Pyroglutamic acid-tetrapeptide-7 derivative and application thereof

Abstract

The invention discloses a derivative of pyroglutamic acid-tetrapeptide-7 and application of the derivative. The pyroglutamic acid-tetrapeptide-7 derivative or the pharmaceutically acceptable salt of the pyroglutamic acid-tetrapeptide-7 derivative has the following structure: # imgabs0 #, and a substituent group R is selected from # imgabs1 #. The pyroglutamic acid-tetrapeptide-7 derivative disclosed by the invention has excellent effects of resisting inflammation, promoting synthesis of collagen and / or elastin and reducing the area or the degree of wrinkles of skin, has smaller onset concentration compared with tetrapeptide-7, and can be applied to medicines, cosmetics or skin care products as a main active component.

Description

Technical Field

[0001] The invention belongs to the fields of chemistry, biotechnology and daily chemical products, and specifically relates to a class of tetrapeptide-7 derivatives and applications thereof. Background Art

[0002] Skin inflammation and ultraviolet radiation can increase the expression of interleukins, thus causing skin inflammation, leading to the degradation of collagen and elastin, and causing the skin to become loose, wrinkled, and uneven in skin tone.

[0003] Palmitoyl Tetrapeptide-7 is a cell messenger peptide composed of four amino acids linked by peptide bonds. It inhibits the production of excessive interleukins by macrophages through signal stimulation and inhibits the production of inflammation. It can also stimulate dermal cells to increase the synthesis of collagen and elastin, thereby achieving the effect of reducing wrinkles and tightening the skin.

[0004] Chinese patent document CN114869796A discloses a skin whitening and repairing composition containing active polypeptides, including: active polypeptide complexes, and functional active substances; the active polypeptide complexes include but are not limited to antioxidant polypeptides, polypeptides that inhibit the release of inflammatory factors, polypeptides that supplement collagen, and skin whitening polypeptides; the polypeptides that inhibit the release of inflammatory factors include palmitoyl tetrapeptide-7, and the functional active substances include but are not limited to one or more of isoferulic acid and isoferulic acid amide derivatives. Although the composition has multiple skin repair effects, due to the form of a compounded composition, the distribution ratio of each group between batches during the production of the finished product will be different, which may lead to differences in the efficacy of the finished product and may also affect the stability of the formula. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a class of tetrapeptide-7 derivatives. By changing the N-terminal modifiers of glycine or arginine in tetrapeptide-7, several derivatives with better anti-inflammatory and anti-wrinkle effects than tetrapeptide-7 are screened out. Compared with tetrapeptide-7, the derivatives have a smaller effective concentration, can inhibit the formation of wrinkles, improve skin elasticity, and can be used as the main active ingredient in medicines, cosmetics or skin care products.

[0006] The specific technical solutions of the present invention are as follows: A class of tetrapeptide-7 derivatives has the following structure: or , in formula I or formula II, the substituent R is selected from , , , or .

[0007] Another object of the present invention is to provide a salt of a derivative of tetrapeptide-7 and an acid or a base, wherein 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 alkaline 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 and triethanolamine.

[0008] Another object of the present invention is to provide the use of the tetrapeptide-7 derivative or its salt in the preparation of anti-inflammatory, collagen and / or elastin production-promoting drugs or daily chemicals. The tetrapeptide-7 derivative or its salt can inhibit the formation of wrinkles.

[0009] Preferably, the medicine or daily chemical product is a skin external product.

[0010] Preferably, the daily chemical product is a cosmetic or a skin care product. The content of the tetrapeptide-7 derivative in the daily chemical product is 0.01-1.00%, w / w.

[0011] Advantages of the present invention: 1. After the present invention introduces nicotinic acid, pyroglutamic acid, tranexamic acid, acetylferulic acid and sorbic acid structures into the molecular structure of tetrapeptide-7, the obtained derivatives have significantly improved activities in inhibiting the expression of IL-1-α, TNF-α and MMP-1 and promoting the production of Col-1 compared with tetrapeptide-7.

[0012] 2. The tetrapeptide-7 derivatives of the present invention have a lower effective concentration than existing polypeptide active ingredients. At the same addition amount, they have a higher effect of promoting collagen synthesis, inhibiting collagen degradation, and inhibiting the expression of inflammatory factors, thereby improving skin firmness, reducing the occurrence of inflammation, and having anti-aging, anti-wrinkle, and repairing effects. DETAILED DESCRIPTION

[0013] The specific steps of the present invention are described below by way of examples, but are not limited to the examples.

[0014] The terms used in the present invention, unless otherwise specified, generally have the meanings commonly understood by those of ordinary skill in the art.

[0015] The present invention is further described in detail below in conjunction with specific examples and with reference to data. It should be understood that these embodiments are only for illustrating the present invention and are not intended to limit the scope of the present invention in any way.

[0016] In the following examples, various processes and methods not described in detail are conventional methods known in the art. The present invention introduces active small molecules with skin care effects into the molecular structure of tetrapeptide-7 through amide bonds, and compares the activity of derivatives and unmodified prototype tetrapeptide-7, as well as the marketed product palmitoyl tetrapeptide-7 in tests on inhibiting inflammation and wrinkle formation.

