Retinol derivative or salt thereof, as well as preparation method therefor and use thereof

Abstract

A retinol derivative or a salt thereof, as well as a preparation method therefor and the use thereof. The retinol derivative or the salt thereof retains the anti-aging effect of retinol and reduces the side effects skin irritation and allergy thereof. In addition, the retinol derivative or the salt thereof further has the effects of whitening, resisting light-induced injury, resisting inflammation, resisting oxidation, repairing and the like, and thus has good application prospects in the field of cosmetic raw materials.

Description

A retinol derivative or its salt, and its preparation method and application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to a Chinese patent application filed on October 17, 2023, with application number 2023113464677 and invention name “A retinol derivative or its salt, and its preparation method and application”, the entire contents of which are incorporated into this disclosure as a whole. Technical Field

[0003] The present disclosure relates to the field of cosmetic raw materials, and in particular to a retinol derivative or a salt thereof, and a preparation method and application thereof. Background Art

[0004] Retinol, also known as retinol, is a member of the vitamin A family. As a classic and effective anti-aging ingredient, it plays a vital role in skincare products. Retinol can significantly improve skin aging and the skin barrier, promote epidermal cell proliferation, maintain normal skin circulation, repair lost collagen, reduce wrinkles and pigmentation, and protect the epidermis and mucous membranes from bacterial invasion. It has multiple benefits, including wrinkle reduction, photoaging resistance, acne treatment, and whitening.

[0005] While retinol boasts numerous benefits, it suffers from limitations such as poor stability, irritation, and potential side effects such as skin allergies and redness. Retinol's instability manifests itself in structural changes under conditions such as ultraviolet light, light, oxygen, temperature, and metal ions, which can affect the formulation, application, and storage of cosmetic products. Side effects of retinol include the potential for TRPV1 receptor stimulation, the release of inflammatory factors, and AQP3 overexpression, leading to skin irritation, manifested as stinging, erythema, rash, dryness, and barrier dysfunction.

[0006] In order to solve the problems of retinol stability and irritation, retinol ester derivatives obtained by esterification of retinol with fatty acids, such as retinol acetate and retinol palmitate, have been developed one after another. These retinoids have better stability and lower irritation than retinol, but their effects are worse than those of direct use of retinol.

[0007] Therefore, developing a retinol derivative or a salt thereof with better stability and lower irritation, whose use effect is the same as or better than the effect of direct use of retinol, is a technical problem that needs to be solved urgently by those skilled in the art.

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present disclosure is to provide a retinol compound having the effects of retinol while having better stability and lower irritation.

[0010] Technical means used to solve technical problems:

[0011] Cinnamic acid can inhibit skin aging, reduce the formation of spots and whiten the skin, and is therefore widely used in cosmetics.

[0012] The present invention adopts the prodrug strategy in medicinal chemistry to rationally design new compounds by combining cinnamic acid derivatives with retinol. This series of compounds can release retinol and corresponding molecules with synergistic effects in cells through hydrolysis or other means, thereby retaining the anti-aging effect of retinol and reducing its side effects of skin irritation and allergies.

[0013] In one aspect of the present disclosure, a retinol derivative and a pharmaceutically acceptable salt thereof are provided. The retinol derivative has a structure represented by formula (I) or formula (II).

[0014] Wherein, R1 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0015] R2, R3, R4, R5 are independently hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl;

[0016] Wherein, R6 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0017] R7, R8 are independently hydrogen or halogen or amino or hydroxy or alkoxy or alkylamide or alkoxycarbonyl ring or carboxyl.

[0018] In a preferred embodiment, in formula (I),

[0019] R1 is hydrogen;

[0020] R2 is hydrogen;

[0021] R3 is hydrogen;

[0022] R4 is hydrogen;

[0023] R5 is hydrogen;

[0024] The retinol derivative is represented by the following formula (I-1):

[0025] In a preferred embodiment, in formula (I),

[0026] R1 is hydrogen;

[0027] R2 is hydrogen;

[0028] R3 is a hydroxyl group;

[0029] R4 is hydrogen;

[0030] R5 is hydrogen;

[0031] The retinol derivative is shown in the following formula (I-2):

[0032] In a preferred embodiment, in formula (I),

[0033] R1 is hydrogen;

[0034] R2 is a methoxy group;

[0035] R3 is a hydroxyl group;

[0036] R4 is a methoxy group;

[0037] R5 is hydrogen;

[0038] The retinol derivative is shown in the following formula (I-3):

[0039] In a preferred embodiment, in formula (I),

[0040] R1 is hydrogen;

[0041] R2 is hydrogen;

[0042] R3 is a hydroxyl group;

[0043] R4 is a methoxy group;

[0044] R5 is hydrogen;

[0045] The retinol derivative is shown in the following formula (I-4):

[0046] In a preferred embodiment, in formula (I),

[0047] R1 is hydrogen;

[0048] R2 is hydrogen;

[0049] R3 is a hydroxyl group;

[0050] R4 is a hydroxyl group;

[0051] R5 is hydrogen;

[0052] The retinol derivative is shown in the following formula (I-5):

[0053] In a preferred embodiment, in formula (II),

[0054] R6 is hydrogen;

[0055] R7 is hydrogen;

[0056] R8 is hydrogen;

[0057] The retinol derivative is represented by the following formula (II-1):

[0058] In a preferred embodiment, in formula (I),

[0059] R1 is hydrogen;

[0060] R2 is hydrogen;

[0061] R3 is a methoxy group;

[0062] R4 is an acetoxy group;

[0063] R5 is hydrogen;

[0064] The retinol derivative is shown in the following formula (I-6):

[0065] In a preferred embodiment, in formula (I),

[0066] R1 is hydrogen;

[0067] R2 is hydrogen;

[0068] R3 is a methoxy group;

[0069] R4 is hydrogen;

[0070] R5 is a methoxy group;

[0071] The retinol derivative is represented by the following formula (I-7):

[0072] In a preferred embodiment, in formula (I),

[0073] R1 is hydrogen;

[0074] R2 is hydrogen;

[0075] R3 is a hydroxyl group;

[0076] R4 is hydrogen;

[0077] R5 is a hydroxyl group;

[0078] The retinol derivative is represented by the following formula (I-8): (Example 10)

[0079] In a preferred embodiment, in formula (I),

[0080] R1 is hydrogen;

[0081] R2 is hydrogen;

[0082] R3 is a methoxy group;

[0083] R4 is a hydroxyl group;

[0084] R5 is hydrogen.

[0085] In a preferred embodiment, in formula (I),

[0086] R1 is hydrogen;

[0087] R2 is a methoxy group;

[0088] R3 is a methoxy group;

[0089] R4 is a methoxy group;

[0090] R5 is hydrogen.

[0091] In a preferred embodiment, in formula (I),

[0092] R1 is hydrogen;

[0093] R2 is a methoxy group;

[0094] R3 is a hydroxyl group;

[0095] R4 is a methoxy group;

[0096] R5 is hydrogen.

