Decarboxylated carnosine derivatives, their preparation methods and applications

Abstract

The present invention relates to a decarboxylated carnosine derivative, a preparation method thereof and an application. The structural formula of the decarboxylated carnosine derivative of the present invention is shown in formula (I), wherein R is selected from: C5-C 21 alkyl group, C5-C 21 unsaturated hydrocarbon group. The decarboxylated carnosine derivative of the present invention has a more excellent anti-glycation effect compared with decarboxylated carnosine; meanwhile, it has good antioxidant effect; and, the decarboxylated carnosine derivative of the present invention has certain lipophilicity, is relatively easy to penetrate through the skin cutin layer, has good skin penetration performance, and has good stability at the same time. It can be used for preparing cosmetics with anti-glycation, antioxidant, anti-skin aging and other functions, and has important market value#imgabs0#(I).

Description

Technical Field

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

[0002] Research shows that excessive intake of refined sugar has certain adverse effects on the skin. 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 finally generate a series of irreversible advanced glycation end products (AGEs). AGEs are closely related to skin aging. AGEs will not only exacerbate oxidative stress and promote the generation of a large amount of reactive oxygen species (ROS), thereby triggering the body's inflammatory response; excessive AGEs will also undergo glycation cross-linking reactions with skin elastic fibers and collagen, directly damaging the skin's homeostasis, and AGEs are brown, ultimately causing the skin to show yellowing, reduced elasticity, resulting in dull skin color, and accelerating the natural aging process of the skin. To solve the problem of skin glycation, anti-glycation has become one of the research hotspots in the cosmetics field, and there is a large market demand for anti-glycation efficacy raw materials.

[0003] Decarboxylated carnosine is a cosmetic efficacy raw material that can effectively scavenge free sugars, and binds to sugars as a protein substitute to protect proteins from cross-linking and prevent the formation of skin AGEs. At the same time, it can also replace the glycated proteins through the glycation reversal mechanism, thereby reducing the generation and accumulation of AGEs. On the other hand, decarboxylated carnosine has the function of capturing hydroxyl radicals, singlet oxygen, and hydrogen peroxide radicals, can effectively protect cells from oxidative damage, and has certain market value. However, the molecular structure of decarboxylated carnosine contains multiple hydrophilic groups, forms hydrogen bonds with water molecules, has high hydrophilicity, and thus is difficult to penetrate the stratum corneum, and the skin utilization rate is low. 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 good skin permeability, and is relatively easy to penetrate the skin stratum corneum.

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

[0006] In the first aspect, the present invention provides a decarboxylated carnosine derivative or its salt, and the structural formula of the decarboxylated carnosine derivative is shown in formula (I):

[0007] ;

[0008] (I)

[0009] Wherein, R is selected from: C5~C21 alkyl group, C5-C 21 unsaturated hydrocarbon group.

[0010] In some embodiments, R is selected from: 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.

[0011] In some embodiments, the decarboxylated carnosine derivative is selected from the following compounds:

[0012] .

[0013] In a second aspect, the present invention provides the use of the decarboxylated carnosine derivative or a salt thereof as an active ingredient in the preparation of an anti-glycation cosmetic.

[0014] In a third aspect, the present invention provides the use of the decarboxylated carnosine derivative or a salt thereof as an active ingredient in the preparation of an antioxidant cosmetic.

[0015] In a fourth aspect, the present invention provides the use of the decarboxylated carnosine derivative or a salt thereof as an active ingredient in the preparation of an anti-skin aging cosmetic.

[0016] In a fifth aspect, the present invention provides a method for preparing the decarboxylated carnosine derivative, comprising the following steps:

[0017] The decarboxylated carnosine dihydrochloride reacts with an acyl halide compound in the presence of a base to obtain the decarboxylated carnosine derivative;

[0018] The structural formula of the acyl halide compound is shown in formula (II):

[0019] ;

[0020] (II)

[0021] wherein, R is selected from: C5-C 21 alkyl group, C5-C 21 unsaturated hydrocarbon group;

[0022] X is selected from: -Cl, -Br.

[0023] In some embodiments, R is selected from: 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.

[0024] In some embodiments, the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and pyridine.

[0025] In some embodiments, the reaction is carried out in an organic solvent, and the organic solvent is preferably selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, N-ethyl-pyrrolidone, and N-butyl-pyrrolidone.