[0017] Example 1 Preparation of derivatives of tetrapeptide-7 1. Preparation of Nicotinic Acid-Tetrapeptide-7 Derivative (I) (SL-PP-004): 1. In a 500 mL double-necked round-bottom flask, add M1 (30.0 g, 46.24 mmol, 1.0 eq.), add 232 mL of dry DCM, and then add tert-butyl trichloroacetimidate (101.0 g, 462.41mmol 10.0eq) and react at room temperature for 20 h. Concentrate the reaction solution to remove the solvent, and then 30%~50% EA / PE column chromatography to obtain M2, a white foamy solid (27.0 g, yield 75%). HMRS (ESI-MS): Calcd.For [M+H] + =705.3333 found:705.3322.

[0018] .

[0019] 2. Add M2 (27.0 g, 38.30 mmol. 1.0 eq.) to a 500 mL three-necked flask, dissolve it with dry DMF (255 mL), and cool it to -5°C. Then add piperidine (13.7 g, 160.88mmol, 4.2 eq.) and DBU (5.8 g, 22.98 mmol. 0.6 eq.). The reaction solution is a light yellow solution. A large amount of white solid precipitates in the system after reacting at -5°C for 1 h. TLC shows that the reaction is complete. Pour the reaction solution into 200 mL saturated ammonium chloride aqueous solution, extract twice with 500 mL EA, combine the organic phases, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and chromatograph on a 5% DCM / MeOH column to obtain M3 as a white foamy solid (17.0 g, yield 92%). HMRS (ESI-MS): Calcd.For [M+H] + =483.2627 found:483.2641.

[0020] .

[0021] 3. Add N-Fmoc-L-proline (12.48 g, 36.98 mmol. 1.05 eq.) and dry DMF (176 mL) to a 250 mL three-necked flask, cool to -10 °C, add HATU (14.73 g, 38.75 mmol, 1.1 eq.) and stir for 10 min, then add DIPEA (9.10 g, 70.45 mmol. 2.0 eq.) and M3 (17.10 g, 35.22 mmol. 1.0 eq.). Stir the reaction at 0 °C for 16 h. TLC shows that the reaction is complete, and the reaction solution is slowly poured into 500 mL of ice water. At this time, a white solid precipitates, which is filtered, and the filter cake is re-dissolved in DCM, dried with anhydrous sodium sulfate, and concentrated to remove the solvent to obtain M4 as a white solid (27.5 g, yield 95%), which is directly used in the next step.

[0022] .

[0023] 4. Add M4 (27.5 g, 34.29 mmol. 1.0 eq.) and dry DMF (228 mL) to a 500 mL three-necked flask and dissolve, then cool to -5°C. Then add piperidine (12.26 g, 144.01 mmol, 4.2 eq.) and DBU (5.16 g, 20.57 mmol. 0.6 eq.). The reaction solution is a pale yellow homogeneous phase. After reacting at -5°C for 1 h, a large amount of white solid precipitates in the system. TLC shows that the reaction is complete. Pour the reaction solution into 200 mL of saturated ammonium chloride aqueous solution, extract three times with EA 300 mL / time, combine the organic phases, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and chromatograph on a 5% DCM / MeOH column 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.

[0024] .

[0025] 5. In a 250 mL three-necked flask, add (S)-2-(Fmoc-amino)-5-oxo-5-(tritylamino)pentanoic acid (19.58 g, 32.06 mmol. 1.05 eq.) and dry DMF (152 mL) to dissolve, cool to -10 ℃, add HATU (12.77 g, 33.58 mmol, 1.1 eq.) and stir for 10 min. Then add DIPEA (7.89 g, 61.06mmol. 2.0 eq.) and M5 (17.70 g, 30.53 mmol. 1.0 eq.) and react at -10 ℃ for 3 h. After TLC showed that the reaction was complete and there was no obvious change in the system, the reaction solution was slowly poured into 500 mL of ice water, and a white solid precipitated. It was filtered, and the filter cake was redissolved in DCM, dried with anhydrous sodium sulfate, and concentrated to remove the solvent to obtain M6 as a white solid (37.5 g, yield: 94%), which was directly used in the next step. HMRS (ESI-MS): Calcd.For [M+H] + =1172.5527 found: 1172.5531.

[0026] .

[0027] 6. Add M6 (37.00 g, 31.56 mmol. 1.0eq.) and dry DMF (228 mL) to a 500 mL three-necked flask and dissolve, then cool to -5°C. Then add piperidine (11.29 g, 144.01 mmol, 4.2 eq.) and DBU (4.75 g, 20.57 mmol. 0.6 eq.). The reaction solution is a pale yellow homogeneous phase. After reacting at -5°C for 1 h, a large amount of white solid precipitates in the system. TLC shows that the reaction is complete. Pour the reaction solution into 200 mL of saturated ammonium chloride aqueous solution, extract three times with EA 300 mL / time, combine the organic phases, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate to remove the solvent. Column chromatography with DCM~5%DCM / MeOH gives M7 as a white foamy solid (27.40 g, yield 91%). HMRS(ESI-MS):Calcd.For[M+H] + =950.4827 found:950.4850.

[0028] .

