Decarboxylated carnosine derivative as well as preparation method and application thereof

Abstract

The invention relates to a decarboxylated carnosine derivative as well as a preparation method and application thereof. The structural formula of the decarboxylated carnosine derivative is shown as a formula (I), wherein R is selected from C5-C21 alkyl and C5-C21 unsaturated chain alkyl. Compared with decarboxylated carnosine, the decarboxylated carnosine derivative disclosed by the invention has a more excellent anti-saccharification effect; meanwhile, a relatively good anti-oxidation effect is achieved; moreover, the decarboxylated carnosine derivative disclosed by the invention has certain lipophilicity, is relatively easy to penetrate through a skin cuticle, is good in skin permeability and relatively good in stability, can be used for preparing cosmetics for resisting saccharification, resisting oxidation, resisting skin aging and the like, and has an important market value. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of cosmetics and relates to polypeptide compounds, in particular to a decarboxylated carnosine derivative and a preparation method and application thereof. Background Art

[0002] Studies have shown that excessive intake of refined sugar has a certain degree of adverse effects on the skin, and long-term high-sugar diet will affect the dynamic balance of blood sugar index and glycemic load. Among them, non-enzymatic glycosylation will react with the amino groups at the ends of biological macromolecules such as proteins, nucleic acids, and lipids through reducing sugars, and eventually generate a series of irreversible advanced glycation end products (AGEs). AGEs are closely related to skin aging. AGEs will not only aggravate oxidative stress and promote the generation of a large number of reactive oxygen species (ROS), thereby triggering the body's inflammatory response; excessive AGEs will also undergo glycation and cross-linking reactions with skin elastic fibers and collagen, directly damaging the homeostasis of the skin, and AGEs are brown, which will eventually cause the skin to yellow and reduce elasticity, leading to a dull complexion and accelerating the natural aging process of the skin. In order to solve the problem of skin glycation, anti-glycation has become one of the research hotspots in the field of cosmetics, and there is a large market demand for anti-glycation functional raw materials.

[0003] Decarboxylated carnosine is a cosmetic ingredient that can effectively remove free sugars, and as a protein substitute, it combines with sugar to protect proteins from cross-linking and prevent the formation of skin AGEs. At the same time, it can also replace glycosylated proteins through a glycosylation turnover mechanism, thereby reducing the formation and accumulation of AGEs. On the other hand, decarboxylated carnosine has the function of capturing hydroxyl radicals, elemental oxygen and hydrogen peroxide radicals, which can effectively protect cells from damage by oxidative reactions and has a certain market value. However, the molecular structure of decarboxylated carnosine contains multiple hydrophilic groups, which form hydrogen bonds with water molecules and have a high hydrophilicity. Therefore, it is difficult to penetrate the stratum corneum and has a low skin utilization rate. Summary of the invention

[0004] Based on this, the present invention provides a decarboxylated carnosine derivative with anti-glycation efficacy, which has a good anti-glycation effect on the skin and has good skin permeability and is easier to penetrate the stratum corneum of the skin.

[0005] The present invention includes the following technical solutions.

[0006] In the first aspect, the present invention provides a decarboxylated carnosine derivative or a salt thereof, wherein the structural formula of the decarboxylated carnosine derivative is shown in formula (I): ; (I) Wherein, R is selected from: C 5 ~C 21 Alkyl, C 5 ~C21 Unsaturated chain hydrocarbon group.

[0007] In some embodiments, R is selected from the group consisting of n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, n-heneicosyl, 1-hexyl-nonyl, -(CH 2 ) 8 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 7 (CH=CH)(CH 2 ) 7 CH 3 、-(CH 2 ) 9 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 8 (CH=CH)(CH 2 ) 7 CH 3 .

[0008] In some embodiments, the decarboxylated carnosine derivative is selected from the following compounds: .

[0009] In a second aspect, the present invention provides the use of the decarboxylated carnosine derivative or a salt thereof as an effective ingredient in the preparation of anti-glycation cosmetics.

[0010] In a third aspect, the present invention provides the use of the decarboxylated carnosine derivative or its salt as an effective ingredient in the preparation of antioxidant cosmetics.

[0011] In a fourth aspect, the present invention provides the use of the decarboxylated carnosine derivative or a salt thereof as an effective ingredient in the preparation of anti-skin aging cosmetics.

