure 7 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), paclitaxel (Picea), podophyllin (PA), cypermethrin, raspberry extract (RI), and combinations of paclitaxel (Picea), podophyllin (PA), cypermethrin, and raspberry extract (RI).

[0055] exist Figure 7 In this context, the following labels are used for comparisons in one-way ANOVA:

[0056] P-value: 0.0018 (Statistically significant compared to DMSO)

[0057] P-value: <0.0001 (Statistically significant compared to DMSO)

[0058] ##P-value: 0.0033 (Statistically significant compared to paclitaxel)

[0059] ###P-value: 0.0006–0.0008 (Statistically significant compared to podophyllin and cephalotaxic acid)

[0060] Figure 8 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), paclitaxel (Picea), podophyllin (PA), tsucralose, Arctostaphylos uva-ursi extract (AUU), and combinations of paclitaxel (Picea), podophyllin (PA), tsucralose, and Arctostaphylos uva-ursi extract (AUU).

[0061] exist Figure 8 In this context, the following labels are used for comparisons in one-way ANOVA:

[0062] P-value: 0.0002–0.0003 (Statistically significant compared to DMSO)

[0063] P-value: <0.0001 (Statistically significant compared to DMSO)

[0064] ##P-value: 0.0027–0.0092 (Statistically significant compared to paclitaxel, podophyllin, and cephalotaxel)

[0065] Figure 9 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), paclitaxel (Picea), podophyllin (PA), thujol, ivy extract (HH), and combinations of paclitaxel (Picea), podophyllin (PA), thujol, and ivy extract (HH).

[0066] exist Figure 9 In this context, the following labels are used for comparisons in one-way ANOVA:

[0067] P-value: 0.0003–0.0006 (Statistically significant compared to DMSO)

[0068] P-value: <0.0001 (Statistically significant compared to DMSO)

[0069] #P-value: 0.0442 (Statistically significant compared to paclitaxel)

[0070] ##P-value: 0.0031–0.0075 (Statistically significant compared to podophyllin and cephalotaxic acid)

[0071] Figure 10The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), paclitaxel (Spruce), podophyllin (PA), tsucralose, European holly extract (IA), and combinations of paclitaxel (Spruce), podophyllin (PA), tsucralose, and European holly extract (IA).

[0072] exist Figure 10 In this context, the following labels are used for comparisons in one-way ANOVA:

[0073] P-value: 0.0015 (Statistically significant compared to DMSO)

[0074] P-value: <0.0001 (Statistically significant compared to DMSO)

[0075] ##P-value: 0.0024 (Statistically significant compared to podophyllin)

[0076] ###P value: 0.0007 (Statistically significant compared to cephalotaxine)

[0077] Figure 11 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), paclitaxel (Spruce), podophyllin (PA), cypermethrin, Wolfiporia extensa extract (WE), and combinations of paclitaxel (Spruce), podophyllin (PA), cypermethrin, and Wolfiporia extensa extract (WE).

[0078] exist Figure 11 In this context, the following labels are used for comparisons in one-way ANOVA:

[0079] P-value: 0.0008 (Statistically significant compared to DMSO)

[0080] P-value: <0.0001 (Statistically significant compared to DMSO)

[0081] #P-value: 0.0156 (Statistically significant compared to paclitaxel)

[0082] ##P-value: 0.0012 (Statistically significant compared to podophyllin)

[0083] ###P-value: 0.0003 (Statistically significant compared to cephalotaxine)

[0084] Figure 12 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), paclitaxel (Picea), mangosteen pericarp extract (GMP), and combinations of paclitaxel (Picea) and mangosteen pericarp extract (GMP).

[0085] exist Figure 12 In this context, the following labels are used for comparisons in one-way ANOVA:

[0086] P-value: 0.0001 (Statistically significant compared to DMSO)

[0087] P-value: <0.0001 (Statistically significant compared to DMSO)

[0088] ##P-value: 0.0030 (Statistically significant compared to paclitaxel)

[0089] Figure 13 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), δ-3,2-hydroxypsoralen (D32HB), wild strawberry extract (FV), raspberry extract (RI), a combination of δ-3,2-hydroxypsoralen (D32HB) and wild strawberry extract (FV), and a combination of δ-3,2-hydroxypsoralen (D32HB) and raspberry extract (RI).

[0090] exist Figure 13 In this context, the following labels are used for comparisons in one-way ANOVA:

[0091] P-value: <0.0001 (Statistically significant compared to DMSO)

[0092] #P-value: 0.0232 (Statistically significant compared to δ 3,2-hydroxypsoralen)

[0093] ###P value: 0.0009 (Statistically significant compared to δ 3,2-hydroxypsoralen)

[0094] Figure 14 The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), δ-3,2-hydroxypsoralen (D32HB), bearberry (Arctostaphylos uva ursi) extract (AUU), ivy extract (HH), a combination of δ-3,2-hydroxypsoralen (D32HB) and bearberry extract (AUU), and a combination of δ-3,2-hydroxypsoralen (D32HB) and ivy extract (HH).

[0095] exist Figure 14 In this context, the following labels are used for comparisons in one-way ANOVA:

[0096] P-value: <0.0001 (Statistically significant compared to DMSO)

[0097] Figure 15The average fluorescence intensity obtained by flow cytometry of sebaceous gland cells treated with AdipoRed™ dye is shown. Cells were incubated with the test composition for 3 days. According to an embodiment of the invention, from left to right, DMSO (negative control), epigallocatechin gallate (EGCG, positive control), δ-3,2-hydroxypsoralen (D32HB), European wintergreen extract (IA), Poria cocos extract (WE), a combination of δ-3,2-hydroxypsoralen (D32HB) and European wintergreen extract (IA), and a combination of δ-3,2-hydroxypsoralen (D32HB) and Poria cocos extract (WE).

[0098] exist Figure 15 In this context, the following labels are used for comparisons in one-way ANOVA:

[0099] P-value: <0.0001 (Statistically significant compared to DMSO) Detailed Implementation

[0100] This invention relates to compositions comprising a combination of plant or fungal extracts and phenolic compounds, and the use of the composition in methods for reducing lipid production in sebaceous gland cells. It also provides the use of the composition in cosmetic methods for reducing lipid production in individual skin, and in methods for treating skin diseases or conditions associated with increased lipid production in sebaceous gland cells.

[0101] The following preferred options are applicable to all aspects of the invention as described above. These preferred options can be combined in any combination.

[0102] Phenolic compounds

[0103] The compositions of the present invention contain phenols and plant extracts. The phenols may be stilbene compounds, such as pterostilbene or paclitaxel, mixed terpenes, such as psoralen or δ-3,2-hydroxypsoralen, or rosinane diterpenes, such as ferruginol, thujol, or podophyllin.

[0104] In one embodiment, the phenolic compound is a phenol that is not present in or derived from the plant extract used in combination with it.

[0105] The compositions of the present invention comprise a phenolic compound according to formula (I):

[0106]

[0107] in:

[0108] R1 R 2 R 3 and R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl;

[0109] L represents -CH=CH-, -CH2-CH2-, or -C(=O)CH2-;

[0110] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0111] R 6 R 7 R 8 R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl and C 1-4 Halogenated alkyl groups.

[0112] When R 5 C 6-14 When carbonyl aryl, for example when R 5 When the phenyl group is present, the compound can be called a stilbene compound. An example compound is pterostilbene.

[0113] When R 5 C 2-15 When alkenyl, for example when R 5 When a compound contains two or more double bonds, it may be called a mixed-origin terpene. An example compound is psoralen.

[0114] When R 5 C 5-14 cycloalkyl, and the group R 4 With C 5-14When cycloalkyl groups form covalent bonds, resulting in a 6-membered ring, the compound can be called a rosinane diterpene. An example compound is ferrugin.

[0115] Alkyl groups are monovalent saturated hydrocarbon groups. Alkyl groups can be C10, C20, C30 1-6 Alkyl, such as C 1-4 C 1-3 Or C 1-2 Alkyl, such as C1 alkyl (methyl). In this context, the prefix (e.g., C...) 1-6 () indicates the number of carbon atoms in the hydrocarbon backbone. Alkyl groups can be linear or branched.

[0116] C 1-6 Examples of linear alkyl groups include methyl (-Me), ethyl (-Et), n-propyl (-nPr), n-butyl (-nBu), n-pentyl (-Amyl), and n-hexyl.

[0117] C 1-6 Examples of branched alkyl groups include isopropyl (-iPr), isobutyl (-iBu), sec-butyl (-sBu), tert-butyl (-tBu), isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, and neohexyl.

[0118] A haloalkyl group is an alkyl group in which one or more hydrogen atoms, for example, one or all hydrogen atoms, are replaced by halogen atoms such as F, Cl, Br, and I. Haloalkyl groups can be C10, C20, C30, C40, C50, C60, C7 ... 1-4 Haloalkyl, such as C 1-3 Or C 1-2 Haloalkyl, and these can be monohalogenated or perhalogenated. In this context, prefixes (e.g., C) 1-4 () indicates the number of carbon atoms in the hydrocarbon backbone.

[0119] C 1-4 Examples of alkyl halogens include chloromethyl (-CH2Cl), fluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), chloroethyl (-C2H4Cl), monofluoroethyl (-C2H4F), pentafluoroethyl (-C2F3), heptafluoropropyl (-C3F7), and nonafluorobutyl (-C4F9).

[0120] A hydroxyalkyl group is an alkyl group in which one or more hydrogen atoms are replaced, for example, one hydrogen atom is replaced by a hydroxyl group (-OH). Hydroxyalkyl groups can be C10-30000. 1-4 Hydroxyalkyl, such as C 1-3 Or C 1-2 Hydroxyalkyl, such as C1 hydroxyalkyl. Hydroxyalkyl can be monohydroxyalkyl. In this context, the prefix (e.g., C...) 1-4 () indicates the number of carbon atoms in the hydrocarbon backbone.

[0121] C1-4 Examples of hydroxyalkyl groups include hydroxymethyl (-CH2OH) and hydroxyethyl (e.g., -CH2CH2OH).

[0122] An alkenyl group is a monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. The alkenyl group can be C... 2-15 alkenyl groups, such as C 2-5 C 2-4 Or C 2-3 alkenyl, or alternatively C 4-15 C 4-12 C 4-10 C 6-10 Or C 10 Alkenyl group.

[0123] C 2-15 Examples of linear alkenyl groups include vinyl (vinyl), 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl and 4-hexenyl.

