2,4-dihydroxyphenyl thiazole derivatives and use thereof

Abstract

The application belongs to the technical field of cosmetic and pharmaceutical chemistry, and discloses a 2,4-dihydroxyphenyl thiazole derivative and application thereof. The 2,4-dihydroxyphenyl thiazole derivative has the structure shown in the following formula: wherein n1 and n2 are each independently 1, 2, 3 or 4; and R is methyl or ethyl. Compared with existing peptide amido compounds, the 2,4-dihydroxyphenyl thiazole derivative of the 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. The derivative can effectively inhibit the activity of tyrosinase, and can be used as an active ingredient to prepare a novel tyrosinase inhibitor, related whitening and freckle-removing cosmetics and a drug for 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.

[0009] In a first aspect, the present application provides a 2,4-dihydroxyphenyl thiazole derivative, having the following structure:

[0010] ;

[0011] wherein n1 and n2 are each independently 1, 2, 3 or 4; and R is methyl or ethyl.

[0012] In an embodiment of the present application, the 2,4-dihydroxyphenyl thiazole derivative has any one of the following structures:

[0013] , ,

[0014] , ,

[0015] , ,

[0016] , ,

[0017] .

[0018] In a second aspect, the present application provides a preparation method of a 2,4-dihydroxyphenyl thiazole derivative, comprising the following steps:

[0019] ;

[0020] protecting the phenolic hydroxyl group of compound 1 to obtain compound 2;

[0021] reacting compound 2 with N,N-carbonyldiimidazole to obtain compound 3;

[0022] condensing compound 3 with a secondary amine to obtain compound A;

[0023] deprotecting compound A under acidic conditions to obtain the 2,4-dihydroxyphenyl thiazole derivative.

[0024] 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.

[0025] In an embodiment of the present application, the phenolic hydroxyl protecting group is TBS.

[0026] In an embodiment of the present application, the phenolic hydroxyl protecting group reagent can be selected from TBSCl.

[0027] In an embodiment of the present application, compound 1 is used as a starting material, solvent, imidazole, DMAP and TBSCl are added to react, and phenolic hydroxyl protection is performed to obtain compound 2.

[0028] In an embodiment of the present application, compound 1 is used as a starting material, solvent, imidazole, DMAP and TBSCl are added to react at 10-30°C, and phenolic hydroxyl protection is performed to obtain compound 2.

[0029] In an embodiment of the present application, the molar ratio of compound 2 to N,N-carbonyldiimidazole is 1:1-2.

[0030] In an embodiment of the present application, the temperature for the reaction of compound 2 with N,N-carbonyldiimidazole is 10-30°C.

[0031] In an embodiment of the present application, the temperature for the reaction of compound 2 with N,N-carbonyldiimidazole is 20-30°C.

[0032] In an embodiment of the present application, the secondary amine is selected from N,N-di(alkoxyalkyl)amine.

[0033] 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.

[0034] In an embodiment of the present application, the temperature for the condensation reaction of compound 3 with the secondary amine is 10-30°C.

[0035] In an embodiment of the present application, the temperature for the condensation reaction of compound 3 with the secondary amine is 20-30°C.

[0036] In an embodiment of the present application, during the condensation reaction of compound 3 with the secondary amine, triethylamine is also added.

[0037] In one embodiment of this application, the acid used in the acidic conditions is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

[0038] In one embodiment of this application, the temperature of the deprotection reaction is 0±5℃.

[0039] In one embodiment of this application, the deprotection reaction takes 1-6 hours.

[0040] In one embodiment of this application, the deprotection reaction takes 4-6 hours.

[0041] Thirdly, this application provides a composition comprising a 2,4-dihydroxyphenylthiazole derivative and a pharmaceutically acceptable salt thereof.

[0042] Fourthly, a formulation comprising a composition and optionally one or more pharmaceutically acceptable carriers or excipients is also within the scope of protection of this application.

[0043] In one embodiment of this application, the amount of 2,4-dihydroxyphenylthiazole derivative added to the composition is 0.000001% to 10% of the total weight of the formulation.

[0044] Fifthly, the use of 2,4-dihydroxyphenylthiazole derivatives in the preparation of tyrosinase inhibitor drugs is also within the scope of protection of this application.

[0045] The use of 2,4-dihydroxyphenylthiazole derivatives in the preparation of skin whitening products is also within the scope of protection of this application.