[0026] In some embodiments, the molar ratio of the decarboxylated carnosine dihydrochloride to the acyl halide compound is 1:1 to 1.5, preferably 1:1 to 1.2.

[0027] In some embodiments, the molar ratio of the decarboxylated carnosine dihydrochloride to the base is 1:2 to 6, preferably 1:3 to 5.

[0028] In some embodiments, the temperature of the reaction is -5°C to 50°C, preferably 0°C to 30°C.

[0029] In some embodiments, the reaction time is 4 hours to 10 hours, preferably 6 hours to 8 hours.

[0030] In some embodiments, the method for preparing the decarboxylated carnosine derivative comprises the following steps:

[0031] Dissolve the decarboxylated carnosine dihydrochloride in an organic solvent, add a base, cool down to 0°C to 5°C, add the acyl halide compound, keep the temperature at 0°C to 5°C for 1 to 3 hours, then heat up to 20°C to 30°C and react for another 3 to 7 hours to obtain the decarboxylated carnosine derivative.

[0032] The present invention has the following beneficial effects:

[0033] The decarboxylated carnosine derivatives of the present invention have more excellent anti-glycation effects on the skin compared to decarboxylated carnosine; meanwhile, they have good antioxidant effects on the skin; in particular, preferably myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine are significantly superior to decarboxylated carnosine in both anti-glycation and antioxidant effects.

[0034] Moreover, the decarboxylated carnosine derivatives of the present invention have certain lipophilicity, are relatively easy to penetrate through the skin cutin layer, have good skin permeability, and have good stability at the same time. They can be used to prepare cosmetics with anti-glycation, antioxidant, anti-skin aging effects, etc., and have important market value. Description of the Drawings

[0035] Figure 1 It is a bar chart of the skin penetration amount and skin retention amount of decarboxylated carnosine or its derivatives prepared in Example 4, 6 and Comparative Example 1, 2. Detailed Embodiments

[0036] For the convenience of understanding the present invention, the present invention will be described more comprehensively 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 disclosed content of the present invention more thorough and comprehensive.

[0037] The experimental methods without specific conditions noted in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. All kinds of common chemical reagents used in the examples are commercially available products.

[0038] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not used 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.

[0039] 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 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...".

[0040] The term "alkyl" in the present invention refers to branched and straight-chain saturated aliphatic hydrocarbon groups including those with a specific number of carbon atoms. For example, the definition of "C1-C6 alkyl" in "C1-C6 alkyl" includes groups with 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight chain or a branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0041] The term "unsaturated hydrocarbon group" in the present invention refers to branched and straight-chain unsaturated aliphatic hydrocarbon groups with a specific number of carbon atoms, that is, non-cyclic chain hydrocarbon groups, and the carbon chain contains one or more carbon-carbon double bonds or contains carbon-carbon triple bonds, such as: -(CH2)7(CH=CH)(CH2)7CH3, -(CH2)8(CH=CH)(CH2)5CH3, -(CH2)8(CH=CH)(CH2)7CH3, -(CH2)8(CH=CH)(CH2)9CH3, -(CH2)8(CH=CH)CH2(CH=CH)(CH2)2CH3, -(CH2)8(CH=CH)CH2(CH=CH)(CH2)4CH3, -(CH2)8(CH=CH)CH2(CH=CH)(CH2)6CH3, etc.

[0042] In some of the embodiments, a decarboxylated carnosine derivative is involved, and the structural formula of the decarboxylated carnosine derivative is shown as formula (I):

[0043] ;

[0044] (I)

[0045] Wherein, R is selected from: C5~C 21 alkyl, C5~C 21 unsaturated hydrocarbon group.

[0046] In some of the preferred embodiments, 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 21Alkyl group, C5 unsaturated hydrocarbon group with one or two carbon-carbon double bonds, C6 unsaturated hydrocarbon group with one or two carbon-carbon double bonds, C7 unsaturated hydrocarbon group with one or two carbon-carbon double bonds, C8 unsaturated hydrocarbon group with one or two carbon-carbon double bonds, C9 unsaturated hydrocarbon group with one or two carbon-carbon double bonds, C 10 unsaturated hydrocarbon group, C 11 unsaturated hydrocarbon group, C 12 unsaturated hydrocarbon group, C 13 unsaturated hydrocarbon group, C 14 unsaturated hydrocarbon group, C 15 unsaturated hydrocarbon group, C 16 unsaturated hydrocarbon group, C 17 unsaturated hydrocarbon group, C 18 unsaturated hydrocarbon group, C 19 unsaturated hydrocarbon group, C 20 unsaturated hydrocarbon group, C 21 unsaturated hydrocarbon group; preferably, the unsaturated hydrocarbon group contains one carbon-carbon double bond.