[0029] 7. Add Fmoc-glycine (8.87 g, 29.84 mmol. 1.05eq.) and dry DMF (142 mL) to a 250 mL three-necked flask, cool to -10 °C, add HATU (11.88 g, 31.26 mmol, 1.1eq.) and stir for 10 min, then add DIPEA (7.35 g, 61.06 mmol. 2.0 eq.) and M7 (27.01 g, 28.41mmol. 1.0 eq.) and react at -10 °C for 3 h. After TLC showed that the reaction was complete and there was no obvious change in the system, the reaction solution was slowly poured into 500 mL of ice water, and a white solid precipitated. Filter, dissolve the filter cake in DCM, add anhydrous sodium sulfate to dry, and then concentrate to remove the solvent to obtain M8 as a white solid (30.01 g, yield 86%), which was directly used in the next step. HMRS(ESI-MS):Calcd.For[M+H] + =1229.5771 found: 1229.5746.

[0030] .

[0031] 8. Add M8 (10.00 g, 8.13 mmol. 1.0eq.) and dry DMF (55 mL) to a 100 mL three-necked flask and dissolve, then cool to -5°C. Then add piperidine (2.91 g, 34.16 mmol, 4.2 eq.) and DBU (1.22 g, 4.88 mmol. 0.6 eq.). The reaction solution is a pale yellow homogeneous phase. After reacting at -5°C for 1 h, a large amount of white solid precipitates in the system. TLC shows that the reaction is complete. Pour the reaction solution into 200 mL of saturated ammonium chloride aqueous solution, extract three times with EA 300 mL / time, combine the organic phases, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and perform DCM~5%DCM / MeOH column chromatography to obtain M9 as a white foamy solid (8.11 g, yield 98%). HMRS(ESI-MS):Calcd.For[M+H] + =1007.5180 found: 1007.5065.

[0032] .

[0033] 9. In a 100 mL reaction bottle, add M9 (1.00 g, 0.99 mmol, 1.00 eq) and dissolve it in dry DMF (12 mL), and cool to -5 °C. Then add nicotinic acid (146.67 mg, 1.19 mmol, 1.20 eq.) and HATU (453.00 mg, 1.19 mmol, 1.20 eq.) to the reaction in sequence; then add DIPEA (256.63 mg, 1.99mmol, 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 and is filtered. The solid is dissolved in DCM (200 mL) again, dried over sodium sulfate, and spin-dried. The crude product was purified by column chromatography (100-200 mesh, 2%-4% MeOH / DCM) to obtain the product M10 (0.98 g, light yellow solid, yield 88%).

[0034] .

[0035] 10. Dissolve M10 (980.0 mg, 0.88 mmol, 1.00 eq) in freshly prepared TFA:EDT:TiPS:H 2 O 94:2.5:1:2.5 (v / v%) (10 mL) in a 100 mL single-mouth bottle. Stir at room temperature for 2 h. The reaction was completed by mass spectrometry monitoring. The reaction was poured into iced ether, and a large amount of solid precipitated, which was filtered. After the solid was dissolved in pure water, it was freeze-dried to obtain the product SL-PP-004 (480.0 mg, off-white powder, yield 97%).

[0036] 1 H NMR (500 MHz, methanol-d4) δ9.25(d, 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).

[0037] .

[0038] 2. Preparation of tranexamic acid-tetrapeptide-7 derivative (I) (SL-PP-005) .

[0039] Referring to the preparation of compound SL-PP-004, Boc-tranexamic acid was used as the raw material to obtain compound SL-PP-005 (477 mg, off-white powder, 2-step yield 81%).

[0040] 1 H NMR (500 MHz, methanol-d4) δ4.64 (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).

[0041] 3. Preparation of pyroglutamic acid-tetrapeptide-7 derivative (I) (SL-PP-008) .

[0042] Referring to the preparation of compound SL-PP-004, L-pyroglutamic acid was used as the raw material 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).

[0043] 4. Preparation of acetylferulic acid-tetrapeptide-7 derivative (I) (SL-PP-016): .

[0044] Referring to the preparation of compound SL-PP-004, acetylferulic acid was used as the raw material 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).

[0045] 5. Preparation of sorbic acid-tetrapeptide-7 derivative (I) (SL-PP-017): .

[0046] Referring to the preparation of compound SL-PP-004, sorbic acid was used as the raw material to obtain compound SL-PP-017 (485 mg, off-white powder, 2-step yield 88%). 1 H 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).

[0047] Preparation of 6-tetrapeptide-7 (SL-PP-006): M9 (1.0 g, 0.99 mmol, 1.0 eq) was dissolved in freshly prepared TFA:EDT:TiPS:H 2 O 94:2.5:1:2.5 (v / v%) (10 mL) in a 100 mL single-mouth bottle. Stir at room temperature for 2 h. The reaction was completed by mass spectrometry monitoring. The reaction was poured into iced ether, and a large amount of solid precipitated and filtered. After the solid was dissolved in pure water, it was lyophilized to obtain the product tetrapeptide-7SL-PP-006 (396.0 mg, off-white powder, yield 87%).

[0048] 1 H 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).

[0049] .