[0124] C 2-15 Examples of branched alkenyl groups include isopropenyl (1-methylvinyl), isobutenyl (2-methyl-1-propenyl), 1-isopentenyl (3-methyl-1-butenyl), 2-isopentenyl (3-methyl-2-butenyl), 5-methyl-4-hexenyl, 1,5-dimethyl-4-hexenyl, and 1-vinyl-1,5-dimethyl-4-hexenyl.

[0125] A carbonyl aryl group is a monovalent hydrocarbon group consisting of an aromatic ring in which all ring atoms are carbon atoms. The carbonyl aryl group can be C... 6-14 Carbonyl aryl groups, such as C 6-10 Or C6 carbonyl aryl. In this context, the prefix (e.g., C...) 6-10 The ) indicates the number or range of ring atoms. The carbonyl aryl group can be monocyclic, or it can contain two or more rings.

[0126] Examples of monocyclic carbonyl aryl groups include those derived from benzene (phenyl).

[0127] Carbonyl aryl groups can be part of a fused-ring system. In a fused-ring system, the carbonyl aryl group comprises two or more rings, wherein at least one ring is an aromatic ring in which all ring atoms are carbon atoms, and wherein each ring shares two adjacent ring atoms with each adjacent (fused) ring. Therefore, the bridgehead atoms are directly bonded. The carbonyl aryl group is linked via aromatic rings in the fused-ring system.

[0128] Examples of carbonyl aryl groups containing fused rings include those derived from the following groups: indane (2,3-dihydro-1H-indane), indane, isoindane; naphthalene, dihydronaphthalene (1,2-dihydronaphthalene), naphthalene (1,2,3,4-tetrahydronaphthalene), azulene; acenaphthene; fluorene, phenaene; and anthracene and phenanthrene.

[0129] A cycloalkyl group is a monovalent hydrocarbon group consisting of a non-aromatic ring in which all ring atoms are carbon atoms. Cycloalkyl groups can be C16-3 ... 5-14 cycloalkyl, such as C 5-10 C 5-10 Or C5, C6 or C 10 Cycloalkyl. In this context, prefixes (e.g., C) 5-10 The ) indicates the number or range of ring atoms. The carbonyl aryl group can be monocyclic, or it can contain two or more rings. Each ring can be partially unsaturated or saturated, and is preferably saturated.

[0130] Examples of monocyclic cycloalkyl groups include those derived from cyclohexane (cyclohexyl) and cyclopentane (cyclopentyl).

[0131] Cycloalkyl groups can be part of a fused-ring system. In a fused-ring system, the cycloalkyl group comprises two or more rings, wherein at least one ring is a cycloalkyl ring in which all ring atoms are carbon atoms, and wherein each ring shares two adjacent ring atoms with each adjacent (fused) ring. Therefore, the bridgehead atoms are directly bonded. The cycloalkyl groups are linked via cycloalkyl rings in the fused-ring system.

[0132] Examples of cycloalkyl groups containing fused rings include groups derived from decahydronaphthalene (decahydronaphthalene group).

[0133] In a preferred embodiment, R 1 R 2 R 3 and R 4 Not all are OH. For example, R 1 R 2 R 3 and R 4 None of them are OH.

[0134] In a preferred embodiment, R 1 R 2 R 3 and R 4 Not all of them are CO2H. For example, R 1 R 2 R 3 and R 4 None of them are CO2H.

[0135] In one implementation, R 1 R2 R 3 and R 4 At least two of them, for example, two or four, are H. For example, R 1 R 2 R 3 and R 4 Each is H or R 1 and R 3 For H.

[0136] The linker L can be -CH=CH-. When R 5 C 2-15 alkenyl or C 6-14 When carbonyl aryl is present, this is preferred. The -CH=CH- group preferably has a trans arrangement.

[0137] The linker L can be -CH2-CH2- or -C(=O)CH2-. When R 5 C 5-14 When cycloalkyl is used, this is preferred. When the group R 4 With C 5-14 When cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring, this is a further preferred option.

[0138] When L is -C(=O)CH2-, the methylene group (-CH2-) can be attached to R. 5 Here, the carbonyl group (-C(O)-) in the linker is attached to the phenolic moiety of the compound of formula (I).

[0139] When R 5 C 5-14 When cycloalkyl, R 4 Preferred and C 5-14 Cycloalkyl groups form covalent bonds, thus forming a 6-membered ring. The covalent bond is located at C, which forms the link with the L group. 5-14 The C atoms adjacent to the carbon ring atoms of cycloalkyl groups 5-14 The cycloalkyl groups are formed between the carbon ring atoms. Here, the compounds of formula (I) are fused tricyclic ring systems, and the example compounds in this embodiment include rosinane diterpenoids.

[0140] In a preferred embodiment:

[0141] R 1 R 2 R 3 and R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl, C 1-4 fluoroalkyl and C 2-6alkenyl;

[0142] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 fluoroalkyl and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0143] R 6 R 7 R 8 R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl and C 1-4 Fluoroalkyl groups.

[0144] A fluoroalkyl group is an alkyl group in which one or more hydrogen atoms, for example, one or all of the hydrogen atoms, are replaced by fluorine atoms, i.e., F. Fluoroalkyl groups can be C10-3 ... 1-4 fluoroalkyl, such as C 1-3 Or C 1-2 Fluoroalkyl groups, and these can be monofluoro or perfluoroalkyl. In this context, prefixes (e.g., C) are used. 1-4 () indicates the number of carbon atoms in the hydrocarbon backbone.

[0145] C 1-4 Examples of fluoroalkyl groups include monofluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), pentafluoroethyl (-C2F3), heptafluoropropyl (-C3F7), and nonafluorobutyl (-C4F9).

[0146] Group R 1 R 2 R 3 and R 4

[0147] In a preferred embodiment:

[0148] R 1 R 2 R 3 and optional R 4 Independently selected from H, F, OH, SH, OR 6 CO2R7 OC(=O)R 8 C 1-6 Alkyl, CF3, C2F5 and C 2-6 alkenyl; and

[0149] R 6 R 7 and R 8 Independently selected from H and C 1-6 Alkyl groups, CF3, and C2F5.

[0150] In a preferred embodiment:

[0151] R 1 R 2 R 3 and optional R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl, CF3 and C 2-6 alkenyl; and

[0152] R 6 R 7 and R 8 Independently selected from H and C 1-6 Alkyl groups and CF3.

[0153] In a preferred embodiment:

[0154] R 1 R 2 R 3 and optional R 4 Independently selected from H, F, OH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl and C 2-6 alkenyl; and

[0155] R 6 R 7 and R 8 Independently selected from H and C 1-6 alkyl.

[0156] In a preferred embodiment:

[0157] R 1 R 2 R 3 and optional R 4 Independently selected from H, OH, OR 6 CO2R 7OC(=O)R 8 C 1-6 Alkyl; and

[0158] R 6 R 7 and R 8 Independently selected from H and C 1-6 alkyl.

[0159] In a preferred embodiment:

[0160] R 1 R 2 R 3 and optional R 4 Independently selected from H, OH, OR 6 CO2R 7 OC(=O)R 8 Me, Et, and Pr; and

[0161] R 6 R 7 and R 8 Independently selected from H, Me, and Et.

[0162] In a preferred embodiment, R 1 R 2 R 3 and optional R 4 It is independently selected from H, OH, OMe, OEt, CO2H, CO2Me, CO2Et, OC(O)Me and OC(O)Et.

[0163] In a preferred embodiment, R 1 R 2 R 3 and optional R 4 It is independently selected from H, OH, OMe, CO2H, CO2Me, and OC(O)Me.

[0164] In a preferred embodiment, R 1 R 2 R 3 and optional R 4 It is independently selected from H, OH, and OMe.

[0165] In a preferred embodiment, R 1 R 2 R 3 and optional R 4 Independently selected from H, OH, OMe and C 1-6 Alkyl groups, such as Me, Et, and Pr, such as Pr.

[0166] In a preferred embodiment, R 1R 2 R 3 One of them is OH or C 1-6 Alkyl group, and other groups are H. Here, R 4 H can be chosen arbitrarily.

[0167] Group R 2 It can be H, OH or C 1-6 Alkyl, and R 1 and R 3 Both can be H. Here, R... 4 H can be chosen arbitrarily.

[0168] Group R 3 It can be H, OH or C 1-6 Alkyl, and R 1 and R 2 Both can be H. Here, R... 4 H can be chosen arbitrarily.

[0169] In a preferred embodiment, R 1 R 2 R 3 and optional R 4 For H.

[0170] The above is for R 1 R 2 and R 3 Each preferred embodiment may be applied, when R 4 With C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring.

[0171] In a preferred embodiment, R 1 R 2 R 3 and R 4 For H.

[0172] In another preferred embodiment, R 1 and R 3 For H, R 2 For H or C 1-6 Alkyl groups, such as propyl, R 5 C 5-14 Cycloalkyl, and R 4 With C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring.

[0173] Group R 5 Substituents on

[0174] In a preferred embodiment:

[0175] R 5 Selected from C 2-15alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, CF3, C2F5 and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0176] R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl groups, CF3, and C2F5.

[0177] In a preferred embodiment:

[0178] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, CF3 and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0179] R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl groups and CF3.

[0180] In a preferred embodiment:

[0181] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl and C 1-4 The hydroxyalkyl group is substituted, and the other group R4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0182] R 9 R 10 and R 11 Independently selected from H and C 1-6 alkyl.

[0183] In a preferred embodiment:

[0184] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from OH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0185] R 9 R 10 and R 11 Independently selected from H and C 1-6 alkyl.

[0186] In a preferred embodiment:

[0187] R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from OH, OR 9 CO2R 10 OC(=O)R 11 Substitution of the groups Me, Et and -CH2OH (hydroxymethyl), and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and

[0188] R 9 R 10 and R 11 Independently selected from H, Me, and Et.

[0189] R 5 As alkenyl

[0190] In one implementation, R 5C 2-15 Alkenyl group. Here, L is preferably -CH=CH-.

[0191] In a preferred embodiment, R 5 C 4-10 Alkenyl groups, which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 fluoroalkyl and C 1-4 Hydroxyl group substitution; and

[0192] R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl and C 1-4 Fluoroalkyl groups.

[0193] In a preferred embodiment, R 5 C 4-10 Alkenyl groups, which may be unsubstituted or composed of one to four independently selected from OH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl and C 1-4 Hydroxyl group substitution; and

[0194] R 9 R 10 and R 11 Independently selected from H and C 1-6 alkyl.

[0195] In a preferred embodiment, R 5 C 4-10 The alkenyl group may be unsubstituted or substituted by one to four independent groups selected from OH, OMe, OEt, CO2H, CO2Me, CO2Et, OC(O)Me, OC(O)Et and CH2OH.

