2, 4-dihydroxy phenyl thiazole derivative and application thereof

Abstract

The invention belongs to the technical field of cosmetics and medicinal chemistry, and discloses a 2, 4-dihydroxy phenyl thiazole derivative and application thereof. The invention discloses a 2, 4-dihydroxy phenyl thiazole derivative, which has a structure as shown in the following formula, wherein n1 and n2 are respectively and independently 1, 2, 3 or 4; r is methyl or ethyl. Compared with the existing peptidomidogen compounds, the 2, 4-dihydroxy phenyl thiazole derivative disclosed by the invention has the advantages that the solubility and the physical and chemical stability are remarkably improved through molecular modification while the active structure of a parent nucleus is maintained, and the pharmacokinetic characteristics are optimized. The derivative can effectively inhibit the activity of tyrosinase, and can be used as an active component for preparing a novel tyrosinase inhibitor, related whitening and freckle-removing cosmetics and drugs for treating tyrosinase-related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cosmetic and pharmaceutical chemistry, and particularly relates to a 2,4-dihydroxyphenyl thiazole derivative and application thereof. BACKGROUND

[0002] The color of the skin is mainly determined by melanin, and the excessive synthesis and abnormal deposition of melanin can cause various pigmentation diseases, such as chloasma, freckle, age spot, and uneven skin tone caused by ultraviolet radiation, inflammation or hormone change. The key rate-limiting step of melanin biosynthesis is catalyzed by tyrosinase, which oxidizes L-tyrosine to L-dopa and then continues to convert to dopaquinone. Therefore, inhibiting the activity of tyrosinase is one of the most effective strategies to control melanin production, achieve skin whitening and treat pigmentation.

[0003] At present, there are many tyrosinase inhibitors on the market, but most of them have defects such as limited effect, poor stability or safety problems. For example, arbutin, a natural product extracted from bearberry leaves, is a hydroquinone glycoside derivative, which can effectively inhibit the biosynthesis of melanin by competitively occupying the active center of tyrosinase, and has high safety, but the whitening effect is relatively weak, and free hydroquinone is easily decomposed under high temperature or acidic conditions, which brings safety hazards. Kojic acid, which is derived from fungal metabolites, can inhibit the function of tyrosinase by chelating copper ions in the active center of the enzyme, but it has poor stability, is easy to oxidize and discolor, and is sensitive to light and heat, and may cause skin irritation or contact dermatitis at high concentrations. In addition, vitamin C and its derivatives mainly whiten through reduction, but they are extremely unstable and easy to be oxidized, and also have poor transdermal absorption performance. In order to overcome the defects of the prior art, developing new tyrosinase inhibitors with high efficiency, safety and stability has always been a research hotspot and difficulty in the field.

[0004] Thiamidol (chemical name: 4-(1-phenylpropyl)-1,3-benzene diol, trade name: Thiamidol) is a breakthrough inhibitor discovered in recent years. Its structural formula is as follows. The molecule can precisely embed into the catalytic active cavity of human tyrosinase (hTyr), interact with key amino acid residues (including H180, H202, H211, F386 and H390, etc.), and thus effectively block the enzyme catalytic function. Clinical studies have proved that it has significantly better efficacy than traditional whitening ingredients.

[0005] .

[0006] However, thiamidol still has certain limitations, such as suboptimal bioavailability and safety that needs to be further clarified, which to some extent limits its more extensive application. SUMMARY

[0007] In view of the above problems existing in the prior art, the purpose of the present application is to provide a 2,4-dihydroxyphenyl thiazole derivative and application thereof.

[0008] To solve the above problems, the present application provides the following technical solutions. In a first aspect, the present application provides a 2,4-dihydroxyphenyl thiazole derivative, having the following structure: ; In the formula, n1 and n2 are each independently 1, 2, 3 or 4; and R is methyl or ethyl.

[0009] In an embodiment of the present application, the 2,4-dihydroxyphenyl thiazole derivative has any one of the following structures: 、 、 、 、 、 、 、 、 .