[0050] VII. Preparation of nicotinic acid, tranexamic acid, acetylferulic acid, pyroglutamic acid, sorbic acid-tetrapeptide-7 derivatives (II) (SL-PP-036~040): 1. In a 1 L double-necked round-bottom flask, add the intermediate (S)-2-(Fmoc-amino)-5-oxo-5-(tritylamino)pentanoic acid (29.8 g, 48.72 mmol, 1.0 eq.), dissolve it in dry DMF (163 mL), and then add HATU (20.3 g, 53.59 mmol, 1.1 eq.) and DIPEA (9.5 g, 73.08 mmol, 1.5 eq.) in sequence. The mixture was stirred at room temperature for 0.5 h and then M15 (10.1 g, 48.72 mmol, 1.0 eq.) was added. The reaction was then stirred at room temperature for 2 h. After TLC showed that the reaction was complete, the reaction solution was slowly poured into 400 mL of ice water, and a white solid precipitated. The filter cake was re-dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain M16 as a white solid (33 g, yield: 84%), and the product was used directly in the next step without purification.

[0051] .

[0052] 2. Add M16 (33.0 g, 41.36 mmol, 1.0 eq.) and dry DMF (270 mL) to a 500 mL three-necked flask and dissolve, then 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 solution is a pale yellow homogeneous phase. After reacting at -5°C for 1 h, a large amount of white solid precipitates in the system. TLC shows that the reaction is complete. Pour the reaction solution into 400 mL saturated ammonium chloride aqueous 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. 0-5% DCM / MeOH column chromatography, concentrate to remove the solvent, and obtain M17 as a white foamy solid (21.0 g, yield 88%).

[0053] .

[0054] 3. In a 250 mL three-necked flask, add Boc-glycine (6.4 g, 36.48 mmol, 1.01 eq.) and dry DMF (121 mL) to dissolve, cool to -10°C, and add 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.) in sequence and react at -10°C for 16 h. TLC showed that the reaction was completed and there was no obvious change in the system. The reaction solution was slowly poured into 500 mL of ice water, at which time a white solid precipitated. The filter cake was re-dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain the crude product. The crude product was purified by 0-1% DCM / MeOH column chromatography and concentrated to remove the solvent to obtain M18 as a white foamy solid (25.0 g, yield 93%).

[0055] .

[0056] 4. Add M18 (25.0 g, 34.11 mmol. 1.0 eq.) to a 500 mL three-necked flask, add methanol (170 mL) to dissolve, and then add Pd / C (0.25 g, 5%). After replacing hydrogen three times, the reaction was stirred at room temperature for 4 h. After TLC showed that the reaction was completed, the reaction solution was filtered through diatomaceous earth to recover palladium carbon. The filtrate was concentrated to remove the solvent to obtain M19 as a white solid (21.5 g, yield 98%). The product was used directly in the subsequent steps without purification.

[0057] .

[0058] 5. Add M20 (50.0 g, 32.06 mmol. 1.0 eq) and dry DCM (420 mL) to a 1 L three-necked flask for dispersion. Add tert-butyl trichloroacetimidate (137.7 g, 630.60 mmol, 5.0 eq) at room temperature. After reacting at room temperature for 40 hours, TLC shows that the reaction is complete and a white solid precipitates out of the system. Slowly pour the reaction solution into 500 mL of water, separate the liquids, and extract the aqueous phase with DCM (300 mL) once. Combine the organic phases and dry them over anhydrous sodium sulfate. After concentrating and removing the solvent, obtain the product M21 (52.0 g, yield 91%). Use it directly in the next step without purification.

[0059] .

[0060] 6. Add one of the above organic acids (1.0 eq.) and dry DMF (10 mL / g) to a 250 mL three-necked flask to dissolve, cool to -10 °C, add HATU (1.1 eq.) and DIPEA (1.5 eq.) in turn, stir for 10 min, add M21 (1.0 eq.) and react at -10 °C for 16 h. TLC shows that the reaction is almost complete. Slowly pour the reaction solution into 150 mL of ice water to precipitate a white solid, filter, re-dissolve the filter cake with DCM, add anhydrous sodium sulfate to dry, and then concentrate to remove the solvent. The obtained products are directly used in the next step.

[0061] .

[0062] 7. Add M22a~e (1.0eq) and dry DMF (10 mL / g) to a 500 mL three-necked flask and dissolve, then cool to -5°C. Add piperidine (4.2 eq) and DBU (0.6 eq), react at -5°C for 1 h, and a large amount of white solid precipitates in the system. After TLC shows that the reaction is complete, pour the reaction solution into a saturated aqueous ammonium chloride solution, extract twice with EA, combine the organic phases, wash once with a saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to remove the solvent. Column chromatography with 0~5% DCM / MeOH, concentrate to remove the solvent, and obtain the product M23a~e.

[0063] .

[0064] 8. Add M19 (1.0eq) to a 100 mL three-necked flask and dissolve it in dry DMF (10 mL / g), and cool it to -5°C. Add HATU (1.1 eq) and DIPEA (1.5 eq) in turn, stir for 10 min, then add M23a~e (1.0eq.) and react at -10°C for 16 h. TLC shows that the reaction is complete. Slowly pour the reaction solution into 150 mL of ice water to precipitate a white solid, filter it, re-dissolve the filter cake in DCM, add anhydrous sodium sulfate to dry it, and then concentrate to remove the solvent. The crude product is chromatographed on a 0~1% DCM / MeOH column, and the product M24a~e is obtained after concentration to remove the solvent.

[0065] .