[0196] In a preferred embodiment, R 5 C 4-10 Alkenyl groups, which may be unsubstituted or substituted by one to four independent groups selected from OH, OMe, CO2H, CO2Me and OC(O)Me.

[0197] In a preferred embodiment, R 5 For unreplaced C 4-10Alkenyl group. Such a group may contain one or more, for example, two carbon-carbon double bonds. Alkenyl group may have one, two, three or more carbon-carbon double bonds, and preferably one or two carbon-carbon double bonds, for example, two carbon-carbon double bonds.

[0198] Carbon-carbon double bonds can exist at the ends of alkenyl groups, including the ends of the main chain or the ends of branches.

[0199] The carbon-carbon double bond may be conjugated or not conjugated with another carbon-carbon double bond in the phenolic compound of formula (I) (e.g., with another double bond of the alkenyl group), and is preferably not conjugated.

[0200] In one implementation, R 5 C 4-15 alkenyl groups, such as C 4-12 C 4-10 For example, C 6-10 , or for example C 10 Alkenyl group. The alkenyl group is preferably branched. The alkenyl group is preferably unsubstituted.

[0201] In one implementation, R 5 It is 1-vinyl-1,5-dimethyl-4-hexen-1-yl.

[0202] When R 5 C 4-15 When alkenyl, R 1 To R 4 Each is typically represented by H.

[0203] R 5 As carbonyl aryl

[0204] In one implementation, R 5 C 6-14 Carbonyl aryl group. Here, L is preferably -CH=CH-.

[0205] In one implementation, R 5 For C6 or C 10 Carbonyl aryl group. R is preferred. 5 It is a phenyl group, which can be unsubstituted or substituted.

[0206] In a preferred embodiment, R 5 It is a C6 carbonyl aryl (phenyl) group, which may be unsubstituted or composed of one to four independently selected groups: F, OH, SH, OR. 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 fluoroalkyl and C 1-4 Hydroxyl group substitution; and

[0207] R9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl and C 1-4 Fluoroalkyl groups.

[0208] In a preferred embodiment, R 5 It is a C6 carbonyl aryl group, which can be unsubstituted or composed of one to four independently selected OH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl and C 1-4 Hydroxyl group substitution; and

[0209] R 9 R 10 and R 11 Independently selected from H and C 1-6 alkyl.

[0210] In a preferred embodiment, R 5 It is a C6 carbonyl aryl group, which may be unsubstituted or substituted by one to four groups independently selected from OH, OMe, OEt, CO2H, CO2Me, CO2Et, OC(O)Me, OC(O)Et and CH2OH.

[0211] In a preferred embodiment, R 5 It is a C6 carbonyl aryl group, which may be unsubstituted or substituted by one to four independent groups selected from OH, OMe, CO2H, CO2Me and OC(O)Me.

[0212] In a preferred embodiment, R 5 It is a C6 carbonyl aryl group, which is substituted by one to four groups, such as two groups, independently selected from OH and OMe, such as one to four groups, such as two OMe groups.

[0213] In one implementation, R 5 It is 3,5-dimethoxyphenyl-1-yl.

[0214] In one implementation, R 5 It is 3,5-dihydroxyphenyl-1-yl. When R 1 To R 4 One of them, for example, R 2 Or R 3 When the OH group is present, this group can exist.

[0215] In one implementation, R 5 It is not dihydroxyphenyl, such as 3,5-dihydroxyphenyl-1-yl, or hydroxymethoxyphenyl, such as 3-hydroxy-5-methoxyphenyl-1-yl.

[0216] When R 5 C 6-14 When carbonyl aryl, R 1 R 2 and R 4 Each is typically represented by H.

[0217] When R 5 C 6-14 When carbonyl aryl, R 3 Typically H, OH, or OR 6 For example, H or OH.

[0218] R 5 As cyclohexyl

[0219] In one implementation, R 5 C 5-14 Cycloalkyl, and the R group 4 With C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring. Here, L is preferably -CH2-CH2- or -C(=O)CH2-.

[0220] In a preferred embodiment, R 5 It is a C6 cycloalkyl group (cyclohexyl), which may be unsubstituted or substituted by one to four independently selected from F, OH, SH, OR. 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 1-4 The hydroxyalkyl group is substituted, and the group R 4 It forms a covalent bond with the cyclohexyl group, thus forming a 6-membered ring.

[0221] R 4 The connection with the cyclohexyl group provides a fused tricyclic system with a rosinane diterpenoid core. The position and identity of the substituents in the fused tricyclic system are described below using the ring numbering conventions for rosinane diterpenoids. The ring numbering system is shown below for reference:

[0222]

[0223] The 1-, 2-, 3-, 4-, 5-, and 10-positions are cyclohexyl ring atoms. These positions can each be converted to R under appropriate conditions. 5 Substitution, such as mono- or di-substitution.

[0224] The 5-position preferably has an S-stereochemistry. The 10-position preferably has an -S-stereochemistry. The 5- and 10-positions may have the stereochemical configuration present in natural ferrugin.

[0225] The 1- and 2-positions are preferably unsubstituted.

[0226] The 3-position is preferably unsubstituted or substituted with OH.

[0227] The 4-position can be disubstituted (gem substitution). One substituent can be C. 1-6 Alkyl groups, such as methyl. Other substituents may be selected from C10. 1-6 Alkyl groups, such as methyl groups, CO2R 10 For example, CO2H and CO2Me, and C 1-4 Hydroxyalkyl, such as hydroxymethyl. Preferably, the 4-position is 4-dimethyl-substituted, 4-CO2H-4-Me-substituted, or 4-CO2Me-4-Me-substituted.

[0228] The 5-position corresponds to the carbon ring atom of the cyclohexyl group attached to the linker L. The 5-position is preferably not further substituted.

[0229] Positions 6 and 7 correspond to linker L in the compounds of the present invention. The bond between positions 6 and 7 of the ring can be saturated or unsaturated, but is preferably saturated.

[0230] The 6-position is preferred and cannot be replaced.

[0231] The 7th bit is either unsubstituted or substituted (=O).

[0232] The 8-position corresponds to the carbon ring atom attached to the phenolic group of the linker L.

[0233] 9-bit corresponds to R 4 The substituted phenolic group's carbocyclic atom. Here, R 4 It forms a covalent bond with the cyclohexyl group, thus forming a 6-membered ring.

[0234] The 10-position is a cyclohexyl group on the carbon ring. This ring is attached to the 9-position carbon ring atom, which is R... 4 The ring atom of the substituted phenolic group. The 10-position either remains unsubstituted or is replaced by a C-position. 1-6 Alkyl groups, such as methyl groups, are substituted.

[0235] 11-bit corresponds to R 3 The substituted phenolic group has a carbon ring atom. Preferably, H is a substituent at that position.

[0236] The 12-position corresponds to the carbon ring atom of the phenolic group with a phenolic hydroxyl group.

[0237] 13-bit corresponds to R 2 The substituted phenolic group's carbocyclic atom. Preferably C 1-6 Alkyl, such as propyl or isopropyl, is a substituent at that position.

[0238] 14-bit corresponds to R 1 The substituted phenolic group has a carbon ring atom. Preferably, H is a substituent at that position.

[0239] When R 5 C 5-14 When cycloalkyl, then R 1 and R 3 Typically, it is H.

[0240] When R 5 C 5-14 When cycloalkyl, then R 2 Typically H or C 1-6 Alkyl groups, such as H or Pr.

[0241] Preferred compounds

[0242] In a particularly preferred embodiment, the phenolic compound is selected from compounds of formulas (II) to (VIII):

[0243]

[0244]

[0245] (VII)

[0246]

[0247] (VIII)

[0248] For example, phenolic compounds may be selected from compounds of formula (II), (III) and (IV).

[0249] The phenolic compound may be psoralen or δ-3,2-hydroxypsoralen.

[0250] The phenolic compound may be pterostilbene or paclitaxel.

[0251] Phenolic compounds may be ferric alcohol, cedrol, or podophyllin.

[0252] In one embodiment, the phenolic compound is not one or more compounds selected from resveratrol and pinostilbene.

[0253] The phenolic compounds described herein, such as those of formula (I), may be provided in the form of a free base. Alternatively, the phenolic compounds may be provided in the form of salts, such as pharmaceutically or cosmetically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1–19.

[0254] In some embodiments, the phenolic compounds described herein are provided in protonated form along with a suitable counter anion.

[0255] Suitable counter anions include both organic and inorganic anions. Examples of inorganic anions include those derived from inorganic acids, including chlorine (Cl₂). - ), bromine (Br) - ), iodine (I - ), sulfate (SO4 2- ), sulfite (SO3) 2- ), nitrate (NO3) - ), nitrite (NO2) - ), phosphate (PO4) 3- ) and phosphate (PO3) 3- Examples of organic anions include 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, ethylenediaminetetraacetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, lactate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, benzenesulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartrate, toluenesulfonate, and valerate. Suitable examples of polymeric organic anions include those derived from tannins and carboxymethyl cellulose.

[0256] In some embodiments, the phenolic compounds disclosed herein are provided in a deprotonated form together with a suitable countercation.

[0257] Suitable counter cations include both organic and inorganic cations. Examples of suitable inorganic cations include alkali metal ions such as Na+. + and K + Alkaline earth metal cations, such as Ca 2+ and Mg 2+and other cations such as Al 3+ Examples of suitable organic cations include ammonium ions (i.e., NH4+). + ) and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Examples of substituted ammonium ions include those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4. + .

[0258] Unless otherwise stated, references to a particular compound also include its salt form.

[0259] The phenolic compounds described herein may be provided in the form of solvates (complexes of solute (e.g., compounds, salts of compounds) and solvents). Examples of solvates include hydrates, such as monohydrates, dihydrates, and trihydrates.

[0260] The phenolic compounds described herein may be provided in a desolvated form, such as in a dehydrated form.

[0261] The compositions of the present invention may contain an effective amount, for example a therapeutic or cosmetic effective amount, of a phenolic compound described herein, such as a phenolic compound of formula (I).

[0262] In some embodiments, the compositions of the present invention contain phenolic compounds in amounts from 0.0005% to 10% by weight, for example, based on the total weight of the composition. In preferred embodiments, the compositions of the present invention contain phenolic compounds in amounts of 0.1% to 5% by weight, for example, 0.1% to 3% by weight, and for example, 0.2% to 3% by weight, and more preferably 0.2% to 2% by weight.

[0263] Phenolic compounds may be present in amounts of up to 2% by weight, 3% by weight, 5% by weight, or 10% by weight.