[0097] In a second aspect of the present disclosure, a method for preparing the above-mentioned retinol derivative is provided, which specifically comprises the steps of esterifying cinnamic acid or its derivatives with retinol.

[0098] In a specific embodiment, the cinnamic acid derivative is

[0099] p-Hydroxycinnamic acid, 3,5-dimethoxy-p-hydroxycinnamic acid, ferulic acid, 3,5-dihydroxycinnamic acid, 3,4-methylenedioxycinnamic acid, 3-acetoxycinnamic acid-4-methoxycinnamic acid, 4,6-dimethoxycinnamic acid, 2,4-dihydroxycinnamic acid,

[0100] trans-isoferulic acid, 3,4,5-trimethoxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid,

[0101] p-Methylcinnamic acid, 4-acrylic acid cinnamic acid, 2-methylcinnamic acid, 3-(1-naphthyl))acrylic acid, biphenyl-4-acrylic acid, 3-methylcinnamic acid, 2,4-dimethylcinnamic acid, 3-(2-naphthyl))acrylic acid, biphenyl-3-acrylic acid, 4-formylcinnamic acid, 2,5-dimethylcinnamic acid, 2,6-dimethylcinnamic acid, 2,4,6-trimethylcinnamic acid, pentamethylcinnamic acid, 3,5-dimethylcinnamic acid, 2,3-dimethylcinnamic acid, 2,4,5-trimethylcinnamic acid,

[0102] 3,4-dihydroxycinnamic acid, trans-4-hydroxycinnamic acid, 3-hydroxycinnamic acid, 3,5-dihydroxycinnamic acid, 3,5-dimethyl-p-hydroxycinnamic acid, 2,6-dimethyl-p-hydroxycinnamic acid, 2-methyl-p-hydroxycinnamic acid, 3-methyl-p-hydroxycinnamic acid,

[0103] One of 6-methoxy-o-hydroxycinnamic acid, 4-methoxy-o-hydroxycinnamic acid, 3-methoxy-p-methylcinnamic acid, 3-methoxy-o-hydroxycinnamic acid, 4-methoxy-3-methylcinnamic acid, 2-hydroxy-5-methoxycinnamic acid, 2,4,6-trihydroxycinnamic acid, and 3,4-dimethoxy-o-hydroxycinnamic acid.

[0104] In a preferred embodiment, the cinnamic acid derivative is ferulic acid.

[0105] The third aspect of the present disclosure provides a method for preparing the pharmaceutically acceptable salt of the retinol derivative described above, which is obtained by reacting the retinol derivative obtained according to the aforementioned preparation method with an acid or a base.

[0106] The fourth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient.

[0107] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting the proliferation of skin epidermal cells;

[0108] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting skin keratinocyte differentiation;

[0109] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting increase in epidermal cell thickness;

[0110] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating skin metabolism;

[0111] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating keratinocyte shedding;

[0112] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting collagen degradation in the basal layer and / or dermal layer;

[0113] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing collagen degradation in the basal layer and / or dermis;

[0114] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the degradation of elastin in the basal layer and / or dermal layer;

[0115] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing elastin degradation in the basal layer and / or dermal layer.

[0116] The fifth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-wrinkle ingredient.

[0117] Specifically, the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as the retinol derivative as an anti-wrinkle ingredient;

[0118] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for removing wrinkles and reducing fine lines;

[0119] Or the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating the synthesis of GAGs in the skin extracellular matrix;

[0120] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating collagen synthesis;

[0121] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the activity of matrix metalloproteinases (MMPs);

[0122] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for tightening the skin;

[0123] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for enhancing skin elasticity.

[0124] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of matrix metalloproteinase MMP3;

[0125] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9.

[0126] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP3 in Hacat cells;

[0127] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9 in Hacat cells.

[0128] A sixth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a whitening ingredient or a freckle-removing ingredient.

[0129] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing pigmentation;

[0130] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting uniform distribution of melanin;

[0131] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of tyrosinase and tyrosinase-related proteins;

[0132] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting melanin production;

[0133] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing melanocyte activity;

[0134] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for preventing melanin from being transported to the skin surface.

[0135] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting melanin production in B16 cells.

[0136] A seventh aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an acne-removing ingredient or an oil-controlling ingredient.

[0137] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting acne;

[0138] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an oil-controlling ingredient;

[0139] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating oil secretion of sebaceous glands;

[0140] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting 5α-reductase activity;

[0141] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for protecting epidermal mucosa from bacterial invasion;

[0142] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for eliminating sebaceous gland blockage;

[0143] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing the number of Propionibacterium acnes flora.

[0144] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an ingredient for refining pores;

[0145] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing the skin barrier;

[0146] The eighth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an antioxidant ingredient.

[0147] In one embodiment, the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof is used as a component for inhibiting reactive oxygen species (ROS).

[0148] Furthermore, the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof is used as a component for inhibiting reactive oxygen species (ROS) in Hacat cells.

[0149] The ninth aspect of the present disclosure provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a moisturizing ingredient;

[0150] The tenth aspect of the present disclosure provides a use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-inflammatory ingredient;

[0151] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of inflammatory cytokines;

[0152] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective component for inhibiting the infiltration of CD4+ and CD8+ lymphocytes and macrophages.

[0153] In some embodiments, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor NO.

[0154] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of inflammatory cytokine NO in RAW cells.

[0155] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the inflammatory factor TNF-α;

[0156] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor IL-6.

[0157] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor TNF-α in HaCaT cells; or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor IL-6 in HaCaT cells.

[0158] The eleventh aspect of the present disclosure provides a use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photoaging ingredient;

[0159] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photodamage efficacy ingredient;

[0160] Or the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective component for repairing photodamage.

[0161] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is an effective component for inhibiting UVB-induced cellular reactive oxygen species. Further, the retinol derivative or a pharmaceutically acceptable salt thereof is an effective component for inhibiting UVB-induced cellular reactive oxygen species in Hacat cells.

[0162] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of UVB-induced inflammatory factors IL-6 and / or TNF-α.

[0163] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor IL-6 induced by UVB in Hacat cells;

[0164] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor TNF-α induced by UVB in Hacat cells.

[0165] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting UVB-induced expression of matrix metalloproteinases MMP3 and / or MMP9.

[0166] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting UVB-induced matrix metalloproteinase MMP3 expression in Hacat cells;

[0167] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting UVB-induced matrix metalloproteinase MMP9 expression in Hacat cells.

[0168] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of UVA-induced inflammatory factor proIL-1β.

[0169] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of the inflammatory factor IL-1β induced by UVA.

[0170] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for upregulating UVA-induced decreased collagen III expression. Further, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for upregulating UVA-induced decreased collagen III expression in 3T3 cells.