[0012] In a fifth aspect, the present invention provides a method for preparing the decarboxylated carnosine derivative, comprising the steps of: Decarboxylated carnosine dihydrochloride and an acyl halide compound react in the presence of a base to obtain the decarboxylated carnosine derivative; The structural formula of the acyl halide compound is shown in formula (II): ; (II) Wherein, R is selected from: C5 ~C 21 Alkyl, C 5 ~C 21 Unsaturated chain hydrocarbon group; X is selected from: -Cl, -Br.

[0013] In some embodiments, R is selected from the group consisting of n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, n-heneicosyl, 1-hexyl-nonyl, -(CH 2 ) 8 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 7 (CH=CH)(CH 2 ) 7 CH 3 、-(CH 2 ) 9 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 8 (CH=CH)(CH 2 ) 7 CH 3 .

[0014] In some embodiments, the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and pyridine.

[0015] In some embodiments, the reaction is carried out in an organic solvent, and the organic solvent is preferably one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, N-ethyl-pyrrolidone and N-butyl-pyrrolidone.

[0016] In some embodiments, the molar ratio of decarboxylated carnosine dihydrochloride to the acyl halide compound is 1:1-1.5, preferably 1:1-1.2.

[0017] In some embodiments, the molar ratio of decarboxylated carnosine dihydrochloride to base is 1:2-6, preferably 1:3-5.

[0018] In some embodiments, the reaction temperature is -5°C to 50°C, preferably 0°C to 30°C.

[0019] In some embodiments, the reaction time is 4 hours to 10 hours, preferably 6 hours to 8 hours.

[0020] In some embodiments, the preparation method of the decarboxylated carnosine derivative comprises the steps of: The decarboxylated carnosine dihydrochloride is dissolved in an organic solvent, a base is added, the temperature is lowered to 0°C-5°C, an acyl halide compound is added, the temperature is kept at 0°C-5°C for 1-3 hours, the temperature is raised to 20°C-30°C and the temperature is further reacted for 3 hours-7 hours to obtain the decarboxylated carnosine derivative.

[0021] The present invention has the following beneficial effects: The decarboxylated carnosine derivatives of the present invention have a more excellent anti-glycation effect on the skin than decarboxylated carnosine; at the same time, they have a better anti-oxidation effect on the skin; in particular, the preferred myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine are significantly better than decarboxylated carnosine in both anti-glycation and anti-oxidation effects.

[0022] In addition, the decarboxylated carnosine derivative of the present invention has certain lipophilicity, is easier to penetrate the stratum corneum of the skin, has good skin permeability, and has good stability. It can be used to prepare anti-glycation, anti-oxidation, anti-skin aging and other cosmetics, and has important market value. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The following is a bar graph showing the skin permeation and skin retention of decarboxylated carnosine or its derivatives prepared in Examples 4 and 6 and Comparative Examples 1 and 2. DETAILED DESCRIPTION

[0024] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0025] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0026] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0027] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0028] The term "alkyl" of the present invention refers to a saturated aliphatic hydrocarbon group including branched and straight chains having a specific number of carbon atoms. 1 -C 6 "C" in "alkyl" 1 -C 6 The definition of " includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain. For example: "C 1 -C 6 The "alkyl group" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl and hexyl.

[0029] The term "unsaturated chain hydrocarbon group" of the present invention refers to a branched or straight chain unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms, i.e., a non-cyclic chain hydrocarbon group, and the carbon chain contains one or more carbon-carbon double bonds, or a carbon-carbon triple bond, such as: -(CH 2 ) 7 (CH=CH)(CH 2 ) 7 CH 3 ,-(CH 2 ) 8 (CH=CH)(CH 2 ) 5 CH 3 ,-(CH 2 ) 8 (CH=CH)(CH 2 ) 7 CH 3 ,-(CH 2 ) 8 (CH=CH)(CH 2 ) 9 CH 3 ,-(CH 2 ) 8 (CH=CH)CH 2 (CH=CH)(CH 2 ) 2 CH 3 ,-(CH 2 ) 8 (CH=CH)CH2 (CH=CH)(CH 2 ) 4 CH 3 ,-(CH 2 ) 8 (CH=CH)CH 2 (CH=CH)(CH 2 ) 6 CH 3 wait.

