An organic compound or a pharmaceutically acceptable salt thereof and use

Abstract

The application discloses an organic compound or a pharmaceutically acceptable salt thereof, and provides the organic compound or the pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same, wherein the organic compound is independently selected from the following compounds:

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and organic compound synthesis technology, specifically relating to an organic compound and its application. Background Technology

[0002] Malignant tumors are among the most serious diseases threatening human health. Their incidence rate is second only to cardiovascular and cerebrovascular diseases, making them the second leading cause of death worldwide. Furthermore, their mortality rate surpasses that of cardiovascular and cerebrovascular diseases, ranking first among all diseases. Therefore, finding and developing new drugs to treat tumors is a major challenge we currently face.

[0003] Colorectal cancer is a common malignant tumor of the digestive tract that occurs in the colon. It is strongly associated with the consumption of red meat (such as beef). It commonly occurs at the junction of the rectum and sigmoid colon, with the highest incidence in the 40-50 age group, and a male-to-female ratio of 2-3:1. It ranks third in incidence among gastrointestinal tumors. Colorectal cancer is mainly adenocarcinoma, mucinous adenocarcinoma, or undifferentiated carcinoma. Grossly, it presents as polyps or ulcers. Colorectal cancer can develop circumferentially along the intestinal wall, spread longitudinally along the intestinal tract, or infiltrate deep into the intestinal wall. Besides metastasis via lymphatic vessels, bloodstream, and local invasion, it can also implant in the abdominal cavity or spread along sutures and incision surfaces. Patients with chronic colitis, colorectal polyps, and obese men are susceptible populations. Summary of the Invention

[0004] To achieve the above objectives, the present invention provides an organic compound or a pharmaceutically acceptable salt thereof and its application. In a first aspect, the present invention provides an organic compound or a pharmaceutically acceptable salt thereof, said organic compound being independently selected from the following compounds:

[0005]

[0006] In a second aspect, the present invention provides a pharmaceutical composition comprising the said organic compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0007] Thirdly, the present invention provides the use of the aforementioned organic compound or a pharmaceutically acceptable salt thereof for the preparation of an anticancer drug.

[0008] Fourthly, the present invention provides the use of the pharmaceutical composition for the preparation of an anticancer drug.

[0009] Compared with the prior art, the present invention has the following beneficial effects:

[0010] The organic compounds or their pharmaceutically acceptable salts provided by this invention, as well as pharmaceutical compositions comprising them, have very good antitumor effects, specifically in the following aspects:

[0011] In vitro experiments demonstrated cytotoxicity: Cytotoxicity assays showed that compounds 10, 34, 45, 66, 72, 73, and 86 exhibited significant cytotoxic effects on HCT-116 cells, with cell viability 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 novel anticancer drugs.

[0012] This invention lays the foundation for the development of anticancer drugs: the organic compounds or their pharmaceutically acceptable salts can be used to prepare anticancer drugs, and their good antitumor effects lay the foundation for further research and development of therapeutic drugs for malignant tumors such as colon cancer. It is hoped that through in-depth research on their mechanisms of action and optimization of drug formulations, more effective anticancer therapies can be developed, bringing new treatment options to cancer patients.

[0013] Expanding the field of anticancer drug development: The discovery of these organic compounds has enriched the resources for anticancer drug development, providing possibilities for exploring new drug targets and treatment strategies. Their unique chemical structures and antitumor activities may offer new ideas and methods for solving problems such as drug resistance in current cancer treatments, thus promoting the development of the anticancer drug field. Attached Figure Description

[0014] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0015] Figure 1 This is a statistical result graph showing the effect of the compounds of the present invention on the antiproliferative activity of HCT-116 cells. Detailed Implementation

[0016] To provide a more detailed understanding of the features and technical content of this invention, the implementation of the invention will be described in detail below with reference to the accompanying drawings. The drawings are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art can make some non-essential improvements and adjustments to this invention based on the above description. In the following embodiments, unless otherwise specified, all reagents used are commercially available.

