Pyroglutamic acid-tetrapeptide-7 derivatives and uses thereof

Abstract

The application discloses derivatives of pyroglutamic acid-tetrapeptide-7 and application thereof. The derivatives of pyroglutamic acid-tetrapeptide-7 or pharmaceutically acceptable salts thereof have the following structure: the substituent R is selected from the group consisting of. The derivatives of pyroglutamic acid-tetrapeptide-7 have excellent effects of anti-inflammation, promoting synthesis of collagen and / or elastin, reducing wrinkle area or wrinkle degree, and have a smaller effective concentration compared with tetrapeptide-7, and can be applied to medicines, cosmetics or skin care products as main active ingredients.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemistry, biotechnology, daily chemical products, and specifically relates to a kind of tetrapeptide-7 derivative and its application. BACKGROUND

[0002] Inflammation of skin and ultraviolet radiation can cause increased expression of interleukins, thereby forming skin inflammation, leading to degradation of collagen and elastin, and further making the skin loose, wrinkled and uneven in color.

[0003] Tetrapeptide-7 (Palmitoyl Tetrapeptide-7) is a kind of cell messenger peptide linked by four amino acids with peptide bond, which inhibits the production of excessive interleukins by macrophages through signal stimulation, and inhibits the production of inflammation. At the same time, it can also stimulate dermal cells to increase the synthesis of collagen and elastin, thereby achieving the effect of lightening wrinkles and tightening skin.

[0004] Chinese patent document CN114869796A discloses a whitening and skin lightening repair composition containing active polypeptides, which comprises: an active polypeptide complex, and a functional active substance; the active polypeptide complex includes but is not limited to antioxidant polypeptides, inflammation factor release inhibiting polypeptides, collagen supplementing polypeptides, and skin lightening polypeptides; the inflammation factor release inhibiting polypeptides include palmitoyl tetrapeptide-7, and the functional active substance includes but is not limited to one or more of isoferulic acid and isoferulic acid amide derivatives. Although the composition has multiple skin repair effects, since it is a compounded composition, the allocation ratio of each component may differ between batches during production of the finished product, which may lead to differences in the effects of the finished product and may also affect the stability of the formula. SUMMARY

[0005] The present application provides a kind of tetrapeptide-7 derivative, which screens several derivatives with more excellent anti-inflammatory and anti-wrinkle effects than tetrapeptide-7 by changing the N-terminal modifier of glycine or arginine in tetrapeptide-7, has a smaller effective concentration than tetrapeptide-7, can inhibit the formation of wrinkles, improve skin elasticity, and can be used as a main active ingredient in pharmaceuticals, cosmetics or skin care products.

[0006] The specific technical solutions of the present application are as follows:

[0007] The tetrapeptide-7 derivative has the following structure:

[0008] or , wherein the substituent R in formula I or formula II is selected from , , , or .

[0009] Another object of the present application provides a salt of the derivative of tetrapeptide-7 with an acid or a base, the acid is an organic acid or an inorganic acid salt, the organic acid is selected from one or more of acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoic acid or gluconic acid; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, boric acid or carbonic acid; the base is an inorganic base or an organic base, the inorganic base is an inorganic basic substance containing lithium, sodium, potassium, calcium, magnesium, manganese, copper, iron, zinc or aluminum ions; the organic base is selected from one or more of ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine.

[0010] Another object of the present application is to provide the use of the derivative of tetrapeptide-7 or a salt thereof in the preparation of an anti-inflammatory, collagen and / or elastin production promoting drug or a daily chemical product. The derivative of tetrapeptide-7 or a salt thereof can inhibit the production of wrinkles.

[0011] Preferably, the drug or daily chemical product is an external skin product.

[0012] Preferably, the daily chemical product is a cosmetic or a skin care product. The content of the derivative of tetrapeptide-7 in the daily chemical product is 0.01-1.00%, w / w.

[0013] Advantages of the present application:

[0014] 1. After introducing the structures of nicotinic acid, pyroglutamic acid, aminopicolinic acid, acetylferulic acid and sorbic acid into the molecular structure of tetrapeptide-7, the obtained derivative has a significantly improved activity of inhibiting the expression of IL-1-α, TNF-α and MMP-1 and promoting the production of Col-1 compared with tetrapeptide-7.

[0015] 2. The derivative of tetrapeptide-7 has a lower effective concentration and a higher effect of promoting collagen synthesis, inhibiting collagen degradation and inhibiting the expression of inflammatory factors than existing polypeptide active substances under the same addition amount, thereby improving skin firmness and reducing the production of inflammation, and having the effects of anti-aging, anti-wrinkle and repair. DETAILED DESCRIPTION

[0016] The specific steps of the present application are illustrated by the following examples, but are not limited by the examples.

[0017] In the present application, the terms used have the meanings generally understood by those of ordinary skill in the art unless otherwise specified.

[0018] The present application will be described in further detail below with specific examples and reference to data. It should be understood that these examples are merely for the purpose of illustration of the present application and do not limit the scope of the present application in any way.

[0019] In the following examples, various processes and methods that are not described in detail are conventional methods well known in the art. The present application introduces active small molecules with skin care efficacy into the molecular structure of tetrapeptide-7 through amide bonds, and compares the activity of the derivatives with the unmodified prototype tetrapeptide-7 and the marketized product palmitoyl tetrapeptide-7 in tests of inhibiting inflammation and wrinkle formation.

[0020] Example 1 Preparation of derivatives of tetrapeptide-7

[0021] I. Preparation of nicotinic acid-tetrapeptide-7 derivative (I) (SL-PP-004):

[0022] 1. In a 500 mL two-necked round-bottom flask, M1 (30.0 g, 46.24 mmol, 1.0 eq.) was added, followed by 232 mL of dry DCM, and then tert-butyltrichloroacetimidate (101.0 g, 462.41 mmol, 10.0 eq.) was added. The reaction was carried out at room temperature for 20 h. The reaction solution was concentrated to remove the solvent, and then column chromatography was performed on a 30%-50% EA / PE column to obtain M2 in the form of white foamy solid (27.0 g, yield 75%). HMRS (ESI-MS): Calcd. For [M+H] + = 705.3333 found: 705.3322.

[0023] .

