A compound or composition and use thereof in the manufacture of a medicament for the treatment of cancer
By developing a combination of compounds of formula I and formula III, the problem of inconsistent efficacy of existing drugs was solved, and the therapeutic effect of pancreatic cancer was significantly improved, with a substantial reduction in IC50 value, demonstrating excellent anti-pancreatic cancer activity.
Patent Information
- Application Number
- CN202511140763.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-15
- Publication Date
- 2025-11-21
- Estimated Expiration
- 2045-08-15
AI Technical Summary
Existing pancreatic cancer treatments have varying effects on different patients, and there is a lack of highly effective anti-pancreatic cancer drugs.
A composition consisting of compounds with the structures shown in Formula I and Formula III in a mass ratio of 1:1 has been developed, exhibiting synergistic anti-pancreatic cancer activity superior to either Formula I or Formula III alone.
This composition significantly improved the therapeutic effect against pancreatic cancer, with an IC50 value reduced to 2.6 μg/mL, which is much lower than that of the individual compounds, demonstrating excellent anti-pancreatic cancer activity.
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Figure CN120737090B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of biological medicine, in particular to a compound or composition and application thereof in preparation of a medicine with anti-cancer effect. BACKGROUND
[0002] Pancreatic cancer is a malignant tumor originating from pancreatic duct epithelial and acinar cells. Symptoms of advanced pancreatic cancer include jaundice, weight loss, abdominal discomfort or pain. Currently, the treatment of pancreatic cancer includes surgery, chemotherapy, radiotherapy, interventional therapy and supportive treatment.
[0003] For the drug of chemotherapy, currently mainly includes gemcitabine, carboplatin, oxaliplatin, erlotinib and bevacizumab, etc. However, different drugs have different effects on different patients; therefore, it has important application value to develop more drugs with anti-pancreatic cancer effect. SUMMARY
[0004] In order to overcome at least one of the technical problems existing in the prior art, the present application provides a compound or composition and application thereof in preparation of a medicine with anti-cancer effect.
[0005] The technical scheme of the present application is as follows:
[0006] The present application first provides a compound having a structure shown in formula I, formula II or formula III:
[0007] Formula I;
[0008] Formula II;
[0009] Formula III.
[0010] It is found in research that the compound having the structure shown in formula I, formula II and formula III has anti-pancreatic cancer effect; wherein the anti-pancreatic cancer effect of the compound having the structure shown in formula I is the best, which is significantly higher than that of the compound having the structure shown in formula II and formula III.
[0011] The present application further provides a composition comprising the compound having the structure shown in formula I and formula III.
[0012] Preferably, the mass ratio of the compound having the structure shown in formula I and formula III is 1-5:1-5.
[0013] Preferably, the mass ratio of the compound having the structure shown in formula I and formula III is 1-3:1-3.
[0014] Most preferably, the mass ratio of the compound having the structure shown in formula I and formula III is 1:1.
[0015] Further research surprisingly showed that compositions consisting of compounds with structures shown in Formula I and Formula III exhibit superior anti-pancreatic cancer activity, significantly higher than that of compounds with structures shown in Formula I or Formula III alone; compositions consisting of compounds with structures shown in Formula I and Formula III also exhibit synergistic anti-pancreatic cancer activity.
[0016] The study also found that only compositions of compounds with the structures shown in Formula I and Formula III exhibited significantly higher anti-pancreatic cancer activity than compounds with the structures shown in Formula I, Formula II, and Formula III alone, thus producing a synergistic anti-pancreatic cancer effect. However, compositions of compounds with the structures shown in Formula I and Formula II, or compounds with the structures shown in Formula II and Formula III, did not exhibit significantly higher anti-pancreatic cancer activity than compounds with the structures shown in Formula I, Formula II, and Formula III alone, and did not produce a synergistic anti-pancreatic cancer effect.
[0017] The present invention also provides the use of the above-mentioned compound or composition in the preparation of a drug with anticancer activity.
[0018] Preferably, the cancer is pancreatic cancer.
[0019] Preferably, the dosage form of the drug is tablets, capsules, pills, or injections.
[0020] Beneficial effects: This invention provides a novel compound; studies have shown that the compound of this invention has anti-pancreatic cancer activity; this invention also provides a novel composition, studies have shown that the composition composed of compounds with the structures shown in Formula I and Formula III has a superior anti-pancreatic cancer activity, which is significantly higher than that of compounds with the structures shown in Formula I or Formula III alone. Attached Figure Description
[0021] Figure 1 The 1H NMR spectrum is shown for the compound with the structure shown in Formula I.
[0022] Figure 2 The 1H NMR spectrum is shown for the compound with the structure shown in Formula II.
[0023] Figure 3 The 1H NMR spectrum is shown for the compound with the structure shown in Formula III. Detailed Implementation
[0024] The present invention will be further explained below with reference to specific embodiments, but the embodiments do not limit the present invention in any way.
