Thiazole derivative, preparation method and application thereof

Abstract

The present invention belongs to the technical fields of medicinal chemistry and pharmacology, and discloses a thiazole derivative, its preparation method, and application. The thiazole derivative has a structure represented by formula (I) and is prepared by dissolving cedrinone and ferric acetylacetonate in a mixed solution of ethanol and ethylene glycol, adding phenylsilane, and reacting to obtain compound 2. Compound 2 is then reacted with pyridinium tribromide in THF at room temperature to obtain compound 3. Compound 3 undergoes a [3+2] cycloaddition reaction with thiourea to obtain thiazole derivative 4a. 4a is then reacted with a benzoic acid compound to obtain thiazole derivative 4. This thiazole derivative has been found to have strong tumor cell growth inhibition activity and is expected to be used as an anti-tumor drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to a thiazole derivative and a preparation method and application thereof. Background Art

[0002] The development of medicinal plants has become a hot research topic in the pharmaceutical field. Over the past few decades, natural products have garnered increasing attention due to their excellent therapeutic effects and low toxicity. Nootkatone was initially considered an insect repellent with insecticide activity against ticks, mosquitoes, and termites, as well as for the treatment of human-related diseases such as chikungunya, dengue fever, and Zika virus. Recent research data indicate that nootkatone exhibits a wide range of pharmacological activities, including anti-inflammatory, antimicrobial, anticancer, neuroprotective, cardioprotective, and hepatoprotective properties. Microbial transformation of nootkatone by fungal strains (Botrytis cinerea, Bispora spp., Aspergillus niger, Trichoderma spp., and Fusarium spp.) produces a variety of metabolites that have been shown to be cytotoxic to A549 (human lung adenocarcinoma) and HL60 (human promyelocytic leukemia) cells. The thiazole ring is an important five-membered aromatic heterocycle containing nitrogen and sulfur heteroatoms. It is electron-rich and readily forms hydrogen bonds, coordinates with metal ions, and interacts with various non-covalent bonds, including π-π stacking, electrostatic, and hydrophobic interactions. In the pharmaceutical field, thiazole compounds can bind to a variety of targets within organisms, including enzymes and receptors, thereby exhibiting diverse biological activities. They show promising applications in antibacterial, antifungal, antituberculosis, anticancer, antiviral, anti-inflammatory, analgesic, hypoglycemic, anti-epileptic, antiparasitic, and antioxidant activities. In recent years, structural studies of chalcogenol derivatives have focused more on their biotransformation rather than their chemical transformation. Summary of the Invention

[0003] In view of this, the present invention aims to perform bone remodeling on cinquefoil by chemical transformation to obtain a novel tetracyclic thiazole derivative having strong tumor cell proliferation inhibitory activity.

[0004] The present invention provides a thiazole derivative having a structure shown in formula (I):

[0005]

[0006] Here, R represents one of H, benzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl and 4-fluorobenzoyl.

[0007] Furthermore, the thiazole derivative has a structure as shown in any one of Formulas 4a to 4c:

[0008]

[0009] in,

[0010] When R is H, the thiazole derivative is a compound having a structure shown in Formula 4a;

[0011] When R is a benzoyl group, the thiazole derivative is a compound having a structure shown in Formula 4b;

[0012] When R is 4-methylbenzoyl, the thiazole derivative is a compound having a structure shown in formula 4c.

[0013] The present invention also provides a method for preparing a thiazole derivative, comprising the following steps:

[0014] Cinnamaldehyde 1 and ferric acetylacetonate were dissolved in ethanol:ethylene glycol, and phenylsilane was added to react to yield compound 2. Compound 2 then reacted with pyridinium tribromide in THF at room temperature to yield compound 3. Compound 3 then reacted with thiourea to yield thiazole derivative 4a through a [3+2] cycloaddition reaction. 4a then reacted with a benzoic acid compound to yield thiazole derivative 4.

[0015] Wherein, the reaction formula of the reaction is:

[0016]

[0017] Here, R represents one of benzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl and 4-fluorobenzoyl.