[0264] The phenolic compound may be present in amounts of at least 0.0005 wt%, 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, or 1.0 wt%.

[0265] Plant or fungal extracts

[0266] The compositions of the present invention comprise plant or fungal extracts.

[0267] Plant or fungal extracts may be selected from extracts of plants belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex*, and *Rubus*, as well as extracts of the fungus *Poria*.

[0268] Plant or fungal extracts may be derived from any suitable species of the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ivy*, *Ilex*, and *Rubus*, as well as extracts from the fungus *Poria*.

[0269] Suitable plant or fungal extracts are commercially available and can be purchased from sources such as BOCSCI (New York, USA).

[0270] Suitable plant species belonging to the genus *Arctostaphylos* include *Arctostaphylos uva-ursi* (bearberry). Bearberries are widely distributed throughout the northern latitudes and are native to places such as the United States and Canada.

[0271] Suitable plant species belonging to the genus *Fragaria* include wild strawberry (*Fragaria vesca*) and pineapple strawberry (*Fragaria × ananassa*). Wild strawberry is widely distributed throughout Europe and is native to countries such as the United Kingdom. Pineapple strawberry is widely cultivated throughout Europe, including the United Kingdom.

[0272] Suitable plant species belonging to the Garcinia genus include mangosteen (Garcinia mangostana).

[0273] Suitable plant species belonging to the genus *Hedera* include *Hedera helix* (common ivy). *Hedera helix* is widely distributed throughout Europe and is native to countries such as England.

[0274] Suitable plant species belonging to the genus *Ilex* include *Ilex aquifolium* (common holly). *Ilex aquifolium* is widely distributed throughout Europe and is native to, for example, Britain.

[0275] Suitable plant species belonging to the genus Rubus include Rubus idaeus (red raspberry). Rubus is widely distributed throughout Europe and is native to places such as the United Kingdom.

[0276] Suitable fungal species belonging to the genus *Wolfiporia* include *Poria cocos* (also known as Chinese root).

[0277] Plant or fungal extracts may be derived from any suitable part of a plant or fungus. Suitable parts of a plant include roots, stems, leaves, flowers, fruits, and seeds. Suitable parts of a fungus include mycelium or fruiting bodies.

[0278] Examples of suitable leaf extracts include bearberry leaf extract, ivy leaf extract, and European holly leaf extract.

[0279] Examples of suitable fruit extracts include Rubus fruit extract, mangosteen peel extract, wild strawberry fruit extract, and pineapple strawberry fruit extract.

[0280] Plant or fungal extracts can be prepared using any suitable extraction method. Suitable extraction methods include extraction using organic solvents and extraction using aqueous solvents (aqueous extraction).

[0281] Typically, plant or fungal extracts are aqueous extracts.

[0282] In a preferred embodiment, the plant or fungal extract is selected from bearberry extract, wild strawberry extract, pineapple strawberry extract, English ivy extract, European holly extract, mangosteen extract, raspberry extract, and poria cocos extract.

[0283] In a preferred embodiment, the plant or fungal extract is selected from bearberry leaf extract, ivy extract, European holly leaf extract, mangosteen peel extract, and poria cocos extract.

[0284] In a preferred embodiment, the plant or fungal extract is selected from extracts of plants belonging to the Garcinia genus. In a preferred embodiment, the plant or fungal extract is mangosteen extract.

[0285] In a preferred embodiment, the plant or fungal extract is selected from extracts of plants belonging to the genera *Ardisia*, *Ilex*, and *Ilex*, as well as extracts of the fungus *Poria*. In a preferred embodiment, the plant or fungal extract is selected from *Ardisia* extract, *Ilex* extract, *Ilex* extract, and *Poria* extract.

[0286] In a preferred embodiment, the plant or fungal extract is selected from extracts of plants belonging to the genera *Fragaria* and *Rubus*. In a preferred embodiment, the plant or fungal extract is selected from wild strawberry extract, pineapple strawberry extract, and *Rubus* extract.

[0287] In a preferred embodiment, the plant extract is wild strawberry extract or pineapple strawberry extract.

[0288] In another embodiment, the plant extract is wild strawberry fruit extract or pineapple strawberry fruit extract.

[0289] In a preferred embodiment, the plant extract is ivy extract.

[0290] In a further embodiment, the plant extract is ivy leaf extract.

[0291] In a preferred embodiment, the plant extract is a Rubus idaeus extract.

[0292] In a further embodiment, the plant extract is a Rubus idaeus fruit extract.

[0293] In a preferred embodiment, the plant extract is European wintergreen extract.

[0294] In a further embodiment, the plant extract is European holly leaf extract.

[0295] Phenolic compounds, such as those of formula (I), may not be present in or derived from plant extracts used in combination with them.

[0296] The compositions of the present invention may contain an effective amount, for example a therapeutic or cosmetic effective amount, of the plant or fungal extracts described herein.

[0297] Arbutin extracts, such as bearberry extract, are characterized by the presence of ursolic acid and / or arbutin. Ursolic acid may be present in amounts ranging from 1.5% by weight to 0.0005% by weight, for example, from 1.0% by weight to 0.001% by weight. For example, ursolic acid may be present in an amount of about 1.0% by weight. Alternatively, ursolic acid may be present in an amount of about 0.001% by weight. Arbutin may be present in amounts ranging from 3.5% by weight to 0.0001% by weight, for example, from 3.0% by weight to 0.0005% by weight. For example, arbutin may be present in an amount of about 3.0% by weight. Alternatively, arbutin may be present in an amount of about 0.0005% by weight. Alternatively, the extract may further comprise one or more of the following, for example, all of them: gallic acid (e.g., 0.14 wt%), ellagic acid (e.g., 0.064 wt%), rutin (e.g., 0.011 wt%), hyperoside (e.g., 0.44 wt%), quercitrin (e.g., 0.014 wt%), catechin (e.g., 0.28 wt%), euscapic acid (e.g., 0.038 wt%), tormentinic acid (e.g., 0.017 wt%), uavol (e.g., 0.35 wt%), oleanolic acid (e.g., 0.16 wt%), erythrodiol (e.g., 0.16 wt%), betulin (e.g., 0.13 wt%), and lupeol (e.g., 0.37 wt%). The presence of such characteristic compounds in bearberry extract is as described by Chaika et al. (ScienceRise: Pharmaceutical Science 2020, 6, 74).

[0298] Fructus strawberry extract, such as wild strawberry extract, may contain, for example, one or more, or all of, the compounds listed in Table 1 in amounts within a given range. The extract may be a dry extract.

[0299] Table 1. Components of Wild Strawberry Solid Plant Extract

[0300]

[0301] Wild strawberry extract can be obtained from or can be obtained from strawberry fruit. The extract can be obtained by water extraction, concentration and spray drying.

[0302] Garcinia extracts, such as mangosteen extract, are characterized by the presence of one or more, for example, all of, α-dextrin, γ-dextrin, and gartanin. α-dextrin may be present in amounts ranging from 4.0 to 40.0% by weight, for example, from 8.5 to 13.9% by weight. γ-dextrin may be present in amounts ranging from 6.0 to 8.3% by weight. Gartanin may be present in amounts ranging from 8.1% to 17.3% by weight. The presence of such characteristic compounds in mangosteen extract is as described by Muchtaridi et al. (J. Appl. Pharm. Sci. 2017, 7, 125).

[0303] Extracts of *Ivy* species, such as *Hedera helix* extract, are characterized by the presence of triterpenoid saponins, for example, in amounts ranging from 2.5% to 6% by weight. The extract may contain one or more, for example, all of the following: hederin C (for example, in amounts ranging from 1.7% to 4.8% by weight), hederin D (for example, in amounts ranging from 0.4% to 0.8% by weight), and hederin B (for example, in amounts ranging from 0.1% to 0.2% by weight). Alternatively or additionally, the extract may contain α-hederin, for example, in amounts ranging from 0.1% to 0.3% by weight. Alternatively or additionally, the extract may contain hederagenin, for example, in amounts ranging from 0.1% to 1.5% by weight, for example, 0.89% or 0.9% by weight. The presence of such characteristic compounds in *Hedera helix* extract is as described by Tatia et al. (Rev. Chim. 2019, 70, 1157).

[0304] In one embodiment, the ivy extract is characterized by having a minimum content of 3.0% by weight of hedyotis diffusa C.

[0305] English ivy extract can be obtained from or can be obtained from the whole plant or leaves of English ivy. The extract can be obtained by water extraction, concentration and drying.

[0306] Wintergreen extracts, such as European wintergreen extract, are characterized by the presence of ursolic acid and oleanolic acid. Ursolic acid may be present in amounts ranging from 1.35% by weight to 0.0005% by weight, for example, from 1.30% by weight to 0.001% by weight. For example, ursolic acid may be present in an amount of about 1.30% by weight. Alternatively, ursolic acid may be present in an amount of about 0.001% by weight. Oleanolic acid may be present in an amount of about 0.50% by weight. Additionally or alternatively, wintergreen extracts may contain amino acids, sugars, carotenoids, phenolic derivatives, fatty acids, flavonoids, anthocyanins, and triterpenes, such as α-amyrin, β-amyrin, ursolic acid, and erythritol. The presence of such characteristic compounds in European wintergreen extracts is as described by Palu et al. (Molecules 2019, 24, 4413).

[0307] European holly extract can be obtained from or can be obtained from the whole plant or leaves of English holly, such as the leaves. The extract can be obtained by water extraction, concentration and drying.

[0308] Arbutin extracts, such as bearberry extract, are characterized by the presence of ursolic acid and / or arbutin. Ursolic acid may be present in an amount ranging from 1.5% by weight to 0.0005% by weight, for example, from 1.0% by weight to 0.001% by weight. For example, ursolic acid may be present in an amount of about 1.0% by weight. Alternatively, ursolic acid may be present in an amount of about 0.001% by weight. Arbutin may be present in an amount ranging from 3.5% by weight to 0.0001% by weight, for example, from 3.0% by weight to 0.0005% by weight. For example, arbutin may be present in an amount of about 3.0% by weight. Alternatively, arbutin may be present in an amount of about 0.0005% by weight. Additionally or alternatively, the extract may further comprise one or more of the following, for example, all of them: gallic acid (e.g., 0.14 wt%), ellagic acid (e.g., 0.064 wt%), rutin (e.g., 0.011 wt%), hyperoside (e.g., 0.44 wt%), quercetin (e.g., 0.014 wt%), catechin (e.g., 0.28 wt%), euscapic acid (e.g., 0.038 wt%), tormentinic acid (e.g., 0.017 wt%), ursolic acid (e.g., 0.35 wt%), oleanolic acid (e.g., 0.16 wt%), erythritol (e.g., 0.16 wt%), betulin (e.g., 0.13 wt%), and lupeol (e.g., 0.37 wt%). The presence of such characteristic compounds in bearberry extract is as described by Chaika et al. (ScienceRise: Pharmaceutical Science 2020, 6, 74).