[0030] Some of the embodiments involve a decarboxylated carnosine derivative, the structural formula of which is shown in formula (I): ; (I) Wherein, R is selected from: C 5 ~C 21 Alkyl, C 5 ~C 21 Unsaturated chain hydrocarbon group.

[0031] In some preferred embodiments, R is selected from: 5 Alkyl, C 6 Alkyl, C 7 Alkyl, C 8 Alkyl, C 9 Alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl, C 21 Alkyl, C containing one or two carbon-carbon double bonds 5 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 6 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 7 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 8 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 9 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 10 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 11 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 12 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 13Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 14 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 15 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 16 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 17 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 18 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 19 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 20 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 21 Unsaturated chain hydrocarbon group; the unsaturated chain hydrocarbon group preferably contains one carbon-carbon double bond.

[0032] In some preferred embodiments, R is selected from the group consisting of n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, n-heneicosyl, 1-hexyl-nonyl, -(CH 2 ) 8 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 7 (CH=CH)(CH 2 ) 7 CH 3 、-(CH 2 ) 9 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 8 (CH=CH)(CH 2 ) 7 CH 3 .

[0033] In some preferred embodiments, the decarboxylated carnosine derivative is selected from the following compounds: .

[0034] In some preferred embodiments, the decarboxylated carnosine derivative is selected from .

[0035] The decarboxylated carnosine derivative provided by the present invention can be prepared by decarboxylated carnosine dihydrochloride and a corresponding acyl halide compound according to a conventional method in the art, for example, by the following method: Decarboxylated carnosine dihydrochloride and an acyl halide compound react in the presence of a base to obtain the decarboxylated carnosine derivative; The structural formula of the acyl halide compound is shown in formula (II): ; (II) Wherein, R is selected from: C 5 ~C 21 Alkyl, C 5 ~C 21 Unsaturated chain hydrocarbon group; X is selected from: -Cl, -Br.

[0036] In some preferred embodiments, R is selected from the group consisting of n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, n-heneicosyl, 1-hexyl-nonyl, -(CH 2 ) 8 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 7 (CH=CH)(CH 2 ) 7 CH 3 、-(CH 2 ) 9 (CH=CH)(CH 2 ) 5 CH 3 、-(CH 2 ) 8 (CH=CH)(CH 2 ) 7 CH 3 .

[0037] In some preferred embodiments, the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and pyridine.

[0038] In some preferred embodiments, the reaction is carried out in an organic solvent, and the organic solvent is preferably at least one selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, N-ethyl-pyrrolidone and N-butyl-pyrrolidone.

[0039] In some preferred embodiments, the molar ratio of decarboxylated carnosine dihydrochloride to the acyl halide compound is 1:1-1.5, preferably 1:1-1.2.

[0040] In some preferred embodiments, the molar ratio of decarboxylated carnosine dihydrochloride to base is 1:2-6, preferably 1:3-5.

[0041] In some preferred embodiments, the reaction temperature is -5°C to 50°C, preferably 0°C to 30°C.

[0042] In some preferred embodiments, the reaction time is 4 hours to 10 hours, preferably 6 hours to 8 hours.

[0043] In some preferred embodiments, the preparation method of the decarboxylated carnosine derivative comprises the steps: The decarboxylated carnosine dihydrochloride is dissolved in an organic solvent, a base is added, the temperature is lowered to 0°C-5°C, an acyl halide compound is added, the temperature is kept at 0°C-5°C for 1-3 hours, the temperature is raised to 20°C-30°C and the temperature is further reacted for 3 hours-7 hours to obtain the decarboxylated carnosine derivative.

[0044] The invention relates to a series of decarboxylated carnosine derivatives modified with hydrocarbon side chains, by reacting the amino group of decarboxylated carnosine with an acyl halide compound, and inserting different hydrocarbon side chains on the basis of the molecular structure of decarboxylated carnosine. The decarboxylated carnosine derivatives of the invention have a more excellent anti-glycation effect on the skin than decarboxylated carnosine; at the same time, the decarboxylated carnosine derivatives of the invention also have an antioxidant effect on the skin similar to that of decarboxylated carnosine; in particular, the preferred myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine are significantly superior to decarboxylated carnosine in both anti-glycation and antioxidant effects.

