Thiazole derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry and pharmacology, and discloses a thiazole derivative as well as a preparation method and application thereof. The thiazole derivative has a structure as shown in a formula (I), and the preparation method comprises the following steps: dissolving coumarone and ferric acetylacetonate in a mixed solution of ethanol and ethylene glycol, adding phenylsilane, and reacting to obtain a compound 2. Reacting the compound 2 with pyridinium tribromide in THF (tetrahydrofuran) at room temperature to obtain a compound 3; the compound 3 and thiourea are subjected to [3 + 2] cyclization addition to obtain a thiazole derivative 4a, 4a then reacts with a benzoic acid compound to obtain a thiazole derivative 4, and the thiazole derivative is found to have high tumor cell growth inhibition activity and can be expected to be used as an anti-tumor drug. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and pharmacology, and specifically 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 direction in the field of medicine. In the past few decades, natural products have attracted increasing attention due to their excellent therapeutic effects and low toxicity. Nootkatone was originally considered as an insect repellent with insecticidal activity against ticks, mosquitoes and termites, as well as for the treatment of human-related diseases such as chikungunya, dengue fever and Zika virus. The latest research data results show that nootkatone has a wide range of pharmacological activities, including anti-inflammatory, antibacterial, anticancer, neuroprotective, cardioprotective, and hepatoprotective effects. 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 class of five-membered aromatic heterocycles containing nitrogen and sulfur heteroatoms, which are rich in electrons and easily form hydrogen bonds, coordinate with metal ions, and form a variety of non-covalent interactions such as π-π stacking, electrostatic and hydrophobic interactions. In the field of medicine, thiazole compounds can bind to various enzymes and receptors in the body to show a variety of biological activities, and show broad application prospects in the fields of antibacterial, antifungal, antituberculosis, anticancer, antiviral, anti-inflammatory and analgesic, hypoglycemic, anti-epileptic, anti-parasitic and antioxidant. In recent years, in the process of structural research on cedarwood derivatives, more attention has been paid to its biological transformation rather than chemical transformation. Summary of the invention

[0003] In view of this, the purpose of the present invention is to perform bone remodeling on chambordone by chemical transformation to obtain a novel tetracyclic thiazole derivative having a 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 Formulae 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] Dissolve chalcone 1 and ferric acetylacetonate in ethanol:ethylene glycol, add phenylsilane, and react to obtain compound 2. Compound 2 is then reacted with pyridinium tribromide in THF at room temperature to obtain compound 3. Compound 3 undergoes [3+2] cycloaddition with thiourea to obtain thiazole derivative 4a, and 4a is then reacted with a benzoic acid compound to obtain 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, the reaction is 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. Water was added to the second reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was collected and washed with water, saturated brine, dried with anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography was performed to obtain a colorless oil 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 the mixture was 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, and 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 a white solid thiazole derivative 4 is obtained by flash column chromatography. 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, in the mixed solution of ethanol and ethylene glycol, the volume ratio of ethanol to 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 an application 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, the present application provides a class of thiazole derivatives and preparation methods and applications thereof, adopts a ring distortion strategy, and proposes a chemical transformation method for thiazole derivatives. 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 drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[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 NMR of compound 3 provided in Example 2 of the present invention is 1 H spectrum;

[0034] Figure 4 The NMR of compound 3 provided in Example 2 of the present invention is 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 technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work 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), 106mg (0.3mmol) of ferric acetylacetonate and 162mg (1.5mmol) of phenylsilane were added, and the reaction was carried out 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 obtain a red oil. 108mg of a colorless oily liquid, i.e., compound 2 (yield 91%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 150:1).

[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), and then 320 mg (1.0 mmol) of pyridinium tribromide was added, and the mixture was reacted at 25° C. for 20 minutes. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was collected and washed with water, saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. 268 mg of a colorless oily liquid, i.e., compound 3 (yield 90%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 200: 1).

[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), and then 152 mg (2.0 mmol) of thiourea and 142 mg (2.0 mmol) of pyrrolidine were added, and the mixture was reacted at 45° C. for 3 hours. The reaction was quenched with water, extracted three times with ethyl acetate, and the organic phase was collected and concentrated under reduced pressure. 220 mg of a white solid, i.e., thiazole derivative 4a (yield 80%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 30:1).

[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, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and flash column chromatography (petroleum ether: ethyl acetate = 80: 1) was performed to obtain 319 mg of a white solid, namely, 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] Listed below are the physicochemical data of thiazole derivative 4c:

[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] In order to better understand the essence of the present invention, the pharmacological experimental results of the inhibitory effect of the thiazole derivatives provided by the present invention on the growth of four tumor cell lines are used below to illustrate its new use in the field of anti-tumor drug research. The pharmacological examples provide partial activity data of representative compounds 4a-4c. It must be noted that the pharmacological examples of the present invention are used to illustrate the present invention rather than to limit the present invention. Simple improvements made to the present invention according to the essence of the present invention all belong to the scope of protection claimed by the present invention.

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

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

[0059] Compounds 4a-4c were dissolved in DMSO and prepared into 1×10 -2 mol / L stock solution, dilute the stock solution to the corresponding concentration with complete medium, take cells in logarithmic growth phase and inoculate them in 96-well plates, add compound solutions of different concentrations after 24 hours of attachment, set 4 parallel wells for each concentration, add tetramethylthiazolium (MTT) solution after 68 hours of culture, continue to culture for 4 hours, discard the culture medium, add 150μL of dimethyl sulfoxide, shake for 10 minutes, measure the absorbance (A) value at 570nm with an enzyme reader, and calculate the half inhibitory concentration (IC 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 Experiment Example 2-4: Cytotoxic activity test of compounds 4a-4c and etoposide on human ovarian adenocarcinoma cells (SK-OV-3), human lung adenocarcinoma cells (A549), and human liver cancer cells (HepG2).

[0061] Using the method shown in Drug Experiment Example 1, pharmacological experiments were performed 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), and the half 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 important biological activities. 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) show that the thiazole derivatives of the structure shown in formula (1) have an inhibitory effect on tumor cell growth and may be developed into new tumor prevention and treatment drugs. From the above pharmacological examples, we can see that these compounds show strong cytotoxic activity on these four types of tumor cells, and the cytotoxic activity exceeds or is equivalent to that 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 principle of the present invention. These improvements and modifications should also be regarded as 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. dissolving cedrin 1 and ferric acetylacetonate in a mixed solution of ethanol and ethylene glycol, adding phenylsilane, and reacting at 50 to 70° C. to obtain a first reaction solution; collecting the organic phase, concentrating under reduced pressure, and 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 is dissolved in anhydrous ethanol, pyrrolidine and thiourea are added, and the mixture is reacted at 40 to 50° C. to obtain a third reaction solution, and the third reaction solution is cooled to room temperature, and the organic phase is collected and concentrated under reduced pressure, and the thiazole derivative 4a is obtained by flash column chromatography; wherein the molar ratio of compound 3, pyrrolidine and thiourea is 1:2:2; S4. Dissolve the thiazole derivative 4a in dichloromethane, add HATU, DIPEA and a benzoic acid compound, 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.

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