[0171] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for upregulating UVA-induced decreased expression of collagen I. Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for upregulating UVA-induced decreased expression of collagen I in 3T3 cells.

[0172] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of MMP1 induced by UVA. Further, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of MMP1 induced by UVA in 3T3 cells.

[0173] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for repairing DNA damage caused by UVA; specifically, as an effective ingredient for downregulating UVA-induced increased expression of γH2AX; further, as an effective ingredient for downregulating UVA-induced increased expression of γH2AX in 3T3 cells.

[0174] A twelfth aspect of the present disclosure provides a pharmaceutical composition, characterized in that it at least comprises:

[0175] The above-mentioned retinol derivatives;

[0176] and a pharmaceutically acceptable excipient or carrier.

[0177] A thirteenth aspect of the present disclosure is a nutritional composition, characterized in that it at least comprises:

[0178] The above-mentioned retinol derivatives;

[0179] and nutritionally acceptable excipients or carriers.

[0180] A fourteenth aspect of the present disclosure is a skin care composition, characterized in that it at least comprises:

[0181] The above-mentioned retinol derivatives;

[0182] and a dermatologically acceptable excipient or carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0183] The present disclosure also provides drawings related to the provided technical solutions to illustrate the technical solutions of the present disclosure. The purpose of the drawings and descriptions is only to more clearly describe the present disclosure and should not be regarded as limiting the scope of protection claimed in the present disclosure.

[0184] Figure 1 Mass spectrum of retinol ferulate in negative ion mode.

[0185] Figure 2 Mass spectrum of retinol ferulate in positive ion mode.

[0186] Figure 3 Nuclear magnetic resonance spectrum of retinol ferulate.

[0187] Figure 4. Viability of retinol ferulate RAW cells.

[0188] Figure 5 Results of LPS inflammation experiment.

[0189] Figure 6. Viability of retinyl ferulate Hacat cells.

[0190] FIG7 Effects on UVB-induced TNF-α elevation.

[0191] FIG8 Effects on UVB-induced IL-6 elevation.

[0192] FIG9 Effects on UVB-induced increase in MMP3.

[0193] FIG10 Effects on UVB-induced increase in MMP9.

[0194] FIG11 Retinyl ferulate 3T3 cell viability.

[0195] FIG12 shows the regulation of UVA-induced decrease in collagen III.

[0196] FIG13 shows the regulation of UVA-induced MMP1 elevation.

[0197] Figure 14 is a Western blot image of γH2AX.

[0198] FIG15 shows the regulation of UVA-induced upregulation of γH2AX expression.

[0199] Figure 16 Retinyl ferulate B16 activity.

[0200] Figure 17B16 Relative melanin content. DETAILED DESCRIPTION

[0201] In order to make the purpose, technical solutions and advantages of the embodiments of the present disclosure clearer, the technical solutions in the embodiments of the present disclosure will be clearly and completely described below. Obviously, the described embodiments are not all embodiments.

[0202] The elements and features described in one embodiment of the present disclosure may be combined with the elements and features shown in one or more other embodiments. It should be noted that for the purpose of clarity, the representation and description of components and processes that are not related to the present disclosure and are known to those of ordinary skill in the art are omitted in the description.

[0203] As used herein, "retinol" refers to: a substance having the structure of formula (III);

[0204] As used herein, "cinnamic acid" refers to: a substance having the structure of formula (IV);

[0205] Herein, "cinnamic acid derivatives" refer to compounds obtained by modifying the benzene ring of cinnamic acid with functional groups.

[0206] Herein, "ferulic acid" refers to: a substance having the structure of formula (V), ferulic acid is a derivative of cinnamic acid;

[0207] Herein, "pharmaceutically acceptable salt" refers to a product prepared from a compound salt of the compound of formula (I) or formula (II) itself.

[0208] In a first aspect, the present disclosure provides a retinol derivative having a structure represented by formula (I) or formula (II),

[0209] Wherein, R1 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0210] R2, R3, R4, R5 are independently hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl;

[0211] Wherein, R6 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0212] R7, R8 are independently hydrogen or halogen or amino or hydroxy or alkoxy or alkylamide or alkoxycarbonyl ring or carboxyl.

[0213] Preparation method of retinol derivatives

[0214] The present disclosure provides a method for preparing the above-mentioned retinol derivatives, which specifically comprises the steps of esterifying cinnamic acid and its derivatives with retinol.

[0215] Optionally, the cinnamic acid derivative is

[0216] p-Hydroxycinnamic acid, 3,5-dimethoxy-p-hydroxycinnamic acid, ferulic acid, 3,5-dihydroxycinnamic acid, 3,4-methylenedioxycinnamic acid, 3-acetoxycinnamic acid-4-methoxycinnamic acid, 4,6-dimethoxycinnamic acid, 2,4-dihydroxycinnamic acid,

[0217] trans-isoferulic acid, 3,4,5-trimethoxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid,

[0218] p-Methylcinnamic acid, 4-acrylic acid cinnamic acid, 2-methylcinnamic acid, 3-(1-naphthyl))acrylic acid, biphenyl-4-acrylic acid, 3-methylcinnamic acid, 2,4-dimethylcinnamic acid, 3-(2-naphthyl))acrylic acid, biphenyl-3-acrylic acid, 4-formylcinnamic acid, 2,5-dimethylcinnamic acid, 2,6-dimethylcinnamic acid, 2,4,6-trimethylcinnamic acid, pentamethylcinnamic acid, 3,5-dimethylcinnamic acid, 2,3-dimethylcinnamic acid, 2,4,5-trimethylcinnamic acid,

[0219] 3,4-dihydroxycinnamic acid, trans-4-hydroxycinnamic acid, 3-hydroxycinnamic acid, 3,5-dihydroxycinnamic acid, 3,5-dimethyl-p-hydroxycinnamic acid, 2,6-dimethyl-p-hydroxycinnamic acid, 2-methyl-p-hydroxycinnamic acid, 3-methyl-p-hydroxycinnamic acid,

[0220] One of 6-methoxy-o-hydroxycinnamic acid, 4-methoxy-o-hydroxycinnamic acid, 3-methoxy-p-methylcinnamic acid, 3-methoxy-o-hydroxycinnamic acid, 4-methoxy-3-methylcinnamic acid, 2-hydroxy-5-methoxycinnamic acid, 2,4,6-trihydroxycinnamic acid, and 3,4-dimethoxy-o-hydroxycinnamic acid.

[0221] The cinnamic acid derivatives suitable for the present disclosure can be obtained by synthesizing / modifying them by known synthesis / modification methods, or by directly purchasing the cinnamic acid derivatives.

[0222] Preferably, the cinnamic acid derivative is ferulic acid.