[0010] In a second aspect, the present application provides a preparation method of a 2,4-dihydroxyphenyl thiazole derivative, comprising the following steps: ; protecting the phenolic hydroxyl group of compound 1 to obtain compound 2; reacting compound 2 with N,N-carbonyldiimidazole to obtain compound 3; condensing compound 3 with a secondary amine to obtain compound A; deprotecting compound A under acidic conditions to obtain the 2,4-dihydroxyphenyl thiazole derivative.

[0011] In an embodiment of the present application, the phenolic hydroxyl protecting group can be selected from one of MOM, BOM, TMS, TBS, TES, TBDPS or TIPS.

[0012] In an embodiment of the present application, the phenolic hydroxyl protecting group is TBS.

[0013] In an embodiment of the present application, the phenolic hydroxyl protecting group reagent can be selected from TBSCl.

[0014] In an embodiment of the present application, compound 1 is used as the starting material, solvent, imidazole, DMAP and TBSCl are added and reacted to protect the phenolic hydroxyl group to obtain compound 2.

[0015] In an embodiment of the present application, compound 1 is used as the starting material, solvent, imidazole, DMAP and TBSCl are added and reacted at 10-30°C to protect the phenolic hydroxyl group to obtain compound 2.

[0016] In an embodiment of the present application, the molar ratio of compound 2 to N,N-carbonyldiimidazole is 1:1-2.

[0017] In an embodiment of the present application, the temperature for the reaction of compound 2 with N,N-carbonyldiimidazole is 10-30°C.

[0018] In an embodiment of the present application, the temperature for the reaction of compound 2 with N,N-carbonyldiimidazole is 20-30°C.

[0019] In an embodiment of the present application, the secondary amine is selected from N,N-di(alkoxyalkyl)amines.

[0020] In an embodiment of the present application, the N,N-di(alkoxyalkyl)amine is selected from one of bis(2-methoxyethyl)amine, bis(2-methoxypropyl)amine, bis(2-methoxybutyl)amine, 2-methoxy-N-(methoxymethyl)ethan-1-amine, 4-methoxy-N-(methoxymethyl)butan-1-amine, bis(2-ethoxyethyl)amine, 3-ethoxy-N-(2-ethoxyethyl)propan-1-amine, 4-ethoxy-N-(3-ethoxypropyl)butan-1-amine.

[0021] In an embodiment of the present application, the temperature for the condensation reaction of compound 3 with the secondary amine is 10-30°C.

[0022] In an embodiment of the present application, the temperature for the condensation reaction of compound 3 with the secondary amine is 20-30°C.

[0023] In an embodiment of the present application, triethylamine is also added during the condensation reaction of compound 3 with the secondary amine.

[0024] In an embodiment of the present application, the acid used in the acidic condition is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid.

[0025] In an embodiment of the present application, the temperature for the deprotection reaction is 0±5°C.

[0026] In an embodiment of the present application, the time for the deprotection reaction is 1-6 h.

[0027] In an embodiment of the present application, the time of the deprotection reaction is 4-6 h.

[0028] In a third aspect, the present application provides a composition comprising a 2,4-dihydroxyphenylthiazole derivative, or a pharmaceutically acceptable salt thereof.

[0029] In a fourth aspect, a preparation comprising the composition and optionally one or more pharmaceutically acceptable carriers or excipients is also within the scope of the present application.

[0030] In an embodiment of the present application, the amount of the 2,4-dihydroxyphenylthiazole derivative added in the composition is 0.000001% to 10% of the total weight of the preparation.

[0031] In a fifth aspect, the use of a 2,4-dihydroxyphenylthiazole derivative in the preparation of a tyrosinase inhibitor drug is also within the scope of the present application.

[0032] The use of a 2,4-dihydroxyphenylthiazole derivative in the preparation of a whitening product is also within the scope of the present application.

[0033] The use of a 2,4-dihydroxyphenylthiazole derivative in the preparation of a drug for pigmentary diseases is also within the scope of the present application.