[0017] Example 1: Synthesis of Organic Compound 10

[0018]

[0019] Weigh p-nitrobenzaldehyde (46 mg, 0.3 mmol) into 10 mL of vial, add trifluorotoluene (3.0 mL) and potassium bromide (54 mg, 0.45 mmol). Add potassium persulfate double salt (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 raise to room temperature, and then stir rapidly for 24–36 h. After thin-layer chromatography analysis shows that the p-nitrobenzaldehyde substrate has been completely consumed, filter the reaction solution with diatomaceous earth. Remove the solvent from the filtrate using a rotary evaporator and use it directly for the next step without further purification. Under a nitrogen atmosphere, add the product from the previous step and dried toluene (3 mL) and methanol (0.3 mL) to a sealed tube that has been dried in an oven. Heat the reaction mixture to 100 °C and stir for 2 h, then cool to room temperature. The solvent was removed using a rotary evaporator, and the product was purified by silica gel column chromatography with eluent (PE:EA = 10:1) to obtain the desired target product. 10.34 mg, 58% yield; pale 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.

[0020] Example 2: Synthesis of Organic Compound 34

[0021]

[0022] Following the synthetic steps of Example 1, weigh p-tert-butylbenzaldehyde (49 mg, 0.3 mmol) into 10 mL of vial, add trifluorotoluene (3.0 mL) and potassium bromide (54 mg, 0.45 mmol). Add potassium persulfate double salt (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 raise it to room temperature, and then stir rapidly for 24–36 h. After thin-layer chromatography analysis shows that the substrate has been completely consumed, filter the reaction solution with diatomaceous earth. Remove the solvent from the filtrate using a rotary evaporator and use it directly for the next step without further purification. Under a nitrogen atmosphere, add the product from the previous step and dried toluene (3 mL) and methanol (0.3 mL) to a sealed tube that has been dried in an oven. Heat the reaction mixture to 100 °C and stir for 2 h, then cool to room temperature. The solvent was removed using a rotary evaporator, and the product was purified by silica gel column 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.

[0023] Example 3: Synthesis of Organic Compound 45

[0024]

[0025] Following the synthetic steps of Example 1, weigh 66 mg (0.3 mmol) of p-3-chloro-4-bromobenzaldehyde into 10 mL of vial, add 3.0 mL of trifluorotoluene and 54 mg (0.45 mmol) of potassium bromide. Add potassium persulfate double salt (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 raise it to room temperature and then stir rapidly for 24–36 h. After thin-layer chromatography analysis shows that the substrate has been completely consumed, filter the reaction solution with diatomaceous earth. Remove the solvent from the filtrate using a rotary evaporator and use it directly for the next step without further purification. Under a nitrogen atmosphere, add the product from the previous step and dried toluene (3 mL) and methanol (0.3 mL) to a sealed tube that has been dried in an oven. Heat the reaction mixture to 100 °C and stir for 2 h, then cool to room temperature. The solvent was removed using a rotary evaporator, and the product was purified by silica gel column 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, found 263.9418.

[0026] Example 4: Synthesis of Organic Compound 66

[0027]

[0028] 1. Preparation of amides

[0029] 3 mmol of the compound acid was dissolved in 3 ml of anhydrous toluene. 0.44 ml of thionyl chloride and two drops of DMF were added dropwise to the stirred system. The mixture was then heated to 50 °C and reacted for 2 h, monitored by TLC. After the reaction was complete, excess thionyl chloride was removed by rotary evaporation, and 1 ml of anhydrous toluene was added again. This residue was then aspirated and added dropwise to 2 ml of ammonia water, and the reaction was allowed to proceed for 3 h. After the reaction was completed by TLC, the mixture was extracted with EA, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate for 30 min, and evaporated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (PE:acetone = 2:1).

[0030] 2. Hofmann rearrangement

[0031] The fatty amide substrate (0.3 mmol) was stirred in a MeCN / H2O (10 / 1, 1.1 mL) solution at 0 °C. KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were then added. After addition, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After complete consumption of the fatty amide substrate by TLC analysis, methanol (1.5 mL) and Cs2CO3 (293 mg, 0.9 mmol) were added sequentially. The reaction was monitored by TLC spotting. After 5 h, the reaction was quenched with saturated sodium sulfite solution. Methanol was removed by vacuum rotary evaporation, and the product was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography with eluent (PE:EA = 10:1) to obtain the desired product: 66.50 mg, 84% yield; a 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).