[0223] The method for esterifying the cinnamic acid and its derivatives with retinol suitable for the present disclosure can be a conventional esterification method, which is not particularly limited in the present disclosure. As a non-limiting example, appropriate amounts of cinnamic acid or a cinnamic acid derivative, retinol, EDCI (carbodiimide), and DMAP (4-dimethylaminopyridine) are weighed, dissolved in THF (tetrahydrofuran), and then TEA (triethylamine) is added and stirred to obtain the product.

[0224] Optionally, the groups on the cinnamic acid derivative that may affect the efficiency of the esterification reaction are pre-protected according to the structure of the cinnamic acid derivative before the esterification reaction, and deprotection is performed after the esterification reaction.

[0225] Preferably, tert-butyldimethylsilyl chloride is used to protect the hydroxyl and / or alkoxy groups of the cinnamic acid derivative.

[0226] Pharmaceutically acceptable salt of retinol derivative and preparation method thereof

[0227] The present disclosure also provides pharmaceutically acceptable salts of the above-mentioned retinol derivatives, the preparation method of which comprises the following specific steps:

[0228] Obtained by reacting the above retinol derivatives with acid or base.

[0229] Optionally, the acid includes at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, oxalic acid, lactic acid, malic acid, tartaric acid, citric acid, succinic acid, salicylic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid and methanesulfonic acid.

[0230] Optionally, the base includes at least one of sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, sodium hydroxide, calcium chloride, calcium acetate, magnesium chloride, tromethamine salt, aminoethanol salt, lysine salt, and arginine salt.

[0231] Use of retinol derivatives or pharmaceutically acceptable salts thereof

[0232] The present disclosure provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient.

[0233] The fourth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient.

[0234] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting the proliferation of skin epidermal cells;

[0235] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting skin keratinocyte differentiation;

[0236] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting increase in epidermal cell thickness;

[0237] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating skin metabolism;

[0238] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating keratinocyte shedding;

[0239] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting collagen degradation in the basal layer and / or dermal layer;

[0240] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing collagen degradation in the basal layer and / or dermis;

[0241] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the degradation of elastin in the basal layer and / or dermal layer;

[0242] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing elastin degradation in the basal layer and / or dermal layer.

[0243] The fifth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-wrinkle ingredient.

[0244] Specifically, the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as the retinol derivative as an anti-wrinkle ingredient;

[0245] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for removing wrinkles and reducing fine lines;

[0246] Or the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating the synthesis of GAGs in the skin extracellular matrix;

[0247] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating collagen synthesis;

[0248] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the activity of matrix metalloproteinases (MMPs);

[0249] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for tightening the skin;

[0250] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for enhancing skin elasticity.

[0251] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of matrix metalloproteinase MMP3;

[0252] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9.

[0253] The sixth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a whitening ingredient or a freckle-removing ingredient.

[0254] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing pigmentation;

[0255] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting uniform distribution of melanin;

[0256] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of tyrosinase and tyrosinase-related proteins;

[0257] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting melanin production;

[0258] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing melanocyte activity;

[0259] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for preventing melanin from being transported to the skin surface.

[0260] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting melanin production in B16 cells.

[0261] A seventh aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an acne-removing ingredient or an oil-controlling ingredient.

[0262] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting acne;

[0263] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an oil-controlling ingredient;

[0264] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating oil secretion of sebaceous glands;

[0265] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting 5α-reductase activity;

[0266] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for protecting epidermal mucosa from bacterial invasion;

[0267] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for eliminating sebaceous gland blockage;

[0268] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing the number of Propionibacterium acnes flora.

[0269] or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an ingredient for refining pores;

[0270] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing the skin barrier;

[0271] The eighth aspect of the present disclosure provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an antioxidant ingredient.

[0272] In one embodiment, the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof is used as a component for inhibiting reactive oxygen species (ROS).

[0273] Furthermore, the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof is used as a component for inhibiting reactive oxygen species (ROS) in Hacat cells.

[0274] The ninth aspect of the present disclosure provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a moisturizing ingredient;

[0275] Specifically, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for promoting the expression of hyaluronic acid in the skin.

[0276] The tenth aspect of the present disclosure provides a use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-inflammatory ingredient;

[0277] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of inflammatory cytokines;

[0278] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective component for inhibiting the infiltration of CD4+ and CD8+ lymphocytes and macrophages.

[0279] In some embodiments, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor NO.

[0280] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of inflammatory cytokine NO in RAW cells.

[0281] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the inflammatory factor TNF-α.

[0282] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor TNF-α;

[0283] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor IL-6.

[0284] The eleventh aspect of the present disclosure provides a use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photoaging ingredient;

[0285] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photodamage efficacy ingredient;

[0286] Or the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective component for repairing photodamage.

[0287] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is an effective component for inhibiting UVB-induced cellular reactive oxygen species.

[0288] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of UVB-induced inflammatory factors.

[0289] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of the inflammatory factor IL-6 induced by UVB;

[0290] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of UVB-induced inflammatory factor TNF-α.

[0291] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting UVB-induced matrix metalloproteinase expression.

[0292] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting UVB-induced matrix metalloproteinase MMP3 expression;

[0293] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting UVB-induced matrix metalloproteinase MMP9 expression.

[0294] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for upregulating UVA-induced decreased collagen III expression.

[0295] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for upregulating UVA-induced decreased collagen I expression.

[0296] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of UVA-induced MMP1.

[0297] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of UVA-induced inflammatory factor proIL-1β.

[0298] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for downregulating the increase of the inflammatory factor IL-1β induced by UVA.

[0299] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for repairing induced DNA damage; specifically, as an effective ingredient for downregulating UVA-induced increased γH2AX expression; further, as an effective ingredient for downregulating UVA-induced increased γH2AX expression in 3T3 cells.

[0300] Pharmaceutical composition

[0301] The pharmaceutical composition of the present disclosure comprises at least:

[0302] The above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof;

[0303] and a pharmaceutically acceptable excipient or carrier.

[0304] Pharmaceutically acceptable excipients or carriers can be conventional excipients or carriers that are not pharmaceutically, biologically, or otherwise undesirable. Non-limiting examples of excipients include solvents such as water and alcohol that serve as media for dissolving drugs. Binders such as gelatin and sodium carboxymethylcellulose that are used to solidify granules or powders to form tablets or granules. Plasticizers such as glycerol and polyethylene glycol that increase the softness and plasticity of the formulation. Emulsifiers such as polysorbates and polyoxyethylene glycol esters that are used to prepare emulsions. Dispersants such as polyvinyl pyrrolidone and hydroxypropyl methylcellulose that are used to uniformly disperse the drug in a liquid medium. Stabilizers such as common antioxidants and preservatives that protect the drug from damage by light, heat, oxidation, and microbial contamination. Sustained-release agents such as polyvinyl alcohol and hydroxyethyl cellulose that are used to regulate the release rate of the drug in the body. Non-limiting examples of carriers include nanoparticles such as polymer nanoparticles and liposomes that can be used to encapsulate and deliver drugs and achieve targeted delivery and controlled release. Examples include microspheres and microparticles such as polymer microspheres and capsules that can encapsulate drugs and achieve controlled release, commonly used for oral administration or topical application. Examples include drug-loaded films such as polymer coatings and controlled-release membranes that are used to encapsulate drugs and control the release rate of the drugs by dissolution, diffusion, or degradation. Examples include sustained-release matrices such as poly(lactic-co-glycolic acid) copolymers and gelatin that can be used as drugs, and polymer matrices that release drugs through degradation. Examples include liposomes and cholesterol systems such as lipid nanoparticles and lipid cholesterol nanoparticles that are used to encapsulate and deliver drugs and achieve targeted delivery in vivo. Examples include polymer gels and natural biogels that can be used to prepare pharmaceutical dosage forms for topical application, providing gels that provide adhesion and sustained-release effects.

