Organic compound or pharmaceutically acceptable salt and application thereof

Abstract

The invention discloses an organic compound or a pharmaceutically acceptable salt thereof, the organic compound or the pharmaceutically acceptable salt thereof provided by the invention and a pharmaceutical composition containing the organic compound or the pharmaceutically acceptable salt thereof provided by the invention have very good anti-tumor effect, and the organic compound is independently selected from the following compounds: # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and organic compound synthesis, and specifically relates to an organic compound and its application. Background Art

[0002] Malignant tumors are the most serious type of disease that endangers human health. Their incidence rate is second only to cardiovascular and cerebrovascular diseases, making them the second largest "killer" of human health, and their mortality rate even exceeds that of cardiovascular and cerebrovascular diseases, ranking first among all diseases. Therefore, finding and developing new drugs to treat tumors is a major issue currently faced.

[0003] Colon cancer is a common malignant tumor of the digestive tract that occurs in the colon. It is highly correlated with people's consumption of red meat (such as beef). It often occurs at the junction of the rectum and the sigmoid colon, with the highest incidence in the 40-50 age group, and the male-female ratio is 2-3:1. The incidence ranks third among gastrointestinal tumors. Colon cancer is mainly adenocarcinoma, mucinous adenocarcinoma, and undifferentiated carcinoma. The gross morphology is polyp-like, ulcerative, etc. Colon cancer can develop in a circular manner along the intestinal wall, spread up and down along the longitudinal diameter of the intestine, or infiltrate into the deep layer of the intestinal wall. In addition to metastasis through lymphatic vessels and blood flow and local invasion, it can also be implanted in the abdominal cavity or spread and metastasize along sutures and incision surfaces. Patients with chronic colitis, colon polyps, and obese men are susceptible populations. Summary of the invention

[0004] Based on the above purpose, the present invention provides an organic compound or a pharmaceutically acceptable salt thereof and application. In a first aspect, the present invention provides an organic compound or a pharmaceutically acceptable salt thereof, wherein the organic compound is independently selected from the following compounds:

[0005] In a second aspect, the present invention provides a pharmaceutical composition comprising the organic compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0006] In a third aspect, the present invention provides a use of the organic compound or a pharmaceutically acceptable salt thereof, wherein the organic compound or a pharmaceutically acceptable salt thereof is used to prepare an anticancer drug.

[0007] In a fourth aspect, the present invention provides the use of the pharmaceutical composition, wherein the pharmaceutical composition is used to prepare anticancer drugs.

[0008] Compared with the prior art, the present invention has the following beneficial effects: The organic compound or its pharmaceutically acceptable salt provided by the present invention and the pharmaceutical composition comprising the same have very good anti-tumor effects, which are specifically reflected in the following aspects: In vitro experiments showed cytotoxicity: Through cytotoxicity assays, organic compounds were co-cultured with HCT-116 (human colon cancer cells), and the results showed that compounds 10, 34, 45, 66, 72, 73, 86, etc. showed significant cytotoxic effects on HCT-116 cells, with cell survival rates below 50%. This indicates that these compounds can effectively inhibit the growth and proliferation of tumor cells, providing potential active ingredients for the development of new anticancer drugs.

[0009] Providing a basis for the development of anticancer drugs: The organic compound or its pharmaceutically acceptable salt can be used to prepare anticancer drugs, and its good anti-tumor effect lays a foundation for further research and development of therapeutic drugs for malignant tumors such as colon cancer. It is expected that more effective anticancer therapies can be developed through in-depth research on its mechanism of action and optimization of drug formulations, thus providing new treatment options for cancer patients.

[0010] Expanding the field of anticancer drug research and development: The discovery of these organic compounds has enriched the research and development resources of anticancer drugs and provided the possibility for exploring new drug targets and treatment strategies. Their unique chemical structure and anti-tumor activity may provide new ideas and methods for solving problems such as drug resistance in current cancer treatment and promote the development of the field of anticancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0013] Figure 1 This is a statistical result diagram of the effect of the compounds of the present invention on the anti-proliferative activity of HCT-116 cells. DETAILED DESCRIPTION

[0014] In order to be able to understand the characteristics and technical contents of the present invention in more detail, the implementation of the present invention is described in detail below in conjunction with the accompanying drawings, which are only for reference and explanation purposes and are not used to limit the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above-mentioned content of the present invention. In the following examples, unless otherwise indicated, the reagents used can be obtained from commercial channels.