[0024] 2. In a 500 mL three-necked flask, M2 (27.0 g, 38.30 mmol, 1.0 eq.) was added and dissolved in dry DMF (255 mL), and then the temperature was lowered to -5℃. Piperidine (13.7 g, 160.88 mmol, 4.2 eq.), DBU (5.8 g, 22.98 mmol, 0.6 eq.) were added, and the reaction solution was a light yellow solution. After being reacted at -5℃ for 1 h, a large amount of white solid was precipitated in the system, and TLC showed that the reaction was complete. The reaction solution was poured into 200 mL of saturated aqueous ammonium chloride solution, extracted with 500 mL of EA twice, and the combined organic phase was washed with saturated sodium chloride once, dried over anhydrous sodium sulfate, and then concentrated to remove the solvent. Column chromatography was performed on a 5% DCM / MeOH column to obtain M3 in the form of white foamy solid (17.0 g, yield 92%). HMRS (ESI-MS): Calcd. For [M+H] += 483.2627 found: 483.2641.

[0025] .

[0026] 3. In a 250 mL three-necked flask, N-Fmoc-L-proline (12.48 g, 36.98 mmol, 1.05 eq.) was dissolved in dry DMF (176 mL) and cooled to -10 °C. HATU (14.73 g, 38.75 mmol, 1.1 eq.) was added and stirred for 10 min. DIPEA (9.10 g, 70.45 mmol, 2.0 eq.) and M3 (17.10 g, 35.22 mmol, 1.0 eq.) were added. The reaction was stirred at 0 °C for 16 h. TLC showed that the reaction was complete. The reaction solution was slowly poured into 500 mL ice water, and a white solid was precipitated. The solid was filtered, and the filter cake was redissolved in DCM. After drying with anhydrous sodium sulfate, the solvent was removed by concentration to obtain M4 as a white solid (27.5 g, yield 95%), which was directly used in the next step.

[0027] .

[0028] 4. In a 500 mL three-necked flask, M4 (27.5 g, 34.29 mmol, 1.0 eq.) was dissolved in dry DMF (228 mL) and cooled to -5 °C. Piperidine (12.26 g, 144.01 mmol, 4.2 eq.) and DBU (5.16 g, 20.57 mmol, 0.6 eq.) were added. The reaction solution was a light yellow homogeneous solution, and a large amount of white solid was precipitated in the system at -5 °C. TLC showed that the reaction was complete. The reaction solution was poured into 200 mL saturated aqueous ammonium chloride solution, and extracted with EA (300 mL) three times. The organic phase was combined and washed with saturated sodium chloride solution once. After drying with anhydrous sodium sulfate, the solvent was removed by concentration. Column chromatography was performed with 5% DCM / MeOH to obtain M5 as a white foamy solid (18.7 g, yield 94%). HMRS (ESI-MS): Calcd. for [M+H] + = 580.3153 found: 580.3169.

[0029] .

[0030] 5. Dissolve (S)-2-(Fmoc-amino)-5-oxo-5-(triphenylmethylamino)valeric acid (19.58 g, 32.06 mmol, 1.05 eq.) in dry DMF (152 mL) in a 250 mL three-necked flask. Cool to -10 °C, add HATU (12.77 g, 33.58 mmol, 1.1 eq.) and stir for 10 min. Then add DIPEA (7.89 g, 61.06 mmol, 2.0 eq.) and M5 (17.70 g, 30.53 mmol, 1.0 eq.) and react at -10 °C for 3 h. Subsequent TLC showed the reaction was complete with no significant changes in the system. The reaction solution was slowly poured into 500 mL of ice water, at which point a white solid precipitated. This was filtered, and the filter cake was redissolved with DCM. After drying with anhydrous sodium sulfate, the solution was concentrated to remove the solvent, yielding M6 as a white solid (37.5 g, yield: 94%), which was used directly in the next step. HMRS (ESI-MS): Calcd. For [M+H] + =1172.5527 found: 1172.5531.

[0031] .

[0032] 6. In a 500 mL three-necked flask, M6 (37.00 g, 31.56 mmol, 1.0 eq.) was dissolved in 228 mL of dried DMF and cooled to -5 °C. Then piperidine (11.29 g, 144.01 mmol, 4.2 eq.) and DBU (4.75 g, 20.57 mmol, 0.6 eq.) were added. The reaction solution was a pale yellow homogeneous phase. After reacting at -5 °C for 1 h, a large amount of white solid precipitated, indicating the reaction was complete by TLC. The reaction solution was poured into 200 mL of saturated ammonium chloride aqueous solution and extracted three times with EA 300 mL / time. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and then subjected to DCM~5% DCM / MeOH column chromatography to obtain M7, a white foamy solid (27.40 g, yield 91%). HMRS (ESI-MS): Calculated for [M+H] + =950.4827 found: 950.4850.

[0033] .

[0034] 7、In a 250 mL three-necked flask, Fmoc-glycine (8.87 g, 29.84 mmol. 1.05 eq.) was dissolved in dry DMF (142 mL), and the temperature was lowered to -10 °C. HATU (11.88 g, 31.26 mmol, 1.1 eq.) was added and stirred for 10 min. DIPEA (7.35 g, 61.06 mmol. 2.0 eq.) and M7 (27.01 g, 28.41 mmol. 1.0 eq.) were added and the reaction was allowed to proceed at -10 °C for 3 h. Post TLC showed that the reaction was complete, and there was no significant change in the system. The reaction mixture was slowly poured into 500 mL ice water, and a white solid was precipitated. The solid was filtered, and the filter cake was redissolved in DCM. Anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by concentration. M8 was obtained as a white solid (30.01 g, yield 86%) and was used directly in the next step. HMRS (ESI-MS): Calcd. For [M+H] = 1229.5771 found: 1229.5746. +

[0035] .

[0036] 8、In a 100 mL three-necked flask, M8 (10.00 g, 8.13 mmol. 1.0 eq.) was dissolved in dry DMF (55 mL), and the temperature was lowered to -5 °C. Piperidine (2.91 g, 34.16 mmol, 4.2 eq.) and DBU (1.22 g, 4.88 mmol. 0.6 eq.) were added, and the reaction mixture was a light yellow homogeneous solution. The reaction was allowed to proceed at -5 °C for 1 h, and a large amount of white solid was precipitated. Post TLC showed that the reaction was complete. The reaction mixture was poured into 200 mL saturated aqueous ammonium chloride solution, and extracted with EA (300 mL) three times. The organic phase was combined and washed with saturated sodium chloride solution once. Anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by concentration. M9 was obtained as a white foamy solid (8.11 g, yield 98%) after column chromatography using DCM ~ 5% DCM / MeOH. HMRS (ESI-MS): Calcd. For [M+H] = 1007.5180 found: 1007.5065. +

[0037] .