[0046] The use of 2,4-dihydroxyphenylthiazole derivatives in the preparation of drugs for pigmentation disorders is also within the scope of protection of this application.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] This application uses compound 1 as the starting material. The phenolic hydroxyl group is protected with TBS, and the amino group reacts with N,N-carbonyldiimidazole followed by condensation with a secondary amine, ultimately deprotecting to obtain 2,4-dihydroxyphenylthiazole derivatives. Compared with existing peptide-based compounds, the 2,4-dihydroxyphenylthiazole derivatives of this invention, while maintaining the active structure of the parent nucleus, significantly improve solubility and physicochemical stability through molecular modification, and optimize pharmacokinetic characteristics. These derivatives can effectively inhibit tyrosinase activity and can be used as active ingredients in the preparation of novel tyrosinase inhibitors and related whitening and spot-removing cosmetics and drugs for tyrosinase-related diseases. Detailed Implementation

[0049] The technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0050] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0051] Example 1: Synthesis of Compound 2

[0052] ;

[0053] Compound 1 (25.00 g) and DMF (75.0 mL) were added to a reaction flask at 20-30℃. The temperature was lowered to 0±5℃, and imidazole (24.54 g) and DMAP (45.29 g) were added. Then, a solution of TBSCl (45.29 g) in DMF (75.0 mL) was slowly added dropwise. The temperature was raised to 20-30℃ and the reaction was stirred for 5.0 h. The reaction of the starting material was detected by TLC to be complete. The temperature was lowered to 0±5℃, and the reaction was quenched with saturated ammonium chloride (75.0 mL). The mixture was extracted with dichloromethane (75.0 mL × 2), and the organic phases were combined and washed with saturated brine (25.0 mL × 2). The organic phases were concentrated under reduced pressure at 40-45℃ to obtain the crude product. Column chromatography yielded 40.95 g of compound 2, with a yield of 78%.

[0054] Example 2: Synthesis of Compound 3

[0055] ;

[0056] At 20-30℃, N,N-carbonyldiimidazole (4.46 g, 27.52 mmol) and dichloromethane (50.0 mL) were added to the reaction flask. The temperature was controlled not to exceed 30℃. A solution of compound 2 (10.0 g, 22.93 mmol) in dichloromethane (50.0 mL) was slowly added dropwise over 3.0 h. The reaction was continued for another 8.0 h. TLC showed that the starting materials had basically reacted completely. The mixture was filtered, and the filtrate was used directly for the next reaction.

[0057] Example 3: Synthesis of compounds A1-A9

[0058] ;

[0059] At 20-30°C, a dichloromethane solution of compound 3 obtained in the previous step was added to the reaction flask, followed by the dropwise addition of bis(2-methoxyethyl)amine (4.83 g, 29.81 mmol), while maintaining the temperature below 30°C. Then, triethylamine (5.64 g, 45.86 mmol) was added dropwise, while maintaining the temperature below 30°C. The mixture was stirred at 20-30°C for 12.0 h. TLC analysis showed that the starting material had reacted completely. The mixture was washed with water (20.0 mL), and the organic phase was concentrated under reduced pressure at 40-45°C to obtain the crude product. Column chromatography yielded 9.85 g of the product, with a two-step yield of 72%.

[0060] The above-mentioned bis(2-methoxyethyl)amine was successively replaced with equimolar amounts of bis(2-methoxymethyl)amine, bis(2-methoxypropyl)amine, bis(2-methoxybutyl)amine, 2-methoxy-N-(methoxymethyl)ethyl-1-amine, 4-methoxy-N-(methoxymethyl)but-1-amine, bis(2-ethoxyethyl)amine, 3-ethoxy-N-(2-ethoxyethyl)propyl-1-amine, and 4-ethoxy-N-(3-ethoxypropyl)but-1-amine to obtain A1, A3, A4, A5, A6, A7, A8, and A9, with yields of 70%–85%.

[0061] Example 4: Synthesis of compounds B1-B9

[0062] ;

[0063] At 20-30℃, add A (8.40 mmol) and THF (25.0 mL) to the reaction flask, cool to 0±5℃, add 2N hydrochloric acid (25.0 mL) dropwise, and continue the reaction for 5.0 h. TLC showed that the starting material was completely reacted and separated into layers. The aqueous phase was extracted with THF (25.0 mL × 2), the organic phases were combined, and the THF was removed by vacuum concentration at 35-40℃ to obtain the crude product. Column chromatography was used to obtain product B, with a yield of 75-80%.