[0015] Example 1: Synthesis of organic matter 10

[0016] Weigh p-nitrobenzaldehyde (46 mg, 0.3 mmol) in 10 mL vial, add trifluorotoluene (3.0 mL), potassium bromide (54 mg, 0.45 mmol). Add potassium persulfate (166 mg, 0.54 mmol) at 0 °C and stir for 5 min. Then add sodium azide (49 mg, 0.75 mmol). After the addition is complete, stir the resulting mixture for 5 min, then warm to room temperature, and then stir rapidly for 24-36 h. When the p-nitrobenzaldehyde substrate is completely consumed as determined by thin layer chromatography analysis, filter the reaction solution through celite. The filtrate is freed from the solvent by rotary evaporator and used directly in the next step without further purification. Under a nitrogen atmosphere, add the product of the previous step and dry toluene (3 mL) and methanol (0.3 mL) to an oven-dried sealed tube. Heat the reaction mixture to 100 °C and stir for 2 h, then cool to room temperature. After removing the solvent by rotary evaporator, the product was purified by silica gel chromatography with eluent (PE:EA=10:1) to obtain the desired target product. 10. 34mg, 58% yield; light yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.20 (d, J = 9.2 Hz, 2H),7.56 (d, J = 9.2 Hz, 2H), 7.04 (br, 1H), 3.82 (s, 3H). 13 C NMR (100 MHz, CDCl3)δ: 153.4, 144.0, 143.1, 125.4 (2×C), 117.8 (2×C), 53.1. Example 2: Synthesis of organic compound 34

[0017] Refer to the synthesis steps of Example 1. Weigh p-tert-butylbenzaldehyde (49 mg, 0.3mmol) in 10 mL vial, add trifluorotoluene (3.0 mL), potassium bromide (54 mg, 0.45 mmol). Add potassium persulfate (166 mg, 0.54 mmol) at 0 ℃ and stir for 5 min. Then add sodium azide (49 mg, 0.75 mmol). After the addition is complete, stir the resulting mixture for 5 min, then warm to room temperature, and then stir rapidly for 24-36 h. When the substrate is completely consumed as determined by thin layer chromatography analysis, filter the reaction solution with diatomaceous earth. The filtrate is freed from the solvent by rotary evaporator and used directly in the next step without further purification. Under a nitrogen atmosphere, add the product of the previous step and dry toluene (3 mL) and methanol (0.3 mL) to an oven-dried sealed tube. Heat the reaction mixture to 100 ℃ and stir for 2 h, then cool to room temperature. After removing the solvent by rotary evaporator, the product was purified by silica gel chromatography with eluent (PE:EA= 10:1) to obtain the desired target product. 34. 44 mg, 71% yield; white solid. 1 H NMR (400 MHz, CDCl3) δ 7.31 (s, 4H), 6.66(br, 1H), 4.23 (q, J = 7.1 Hz, 2H), 1.30 (d, J = 1.6 Hz, 12H). 13 C NMR (100 MHz, CDCl3) δ 153.8, 146.3, 135.3, 125.9 (2×C), 118.6 (2×C), 61.2, 34.3, 31.4 (3×C), 14.6. Example 3: Synthesis of Organic Compound 45

[0018] Refer to the synthesis steps of Example 1. Weigh p-3-chloro-4-bromobenzaldehyde (66 mg, 0.3mmol) in 10 mL vial, add trifluorotoluene (3.0 mL), potassium bromide (54 mg, 0.45 mmol). Add potassium persulfate (166 mg, 0.54 mmol) at 0 ℃ and stir for 5 min. Then add sodium azide (49 mg, 0.75 mmol). After the addition is complete, stir the resulting mixture for 5 min, then warm to room temperature, and then stir rapidly for 24-36 h. When the substrate is completely consumed as determined by thin layer chromatography analysis, filter the reaction solution with diatomaceous earth. The filtrate is freed from the solvent by rotary evaporator and used directly in the next step without further purification. Under a nitrogen atmosphere, add the product of the previous step and dry toluene (3 mL) and methanol (0.3 mL) to an oven-dried sealed tube. Heat the reaction mixture to 100 ℃ and stir for 2 h, then cool to room temperature. After removing the solvent by rotary evaporator, the product was purified by silica gel chromatography with eluent (PE:EA= 10:1) to obtain the desired target product. 45. 65 mg, 81% yield; white solid. 1 H NMR (400 MHz, CDCl3) δ 7.67 – 7.57 (m,1H), 7.50 (d, J = 8.7 Hz, 1H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 6.74 (s, 1H), 3.78(s, 3H). 13 C NMR (100 MHz, CDCl3) δ 153.6, 138.1, 134.9, 133.8, 120.2, 118.1,115.8, 52.7. HRMS (ESI) m / z calculated for C8H8O2NClBr + [M+H] + 263.9422, found263.9418. Example 4: Synthesis of Organic Compound 66