[0038] ​​9. In a 100 mL reaction flask, add M9 (1.00 g, 0.99 mmol, 1.00 eq) dissolved in dry DMF (12 mL) and cool to -5 °C. Add nicotinic acid (146.67 mg, 1.19 mmol, 1.20 eq.) and HATU (453.00 mg, 1.19 mmol, 1.20 eq) sequentially to the reaction; then add DIPEA (256.63 mg, 1.99 mmol, 2.00 eq). Stir at -5 °C for 48 h. Monitor by TLC (Rf = 0.5, 5% MeOH / DCM). Slowly pour the reaction into water (300 mL) and a large amount of solid precipitates out and is filtered. The solid is again dissolved in DCM (200 mL), dried over sodium sulfate and rotary evaporated. The crude product is purified by column chromatography (100-200 mesh, 2-4% MeOH / DCM) to give the product M10 (0.98 g, light yellow solid, 88% yield).

[0039] .

[0040] 10. At room temperature, dissolve M10 (980.0 mg, 0.88 mmol, 1.00 eq) in freshly prepared TFA:EDT:TiPS:H2O 94:2.5:1:2.5 (v / v%) (10 mL) in a 100 mL single neck flask. Stir at room temperature for 2 h. Monitor by mass spectrometry and the reaction is complete. Pour the reaction into ice-cold ether and a large amount of solid precipitates out and is filtered. The solid is dissolved in pure water and lyophilized to give the product SL-PP-004 (480.0 mg, off-white powder, 97% yield).

[0041] 1 H NMR (500 MHz, Methanol-d4) δ 9.25 (d, J = 2.0 Hz, 1H), 8.94 (dd, J = 2.0, 0.9 Hz, 1H), 8.81 (dt, J = 5.6, 1.4 Hz, 1H), 8.74 (dd, J = 8.1, 1.8 Hz, 1H), 8.02 (dd, J = 8.1, 5.4 Hz, 1H), 4.70 (dd, J = 8.3, 5.9 Hz, 1H), 4.47 (ddd, J = 12.7, 8.6, 4.8 Hz, 2H), 4.15 (d, J = 2.5 Hz, 2H), 3.89 (dd, J = 12.7, 2.5 Hz, 2H). J = 2.0 Hz, 1H), 8.94 (dd, J = 5.6,1.4 Hz, 1H), 8.81 (dt, J = 8.1, 1.8 Hz, 1H), 8.02 (dd, J = 8.1, 5.4 Hz, 1H), 4.70(dd, J = 8.3, 5.9 Hz, 1H), 4.47 (ddd, J = 12.7, 8.6, 4.8 Hz, 2H), 4.15 (d, J = 2.5Hz, 2H), 3.89 (dd, J= 11.6, 5.0 Hz, 1H), 3.81 – 3.71 (m, 1H), 3.24 (q, J = 7.2Hz, 2H), 2.40 (td, J = 7.3, 3.6 Hz, 3H), 2.29 – 2.22 (m, 1H), 2.17 – 2.07 (m, 2H), 2.05 – 1.93 (m, 4H), 1.85 – 1.67 (m, 2H).

[0042] .

[0043] II. Preparation of Tranexamic Acid-Tetrapeptide-7 Derivative (I) (SL-PP-005)

[0044] .

[0045] Following the preparation of compound SL-PP-004, Boc-tranexamic acid was used as the starting material to obtain compound SL-PP-005 (477 mg, off-white powder, 2-step yield 81%).

[0046] 1 ¹H NMR (500 MHz, methanol-d⁴) δ 4.64 (dd, J = 8.3, 5.8 Hz, 1H), 4.45 (dt, J =9.3, 4.8 Hz, 2H), 3.89 – 3.81 (m, 3H), 3.72 (dt, J = 10.4, 6.5 Hz, 1H), 3.28 –3.15 (m, 2H), 2.80 (d, J = 6.9 Hz, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.31 – 2.19 (m,2H), 2.15 – 2.05 (m, 2H), 1.94 (dddd, J = 32.7, 13.6, 8.0, 4.5 Hz, 8H), 1.79 –1.68(m, 3H), 1.63 (ddt, J = 11.7, 7.7, 3.7 Hz, 1H), 1.50 (qd, J = 12.9, 3.4 Hz, 2H), 1.09 (qd) , J = 12.9, 3.5 Hz, 2H).

[0047] III. Preparation of Pyroglutamic acid-Tetrapeptide-7 derivative (I) (SL-PP-008)

[0048] .

[0049] Following the procedure for the preparation of compound SL-PP-004, starting material L-pyroglutamic acid was used to obtain compound SL-PP-008 (441 mg, white powder, 2 step yield 78%). 1 H NMR (500 MHz, Methanol-d4) δ 4.62 (dd, J = 8.5, 4.7 Hz, 1H), 4.45 (dtt, J = 7.5, 5.5, 3.0 Hz, 2H), 4.26 (dd, J = 8.9, 4.9, 2.1 Hz, 1H), 3.96 – 3.89 (m, 2H), 3.89 – 3.82 (m, 1H), 3.75 – 3.67 (m, 1H), 3.24 – 3.21 (m, 2H), 2.55 – 2.44 (m, 1H), 2.45 – 2.29 (m, 4H), 2.28 – 2.19 (m, 1H), 2.17 – 2.06 (m, 3H), 2.04 – 1.90 (m, 4H), 1.82 – 1.67 (m, 3H).

[0050] IV. Preparation of Acetylferulic acid-Tetrapeptide-7 derivative (I) (SL-PP-016):

[0051] .

[0052] Following the procedure for the preparation of compound SL-PP-004, starting material acetylferulic acid was used to obtain compound SL-PP-016 (530 mg, off-white powder, 2 step yield 79%). 1 H NMR (500 MHz, Methanol-d4) δ 7.54 (d, J = 15.7 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.2, 1.9 Hz, 1H), 7.06 (dd, J = 8.1, 2.1 Hz, 1H), 6.68 (d, J = 15.8 Hz, 1H), 4.67 (dd, J= 8.3, 5.9 Hz, 1H), 4.45 (dd, J = 8.6, 4.5 Hz, 2H), 4.01 (s, 1H), 3.86 (s, 3H), 3.73 (dt, J = 10.4, 6.8 Hz,1H), 3.26 – 3.15 (m, 2H), 2.36 (t, J = 7.7 Hz, 2H), 2.27 (s, 3H), 2.22 (td, J =7.2, 2.1 Hz, 1H), 2.09 (dt, J = 12.7, 7.2 Hz, 2H), 2.03 – 1.89 (m, 5H), 1.80 –1.65 (m, 4H).

[0053] V. Preparation of sorbic acid-tetrapeptide-7 derivative (I) (SL-PP-017):

[0054] .