[0018] Specifically, the preparation method comprises the following steps:

[0019] (1) Dissolve cedrin 1 and ferric acetylacetonate in a mixed solution of ethanol and ethylene glycol, then add phenylsilane and react at 50-70°C to obtain a first reaction solution. The first reaction solution is cooled to room temperature, quenched with water, washed three times with saturated brine, extracted three times with ethyl acetate, and the organic phase is collected and concentrated under reduced pressure to obtain a red oil. A colorless oil is obtained by flash column chromatography, and the colorless oil is compound 2, wherein the molar ratio of cedrin 1, ferric acetylacetonate and phenylsilane is 1:0.3:1.5;

[0020] (2) Compound 2 was dissolved in anhydrous THF, pyridinium tribromide was added, and the mixture was reacted at room temperature to obtain a second reaction solution. The second reaction solution was quenched with water, extracted three times with ethyl acetate, and the organic phase was collected and washed with water, saturated brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography was performed to obtain a colorless oily compound 3. The molar ratio of compound 2 to pyridinium tribromide was 1:1.

[0021] (3) Compound 3 was dissolved in anhydrous ethanol, pyrrolidine and thiourea were added, and the mixture was reacted at 40-50°C to obtain a third reaction solution. The third reaction solution was cooled to room temperature, the reaction was quenched with water, and extracted with ethyl acetate three times. The organic phase was collected and concentrated under reduced pressure, and a white solid thiazole derivative 4a was obtained by flash column chromatography. The molar ratio of compound 3, pyrrolidine and thiourea was 1:2:2;

[0022] (4) The thiazole derivative 4a is dissolved in dichloromethane, and HATU, DIPEA, and a benzoic acid compound are added. The mixture is reacted at room temperature for 12 hours to obtain a fourth reaction solution. The fourth reaction solution is concentrated under reduced pressure and subjected to flash column chromatography to obtain a white solid thiazole derivative 4. Wherein, R represents one of benzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl, and 4-fluorobenzoyl; the molar ratio of the thiazole derivative 4a, HATU, DIPEA, and the benzoic acid compound is 1:2:2:1. The benzoic acid compound is one of benzoic acid, 4-methylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid, and 4-fluorobenzoic acid.

[0023] Furthermore, in step (1) of the above preparation method, the volume ratio of ethanol to ethylene glycol in the mixed solution of ethanol and ethylene glycol is 5:1.

[0024] Furthermore, in step (1) of the above preparation method, the reaction temperature is 60° C. and the reaction time is 1 h.

[0025] Furthermore, in step (2) of the above preparation method, the reaction temperature is 25° C. and the reaction time is 20 min.

[0026] Furthermore, in step (3) of the above preparation method, the reaction temperature is 45° C. and the reaction time is 3 h.

[0027] Furthermore, in step (4) of the above preparation method, the reaction temperature is 25° C. and the reaction time is 12 h.

[0028] Furthermore, the present invention also provides a use of the above-mentioned thiazole derivative in the preparation of a drug for preventing and treating cancer, wherein the cancer is one of gastric cancer, ovarian cancer, lung cancer and liver cancer.

[0029] Compared with the prior art, this application provides a class of thiazole derivatives, their preparation methods, and applications. By adopting a ring distortion strategy, a chemical transformation method for thiazole derivatives is proposed. Such compounds have novel structures and excellent pharmacological activities. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for describing the embodiments or the prior art.

[0031] Figure 1 The NMR of compound 2 provided in Example 1 of the present invention is 1 H spectrum;

[0032] Figure 2 The NMR of compound 2 provided in Example 1 of the present invention is 13 C spectrum;

[0033] Figure 3 The nuclear magnetic resonance of compound 3 provided in Example 2 of the present invention 1 H spectrum;

[0034] Figure 4 The nuclear magnetic resonance of compound 3 provided in Example 2 of the present invention 13 C spectrum;

[0035] Figure 5 The NMR of compound 4a provided in Example 5 of the present invention is 1 H spectrum;

[0036] Figure 6 The NMR of compound 4a provided in Example 5 of the present invention is 13 C spectrum;

[0037] Figure 7 This is the 1H NMR spectrum of compound 4b provided in Example 5 of the present invention;

[0038] Figure 8 The NMR of compound 4b provided in Example 5 of the present invention is 13 C spectrum. DETAILED DESCRIPTION

[0039] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0040] Example 1

[0041] 218mg (1.0mmol) of cedar ketone 1 was dissolved in an ethanol-ethylene glycol mixed solution (5mL, ethanol: ethylene glycol volume ratio of 5: 1) and 106mg (0.3mmol) of ferric acetylacetonate and 162mg (1.5mmol) of phenylsilane were added and reacted at 60°C for 1 hour. The reaction solution was cooled to room temperature, quenched with water, washed three times with saturated brine, extracted three times with ethyl acetate, and the organic phase was collected and concentrated under reduced pressure to give a red oil. 108mg of a colorless oily liquid was obtained by flash column chromatography (petroleum ether: ethyl acetate = 150: 1), i.e., compound 2 (yield 91%).