[0034] Compared with the prior art, the present application has the following beneficial effects: The present application uses compound 1 as a starting material, protects the phenolic hydroxyl group with TBS, reacts the amino group with N,N-carbonyldiimidazole, then condenses with a secondary amine, and finally deprotects to obtain a 2,4-dihydroxyphenylthiazole derivative. Compared with existing peptide anmides, the 2,4-dihydroxyphenylthiazole derivative of the present application, while maintaining the active structure of the parent nucleus, significantly improves the solubility and physicochemical stability through molecular modification, and optimizes the pharmacokinetic characteristics. This kind of derivative can effectively inhibit the activity of tyrosinase, and can be used as an active ingredient to prepare a new tyrosinase inhibitor and related whitening and freckle-removing cosmetics and drugs for tyrosinase-related diseases. DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0036] The materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.

[0037] Example 1: Synthesis of compound 2 ; To the reaction flask was added compound 1 (25.00 g) and DMF (75.0 mL) at 20-30 °C, and the temperature was lowered to 0±5 °C. Imidazole (24.54 g) and DMAP (45.29 g) were added, and a solution of TBSCl (45.29 g) in DMF (75.0 mL) was slowly added dropwise. The temperature was raised to 20-30 °C, and the reaction was stirred for 5.0 h. TLC detection showed that the starting material was completely reacted. The temperature was lowered to 0±5 °C, and the reaction was quenched with saturated ammonium chloride (75.0 mL). The reaction was extracted with dichloromethane (75.0 mL x 2), and the combined organic phases were washed with saturated brine (25.0 mL x 2). The organic phase was concentrated under reduced pressure at 40-45 °C to obtain a crude product. Column chromatography gave 40.95 g of compound 2, with a yield of 78%.

[0038] Example 2: Synthesis of compound 3 ; To the reaction flask was added N,N-carbonyldiimidazole (4.46 g, 27.52 mmol) and dichloromethane (50.0 mL) at 20-30 °C. A solution of compound 2 (10.0 g, 22.93 mmol) in dichloromethane (50.0 mL) was slowly added dropwise at a temperature not exceeding 30 °C. The addition was completed in 3.0 h, and the reaction was continued for 8.0 h. TLC detection showed that the starting material was substantially completely reacted. Filtration was performed, and the filtrate was directly used in the next step.

[0039] Example 3: Synthesis of compounds A1-A9 ; To the reaction flask was added a dichloromethane solution of compound 3 obtained in the previous step at 20-30 °C. Bis(2-methoxyethyl)amine (4.83 g, 29.81 mmol) was added dropwise, and the temperature was controlled to not exceed 30 °C. Triethylamine (5.64 g, 45.86 mmol) was then added dropwise, and the temperature was controlled to not exceed 30 °C. The reaction was stirred at 20-30 °C for 12.0 h. TLC detection showed that the starting material was completely reacted. The reaction was washed with water (20.0 mL), and the organic phase was concentrated under reduced pressure at 40-45 °C to obtain a crude product. Column chromatography gave 9.85 g of the product, with a two-step yield of 72%.

[0040] The above bis (2-methoxyethyl) amine is replaced with equimolar bis (2-methoxy methyl) amine, bis (2-methoxy propyl) amine, bis (2-methoxy butyl) amine, 2-methoxy-N- (methoxymethyl) ethyl-1-amine, 4-methoxy-N- (methoxymethyl) butyl-1-amine, bis (2-ethoxy ethyl) amine, 3-ethoxy-N- (2-ethoxy ethyl) propyl-1-amine, 4-ethoxy-N- (3-ethoxy propyl) butyl-1-amine, respectively, to obtain A1, A3, A4, A5, A6, A7, A8 and A9, respectively, in a yield of 70% to 85%.

[0041] Example 4: Synthesis of compounds B1-B9 ; At 20-30 °C, A (8.40 mmol) and THF (25.0 mL) are added to a reaction bottle, cooled to 0±5 °C, 2N hydrochloric acid (25.0 mL) is added dropwise, and the reaction is continued for 5.0 h. TLC detects that the raw material is completely reacted, the layers are separated, the water phase is extracted with THF (25.0 mL x 2), and the organic phases are combined. The THF is removed by concentration under reduced pressure at 35-40 °C to obtain the crude product, and column chromatography gives the product B in a yield of 75-80%.