[0309] Rubus extracts, such as Rubus idaeus extract, may contain, for example, one or more of the compounds given in Table 2, such as all of the following compounds, in amounts within a given range. The extracts herein may be dry extracts.

[0310] Table 2. Components of Rubus idaeus solid plant extract

[0311]

[0312] Rubus extract can be obtained from or can be obtained from raspberry fruit. The extract can be obtained by water extraction, concentration and spray drying.

[0313] Extracts of the genus *Poria*, such as *Poria cocos* extract, are characterized by the presence of triterpenoid acids, such as poricoic acid A and / or pachymic acid. The extract may contain one or more of, for example, all of, the following: poricoic acid A (e.g., 18.0 wt%), poricoic acid B (e.g., 4.6 wt%), dehydrotumulosic acid (e.g., 1.1 wt%), polyporenic acid C (e.g., 1.7 wt%), and pachymic acid (e.g., 0.71 wt%). The presence of such characteristic compounds in alcoholic extracts of *Poria cocos* is as described by Cai et al. (Drug Metabolism and Disposition 2021, 49, 353).

[0314] In some embodiments, the compositions of the present invention comprise 0.005% to 50% by weight of plant or fungal extracts, for example, based on the total weight of the composition. In preferred embodiments, the compositions of the present invention comprise 0.005% to 30% by weight, for example, 0.05% to 10% by weight, more preferably 0.1% to 3% by weight of plant or fungal extracts.

[0315] Plant extracts may be present in amounts of up to 2% by weight, 3% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 45% by weight, or 50% by weight.

[0316] The plant extract may be present in amounts of at least 0.005% by weight, 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.5% by weight, or 1% by weight.

[0317] Phenolic compounds may be substantially absent in plant extracts used in combination with them, for example, they may not be present in or derived from plant extracts used in combination with them. For example, when the plant extracts are from the genera *Ardisia*, *Fructus*, *Garcinia*, *Hedera*, *Ilex*, *Rubus*, or *Poria*, such as *Ardisia* leaf extract, wild strawberry extract, pineapple strawberry extract, *Hedera helix* extract, European holly extract, mangosteen extract, *Rubus* extract, and *Poria*, these extracts are substantially free of phenolic compounds, any or all of the phenolic compounds of formula (I).

[0318] For example, the total amount of the phenolic compound of formula (I) in the plant extract may be less than 1% by weight, for example less than 0.1% by weight, for example less than 0.01% by weight. For example, the phenolic compound of formula (I) in combination with the plant extract may be present in the plant extract in less than 1% by weight, for example less than 0.1% by weight, for example less than 0.01% by weight.

[0319] Composition

[0320] The compositions of the present invention can be formulated for cosmetic or therapeutic purposes. Therefore, the compositions of the present invention may additionally contain one or more pharmaceutical or cosmetic ingredients.

[0321] Pharmaceutically and cosmetically acceptable ingredients are those that, within a reasonable judgment, are suitable for contact with the tissues of the subjects under discussion (e.g., humans) without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio. Each ingredient must also be compatible with the other components of the composition.

[0322] In one embodiment, the composition comprises one or more ingredients selected from solvents, oils, surfactants, thickeners, humectants, and preservatives.

[0323] Examples of suitable solvents include water; monohydric alcohols such as ethanol, isopropanol, benzyl alcohol, and phenethyl alcohol; polyhydric alcohols such as ethylene glycol, propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and erythritol; and glycol ethers such as ethylene glycol monomethyl ether and diethylene glycol monomethyl ether.

[0324] Examples of suitable oils include mineral oils, vegetable oils, and waxes.

[0325] Examples of suitable vegetable oils include algae oil, annatto oil, argan oil, almond oil, avocado oil, babassu oil, Brazil nut butter, butter, cashew butter, castor oil, camellia oil, cherry kernel oil, cocoa butter, coconut oil, corn oil, cottonseed oil, fish oil, grapeseed oil, gardenia oil, ghee, hazelnut oil, jatropha oil, jojoba oil, kokum oil, flaxseed oil, macadamia oil, corn oil, mango seed oil, mango butter, mineral oil, mink oil, olive oil, palm oil, palm kernel oil, peach kernel oil, peanut butter, peanut oil, plum kernel oil, pomegranate oil, rapeseed oil, rice bran oil, rosehip oil, sal oil, sesame oil, shea butter, soybean oil, squalene, sunflower oil, tea seed oil, and walnut oil.

[0326] Examples of suitable waxes include waxes such as wax, beeswax, carnauba wax (palm wax), candelilla wax, pure ceresin wax, jojoba oil, lanolin wax, lignite wax, ceresin wax, polyglyceryl-3-beeswax, polyglyceryl-6-pentastearate, Japanese wax, microcrystalline wax, paraffin wax, isoparaffin, petrolatum solid paraffin, squalene, oligomeric olefins, synthetic candelilla wax, synthetic carnauba wax, and synthetic beeswax.

[0327] Surfactants (surfactant reagents) can act as dispersants or wetting agents. Examples of suitable surfactants include anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric (amphoionic) surfactants.

[0328] Examples of suitable anionic surfactants include ammonium lauryl sulfate, ammonium laureth sulfate, triethylamine lauryl sulfate, triethylamine lauryl sulfate, triethanolamine lauryl sulfate, triethanolamine lauryl sulfate, monoethanolamine lauryl sulfate, monoethanolamine lauryl sulfate, diethanolamine lauryl sulfate, diethanolamine lauryl sulfate, sodium monolaurate sulfate, sodium lauryl sulfate, sodium lauryl sulfate, potassium lauryl sulfate, potassium lauryl sulfate, sodium lauryl sarcosinate, sodium lauroyl sarcosinate, lauryl sarcosinate, and cocoyl sarcosinate. Sarcosine), Ammonium cocoyl sulfate, Ammonium lauroyl sulfate, Sodium cocoyl sulfate, Sodium lauroyl sulfate, Potassium cocoyl sulfate, Potassium lauryl sulfate, Triethanolamine lauryl sulfate, Triethanolamine lauryl sulfate, Monoethanolamine cocoyl sulfate, Monoethanolamine lauryl sulfate, Sodium tridecylbenzenesulfonate, and Sodium dodecylbenzenesulfonate.

[0329] Examples of suitable cationic surfactants include behenyltrimethylammonium chloride, cocoyltrimethylammonium chloride, cetylethyldimethylammonium bromide, dibenzyldimethylammonium chloride, dihydrotallowylbenzylmethylammonium chloride, disoyadimonium chloride, ditallowyldimethylammonium chloride, hydroxycetylhydroxyethyldimethylammonium chloride, hydroxyethylbenzylpropyldimethylammonium chloride, hydroxyethylcetyldimethylammonium chloride, hydroxyethyltallowyldimethylammonium chloride, myristalkonium chloride, PEG-2 oleamonium chloride, PEG-5 stearmonium chloride, PEG-15 cocoylquaternium 4, and PEG-2 stearalkonium chloride. 4) Lauryltrimethylammonium chloride; Quaternium-16; Quaternium-18; Lauralkonium chloride; Olealkmonium chloride; Pyridinium hexadecyl chloride; Polyquaternium-5; Polyquaternium-6; Polyquaternium-7; Polyquaternium-10; Polyquaternium-22; Polyquaternium-37; Polyquaternium-39; Polyquaternium-47; Cetyltrimethylammonium chloride; Dilauryldimethylammonium chloride; Cetalkonium chloride; Diceryldimethylammonium chloride; Soyatrimonium chloride; and Stearyloctyl dimonium methosulfate.

[0330] Examples of suitable nonionic surfactants include fatty alcohol ethoxylates such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether; alkylphenol ethoxylates (APE or APEO) such as nonoxynol-4, nonoxynol-7, nonoxynol-9, nonoxynol-14, nonoxynol-15, nonoxynol-18 and triton X-100; glycerol fatty acid esters such as glycerol monostearate and glycerol monolaurate; sorbitol fatty acid esters such as sorbitol monolaurate, sorbitol monostearate, sorbitol tristearate, polysorbate (Tween) 20, polysorbate 40, polysorbate 60 and polysorbate 80.

[0331] Examples of suitable amphoteric (amphoionic) surfactants include cocamidopropyl hydroxysulfonate betaine, cocamidopropyl betaine, lauryl betaine, lauryl dimethylamine oxide, and myristamine oxide.

[0332] Examples of suitable thickeners (rheology modifiers) include gums such as alginate, carrageenan, acacia gum, gum arabic, gatatan (Indian gum), gum karaya, tragacanth gum, guar gum; guar gum hydroxypropyltrimethylammonium chloride, xanthan gum, or gellan gum; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl carboxyethyl cellulose, hydroxymethyl carboxypropyl cellulose, ethyl cellulose, sulfated cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose; agar; pectin; gelatin; starch and its derivatives; chitosan and its derivatives such as hydroxyethyl chitosan; synthetic polymers such as polyvinyl alcohol, PVM / MA copolymer, PVM / MA decadiene crosslinked polymer, and poly(ethylene oxide) based thickeners.

[0333] Humectants act as moisture absorbers, increasing the amount of water absorbed or retained by the composition. Examples of suitable humectants include acetamide MEA, ammonium lactate, chitosan and its derivatives, colloidal oatmeal, galactoarabinogalactan, glucosamine glutamate, glerecyth-7, glycerol ether-12, glycerol ether-26, glycerol ether-31, glycerin, lactamide MEA, lactamide DEA, lactic acid, methyl gluceth-10, methyl gluceth-20, panthenol, propylene glycol, sorbitol, polyethylene glycol, 1,3-butanediol, 1,2,6-hexanetriol, hydrogenated starch hydrolysate, inositol, mannitol, PEG-5 pentaerythritol ether, polyglycerol sorbitol, xylitol, sucrose, sodium hyaluronate, and sodium PCA.

[0334] Examples of suitable preservatives include methylparaben, propylparaben, and sorbic acid. Other suitable preservatives include methyldibromoglutaronitrile (MDBGN), benzyl alcohol, imidazolidinyl urea 1,3-bis(hydroxymethyl)-5,5-dimethyl-2,3-imidazolidinedione (DMDM hydantoin), methylchloroisothiazolinone and methylisothiazolinone, phenoxyethanol, and sodium benzoate.