[0045] In addition, the decarboxylated carnosine derivative of the present invention has certain lipophilicity, is easier to penetrate the stratum corneum of the skin, has good skin permeability, and has good stability. It can be used to prepare anti-glycation, anti-oxidation, anti-skin aging and other cosmetics, and has important market value.

[0046] In the following examples, room temperature or normal temperature refers to 20°C-25°C.

[0047] The present invention is further described in detail below with reference to specific embodiments.

[0048] Example 1 Synthesis of Octanoyl-Decarboxylated Carnosine

[0049] Dissolve decarboxylated carnosine dihydrochloride (25.5 g, 0.1 mol) in N,N-dimethylformamide (100 mL), add triethylamine (40.4 g, 0.4 mol), cool to 0-5 °C, add octanoyl chloride (16.3 g, 0.1 mol), keep warm for 2 hours, warm to room temperature for 5 hours, add dichloromethane (1000 mL) and purified water (500 mL), separate the water layer, wash the dichloromethane layer with saturated brine (200 mL), concentrate to obtain crude octanoyl-decarboxylated carnosine, purify by column chromatography (100% dichloromethane → methanol: dichloromethane = 1:5) to obtain 25.5 g of pure octanoyl-decarboxylated carnosine, with a yield of 82.7%. MS-ESI: 309.20 [M+1] + .

[0050] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 ( t, 2H), 2.16-2.13 (t, 2H), 1.59-1.57 (m, 2H), 1.32-1.21 (m, 8H), 0.91-0.88 (t, 3H).

[0051] Example 2 Synthesis of decanoyl-decarboxylated carnosine

[0052] The reaction was carried out according to the method of Example 1 using decanoyl chloride instead of octanoyl chloride to obtain 28.8 g of decanoyl-decarboxylated carnosine with a yield of 85.5%. MS-ESI: 337.24 [M+1] + .

[0053] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 (t , 2H), 2.16-2.13 (t, 2H), 1.59-1.57 (m, 2H), 1.32-1.21 (m, 12H), 0.91-0.88 (t, 3H).

[0054] Example 3 Synthesis of lauroyl-decarboxylated carnosine

[0055] The reaction was carried out according to the method of Example 1 using lauroyl chloride instead of octanoyl chloride to obtain 32.8 g of lauroyl-decarboxylated carnosine with a yield of 90.0%. MS-ESI: 365.10[M+1] + .

[0056] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 (t , 2H), 2.16-2.13 (t, 2H), 1.59-1.57 (m, 2H), 1.32-1.21 (m, 16H), 0.91-0.88 (t, 3H).

[0057] Example 4 Synthesis of Myristoyl-Decarboxylated Carnosine

[0058] The reaction was carried out according to the method of Example 1 using myristoyl chloride instead of octanoyl chloride to obtain 33.7 g of myristoyl-decarboxylated carnosine with a yield of 86.0%. MS-ESI: 393.16 [M+1] + .

[0059] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 (t , 2H), 2.16-2.13 (t, 2H), 1.59-1.57 (m, 2H), 1.32-1.21 (m, 20H), 0.91-0.88 (t, 3H).

[0060] Example 5 Synthesis of palmitoyl-decarboxylated carnosine

[0061] The reaction was carried out according to the method of Example 1 using palmitoyl chloride instead of octanoyl chloride to obtain 34.9 g of palmitoyl-decarboxylated carnosine with a yield of 83.0%. MS-ESI: 421.30 [M+1] + .

[0062] 1 H-NMR (500 MHz, CD 3OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 (t , 2H), 2.16-2.13 (t, 2H), 1.59-1.57 (m, 2H), 1.32-1.21 (m, 24H), 0.91-0.88 (t, 3H).

[0063] Example 6 Synthesis of oleoyl-decarboxylated carnosine

[0064] The reaction was carried out according to the method of Example 1 using oleoyl chloride instead of octanoyl chloride to obtain 35.7 g of oleoyl-decarboxylated carnosine with a yield of 80.0%. MS-ESI: 447.35[M+1] + .

[0065] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 5.23-5.25 (m, 2H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 (t , 2H), 2.16-2.13 (t, 2H), 1.80-1.85 (m, 4H), 1.59-1.57 (m, 2H), 1.32-1.21 (m, 20H), 0.91-0.88 (t, 3H).

