Retinol derivative or salt thereof, and preparation method and application thereof

Abstract

The invention discloses a retinol derivative or a salt thereof as well as a preparation method and application thereof, the retinol derivative or the salt thereof retains the anti-aging effect of retinol and reduces the side effects of skin irritation and allergy, and in addition, the retinol derivative or the salt thereof also has the effects of whitening, light damage resistance, inflammation resistance, oxidation resistance, repair and the like. Good application prospects in the field of cosmetic raw materials are realized.

Description

Technical Field

[0001] The present invention 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

[0002] Retinol is a member of the vitamin A family, also known as retinol. As a classic and effective anti-aging ingredient, it plays an important role in skin care products. Retinol can significantly improve skin aging and skin barrier, promote skin epidermal cell reproduction, maintain normal skin circulation, repair lost collagen, reduce wrinkles and pigmentation, protect the epidermal mucosa from bacterial invasion, and has many effects such as wrinkle removal, anti-photoaging, acne removal, and whitening.

[0003] Although retinol has many benefits, it has limitations such as poor stability, irritation, and the tendency to cause skin allergies, redness, and other side effects. The instability of retinol is manifested in that it is prone to structural changes under conditions such as ultraviolet rays, light, oxygen, temperature, and metal ions, which affects the formulation, application, and storage of cosmetic products; the side effects of retinol include the possibility of causing TRPV1 receptor excitation, the release of inflammatory factors, and overexpression of AQP3, which can cause skin irritation, specifically manifested as stinging, erythema, rash, dryness, and barrier dysfunction.

[0004] 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 successively. These retinol-like substances have better stability and lower irritation than retinol, but their use effect is worse than that of directly using retinol.

[0005] Therefore, it is a technical problem to be solved urgently by those skilled in the art to develop 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 directly using retinol. Summary of the invention

[0006] The technical problem to be solved by the present application is to provide a retinol compound having the effects of retinol and having better stability and lower irritation.

[0007] Technical means used to solve technical problems:

[0008] Cinnamic acid can inhibit skin aging, reduce the formation of spots and whiten the skin, so it is widely used in cosmetics.

[0009] The present invention adopts the prodrug strategy in medicinal chemistry to rationally design new compounds from cinnamic acid derivatives and retinol. This series of compounds can release retinol and corresponding molecules with synergistic effects in cells through hydrolysis or other means, so as to retain the anti-aging effect of retinol and reduce its side effects of skin irritation and allergies.

[0010] In one aspect of the present invention, a retinol derivative and a pharmaceutically acceptable salt thereof are provided, wherein the retinol derivative has a structure represented by formula (I) or formula (II),

[0011]

[0012] Among them, R 1 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0013] R 2 , R 3 , R 4 , R 5 are independently hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl;

[0014]

[0015] Among them, R 6 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0016] R 7 , R 8 Independently are hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl.

[0017] In a preferred embodiment, in formula (I),

[0018] R 1 is hydrogen;

[0019] R 2 is hydrogen;

[0020] R 3 is hydrogen;

[0021] R 4 is hydrogen;

[0022] R 5 is hydrogen;

[0023] The retinol derivative is shown in the following formula (I-1):

[0024]

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

[0026] R 1 is hydrogen;

[0027] R 2 is hydrogen;

[0028] R 3 is hydroxyl group;

[0029] R 4 is hydrogen;

[0030] R 5 is hydrogen;

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

[0032]

[0033] In a preferred embodiment, in formula (I),

[0034] R 1 is hydrogen;

[0035] R 2 is methoxy;

[0036] R 3 is hydroxyl group;

[0037] R 4 is methoxy;

[0038] R 5 is hydrogen;

[0039] The retinol derivative is shown in the following formula (I-3):

[0040] In a preferred embodiment, in formula (I), R 1 is hydrogen;

[0041] R 2 is hydrogen;

[0042] R 3 is hydroxyl group;

[0043] R 4 is methoxy;

[0044] R 5 is hydrogen;

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

[0046] In a preferred embodiment, in formula (I), R 1 is hydrogen;

[0047] R 2 is hydrogen;

[0048] R 3 is hydroxyl group;

[0049] R 4 is hydroxyl group;

[0050] R 5 is hydrogen;

[0051] The retinol derivative is shown in the following formula (I-5):

[0052] In a preferred embodiment, in formula (II), R 6 is hydrogen;

[0053] R 7 is hydrogen;

[0054] R 8 is hydrogen;

[0055] The retinol derivative is shown in the following formula (II-1):

[0056] In a preferred embodiment, in formula (I), R 1 is hydrogen;

[0057] R 2 is hydrogen;

[0058] R 3 is methoxy;

[0059] R 4 is acetoxy;

[0060] R 5 is hydrogen;

[0061] The retinol derivative is shown in the following formula (I-6):

[0062] In a preferred embodiment, in formula (I), R 1 is hydrogen;