[0047] In some preferred embodiments, R is selected from: 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-henicosyl, 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.

[0048] In some preferred embodiments, the decarboxylated carnosine derivative is selected from the following compounds:

[0049] .

[0050] In some preferred embodiments, the decarboxylated carnosine derivative is selected from .

[0051] The decarboxylated carnosine derivative provided by the present invention can be prepared from decarboxylated carnosine dihydrochloride and the corresponding acyl halide compound according to conventional methods in the art. For example, it can be prepared by the following method:

[0052] The decarboxylated carnosine dihydrochloride and the acyl halide compound react in the presence of a base to obtain the decarboxylated carnosine derivative;

[0053] The structural formula of the acyl halide compound is shown in formula (II):

[0054] ;

[0055] (II)

[0056] Among them, R is selected from: C5-C 21 alkyl, C5-C 21 unsaturated hydrocarbon radical;

[0057] X is selected from: -Cl, -Br.

[0058] In some preferred embodiments, R is selected from: 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.

[0059] In some preferred embodiments, the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and pyridine.

[0060] In some preferred embodiments, the reaction is carried out in an organic solvent, and the organic solvent is preferably selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, N-ethyl-pyrrolidone and N-butyl-pyrrolidone.

[0061] In some preferred embodiments, the molar ratio of the decarboxylated carnosine dihydrochloride to the acyl halide compound is 1:1 to 1.5, preferably 1:1 to 1.2.

[0062] In some preferred embodiments, the molar ratio of the decarboxylated carnosine dihydrochloride to the base is 1:2 to 6, preferably 1:3 to 5.

[0063] In some of the preferred embodiments, the temperature of the reaction is -5°C to 50°C, preferably 0°C to 30°C.

[0064] In some of the preferred embodiments, the reaction time is 4 hours to 10 hours, preferably 6 hours to 8 hours.

[0065] In some of the preferred embodiments, the method for preparing the decarboxylated carnosine derivative comprises the following steps:

[0066] Dissolve the decarboxylated carnosine dihydrochloride in an organic solvent, add a base, cool down to 0°C to 5°C, add an acyl halide compound, keep the temperature at 0°C to 5°C for heat preservation reaction for 1 to 3 hours, then raise the temperature to 20°C to 30°C and react for another 3 to 7 hours to obtain the decarboxylated carnosine derivative.

[0067] In the present invention, the amino group of decarboxylated carnosine reacts with an acyl halide compound, and different hydrocarbon side chains are introduced on the basis of the molecular structure of decarboxylated carnosine to obtain a series of decarboxylated carnosine derivatives modified with hydrocarbon side chains. The decarboxylated carnosine derivatives of the present invention have more excellent anti-glycation effects on the skin compared with decarboxylated carnosine; meanwhile, the decarboxylated carnosine derivatives of the present invention also have an antioxidant effect similar to that of decarboxylated carnosine on the skin; in particular, the preferably myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine are significantly superior to decarboxylated carnosine in both anti-glycation and antioxidant effects.

[0068] Moreover, the decarboxylated carnosine derivatives of the present invention have certain lipophilicity, are relatively easy to penetrate through the skin cutin layer, have good skin penetration performance, and have good stability at the same time, and can be used for preparing cosmetics with anti-glycation, antioxidant, anti-skin aging and other functions, and have important market value.

[0069] In the following examples, room temperature or normal temperature refers to 20°C - 25°C.

[0070] The following further describes the present invention in detail with specific examples.