[0066] Example 7 Synthesis of (2-hexyl-decanoyl)-decarboxylated carnosine

[0067] The reaction was carried out according to the method of Example 1 using 2-hexyl-decanoyl chloride instead of octanoyl chloride to obtain 38.3 g of 2-hexyl-decanoyl-decarboxylated carnosine with a yield of 90.0%. MS-ESI: 421.20 [M+1] + .

[0068] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.3 8-2.34 (m, 3H), 1.61-1.57 (m, 4H), 1.32-1.21 (m, 20H), 0.91-0.88 (t, 6H).

[0069] Example 8 Hexanoyl-decarboxylated carnosine ; Hexanoyl-decarboxylated carnosine The reaction was carried out according to the method of Example 1 using hexanoyl chloride instead of octanoyl chloride to obtain 19.6 g of hexanoyl-decarboxylated carnosine with a yield of 70%. MS-ESI: 281.10 [M+1] + .

[0070] 1 H-NMR (500 MHz, CD 3 OD): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 2.38-2.34 ( t, 2H), 2.16-2.13 (t, 2H), 1.59-1.57 (m, 2H), 1.35-1.21 (m, 4H), 0.91-0.88 (t, 3H).

[0071] Comparative Example 1 Decarboxylated carnosine

[0072] Boc-β-Ala-OH (18.8 g, 0.1 mol) and histamine dihydrochloride (20.2 g, 0.11 mol) were dissolved in dichloromethane (500 mL), cooled to 0-5°C, triethylamine (24.5 g, 0.22 mol), HOBt (13.5 g, 0.1 mol) and EDCI (28.8 g, 0.15 mol) were added, and the temperature was naturally raised to room temperature for 2 hours. 100 mL of water was added to dissolve, stirred for 5 minutes, and allowed to stand to separate the water layer. The dichloromethane layer was washed once with a saturated sodium carbonate aqueous solution and concentrated to obtain 22.5 g of Boc-decarboxylated carnosine with a yield of 80%.

[0073] Dissolve Boc-decarboxylated carnosine in 2N HCl tetrahydrofuran solution, react at room temperature for 2 hours, and concentrate to obtain 20.4 g of white solid decarboxylated carnosine dihydrochloride, with a yield of 100%. MS-ESI: 183.12[M+1] + .

[0074] 1 H-NMR (500 MHz, D 2 O): δ7.59 (s, 1H), 6.85 (s, 1H), 3.43-3.38 (m, 4H), 2.78-2.74 (t, 2H), 1.99 (s, 3H).

[0075] Comparative Example 2 Acetyl-decarboxylated carnosine

[0076] Ac-β-Ala-OH (13.1 g, 0.1 mol) and histamine dihydrochloride (20.2 g, 0.11 mol) were dissolved in dichloromethane (500 mL), cooled to 0-5 °C, triethylamine (24.5 g, 0.22 mol), HOBt (13.5 g, 0.1 mol) and EDCI (28.8 g, 0.15 mol) were added, and the mixture was naturally heated to room temperature for 2 hours, 100 mL of water was added to dissolve, stirred for 5 minutes, and the water layer was separated by standing. The dichloromethane layer was washed once with a saturated sodium carbonate aqueous solution and concentrated to obtain 12.0 g of acetyl-decarboxylated carnosine, with a yield of 53.5%. MS-ESI: 225.10 [M+1] + .

[0077] 1 H-NMR (500 MHz, D 2 O): δ8.61 (s, 1H), 7.30 (s, 1H), 3.53-3.50 (t, 4H), 3.30-3.10 (t, 2H), 3.00-2.97 (t, 3H), 2.67-2.63 (t, 2H).

[0078] Example 9 Stability Test The decarboxylated carnosine derivatives prepared in Examples 1 to 8 were respectively dissolved in an aqueous solution containing 5% acetic acid and 20% ethanol to prepare a decarboxylated carnosine derivative solution with a concentration of 0.5%. The resulting solutions were stored under lighting conditions of 25° C., 40±2° C., 4° C. and 40° C. (illuminance of 4500IX±500IX), respectively. The content of the decarboxylated carnosine derivative in each solution was detected at 0 day, 30 days, 60 days and 90 days. The test results are shown in Table 1.