[0335] In one embodiment, the composition comprises one or more ingredients selected from emollients, anti-inflammatory agents, antioxidants, and UV blockers.

[0336] Examples of suitable emollients include fatty esters such as isopropyl myristate, isopropyl palmitate, caprylic / capric triglyceride, cetyl lactate, cetyl palmitate, hydrogenated castor oil, glycerides, hydroxycetyl isostearate, hydroxycetyl phosphate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, PPG-5-Ceteth-20, 2-ethylhexyl isononanoate, 2-ethylhexyl stearate, C12 to C16 fatty alcohol lactates, isopropyl lanolinate, and 2-ethylhexyl salicylate.

[0337] Examples of suitable anti-inflammatory ingredients include cyclooxygenase (e.g., COX-1 or COX-2) or lipoxygenase (e.g., LOX-5) enzyme inhibitors, such as ascorbic acid, ascorbic acid derivatives, vitamin E, vitamin E derivatives, tocotrienols, rutin, quercetin, hesperidin (Citrus sinensis), hesperidin (Citrus sinensis), diosmin (Citrus sinensis), mangiferin (Mangifera indica), mangostin (Garcinia mangostana), cyanidin (Vaccinium myrtillus), astaxanthin (Haematococcus algae), lutein (Tagetes patula), lycopene (Lycopersicum esculentum), and resveratrol (Polygonum cuspidatum). The extracts include: cuspidatum, tetrahydrocurcumin (Curcuma longa), rosmarinic acid (Rosmarinus officinalis), hypericin (Hypericum perforatum), tannic acid (Punica granatum), chlorogenic acid (Vaccinium vulgaris), oleuropein (Olea europaea), alpha-lipoic acid, glutathione, andrographolide (Andrographis paniculata), grape seed extract, green tea extract, polyphenols, pycnogenol (pine bark extract), white tea extract, black tea extract (Andrographis paniculata), carnosine, and nicotinamide.Other examples of suitable anti-inflammatory compositions may be selected from horse chestnut extract (Aesculus hippocastanum extract), esculin, escin, yohimbine, capsicum oleoresin, capsaicin, niacin, nicotinic acid ester, methyl nicotinate, benzyl nicotinate, ruscogenins (Butchers Broom extract; Ruscus aculeatus extract), diosgenin (Trigonel afoenumgraecum, fenugreek), emblica extract (Phyllanthus emblica extract), and asiaticoside. Centella asiatica extract, Boswellia serrata extract, sericoside, visnadine, thiocolchicoside, grape seed extract, ginger root extract, piperine, vitamin K, melilot (Melilotus officinalis extract), glycyrrhetinic acid, ursolic acid, sericoside (Terminalia sericea extract), darutoside (Siegesbeckia orientalis extract), Amni visnaga extract, grape leaf extract (Vitis vinifera extract). vinifera), apigenin, phytosan, and luteolin.

[0338] Examples of suitable antioxidant ingredients include ascorbic acid, ascorbic acid derivative glucosamine ascorbate, arginine ascorbate, lysine ascorbate, glutathione ascorbate, nicotinamide ascorbate, niacin ascorbate, allantoin ascorbate, creatine ascorbate, creatinine ascorbate, chondroitin ascorbate, chitosan ascorbate, and carnosine ascorbate. Ascorbate, Vitamin E, Vitamin E derivatives, Tocotrienol, Rutin, Quercetin, Hesperidin (sweet orange), Hesperidin (sweet orange), Diosmin (sweet orange), Mangiferin (mango), Mangosteen, Cyanobacterium (blueberry), Astaxanthin (haepococcus pluvialis), Lutein (Taraxacum mongolicum), Lycopene (tomato), Resveratrol (Polygonum cuspidatum), Tetrahydrocurcumin (turmeric), Rosmarinic acid (rosemary), Hypericin (hypericum), Tannic acid (pomegranate), Chlorogenic acid (Vaccinium vulgaris), Olive oil oleuropein, Alpha-lipoic acid, Niacinamide lipoate, Glutathione, Andrographolide (Andrographis paniculata), Carnosine, Niacinamide, Potentilla The ingredients include *Prunus erecta* extract, polyphenols, grape seed extract, pycnogenol (pine bark extract), pyridoxine, magnolol, honokiol, paeonol, resacetophenone, quinacetophenone, arbutin, and kojicacid.

[0339] Examples of suitable UV blockers (sunscreen actives) include octyl methoxycinnamate (ethylhexyl p-methoxycinnamate), octyl salicylate oxybenzone (benzophenone-3), benzophenone-4, menthyl anthranilate, dioxybenzone, aminobenzoic acid, pentyl dimethyl PABA, diethanolamine p-methoxy cinnamate, ethyl 4-bis(hydroxypropyl)aminobenzoate, 2-ethylhexyl 1-2-cyano-3,3-diphenylacrylate, high-menthol salicylate, glyceryl aminobenzoate, dihydroxyacetone, octyl dimethyl PABA, 2-phenylbenzimidazole-5-sulfonic acid, triethanolamine salicylate, zinc oxide, titanium dioxide, and mixtures thereof.

[0340] Other components suitable for use in the composition include fragrances, pH adjusters, pigments, odor absorbers, antimicrobial agents, antifungal agents, chelating agents, and sugars.

[0341] The compositions of the present invention are typically formulated for topical use.

[0342] The compositions of the present invention can be formulated as solutions, liquids, lotions, creams, emulsions, dispersions, gels, or pastes. Examples of suitable emulsions include two-phase emulsions comprising an aqueous phase and an oil phase, such as oil-in-water (O / W) and water-in-oil (W / O), as well as complex emulsions, such as triple emulsions (O / W / O and W / O / W).

[0343] Compositions and formulations can be prepared by any method well known in the art. Such methods involve combining phenolic compounds and / or plant or fungal extracts with a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by uniformly mixing phenolic compounds and / or plant or fungal extracts with a carrier (e.g., a liquid carrier, a finely chopped solid carrier, etc.).

[0344] The compositions of the present invention can be formulated into both cosmetic and pharmaceutical products.

[0345] In one embodiment, a personal care product comprising the composition of the present invention is provided. Suitable personal care products include skin care products, hair care products, cleansing products, and cosmetic powders and liquids.

[0346] Examples of suitable skincare products include skin / hand washes, skin / hand creams, skin / hand ointments, skin / hand pastes, toners, shaving gels, shaving creams, sunscreens, deodorants, antiperspirants, sunscreen washes, after-sun lotions, aftershaves, body oils, bath oils, and bubble baths. Examples of suitable haircare products include conditioners, hair detangling lotions, styling gels, styling creams, styling waxes, styling washes, mousses, spray gels, hair growth products, sprays, and hair oils. Examples of suitable cleansing products include liquid soaps, bar soaps, shower gels, skin cleansers, and shampoos. Examples of suitable cosmetic powders and liquids include blush, talcum powder, bronzer, eyeshadow, foundation, face powder, lip powder, powder makeup, liquid bronzer, eyeliner, lip gloss, lipstick, and mascara.

[0347] Methods and uses for reducing lipid production

[0348] The compositions of the present invention reduce lipid production in sebaceous gland cells.

[0349] The present invention also provides a method for reducing lipid production in sebaceous gland cells, the method comprising contacting the sebaceous gland cells with a composition of the present invention, for example, a composition comprising:

[0350] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0351] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from the fungus *Poria*.

[0352] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, as described above.

[0353] In one embodiment, the method for reducing lipid production in sebaceous gland cells is in vivo. In another embodiment, the method for reducing lipid production in sebaceous gland cells is ex vivo, for example, in vitro.

[0354] In one embodiment, a method for reducing lipid production in sebaceous gland cells includes contacting the sebaceous gland cells with an effective amount of the composition of the present invention. The effective amount of the composition provides a detectable reduction in lipid production in the sebaceous gland cells. Methods for detecting and quantifying lipid production in sebaceous gland cells include, for example, fluorescence assays using a suitable lipid detection dye such as AdipoRed™.

[0355] In one embodiment, a method for reducing lipid production in sebaceous gland cells includes contacting the sebaceous gland cells with a composition of the present invention in an amount suitable for reducing lipid production by 10% or more, preferably 15% or more, more preferably 20% or more, even more preferably 20% or more, and most preferably 30% or more.

[0356] In one embodiment, the method for reducing lipid production in sebaceous gland cells reduces lipid production by 5% or more, preferably 10% or more, preferably 15% or more, more preferably 20% or more, even more preferably 20% or more, and most preferably 30% or more.

[0357] The present invention also provides compositions of the present invention, for example, compositions comprising the following, for use in methods of reducing lipid production in sebaceous gland cells:

[0358] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0359] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from the fungus *Poria*.

[0360] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, are as described above. Preferred features of the method for reducing lipid production in sebaceous gland cells are also as described above.

[0361] The present invention also provides the use of compositions of the present invention, such as those comprising the following, for reducing lipid production in sebaceous gland cells:

[0362] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0363] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from the fungus *Poria*.

[0364] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, are as described above. Preferred features of the method for reducing lipid production in sebaceous gland cells also apply to the use of the composition for reducing lipid production in sebaceous gland cells.

[0365] Beauty methods and uses

[0366] The compositions of the present invention reduce lipid production in sebaceous gland cells, such as in individual skin. Therefore, the compositions of the present invention can reduce or improve cosmetic problems associated with excessive lipid production in the skin. Cosmetic problems associated with excessive lipid production in the skin include oily or shiny skin, oily hair, enlarged pores, undesirable body odor, and reduced retention of cosmetic products on the skin.

[0367] Therefore, the present invention provides a cosmetic method for reducing lipid production in individual skin, the method comprising contacting the skin with a composition of the present invention, for example, a composition comprising:

[0368] (a) A phenolic compound of formula (I) or its cosmetically acceptable salt, prodrug, solvate, tautomer or stereoisomer; and

[0369] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from the fungus *Poria*.

[0370] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, as described above.

[0371] In one embodiment, the cosmetic method for reducing lipid production in an individual's skin is not a treatment method. In one embodiment, the cosmetic method for reducing lipid production in an individual's skin is not a method of treating a human or animal body through therapy.

[0372] In one implementation, the cosmetic procedure reduces lipid production in the sebaceous gland cells of an individual's skin.

[0373] In one embodiment, the skin is the skin on the head, such as the skin on the face, mouth, neck, or scalp. In another embodiment, the skin is the skin on the chest, back, arms, legs, or hands.

[0374] The benefits of reducing lipid production in an individual's skin include reducing the oily appearance of the skin, controlling surface oil, minimizing skin pores, and reducing undesirable body odor. In one embodiment, a cosmetic method reduces lipid production in the skin, thereby achieving effects selected from: reducing the oily appearance of the skin, controlling surface oil, minimizing skin pores, and reducing undesirable body odor.