[0055] Following the preparation of compound SL-PP-004, sorbic acid was used as the starting material to obtain compound SL-PP-017 (485 mg, off-white powder, 2-step yield 88%). 1 ¹H NMR (500 MHz, methanol-d⁴) δ 7.14 (dd, J = 15.2, 10.7Hz, 1H), 6.24 (ddd, J = 14.8, 10.6, 1.8 Hz, 1H), 6.14 (dd, J = 15.1, 6.7 Hz, 1H), 5.97 (d, J = 15.2 Hz, 1H), 4.65 (dd, J = 8.4, 5.8 Hz, 1H), 4.50 – 4.40 (m, 2H), 3.94 (s, 2H), 3.85 (dt, J = 10.0, 6.5 Hz, 1H), 3.72 (dt, J = 10.4, 6.5 Hz, 1H),3.28 – 3.16 (m, 2H),2.35 (t, J = 7.3 Hz, 2H), 2.22 (tt, J = 7.3, 3.9 Hz, 1H), 2.09 (dd,J = 13.6, 7.4 Hz, 2H), 2.02 – 1.90 (m, 4H), 1.84 (dd, J = 6.6, 1.4 Hz, 3H), 1.79 – 1.67 (m, 3H).

[0056] VI. Preparation of Tetrapeptide-7 (SL-PP-006):

[0057] At room temperature, M9 (1.0 g, 0.99 mmol, 1.0 eq) was dissolved in freshly prepared TFA:EDT:TiPS:H2O 94:2.5:1:2.5 (v / v%) (10 mL) in a 100 mL single-necked flask. The mixture was stirred at room temperature for 2 h. The reaction was considered complete by mass spectrometry. The reaction mixture was poured into chilled diethyl ether, and a large amount of solid precipitated out. The solid was filtered. After dissolving the solid in purified water, it was lyophilized to give the product tetrapeptide-7SL-PP-006 (396.0 mg, off-white powder, yield 87%).

[0058] 1 ¹H NMR (500 MHz, methanol-d⁴) δ 4.74–4.67 (m, 1H), 4.49–4.40 (m, 2H), 3.94–3.85 (m, 1H), 3.80–3.74 (m, 1H), 3.71 (d, J = 10.5 Hz, 1H), 3.22 (q, J =6.8 Hz, 2H), 2.36 (t, J = 7.6 Hz, 2H), 2.28 – 2.20 (m, 1H), 2.15 – 2.05 (m, 2H), 2.06 – 1.88 (m, 5H), 1.83 – 1.67 (m, 3H).

[0059] .

[0060] VII. Preparation of nicotinic acid, tranexamic acid, acetylarinic acid, pyroglutamic acid, and sorbic acid-tetrapeptide-7 derivative (II) (SL-PP-036~040):

[0061] 1. Into a 1 L two-necked round bottom flask, add intermediate (S)-2-(Fmoc-amino)-5- oxo-5-(tritylamino)pentanoic acid (29.8 g, 48.72 mmol, 1.0 eq.) dissolved in dry DMF (163 mL), then add HATU (20.3 g, 53.59 mmol, 1.1 eq.), DIPEA (9.5 g, 73.08 mmol, 1.5 eq.) successively. Stir the mixture at room temperature for 0.5 h, then add M15 (10.1 g, 48.72 mmol, 1.0 eq.). Stir the reaction at room temperature for 2 h. After TLC shows the reaction is complete, slowly pour the reaction into 400 mL ice water, at which time white solids precipitate, filter, redissolve the filter cake in DCM, dry over anhydrous sodium sulfate, and concentrate to remove the solvent to give M16 as a white solid (33 g, yield: 84%), which is used directly in the next step without purification.

[0062] .

[0063] 2. Into a 500 mL three-necked flask, add M16 (33.0 g, 41.36 mmol, 1.0 eq.) dissolved in dry DMF (270 mL), and cool to -5 °C. Then add piperidine (14.8 g, 173.71 mmol, 4.2 eq.) and DBU (3.8 g, 24.82 mmol, 0.6 eq.). The reaction is a light yellow homogeneous solution, and is allowed to react at -5 °C for 1 h. A large amount of white solids precipitates from the system, and TLC shows that the reaction is complete. Pour the reaction into 400 mL saturated aqueous ammonium chloride solution, extract twice with 500 mL EA, combine the organic phases, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to remove the solvent. Column chromatography using 0-5% DCM / MeOH gives M17 as a white foamy solid (21.0 g, yield 88%).

[0064] .

[0065] 3. In a 250 mL three-necked flask, Boc-glycine (6.4 g, 36.48 mmol, 1.01 eq.) was dissolved in dry DMF (121 mL) and cooled to -10 °C. HATU (15.3 g, 40.12 mmol, 1.1 eq.), DIPEA (7.1 g, 70.45 mmol. 2.0 eq.), and M17 (21.0 g, 36.48 mmol, 1.0 eq.) were added successively. The reaction was allowed to proceed at -10 °C for 16 h. TLC showed that the reaction was complete, and no obvious change was observed in the system. The reaction solution was slowly poured into 500 mL ice water, and white solids were precipitated at this time. The solids were filtered, redissolved in DCM, dried with anhydrous sodium sulfate, and concentrated to remove the solvent to obtain the product crude. The product was purified by column chromatography with 0-1% DCM / MeOH. After the solvent was removed by concentration, M18 was obtained as a white foamy solid (25.0 g, yield 93%).

[0066] .

[0067] 4. In a 500 mL three-necked flask, M18 (25.0 g, 34.11 mmol. 1.0 eq.) was dissolved in methanol (170 mL), and Pd / C (0.25 g, 5%) was added. After three times of replacement of hydrogen, the reaction was stirred at room temperature for 4 h. TLC showed that the reaction was complete, and the reaction solution was filtered through celite to recover the palladium carbon. After the solvent was removed by concentration, M19 was obtained as a white solid (21.5 g, yield 98%). The product was directly used in the subsequent step without purification.

[0068] .

[0069] 5. In a 1 L three-necked flask, M20 (50.0 g, 32.06 mmol. 1.0 eq.) was dispersed in dry DCM (420 mL), and tert-butyl trichloroacetimidate (137.7 g, 630.60 mmol, 5.0 eq.) was added at room temperature. After the reaction was allowed to proceed at room temperature for 40 h, TLC showed that the reaction was complete, and white solids were precipitated in the system. The reaction solution was slowly poured into 500 mL water, and the aqueous phase was extracted once with DCM (300 mL). The combined organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by concentration to obtain the product M21 (52.0 g, yield 91%). The product was directly used in the next step without purification.

[0070] .