[0066] 9. Dissolve M24a~e in freshly prepared TFA:EDT:TiPS:H 2O 94:2.5:1:2.5 (v / v%) (20 mL / g) in a 100 mL single-mouth bottle. Stir at room temperature for 2 h. The reaction is completed by mass spectrometry monitoring. Pour the reaction into iced ether, a large amount of solid precipitates, and filter. The solid is rinsed with ether and dissolved in purified water, and freeze-dried to obtain the product SL-PP-036~040.

[0067] .

[0068] 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, 5.4Hz, 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).

[0069] 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).

[0070] 1 H 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).

[0071] 1 H 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, J = 8.3, 5.9 Hz, 1H), 4.45 (dd, J = 8.6, 4.5 Hz, 2H), 3.86 (s, 1H), 3.74 (s, 3H), 3.72 (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).

[0072] 1 H 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).

[0073] Example 2 Effects of tetrapeptide-7 derivatives on the expression of tumor necrosis factor-α (TNF-α) in human immortalized keratinocytes (HaCat) Test principle: Skin exposed to toxic and harmful substances in the living environment may cause a certain degree of skin inflammation, such as skin redness, swelling, itching, etc. The irritation phenotype of cosmetics on the skin is mainly manifested as skin inflammation. In the early stage of inflammation, it is mainly manifested as capillary dilation, hyperpermeability and edema. Various inflammatory factors play a key role in the occurrence of acute and chronic inflammation, such as Interleukin-1α (IL-1α) and Tumor Necrosis Factor-A (TNF-α). A photoaging model was established using HaCat and UVB. After the test article was applied to HaCat damaged by UVB, the expression levels of TNF-α and IL-1α were detected, which can evaluate the anti-inflammatory and soothing effects of the test article.

[0074] Test method: After HaCat cells were revived, they were cultured in DMEM high-glucose medium containing 10% FBS at 37°C and 5% CO 2 Culture in an incubator and subculture at a ratio of 1:3. Take the HaCat in the logarithmic growth phase, digest it, resuspend it, and count it; 4 Each well was inoculated into a 96-well plate and incubated in DMEM high-glucose medium containing 10% FBS at 37°C and 5% CO 2 Culture overnight to allow the cells to adhere to the wall; discard the old culture medium and gently rinse the cells once with 200 μL PBS; set up a blank group, a model group, and a test group; the blank group was replaced with 200 μL 1% FBS culture medium at 37°C and 5% CO 2 After 24 h of culture, the model group and the test group were replaced with 50 μL PBS. The model group and the test group were irradiated with 30 mJ UVB in the UV crosslinker. PBS was discarded, and 200 μL 1% FBS medium was added to the model group, and 200 μL of the test sample solution prepared with the above medium to a final concentration of 0.05 mg / mL was added to each well of the test group. The cells were incubated at 37°C and 5% CO. 2 After culturing for 24 h, the cell supernatant was collected and the expression levels of TNF-α and IL-1α were detected using ELISA kits.

[0075] Calculation formula: TNF-α expression inhibition rate = (UT) / U×100%.

[0076] Where: T is the average value of TNF-α expression in the test sample; U is the average value of TNF-α expression in the model group.

[0077] Experimental groups: Blank group: cultured in medium containing 1% FBS. Model group: cultured in 30 mJ UVB + 1% FBS medium. Test group: cultured in 30 mJ UVB + test sample with a final concentration of 0.05 mg / mL + 1% FBS medium. For physically mixed test samples, the preparation ratio is to mix the two samples at a molar ratio of 1:1, and then prepare the test sample with a final concentration of 0.05 mg / mL.

[0078] Result analysis: The test results are shown in Table 1: Table 1. TNF-α expression inhibition rate test results 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 derivatives (Ⅰ) 3.3510 25.13% Nicotinic acid-tetrapeptide-7 derivative (Ⅱ) 3.1368 29.92% niacin 4.3391 3.06% Tetrapeptide-7 + Niacin 4.4657 0.23% Tranexamic acid-tetrapeptide-7 derivative (Ⅰ) 3.3360 25.47% Tranexamic acid-tetrapeptide-7 derivative (Ⅱ) 3.4810 22.23% Tranexamic acid 5.4373 -21.48% Tetrapeptide-7 + Tranexamic Acid 4.7302 -5.68% Acetylferulic acid-tetrapeptide-7 derivative (Ⅰ) 3.2270 27.90% Acetylferulic acid-tetrapeptide-7 derivative (Ⅱ) 3.3534 25.08% Acetylferulic acid 4.2091 5.96% Tetrapeptide-7 + acetylferulic acid 4.3901 1.92% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅰ) 3.8150 14.77% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅱ) 4.9343 10.24% Pyroglutamate 6.9550 -55.38% Tetrapeptide-7 + pyroglutamic acid 5.8322 -30.30% Sorbic acid-tetrapeptide-7 derivatives (Ⅰ) 3.3930 24.20% Sorbic acid-tetrapeptide-7 derivatives (Ⅱ) 4.2692 4.62% Sorbic acid 5.0906 -13.73% Tetrapeptide-7+sorbic acid 6.5005 -45.23% From the results in Table 1, it can be seen that the single use of tetrapeptide-7, tranexamic acid, pyroglutamic acid, and sorbic acid has no effect of inhibiting TNF-α, and the effect of nicotinic acid and acetylferulic acid in inhibiting TNF-α is very weak. The combination of tetrapeptide-7 with nicotinic acid, tranexamic acid, acetylferulic acid, pyroglutamic acid, and sorbic acid also has no effect of inhibiting TNF-α. In addition to pyroglutamic acid-tetrapeptide-7 derivatives (II) and sorbic acid-tetrapeptide-7 derivatives (II), the tetrapeptide-7 derivatives of the present invention have significantly improved effects of inhibiting TNF-α, among which the derivatives of formula (I) have better effects than the derivatives of formula (II), indicating that the derivatives of the present invention have excellent anti-inflammatory activity.