[0305] Nutritional composition

[0306] The nutritional composition of the present disclosure comprises at least:

[0307] The above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof;

[0308] and nutritionally acceptable excipients or carriers.

[0309] Nutritically acceptable excipients or carriers can be conventional excipients or carriers that are not undesirable in nutrition, biology or other aspects. Non-limiting examples of excipients can include: hydroxypropyl methylcellulose (HPMC), which is used to prepare capsule shells or granules to improve the packaging and release properties of drugs or nutrients. Gelatin is used as a colloid material in some soft candies, oral capsules or soft capsules to provide structure and stability. Glycerol is used as a stabilizer and increases mouthfeel in some liquid nutritional supplements. Polyvinylpyrrolidone (PVP) may be used in tablets or granules to provide good dispersibility and solubility. Non-limiting examples of carriers can include liposomes, nanoparticles, protein packages and high fiber matrices.

[0310] Skin care compositions

[0311] The skin care composition of the present disclosure comprises at least:

[0312] The above-mentioned retinol derivative is obtained as a pharmaceutically acceptable salt;

[0313] and a dermatologically acceptable excipient or carrier.

[0314] A dermatologically acceptable excipient or carrier.

[0315] The dermatologically acceptable excipient or carrier can be a conventional excipient or carrier that is not dermatologically, biologically, or otherwise undesirable. Non-limiting examples of excipients include any one or more forms of bases commonly used in the field of skin care products or cosmetics, such as cream bases, gel bases, liposomes, emulsion bases, and oil beads. Non-limiting examples of carriers include any one or more forms of carriers commonly used in the field of skin care products or cosmetics, such as lotions, emulsions, foundations, hand creams, beauty serums, shampoos, conditioners, hair sprays, styling agents, facial masks, soaps, and facial cleansers.

[0316] Without affecting the technical effects of the composition of the present invention, the composition of the present invention may also contain ingredients commonly used in the cosmetics field, such as stabilizers, surfactants, lubricants, buffers, sweeteners and flavorings, adhesives, antioxidants, coating agents, wetting agents, flavorings, colorants, coating agents, tonicity agents, emulsifiers, thickeners, pH regulators, excipients, dispersants, disintegrants, preservatives, solubilizers, oils, moisturizers, UV absorbers, fillers, chelating agents, sunscreens, defoaming agents, softeners, propellants, acidulants, or, depending on the purpose, alkalizers, silicones, vitamins, dyes, pigments, nanopigments, organic solvents such as alcohols, water, etc. may be optionally mixed.

[0317] The skin care composition of the present disclosure can be a skin care product or a cosmetic. The dosage form of the external skin preparation of the present disclosure can be any one of lotion, essence, spray, emulsion, cream, mask, gel, sunscreen, and isolation.

[0318] Preparation Example of Retinol Derivatives

[0319] Example 1

[0320] This embodiment provides a method for preparing retinol ferulate as shown in the following formula (I-4):

[0321] The specific steps include:

[0322] Step S1. Protection of hydroxyl and methoxy groups of ferulic acid:

[0323] To a 50 mL round-bottom flask, 466 mg of ferulic acid (3-methoxy-4-hydroxycinnamic acid) was added and dissolved in 10 mL of dichloromethane. 1.4 mL of triethylamine was then added. The resulting reaction solution was magnetically stirred and cooled to 0-5°C in an ice-water bath. 900 mg of tert-butyldimethylsilyl chloride (Compound 2) was slowly added and stirred at room temperature for 4 hours. After the reaction, 25 mL of ice water was added to quench the reaction. The aqueous layer was extracted with dichloromethane (25 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was dissolved in 20 mL of tetrahydrofuran and 2 mL of water, and 200 mg of anhydrous potassium carbonate was added. The reaction was stirred at room temperature for 6 hours. After the reaction, 25 mL of water was added and the aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic layers were combined, concentrated in vacuo, and recrystallized from petroleum ether to obtain 493 mg of the first intermediate (Compound 3) as a white solid (80% yield).

[0324] Step S2. Esterification reaction:

[0325] In a 50 mL brown round-bottom flask, 308 mg of the first intermediate (compound 3), 343 mg of retinol, 288 mg of EDCI, and 12 mg of DMAP were added. 5 mL of tetrahydrofuran was added for dissolution, and finally 270 μL of TEA was added. The reaction was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated in vacuo, 25 mL of water was added, and the aqueous layer was extracted with ethyl acetate (25 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 as eluent) was used to obtain 385 mg of the second intermediate (compound 5) (yellow oily liquid, yield: 67%).

[0326] Step S3. Deprotection:

[0327] To a 50 mL brown round-bottom flask, 384 mg of the second intermediate (Compound 5) was added and dissolved in 8 mL of tetrahydrofuran. The mixture was cooled to 0-5°C in an ice-water bath. 600 μL of tetrabutylammonium fluoride was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. The crude product was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 as eluent) to obtain 226 mg of the final product, retinyl ferulate (Compound 6), as a yellow oily liquid (yield: 73%).

[0328] The mass spectrometry data of compound 6 are as follows:

[0329] MS(ESI)m / z:[MH]-calcd.for C30H37O4-461,found:461.

[0330] Mass Spectrometry: Negative Ions

[0331] The spectrum is shown in Figure 1

[0332] Positive ions

[0333] The spectrum is shown in Figure 2

[0334] The NMR data of compound 6 (as shown in Figure 3) are as follows:

[0335] 1H NMR (400MHz, CDCl3) δ7.62(d,J=15.9Hz,1H),7.05(d,J=1.9Hz,1H),7.02(d,J=1.9Hz,1H) ,6.90(d,J=8.1Hz,1H),6.65(dd,J=15.2,11.3Hz,1H),6.30(d,J=15.9Hz,2H),6.23–6.05 (m,3H),5.69(t,J=7.2Hz,1H),4.86(d,J=7.2Hz,2H),3.90(s,3H),2.01(t,J=6.3Hz,2H), 1.96(s,3H),1.93(s,3H),1.71(s,3H),1.65–1.57(m,2H),1.50–1.42(m,2H),1.02(s,6H).