[0063] R 2 is hydrogen;

[0064] R 3 is methoxy;

[0065] R 4 is hydrogen;

[0066] R 5 is methoxy;

[0067] The retinol derivative is shown in the following formula (I-7):

[0068] In a preferred embodiment, in formula (I), R 1 is hydrogen;

[0069] R 2 is hydrogen;

[0070] R 3 is hydroxyl group;

[0071] R 4 is hydrogen;

[0072] R 5 is hydroxyl group;

[0073] The retinol derivative is shown in the following formula (I-8): (Example 10)

[0074]

[0075] In a preferred embodiment, in formula (I),

[0076] R 1 is hydrogen;

[0077] R 2 is hydrogen;

[0078] R 3 is methoxy;

[0079] R 4 is hydroxyl group;

[0080] R 5 For hydrogen.

[0081] In a preferred embodiment, in formula (I),

[0082] R 1 is hydrogen;

[0083] R 2 is methoxy;

[0084] R 3 is methoxy;

[0085] R 4 is methoxy;

[0086] R 5 For hydrogen.

[0087] In a preferred embodiment, in formula (I),

[0088] R 1 is hydrogen;

[0089] R 2 is methoxy;

[0090] R 3 is hydroxyl group;

[0091] R 4 is methoxy;

[0092] R 5 For hydrogen.

[0093] The second aspect of the present application provides a method for preparing the above-mentioned retinol derivatives, which specifically comprises the steps of esterifying cinnamic acid or its derivatives with retinol.

[0094] In a specific embodiment, the cinnamic acid derivative is

[0095] 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,

[0096] trans-isoferulic acid, 3,4,5-trimethoxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid,

[0097] 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,

[0098] 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,

[0099] 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.

[0100] In a preferred embodiment, the cinnamic acid derivative is ferulic acid.

[0101] The third aspect of the present invention provides a method for preparing the pharmaceutically acceptable salt of the retinol derivatives mentioned above, which is obtained by reacting the retinol derivatives obtained according to the above preparation method with an acid or a base.

[0102] The fourth aspect of the present invention provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient.

[0103] 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;

[0104] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting skin keratinocyte differentiation;

[0105] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting the increase of epidermal cell thickness;

[0106] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating skin metabolism;

[0107] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating keratinocyte shedding;

[0108] 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;

[0109] 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;

[0110] 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;

[0111] 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.

[0112] The fifth aspect of the present invention provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-wrinkle ingredient.

[0113] Specifically, the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as the retinol derivative as an anti-wrinkle ingredient;

[0114] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for removing wrinkles and reducing fine lines;

[0115] 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;

[0116] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating collagen synthesis;

[0117] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the activity of matrix metalloproteinases (MMPs);

[0118] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for tightening the skin;

[0119] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for enhancing skin elasticity.

[0120] 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;

[0121] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9.

[0122] 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;

[0123] 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.

[0124] The sixth aspect of the present invention provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a whitening ingredient or a freckle removing ingredient.

[0125] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing pigmentation;

[0126] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting uniform distribution of melanin;

[0127] 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;

[0128] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting melanin production;

[0129] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing melanocyte activity;

[0130] 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.

[0131] 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.

[0132] The seventh aspect of the present invention provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an acne-removing ingredient or an oil-controlling ingredient.

[0133] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting acne;

[0134] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an oil-controlling ingredient;

[0135] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating sebaceous gland oil secretion;

[0136] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting 5α-reductase activity;

[0137] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for protecting epidermal mucosa from bacterial invasion;

[0138] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for eliminating sebaceous gland blockage;

[0139] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing the number of Propionibacterium acnes flora.

[0140] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for refining pores;

[0141] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing the skin barrier;

[0142] The eighth aspect of the present invention provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an antioxidant ingredient.

[0143] 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).

[0144] 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.

[0145] The ninth aspect of the present invention provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a moisturizing ingredient;

[0146] The tenth aspect of the present invention provides the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-inflammatory ingredient;

[0147] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of inflammatory cytokines;

[0148] 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.

[0149] In some embodiments, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of inflammatory factor NO.

[0150] 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.

[0151] 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;

[0152] 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.

[0153] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of TNF-α, an inflammatory factor in HaCaT cells; or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of IL-6, an inflammatory factor in HaCaT cells.

[0154] The eleventh aspect of the present invention provides the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photoaging ingredient;

[0155] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photodamage efficacy ingredient;

[0156] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing photodamage.

[0157] 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.

[0158] 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.

[0159] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of UVB-induced inflammatory factor IL-6 in Hacat cells;

[0160] 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 in Hacat cells.

[0161] 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.

[0162] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP3 induced by UVB in Hacat cells;

[0163] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9 induced by UVB in Hacat cells.

[0164] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of UVA-induced inflammatory factor proIL-1β.

[0165] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of UVA-induced inflammatory factor IL-1β.