[0071] 6. Dissolve one of the above organic acids (1.0 eq.) in dried DMF (10 mL / g) in a 250 mL three-necked flask. Cool to -10 °C, then add HATU (1.1 eq.) and DIPEA (1.5 eq.) sequentially. Stir for 10 min, then add M21 (1.0 eq.) and react at -10 °C for 16 h. TLC showed that the reaction was essentially complete. Slowly pour the reaction solution into 150 mL of ice water, and a white solid precipitated. Filter, redissolve the filter cake with DCM, dry with anhydrous sodium sulfate, and concentrate to remove the solvent. The resulting products were used directly in the next step.

[0072]

[0073] .

[0074] 7. Dissolve M22a~e (1.0 eq) in dry DMF (10 mL / g) in a 500 mL three-necked flask and cool to -5 °C. Add piperidine (4.2 eq) and DBU (0.6 eq), and react at -5 °C for 1 h to precipitate a large amount of white solid. After the reaction is complete, pour the reaction solution into a saturated ammonium chloride aqueous solution, extract twice with EA, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate to remove the solvent, and precipitate by 0-5% DCM / MeOH column chromatography. After concentration to remove the solvent, obtain product M23a~e.

[0075] .

[0076] 8. Dissolve M19 (1.0 eq) in dry DMF (10 mL / g) in a 100 mL three-necked flask and cool to -5 °C. Add HATU (1.1 eq) and DIPEA (1.5 eq) sequentially, stir for 10 min, then add M23a~e (1.0 eq.) and react at -10 °C for 16 h. TLC showed that the reaction was complete. Slowly pour the reaction solution into 150 mL of ice water, and a white solid precipitated. Filter, redissolve the filter cake with DCM, dry with anhydrous sodium sulfate, and concentrate to remove the solvent. The crude product was precipitated by 0-1% DCM / MeOH column chromatography, and the solvent was removed by concentration to obtain product M24a~e.

[0077] .

[0078] 9. M24a~e was dissolved in freshly prepared TFA:EDT:TiPS:H2O 94:2.5:1:2.5 (v / v%) (20 mL / g) in 100 mL single neck flask at room temperature. Stirring at room temperature for 2 h. The reaction was monitored by mass spectrometry and ended. The reaction was poured into ice-cold ether and a large amount of solid was precipitated, filtered. The solid was rinsed with ether and then dissolved with purified water, freeze-dried to obtain the product SL-PP-036~040.

[0079] .

[0080] 1 H NMR (SL-PP-036, 500 MHz, Methanol-d4) δ 9.28 (d, J = 2.0 Hz, 1H), 8.97 (dd, J = 5.8, 1.4 Hz, 1H), 8.84 (dt, J = 8.2, 2.0 Hz, 1H), 8.06 (dd, J = 8.2, 5.4 Hz, 1H), 4.77 (dd, J = 8.5, 5.6 Hz, 1H), 4.49 (m, 2H), 3.89 (m, 1H), 3.81 – 3.71 (m, 1H), 3.59 (d, J = 2.5 Hz, 2H), 3.24 (m, 2H), 2.40 (td, J = 7.3, 3.6 Hz, 3H), 2.29 – 2.22 (m, 1H), 2.17 – 2.07 (m, 2H), 2.05 – 1.93 (m, 4H), 1.85 – 1.67 (m, 2H).

[0081] 1 H NMR (SL-PP-037, 500 MHz, Methanol-d4) δ 4.60 (dd, J = 8.0, 5.6 Hz, 1H), 4.49 (dt, J = 9.1, 4.6 Hz, 2H), 3.72 (m, 1H), 3.55 (d, J = 5.8 Hz, 2H), 3.28 – 3.15 (m, 3H), 2.50 (d, J = 6.7 Hz, 2H), 2.34 (t, J= 7.2 Hz, 2H), 2.31 – 2.19 (m, 2H), 2.15 – 2.05 (m, 2H), 1.94 (m, 8H), 1.79 – 1.68 (m, 3H), 1.63 (m, 1H), 1.50 (m, 2H), 1.09 (qd, J = 12.7, 3.5 Hz, 2H).

[0082] 1 1H NMR (SL-PP-038, 500 MHz, methanol-d4) δ 4.62 (dd, J = 8.5, 4.7 Hz, 1H), 4.49 – 4.43 (m, 2H), 4.26 (dd, J = 8.9, 4.9, 2.1 Hz, 1H), 3.87 – 3.82 (m, 1H), 3.77 – 3.69 (m, 1H), 3.56 (d, J = 5.5 Hz, 2H), 3.25 – 3.22 (m, 2H), 2.54 – 2.43 (m, 1H), 2.48 – 2.33 (m, 4H), 2.28 – 2.19 (m, 1H), 2.17 – 2.06 (m, 3H), 2.00 – 1.83 (m, 4H), 1.77 – 1.70 (m, 3H).

[0083] 1 1H NMR (SL-PP-039, 500 MHz, methanol-d4) δ 7.55 (d, J = 15.7 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.2, 1.9 Hz, 1H), 7.07 (dd, J = 8.0, 2.1 Hz, 1H), 6.69 (d, J = 10.8 Hz, 1H), 4.66 (dd,<000029​​​​= 10.4, 6.8 Hz, 1H), 3.26– 3.15 (m, 2H), 2.36 (t, J = 7.7 Hz, 2H), 2.27 (s, 3H), 2.22 (td, J = 7.2, 2.1 Hz, 1H), 2.09 (dt, J = 12.7, 7.2 Hz, 2H), 2.03 – 1.89 (m, 5H), 1.80 – 1.65 (m, 4H).

[0084] 1 ¹H NMR (SL-PP-040, 500 MHz, methanol-d⁴) δ 7.20 (dd, J = 15.2, 10.7 Hz,1H), 6.30 (ddd, J = 14.8, 10.6, 1.8 Hz, 1H), 6.12 (m, 1H), 5.97 (d, J = 15.2 Hz, 1H), 4.72 (dd, J = 8.4, 5.8 Hz, 1H), 4.44 – 4.37 (m, 2H), 3.76 – 3.71 (m, 2H), 3.23 – 3.19 (m, 2H), 3.08 –3.02(m, 2H), 2.37 – 2.32 (m, 2H), 2.25 (s, 3H), 2.20 – 2.10 (m, 1H), 1.99 – 1.95 (m, 2H), 2.01 – 1.93 (m, 4H), 1.77 – 1.69 (m, 3H).

[0085] Example 2: Effects of tetrapeptide-7 derivatives on the expression of tumor necrosis factor-α (TNF-α) in human immortalized keratinocytes (HaCat).

