Compound and application thereof in preparation of medicine capable of inhibiting Wnt signal channel activity

Abstract

The invention relates to the technical field of medicinal chemistry, and particularly discloses a compound and application thereof in preparation of a medicine with Wnt signal channel inhibition activity. The compound has a structure as shown in a formula I which is described in the specification. Researches show that the compound disclosed by the invention has the activity of inhibiting a Wnt signal channel; particularly, the IC50 value of the compound Wnt-131 is greatly smaller than that of the compound Wnt-120 and the compound Wnt-133; meanwhile, the compound is also greatly smaller than all compounds in the invention patent CN202410961646. X, and has very excellent activity of inhibiting a Wnt signal channel; therefore, the compound serving as an active ingredient has important application value in preparing the medicine for inhibiting the activity of the Wnt signal channel.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry; specifically, it relates to a compound and its use in the preparation of drugs that inhibit the Wnt signaling pathway. Background Technology

[0002] Porcupine is an O-acyltransferase found on the endoplasmic reticulum membrane, playing a crucial role in WNT secretion. Porcupine inhibitors can suppress WNT secretion, thereby inhibiting the WNT signaling pathway. The WNT / β-catenin signaling pathway plays a vital role in regulating human development and tissue homeostasis. Increasing research indicates that the WNT pathway in hepatocytes is continuously activated during liver fibrosis, and downregulating the WNT / β-catenin signaling pathway can inhibit hepatic stellate cell activation and liver fibrosis. Therefore, developing a series of compounds with inhibitory activity against the Wnt signaling pathway is of significant application value in the screening of drugs for the prevention and / or treatment of liver fibrosis.

[0003] The inventors of this invention disclosed the use of a compound in the preparation of a drug with preventive and / or therapeutic effects on liver fibrosis in a previous patent, CN202410961646.X. While this patent disclosed compounds with this general formula structure that inhibit the Wnt signaling pathway, most of these compounds had high IC50 values, and some even showed no related activity. Developing a compound with a new general formula structure, especially one with a new general formula structure that exhibits better overall activity, has significant application value. Summary of the Invention

[0004] In order to solve at least one of the technical problems existing in the prior art, the present invention provides a compound and its use in the preparation of a drug having activity of inhibiting the Wnt signaling pathway.

[0005] The technical solution of the present invention is as follows: This invention first provides a compound having the structure shown in Formula I: Formula I.

[0006] Preferably, in formula I, A is selected from C0 to C3; X is selected from C1 to C3; Y is selected from C, N, or S atoms; R1 is selected from nitrogen-containing groups or halogen atoms; R2 is selected from nitrogen-containing groups or halogen atoms.

[0007] Preferably, in Formula I, A is selected from C0 or C1 structures; X is selected from C1 or C2 structures; and Y is selected from C atoms or N atoms.

[0008] Preferably, in Formula I, R1 is selected from nitro groups; R2 is selected from halogen atoms.

[0009] Preferably, the halogen atom is a bromine atom.

[0010] Preferably, the compound is selected from any one of the following structures: ; ; .

[0011] Preferably, the compound is a compound that inhibits the activity of the Wnt signaling pathway.

[0012] The present invention also provides the use of the above-mentioned compound in the preparation of a drug having activity that inhibits the Wnt signaling pathway.

[0013] Preferably, the dosage form of the drug is tablets, capsules, pills, or injections.

[0014] Beneficial Effects: This invention provides a compound with a novel structure. Studies have shown that the compound described in this invention has inhibitory activity against the Wnt signaling pathway; in particular, compound Wnt-131 has an IC50 value that is significantly lower than that of compounds Wnt-120 and Wnt-133, and also significantly lower than that of all compounds in invention patent CN202410961646.X, exhibiting excellent inhibitory activity against the Wnt signaling pathway. Therefore, using it as an active ingredient to prepare drugs with inhibitory activity against the Wnt signaling pathway has significant application value. Attached Figure Description

[0015] Figure 1 This is the proton NMR spectrum of compound WNT120.

[0016] Figure 2 This is the proton NMR spectrum of compound WNT131.

[0017] Figure 3 This is the proton NMR spectrum of compound WNT133. Detailed Implementation

[0018] The present invention will be further illustrated below with reference to specific embodiments, but these embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field. Unless otherwise specified, the reagents and materials used in the following embodiments are commercially available.