[0042] 1H NMR(400MHz,Chloroform-d)δ2.39(dqd,J=13.3,6.7,4.4Hz,1H,H-1),2.30–2.24(m,1H),2.2 0(s,1H),2.17–2.11(m,1H),2.05(ddd,J=14.4,4.5,1.7Hz,1H),1.90(dt,J=12.6,3.5Hz,1H) ,1.78–1.73(m,1H),1.72–1.69(m,2H),1.41(ddd,J=12.8,11.2,4.9Hz,1H),1.24–1.13(m,1H ),1.07(d,J=12.7Hz,1H),1.03(s,6H,CH3),0.92(s,3H,CH3),0.87(dd,J=6.7Hz,3H,1-CH3). 13 C NMR (100MHz, CDCl3) δ213.3,55.0,50.0,46.3,45.2,43.4,42.3,41.4,38.9,32.6,26.5,23.5,22.5,18.1,16.6.

[0043] Example 2

[0044] 220 mg (1.0 mmol) of compound 2 was dissolved in THF (5 ml), followed by the addition of 320 mg (1.0 mmol) of pyridinium tribromide, and the mixture was allowed to react at 25°C for 20 minutes. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phase was collected and washed sequentially with water and saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. Flash column chromatography (petroleum ether:ethyl acetate = 200:1) afforded 268 mg of a colorless oily liquid, compound 3 (yield 90%).

[0045] 1H NMR(400MHz,Chloroform-d)δ4.22(d,J=1.6Hz,1H,Br-H),3.05(t,J=13.8Hz,1H,H-2),2.30( dqd,J=13.6,6.7,3.4Hz,1H,H-1),2.14–2.03(m,1H),1.95(ddd,J=13.5,3.5,1.6Hz,1H,H-2) ,1.86(ddd,J=12.6,4.2,2.6Hz,1H),1.77(t,J=4.3Hz,1H),1.74–1.61(m,2H),1.20(s,3H,CH 3),1.18–1.11(m,1H),1.04(d,J=12.6Hz,1H),0.97(s,6H,CH3),0.87(d,J=6.7Hz,3H,1-CH3). 13 C NMR (100MHz, CDCl3) δ205.3,57.2,56.3,52.5,47.7,44.8,43.0,40.4,39.8,34.0,26.1,23.5,23.2,19.2,17.3.HRMS(ESI):m / z calcdfor C 15 H 23 OBrNa:321.0830; found:321.0822[M+Na] + .

[0046] Example 3

[0047] 298 mg (1.0 mmol) of compound 3 was dissolved in anhydrous ethanol (5 ml), followed by the addition of 152 mg (2.0 mmol) of thiourea and 142 mg (2.0 mmol) of pyrrolidine, and the mixture was reacted at 45° C. for 3 hours. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phase was collected and concentrated under reduced pressure. Flash column chromatography (petroleum ether:ethyl acetate = 30:1) afforded 220 mg of a white solid, thiazole derivative 4a (yield 80%).

[0048] 1H NMR(400MHz,)δ5.05(s,2H,NH2),3.11(dtd,J=9.9,7.1,6.6,3.1Hz,1H,H-1),2.54( dd,J=18.4,2.4Hz,1H,H-2),2.39(dd,J=18.4,3.0Hz,1H,H-2),1.91(dt,J=12.6,3. 7Hz,1H),1.86–1.65(m,3H),1.60–1.47(m,1H),1.37–1.19(m,1H),1.18–1.09(m,1H ),1.13(d,J=7.0Hz,3H,CH3),1.05(s,3H,CH3),0.97(s,3H,CH3),0.92(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ165.2,144.0,123.9,51.5,49.7,46.6,44.6,43.6,40.0,33.8,27.6,26.7,23.5,22.2,19.5,18.0.HRMS(ESI):m / z calcd for C 16 H 25 N2S:277.1738; found:277.1742[M+H] + .

[0049] Example 4

[0050] 276 mg (1.0 mmol) of thiazole derivative 4a was dissolved in DCM, and 760 mg (2.0 mmol) of HATU, 258 mg (2.0 mmol) of DIPEA, and 122 mg (1.0 mmol) of benzoic acid were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether:ethyl acetate = 80:1) to obtain 319 mg of a white solid, thiazole derivative 4b (yield 84%).