[0086] Test Principle: Skin exposed to toxic or harmful substances in the living environment may experience a certain degree of skin inflammation, resulting in redness, swelling, itching, and other symptoms. The irritant phenotype of cosmetics on the skin is mainly manifested as skin inflammation, with early-stage inflammation primarily characterized by capillary dilation, increased permeability, and edema. Various inflammatory factors play key roles in the development of acute and chronic inflammation, such as interleukin-1α (IL-1α) and tumor necrosis factor-A (TNF-α). Using a photoaging model established with HaCat and UVB, the expression levels of TNF-α and IL-1α are measured after the test sample is applied to UVB-damaged HaCat, allowing for the assessment of the anti-inflammatory and soothing effects of the test substance.

[0087] Test method: After HaCat cells were resuscitated, they were cultured in DMEM high-glucose medium containing 10% FBS and incubated at 37°C in a 5% CO2 incubator, and passaged at a ratio of 1:3. HaCat cells in the logarithmic growth phase were digested, resuspended, and counted; at a ratio of 2 × 10⁻⁶ cells / year... 4 Cells were seeded per well in 96-well plates and cultured overnight at 37°C with 5% CO2 in DMEM high-glucose medium containing 10% FBS to allow adherence. The old medium was discarded, and the cells were gently washed once with 200 μL PBS. Three control, model, and test sample groups were set up. The control group was replaced with 200 μL 1% FBS medium and cultured at 37°C with 5% CO2 for 24 h. The model and test sample groups were replaced with 50 μL PBS. The model and test sample groups were exposed to 30 mJ UVB radiation in a UV crosslinker. The PBS was discarded. 200 μL of 1% FBS medium was added to each well of the model group, and 200 μL of the test sample solution (prepared with the above medium) was added to each well of the test sample group to a final concentration of 0.05 mg / mL. The cells were cultured at 37°C with 5% CO2 for 24 h. The cell supernatant was collected, and the expression levels of TNF-α and IL-1α were detected using an ELISA kit.

[0088] Calculation formula: TNF-α expression inhibition rate = (UT) / U × 100%.

[0089] Where: T—the average value of TNF-α expression level measured in the test sample; U—the average value of TNF-α expression level measured in the model group.

[0090] Experimental Groups:

[0091] Blank group: cultured in 1% FBS medium. Model group: 30 mJ UVB + 1% FBS medium culture. Test product group: 30 mJ UVB + test product with a final concentration of 0.05 mg / mL + 1% FBS medium culture. For the physical mixing test product, the ratio is 1:1 by molar ratio, and then the test product with a final concentration of 0.05 mg / mL is prepared.

[0092] Result analysis:

[0093] The test results are shown in Table 1:

[0094] Table 1. TNF-α expression inhibition rate test results

[0095] Experimental group T (pg / mL) Inhibition rate Blank group 2.5529 / Model group 4.4760 0.00% Palmitoyl tetrapeptide-7 3.8660 13.63% Tetrapeptide-7 6.9660 -55.63% Nicotinic acid-tetrapeptide-7 derivative (I) 3.3510 25.13% Nicotinic acid-tetrapeptide-7 derivative (II) 3.1368 29.92% Nicotinic acid 4.3391 3.06% Tetrapeptide-7+nicotinic acid 4.4657 0.23% Caffeic acid-tetrapeptide-7 derivative (I) 3.3360 25.47% Caffeic acid-tetrapeptide-7 derivative (II) 3.4810 22.23% Caffeic acid 5.4373 -21.48% Tetrapeptide-7+caffeic acid 4.7302 -5.68% Pyroglutamic acid-tetrapeptide-7 derivative (I) 3.2270 27.90% Pyroglutamic acid-tetrapeptide-7 derivative (II) 3.3534 25.08% Pyroglutamic acid 4.2091 5.96% Tetrapeptide-7+pyroglutamic acid 4.3901 1.92% Sorbic acid-tetrapeptide-7 derivative (I) 3.8150 14.77% Sorbic acid-tetrapeptide-7 derivative (II) 4.9343 10.24% Sorbic acid 6.9550 -55.38% Tetrapeptide-7+sorbic acid 5.8322 -30.30% Experimental group 3.3930 24.20% I (pg / mL) 4.2692 4.62% Inhibition rate 5.0906 -13.73% Blank group 6.5005 -45.23%

[0096] From the results in Table 1, it can be seen that the single use of tetrapeptide-7, citric acid, pyroglutamic acid, sorbic acid does not have the effect of inhibiting TNF-α, and nicotinic acid and acetylferulic acid have weak inhibitory effect on TNF-α. The combination of tetrapeptide-7 and one of nicotinic acid, citric acid, acetylferulic acid, pyroglutamic acid and sorbic acid also has no effect on inhibiting TNF-α. Except for pyroglutamic acid-tetrapeptide-7 derivative (II) and sorbic acid-tetrapeptide-7 derivative (II), the tetrapeptide-7 derivatives described in the present application have significantly improved effect on inhibiting TNF-α, and the effect of the derivative of formula (I) is better than that of the derivative of formula (II), which indicates that the derivative described in the present application has excellent anti-inflammatory activity.

[0097] Example 3 Influence of derivatives of tetrapeptide-7 on interleukin-1α (IL-1α) expression in human immortalized keratinocytes (HaCat).

[0098] The test method is described in Example 2.

[0099] Calculation formula: IL-1α expression inhibition rate = (U-I) / U × 100%.

[0100] In the formula: I is the average value of the IL-1α expression of the test product; U is the average value of the IL-1α expression of the model group.

[0101] Experimental grouping:

[0102] Blank group: cultured in 1% FBS medium. Model group: 30 mJ UVB + 1% FBS medium culture. Test product group: 30 mJ UVB + test product with a final concentration of 0.05 mg / mL + 1% FBS medium culture. For the physical mixing test product, the ratio is 1:1 by molar ratio, and then the test product with a final concentration of 0.05 mg / mL is prepared.

[0103] Result analysis: The test results are shown in Table 2.