[0071] Example 1 Synthesis of octanoyl-decarboxylated carnosine

[0072]

[0073] Dissolve decarboxy carnosine dihydrochloride (25.5 g, 0.1 mol) in N,N-dimethylformamide (100 mL), add triethylamine (40.4 g, 0.4 mol), cool down to 0 - 5 °C, dropwise add octanoyl chloride (16.3 g, 0.1 mol), keep the temperature for reaction for 2 hours, raise the temperature to room temperature and react for 5 hours, add dichloromethane (1000 mL) and purified water (500 mL), separate the aqueous layer, wash the dichloromethane layer with saturated brine (200 mL), concentrate to obtain the crude product of octanoyl-decarboxy carnosine, and purify by column chromatography (100% dichloromethane → methanol:dichloromethane = 1:5) to obtain 25.5 g of pure octanoyl-decarboxy carnosine, with a yield of 82.7%. MS-ESI: 309.20[M + 1] + 。

[0074] 1 1H-NMR (500 MHz, CD3OD): δ 7.59 (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).

[0075] Example 2 Synthesis of decanoyl-decarboxy carnosine

[0076]

[0077] React according to the method of Example 1 with decanoyl chloride instead of octanoyl chloride to obtain 28.8 g of decanoyl-decarboxy carnosine, with a yield of 85.5%. MS-ESI: 337.24[M + 1] + 。

[0078] 1 1H-NMR (500 MHz, CD3OD): δ 7.59 (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).

[0079] Example 3 Synthesis of lauroyl-decarboxy carnosine

[0080]

[0081] Using lauroyl chloride instead of octanoyl chloride, the reaction was carried out according to the method of Example 1 to obtain 32.8 g of lauroyl - decarboxylated carnosine, with a yield of 90.0%. MS - ESI: 365.10[M + 1] + 。

[0082] 1 H - NMR (500 MHz, CD3OD): δ 7.59 (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).

[0083] Example 4 Synthesis of myristoyl - decarboxylated carnosine

[0084]

[0085] Using myristoyl chloride instead of octanoyl chloride, the reaction was carried out according to the method of Example 1 to obtain 33.7 g of myristoyl - decarboxylated carnosine, with a yield of 86.0%. MS - ESI: 393.16[M + 1] + 。

[0086] 1 H - NMR (500 MHz, CD3OD): δ 7.59 (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).

[0087] Example 5 Synthesis of palmitoyl - decarboxylated carnosine

[0088]

[0089] Using palmitoyl chloride instead of octanoyl chloride, the reaction was carried out according to the method of Example 1 to obtain 34.9 g of palmitoyl - decarboxylated carnosine, with a yield of 83.0%. MS - ESI: 421.30[M + 1] + 。

[0090] 11H-NMR (500 MHz, CD3OD): δ 7.59 (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).

[0091] Example 6 Synthesis of Oleoyl - Decarboxylated Carnosine

[0092]

[0093] The reaction was carried out according to the method of Example 1 with oleoyl chloride instead of octanoyl chloride, and 35.7 g of oleoyl - decarboxylated carnosine was obtained with a yield of 80.0%. MS - ESI: 447.35 [M + 1] + .

[0094] 1 1H-NMR (500 MHz, CD3OD): δ 7.59 (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).

[0095] Example 7 Synthesis of (2 - Hexyl - Decanoyl) - Decarboxylated Carnosine

[0096]

[0097] The reaction was carried out according to the method of Example 1 with 2 - hexyl - decanoyl chloride instead of octanoyl chloride, and 38.3 g of 2 - hexyl - decanoyl - decarboxylated carnosine was obtained with a yield of 90.0%. MS - ESI: 421.20 [M + 1] + .

[0098] 1 1H-NMR (500 MHz, CD3OD): δ 7.59 (s, 1H), 6.85 (s, 1H), 3.43 - 3.38 (m, 4H), 2.78 - 2.74 (t, 2H), 2.38 - 2.34 (m, 3H), 1.61 - 1.57 (m, 4H), 1.32 - 1.21 (m, 20H), 0.91 - 0.88 (t, 6H).

[0099] Example 8 Hexanoyl - Decarboxylated Carnosine

[0100] ;

[0101] Hexanoyl - decarboxylated carnosine

[0102] 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] + 。

[0103] 1 1H - NMR (500 MHz, CD3OD): δ 7.59 (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).