[0166] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for up-regulating UVA-induced decreased collagen III expression. Further, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for up-regulating UVA-induced decreased collagen III expression in 3T3 cells.

[0167] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for up-regulating UVA-induced decreased expression of collagen I. Further, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for up-regulating UVA-induced decreased expression of collagen I in 3T3 cells.

[0168] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of MMP1 induced by UVA. Further, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of MMP1 induced by UVA in 3T3 cells.

[0169] 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.

[0170] The twelfth aspect of the present invention provides a pharmaceutical composition, characterized in that it at least comprises:

[0171] The above retinol derivatives;

[0172] and a pharmaceutically acceptable excipient or carrier.

[0173] The thirteenth aspect of the present invention is a nutritional composition, characterized in that it at least comprises:

[0174] The above retinol derivatives;

[0175] and nutritionally acceptable excipients or carriers.

[0176] A fourteenth aspect of the present invention is a skin care composition, characterized in that it at least comprises:

[0177] The above retinol derivatives;

[0178] and a dermatologically acceptable excipient or carrier.

[0179] Beneficial effects:

[0180] The retinol derivative or the pharmaceutically acceptable salt thereof provided by the present invention has good stability and low irritation.

[0181] The retinol derivatives or pharmaceutically acceptable salts thereof obtained by esterification of cinnamic acid and its derivatives with retinol in the present invention can release retinol and corresponding molecules with synergistic effects in cells by hydrolysis or other means, so as to retain the anti-aging effect of retinol and reduce its side effects of skin irritation and allergy.

[0182] Through experimental studies, it was found that retinol ferulate obtained by esterification of ferulic acid, a cinnamic acid derivative, with retinol has the effects of inhibiting the expression of inflammatory factor NO, inhibiting the expression of inflammatory factors, inhibiting the expression of matrix metalloproteinases, repairing collagen damage, regulating abnormal increase of matrix metalloproteinases, repairing DNA damage, inhibiting melanin, etc., and the above effects are close to or better than those of retinol. All compounds represented by formula (I) and (II) have the same parent structure as retinol ferulate, so it can be reasonably inferred that they have the same effects.

[0183] In addition, the retinol derivatives or pharmaceutically acceptable salts thereof provided by the present invention have the effects of anti-aging, anti-wrinkle, whitening, freckle removal, anti-oxidation, moisturizing, acne removal, oil control, anti-inflammatory, and anti-photoaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0184] The present application also provides drawings related to the provided technical solution to illustrate the technical solution of the present application. The purpose of the drawings and descriptions is only to more clearly describe the present application and should not be regarded as limiting the scope of protection claimed in the present application.

[0185] Figure 1 Mass spectrum of retinol ferulate in negative ion mode.

[0186] Figure 2 Mass spectrum of retinol ferulate in positive ion mode.

[0187] Figure 3 NMR spectrum of retinol ferulate.

[0188] Figure 4 Retinyl ferulate RAW cell viability.

[0189] Figure 5 Results of LPS inflammation experiment.

[0190] Figure 6 Retinyl ferulate Hacat cell viability.

[0191] Figure 7 Effects of UVB-induced elevation of TNF-α.

[0192] Figure 8Effects of UVB-induced IL-6 elevation.

[0193] Fig. 9 Effects on UVB-induced increase in MMP3.

[0194] Fig.10 Effects on UVB-induced increase in MMP9.

[0195] Fig.11 Retinyl ferulate 3T3 cell viability.

[0196] Fig.12 For the regulation of UVA-induced decrease in collagen III.

[0197] Fig.13 Regulation of UVA-induced increase in MMP1.

[0198] Fig.14 Western blot of γH2AX.

[0199] Fig.15 Regulation of UVA-induced upregulation of γH2AX expression.

[0200] Fig.16 Retinyl ferulate B16 activity.

[0201] Fig.17 B16 relative melanin content. DETAILED DESCRIPTION

[0202] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are not all embodiments.

[0203] The elements and features described in one embodiment of the present application 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 application and are known to those of ordinary skill in the art are omitted in the description.

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

[0205]

[0206] As used herein, "cinnamic acid" refers to: a substance having the structure of formula (IV);

[0207]

[0208] Herein, "cinnamic acid derivatives" refer to compounds obtained by modifying the benzene ring of cinnamic acid with a functional group.

[0209] Herein, "ferulic acid" refers to: a substance having a structure of formula (V), wherein ferulic acid is a derivative of cinnamic acid;

[0210]

[0211] As used herein, "pharmaceutically acceptable salt" refers to a product prepared from a compound salt of the compound of formula (I) or (II) itself.

[0212] In a first aspect, the present invention provides a retinol derivative having a structure represented by formula (I) or formula (II),

[0213]

[0214] Among them, R 1 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0215] R 2 , R 3 , R 4 , R 5 are independently hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl;

[0216]

[0217] Among them, R 6 is hydrogen or halogen or amino or hydroxy or alkyl or alkylamide or benzene ring or aromatic heterocycle or alkyl-substituted aromatic heterocycle;

[0218] R 7 , R 8 Independently are hydrogen or, halogen or, amino or, hydroxy or, alkoxy or, alkylamide or, alkoxycarbonyl ring or, carboxyl.

