Amide compounds containing thiazolylmethoxyphenyl disulfourea groups, preparation methods and applications thereof

Abstract

The present invention relates to an amide compound containing a thiazolylmethoxyphenyl dithiourea group, a preparation method thereof and an application thereof. It is obtained by the reaction of benzoic acid containing a thiazolylmethoxyphenyl dithiourea group with a substituted o-phenylenediamine. The amide compound containing a thiazolylmethoxyphenyl dithiourea group shows excellent inhibitory effects on tumor cells, and this compound can be used for preparing anti-tumor cell drugs. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to an amide compound containing a thiazolylmethoxyphenyl dithiourea group, a preparation method thereof, and an application thereof. Background Art

[0002] Malignant tumors are one of the three major diseases threatening human health, and the incidence of cancer has been showing an upward trend in recent years. Therefore, searching for and discovering effective anti-cancer drugs and treatment methods is one of the important research hotspots in the medical field at present.

[0003] Thiazole compounds are an important class of nitrogen-containing heterocycles, and many thiazole heterocyclic compounds show excellent inhibitory effects on tumor cells. Some drugs containing thiazole rings, such as famotidine, have been used to treat various diseases.

[0004] Amide bonds are widely present in natural and synthetic products, and many drugs contain amide bond pharmacophores. Drugs such as atorvastatin used to treat hypercholesterolemia and the natural product novobiocin belong to amide drugs.

[0005] Therefore, in order to search for and discover drugs with good anti-tumor activity from amide compounds, a substituted thiazole ring unit is reasonably connected to an amide skeleton. The present invention discloses a class of amide compounds containing a thiazolylmethoxyphenyl dithiourea group with medicinal value. Summary of the Invention

[0006] The purpose of the present invention is to provide a class of amide compounds containing a thiazolylmethoxyphenyl dithiourea group, which have good inhibitory effects on human gastric cancer cells HGC-27 and human liver cancer cells HepG2.

[0007] Another purpose of the present invention is to provide a preparation method of the above compound.

[0008] Another purpose of the present invention is to provide the use of the above compound in the preparation of anti-tumor cell drugs.

[0009] To solve the above technical problems, the present invention provides an amide compound containing a thiazolylmethoxyphenyl dithiourea group, which has a general formula I structure,

[0010]

[0011] Preferably, the amide compound containing a thiazolylmethoxyphenyl dithiourea group has the following structure:

[0012]

[0013] The present invention provides a preparation method of the above amide compound containing a thiazolylmethoxyphenyl dithiourea group, which is characterized by including the following steps:

[0014] Dissolve intermediate II in an organic solvent, then add intermediate III. After reacting for a period of time, stop the reaction. The crude product obtained after removing the solvent is purified by silica gel column chromatography to obtain the target compound I.

[0015]

[0016] Preferably, the preparation method of the amide compound containing a thiazolylmethoxyphenyl bi-thiourea group comprises the following steps:

[0017]

[0018]

[0019] Compound I shows good inhibitory effects on tumor cells, such as human gastric cancer cells HGC-27, human liver cancer cells HepG2, etc.

[0020] The amide compound containing a thiazolylmethoxyphenyl bi-thiourea group disclosed in the present invention shows good inhibitory activities against human gastric cancer cells HGC-27 and human liver cancer cells HepG2, and thus can be used to prepare anti-tumor cell drugs. Detailed implementation manners

[0021] For the convenience of further understanding of the present invention, the following examples provide more detailed descriptions thereof. These examples are only for narration and are not intended to limit the scope or implementation principles of the present invention.

[0022] Example 1:

[0023]

[0024] Dissolve 6 mmol of intermediate IIa and 7 mmol of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) in 30 mL of N,N-dimethylacetamide (DMA). Under ice bath conditions, add 15 mmol of N,N-diisopropylethylamine (DIPEA) and 5 mmol of intermediate IIIa thereto. After adding, react at room temperature for 19 hours. After removing the solvent, the obtained crude product is purified by silica gel column chromatography to obtain the target product Ia; 11H NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H, NH), 9.57 (s, 1H, NH), 8.37 (s, 1H, NH), 7.93 - 7.95 (m, 2H, Ar-H), 7.80 (s, 1H, Thiazole-H), 7.61 - 7.63 (m, 2H, Ar-H), 7.45 (m, 1H, Ar-H), 7.27 - 7.33 (m, 2H, Ar-H), 7.16 - 7.18 (m, 1H, Ar-H), 6.95 - 6.99 (m, 1H, Ar-H), 6.77 - 6.79 (m, 1H, Ar-H), 6.58 - 6.62 (m, 1H, Ar-H), 5.43 (s, 2H, CH2), 4.91 (s, 2H, NH2), 4.70 (d, J = 5.6 Hz, 2H, CH2).

[0025] Example 2:

[0026]

[0027] Dissolve 5 mmol of intermediate II b and 6 mmol of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) in 30 mL of N,N-dimethylformamide (DMF). Under ice bath conditions, add 20 mmol of triethylamine and 5 mmol of intermediate IIIa thereto. After adding, control the temperature at 35 °C and react for 10 hours. After removing the solvent, the obtained crude product is purified by silica gel column chromatography to obtain the target product Ib; 1 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H, NH), 9.57 (s, 1H, NH), 8.27 (s, 1H, NH), 7.92 - 7.95 (m, 2H, Ar-H), 7.77 (s, 1H, Thiazole-H), 7.63 - 7.65 (m, 2H, Ar-H), 7.14 - 7.17 (m, 2H, Ar-H), 6.95 - 6.98 (m, 3H, Ar-H), 6.77 - 6.79 (m, 1H, Ar-H), 6.58 - 6.62 (m, 1H, Ar-H), 5.29 (s, 2H, CH2), 4.87 (s, 2H, NH2), 4.66 (d, J = 5.2 Hz, 2H, CH2), 3.76 (s, 3H, OCH3).