[0079] Example 3 Effects of tetrapeptide-7 derivatives on the expression of interleukin-1α (IL-1α) in human immortalized keratinocytes (HaCat).

[0080] See Example 2 for the test method.

[0081] Calculation formula: IL-1α expression inhibition rate = (UI) / U×100%.

[0082] Wherein: I—average value of IL-1α expression level of the test sample; U—average value of IL-1α expression level of the model group.

[0083] Experimental groups: Blank group: cultured in medium containing 1% FBS. Model group: cultured in 30 mJ UVB + 1% FBS medium. Test group: cultured in 30 mJ UVB + test sample with a final concentration of 0.05 mg / mL + 1% FBS medium. For physically mixed test samples, the preparation ratio is to mix the two samples at a molar ratio of 1:1, and then prepare the test sample with a final concentration of 0.05 mg / mL.

[0084] Result analysis: The test results are shown in Table 2.

[0085] Table 2. IL-1α expression inhibition rate test results Experimental Group I (pg / mL) Inhibition rate Blank group 26.9737 / Model Group 30.3644 0.00% Palmitoyl Tetrapeptide-7 27.9659 7.90% Tetrapeptide-7 32.204 -6.06% Nicotinic acid-tetrapeptide-7 derivatives (Ⅰ) 25.6284 15.60% Nicotinic acid-tetrapeptide-7 derivative (Ⅱ) 23.9788 21.03% niacin 34.7119 -14.32% Tetrapeptide-7 + Niacin 33.4707 -10.23% Tranexamic acid-tetrapeptide-7 derivative (Ⅰ) 25.0535 17.49% Tranexamic acid-tetrapeptide-7 derivative (Ⅱ) 32.9727 -8.59% Tranexamic acid 28.5597 5.94% Tetrapeptide-7 + Tranexamic Acid 29.8421 1.72% Acetylferulic acid--tetrapeptide-7 derivative (Ⅰ) 25.0535 17.49% Acetylferulic acid-tetrapeptide-7 derivative (Ⅱ) 26.8361 11.62% Acetylferulic acid 32.204 -6.06% Tetrapeptide-7 + acetylferulic acid 31.6822 -4.34% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅰ) 26.2071 13.69% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅱ) 33.6013 -10.66% Pyroglutamate 39.9202 -31.47% Tetrapeptide-7 + pyroglutamic acid 36.3401 -19.68% Sorbic acid-tetrapeptide-7 derivatives (Ⅰ) 23.3512 23.10% Sorbic acid-tetrapeptide-7 derivatives (Ⅱ) 35.4262 -16.67% Sorbic acid 26.7896 11.77% Tetrapeptide-7+sorbic acid 29.5537 2.67% From the results in Table 2, it can be seen that the single use of tetrapeptide-7, nicotinic acid, acetylferulic acid, and pyroglutamic acid has no effect of inhibiting TNF-α, and the effect of tranexamic acid and sorbic acid on inhibiting IL-1α is not high. When tetrapeptide-7 is used in combination with one of nicotinic acid, tranexamic acid, acetylferulic acid, pyroglutamic acid, and sorbic acid, some of them have no effect of inhibiting IL-1α, and some have weak effects. The tetrapeptide-7 derivatives of formula (I) and nicotinic acid-tetrapeptide-7 derivatives (II) of the present invention have significantly improved effects on inhibiting IL-1α, indicating that the derivatives of the present invention have excellent anti-inflammatory activity.

[0086] Example 4 Effect of the derivatives of tetrapeptide-7 of the present invention on the expression of matrix metalloproteinase MMP-1 in human foreskin fibroblasts (HFF-1) Test principle: Photoaging is mainly caused by ultraviolet light exposure, free radicals and physical stimulation. The ultraviolet rays that reach our skin are mainly composed of UVA and UVB. Excessive exposure to UVA and UVB is associated with skin aging, and external manifestations include wrinkles, spots and sagging skin. Ultraviolet radiation causes dermal fibroblasts to secrete matrix metalloproteinases (MMPs), thereby degrading a series of extracellular matrices including collagen, ultimately leading to the formation of wrinkles. Among the enzymes produced by UV, MMP-1 plays one of the most important roles in the process of degrading collagen, so it has become one of the important targets for alleviating photoaging and evaluating anti-wrinkle efficacy. Human skin fibroblasts were irradiated with UVB to model photoaging, and then the test sample was added. The anti-photoaging effect of the test sample was evaluated by comparing the content of MMP-1 secreted by fibroblasts with and without the test sample.