[0219] Preparation method of retinol derivatives

[0220] The present invention provides a method for preparing the above retinol derivatives, which specifically comprises the steps of carrying out an esterification reaction between cinnamic acid and its derivatives and retinol.

[0221] Optionally, the cinnamic acid derivative is

[0222] 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,

[0223] trans-isoferulic acid, 3,4,5-trimethoxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid,

[0224] 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,

[0225] 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,

[0226] 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.

[0227] The method for obtaining the cinnamic acid derivatives suitable for the present invention can be to synthesize / modify them by known synthesis / modification methods, or to directly purchase the cinnamic acid derivatives.

[0228] Preferably, the cinnamic acid derivative is ferulic acid.

[0229] The method suitable for the present invention to carry out esterification reaction of the cinnamic acid and its derivatives with retinol can be a conventional esterification method, and the present application does not impose any particular limitation on this. As a non-limiting example, appropriate amounts of cinnamic acid or cinnamic acid derivatives, retinol, EDCI (carbodiimide) and DMAP (4-dimethylaminopyridine) are weighed, dissolved in THF (tetrahydrofuran), and then TEA (triethylamine) is added and stirred to obtain.

[0230] 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 the groups are deprotected after the esterification reaction.

[0231] Preferably, tert-butyldimethylsilyl chloride is used to protect the hydroxyl group and / or alkoxy group of the cinnamic acid derivative.

[0232] Pharmaceutically acceptable salt of retinol derivative and preparation method thereof

[0233] The present invention also provides a pharmaceutically acceptable salt of the above retinol derivative, the preparation method of which comprises the following specific steps:

[0234] The above retinol derivatives are obtained by reacting with an acid or a base.

[0235] 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.

[0236] 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 salts, aminoethanol salts, lysine salts, and arginine salts.

[0237] Use of retinol derivatives or pharmaceutically acceptable salts thereof

[0238] The present invention provides the use of the above retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient.

[0239] The fourth aspect of the present invention provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-aging ingredient.

[0240] 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;

[0241] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting skin keratinocyte differentiation;

[0242] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting the increase of epidermal cell thickness;

[0243] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating skin metabolism;

[0244] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating keratinocyte shedding;

[0245] 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;

[0246] 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;

[0247] 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;

[0248] 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.

[0249] The fifth aspect of the present invention provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an anti-wrinkle ingredient.

[0250] Specifically, the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as the retinol derivative as an anti-wrinkle ingredient;

[0251] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for removing wrinkles and reducing fine lines;

[0252] 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;

[0253] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating collagen synthesis;

[0254] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the activity of matrix metalloproteinases (MMPs);

[0255] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for tightening the skin;

[0256] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for enhancing skin elasticity.

[0257] 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;

[0258] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9.

[0259] The sixth aspect of the present invention provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a whitening ingredient or a freckle removing ingredient.

[0260] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing pigmentation;

[0261] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for promoting uniform distribution of melanin;

[0262] 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;

[0263] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting melanin production;

[0264] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing melanocyte activity;

[0265] 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.

[0266] 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.

[0267] The seventh aspect of the present invention provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an acne-removing ingredient or an oil-controlling ingredient.

[0268] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting acne;

[0269] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an oil-controlling ingredient;

[0270] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for regulating sebaceous gland oil secretion;

[0271] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting 5α-reductase activity;

[0272] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for protecting epidermal mucosa from bacterial invasion;

[0273] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for eliminating sebaceous gland blockage;

[0274] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for reducing the number of Propionibacterium acnes flora.

[0275] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for refining pores;

[0276] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing the skin barrier;

[0277] The eighth aspect of the present invention provides use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as an antioxidant ingredient.

[0278] 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).

[0279] 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.

[0280] The ninth aspect of the present invention provides the use of the above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof as a moisturizing ingredient;

[0281] 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.

[0282] The tenth aspect of the present invention provides the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-inflammatory ingredient;

[0283] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for inhibiting the expression of inflammatory cytokines;

[0284] 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.

[0285] In some embodiments, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of inflammatory factor NO.

[0286] 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.

[0287] 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.

[0288] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of inflammatory factor TNF-α;

[0289] 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.

[0290] The eleventh aspect of the present invention provides the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photoaging ingredient;

[0291] Specifically, the use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photodamage efficacy ingredient;

[0292] Or use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for repairing photodamage.

[0293] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is an effective component for inhibiting UVB-induced cellular reactive oxygen species.

[0294] 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.

[0295] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting the expression of UVB-induced inflammatory factor IL-6;

[0296] 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.