[0104] Table 2. IL-1α expression inhibition rate test results

[0105] Model group Palmitoyl tetrapeptide-7 Tetrapeptide-7 Nicotinic acid-tetrapeptide-7 derivative (I) 26.9737 / Nicotinic acid-tetrapeptide-7 derivative (II) 30.3644 0.00% Nicotinic acid 27.9659 7.90% Tetrapeptide-7+nicotinic acid 32.204 -6.06% Caffeic acid-tetrapeptide-7 derivative (I) 25.6284 15.60% Caffeic acid-tetrapeptide-7 derivative (II) 23.9788 21.03% Caffeic acid 34.7119 -14.32% Tetrapeptide-7+caffeic acid 33.4707 -10.23% Pyroglutamic acid-tetrapeptide-7 derivative (I) 25.0535 17.49% Pyroglutamic acid-tetrapeptide-7 derivative (II) 32.9727 -8.59% Pyroglutamic acid 28.5597 5.94% Tetrapeptide-7+pyroglutamic acid 29.8421 1.72% Sorbic acid-tetrapeptide-7 derivative (I) 25.0535 17.49% Sorbic acid-tetrapeptide-7 derivative (II) 26.8361 11.62% Sorbic acid 32.204 -6.06% Tetrapeptide-7+sorbic acid 31.6822 -4.34% Experimental group 26.2071 13.69% M (ng / mL) 33.6013 -10.66% Inhibition rate 39.9202 -31.47% Blank group 36.3401 -19.68% Model group 23.3512 23.10% Palmitoyl tetrapeptide-7 35.4262 -16.67% Tetrapeptide-7 26.7896 11.77% Nicotinic acid-tetrapeptide-7 derivative (I) 29.5537 2.67%

[0106] From the results in Table 2, it can be seen that the use of tetrapeptide-7, nicotinic acid, acetylferulic acid, pyroglutamic acid alone does not have the effect of inhibiting TNF-α, and the effect of sorbic acid and citric acid on inhibiting IL-1α is not high. The combination of tetrapeptide-7 with one of nicotinic acid, citric acid, acetylferulic acid, pyroglutamic acid and sorbic acid has no effect on inhibiting IL-1α, and some have weak effect. The IL-1α inhibiting effect of the tetrapeptide-7 derivative of formula (I) and the nicotinic acid-tetrapeptide-7 derivative (II) described in the present application is significantly improved, indicating that the derivative described in the present application has excellent anti-inflammatory activity.

[0107] Example 4 Effect of tetrapeptide-7 derivative of the present application on the expression of matrix metalloproteinase MMP-1 in human foreskin fibroblasts (HFF-1)

[0108] Test principle: Photoaging is mainly caused by ultraviolet light exposure, free radicals and physical stimuli. The ultraviolet light reaching our skin is mainly composed of UVA and UVB, and excessive exposure to UVA and UVB is associated with skin aging, which is manifested externally as the formation of wrinkles, pigmentation and skin laxity. Ultraviolet radiation can cause dermal fibroblasts to secrete matrix metalloproteinases (MMPs), thereby degrading a series of extracellular matrix including collagen, ultimately leading to the formation of wrinkles. Among the enzymes produced by UV mediation, MMP-1 plays one of the most important roles in the process of degrading collagen, and therefore it becomes one of the important targets for alleviating photoaging and evaluating anti-wrinkle efficacy. By irradiating human skin fibroblasts with UVB to model photoaging, and then adding the test product, the anti-photoaging effect of the test product is evaluated by comparing the MMP-1 content secreted by fibroblasts with and without the test product.

[0109] Test method: After the HFF-1 cells were resuscitated, they were cultured in DMEM high-sugar medium containing 10% FBS in a 37°C, 5% CO2 incubator, and subcultured at a ratio of 1:3. The logarithmically growing HFF-1 was counted after digestion and resuspension; 2x104 Inoculate 1 cell / hole in a 96-well plate, add DMEM high-sugar medium containing 10% FBS, and culture at 37°C, 5% CO2 overnight to allow adhesion; discard the old culture medium, and gently wash the cells once with 200 μL PBS; set up a blank group, a model group, and a test product group; replace the blank group with 200 μL of 1% FBS medium, and culture at 37°C, 5% CO2 for 24 h; replace the model group and the test product group with 50 μL of PBS; give the model group and the test product group 30 mJ UVB radiation with an ultraviolet crosslinking instrument. Discard the PBS, add 200 μL of 1% FBS medium to the model group, and add 200 μL of the test sample solution prepared in the above-mentioned medium to the test product group, so that the final concentration of the test product is 0.05 mg / mL, and culture at 37°C, 5% CO2 for 24 h; collect the cell supernatant, and detect the expression amount of MMP-1 by using a human matrix metalloproteinase 1 (MMP-1) ELISA kit.

[0110] The calculation formula is: the inhibition rate of MMP-1 expression = (U-M) / U x 100%.

[0111] In the formula: M is the average value of the MMP-1 expression amount of the test product; and U is the average value of the MMP-1 expression amount of the model group.

[0112] Experimental grouping:

[0113] The blank group: cultured with 1% FBS medium. The model group: 30 mJ UVB + 1% FBS medium culture. The test product group: 30 mJ UVB + test product with a final concentration of 0.05 mg / mL + 1% FBS medium culture. For the physical mixture of the test product, the preparation ratio is to mix the two by a molar ratio of 1:1, and then prepare the test product with a final concentration of 0.05 mg / mL.

[0114] Result analysis: the test results are shown in Table 3.

[0115] Table 3. Inhibition rate test results of the expression amount of MMP-1

[0116] Nicotinic acid-tetrapeptide-7 derivative (II) Nicotinic acid Tetrapeptide-7+nicotinic acid Caffeic acid-tetrapeptide-7 derivative (I) 0.3960 / Caffeic acid-tetrapeptide-7 derivative (II) 1.5200 0.00% Caffeic acid 0.8856 41.74% Tetrapeptide-7+caffeic acid 1.1908 21.66% Pyroglutamic acid-tetrapeptide-7 derivative (I) 0.3220 78.82% Pyroglutamic acid-tetrapeptide-7 derivative (II) 0.3400 77.63% Pyroglutamic acid 1.3515 11.08% Tetrapeptide-7+pyroglutamic acid 1.2973 14.65% Sorbic acid-tetrapeptide-7 derivative (I) 0.5911 61.11% Sorbic acid-tetrapeptide-7 derivative (II) 0.8767 42.32% Sorbic acid 1.3515 11.08% Tetrapeptide-7+sorbic acid 1.3183 13.27% Experimental group 0.2950 80.59% T (ng / mL) 0.6065 60.10% Up-regulation ratio 1.5336 -0.90% Blank group 1.1941 21.44% Model group 1.5160 0.26% Palmitoyl tetrapeptide-7 1.2666 16.67% Tetrapeptide-7 1.6570 -9.01% Nicotinic acid-tetrapeptide-7 derivative (I) 1.5372 -1.13% Nicotinic acid-tetrapeptide-7 derivative (II) 0.3660 75.92% Nicotinic acid 1.1908 21.66% Tetrapeptide-7+nicotinic acid 1.1908 21.66% Caffeic acid-tetrapeptide-7 derivative (I) 1.1695 23.06%

[0117] As can be seen from the results in Table 3, although the inhibition rate of tetrapeptide-7 on MMP-1 is 21.66%, but when it is used in combination with one of niacin, trihydroxybenzoic acid, pyroglutamic acid, the inhibition rate is significantly reduced, and when it is used in combination with acetylferulic acid or sorbic acid, the inhibition rate does not change significantly. The derivatives described in the present application have a significantly improved inhibition effect on MMP-1 except for pyroglutamic acid-tetrapeptide-7 derivative (I) and sorbic acid-tetrapeptide-7 derivative (II), which indicates that the derivatives described in the present application have excellent anti-wrinkle activity.

