Preparation and application of an amide compound containing a substituted phenylthiopyridine structural unit

Abstract

The present invention relates to the preparation and application of an amide compound containing a substituted phenylmercaptopyridine structural unit. The amide compound is formed by the reaction of an aromatic amine with benzoic acid containing a substituted phenylmercaptopyridine methylthiourea unit. The amide compound containing a substituted phenylmercaptopyridine structural unit exhibits a potent inhibitory effect on tumor cells and can be used to prepare an anti-tumor cell drug.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to the preparation and application of an amide compound containing a substituted phenylmercaptopyridine structural unit. Background Art

[0002] In recent years, malignant tumors have been threatening human life and health, and the incidence of cancer has been increasing. Therefore, it is necessary for researchers to find and develop highly effective anti-tumor drugs.

[0003] Amide drugs are a very important class of compounds. Due to their excellent biological and pharmacological activities, drugs containing amide backbone units, such as dasatinib and capecitabine, have been used to treat tumors. Substituted pyridine groups are also important pharmacophores, and many substituted pyridine derivatives exhibit potent antiproliferative effects against tumor cells, leading to widespread applications in healthcare.

[0004] In order to further develop new compounds with excellent anti-tumor effects from amide derivatives, a substituted phenylmercaptopyridine structure is connected with an amide active fragment. The present invention discloses a class of amide compounds containing a substituted phenylmercaptopyridine structural unit with medicinal value. Summary of the Invention

[0005] The purpose of the present invention is to provide an amide compound containing a substituted phenylthiopyridine structural unit that exhibits an inhibitory effect on tumor cells HCT116 and HGC-27.

[0006] Another object of the present invention is to provide a method for preparing the above compound.

[0007] Another object of the present invention is to provide the use of the above compound in the preparation of anti-tumor cell drugs.

[0008] In order to solve the above technical problems, the present invention provides an amide compound containing a substituted phenylthiopyridine structural unit, which has the following structure:

[0009]

[0010]

[0011] The present invention provides a method for preparing the above-mentioned amide compound containing a substituted phenylthiopyridine structural unit, characterized in that the reaction steps are as follows:

[0012]

[0013] The present invention discloses an amide compound containing a substituted phenylthiopyridine structural unit, which exhibits an inhibitory effect on tumor cells HCT116 and HGC-27 and can therefore be used to prepare anti-tumor cell drugs. DETAILED DESCRIPTION

[0014] In order to facilitate a further understanding of the present invention, the following examples are provided to illustrate it in more detail. These examples are for narration only and are not intended to limit the scope or implementation principles of the present invention.

[0015] Example 1:

[0016]

[0017] Dissolve 2 mmol of intermediate IIa and 2 mmol of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) in 20 mL of DMSO. Add 8 mmol of N,N-diisopropylethylamine (DIPEA) and 2 mmol of intermediate IIIa sequentially with stirring at room temperature. After addition, react at room temperature for 18 hours. After removing the solvent, the crude product is purified by silica gel column chromatography to obtain the target compound Ia. 1 H NMR (400MHz, DMSO-d6): δ9.93 (s, 1H, NH), 9.60 (s, 1H, NH), 8.40~8.42 (m, 2H, NH and Py-H), 7.67~7.95 (m, 3H, Ar-H and Py-H), 7.48~7.59 (m, 7H, Ar-H and Py-H), 7.15 (d, J=7.2Hz, 1H, Ar-H), 6.95~6.99 (m, 2H, Ar-H), 6.57~6.79 (m, 2H, Ar-H), 4.91 (s, 2H, NH2), 4.71 (d, J=5.6Hz, 2H, CH2).

[0018] Example 2:

[0019]

[0020] Dissolve 3 mmol of intermediate IIb and 4 mmol of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) in 25 mL of DMF. Add 12 mmol of triethylamine and 4 mmol of intermediate IIIa sequentially with stirring at room temperature. After addition, react at room temperature for 22 hours. After removing the solvent, the crude product is purified by silica gel column chromatography to obtain the target compound Ib. 1H NMR (400MHz, DMSO-d6): δ9.94 (s, 1H, NH), 9.59 (s, 1H, NH), 8.41~8.43 (m, 2H, NH and Py-H), 7.67~7.95 (m, 3H, Ar-H and Py-H), 7.53~7.59 (m, 6H, Ar-H and Py-H), 6.95~7.16 (m, 3H, Ar-H), 6.58~6.79 (m, 2H, Ar-H), 4.89 (s, 2H, NH2), 4.70 (d, J=5.2Hz, 2H, CH2).

[0021] Example 3:

[0022] Determination of compound activity against tumor cells

[0023] The in vitro antitumor activity of the compounds was tested by methyl tetrazolium blue colorimetry (MTT). Human gastric cancer cells HGC-27 and human colon cancer cells HCT116 were selected as the research subjects. 5-Fluorouracil (5-FU) was used as the positive control drug. Human gastric cancer cells HGC-27 and human colon cancer cells HCT116 in the exponential growth phase were prepared into 4×10 3 A cell suspension of 10 cells / mL was inoculated into a 96-well plate and cultured in an incubator at 37°C and 5% CO2 for 24 hours. The test solution (10 μL) of the compound to be tested was added to the test well, 5 parallel wells were set for each concentration, and an equal amount of DMSO was used as a blank control. The cells were then cultured in an incubator at 5% CO2 for 72 hours, and then the supernatant was discarded. 20 μL of MTT (2 mg / mL in PBS) was added to each well. After another 4 hours of culture, the culture medium was discarded, and 150 μL of DMSO was added to each well. The cells were shaken on a vibrator for 10 minutes to dissolve the formed blue-purple precipitate. The OD value was measured at a wavelength of 490 nm using an enzyme marker to calculate the cell inhibition rate. Cell inhibition rate = (OD value of the negative control group - OD value of the test substance group) / OD value of the negative control group × 100%. The IC value of the compound was calculated using the probability unit weighted regression method. 50 value.

[0024] Table 1. Antitumor activity data of Ia-Ib (IC 50 , μM)

[0025] Compound HCT116 HGC-27 Ia 3.57 2.21 Ib 1.02 0.69 5-FU 19.60 34.10

[0026] As shown in Table 1, the prepared compounds Ia-Ib exhibited excellent antitumor activity against both human colon cancer cells HCT116 and human gastric cancer cells HGC-27. These experimental results demonstrate that the rational linkage of the substituted phenylthiopyridine unit with the amide active fragment resulted in compounds exhibiting potent antitumor effects against both human colon cancer cells HCT116 and human gastric cancer cells HGC-27.

[0027] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above examples. The above examples and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications are possible without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. An amide compound I containing a substituted phenylthiopyridine structural unit, characterized in that It has the following structure:

2. The method for preparing an amide compound I containing a substituted phenylthiopyridine structural unit according to claim 1, characterized in that Here’s how:

3. Use of an amide compound I containing a substituted phenylthiopyridine structural unit as claimed in claim 1 in the preparation of an anti-tumor drug, characterized in that: The tumor cells are human colon cancer cells HCT116 or human gastric cancer cells HGC-27.

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