[0297] 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.

[0298] Furthermore, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for inhibiting UVB-induced matrix metalloproteinase MMP3 expression;

[0299] Or the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective component for inhibiting the expression of matrix metalloproteinase MMP9 induced by UVB.

[0300] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for upregulating UVA-induced decrease in collagen III expression.

[0301] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for upregulating UVA-induced decrease in collagen I expression.

[0302] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of MMP1 induced by UVA.

[0303] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of UVA-induced inflammatory factor proIL-1β.

[0304] In one embodiment, the retinol derivative or a pharmaceutically acceptable salt thereof is used as an effective ingredient for down-regulating the increase of UVA-induced inflammatory factor IL-1β.

[0305] 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 elevated γH2AX expression; further, as an effective ingredient for downregulating UVA-induced elevated γH2AX expression in 3T3 cells.

[0306] Pharmaceutical composition

[0307] The pharmaceutical composition of the present invention comprises at least:

[0308] The above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof;

[0309] and a pharmaceutically acceptable excipient or carrier.

[0310] Pharmaceutically acceptable excipients or carriers may be conventional excipients or carriers that are not undesirable in pharmaceutical, biological or other aspects. Non-limiting examples of excipients include solvents such as water, alcohol, etc. as media for dissolving drugs. Adhesives such as gelatin, sodium carboxymethyl cellulose, etc. used to solidify particles or powders to make tablets or granules. Plasticizers such as glycerol, polyethylene glycol, etc. that increase the softness and plasticity of the preparation. Emulsifiers such as polysorbates, polyoxyethylene glycol esters, etc. used to prepare emulsions. Dispersants such as polyvinyl pyrrolidone and hydroxypropyl methylcellulose used to evenly disperse drugs in liquid media. Stabilizers such as common antioxidants, preservatives, etc. used to protect drugs from damage by light, heat, oxidation and microbial contamination. Sustained-release agents such as polyvinyl alcohol, hydroxyethyl cellulose, etc. used to regulate the release rate of drugs in the body. Non-limiting examples of carriers include nanoparticles such as polymer nanoparticles, liposomes, etc. that can be used to encapsulate and deliver drugs, and achieve targeted delivery and controlled release. Microspheres and microparticles such as polymer microspheres, capsules, etc. that can embed drugs and achieve controlled release, which are commonly used for oral administration or topical application. Drug-loaded films such as polymer coatings, controlled release membranes, etc. that are used to encapsulate drugs and control the release rate of drugs by dissolution, diffusion or degradation. Sustained-release matrices such as polylactic acid-glycolic acid copolymers, gelatin, etc. that can be used as drugs, and polymer matrices that release drugs through degradation. Liposomes and cholesterol systems such as lipid nanoparticles, lipid cholesterol nanoparticles, etc. that are used to encapsulate and deliver drugs and achieve targeted delivery in vivo. Pharmaceutical dosage forms such as polymer gels, natural biogels, etc. that can be used to prepare gels that provide adhesion and sustained-release effects.

[0311] Nutritional product composition

[0312] The nutritional composition of the present invention comprises at least:

[0313] The above-mentioned retinol derivative or a pharmaceutically acceptable salt thereof;

[0314] and nutritionally acceptable excipients or carriers.

[0315] 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 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 include liposomes, nanoparticles, protein encapsulation, and high fiber matrix.

[0316] Skin care compositions

[0317] The skin care composition of the present invention comprises at least:

[0318] The above retinol derivative is obtained as a pharmaceutically acceptable salt;

[0319] and a dermatologically acceptable excipient or carrier.

[0320] A dermatologically acceptable vehicle or carrier.

[0321] The dermatologically acceptable excipient or carrier may be a conventional excipient or carrier that is not undesirable dermatologically, biologically or otherwise. 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, oil gel beads, etc. Non-limiting examples of carriers include any one or more forms of carriers commonly used in the field of skin care products or cosmetics, including lotions, emulsions, foundations, hand creams, beauty serums, shampoos, conditioners, hair conditioners, fixatives, facial masks, soaps, facial cleansers, etc.

[0322] Under the premise that the technical effects of the composition of the present application are not affected, the composition of the present application may also contain ingredients commonly used in the field of cosmetics, such as stabilizers, surfactants, lubricants, buffers, sweeteners and flavoring agents, adhesives, antioxidants, coating agents, wetting agents, flavoring agents, colorants, coating agents, tension agents, emulsifiers, thickeners, pH adjusters, excipients, dispersants, disintegrants, preservatives, solubilizers, oils, moisturizers, ultraviolet absorbers, fillers, chelating agents, sunscreens, defoamers, softeners, propellants, acidulants, or, depending on the purpose, alkalizers, silicones, vitamins, dyes, pigments, nano-pigments, organic solvents such as alcohols, water, etc. can be optionally mixed.