[0336] The retinol derivatives or pharmaceutically acceptable salts thereof provided by the present disclosure have good stability and low irritation.

[0337] The retinol derivatives or pharmaceutically acceptable salts thereof obtained by esterifying cinnamic acid and its derivatives with retinol in the present disclosure can release retinol and corresponding molecules with synergistic effects in cells through hydrolysis or other means, thereby retaining the anti-aging effect of retinol and reducing its side effects of skin irritation and allergies.

[0338] Experimental studies have shown that retinol ferulate, obtained by esterifying ferulic acid, a cinnamic acid derivative, with retinol, has the potential to inhibit the expression of inflammatory factors such as NO, matrix metalloproteinases, repair collagen damage, regulate abnormal increases in matrix metalloproteinases, repair DNA damage, and inhibit melanin production. These effects are comparable to or even better than those of retinol. All compounds represented by formulas (I) and (II) share the same parent structure as retinol ferulate, so it is reasonable to assume that they possess similar efficacy.

[0339] In addition, the retinol derivatives or pharmaceutically acceptable salts thereof provided by the present disclosure have the effects of anti-aging, anti-wrinkle, whitening, freckle removal, antioxidant, moisturizing, acne removal, oil control, anti-inflammatory, and anti-photoaging.

[0340] Efficacy testing

[0341] Anti-inflammatory efficacy experiment

[0342] (I) Cell viability was determined by CCK8 assay in RAW cells to determine the sample concentration required for subsequent experiments.

[0343] CCK8 assay: cells were plated in 96-well plates at a density of 1 cell / well and cultured for 24 h before drug addition. Sample concentrations were set as 1%, 0.5%, 0.1%, 0.05%, and 0.01% (v / v).

[0344] CCK8 incubation was performed 24 h after drug addition. Under dark conditions, 10X CCK8 stock solution (Biyuntian, C0040) was diluted to 1X solution with complete culture medium and the medium was replaced;

[0345] The cells were incubated in a cell culture incubator for 2 hours, and the absorbance at 450 nm and 650 nm was measured using a microplate reader.

[0346] According to the CCK8 toxicity results, as shown in FIG4 , retinol ferulate had no cytotoxicity at a concentration range of 6.25-200 uM.

[0347] (II) The RAW cell NO assay was used to determine whether retinol ferulate had an inhibitory effect on inflammatory factors.

[0348] RAW cell NO experiment: Macrophages were seeded in a 12-well plate at a density of 200,000 / ml (counted by a counter) and incubated in an incubator overnight.

[0349] Positive control group: 100 mg / ml dexamethasone was added after 24 h, incubated for 1 h, and then 125 ng / ml LPS was added;

[0350] Experimental group: drug was added after 24 h and incubated for 1 h before adding 125 ng / ml LPS;

[0351] Negative control group: 125 ng / ml LPS was added after 24 h;

[0352] Blank control group: no LPS was added.

[0353] After incubation for 24 h, 50 μl of supernatant was transferred to a 96-well plate, and 50 μl of 1X Griess reagent was added to each well. The plates were incubated for 30 min, and the absorbance at 540 nm was detected using a microplate reader.

[0354] The results are shown in Figure 5.

[0355] In this LPS inflammation experiment, the NO per unit cell was significantly increased in the model group (0.106) compared with the control group (0.0547), indicating that the model was successfully established.

[0356] 50uM ferulic acid does not have the effect of inhibiting the inflammatory factor NO; 50uM retinol, 50uM and 100uM retinol ferulate have a certain effect of inhibiting the inflammatory factor NO. The effect of low concentration (50uM) retinol ferulate in inhibiting inflammatory factors is equivalent to that of 50uM retinol, while the effect of high concentration (100uM) retinol ferulate in inhibiting inflammatory factors is stronger.

[0357] Anti-photodamage efficacy experiment

[0358] (I) Hacat cell viability was detected by CCK8 assay to determine the sample concentration required for subsequent experiments.

[0359] Cells were plated in 96-well plates at a density of 2 cells / well and cultured for 24 hours before drug addition. Sample concentrations were set as 1%, 0.5%, 0.1%, 0.05%, and 0.01% (v / v). CCK8 incubation was performed 24 hours after drug addition. Under dark conditions, the 10X CCK-8 stock solution (Biyuntian, C0040) was diluted to a 1X solution with complete culture medium and the medium was replaced. Incubation was continued in a cell culture incubator for 2 hours. The absorbance at reference wavelengths of 450nm and 650nm was measured using a microplate reader.

[0360] According to the CCK8 toxicity results, as shown in FIG6 , retinol ferulate had no cytotoxicity within a dose range of 125 uM.

[0361] (II) qPCR:

[0362] (1) Hacat cells were seeded in a 6-well plate at a density of 800,000 cells / ml (counted by an automatic counter) and incubated in a culture incubator overnight;

[0363] (2) Drug pre-protection: When the cell confluence reached 40-60%, 50 μM retinol, 50 μM ferulic acid, 50 μM retinol palmitate, and 50 μM retinol ferulate were added to the drug group, respectively, at 2 mL / well, and culture was continued for 24 h.

[0364] (3) UVB irradiation: After 24 h of culture, the culture medium of the model group and the drug group was irradiated with 25 mj / cm2 UVB.

[0365] (4) Drug incubation after UVB irradiation: The blank group and the model group were replaced with fresh culture medium, and the drug group was treated with drugs. Then, the cells were incubated in a cell culture incubator for 6 h, and the samples were collected to detect the mRNA levels of MMP3, MMP9, TNF-α, and IL-6.

[0366] The Ct values ​​of β-actin, MMP3, MMP9, TNF-α and IL-6 in each experimental group were calculated, and the mRNA expression levels of related genes were analyzed using the 2-△△Ct method. The data between the groups were analyzed using TTEST statistical analysis. P < 0.05 indicated a significant difference, which was statistically significant.

[0367] The calculation formula is as follows:

[0368] ΔCt=Ct target gene-Ctβ-actin

[0369] △△Ct=Average value of △Ct blank group-△Ct experimental group

[0370] Relative mRNA expression = 2 (-△△Ct)

[0371] Experimental results:

[0372] As shown in Figure 7, in the UVB-damaged cell experiment, 50 μM retinol ferulate inhibited the inflammatory factor TNF-α by 22.77%, while 50 μM retinol inhibited it by 20.49%. 50 μM ferulic acid showed no inhibitory effect on TNF-α. Retinol ferulate showed a superior inhibitory effect on TNF-α to retinol.

[0373] As shown in Figure 8, 50uM retinol, 50uM ferulic acid and 50uM retinol ferulate all have an inhibitory trend on the inflammatory factor IL-6, and the inhibition rate of retinol ferulate and retinol on the inflammatory factor IL-6 is not much different.