[0079] Table 1. Stability test results of decarboxylated carnosine derivatives under different conditions ; ;

[0080] It can be seen from Table 1 that the decarboxylated carnosine derivatives prepared in Examples 1 to 8 have no significant decrease in content under various storage conditions, have good stability, and meet the actual application requirements in cosmetics.

[0081] Example 10 Anti-glycation activity test Exogenous aging of human skin includes sun exposure, oxidation and glycation, where glycation refers to the formation of advanced glycation end products (AGEs) through a series of reactions between free amino groups of macromolecules such as proteins, amino acids, lipids or nucleic acids and carbonyl groups of reducing sugars under non-enzymatic conditions. Therefore, the anti-glycation activity of different compounds can be reflected by detecting the level of inhibition of AGEs. In this example, the anti-glycation activity of decarboxylated carnosine derivatives was detected using a glucose-bovine serum albumin model. The specific steps are as follows: Weigh an appropriate amount of glucose and dissolve it in pure water to prepare a glucose working solution with a concentration of 4%; weigh an appropriate amount of bovine serum albumin and dissolve it in pure water to prepare a bovine serum albumin working solution with a concentration of 4%; dissolve the decarboxylated carnosine or its derivatives prepared in each embodiment and comparative example in 50% ethanol aqueous solution (containing 4.8 mM citric acid) to prepare a test solution with a concentration of 4.8 mM.

[0082] 1000 μL of the test solution was added to the EP tube in the sample group, and 1000 μL of 50% ethanol aqueous solution (containing 4.8 mM citric acid) was added to the blank group, and then 500 μL of glucose working solution and 500 μL of bovine serum albumin working solution were added. The reaction was carried out at 60°C for 48 hours. 200 μL of the reaction solution was taken at 0 h and 48 h of the reaction and added to a 96-well black transparent bottom plate. The changes in the content of AGEs under the fluorescence conditions of 370 nm / 440 nm were detected using an ELISA instrument, and the inhibition rate of AGEs in each group was calculated according to formula (1). Three parallel groups were set for each concentration. The results are shown in Table 2.

[0083] AGEs inhibition rate (%) = (1) Where: C48—48h fluorescence value of blank group C0—Blank group 0h fluorescence value T48—48h fluorescence value of sample group T0—fluorescence value of sample group 0h Table 2 Relative inhibition rate of each group on AGEs

[0084] As shown in Table 2, the anti-glycation activity of decarboxylated carnosine can be improved after the amino group of decarboxylated carnosine is modified with a carbon chain, and the inhibitory ability of decarboxylated carnosine derivatives with different side chains on AGEs is different. Among them, the inhibition rate of myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine prepared in Example 4 and Example 6 on AGEs is significantly higher than that of decarboxylated carnosine and other examples, which is more than 10 times that of decarboxylated carnosine, and its anti-glycation activity is significantly better than that of decarboxylated carnosine.

[0085] Example 11 Biochemical method-DPPH free radical scavenging test Weigh 3.9 mg of DPPH, dissolve it in an appropriate amount of anhydrous ethanol, and dissolve it completely in the dark by ultrasound. Use anhydrous ethanol to make it dilute to 100 mL to prepare a DPPH working solution with a concentration of 0.1 mmol / L. Decarboxylated carnosine or its derivatives prepared in each embodiment and comparative example are prepared into a test solution with a concentration of 24 mM, and the solvent is a 50% ethanol aqueous solution (containing citric acid in an equal molar concentration). In a 96-well plate, 50 μL of the test solution is first added to the sample group, 50 μL of the solvent is added to the blank group, and then 200 μL of DPPH working solution is added to each. A background group (DPPH working solution is replaced with an equal amount of ethanol) is set up and mixed. The reaction is carried out at room temperature and in the dark for 1 h. The absorbance of each group at a wavelength of 517 nm is detected by an ELISA instrument. The DPPH free radical scavenging rate is calculated according to the absorbance according to formula (2). Three replicates are set for each concentration. The results are shown in Table 3.