[0025] The methoxycapsaicin, styracin glucoside, and gentamicin lactone used in the following examples are all compounds known in the art.
[0026] Example 1: Preparation of compounds with the structure shown in Formula I
[0027] N-([1,1'-biphenyl]-4-yl)-2-chloroacetamide (245 mg, 1 mmol, 1 eq), 2 mL of N,N-dimethylformamide, potassium carbonate (276 mg, 2 mmol, 2 eq), and sitagliptin (407 mg, 1 mmol, 1 eq) were added sequentially to the reaction flask. After addition, the reaction was carried out at 60 °C for 4 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) was used to monitor the reaction completion. 10 mL of ethyl acetate and 5 mL of water were added to the reaction mixture, and the mixture was extracted and separated. The organic phase was collected. The organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 190 mg of the compound with the structure shown in Formula I (i.e., WNT128 in the above reaction formula), with a yield of 31%.
[0028] The proton NMR spectra of the compounds with the structure shown in Formula I are as follows: 1 H NMR (500 MHz, DMSO) δ 9.93 (s,1H), 7.74 – 7.68 (m, 2H), 7.66 – 7.60 (m, 5H), 7.57 – 7.51 (m, 1H), 7.49 –7.41 (m, 4H), 7.34 – 7.30 (m, 1H), 5.00 – 4.90 (m, 2H), 4.25 – 4.22 (m, 1H), 4.16 – 4.04 (m, 2H), 4.01 – 3.92 (m, 2H), 3.38 (s, 2H), 2.97 – 2.85 (m, 2H), 2.69 – 2.62 (m, 2H).
[0029] Example 2 Preparation of compounds with the structure shown in Formula II
[0030] N-([1,1'-biphenyl]-4-yl)-2-chloroacetamide (245 mg, 1 mmol, 1 eq), 2 mL of N,N-dimethylformamide, potassium carbonate (276 mg, 2 mmol, 2 eq), and olanzapine (312 mg, 1 mmol, 1 eq) were added sequentially to the reaction flask. After addition, the reaction was carried out at 60 °C for 4 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) was used to monitor the reaction completion. 10 mL of ethyl acetate and 5 mL of water were added to the reaction mixture, and the mixture was extracted and separated. The organic phase was collected. The organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 210 mg of the compound with the structure shown in Formula II (i.e., WNT129 in the above reaction formula), with a yield of 40%.
[0031] The proton NMR data of the compound with the structure shown in Formula II are as follows: 1 H NMR (500 MHz, DMSO) δ 11.20 (s,1H), 7.79 – 7.74 (m, 2H), 7.74 – 7.63 (m, 4H), 7.52 – 7.41 (m, 2H), 7.38 –7.31 (m, 1H), 6.97 – 6.79 (m, 3H), 6.76 – 6.70 (m, 1H), 6.42 (s, 1H), 4.62(s, 2H), 3.89 – 3.62 (m, 8H), 3.47 (s, 3H), 2.29 (s, 3H).
[0032] Example 3 Preparation of compounds with the structure shown in Formula III
[0033] N-([1,1'-biphenyl]-4-yl)-2-(5-amino-1H-indazole-1-yl)acetamide (34.2 mg, 1 eq, 0.1 mmol) and 4-dimethylaminopyridine (1.2 mg, 0.1 eq, 0.01 mmol) were added to a reaction flask and dissolved in 2 mL of pyridine. Then, 4-methoxybenzenesulfonyl chloride (21.2 mg, 1 eq, 0.1 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by thin-layer chromatography (dichloromethane / methanol = 10 / 1). 10 mL of ethyl acetate and 5 mL of water were added to the reaction solution, and the mixture was extracted and separated. The organic phase was collected. The organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 44 mg of the compound with the structure shown in Formula III (i.e. WNT145 in the above reaction formula), with a yield of 86%.
[0034] The proton NMR data of the compound with the structure shown in Formula III are as follows: 1 H NMR (500 MHz, DMSO) δ 10.46(s, 1H), 9.96 (s, 1H), 8.03 (s, 1H), 7.83 – 7.57 (m, 8H), 7.57 – 7.51 (m,1H), 7.49 – 7.38 (m, 3H), 7.35 – 7.30 (m, 1H), 7.17 – 7.11 (m, 1H), 7.08 –6.97 (m, 2H), 5.27 (s, 2H), 3.77 (s, 3H).
[0035] Example 4 Preparation of the composition
[0036] The composition is obtained by mixing the compounds with the structures shown in Formula I and Formula III at a mass ratio of 1:1.
[0037] Comparative Example 1: Preparation of the Composition
[0038] The composition is obtained by mixing the compounds with the structures shown in Formula I and Formula II at a mass ratio of 1:1.