[0374] As shown in Figure 9, 50 μM retinol, 50 μM ferulic acid, and 50 μM retinol ferulate all showed an inhibitory effect on the matrix metalloproteinase MMP3. Retinol ferulate significantly inhibited MMP3 gene expression, reaching an inhibition rate of 80% compared to the model group. Retinol ferulate exhibited a significantly superior inhibitory effect on MMP3 than retinol.

[0375] As shown in Figure 10, 50uM retinol ferulate has a tendency to inhibit MMP9, while 50uM retinol and 50uM ferulic acid have no inhibitory effect on MMP9.

[0376] Repair efficacy test

[0377] (I) Cell viability was determined by CCK8 assay in 3T3 cells to determine the sample concentration required for subsequent experiments.

[0378] Plate cells at a density of 10,000 cells / well in a 96-well plate and culture for 24 hours before adding drugs. Sample concentrations were set as 12.5, 50, 100, 150, and 200 μM. CCK8 incubation was performed 24 hours after drug addition. In the dark, a 10X CCK-8 stock solution (Biyuntian, C0040) was diluted to a 1X solution with complete culture medium and the medium was replaced. Incubation continued in a cell culture incubator for 2 hours. Absorbance was measured at reference wavelengths of 450 nm and 650 nm using a microplate reader.

[0379] According to the CCK8 toxicity results, as shown in Figure 11, retinol ferulate had no cytotoxicity at doses ranging from 12.5 to 200 μM. 50 μM was selected for subsequent experiments.

[0380] (II) qPCR

[0381] QPCR:

[0382] (1) 3T3 cells were counted at a density of 100 w / well using an automatic cell counter and plated in a six-well plate. The culture medium was discarded after 24 h.

[0383] (1) When covered with PBS, the UVA model group and drug group were treated with 7J / cm 2 The drug groups were treated with UVA at the dose of 100 mg / kg, and the PBS was then discarded and replaced with complete culture medium containing the test substance;

[0384] (2) The cells were then incubated in a cell culture incubator for 24 h, and samples were collected to detect the mRNA levels of collagen and matrix metalloproteinase-related genes.

[0385] Experimental results:

[0386] As shown in FIG12 , retinyl ferulate has a significant upregulation ability on the decrease of collagen III induced by UVA, and is stronger than ferulic acid and retinol.

[0387] As shown in Figure 13, retinol ferulate has the ability to downregulate the increase of MMP1 induced by UVA. The ability of retinol ferulate to downregulate the increase of MMP1 is better than that of retinol.

[0388] (III) The protein level of γH2AX was detected by Western Blot.

[0389] Western Blot protein immunoblotting experiment:

[0390] (1) 3T3 cells were counted at a density of 1 million per well using an automated cell counter and plated in a six-well plate. The culture medium was discarded after 24 h.

[0391] (2) UVA treatment at a dose of 7 J / cm2 was performed while covering the cells with PBS, and then the PBS was discarded and replaced with complete medium containing the test substance;

[0392] (3) The reaction was then incubated in a cell culture incubator for 24 h, and samples were collected for detection of the protein levels of γH2AX-related genes.

[0393] Experimental results:

[0394] As shown in Figures 14 and 15 , retinol ferulate has the ability to reduce UVA-induced increases in γH2AX expression. This suggests that retinol ferulate can repair DNA damage, and its ability to repair DNA damage is comparable to that of retinol.

[0395] Whitening efficacy test

[0396] (I) Cell viability was determined by CCK8 assay in B16 cells to determine the sample concentration required for subsequent experiments.

[0397] CCK8 assay: Cells were plated in 96-well plates at a density of 10,000 cells / well and cultured for 24 hours before drug addition. Sample concentrations were set as 1%, 0.5%, 0.1%, 0.05%, and 0.01% (v / v). CCK8 incubation was performed 24 hours after drug addition. In the dark, a 10X CCK-8 stock solution (Biyuntian, C0040) was diluted to a 1X solution with complete culture medium and the medium was replaced. Incubation was continued in a cell culture incubator for 2 hours. Absorbance at 450nm and 650nm was measured using a microplate reader.

[0398] According to the CCK8 toxicity results, as shown in Figure 16, retinol ferulate had no cytotoxicity at doses ranging from 12.5 to 200 μM. 50 μM was selected for subsequent experiments.

[0399] (II) B16 relative melanin content

[0400] 1. Add cells to a 6-well plate at a concentration of 5×10 5 Cell suspension of 100 cells / mL, 1 mL per well. (The B16 cells added in this step are grown in 1640 culture medium to ensure no melanin is produced)

[0401] 2. After 24 hours of incubation at 37°C, 5% CO2, aspirate the culture medium, wash the plate once with 1 mL of PBS, and then add the prepared sample culture medium mixture (filter membrane required). Each sample should be plated in triplicate. The blank should be plated in 1640 culture medium, and the model group should be plated in DMEM culture medium, with triplicate wells.

[0402] 3. After 48 hours of culture, discard the supernatant, wash once with PBS solution, change the medium once, and continue to culture for 24 hours.

[0403] At 4.72 h, wash the plate once with 1 mL of PBS, then add 500 μL of trypsin to each well. After digestion for 2 min, add 1 mL of DMEM medium to terminate digestion. Then, add the cell suspension to a 2 mL sterilized EP tube.

[0404] 5. Centrifuge the cell suspension at 1000 rpm for 5 minutes. Then aspirate the supernatant (in this step, try to aspirate as much residual culture medium as possible).

[0405] 6. Add 1 mL of pBS to each tube and resuspend by pipetting. Mix thoroughly and count the cells using a cell counter. Record the cell count for each sample.

[0406] 7. Then centrifuge all samples at 4 degrees and 18000 rpm for ten minutes to ensure that the cells are completely attached to the bottom of the EP tube. Then aspirate the supernatant (this step requires as much PBS as possible).

[0407] 8. Add 100uL of 1mol / L NaOH (containing 10% DMSO) liquid to each tube, i.e., cell lysis solution, and incubate in an 80°C water bath for 1 hour.

[0408] 9. After fully lysing the cells, measure the absorbance A at 490 nm using a microplate reader to obtain the total melanin content.

[0409] Relative melanin content = total melanin content / number of cells (millions)

[0410] Experimental results:

[0411] As shown in Figure 17, in the B16 relative melanin content experiment, the melanin content per unit cell was significantly increased in the model group compared to the control group, and significantly decreased when kojic acid was used as a positive control, indicating that the model was successfully established.

[0412] According to the calculation formula, the relative inhibition rate of melanin content of kojic acid is 98.5%, that of retinol is 77.05%, that of ferulic acid is 25.52%, and that of retinol ferulate is 82.12%.

[0413] In summary, retinol ferulate showed the strongest anti-melanin effect among the four tested substances at a concentration of 50 μM. Retinol ferulate inhibits melanin production. Retinol ferulate is more effective than retinol in inhibiting melanin production.