[0104] Comparative Example 1 Decarboxylated carnosine

[0105]

[0106] Dissolve Boc - β - Ala - OH (18.8 g, 0.1 mol) and histidine dihydrochloride (20.2 g, 0.11 mol) in dichloromethane (500 mL), cool to 0 - 5 °C, add triethylamine (24.5 g, 0.22 mol), HOBt (13.5 g, 0.1 mol) and EDCI (28.8 g, 0.15 mol), allow to warm to room temperature and react for 2 hours. Add 100 mL of water to dissolve, stir for 5 minutes, let stand and separate the aqueous layer. Wash the dichloromethane layer once with saturated sodium carbonate aqueous solution, and concentrate to obtain 22.5 g of Boc - decarboxylated carnosine with a yield of 80%.

[0107] Dissolve Boc - decarboxylated carnosine in 2N HCl in 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] + 。

[0108] 1 1H - NMR (500 MHz, D2O): δ 7.59 (s, 1H), 6.85 (s, 1H), 3.43 - 3.38 (m, 4H), 2.78 - 2.74 (t, 2H), 1.99 (s, 3H).

[0109] Comparative Example 2 Acetyl - decarboxylated carnosine

[0110]

[0111] Dissolve Ac-β-Ala-OH (13.1 g, 0.1 mol) and histidine dihydrochloride (20.2 g, 0.11 mol) in dichloromethane (500 mL). Cool the solution to 0 - 5 °C, add triethylamine (24.5 g, 0.22 mol), HOBt (13.5 g, 0.1 mol), and EDCI (28.8 g, 0.15 mol). Let the reaction mixture warm to room temperature naturally and react for 2 hours. Add 100 mL of water to dissolve, stir for 5 minutes, let it stand, and separate the aqueous layer. Wash the dichloromethane layer once with saturated sodium carbonate aqueous solution, and concentrate to obtain 12.0 g of acetyl-decarboxy carnosine, with a yield of 53.5%. MS-ESI: 225.10[M + 1] + 。

[0112] 1 1H-NMR (500 MHz, D2O): δ 8.61 (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).

[0113] Example 9 Stability Test

[0114] Dissolve the decarboxy carnosine derivatives prepared in Examples 1 - 8 respectively in an aqueous solution containing 5% acetic acid and 20% ethanol to prepare a 0.5% decarboxy carnosine derivative solution. Store the obtained solutions at 25 °C, 40 ± 2 °C, 4 °C, and under 40 °C light conditions (illuminance of 4500 IX ± 500 IX) respectively. Detect the content of the decarboxy carnosine derivatives in each solution at 0 days, 30 days, 60 days, and 90 days. The test results are shown in Table 1.

[0115] Table 1. Stability test results of each decarboxy carnosine derivative under different conditions

[0116] ;

[0117] ;

[0118]

[0119] As can be seen from Table 1, the content of the decarboxy carnosine derivatives prepared in Examples 1 - 8 did not decrease significantly under each storage condition, showing good stability and meeting the actual application requirements in cosmetics.

[0120] Example 10 Anti-glycation Activity Test

[0121] Exogenous aging of human skin includes sun exposure, oxidation, and glycation. Among them, glycation refers to the series of reactions between the free amino groups of macromolecules such as proteins, amino acids, lipids, or nucleic acids and the carbonyl groups of reducing sugars under non-enzymatic conditions, ultimately forming advanced glycation end products (AGEs). Therefore, the anti-glycation activity can be reflected by detecting the level of AGEs inhibited by different compounds. In this example, the glucose-bovine serum albumin model was used to detect the anti-glycation activity of decarboxy carnosine derivatives. The specific steps are as follows:

[0122] Weigh an appropriate amount of glucose and dissolve it in pure water to prepare a 4% glucose working solution; weigh an appropriate amount of bovine serum albumin and dissolve it in pure water to prepare a 4% bovine serum albumin working solution; dissolve the decarboxy carnosine or its derivatives prepared in each example and comparative example with 50% ethanol aqueous solution (containing 4.8 mM citric acid) to prepare a test solution with a concentration of 4.8 mM.

[0123] For the sample group, take 1000 μL of the test solution and add it to an EP tube. For the blank group, add 1000 μL of 50% ethanol aqueous solution (containing 4.8 mM citric acid), and then add 500 μL of glucose working solution and 500 μL of bovine serum albumin working solution to each. React at 60 °C for 48 h. Take 200 μL of the reaction solution at 0 h and 48 h of the reaction, add it to a 96-well black transparent bottom plate, and use an enzyme-linked immunosorbent assay (ELISA) reader to detect the change in the content of AGEs under the fluorescence conditions of 370 nm / 440 nm. Calculate the inhibition rate of AGEs for each group according to formula (1). Set 3 parallel groups for each concentration. The results are shown in Table 2.