[0375] In one implementation, an individual requires cosmetic treatment. The individual requiring cosmetic treatment may have conditions associated with excessive lipid production in the skin, such as oily or shiny skin, oily hair, enlarged pores, and undesirable body odor. In one implementation, the individual has a cosmetic condition selected from the following: oily or shiny skin, oily hair, enlarged pores, and undesirable body odor.

[0376] The present invention also provides compositions of the present invention, such as those comprising the following, for use in cosmetic methods for reducing lipid production in individual skin:

[0377] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0378] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from the fungus *Poria*.

[0379] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, are as described above. Preferred features of the cosmetic method for reducing lipid production in individual skin are also as described above.

[0380] The present invention also provides compositions of the present invention, such as those comprising the following, for use in reducing lipid production in individual skin:

[0381] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0382] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from fungi belonging to the genus *Poria*.

[0383] Preferred features of the composition, such as phenolic compounds and plant or fungal extracts, as described above. Preferred features of cosmetic methods for reducing lipid production in individual skin also apply to using the composition to reduce lipid production in individual skin.

[0384] Medical methods and uses

[0385] The compositions of the present invention reduce lipid production in sebaceous gland cells, such as in individual skin. Therefore, the compositions of the present invention can be used to treat or prevent (avoid) medical problems associated with excessive lipid production in the skin. Medical problems associated with excessive lipid production in the skin include acne vulgaris and rosacea.

[0386] Therefore, the present invention provides compositions of the present invention, for example, compositions comprising the following, for use in therapeutic methods, such as methods of treating a human or animal body by means of therapy:

[0387] (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and

[0388] (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex* and *Rubus*, and extracts from the fungus *Poria*.

[0389] In one embodiment, the treatment method is a method for treating a condition (e.g., a disease) associated with excessive lipid production in the skin. In another embodiment, the treatment method is a method for treating a condition associated with excessive lipid production in sebaceous gland cells.

[0390] In one embodiment, the skin is the skin on the head, such as the skin on the face, mouth, neck, or scalp. In another embodiment, the skin is the skin on the chest, back, arms, legs, or hands.

[0391] In one implementation, the treatment is for acne vulgaris. In another implementation, the treatment is for rosacea.

[0392] In one implementation, the treatment is applied to the subject who requires treatment.

[0393] The subjects (patients) who need treatment can be mammals, such as humans.

[0394] Subjects requiring treatment may be adults or adolescents.

[0395] In a preferred embodiment, the subject requiring treatment is a person, more preferably an adult.

[0396] Alternatively, the subjects requiring treatment are non-human animals used in laboratory studies.

[0397] In one implementation, the treatment is applied via any convenient means of application. In a preferred implementation, the treatment is applied locally (i.e., at the site of desired effect).

[0398] In one embodiment, the treatment includes administering a therapeutically effective amount of the composition to a subject who requires treatment.

[0399] Those skilled in the art will understand that the appropriate dosage of the compositions described herein may vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit with any risks or harmful side effects. The chosen dosage level will depend on a variety of factors, including, but not limited to: the activity of the specific phenolic compound and plant or fungal extract, the route of administration, the time of administration, the excretion rate of the phenolic compound and plant or fungal extract, the duration of treatment, other drugs, compounds and / or materials used in combination, the severity of the condition, and the patient's species, sex, age, weight, condition, general health status and medical history. The amount of the phenolic compound and plant or fungal extract and the route of administration will ultimately be determined by a physician, veterinarian or clinician, although a dosage will generally be chosen to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmful or toxic side effects.

[0400] Throughout the treatment, the dose can be administered in a single dose, continuously, or intermittently (e.g., in fractions at appropriate intervals). Methods for determining the most effective administration method and dosage are well known to those skilled in the art and will vary depending on the formulation used for treatment, the purpose of treatment, the target cells being treated, and the subject being treated. Single or multiple administrations may be performed at dose levels and in patterns chosen by the treating physician, veterinarian, or clinician.

[0401] Other preferred options

[0402] Each compatible combination of the above embodiments is explicitly disclosed herein, as if each combination were described individually and explicitly.

[0403] In view of this disclosure, various further aspects and embodiments of the invention will become apparent to those skilled in the art.

[0404] When used herein, “and / or” should be considered as a specific disclosure of each of the two specified features or components, with or without the other. For example, “A and / or B” should be considered as a specific disclosure of (i) A, (ii) B, and (iii) each of A and B, as if each were stated separately herein.

[0405] Unless the context otherwise requires, the description and definition of the features set forth above are not limited to any particular aspect or implementation of the invention, and are equally applicable to all aspects and implementations described herein.

[0406] Example

[0407] Some aspects and implementations of the invention will now be described by way of examples and with reference to the accompanying drawings.

[0408] Material

[0409] Dimethyl sulfoxide (DMSO), epigallocatechin gallate (EGCG), and salicylic acid (SA) were purchased from Sigma-Aldrich. Oleanolic acid (OA), α-dextrin (AM), psoralen (B), ferricyl alcohol (F), pterostilbene (P), paclitaxel (Picea), tsucralose (S), and podophyllinic acid (PA) were purchased from TargetMol (Boston, USA). δ-3,2-hydroxypsoralen (D32HB) was purchased from Biocrick (Sichuan, China).

[0410] Hedera helix extract (HH), Ilex cornuta extract (IA), Rubus idaeus extract (RI), Fructus virginiana extract (FV), Fructus mangosteen extract (GMP), Arugula serrata extract (AUU), and Poria cocos extract (WE) were purchased from BOCSCI (New York, USA). The extracts were obtained as described below.

[0411]

[0412] Primary sebaceous gland cells were derived from the forehead of a 48-year-old Chinese male. The same cell line was used in all experiments.

[0413] Characterization methods

[0414] Flow cytometry experiments were performed on a BD LSR Fortessa X-20 as follows: Sebaceous gland cells stained with the lipid dye (AdipoRed™) were first analyzed according to size and particle size, with only single-cell groups selected for AdipoRed™ signal intensity measurement. The AdipoRed™ signal was measured using a 488 nm FITC blue laser, and the average fluorescence intensity value of 10,000 cells was obtained. The average fluorescence intensity is a measure of the average amount of lipids in 10,000 sebaceous gland cells. Cells treated with the composition of this invention were compared with vehicle-treated cells to determine the percentage of lipid reduction.

[0415] Primary sebaceous gland cell culture

[0416] Primary sebaceous gland cells were cultured at 37°C and 5% CO2 to 80% confluence in a complete culture medium consisting of Y-27632 (CCMY) composed of 3:1 DMEM (Gibco, 11995-065) / F12 (Gibco, 31765-035), supplemented with 10% fetal bovine serum (Hyclone, SV30160.03), 1x Penstrep (Gibco, 15140-122), 0.2 μg / mL epidermal growth factor (PeproTech, AF-100-15-1MG), 1 μg / mL hydrocortisone (Sigma-Aldrich, H0888), and 10 -9 M cholera toxin (Sigma-Aldrich, C8052-2MG) and 10 µM Y-27632 (Tocris, 1254 / 10). Cells were washed with PBS buffer [5 mL for a 10 cm culture plate] and then incubated at 37°C with 0.125% trypsin-EDTA (Gibco, 15400054) [2 mL for a 10 cm culture plate]. When all cells had detached, neutralization media consisting of 10% FBS and 1x Penstrep in DMEM was added (2 mL for a 10 cm culture plate), and the cells were transferred to 15 mL conical tubes and centrifuged at 1,000 rpm for 5 minutes.

[0417] After centrifugation, a cell pellet is formed. The supernatant is discarded, and the cells are resuspended in the culture medium.

[0418] Cells were cultured in a 170L CelCulture CO2 incubator (Esco Lifesciences).

[0419] Cells were counted by loading them onto a blood cell counter, and observed and counted manually using a CKX41 inverted microscope (Olympus).

[0420] General Test Plan

[0421] The test composition was added to the wells of a 24-well plate to achieve a final concentration of 10 μM of the compound (4 μL of 10 mM stock solution was prepared into 396 μL of medium in DMSO) or a final concentration of 31.25 μg / mL of the extract (4 μL of 3,125 μg / mL stock solution was prepared into 396 μL of medium in DMSO).

[0422] Primary sebaceous gland cells were cultured at 60 × 10⁶ cells per well. 6 Cells (396 μL) were seeded in culture medium. Cells were incubated at 37°C and 5% CO2 for 3 days. The culture medium was discarded, AdipoRed™ dye (0.06% v / v in PBS) was added, and cells were incubated at 37°C for 20 minutes. The staining solution was discarded, trypsin (0.125%; 250 μL) was added, and cells were incubated at 37°C for 5–10 minutes. When all cells had detached, fixative (250 μL, phenol red-free MEM, 10% fetal bovine serum, and 4% paraformaldehyde) was added, and cells were transferred to 5 mL polystyrene tubes. The tubes were stored on ice prior to flow cytometry. The mean fluorescence intensity of the lipid signal was obtained from the flow cytometry plot and was used to determine the inhibitory effect of the compound on sebaceous gland cells.

[0423] Example 1

[0424] The lipid-lowering effects of the compositions of the present invention were measured relative to DMSO as a negative control and relative to known lipid-lowering compounds epigallocatechin gallate (EGCG) and salicylic acid (SA) as positive controls. The results are shown in Table 3 and... Figure 1 middle.

[0425] The results demonstrated that compositions containing phenolic compounds (psoralen (B)) and plant extracts (heder indigo extract (HH), holly extract (IA), or raspberry extract (RI)) provided improved lipid reduction compared to individual compounds or extracts. The results also demonstrated a synergistic effect of the compositions relative to the individual compounds.

[0426] For reference, data are also provided on the activities of xanthone compounds (α-dextrin (AM)) and triterpenoids (oleanolic acid (OA)), both alone and in combination with plant extracts (Rubus extract (RI)).

[0427] Table 3. Percentage reduction in average fluorescence intensity relative to DMSO

[0428]

[0429] Example 2

[0430] The lipid-lowering effect of the compositions of the present invention was measured relative to DMSO as a negative control and relative to epigallocatechin gallate (EGCG), a known lipid-lowering compound, as a positive control. The results are shown in Table 4 and... Figures 2 to 6 middle.

[0431] The results demonstrated that compositions containing phenolic compounds (psoralen (B), ferricyanide (F), or pterostilbene (P)) and plant extracts (Rubus idaeus (RI), hedera helix (HH), holly (IA), mangosteen peel (GMP), or wild strawberry (FV) extracts) provided improved lipid reduction compared to individual compounds or extracts. The results also demonstrated a synergistic effect of the compositions relative to the individual compounds.