[0032] Example 5: Synthesis of Organic Compound 72

[0033]

[0034] The p-trifluoromethoxybenzamide substrate (0.3 mmol) was stirred in a MeCN / H2O (10 / 1, 1.1 mL) solution at 0 °C. KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were then added. After addition, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After complete consumption of the p-trifluoromethoxybenzamide substrate by TLC analysis, trifluoroethanol (0.6 mL) and NaOH (36 mg, 0.9 mmol) were added sequentially. The reaction was monitored by TLC spotting. After 5 h, 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 evaporation, and the product was purified by silica gel column chromatography with eluent (PE:EA = 10:1) to obtain 72.75 mg of the desired product (82% yield); a pale 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.

[0035] Example 6: Synthesis of Organic Compound 73

[0036]

[0037] p-Trifluoromethoxybenzamide substrate (0.3 mmol) was stirred in a MeCN / H2O (10 / 1, 1.1 mL) solution at 0 °C. KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were then added. After addition, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After complete consumption of the p-trifluoromethoxybenzamide substrate by TLC analysis, n-propanol (0.6 mL) and NaOH (36 mg, 0.9 mmol) were added sequentially. The reaction was monitored by TLC spotting. After 5 h, the reaction was quenched with saturated sodium sulfite solution. n-Propanol was removed by vacuum rotary evaporation, and the product was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography with eluent (PE:EA = 10:1) to obtain the desired 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).

[0038] Example 7: Synthesis of Organic Compound 86

[0039]

[0040] 0.3 mmol of 3,5-bis(trifluoromethylbenzamide) substrate was stirred in a MeCN / H₂O solution (10 / 1, 1.1 mL) at 0 °C. KCl (34 mg, 0.45 mmol) and Oxone (138 mg, 0.45 mmol) were then added. After addition, the mixture was stirred for 10 minutes, then heated to room temperature and stirred for another 2 hours. After complete consumption of the 3,5-bis(trifluoromethylbenzamide) substrate by TLC analysis, methanol (0.6 mL) and NaOH (36 mg, 0.9 mmol) were added sequentially. The reaction was monitored by TLC spotting. After 5 h, the reaction was quenched with saturated sodium sulfite solution. Methanol was removed by vacuum rotary evaporation, and the product was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 min. The solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography with eluent (PE:EA = 10:1) to obtain 86.68 mg of the target product (79% yield); a 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.

[0041] Example 8: Cytotoxicity assay

[0042] Cell culture: HCT-116 (human colon cancer cells) were cultured at 37°C and 5% CO2 in 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 passaged when they reached 70-80% confluence, with the experimental passage number not exceeding five.

[0043] Cell treatment: Select cells in the logarithmic growth phase, count the cell suspension using a cell counter, and adjust the concentration to 5 × 10⁻⁶. 4 Cells / mL. The cell suspension was seeded into 96-well plates at a volume of 100 μL per well and cultured overnight to ensure adequate cell adhesion. Subsequently, the original medium was replaced with fresh medium containing a final concentration of the compound (100 μM), and cultured for another 48 hours.

[0044] Cell viability assay: 10 μL of CCK-8 reagent was added to each well of a 96-well plate and incubated at 37°C for 2 hours. The optical density (OD) value of each well was measured at 450 nm using a microplate reader. The cell viability was calculated using the following formula: Viability (%) = (OD value of drug-treated group - OD value of blank control) / (OD value of untreated control group - OD value of blank control group) * 100. Statistical results of cell viability are shown below. Figure 1 As shown, the results indicated that some treatment groups exhibited significant cytotoxic effects on HCT-116 cells, with survival rates below 50%, including compounds 10, 34, 45, 66, 72, 73, and 86. These results suggest that compounds 10, 34, 45, 66, 72, 73, and 86 possess certain in vitro anti-tumor cell proliferation capabilities. The above description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The use of an organic compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-colon cancer drug, characterized in that, The organic compound is selected from the following 66 compounds; ； The colon cancer mentioned is human colon cancer cell line HCT-116.

2. The use of a pharmaceutical composition in the preparation of an anti-colon cancer drug, characterized in that, The pharmaceutical composition comprises the organic compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; The colon cancer mentioned is human colon cancer cell line HCT-116.

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