[0086] DPPH free radical scavenging rate (%) = (2) Where: C1—OD value of blank group containing DPPH system C2—blank group without DPPH system OD value T1—sample group containing DPPH system OD value T2—OD value of sample group without DPPH system Table 3 Scavenging rate of DPPH free radicals in each group

[0087] As can be seen from Table 3, the decarboxylated carnosine derivatives with different side chains have different scavenging abilities for DPPH free radicals. At a concentration of 24 mM, the myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine prepared in Examples 4 and 6 have significantly better scavenging abilities for DPPH free radicals than other examples and comparative examples, indicating that the introduction of myristoyl side chains and oleoyl side chains can significantly improve the antioxidant activity of decarboxylated carnosine.

[0088] Example 12 Cell method - ROS inhibition test of HaCaT cells under AGEs stimulation The decarboxylated carnosine or its derivatives prepared in each example and comparative example were dissolved in 50% anhydrous ethanol aqueous solution (containing citric acid in an equimolar concentration to decarboxylated carnosine or its derivatives) to prepare a sample stock solution. A DMEM complete medium containing 2% modeling agent (AGEs) was prepared, and the stock solution was diluted with the medium containing the modeling agent to a concentration of 40 μM of the test solution.

[0089] HaCaT cells stored in liquid nitrogen were revived and cultured twice in DMEM complete medium. 5 The wells were inoculated into 96-well plates and placed in a 37°C, 5% CO 2Culture in the incubator for 24 h. After the culture, discard the culture medium in the well plate, wash twice with PBS, then add 100 μL of the test solution to each well of the sample group, add 100 μL of DMEM complete culture medium containing an equal amount of modeling agent to each well of the model group, and add 100 μL of DMEM complete culture medium to each well of the blank control group. Place the well plate at 37°C and 5% CO 2 Culture in an incubator for 24 h.

[0090] The stock solution was discarded, and the cells were washed twice with PBS. 100 μL DCHF-DA working solution was added to each well and incubated at 37°C with 5% CO 2 Incubate in the incubator for 1 h, wash with PBS three times, and use a fluorescence microplate reader to detect the fluorescence value of each well at an excitation wavelength of 488 nm and an emission wavelength of 525 nm. The relative inhibition rate of ROS in each group of cells was calculated according to formula (3). Three parallel groups were set for each concentration. The results are shown in Table 4.

[0091] ROS relative inhibition rate (%) = (3) In formula (3): V e —Average fluorescence value of ROS in sample group; V m —Average fluorescence value of ROS in the model group.

[0092] Table 4 Relative inhibition rate of each group on cellular ROS in HaCaT cells stimulated by AGEs

[0093] As can be seen from Table 4, in the cell model, the myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine prepared in Examples 4 and 6 still exhibited a relatively high ROS inhibition ability; and the decanoyl-decarboxylated carnosine prepared in Example 2 also exhibited a relatively high ROS inhibition ability; and although Comparative Example 2 also exhibited a certain ability to scavenge DPPH free radicals and inhibit AGEs in the biochemical test, it may have poor permeability, and in the cell model that can simultaneously exhibit activity and permeability, it exhibited a relatively low ROS inhibition effect.

[0094] Example 13 Skin penetration test The skin permeability of decarboxylated carnosine or its derivatives prepared in Examples 4 and 6 and Comparative Examples 1 and 2 was tested by a vertical Franz diffusion cell method. Physiological saline was used as the receiving medium, and piglet skin with a skin thickness of 0.7 to 0.8 mm was used for the experiment. The specific operation steps are as follows: The pig skin was fixed between the supply tank and the receiving tank. The sample was dissolved in an aqueous solution containing 10% butanol, 5% Tween 80 and 0.01% citric acid. The final concentration of the sample solution was 0.5%. 0.5±0.01 mL of the sample solution of decarboxylated carnosine or its derivatives prepared in Examples 4 and 6 and Comparative Examples 1 and 2 were respectively placed in the supply tank. The rotor speed in the receiving tank was adjusted to 300 rpm, and the permeation test was carried out at 32°C. The receiving medium was absorbed from the receiving tank at 12 h, filtered through a 0.22 µm filter membrane, and the active substance content was detected by HPLC, and the 12 h skin permeation amount was calculated.

[0095] Wipe the sample remaining on the surface of the suckling pig skin with absorbent cotton, cut out the part in contact with the sample and cut into pieces, put them into 2 mL grinding tubes respectively, grind them with a tissue grinder, add 1 mL of ethanol, ultrasonicate for 30 min, centrifuge at 5000 rpm for 15 min, take the supernatant and filter it through a 0.22 µm filter membrane, detect the active ingredient content by HPLC, and calculate the 12 h skin retention amount.