[0432] Table 4. Percentage reduction in average fluorescence intensity relative to DMSO

[0433]

[0434] This indicates that the data was obtained in a separate set of experiments from the other experiments given in the table.

[0435] Example 3

[0436] The lipid-lowering effects of the compositions of the present invention were measured relative to DMSO as a negative control and relative to epigallocatechin gallate (EGCG) as a known lipid-lowering compound as a positive control. Results are shown in Tables 5 to 10 and... Figures 7 to 12 middle.

[0437] The results demonstrated that compositions containing phenolic compounds (taxanthin, podophyllin, or thujol) and plant extracts (Rubus idaeus extract (RI), bearberry extract (AUU), ivy extract (HH), holly extract (IA), mangosteen peel extract (GMP), or Poria cocos extract (WE)) provided improved lipid reduction compared to individual compounds or extracts. The results also demonstrated a synergistic effect of the compositions relative to the individual compounds.

[0438] Table 5. Percentage reduction in average fluorescence intensity relative to DMSO

[0439]

[0440] Table 6. Percentage reduction in average fluorescence intensity relative to DMSO

[0441]

[0442] Table 7. Percentage reduction in average fluorescence intensity relative to DMSO

[0443]

[0444] Table 8. Percentage reduction in average fluorescence intensity relative to DMSO

[0445]

[0446] Table 9. Percentage reduction in average fluorescence intensity relative to DMSO

[0447]

[0448] Table 10. Percentage reduction in average fluorescence intensity relative to DMSO

[0449]

[0450] Example 4

[0451] The lipid-lowering effects of the compositions of the present invention were measured relative to DMSO as a negative control and relative to epigallocatechin gallate (EGCG), a known lipid-lowering compound, as a positive control. The results are shown in Tables 11 to 13 and... Figures 13 to 15 middle.

[0452] The results demonstrated that compositions containing a phenolic compound (δ-3,2-hydroxypsoralen) and plant extracts (Rubus idaeus extract (RI), Strawberry extract (FV), Bearberry extract (AUU), Hedera helix extract (HH), Ilex cornuta extract (IA), or Poria cocos extract (WE)) provided improved lipid reduction compared to individual compounds or extracts. The results also demonstrated a synergistic effect of the compositions relative to the individual compounds.

[0453] Table 11. Percentage reduction in average fluorescence intensity relative to DMSO

[0454]

[0455] Table 12. Percentage reduction in average fluorescence intensity relative to DMSO

[0456]

[0457] Table 13. Percentage reduction in average fluorescence intensity relative to DMSO

[0458]

[0459] References

[0460] Numerous publications have been cited above to more fully describe and disclose the invention and the current state of the art to which it pertains. The full citations of these references are provided below. The entire contents of each of these references are incorporated herein by reference.

[0461] Cai et al. Drug Metabolism and Disposition 2021, 49, 353

[0462] Chaika et al. ScienceRise: Pharmaceutical Science 2020, 6, 74

[0463] Cheng et al. Int. J. Biochem. Cell Biol., 2010, 42, 181

[0464] Muchtaridi et al. J. Appl. Pharm. Sci. 2017, 7, 125

[0465] Palu et al. Molecules 2019, 24, 4413

[0466] Tatia et al. Rev. Chim. 2019, 70, 1157

[0467] WO 2020 / 263188

[0468] Zhao et al. J. Ethnopharmacol. 2015, 169, 210.

Claims

1. A composition comprising: (a) A phenolic compound of formula (I) or a pharmaceutically or cosmetically acceptable salt, prodrug, solvate, tautomer, or stereoisomer thereof; and (b) Extracts from plants or fungi belonging to the genera *Ardisia*, *Fragaria*, *Garcinia*, *Ilex*, *Ilex*, and *Rubus*, and extracts from fungi belonging to the genus *Poria*. in: R 1 R 2 R 3 and R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl; L represents -CH=CH-, -CH2-CH2-, or -C(=O)CH2-; R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, C 1-4 Halogenated alkyl and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and R 6 R 7 R 8 R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl and C 1-4 Halogenated alkyl groups.

2. The composition according to claim 1, wherein: R 1 R 2 R 3 and R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 C 1-6 Alkyl, CF3 and C 2-6 alkenyl; R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 C 1-6 Alkyl, CF3 and C 1-4 The hydroxyalkyl group is substituted, and the other group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring; and R 6 R 7 R 8 R 9 R 10 and R 11 Independently selected from H and C 1-6 Alkyl groups and CF3.

3. The composition according to claim 2, wherein: R 1 R 2 R 3 and R 4 Independently selected from H, F, OH, SH, OR 6 CO2R 7 OC(=O)R 8 Me, Et and propyl; R 5 Selected from C 2-15 alkenyl, C 6-14 carbonyl aryl and C 5-14 Cycloalkyl groups, any one of which may be unsubstituted or composed of one to four independently selected from F, OH, SH, OR 9 CO2R 10 OC(=O)R 11 Substitution of Me, Et and -CH2OH groups; and R 6 R 7 R 8 R 9 R 10 and R 11 Independently selected from H, Me, Et and hydroxymethyl, and with the additional group R 4 Can be used with C 5-14 Cycloalkyl groups form covalent bonds, thereby forming a 6-membered ring.

4. The composition according to any one of claims 1 to 3, wherein: L is -CH=CH-, for example, it has an inverse permutation; R 5 C 4-10 Alkenyl groups, which may be unsubstituted or composed of one to four independently selected from OH, OR 9 CO2R 10 OC(=O)R 11 and C 1-6 Alkyl group substitution; and R 9 R 10 and R 11 Independently selected from H and C 1-6 alkyl.

5. The composition according to claim 4, wherein: R 5 C 4-10 Alkenyl groups, which may be unsubstituted or substituted by one to four independent groups selected from OH, OMe, CO2H, CO2Me and OC(O)Me.

6. The composition according to claim 5, wherein: R 5 For unreplaced C 4-10 Alkenyl groups, such as branched C 4-10 alkenyl groups, such as C 10 Alkenyl, such as 1-vinyl-1,5-dimethyl-4-hexen-1-yl.

7. The composition according to any one of claims 1 to 3, wherein: L is -CH=CH-, for example, it has an inverse permutation; R 5 It is a C6 carbonyl aryl (phenyl) group, which may be unsubstituted or composed of one to four independently selected OH, OR 9 CO2R 10 OC(=O)R 11 and C 1-6 Alkyl group substitution; and R 9 R 10 and R 11 Independently selected from H and C 1-6 alkyl.

8. The composition according to claim 7, wherein: R 5 It is a C6 carbonyl aryl group, which may be unsubstituted or substituted by one to four independent groups selected from OH, OMe, CO2H, CO2Me and OC(O)Me.

9. The composition according to claim 8, wherein: R 5 It is a C6 carbonyl aryl group, which is substituted by one to four independent groups selected from OH and OMe, for example, substituted by two OMe groups.

10. The composition according to any one of claims 1 to 3, wherein: L represents -CH2-CH2- or -C(=O)CH2-; R 5 It is a C6 cycloalkyl (cyclohexyl) group, which may be unsubstituted or composed of one to four independently selected CO2R groups. 10 C 1-6 Alkyl and C 1-4 Hydroxyl group substitution; and R 4 It forms a covalent bond with a C6 cycloalkyl group (cyclohexyl), thereby forming a 6-membered ring.

11. The composition according to claim 1, wherein the phenolic compound is selected from compounds of formulas (II) to (VIII): (VIII).

12. The composition according to claim 11, wherein the phenolic compound is selected from psoralen, δ-3,2-hydroxypsoralen, pterostilbene, paclitaxel, ferric alcohol, tungstenol, and podophyllin.

13. The composition according to any one of claims 1 to 12, wherein the plant extract is selected from bearberry leaf extract, wild strawberry extract, pineapple strawberry extract, ivy extract, European holly extract, mangosteen extract, raspberry extract and poria extract.

14. The composition according to claim 1, wherein the phenolic compound is psoralen, and the plant extract is ivy extract.

15. The composition according to claim 1, wherein the phenolic compound is psoralen, and the plant extract is holly leaf extract.

16. The composition according to any one of claims 1 to 15, wherein the phenolic compound is present in an amount of 0.0005% to 10% by weight, preferably 0.1% to 5% by weight, more preferably 0.1% to 3% by weight, for example 0.2% to 2% by weight.

17. The composition according to any one of claims 1 to 15, wherein the plant extract is present in an amount of 0.005% to 50% by weight, preferably 0.005% to 30% by weight, for example 0.05% to 10% by weight, and more preferably 0.1% to 3% by weight.

18. The composition according to any one of claims 1 to 17, further comprising one or more components selected from solvents, oils, surfactants, thickeners, humectants and preservatives.

19. The composition according to any one of claims 1 to 18, further comprising one or more components selected from emollients, anti-inflammatory agents, antioxidants and UV blockers.

20. A skin care product selected from skin / hand washes, skin / hand creams, skin / hand ointments, skin / hand pastes, toners, shaving gels, shaving creams, sunscreens, deodorants, antiperspirants, sunscreen washes, after-sun lotions, aftershave lotions, body oils, bath oils, and bubble baths, said skin care product comprising a composition according to any one of claims 1 to 19.

21. A hair care product selected from conditioners, hair untangling shampoos, styling gels, styling creams, styling waxes, styling washes, mousses, spray gels, hair growth agents, sprays, and hair oils, said hair care product comprising the composition according to any one of claims 1 to 19.

22. A cosmetic method for reducing lipid production in individual skin, the method comprising contacting the skin with a composition according to any one of claims 1 to 19.

23. A method for reducing lipid production in sebaceous gland cells or skin of an individual, the method comprising contacting the skin with a composition according to any one of claims 1 to 19, wherein the method is not a treatment method.

24. A method for reducing lipid production in sebaceous gland cells, the method comprising contacting the sebaceous gland cells with the composition of any one of claims 1 to 19.

25. The composition according to any one of claims 1 to 19, for reducing lipid production in sebaceous gland cells.

26. The composition according to any one of claims 1 to 19, used in a treatment method.

27. The composition according to any one of claims 1 to 19, in a method of treating skin diseases or conditions associated with excessive production of lipids in the skin.

28. A composition for use according to claim 27, wherein the disease or condition is selected from acne vulgaris and rosacea.

29. Use of the composition according to any one of claims 1 to 19 for reducing lipid production in sebaceous gland cells.

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