[0087] Test method: After HFF-1 cells were revived, they were cultured in DMEM high-glucose medium containing 10% FBS at 37°C and 5% CO 2 Culture in an incubator and subculture at a ratio of 1:3. Take HFF-1 cells in the logarithmic growth phase, digest and resuspend them, and count them; 4 Each well was inoculated into a 96-well plate and incubated in DMEM high-glucose medium containing 10% FBS at 37°C and 5% CO 2 Culture overnight to allow the cells to adhere to the wall; discard the old culture medium and gently rinse the cells once with 200 μL PBS; set up a blank group, a model group, and a test group; the blank group was replaced with 200 μL 1% FBS culture medium at 37°C and 5% CO 2After 24 h of culture, the model group and the test group were replaced with 50 μL PBS; the model group and the test group were irradiated with 30 mJ UVB in a UV crosslinker. PBS was discarded, and 200 μL 1% FBS medium was added to the model group and 200 μL of the test sample solution prepared with the above medium to a final concentration of 0.05 mg / mL was added to each well of the test group. The cells were incubated at 37°C and 5% CO. 2 After culturing for 24 h, the cell supernatant was collected and the expression of human matrix metalloproteinase 1 (MMP-1) was detected using human matrix metalloproteinase 1 (MMP-1) ELISA kit.

[0088] Calculation formula: MMP-1 expression inhibition rate = (UM) / U×100%.

[0089] Wherein: M—the average value of MMP-1 expression in the test sample; U—the average value of MMP-1 expression in the model group.

[0090] Experimental groups: Blank group: cultured in medium containing 1% FBS. Model group: cultured in 30 mJ UVB + 1% FBS medium. Test group: cultured in 30 mJ UVB + test sample with a final concentration of 0.05 mg / mL + 1% FBS medium. For physically mixed test samples, the preparation ratio is to mix the two samples at a molar ratio of 1:1, and then prepare the test sample with a final concentration of 0.05 mg / mL.

[0091] Result analysis: The test results are shown in Table 3.

[0092] Table 3. MMP-1 expression inhibition rate test results Experimental Group M (ng / mL) Inhibition rate Blank group 0.3960 / Model Group 1.5200 0.00% Palmitoyl Tetrapeptide-7 0.8856 41.74% Tetrapeptide-7 1.1908 21.66% Nicotinic acid-tetrapeptide-7 derivative (Ⅰ) 0.3220 78.82% Nicotinic acid-tetrapeptide-7 derivative (Ⅱ) 0.3400 77.63% niacin 1.3515 11.08% Tetrapeptide-7 + Niacin 1.2973 14.65% Tranexamic acid-tetrapeptide-7 derivative (Ⅰ) 0.5911 61.11% Tranexamic acid-tetrapeptide-7 derivative (Ⅱ) 0.8767 42.32% Tranexamic acid 1.3515 11.08% Tetrapeptide-7 + Tranexamic Acid 1.3183 13.27% Acetylferulic acid--tetrapeptide-7 derivative (Ⅰ) 0.2950 80.59% Acetylferulic acid-tetrapeptide-7 derivative (Ⅱ) 0.6065 60.10% Acetylferulic acid 1.5336 -0.90% Tetrapeptide-7 + Acetylferulic acid 1.1941 21.44% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅰ) 1.5160 0.26% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅱ) 1.2666 16.67% Pyroglutamate 1.6570 -9.01% Tetrapeptide-7 + pyroglutamic acid 1.5372 -1.13% Sorbic acid-tetrapeptide-7 derivatives (Ⅰ) 0.3660 75.92% Sorbic acid-tetrapeptide-7 derivatives (Ⅱ) 1.1908 21.66% Sorbic acid 1.1908 21.66% Tetrapeptide-7+sorbic acid 1.1695 23.06% From the results in Table 3, it can be seen that although the inhibition rate of tetrapeptide-7 on MMP-1 is 21.66%, the inhibition rate is significantly reduced when it is used in combination with nicotinic acid, tranexamic acid, and pyroglutamic acid, while the inhibition rate does not change significantly when it is used in combination with acetylferulic acid or sorbic acid. The derivatives described in the present invention, except for the pyroglutamic acid-tetrapeptide-7 derivative (I) and the sorbic acid-tetrapeptide-7 derivative (II), the other derivatives have significantly improved the inhibitory effect of MMP-1, indicating that the derivatives described in the present invention have excellent anti-wrinkle activity.

[0093] Example 5 Effect of the derivatives of tetrapeptide-7 of the present invention on the production of human type I collagen in human foreskin fibroblasts (HFF-1) Test principle: Type I collagen is one of the main components of the extracellular matrix of dermal cells. Type I procollagen is synthesized by dermal fibroblasts in the cells and secreted outside the cells. Under the action of terminal procollagen peptidase, the terminal peptides are separated and polymerized to form collagen fibers. The mesh structure of collagen 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 to study the improvement of type I collagen content in cosmetics. By measuring the increase rate of type I collagen content after blank control and test product administration, the effectiveness of the test product in promoting collagen synthesis can be evaluated.