[0042] The structural characterization data of B1 are as follows: 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 10.13 (s,1H), 9.62 (s, 1H), 7.71 – 7.59 (m, 1H), 7.25 (s, 1H), 6.35 – 6.21 (m, 2H),4.79 (s, 4H), 3.22 (s, 6H). ESI-MS:m / z 340.0 [M+H] + ; The structural characterization data of B2 are as follows: 1 H NMR (400 MHz, DMSO) δ 11.27 (s, 1H), 10.66 (s,1H), 9.45 (s, 1H), 7.63 – 7.55 (m, 1H), 7.25 (s, 1H), 6.32 – 6.25 (m, 2H),3.60 - 3.58 (m, 4H), 3.49 (t, J = 5.4 Hz, 4H), 3.28 (s, 6H). ESI-MS:m / z 367.9[M+H] + ; The structural characterization data of B3 are as follows: 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 10.43 (s, 1H), 9.32 (s, 1H), 7.69 - 7.61 (m, 1H), 7.32 (s, 1H), 6.33 - 6.26 (m, 2H), 3.36 (t, J = 6.5 Hz, 4H), 3.23 - 3.16 (m, 10H), 1.83 (p, J = 6.6 Hz, 4H). ESI-MS: m / z 396.1 [M+H] + ; Structural characterization data for B4 are: 1 H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.91 (s, 1H), 9.66 (s, 1H), 7.77 - 7.61 (m, 1H), 7.37 (s, 1H), 6.39 - 6.28 (m, 2H), 3.36 (t, J = 5.9 Hz, 4H), 3.20 (t, J = 6.2 Hz, 4H), 3.18 (s, 6H), 1.74 - 1.66 (m, 4H), 1.66 - 1.56 (m, 4H). ESI-MS: m / z 424.1 [M+H] + ; Structural characterization data for B5 are: 1 H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.91 (s, 1H), 9.66 (s, 1H), 7.77 - 7.61 (m, 1H), 7.37 (s, 1H), 6.39 - 6.28 (m, 2H), 4.80 (s, 2H), 3.57 (t, J = 5.9 Hz, 2H), 3.43 (t, J = 5.9 Hz, 2H), 3.28 (d, J = 8.4 Hz, 6H). ESI-MS: m / z 354.1 [M+H] + ; Structural characterization data for B6 are: 1H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 9.43 (s,1H), 9.38 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 6.63 – 6.54 (m, 2H), 6.43 (d, J = 2.2 Hz, 1H), 4.79 (s, 2H), 3.38 (t, J = 6.0 Hz, 2H), 3.25 (s, 3H), 3.28 (t, J = 6.2 Hz, 2H), 3.11 (s, 3H), 1.75 – 1.67 (m, 2H), 1.67 – 1.56 (m, 2H). ESI-MS:m / z 382.1 [M+H] + ; Structural characterization data for B7 are: 1 H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 10.11 (s,1H), 9.54 (s, 1H), 7.72 – 7.59 (m, 1H), 7.21 (s, 1H), 6.33 – 6.21 (m, 2H),3.57 (t, J = 6.1 Hz, 4H), 3.50 (q, J = 6.2 Hz, 4H), 3.41 (t, J = 6.0 Hz, 4H),1.06 (t, J = 6.2 Hz, 6H). ESI-MS:m / z 396.1 [M+H] + ; Structural characterization data for B8 are: 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.86 (s,1H), 9.33 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 6.63 - 6.53 (m, 2H), 6.42 (d, J= 2.2 Hz, 1H), 3.59 (t, J = 6.0 Hz, 2H), 3.55 - 3.41 (m, 6H), 3.31 (t, J =6.1 Hz, 2H), 3.22 (t, J = 7.0 Hz, 2H), 1.88 (m, 2H), 1.08 (m, 6H). ESI-MS: m / z 410.2 [M+H] + ; Structural characterization data of B9 are: 1 H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 9.63 (s,1H), 9.34 (s, 1H), 7.59 (d, J = 9.1 Hz, 1H), 6.69 - 6.57 (m, 2H), 6.47 (d, J = 2.3 Hz, 1H), 3.59 - 3.39 (m, 8H), 3.26 - 3.18 (m, 4H), 1.84 (m, 2H), 1.79 -1.64 (m, 2H), 1.65 - 1.52 (m, 2H), 1.18 (t, J = 6.2 Hz, 6H). ESI-MS: m / z 438.2 [M+H] + .