[0039] Comparative Example 2: Preparation of the Composition
[0040] The composition is obtained by mixing the compounds with the structures shown in Formula II and Formula III at a mass ratio of 1:1.
[0041] Experiment Example 1: Anti-pancreatic cancer experiment
[0042] (1) Human pancreatic cancer MIAPaCa-2 cells were added to 96-well plates at a rate of 1×10⁻⁶ cells per well. 5 One, continue
[0043] The culture medium was DMEM (containing 10% fetal bovine serum) and incubated at 37°C in an incubator containing 5% CO2 for 24 hours.
[0044] (2) Remove the culture medium and add DMEM (containing 10% fetal bovine serum) medium containing serially diluted samples of different concentrations and continue culturing for 48 hours;
[0045] (3) Add 20 μL of 4 mg / mL MTT to each well and incubate for 6 h. Then remove the supernatant and add 80 μL of dimethyl sulfoxide to each well. Shake for 15 min in the dark.
[0046] (4) The absorbance of each well at 570 nm was measured using an ELISA reader, and the experiment was repeated three times for each concentration. The cell viability of the test sample against human pancreatic cancer cells was calculated based on the absorbance. Finally, the half-inhibitory concentration (IC50) of the test sample against human pancreatic cancer cells was calculated based on the dose-response curve. 50 The experimental results are shown in Table 1.
[0047] The test samples are compounds with structures shown in Formula I, Formula II and Formula III, and compositions prepared in Example 4 and Comparative Examples 1 and 2.
[0048] Table 1. Results of anti-pancreatic cancer experiments
[0049] IC 50 values (pg / mL) Compound of the structure of Formula I 7.8 μg / mL Compound of the structure of Formula II 18.7 μg / mL Compound of the structure of Formula III 14.5 μg / mL Composition prepared in Example 4 2.6 μg / mL Composition prepared in Comparative Example 1 11.7 μg / mL Composition prepared in Comparative Example 2 16.2 μg / mL
[0050] As can be seen from the experimental results in Table 1, the compounds with structures shown in Formula I, Formula II and Formula III have anti-pancreatic cancer effects; among them, the compound with structure shown in Formula I has the best anti-pancreatic cancer effect, which is significantly higher than that of the compounds with structures shown in Formula II and Formula III.
[0051] The experimental results in Table 1 also show that the composition prepared in Example 4 has an IC50 value. 50 The value is significantly smaller than that of compounds with structures shown in Formula I, Formula II, and Formula III; this indicates that the composition of compounds with structures shown in Formula I and Formula III has a significantly higher anti-pancreatic cancer effect than compounds with structures shown in Formula I or Formula III alone; the composition of compounds with structures shown in Formula I and Formula III can produce a synergistic anti-pancreatic cancer effect and has a more superior anti-pancreatic cancer effect.
[0052] Table 1 shows that the compositions prepared in Comparative Examples 2 and 3 have IC50 values. 50The IC50 value was not reduced compared to the compound with the structure shown in Formula I, and its IC50 value was... 50 The values are also significantly higher than those of the composition prepared in Example 4; this indicates that only compositions consisting of compounds with the structures shown in Formula I and Formula III can have a significantly higher anti-pancreatic cancer effect than compounds with the structures shown in Formula I, Formula II, and Formula III alone, and can produce a synergistic anti-pancreatic cancer effect and have a more superior anti-pancreatic cancer effect; however, compositions consisting of compounds with the structures shown in Formula I and Formula II, or compounds with the structures shown in Formula II and Formula III, cannot have a significantly higher anti-pancreatic cancer effect than compounds with the structures shown in Formula I, Formula II, and Formula III alone, cannot produce a synergistic anti-pancreatic cancer effect, and do not have a more superior anti-pancreatic cancer effect.
Claims
1. A compound, characterized in that, It has the structure shown in Formula I, Formula II or Formula III: Formula I; Formula II; Formula III.
2. A composition, characterized in that, Compounds comprising the structures shown in Formula I and Formula III as described in claim 1.
3. The composition according to claim 2, characterized in that, The mass ratio of the compounds with the structures shown in Formula I and Formula III is 1~5:1~5.
4. The composition according to claim 2, characterized in that, The mass ratio of the compounds with the structures shown in Formula I and Formula III is 1~3:1~3.
5. The composition according to claim 2, characterized in that, The mass ratio of the compounds with the structures shown in Formula I and Formula III is 1:
1.
6. The use of the compound of claim 1 or the composition of any one of claims 2 to 5 in the preparation of a medicament with anticancer activity; wherein the cancer is pancreatic cancer.
7. The application according to claim 6, characterized in that, The dosage form of the drug is tablets, capsules, pills, or injections.
Citation Information
Patent Citations
Maleimide derivatives as modulators of WNT pathway
CN106061974A
Pharmaceutical composition for treating pancreatic cancer and application thereof
CN120131693A