[0124] Inhibition rate of AGEs (%) = (1)

[0125] In the formula: C48—Fluorescence value of the blank group at 48 h

[0126] C0—Fluorescence value of the blank group at 0 h

[0127] T48—Fluorescence value of the sample group at 48 h

[0128] T0—Fluorescence value of the sample group at 0 h

[0129] Table 2 Relative inhibition rate of each group on AGEs

[0130]

[0131] As can be seen from Table 2, after modifying the amino group of decarboxy carnosine with a carbon chain, its anti-glycation activity can be improved, and the decarboxy carnosine derivatives with different side chains have different inhibitory abilities on AGEs. Among them, the myristoyl-decarboxy carnosine and oleoyl-decarboxy carnosine prepared in Example 4 and Example 6 have a significantly higher inhibition rate on AGEs than decarboxy carnosine and other examples, which is more than 10 times that of decarboxy carnosine, and their anti-glycation activity is significantly better than that of decarboxy carnosine.

[0132] Example 11 Biochemical method-DPPH free radical scavenging test

[0133] 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.

[0134] DPPH free radical scavenging rate (%) = (2)

[0135] Where: C1—OD value of blank group containing DPPH system

[0136] C2—blank group without DPPH system OD value

[0137] T1—sample group containing DPPH system OD value

[0138] T2—OD value of sample group without DPPH system

[0139] Table 3 Scavenging rate of DPPH free radicals in each group

[0140]

[0141] 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.

[0142] Example 12 Cell method - ROS inhibition test of HaCaT cells under AGEs stimulation

[0143] Dissolve the decarboxylated carnosine or its derivatives prepared in each example and comparative example with 50% aqueous ethanol solution (containing citric acid with the same molar concentration as decarboxylated carnosine or its derivatives) to prepare a sample stock solution. Prepare a complete DMEM medium containing 2% modeling agent (AGEs), and dilute the stock solution with the medium containing the modeling agent to a test solution with a concentration of 40 μM.

[0144] Resuscitate the keratinocytes (HaCaT) stored in liquid nitrogen. After stable culture and passage twice using a complete DMEM medium, inoculate them at 1×10 5 / well into a 96-well plate. Place the plate in an incubator at 37°C and 5% CO2 for 24 h. After the culture, discard the medium in the plate, wash it twice with PBS, then add 100 μL of the test solution to each well in the sample group, add 100 μL of the complete DMEM medium containing an equal amount of the modeling agent to each well in the model group, and add 100 μL of the complete DMEM medium to each well in the blank control group. Place the plate in an incubator at 37°C and 5% CO2 for 24 h.

[0145] Discard the original solution, wash it twice with PBS, add 100 μL of the DCHF-DA working solution to each well, incubate it in an incubator at 37°C and 5% CO2 for 1 h, wash it three times with PBS, 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. Calculate the relative inhibition rate of ROS in each group of cells according to formula (3). Set 3 parallel groups for each concentration. The results are shown in Table 4.

[0146] Relative inhibition rate of ROS (%) = (3)

[0147] In formula (3):

[0148] V e —Average fluorescence value of ROS in the sample group;

[0149] V m —Average fluorescence value of ROS in the model group.

[0150] Table 4 Relative inhibition rate of ROS in HaCaT cells under AGEs stimulation in each group

[0151]

[0152] As can be seen from Table 4, on the cell model, the myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine prepared in Example 4 and Example 6 still showed high ROS inhibitory ability; and the decanoyl-decarboxylated carnosine prepared in Example 2 also showed high ROS inhibitory ability; although Comparative Example 2 also showed certain ability to scavenge DPPH free radicals and inhibit AGEs in biochemical tests, its permeability might be poor, and in the cell model that could reflect both activity and permeability, it showed a low ROS inhibitory effect.