[0323] The skin care composition of the present application can be a skin care product or a cosmetic, and the dosage form of the external skin preparation of the present application can be any one of a lotion, an essence, a spray, an emulsion, a cream, a mask, a gel, a sunscreen, and a barrier.

[0324] Preparation Example of Retinol Derivatives

[0325] Example 1

[0326] This embodiment provides a method for preparing retinol ferulate as shown in the following formula (I-4):

[0327]

[0328] The specific steps include:

[0329] Step S1. Protection of hydroxyl and methoxy groups of ferulic acid:

[0330]

[0331] Add 466 mg of ferulic acid (3-methoxy-4-hydroxycinnamic acid) to a 50 mL round-bottom flask, dissolve it with 10 mL of dichloromethane, and then add 1.4 mL of triethylamine. The resulting reaction solution is stirred with a magnetic force, cooled to 0-5 ° C with an ice-water bath, and 900 mg of tert-butyldimethylsilyl chloride (Compound 2) is slowly added, and stirred at room temperature for 4 hours. After the reaction is completed, add 25 mL of ice water to quench the reaction, extract the water layer with dichloromethane (25 mL × 3), combine the organic layers, add anhydrous sodium sulfate to dry the organic layer, filter, and concentrate in vacuo to obtain a crude product. Dissolve the crude product with 20 mL of tetrahydrofuran and 2 mL of water, add 200 mg of anhydrous potassium carbonate, and stir at room temperature for 6 hours. After the reaction is completed, add 25 mL of water and extract the water layer with ethyl acetate (25 mL × 3), combine the organic layers, concentrate in vacuo, and recrystallize with petroleum ether to obtain 493 mg of the first intermediate (Compound 3) (white solid, yield: 80%).

[0332] Step S2. Esterification reaction:

[0333]

[0334] 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 to dissolve, and finally 270 μL of TEA was added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was vacuum concentrated, 25 mL of water was added, and the water layer was extracted with ethyl acetate (25 mL×3), the organic layers were combined, anhydrous sodium sulfate was added to dry the organic layers, filtered, and vacuum concentrated to obtain a crude product, and 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%).

[0335] Step S3. Deprotection:

[0336]

[0337] 384 mg of the second intermediate (Compound 5) was added to a 50 mL brown round-bottom flask, dissolved in 8 mL of tetrahydrofuran, cooled to 0-5°C in an ice-water bath, 600 μL of tetrabutylammonium fluoride was slowly added dropwise, and stirred in an ice bath for 10 minutes. The crude product was concentrated in vacuo, and the final product, retinol ferulate (Compound 6), was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 as eluent) 226 mg (yellow oily liquid, yield: 73%).

[0338] The mass spectrum data of compound 6 are as follows:

[0339] MS(ESI)m / z:[MH]-calcd.for C30H37O4-461,found:461.

[0340] Mass Spectrometry: Negative Ions

[0341] Spectrum Figure 1 As shown in

[0342] Positive ions

[0343] Spectrum Figure 2 As shown in

[0344] The NMR of compound 6 (such as Figure 3 ), the data is as follows:

[0345] 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).

[0346] Efficacy Test

[0347] Anti-inflammatory efficacy experiment

[0348] (I) Detect cell viability through RAW cell CCK8 assay and determine the sample concentration required for subsequent experiments.

[0349] CCK8 experiment: 96-well plates were plated at a cell density of 1w / well, and drug treatment was performed after 24h of culture. The sample concentrations were set as: 1%, 0.5%, 0.1%, 0.05%, and 0.01% (v / v);

[0350] CCK8 was incubated 24 hours after drug addition. Under light-protected conditions, 10X CCK8 mother solution (Biyuntian, C0040) was diluted to 1X solution with complete culture medium and the medium was replaced;

[0351] The cells were incubated in the cell culture incubator for 2 hours, and the absorbance at 450 nm and 650 nm was measured using an enzyme-labeled instrument.

[0352] According to the CCK8 toxicity results, such as Figure 4 In the experiment, retinol ferulate had no cytotoxicity in the dose range of 6.25-200uM.

[0353] (II) The RAW cell NO assay was used to determine whether retinol ferulate had an inhibitory effect on inflammatory factors.

[0354] 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.

[0355] Positive control group: 100 mg / ml dexamethasone was added after 24 h, incubated for 1 h, and then 125 ng / ml LPS was added;

[0356] Experimental group: 24 h later, the drug was added and incubated for 1 h before adding 125 ng / ml LPS;

[0357] Negative control group: 125 ng / ml LPS was added after 24 h;

[0358] Blank control group: no LPS was added.

[0359] After incubation for 24 h, 50 ul of supernatant was aspirated into a 96-well plate, 50 ul of 1X Griess reagent was added to each well, and the plate was incubated for 30 min. The absorbance at 540 nm was detected using an enzyme-labeled instrument.

[0360] The results are as follows Figure 5 as shown in .

[0361] In this LPS inflammation experiment, the NO per unit cell amount in the model group (0.106) was significantly increased compared with the control group (0.0547), and the model was successfully established.