[0028] Example 3:

[0029]

[0030] 8 mmol of intermediate II c and 8 mmol of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) were dissolved in 25 mL of N,N-dimethylacetamide (DMA). 21 mmol of triethylamine and 9 mmol of intermediate IIIa were added under ice bath conditions. After addition, the reaction was carried out for 15 hours under ice bath conditions. After removing the solvent, the obtained crude product was purified by silica gel column chromatography to obtain the target product Ic; 1 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H, NH), 9.67 (s, 1H, NH), 9.17 (s, 1H, NH), 7.95 - 7.97 (m, 2H, Ar-H), 7.81 - 7.83 (m, 3H, Ar-H and Thiazole-H), 7.26 - 7.30 (m, 1H, Ar-H), 7.16 - 7.18 (m, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 6.92 - 6.99 (m, 3H, Ar-H), 6.77 - 6.79 (m, 1H, Ar-H), 6.58 - 6.61 (m, 1H, Ar-H), 5.35 (s, 2H, CH2), 4.93 (s, 2H, NH2), 4.76 (d, J = 5.2 Hz, 2H, CH2).

[0031] Example 4:

[0032]

[0033] 5 mmol of intermediate IIb, 5 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and 5 mmol of 1-hydroxybenzotriazole (HOBt) were dissolved in 30 mL of N,N-dimethylacetamide (DMA). 4 mmol of intermediate IIIb was added at room temperature. After addition, the temperature was controlled at 50 °C and the reaction was carried out for 13 hours. After removing the solvent, the obtained crude product was purified by silica gel column chromatography to obtain the target product Id; 11H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H, NH), 9.53 (s, 1H, NH), 8.32 (s, 1H, NH), 7.93 - 7.95 (m, 2H, Ar-H), 7.76 (s, 1H, Thiazole-H), 7.63 - 7.65 (m, 2H, Ar-H), 7.05 - 7.13 (m, 3H, Ar-H), 6.88 - 6.90 (m, 1H, Ar-H), 6.53 - 6.56 (m, 1H, Ar-H), 6.34 - 6.39 (m, 1H, Ar-H), 5.29 (s, 2H, CH2), 5.23 (s, 2H, NH2), 4.68 (d, J = 4.4 Hz, 2H, CH2), 3.78 (s, 3H, OCH3).

[0034] Example 5:

[0035] Activity screening of the sample against tumor cells

[0036] The in vitro anti-tumor activity of the target compound was determined by the methyl thiazolyl tetrazolium (MTT) assay. The test objects were human gastric cancer cells HGC-27 and human liver cancer cells HepG2, and 5-fluorouracil (5-FU) was used as a positive control drug. Cancer cells in the exponential growth phase were made into a cell suspension of 4×10 3 cells / mL, inoculated into 96-well plates, and cultured in an incubator at 37 °C and 5% CO2 for 24 hours. Then, the test solution (10 μL) of the compound to be tested was added to the test wells, with 5 parallel wells set for each concentration, and an equal volume of DMSO was used as a blank control. After culturing in a 5% CO2 incubator for 72 hours, the supernatant was discarded. 20 μL of MTT (2 mg / mL in PBS) was added to each well, and after continuing to culture for 4 hours, the medium was aspirated. 150 μL of DMSO was added to each well, and the blue-violet precipitate formed was dissolved by shaking on a shaker for 10 minutes. Then, the OD value was measured at a wavelength of 490 nm using an enzyme-linked immunosorbent assay (ELISA) reader, and the cell inhibition rate was calculated. The cell inhibition rate = (OD value of the negative control group - OD value of the test compound group) / OD value of the negative control group × 100%. The IC ao value of the compound was calculated by the probit unit weighted regression method.

[0037] Table 1. Anti-tumor activity data of Ia-Id (IC 50 , μM)

[0038] Compound HGC-27 HepG2 Ia 0.97 0.95 Ib 0.89 0.93 Ic 8.66 10.70 Id 1.49 4.33 5-FU 34.10 35.20

[0039] As can be seen from the experimental data in Table 1, the prepared compounds Ia-Id showed good inhibitory effects on human gastric cancer cells HGC-27 and human liver cancer cells HepG2. The experimental results indicate that by organically connecting the thiazolylmethoxyphenyl unit with the amide unit through a thiourea group, the formed compounds have good antitumor effects on human gastric cancer cells HGC-27 and human liver cancer cells HepG2.

[0040] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above examples. The above examples and the description in the specification only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. An amide compound I containing a thiazolylmethoxyphenyl disulfourea group, characterized in that The structure is as follows:

2. The preparation method of the amide compound I containing a thiazolylmethoxyphenyl disulfourea group as described in claim 1, characterized in that The method is as follows:

3. Use of the amide compound I containing a thiazolylmethoxyphenyl disulfourea group as claimed in claim 1 for the preparation of an anti-tumor drug, characterized in that: The amide compound containing thiazolylmethoxyphenyl disulfourea group shows inhibitory effects on human gastric cancer cell line HGC-27 and human hepatoma cell line HepG2.

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