[0118] Example 5 Effect of the derivative of tetrapeptide-7 of the present application on human type I collagen production in human foreskin fibroblast (HFF-1) cells

[0119] Test principle: Type I collagen is one of the main components of the dermal extracellular matrix. It is synthesized in the intracellular type I procollagen by dermal fibroblasts, secreted to the extracellular, and, under the action of terminal procollagen peptidase, the terminal peptide is separated, and then the collagen fibers are polymerized to form a reticular framework of collagen protein, which provides protection and elasticity for the skin. The appearance of skin wrinkles is closely related to the normal synthesis and expression of collagen. HFF-1 can be used as a cell model for studying cosmetics to increase the content of type I collagen. By determining the up-regulation rate of type I collagen content after blank control and test sample administration, the efficacy of the test sample in promoting collagen synthesis is evaluated.

[0120] Test method: After the HFF-1 cells were recovered, they were cultured in DMEM high-sugar medium containing 10% FBS in a 37°C, 5% CO2 incubator, and subcultured at a ratio of 1:3. The logarithmic growth phase HFF-1 was counted after digestion and resuspension; 2x10 4 cells / well were inoculated in a 96-well plate, 200 μL of PBS was added to gently wash the cells once, and the blank group, model group and test sample group were set up; the test sample group was added with culture medium containing a final concentration of 0.05 mg / mL test sample, and the blank control wells were added with normal cell culture medium, 200 μL per well. After the administration was completed, the 96-well plate was placed in a CO2 incubator for 24 h; after the incubation was completed, 200 μL of cell culture supernatant was collected in a 1.5 mL sterile centrifuge tube, and the type I collagen content was detected according to the instructions of the human type I collagen ELISA kit;

[0121] Calculation formula: up-regulation rate=(T-C) / Cx100%.

[0122] In the formula: T is the average value of type I collagen content of the test sample; C is the average value of type I collagen content of the blank control.

[0123] Experimental grouping:

[0124] Blank group: normal cell culture medium culture. Test sample group: culture medium containing a final concentration of 0.05 mg / mL test sample. For physical mixing of test samples, the ratio is 1:1 by molar ratio, and then the test sample with a final concentration of 0.05 mg / mL is prepared.

[0125] Result analysis: the test results are shown in Table 4.

[0126] Table 4. Results of the human collagen type I production promotion test

[0127] Caffeic acid-tetrapeptide-7 derivative (II) Caffeic acid Tetrapeptide-7+caffeic acid Pyroglutamic acid-tetrapeptide-7 derivative (I) 10.2348 / Pyroglutamic acid-tetrapeptide-7 derivative (II) 1.5200 0.00% Pyroglutamic acid 14.9918 46.48% Tetrapeptide-7+pyroglutamic acid 10.0908 -1.41% Sorbic acid-tetrapeptide-7 derivative (I) 17.3879 69.89% Sorbic acid-tetrapeptide-7 derivative (II) 17.9795 75.67% Sorbic acid 11.5755 13.10% Tetrapeptide-7+sorbic acid 10.3013 0.65% ​ 17.8438 74.34% ​ 11.8110 15.40% ​ 10.0818 -1.49% ​ 9.2226 -9.89% ​ 17.8508 74.41% ​ 15.4904 51.35% ​ 8.9788 -12.27% ​ 9.0875 -11.21% ​ 16.2769 59.04% ​ 10.2860 0.50% ​ 10.1228 -1.09% ​ 10.0414 -1.89% ​ 11.5755 13.10% ​ 9.2359 -9.76% ​ 10.1058 -1.26% ​ 10.3433 1.06%

[0128] From the results of Table 4, it can be seen that tetrapeptide-7, trans- aminic acid, acetylferulic acid, pyroglutamic acid, sorbic acid alone, and tetrapeptide-7 combined with one of nicotinic acid, trans-aminic acid, acetylferulic acid, pyroglutamic acid, and sorbic acid have no effect of up-regulating Col-I. The derivatives described in the present application, except for pyroglutamic acid-tetrapeptide-7 derivative (II) and sorbic acid-tetrapeptide-7 derivative (II), have a significant increase in the effect of up-regulating Col-I compared to tetrapeptide-7, indicating that the derivatives described in the present application have an excellent effect of promoting collagen synthesis.

[0129] Abbreviation definitions:

[0130] IL-1-α: interleukin 1 alpha

[0131] TNF-α: tumor necrosis factor (TNF) alpha

[0132] MMP-1: human matrix metalloproteinase 1

[0133] Col-1: human collagen type I

[0134] MeOH: methanol

[0135] DCM: dichloromethane

[0136] EA: ethyl acetate

[0137] PE: petroleum ether

[0138] HATU: 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0139] DIPEA: diisopropylethylamine

[0140] DMF: N,N-dimethylformamide

[0141] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0142] TFA: trifluoroacetic acid

[0143] EDT: 1,2-ethanedithiol

[0144] TIS: triisopropylsilane

Claims

1. Pyroglutamic acid-tetrapeptide-7 derivatives, characterized in that having the following structure: , the substituent R is selected from .

2. The pyroglutamic acid-tetrapeptide-7 derivative salt according to claim 1, characterized by a derivative of pyroglutamic acid-tetrapeptide-7 is salified with an acid or a base.

3. Use of the pyroglutamic acid-tetrapeptide-7 derivative of claim 1 or the salt of the pyroglutamic acid-tetrapeptide-7 derivative of claim 2 in the preparation of a medicament for anti-inflammatory, collagen promotion and / or inhibition of the production of MMP-1 or in the preparation of an anti-inflammatory, anti-wrinkle daily use cosmetic product.

4. The use according to claim 3, wherein The medicament or daily use cosmetic product is a topical product.

5. The use according to claim 3, wherein The daily use cosmetic product is a cosmetic or a skin care product.

6. The use according to claim 3, wherein The pyroglutamic acid-tetrapeptide-7 derivative is present in the daily use cosmetic product in an amount of 0.01% to 1.00%, w / w.

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