[0019] 1. Preparation of amide Dissolve 3 mmol of compound acid in 3 ml of anhydrous toluene, drop 0.44 ml of thionyl chloride and two drops of DMF into the stirred system, then heat to 50 °C for 2 h, monitor with a spot plate, and wait until the reaction is complete. After removing the excess thionyl chloride, add 1 ml of anhydrous toluene again, aspirate and drop into 2 ml of ammonia water, and react for 3 h. After the reaction is completed by spot plate monitoring, extract with EA, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate for 30 minutes, and evaporate under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography (PE:acetone=2:1).

[0020] 2. Hofmann rearrangement The fatty amide substrate (0.3 mmol) was stirred in MeCN / H2O (10 / 1, 1.1 mL) at 0℃, and KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were added. After the addition was completed, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After the fatty amide substrate was completely consumed by TLC analysis, methanol (1.5 mL) and Cs2CO3 (293 mg, 0.9 mmol) were added in sequence. The reaction was monitored by TLC spot plate. After 5 h of reaction, the reaction was quenched with saturated sodium sulfite solution, the methanol was removed by vacuum rotary evaporation, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporator, and the desired target product 66 was purified by silica gel chromatography with eluent (PE:EA= 10:1) to obtain 50 mg, 84% yield; colorless oil. 1 H NMR (400 MHz, CDCl3) δ: 4.57 (br, 1H), 3.62 (s, 3H), 3.43-3.23 (m, 1H), 2.03-1.94 (m, 2H), 1.74-1.67 (m, 2H), 1.46-1.34 (m, 1H),1.10-0.95 (m, 5H), 0.83 (d, J = 6.8 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ: 156.4, 51.9, 50.5, 43.3, 33.7, 32.6 (2×C), 28.5 (2×C), 20.0 (2×C). Example 5: Synthesis of organic compound 72

[0021] The p-trifluoromethoxybenzamide substrate (0.3 mmol) was stirred in MeCN / H2O (10 / 1, 1.1 mL) at 0°C, and KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were added. After the addition was completed, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After the p-trifluoromethoxybenzamide substrate was completely consumed by TLC analysis, trifluoroethanol (0.6 mL) and NaOH (36 mg, 0.9 mmol) were added in sequence. The reaction was monitored by TLC spot plate. After 5 h of reaction, the reaction was quenched with saturated sodium sulfite solution, trifluoroethanol was removed by vacuum rotary evaporation, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporator, and the eluent (PE:EA= 10:1) was used to purify the desired target product 72.75 mg, 82% yield; light yellow solid. 1 H NMR (400 MHz, CDCl3)δ: 7.43 (d, J = 8.5 Hz, 2H), 7.23- 7.16 (m, 2H), 6.95 (br, 1H), 4.57 (q, J = 8.4Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ: 151.6, 145.5, 135.7, 122.2 (2×C),123.0(q, J = 275 Hz) ,120.6 (q, J = 255 Hz), 120.2 (2×C), 61.2 (q, J = 27.2 Hz). 19 F NMR (376 MHz, CDCl3) δ: -74.2 (3×F), -58.3 (3×F). HRMS (ESI) m / z calculated for C 10 H7O3NF6 + [M+H] + 304.0403, found: 304.0398. Example 6: Synthesis of Organic Compound 73