[0096] The liquid phase detection conditions were as follows: chromatographic column C18 (4.6 mm × 250 mm, 5 μm), flow rate 1.0 mL / min, column temperature 35 °C, mobile phase A: 0.1% TFA water, mobile phase B: 0.1% TFA acetonitrile, gradient elution, and detection wavelength 220 nm.

[0097] Test results such as Figure 1 As shown in the figure, compared with Comparative Examples 1 and 2, the myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine prepared in Examples 4 and 6 have higher skin retention and lower penetration, indicating that myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine have stronger ability to penetrate the stratum corneum of the skin, can be effectively retained in the target part of the skin, and have higher bioavailability.

[0098] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Use of a decarboxylated carnosine derivative or a salt thereof as an effective ingredient in the preparation of anti-glycation cosmetics, wherein the structural formula of the decarboxylated carnosine derivative is as shown in formula (I): ； （I） in, R is selected from: C5~C 21 Alkyl, C5~C 21 Unsaturated chain hydrocarbon group.

2. The use according to claim 1, characterized in that: R is selected from: C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl, C 21 alkyl, C5 unsaturated chain hydrocarbon group containing one or two carbon-carbon double bonds, C6 unsaturated chain hydrocarbon group containing one or two carbon-carbon double bonds, C7 unsaturated chain hydrocarbon group containing one or two carbon-carbon double bonds, C8 unsaturated chain hydrocarbon group containing one or two carbon-carbon double bonds, C9 unsaturated chain hydrocarbon group containing one or two carbon-carbon double bonds, C 10 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 11 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 12 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 13 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 14 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 15 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 16 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 17 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 18 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 19 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 20 Unsaturated chain hydrocarbon group, C containing one or two carbon-carbon double bonds 21 Unsaturated chain hydrocarbon group.

3. The use according to claim 1, characterized in that: R is selected from the group consisting of: n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, n-heneicosyl, 1-hexyl-nonyl, -(CH2)8(CH=CH)(CH2)5CH3, -(CH2)7(CH=CH)(CH2)7CH3, -(CH2)9(CH=CH)(CH2)5CH3, -(CH2)8(CH=CH)(CH2)7CH3.

4. The use according to claim 1, characterized in that: The decarboxylated carnosine derivative is selected from the following compounds: 。 5. Use of the decarboxylated carnosine derivative or its salt described in any one of claims 1 to 4 as an effective ingredient in the preparation of antioxidant cosmetics.

6. Use of the decarboxylated carnosine derivative or its salt as claimed in any one of claims 1 to 4 in the preparation of cosmetics for resisting skin aging as an effective ingredient.

7. The decarboxylated carnosine derivative or a salt thereof according to any one of claims 1 to 4.

8. A method for preparing a decarboxylated carnosine derivative according to claim 7, characterized in that: The steps include: Decarboxylated carnosine dihydrochloride and an acyl halide compound react in the presence of a base to obtain the decarboxylated carnosine derivative; The structural formula of the acyl halide compound is shown in formula (II): ； (II) Wherein, R is as described in any one of claims 1 to 4; X is selected from: -Cl, -Br.

9. The method for preparing a decarboxylated carnosine derivative according to claim 8, wherein The base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and pyridine; And / or, the reaction is carried out in an organic solvent, and the organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, N-ethyl-pyrrolidone and N-butyl-pyrrolidone; And / or, the molar ratio of the decarboxylated carnosine dihydrochloride to the acyl halide compound is 1:1-1.5; And / or, the molar ratio of decarboxylated carnosine dihydrochloride to the base is 1:2-6; And / or, the reaction temperature is -5°C to 50°C; And / or, the reaction time is 4 hours to 10 hours.

10. The method for preparing a decarboxylated carnosine derivative according to claim 8 or 9, characterized in that: The preparation method comprises the following steps: The decarboxylated carnosine dihydrochloride is dissolved in an organic solvent, a base is added, the temperature is lowered to 0°C-5°C, an acyl halide compound is added, the temperature is kept at 0°C-5°C for 1-3 hours, the temperature is raised to 20°C-30°C and the temperature is further reacted for 3 hours-7 hours to obtain the decarboxylated carnosine derivative.

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