[0362] 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.

[0363] Anti-photodamage efficacy experiment

[0364] (I) Detect cell viability through Hacat cell CCK8 assay and determine the sample concentration required for subsequent experiments.

[0365] At a cell density of 2w / well, a 96-well plate was plated and the drug was added after 24 hours of culture. The sample concentrations were set as follows: 1%, 0.5%, 0.1%, 0.05%, 0.01% (v / v). CCK8 was incubated 24 hours after drug addition. Under light-proof conditions, the 10X CCK-8 mother solution (Biyuntian, C0040) was diluted to 1X solution with complete culture medium and the medium was replaced. Incubate in the cell culture incubator for 2 hours and detect the absorbance at reference wavelengths of 450nm and 650nm with an ELISA reader.

[0366] According to the CCK8 toxicity results, such as Figure 6 As shown in , retinol ferulate had no cytotoxicity at a dose of 125 uM.

[0367] (II) QPCR:

[0368] (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 an incubator overnight;

[0369] (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.

[0370] (3) UVB irradiation: After 24 hours of continuous culture, the culture medium of the model group and the drug group was irradiated with 25 mj / cm2 UVB.

[0371] (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 samples were collected to detect the mRNA levels of MMP3, MMP9, TNF-α, and IL-6.

[0372] 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.

[0373] The calculation formula is as follows:

[0374] △Ct=Ct target gene-Ctβ-actin

[0375] △△Ct=Average value of △Ct blank group-△Ct experimental group

[0376] Relative mRNA expression = 2 (-△△Ct)

[0377] Experimental results:

[0378] like Figure 7 In the UVB damaged cell experiment, in the expression of inflammatory factors, for the inflammatory factor TNF-α, the inhibition rate of 50uM retinol ferulate was 22.77%, the inhibition rate of 50uM retinol was 20.49%, and 50uM ferulic acid showed no inhibitory effect on TNF-α. The inhibition rate of retinol ferulate on the inflammatory factor TNF-α was better than that of retinol.

[0379] like Figure 8 In the experiment, 50uM retinol, 50uM ferulic acid and 50uM retinol ferulate all showed an inhibitory trend towards the inflammatory factor IL-6, and the inhibitory rates of retinol ferulate and retinol on the inflammatory factor IL-6 were not much different.

[0380] like Fig. 9In the experiment, 50uM retinol, 50uM ferulic acid and 50uM retinol ferulate all showed an inhibitory trend towards matrix metalloproteinase MMP3; among them, 50uM retinol ferulate could significantly inhibit the gene expression of MMP3, with an inhibition rate of 80% compared with the model group. The inhibition rate of retinol ferulate on MMP3 was significantly better than that of retinol.

[0381] like Fig.10 In the experiment, 50uM retinol ferulic acid ester showed a tendency to inhibit MMP9, while 50uM retinol and 50uM ferulic acid had no inhibitory effect on MMP9.

[0382] Repair efficacy test

[0383] (I) Detect cell viability through 3T3 cell CCK8 assay to determine the sample concentration required for subsequent experiments.

[0384] At a cell density of 10,000 / well, a 96-well plate was plated and the cells were treated with drugs after 24 hours of culture. The sample concentrations were set as 12.5, 50, 100, 150, and 200uM. CCK8 was incubated 24 hours after drug addition. Under light-proof conditions, the 10X CCK-8 mother solution (Biyuntian, C0040) was diluted to 1X solution with complete culture medium and the medium was replaced. Incubate in the cell culture incubator for 2 hours and use an ELISA reader to detect the absorbance at reference wavelengths of 450nm and 650nm.

[0385] According to the CCK8 toxicity results, such as Fig.11 As shown in , retinol ferulate had no cytotoxicity within the dose range of 12.5-200uM. 50uM was selected for subsequent experiments.

[0386] (II) QPCR

[0387] QPCR:

[0388] (1) 3T3 cells were counted with an automatic cell counter at a density of 100 w / well and plated in a six-well plate. The culture medium was discarded after 24 h.

[0389] (1) When covered with PBS, the UVA model group and the drug group were treated with 7J / cm 2 The drug group was treated with UVA at a dose of , and then the PBS was discarded and replaced with complete medium with the test substance;

[0390] (2) The reaction was 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.

[0391] Experimental results:

[0392] like Fig.12In the study, retinyl ferulate had a significant upregulatory ability on the decrease of collagen III induced by UVA, and was stronger than ferulic acid and retinol.

[0393] like Fig.13 In the experiment, retinol ferulate had the ability to down-regulate the increase of MMP1 induced by UVA. The ability of retinol ferulate to down-regulate the increase of MMP1 was better than that of retinol.

[0394] (III) The protein level of γH2AX was detected by Western Blot.