[0019] Example 1 Preparation of compound (WNT120)

[0020]

[0021] SM1 (245 mg, 1 mmol, 1 eq), 2 mL DMF, potassium carbonate (276 mg, 2 mmol, 2 eq), and SM2 (241 mg, 1 mmol, 1 eq) were added sequentially to the reaction flask. After addition, the reaction was carried out at 25±5℃ for 4 h. The reaction was monitored by TLC until completion (PE / EtOAc = 2 / 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 (PE / EtOAc = 2 / 1) to obtain 180 mg of product (WNT120) (yield 40.0%). 1 H NMR (500 MHz, DMSO) δ11.24 (s, 1H), 9.08 (s, 1H), 9.01 (s, 1H), 8.28 (s, 1H), 7.81 – 7.75 (m, 2H), 7.68 – 7.63 (m, 4H), 7.45 – 7.43 (m, 2H), 7.35 – 7.31 (m, 1H), 5.65 (s, 2H).

[0022] Example 2 Preparation of compound (WNT131)

[0023] 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 5-nitrodihydroindole (164 mg, 1 mmol, 1 eq) were added sequentially to the reaction flask. After addition, the reaction was carried out at 25±5℃ for 4 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) was used to monitor the completion of the reaction. 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 = 2 / 1) to obtain 127 mg of product (WNT131), with a yield of 34%. 1H NMR (500 MHz, DMSO) δ10.23 (s, 1H), 8.02 – 7.96 (m, 1H), 7.89 – 7.84 (m, 1H), 7.70 – 7.66 (m, 2H), 7.66 – 7.61 (m, 4H), 7.46 – 7.40 (m, 2H), 7.36 – 7.30 (m, 1H), 6.63 – 6.51(m, 1H), 4.25 (s, 2H), 3.79 (t, J = 8.7 Hz, 2H), 3.12 (t, J = 8.6 Hz, 2H).

[0024] Example 3 Preparation of compound (WNT133) 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 6-nitro-1,2,3,4-tetrahydroquinoline (178 mg, 1 mmol, 1 eq) were added sequentially to the reaction flask. After addition, the reaction was carried out at 60 °C for 12 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 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 = 2 / 1) to obtain 166 mg of product (WNT133), with a yield of 43%. 1 H NMR (500 MHz, DMSO) δ 9.90 (s, 1H), 8.05 – 7.95 (m, 2H), 7.77 – 7.73 (m, 2H), 7.66 – 7.59 (m, 4H), 7.47 – 7.41 (m, 3H), 7.35 – 7.30 (m, 1H), 3.90 (s, 2H), 3.40 (m, 2H), 3.03 (t, 2H), 2.90 (t, 2H).

[0025] Experiment Example 1: Inhibition of the Wnt signaling pathway To determine whether the synthesized compound inhibits Wnt signaling pathway activity, we typically use a luciferase reporter gene assay. This assay employed 293T-Wnt-Luciferase-Reporter and LWnt-3A cells. LWnt-3A cells are Wnt protein-producing cells, while 293T-Wnt-Luciferase-Reporter cells are Wnt protein-responsive cells.

[0026] Experimental procedure: 293T-Wnt-Luciferase-Reporter and L Wnt-3A cells were co-cultured at a 1:1 density. After treatment with the test compound for 24 hours, the 50% inhibitory concentration of the test compound on the activation of the Wnt reporter gene in the model was detected using the Bright-Glo Luciferase Assay System.

[0027] Table 1. Inhibitory effect of the compounds of this invention on the Wnt signaling pathway

[0028]

[0029] The results are shown in Table 1. The compounds having the general formula structure of this invention generally have lower IC50 values ​​than the compounds with the structure shown in Formula I of invention patent CN202410961646.X. This indicates that compounds having the general formula structure described in this invention have better activity in inhibiting the Wnt signaling pathway. In particular, compound Wnt-131 has a significantly lower IC50 value than compounds Wnt-120 and Wnt-133; it is also significantly lower than all compounds in invention patent CN202410961646.X. This demonstrates that compound Wnt-131 of this invention has excellent activity in inhibiting the Wnt signaling pathway, and its activity in inhibiting the Wnt signaling pathway is significantly higher than that of known compounds.

Claims

1. A compound, characterized in that, The compound is selected from any one of the following structures: ； ； 。 2. The compound according to claim 1, characterized in that, The compound is a compound that inhibits the activity of the Wnt signaling pathway.

3. The use of the compound of claim 1 in the preparation of a drug having activity that inhibits the Wnt signaling pathway.

4. The application according to claim 3, characterized in that, The dosage form of the drug is tablets, capsules, pills, or injections.

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