[0051] 1H NMR(400MHz,)δ12.79(s,1H,NH),7.95-7.88(m,2H,Ar-H),7.55(dd,J=7.2,1.9Hz,1H,Ar-H), 7.49–7.40(m,2H,Ar-H),3.18(q,J=6.9Hz,1H,H-1),2.12–2.03(m,1H),1.96–1.89(m,2H),1. 87–1.79(m,1H),1.71(d,J=4.7Hz,1H),1.66–1.47(m,2H),1.37–1.21(m,1H),1.27(d,J=7.0H z,3H,1-CH3),1.16–1.01(m,1H),0.94(s,3H,CH3),0.82(s,3H,CH3),0.76–0.71(m,3H,CH3). 13 C NMR (100MHz, CDCl3) δ165.9,157.3,142.9,133.2,132.5,128.7,128.5,128.2,51.3,4 9.7,46.3,44.0,43.8,39.2,33.8,27.6,25.7,23.2,22.3,19.5,17.0.HRMS(ESI):m / z calcd for C 23 H 29 N2OS:381.2001; found:381.1998[M+H] + .

[0052] Example 5

[0053] According to the method of Example 4 above, benzoic acid was replaced with 4-methylbenzoic acid to prepare thiazole derivative 4c.

[0054] The physicochemical data of thiazole derivative 4c are listed below:

[0055] Yield 63%. 1H NMR(400MHz,)δ12.78(s,1H,NH),7.79(d,J=8.0Hz,2H,Ar-H),7.25–7.19(m,2H,Ar-H),3.17(q,J=6.8Hz, 1H,H-1),2.40(s,3H,Ar-CH3),2.04(dd,J=18.3,2.1Hz,1H,H-2),1.98–1.88(m,2H),1.86–1.73(m,2H),1. 70(t,J=4.4Hz,1H),1.63(ddd,J=10.5,7.2,4.1Hz,1H),1.53(dd,J=9.3,5.5Hz,1H),1.27(d,J=6.9Hz,3H ,1-CH3),1.11(d,J=12.5Hz,1H),0.95(s,3H,CH3),0.90–0.84(m,1H),0.82(s,3H,CH3),0.71(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ172.0,165.1,157.9,143.3,141.8,130.1,129.5,129.0,128.2,128.0,51.5, 49.8,46.5,43.9,39.4,33.9,27.6,25.6,23.4,22.3,21.8,21.7,19.5,17.0.HRMS(ESI):m / zcalcd for C 24 H 31 N2OS:395.2157; found:395.2159[M+H] + .

[0056] To better understand the essence of the present invention, the following pharmacological experimental results demonstrating the inhibitory effects of the thiazole derivatives provided herein on the growth of four tumor cell lines illustrate their novel applications in anti-tumor drug research. The pharmacological examples provide partial activity data for representative compounds 4a-4c. It should be noted that the pharmacological examples are intended to illustrate the present invention and are not intended to limit it. Simple modifications to the present invention based on its essence fall within the scope of the present invention.

[0057] Drug Experiment Example 1: Cytotoxicity Test of Compounds 4a-4c and Etoposide (VP-16) against Human Gastric Cancer Cells (MGC803)

[0058] Human gastric cancer cells (MGC803) were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 U / mL streptomycin. Cells were plated at a concentration of 5 × 103 cells per well in a 96-well plate and incubated at 37°C in a humidified atmosphere containing 5% CO2 for 24 hours.

[0059] Compounds 4a-4c were dissolved in DMSO and prepared into 1×10 -2 mol / L stock solution, the stock solution was diluted to the corresponding concentration with complete medium. Cells in logarithmic growth phase were seeded in 96-well plates. After 24 hours of attachment, different concentrations of compound solutions were added. Four parallel wells were set for each concentration. After 68 hours of culture, tetramethylthiazolium (MTT) solution was added. The culture was continued for 4 hours, the culture medium was discarded, 150 μL of dimethyl sulfoxide was added, and the cells were shaken for 10 minutes. The absorbance (A) value at 570 nm was measured with a microplate reader, and the half-maximal inhibitory concentration (IC) was calculated. 50 ), as shown in Table 1. According to Table 1, the IC 50 The positive control etoposide has an IC of 0.2 μM for MGC803 cells. 50 It is 4.6μM.