[0094] Test method: After HFF-1 cells were revived, they were cultured in DMEM high-glucose medium containing 10% FBS at 37°C and 5% CO 2 Culture in an incubator and subculture at a ratio of 1:3. Take HFF-1 cells in the logarithmic growth phase, digest and resuspend them, and count them; 4 Each well was inoculated into a 96-well plate and incubated in DMEM high-glucose medium containing 10% FBS at 37°C and 5% CO 2 Culture overnight to allow the cells to adhere to the wall; discard the old culture medium and gently rinse the cells once with 200 μL PBS; set up a blank group, a model group, and a test group; add culture medium containing a final concentration of 0.05 mg / mL of the test sample to the wells of the test group, and add normal cell culture medium to the control wells of the blank group, 200 μL per well. After the administration, place the 96-well plate in a CO 2 The cells were cultured in an incubator for 24 h. After the incubation, 200 μL of cell culture supernatant was collected from each well 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 enzyme-linked immunosorbent assay kit. Calculation formula: Increase rate = (TC) / C×100%.

[0095] Where: T is the average content of type I collagen in the test sample; C is the average content of type I collagen in the blank control.

[0096] Experimental groups: Blank group: normal cell culture medium culture. Test group: culture medium culture with a final concentration of 0.05 mg / mL test sample. For physically mixed test samples, the preparation ratio is to mix the two samples at a molar ratio of 1:1, and then prepare the test sample with a final concentration of 0.05 mg / mL.

[0097] Result analysis: The test results are shown in Table 4.

[0098] Table 4. Test results of promoting human type I collagen production Experimental Group T (ng / mL) Increase the ratio Blank group 10.2348 / Model Group 1.5200 0.00% Palmitoyl Tetrapeptide-7 14.9918 46.48% Tetrapeptide-7 10.0908 -1.41% Nicotinic acid-tetrapeptide-7 derivatives (Ⅰ) 17.3879 69.89% Nicotinic acid-tetrapeptide-7 derivative (Ⅱ) 17.9795 75.67% niacin 11.5755 13.10% Tetrapeptide-7 + Niacin 10.3013 0.65% Tranexamic acid-tetrapeptide-7 derivative (Ⅰ) 17.8438 74.34% Tranexamic acid-tetrapeptide-7 derivative (Ⅱ) 11.8110 15.40% Tranexamic acid 10.0818 -1.49% Tetrapeptide-7 + Tranexamic Acid 9.2226 -9.89% Acetylferulic acid--tetrapeptide-7 derivative (Ⅰ) 17.8508 74.41% Acetylferulic acid-tetrapeptide-7 derivative (Ⅱ) 15.4904 51.35% Acetylferulic acid 8.9788 -12.27% Tetrapeptide-7 + acetylferulic acid 9.0875 -11.21% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅰ) 16.2769 59.04% Pyroglutamic acid-tetrapeptide-7 derivatives (Ⅱ) 10.2860 0.50% Pyroglutamate 10.1228 -1.09% Tetrapeptide-7 + pyroglutamic acid 10.0414 -1.89% Sorbic acid-tetrapeptide-7 derivatives (Ⅰ) 11.5755 13.10% Sorbic acid-tetrapeptide-7 derivatives (Ⅱ) 9.2359 -9.76% Sorbic acid 10.1058 -1.26% Tetrapeptide-7+sorbic acid 10.3433 1.06% From the results in Table 4, it can be seen that the use of tetrapeptide-7, tranexamic acid, acetylferulic acid, pyroglutamic acid, sorbic acid alone, and the combination of tetrapeptide-7 with niacin, tranexamic acid, acetylferulic acid, pyroglutamic acid, and sorbic acid have no effect of upregulating Col-Ⅰ. The derivatives described in the present invention, except for the pyroglutamic acid-tetrapeptide-7 derivative (II) and the sorbic acid-tetrapeptide-7 derivative (II), have significantly improved the effect of upregulating Col-Ⅰ compared with tetrapeptide-7, indicating that the derivatives described in the present invention have excellent effects in promoting collagen synthesis.

[0099] Abbreviation definitions: IL-1-α: interleukin 1 alpha TNF-α: Tumor necrosis factor (TNF) alpha MMP-1: human matrix metalloproteinase 1 Col-1: Human type I collagen MeOH: Methanol DCM: Dichloromethane EA: Ethyl acetate PE: Petroleum ether HATU: 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIPEA: Diisopropylethylamine DMF: N,N-dimethylformamide DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene TFA: trifluoroacetic acid EDT: 1,2-Ethanedithiol TIS: triisopropylsilane.

Claims

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

2. The salt of the pyroglutamic acid-tetrapeptide-7 derivative according to claim 1, characterized in that The pyroglutamic acid-tetrapeptide-7 derivative forms a salt with an acid or a base.

3. The salt of the pyroglutamic acid-tetrapeptide-7 derivative according to claim 2, characterized in that The acid is an organic acid or an inorganic acid, 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 alkaline 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 and triethanolamine.

4. Use of the pyroglutamic acid-tetrapeptide-7 derivative according to claim 1 or the salt of the pyroglutamic acid-tetrapeptide-7 derivative according to claim 2 or 3 in the preparation of anti-inflammatory drugs or daily chemicals that promote the production of collagen and / or elastin.

5. The use according to claim 4, characterized in that The medicine or daily chemical product is a skin external product.

6. The use according to claim 4, characterized in that The daily chemical products are cosmetics or skin care products.

7. The use according to claim 4, characterized in that The content of the pyroglutamic acid-tetrapeptide-7 derivative in daily chemical products is 0.01%-1.00%, w / w.

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