[0153] Skin Permeability Ability Test of Example 13

[0154] The vertical Franz diffusion cell method was used to test the skin permeability ability of the decarboxylated carnosine or its derivatives prepared in Example 4, 6 and Comparative Example 1, 2. Normal saline was selected as the receiving medium, and the skin of suckling pigs with a skin thickness of 0.7 - 0.8 mm was selected for the experiment. The specific operation steps are as follows:

[0155] The pig skin was fixed between the supply pool and the receiving pool. The samples were 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 solutions of the decarboxylated carnosine or its derivatives prepared in Example 4, 6 and Comparative Example 1, 2 were respectively placed in the supply pool. The rotation speed of the rotor in the receiving pool was adjusted to 300 rpm, and the transdermal test was carried out at 32°C. The receiving medium was aspirated from the receiving pool at 12 h, filtered through a 0.22 µm filter membrane, and the content of the active substance was detected by HPLC, and the skin permeation amount in 12 h was calculated.

[0156] The residual samples on the surface of the suckling pig skin were wiped clean with absorbent cotton, the part in contact with the sample was cut out and shredded, and they were respectively put into 2 mL grinding tubes. After grinding with a tissue grinder, 1 mL of ethanol was added, ultrasonically treated for 30 min, centrifuged at 5000 rpm for 15 min, and the supernatant liquid was filtered through a 0.22 µm filter membrane and the content of the active substance was detected by HPLC, and the skin retention amount in 12 h was calculated.

[0157] The liquid phase detection conditions are as follows: chromatographic column C18 (4.6 mm × 250 mm, 5μm), 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, detection wavelength 220 nm.

[0158] The test results are as Figure 1As shown, 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 amounts and lower permeation amounts, indicating that myristoyl-decarboxylated carnosine and oleoyl-decarboxylated carnosine have stronger abilities to penetrate the stratum corneum of the skin, can be effectively retained at the skin target site, and have higher bioavailability.

[0159] The above embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several deformations and improvements can be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the invention patent should be subject to the appended claims.

Claims

1. Use of a decarboxylated carnosine derivative or a salt thereof as an active ingredient in the preparation of an anti-glycation cosmetic, wherein the decarboxylated carnosine derivative is selected from the following compounds: 。 2. Use of a decarboxylated carnosine derivative or a salt thereof as an active ingredient in the preparation of an antioxidant cosmetic, wherein the decarboxylated carnosine derivative is selected from the following compounds: 。 3. Use of the decarboxylated carnosine derivative or a salt thereof as described in claim 1 as an active ingredient in the preparation of an anti-skin aging cosmetic.

4. A decarboxylated carnosine derivative or a salt thereof, characterized in that, The decarboxylated carnosine derivative is selected from the following compounds: 。 5. A method for preparing the decarboxylated carnosine derivative according to claim 4, characterized in that, Comprising the following steps: Reacting decarboxylated carnosine dihydrochloride with an acyl halide compound in the presence of a base to obtain the decarboxylated carnosine derivative; The structural formula of the acyl halide compound is as shown in formula (II): (II) Wherein, R is selected from: n-pentyl, n-heptyl, n-tridecyl, n-pentadecyl, 1-hexyl-nonyl, -(CH2)7(CH=CH)(CH2)7CH3; X is selected from: -Cl, -Br.

6. The preparation method of the decarboxylated carnosine derivative according to claim 5, characterized in that, 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 to 1.5; And / or, the molar ratio of the decarboxylated carnosine dihydrochloride to the base is 1:2 to 6; And / or, the temperature of the reaction is -5°C to 50°C; And / or, the reaction time is 4 hours to 10 hours.

7. The preparation method of the decarboxylated carnosine derivative according to claim 6, characterized in that, The molar ratio of the decarboxylated carnosine dihydrochloride to the acyl halide compound is 1:1 to 1.

2.

8. The preparation method of the decarboxylated carnosine derivative according to claim 6, characterized in that, The molar ratio of the decarboxylated carnosine dihydrochloride to the base is 1:3 to 5.

9. The preparation method of the decarboxylated carnosine derivative according to any one of claims 5-8, characterized in that, The temperature of the reaction is 0°C to 30°C, and the time is 6 hours to 8 hours.

10. The preparation method of the decarboxylated carnosine derivative according to any one of claims 5-8, characterized in that, The preparation method comprises the following steps: Dissolve the decarboxylated carnosine dihydrochloride in an organic solvent, add a base, cool down to 0°C to 5°C, add the acyl halide compound, keep the temperature at 0°C to 5°C for heat preservation reaction for 1 to 3 hours, then heat up to 20°C to 30°C and react for another 3 hours to 7 hours to obtain the decarboxylated carnosine derivative.

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