[0060] Drug Experimental Example 2-4: Cytotoxic activity test of compounds 4a-4c and etoposide against human ovarian adenocarcinoma cells (SK-OV-3), human lung adenocarcinoma cells (A549), and human liver cancer cells (HepG2).

[0061] The method shown in Drug Experiment Example 1 was used to conduct pharmacological experiments on the growth inhibition of human gastric cancer cells (MGC803), human ovarian adenocarcinoma cells (SK-OV-3), human lung adenocarcinoma cells (A549), and human liver cancer cells (HepG2). The half-maximal inhibitory concentration (IC 50 ), as shown in Table 1.

[0062] Table 1 Cytotoxic activity test results of compounds 4a-4c and etoposide

[0063]

[0064] As shown in Table 1, the thiazole derivatives provided by the present invention have significant biological activity. In vitro cytotoxic activity tests on four types of tumor cells, namely human gastric cancer cells (MGC803), human ovarian adenocarcinoma cells (SK-OV-3), human lung adenocarcinoma cells (A549), and human liver cancer cells (HepG2), showed that the thiazole derivatives having the structure represented by formula (1) have an inhibitory effect on tumor cell growth and may be developed into new anti-tumor drugs. From the above pharmacological examples, we can see that these compounds exhibit strong cytotoxic activity against these four types of tumor cells, with cytotoxic activities exceeding or comparable to those of the positive control, etoposide, and have the potential to be developed into anti-tumor drugs.

[0065] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A thiazole derivative, characterized in that The structure of the thiazole derivative is shown below: Here, R represents one of H, benzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl and 4-fluorobenzoyl.

2. The thiazole derivative according to claim 1, characterized in that The thiazole derivative has a structure as shown in any one of Formulas 4a-4c:

3. A method for preparing a thiazole derivative, characterized in that: The reaction formula of the preparation method is shown below: The preparation method comprises the following steps: S1. Dissolve cedrin 1 and ferric acetylacetonate in a mixed solution of ethanol and ethylene glycol, then add phenylsilane and react at 50 to 70°C to obtain a first reaction solution; collect the organic phase, concentrate under reduced pressure, and then flash column chromatography to obtain compound 2, wherein the molar ratio of cedrin 1, ferric acetylacetonate and phenylsilane is 1:0.3:1.5; S2. Compound 2 was dissolved in anhydrous THF, pyridinium tribromide was added, and the mixture was reacted at room temperature to obtain a second reaction solution; water was added to the second reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with water, saturated brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography was performed to obtain compound 3; wherein the molar ratio of compound 2 to pyridinium tribromide was 1:1; S3. Compound 3 was dissolved in anhydrous ethanol, pyrrolidine and thiourea were added, and the reaction was carried out at 40-50°C to obtain a third reaction solution. The third reaction solution was cooled to room temperature, the organic phase was collected and concentrated under reduced pressure, and the thiazole derivative 4a was obtained by flash column chromatography; wherein the molar ratio of compound 3, pyrrolidine and thiourea was 1:2:2; S4. Dissolve the thiazole derivative 4a in dichloromethane, add HATU, DIPEA and a benzoic acid compound, and react at room temperature to obtain a fourth reaction liquid; concentrate the fourth reaction liquid under reduced pressure, and obtain the thiazole derivative 4 by flash column chromatography; wherein the molar ratio of compound 4a, HATU, DIPEA and the benzoic acid compound is 1:2:2:1; wherein R represents one of benzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl and 4-fluorobenzoyl; the benzoic acid compound is one of benzoic acid, 4-methylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid and 4-fluorobenzoic acid.

4. The preparation method according to claim 3, characterized in that In step S1, in the mixed solution of ethanol and ethylene glycol, the volume ratio of ethanol to ethylene glycol is 5:

1.

5. The preparation method according to claim 3, characterized in that In step S1, the reaction temperature is 60° C. and the reaction time is 1 h.

6. The preparation method according to claim 3, characterized in that In step S2, the reaction temperature is 25° C. and the reaction time is 20 min.

7. The preparation method according to claim 3, characterized in that In step S3, the reaction temperature is 45° C. and the reaction time is 3 h.

8. The preparation method according to claim 3, characterized in that In step S4, the reaction temperature is 25° C. and the reaction time is 12 h.

9. Use of the thiazole derivative according to claim 1 in the preparation of a drug for preventing and treating cancer, wherein the cancer is one of gastric cancer, ovarian cancer, lung cancer and liver cancer.

Images