[0414] Based on the embodiments of the present disclosure, all other embodiments obtained by those skilled in the art without creative work shall fall within the scope of protection of the present disclosure.

[0415] Those skilled in the art may modify the technical solutions described in the above embodiments, or make equivalent replacements for some of the technical features therein; however, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the protection scope of the technical solutions of the embodiments of this disclosure.

Claims

1. A retinol derivative or a pharmaceutically acceptable salt thereof, characterized in that: The retinol derivative has a structure represented by formula (I) or formula (II), Wherein, R1 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle; R2, R3, R4, R5 are independently hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl; Wherein, R6 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle; R7, R8 are independently hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl.

2. The retinol derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is a hydroxyl group; R4 is hydrogen; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is a methoxy group; R3 is a hydroxyl group; R4 is a methoxy group; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is a hydroxyl group; R4 is a methoxy group; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is a hydroxyl group; R4 is a hydroxyl group; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (II), and in formula (II), R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is methoxy; R4 is an acetoxy group; R5 is hydrogen, Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is methoxy; R4 is hydrogen; R5 is methoxy; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is a hydroxyl group; R4 is hydrogen; R5 is a hydroxyl group; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is hydrogen; R3 is methoxy; R4 is a hydroxyl group; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is a methoxy group; R3 is methoxy; R4 is a methoxy group; R5 is hydrogen; Alternatively, the retinol derivative has a structure represented by formula (I), and in formula (I), R1 is hydrogen; R2 is a methoxy group; R3 is a hydroxyl group; R4 is a methoxy group; R5 is hydrogen.

3. A method for preparing a retinol derivative according to any one of claims 1 to 2, characterized in that: The preparation step of the retinol derivative comprises: subjecting cinnamic acid or its derivatives to an esterification reaction with retinol to obtain the retinol derivative.

4. The method for preparing the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in claim 3, characterized in that: The cinnamic acid derivatives include: p-Hydroxycinnamic acid, 3,5-dimethoxy-p-hydroxycinnamic acid, ferulic acid, 3,5-dihydroxycinnamic acid, 3,4-methylenedioxycinnamic acid, 3-acetoxycinnamic acid-4-methoxycinnamic acid, 4,6-dimethoxycinnamic acid, 2,4-dihydroxycinnamic acid, trans-isoferulic acid, 3,4,5-trimethoxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid, p-Methylcinnamic acid, 4-acrylic cinnamic acid, 2-methylcinnamic acid, 3-(1-naphthyl))acrylic acid, biphenyl-4-acrylic acid, 3-methylcinnamic acid, 2,4-dimethylcinnamic acid, 3-(2-naphthyl))acrylic acid, biphenyl-3-acrylic acid, 4-formylcinnamic acid, 2,5-dimethylcinnamic acid, 2,6-dimethylcinnamic acid, 2,4,6-trimethylcinnamic acid, pentamethylcinnamic acid, 3,5-dimethylcinnamic acid, 2,3-dimethylcinnamic acid, 2,4,5-trimethylcinnamic acid, 3,4-dihydroxycinnamic acid, trans-4-hydroxycinnamic acid, 3-hydroxycinnamic acid, 3,5-dihydroxycinnamic acid, 3,5-dimethyl-p-hydroxycinnamic acid, 2,6-dimethyl-p-hydroxycinnamic acid, 2-methyl-p-hydroxycinnamic acid, 3-methyl-p-hydroxycinnamic acid, One of 6-methoxy-o-hydroxycinnamic acid, 4-methoxy-o-hydroxycinnamic acid, 3-methoxy-p-methylcinnamic acid, 3-methoxy-o-hydroxycinnamic acid, 4-methoxy-3-methylcinnamic acid, 2-hydroxy-5-methoxycinnamic acid, 2,4,6-trihydroxycinnamic acid and 3,4-dimethoxy-o-hydroxycinnamic acid.

5. The method for preparing the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in claim 3, characterized in that: The cinnamic acid derivative is ferulic acid.

6. A use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2 as an anti-aging ingredient, or as an anti-wrinkle ingredient, or as a whitening ingredient, or as a freckle-removing ingredient, or as an acne-removing ingredient, or as an antioxidant ingredient, or as a moisturizing ingredient, or as an anti-inflammatory ingredient, or as an anti-photoaging ingredient.

7. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient as claimed in claim 6, characterized in that: Use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting the proliferation of skin epidermal cells; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting skin keratinocyte differentiation; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting the increase of epidermal cell thickness; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating skin metabolism; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating keratinocyte shedding; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting collagen degradation in the basal layer and / or dermal layer; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing collagen degradation in the basal layer and / or dermis; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting degradation of elastin in the basal layer and / or dermal layer; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing elastin degradation in the basal layer and / or dermal layer.

8. Use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-wrinkle ingredient according to any one of claims 6 to 7, characterized in that: Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for removing wrinkles and reducing fine lines; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating the synthesis of GAGs in the skin extracellular matrix; Or the retinol derivative or its pharmaceutically acceptable salt as an effective ingredient for stimulating collagen synthesis The purpose of the points; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the activity of matrix metalloproteinases (MMPs); Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for tightening the skin; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for enhancing skin elasticity.

9. Use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 6 to 8 as a whitening ingredient or a freckle removing ingredient, characterized in that: Use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing pigmentation; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting uniform distribution of melanin; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of tyrosinase and tyrosinase-related proteins; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting melanin production; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing melanocyte activity; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for preventing melanin from being transported to the skin surface.

10. Use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 6 to 9 as an anti-acne ingredient, characterized in that: Use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting acne; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an oil-controlling ingredient; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating sebaceous gland oil secretion; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting 5α-reductase activity; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for protecting epidermal mucosa from bacterial invasion; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for eliminating sebaceous gland blockage; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing the number of Propionibacterium acnes flora. Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for refining pores; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing the skin barrier.

11. Use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 6 to 10 as an anti-acne ingredient, characterized in that: The retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for promoting the expression of hyaluronic acid in the skin.

12. Use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 6 to 11 as an anti-inflammatory ingredient, characterized in that: Use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of inflammatory cytokines; Or the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective component for inhibiting the infiltration of CD4+ and CD8+ lymphocytes and macrophages.

13. Use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 6 to 12 as an anti-photoaging ingredient, characterized in that: Use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photodamage efficacy ingredient; Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing photodamage.

14. A pharmaceutical composition, characterized in that It includes at least: The retinol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2; and a pharmaceutically acceptable excipient or carrier.

15. A nutritional product composition, characterized in that It includes at least: It is characterized in that it at least includes: The retinol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2; and nutritionally acceptable excipients or carriers.

16. A skin care composition, characterized in that It includes at least: The retinol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2; and a dermatologically acceptable excipient or carrier.

Images