[0064] The structural characterization data for 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] + ;

[0065] The structural characterization data for B2 are as follows: 1H 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] + ;

[0066] The structural characterization data for B3 are as follows: 1 H 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] + ;

[0067] The structural characterization data for B4 are as follows: 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] + ;

[0068] The structural characterization data for B5 are as follows: 1H 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] + ;

[0069] The structural characterization data for B6 are as follows: 1 H 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] + ;

[0070] The structural characterization data for B7 are as follows: 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] + ;

[0071] The structural characterization data for B8 are as follows: 1 H 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 / z410.2 [M+H] + ;

[0072] The structural characterization data for B9 are as follows: 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] + .

[0073] The inhibitory activity of compounds against tyrosinase was assessed using the modified MBTH method (Journal of Biochemical and Biophysical Methods, 1994, 28(3): 173-183). 3-Methyl-2-benzothiazolinone (MBTH) was used as the chromogenic reagent. The reaction proceeded via the oxidation of levodopa to levodopaquinone by human tyrosinase, followed by the reaction of MBTH with levodopaquinone to produce a colored product. The reaction was terminated, and the inhibitory activity of compounds B1-B9 against human tyrosinase was determined by measuring the specific absorption of the product at 505 nm. The results are shown in Table 1.

[0074] Table 1

[0075] ;

[0076] ;

[0077] ;

[0078] ;

[0079] ;

[0080] Example 5: Preparation of emulsions containing 2,4-dihydroxyphenylthiazole derivatives

[0081] The formula is shown in Table 2: Table 2

[0082] ;

[0083] ;

[0084] ;

[0085] ;

[0086] ;

[0087] Preparation method:

[0088] According to the mass fractions of each component shown in Table 2, polyglycerol-3-methylglucose distearate, hydrogenated polydecene, oleyl erucic acid ester, ethyl ethyl palmitate, polydimethylsiloxane, methylparaben, and butylated hydroxytoluene were added as the oil phase to the oil phase mixing tank, heated until dissolved, and then cyclopentamethoxydimethylsiloxane was added and stirred to disperse.

[0089] Add water, glycerol, propylene glycol, butylene glycol, dipropylene glycol, betaine salicylate, trisodium EDTA, ammonium acryloyl dimethyl taurate / behenol polyether-25 methacrylate crosspolymer, and carbomer to an aqueous phase mixing tank and heat and stir until completely dissolved.

[0090] First, the aqueous phase is drawn into the emulsification kettle, then the oil phase is added and stirred thoroughly to homogenize it. The mixture is then kept warm and stirred.

[0091] Cool the mixture and add a mixture of glycerol polymethacrylate, C12-C15 benzoate, and aminomethylpropanol. After thorough mixing, 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-( ... A mixture of 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-diethoxydiethylenecyclohexane-1,4-dicarboxylic acid ester, and phenoxyethanol was thoroughly homogenized, cooled to room temperature, and allowed to stand to obtain the desired emulsion.

[0092] The present application has been described in detail above with reference to specific embodiments and exemplary examples; however, these descriptions should not be construed as limiting the present application. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and implementation methods of the present application without departing from the spirit and scope of the present application, and all such modifications and improvements fall within the scope of the present application. The scope of protection of the present application is determined by the appended claims.

Claims

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

2. The 2,4-dihydroxyphenylthiazole derivative according to claim 1, characterized in that, It has any of the following structures: 、 、 、 、 、 、 、 、 。 3. A composition comprising a 2,4-dihydroxyphenylthiazole derivative as described in any one of claims 1-2, or a pharmaceutically acceptable salt thereof.

4. A formulation comprising the composition of claim 3 and optionally one or more pharmaceutically acceptable carriers or excipients.

5. The formulation according to claim 4, characterized in that, The amount of 2,4-dihydroxyphenylthiazole derivative added to the composition is 0.000001% to 10% of the total weight of the formulation.

6. The use of the 2,4-dihydroxyphenylthiazole derivative according to any one of claims 1-2 in the preparation of tyrosinase inhibitor drugs.

7. The use of the 2,4-dihydroxyphenylthiazole derivative according to any one of claims 1-2 in the preparation of skin whitening products.

8. The use of the 2,4-dihydroxyphenylthiazole derivative according to any one of claims 1-2 in the preparation of a medicament for pigmentation disorders.

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