[0395] Western Blot protein immunoblotting experiment:

[0396] (1) 3T3 cells were counted at a density of 1 million per well using an automatic cell counter and plated in a six-well plate. The culture medium was discarded after 24 h.

[0397] (2) UVA treatment at a dose of 7 J / cm2 was performed while covering with PBS, and then the PBS was discarded and replaced with complete medium with the test substance;

[0398] (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.

[0399] Experimental results:

[0400] like Fig.14 and 15 In the experiment, retinol ferulate had the ability to reduce the expression of γH2AX induced by UVA. That is, retinol ferulate can repair DNA damage. And the ability of retinol ferulate to repair DNA damage is equivalent to that of retinol.

[0401] Whitening efficacy test

[0402] (I) The cell viability was detected by CCK8 assay on B16 cells to determine the sample concentration required for subsequent experiments.

[0403] CCK8 experiment: 96-well plates were plated at a cell density of 10,000 cells / well, and the cells were treated with drugs after 24 hours of culture. The sample concentrations were set as follows: 1%, 0.5%, 0.1%, 0.05%, and 0.01% (v / v). CCK8 was incubated 24 hours after drug addition. Under light-proof conditions, 10X CCK-8 mother solution (Biyuntian, C0040) was diluted to 1X solution with complete culture medium and the solution was replaced. Incubate in the cell culture incubator for 2 hours, and use an ELISA reader to detect the absorbance at 450nm and 650nm.

[0404] According to the CCK8 toxicity results, such as Fig.16As shown in , retinol ferulate has no cytotoxicity within the dose range of 12.5-200uM. 50uM was selected for subsequent experiments.

[0405] (II) B16 relative melanin content

[0406] 1. Add cells at a concentration of 5×10 5 Cell suspension of 100 cells / mL, 1 mL suspension per well. (The B16 added in this step is grown in 1640 culture medium to ensure that no melanin is produced)

[0407] 2. At 37°C, 5% CO 2 After 24 hours of incubation in the incubator, the culture medium was aspirated, and the plate was washed once with 1 mL of PBS, and then the prepared sample culture medium mixture was added (a filter membrane is required). Three replicate wells are required for each sample. The blank group is 1640 culture medium, and the model group is DMEM culture medium, with three replicate wells.

[0408] 3. After 48 hours of culture, discard the supernatant, wash once with PBS solution, change the solution once, and continue to culture for 24 hours.

[0409] 4. At 72h, wash the plate once with 1mL PBS, then add 500uL trypsin to each well, digest for 2mins, add 1mL DMEM medium to terminate digestion, and then add the cell suspension into a 2mL sterilized EP tube.

[0410] 5. Centrifuge the cell suspension at 1000 rpm for 5 minutes. Then aspirate the supernatant (this step requires aspirating as much residual culture medium as possible)

[0411] 6. Add 1 mL of pBS to each tube, pipette and resuspend, then count using a cell counter while mixing. Record the cell count of each sample.

[0412] 7. Then centrifuge all samples at 4 degrees and 18000rpm 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 aspirating as much residual PBS as possible)

[0413] 8. Add 100uL 1mol / L NaOH (containing 10% DMSO) liquid to each tube, i.e., cell lysis solution, and incubate in 80°C water bath for 1h.

[0414] 9. After fully lysing the cells, use an ELISA reader to measure the absorbance A at 490 nm to obtain the total melanin content.

[0415] Relative melanin content = total melanin content / number of cells (million)

[0416]

[0417] Experimental results:

[0418] like Fig.17 As shown in the figure, in the B16 relative melanin content experiment, the melanin per unit cell was significantly increased in the model group compared with the control group, and significantly decreased when kojic acid was used as a positive control, indicating that the model was successfully established.

[0419] According to the calculation formula, the relative inhibition rate of kojic acid melanin content is 98.5%, retinol is 77.05%, ferulic acid is 25.52%, and retinol ferulate is 82.12%.

[0420] In summary, at a concentration of 50 μM, retinol ferulate has the strongest anti-melanin effect among the four tested substances. Retinol ferulate has the effect of inhibiting melanin production. Retinol ferulate has a better inhibitory effect on melanin than retinol.

[0421] Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without creative work shall fall within the scope of protection of this application.

[0422] A person skilled in the art may modify the technical solutions described in the above embodiments, or make equivalent substitutions for some of the technical features therein; and these modifications or substitutions 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 application.

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; Or 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; Or 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; Or 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; Or the retinol derivative has a structure represented by formula (II), and in formula (II), R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; Or 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, Or 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. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-wrinkle ingredient as claimed in claim 6, 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 use of the retinol derivative or a pharmaceutically acceptable salt thereof as an effective ingredient for stimulating collagen synthesis; 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. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in claim 6 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. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as claimed in claim 6 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. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-acne ingredient as claimed in claim 6, 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. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-inflammatory 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 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. The use of the retinol derivative or a pharmaceutically acceptable salt thereof as an anti-photoaging ingredient as claimed in claim 6, 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.

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