[0022] The p-trifluoromethoxybenzamide substrate (0.3 mmol) was stirred in MeCN / H2O (10 / 1, 1.1 mL) at 0°C, and KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were added. After the addition was completed, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After the p-trifluoromethoxybenzamide substrate was completely consumed by TLC analysis, n-propanol (0.6 mL) and NaOH (36 mg, 0.9 mmol) were added in sequence. The reaction was monitored by TLC spot plate. After 5 h of reaction, the reaction was quenched with saturated sodium sulfite solution, the n-propanol was removed by vacuum rotary evaporation, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporator, and the eluent (PE:EA= 10:1) was used for purification by silica gel chromatography to obtain the desired target product 73.64 mg, 81% yield; colorless solid. 1 H NMR (400 MHz, CDCl3) δ: 7.42(d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.80 (br,1H), 4.13 (t, J = 6.7 Hz,2H), 1.70 (p, J = 7.1 Hz, 2H), 0.97 (dd, J = 7.9, 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 153.8, 144.7 (d, J = 2.0 Hz), 136.9, 122.0 (2×C), 120.5 (q, J = 255.0Hz), 119.8 (2×C), 67.2, 22.3, 10.4. 19 F NMR (376 MHz, CDCl3) δ: -58.2 (3×F). Example 7: Synthesis of Organic Compound 86

[0023] 3,5-Bis(trifluoromethyl)benzamide substrate (0.3mmol) was stirred in MeCN / H2O (10 / 1, 1.1 mL) at 0℃, and KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were added. After the addition was completed, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After the 3,5-bis(trifluoromethyl)benzamide substrate was completely consumed by TLC analysis, methanol (0.6 mL) and NaOH (36 mg, 0.9 mmol) were added in sequence. The reaction was monitored by TLC spot plate. After 5 hours of reaction, the reaction was quenched with saturated sodium sulfite solution, the methanol was removed by vacuum rotary evaporation, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporator, and the product was purified by silica gel chromatography with eluent (PE:EA= 10:1) to obtain the desired target product 86.68 mg, 79% yield; colorless solid. 1 H NMR (400 MHz, CDCl3) δ: 7.90 (s, 2H), 7.56 (s, 1H), 7.02 (br, 1H), 3.82 (s, 3H). 13 C NMR (100MHz, CDCl3) δ:153.7, 139.5, 132.6 (q, J = 33.3 Hz, 2×C), 123.2 (q, J = 271.1 Hz, 2×C), 118.3(2×C), 116.9 (quint, J = 4.0 Hz), 53.1. 19 F NMR (376 MHz, CDCl3) δ: -63.07. Example 8: Cytotoxicity Assay Cell culture: HCT-116 (human colon cancer cells) were cultured at 37°C and 5% CO2 in a high-glucose Dulbecco's Modified Eagle Medium (DMEM) (purchased from Gibco, catalog number: C11995500BT), supplemented with 10% fetal bovine serum (FBS) (purchased from Vazyme, catalog number: F101-01) and 1% penicillin-streptomycin solution (purchased from Biosharp, catalog number: BL505A). Cells were subcultured when they reached 70-80% confluence, and the experimental generation was within five generations.

[0024] Cell treatment: Select cells in the logarithmic growth phase, count the cell suspension using a cell counter, and adjust the concentration to 5 × 10 4 The cell suspension was inoculated into a 96-well culture plate with a volume of 100 μL per well and cultured overnight to ensure that the cells were fully attached. Subsequently, the original culture medium was replaced with fresh culture medium containing a final concentration of 100 μM compound and cultured for another 48 hours.

[0025] Survival rate detection: Add 10 ul CCK-8 reagent to each well of a 96-well culture plate and incubate at 37°C for 2 hours. Use a microplate reader to measure the optical density (OD) value of each well at a wavelength of 450 nm. The calculation formula for cell survival rate is as follows: Survival rate (%) = (OD value of the drug group - OD value of the blank control group) / (OD value of the non-drug control group - OD value of the blank control group) * 100. The statistical results of cell survival rate are as follows Figure 1 As shown, the results show that some treatment groups exhibited significant cytotoxic effects on HCT-116 cells, with a survival rate of less than 50%, including compounds 10, 34, 45, 66, 72, 73, and 86. The results show that compounds 10, 34, 45, 66, 72, 73, and 86 have certain in vitro anti-tumor cell proliferation capabilities. 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, and these improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An organic compound or a pharmaceutically acceptable salt thereof, characterized in that: The organic compounds are independently selected from the following compounds: 。 2. A pharmaceutical composition, characterized in that It comprises the organic compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

3. The use of an organic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The organic compound or its pharmaceutically acceptable salt is used for preparing anticancer drugs.

4. The use of the pharmaceutical composition according to claim 2, characterized in that: The pharmaceutical composition is used for preparing anticancer drugs.

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