[0043] The inhibitory activity of the compounds on tyrosinase was determined by the improved MBTH method (Journal of biochemical and biophysical methods, 1994, 28(3): 173-183.) 3-methyl-2-benzothiazolinone (MBTH) was used as a chromogenic reagent, and the human tyrosinase oxidized levodopa to levodopaquinone, which then reacted with MBTH to produce a colored product. The reaction was terminated and the specific absorption of the product at 505 nm was determined to determine the inhibitory activity of compounds B1-B9 on human tyrosinase, and the results are shown in Table 1.

[0044] Table 1 ; ; ; ; ; Example 5: Preparation of emulsion containing 2,4-dihydroxyphenyl thiazole derivative The formula is shown in Table 2: Table 2 ; ; ; ; ; Preparation method: According to the mass fraction of each component shown in Table 2, polyglycerol-3-methyl glucose distearate, hydrogenated polydecene, oleyl erucate, ethyl ethyl palmitate, dimethicone, methyl paraben, butylated hydroxytoluene were added as the oil phase into the oil phase preparation tank and heated to dissolve, and cyclopentasiloxane was added and stirred to disperse.

[0045] Water, glycerol, propylene glycol, butylene glycol, dipropylene glycol, betaine salicylate, EDTA trisodium, acryloyldimethyltauramide / benzyl alcohol polyoxyl-25 methacrylate crosslinked polymer, carbomer were added into the water phase preparation tank, heated and stirred until completely dissolved.

[0046] In the emulsification kettle, the water phase was first pumped in, the oil phase was added and fully stirred and homogenized, and the temperature was kept constant and stirred.

[0047] Cool down, add glycerin polymethyl acrylate, C12-C15 alcohol benzoate, mixture of aminomethyl propanol. After mixing well, add 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1,1-bis(methoxymethyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1,1-bis(2-methoxyethyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1,1-bis(3-methoxypropyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1,1-bis(4-methoxybutyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1-(2-methoxyethyl)-1-(methoxymethyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1-(4-methoxybutyl)-1-(methoxymethyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1,1-bis(2-ethoxyethyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1-(2-ethoxyethyl)-1-(3-ethoxypropyl)urea / 3-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-1-(4-ethoxybutyl)-1-(3-ethoxypropyl)urea, fragrance, bis-diethoxydiglycol cyclohexane-1,4-dicarboxylate, phenoxyethanol mixture. After homogenization, cool to room temperature, stand, and the desired emulsion is obtained.

[0048] The above detailed description of the application has been given by way of example only and is not to be taken as limiting. It will be appreciated that those skilled in the art will be able to devise various equivalents of the technical solutions and embodiments of the application without departing from the spirit and scope of the application, and that these are intended to be within the scope of the application. The scope of the application is defined by the appended claims.

Claims

1. A 2,4-dihydroxyphenylthiazole derivative having the following formula: ； wherein n1 and n2 are each independently 1, 2, 3 or 4; and R is methyl or ethyl.

2. The 2,4-dihydroxyphenyl thiazole derivative according to claim 1, characterized in that, having any one of the following structures: 、 、 、 、 、 、 、 、 。 3.A composition comprising the 2,4-dihydroxyphenylthiazole derivative of any one of claims 1-2, or a pharmaceutically acceptable salt thereof. 4.A preparation comprising the composition of claim 3, and optionally one or more pharmaceutically acceptable carriers or excipients.

5. The preparation according to claim 4, characterized in that, The 2,4-dihydroxyphenylthiazole derivative is added in the composition in an amount of 0.000001% to 10% by weight of the total preparation. 6.Use of the 2,4-dihydroxyphenylthiazole derivative of any one of claims 1-2 in the preparation of a tyrosinase inhibitor drug. 7.Use of the 2,4-dihydroxyphenylthiazole derivative of any one of claims 1-2 in the preparation of a whitening product. 8.Use of the 2,4-dihydroxyphenylthiazole derivative of any one of claims 1-2 in the preparation of a drug for pigmentation diseases.

Images