A compound and use thereof in the preparation of a medicament having activity in inhibiting the Wnt signaling pathway

Abstract

The application relates to the technical field of pharmaceutical chemistry, and particularly discloses a compound and application of the compound in preparation of a medicine with Wnt signal pathway inhibiting activity. The compound has the structure shown in formula I. Research shows that the compound has Wnt signal pathway inhibiting activity; in particular, the IC50 value of the compound Wnt-131 is much smaller than that of the compound Wnt-120 and the compound Wnt-133; and the IC50 value of the compound Wnt-131 is also much smaller than that of all the compounds in the invention patent CN202410961646.X, so that the compound has very excellent Wnt signal pathway inhibiting activity; therefore, the compound is used as an active ingredient to prepare the medicine with Wnt signal pathway inhibiting activity, and has important application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry; in particular, it relates to a compound and application of the compound in preparation of a medicine with Wnt signal pathway inhibiting activity. BACKGROUND

[0002] Porcupine is an O-acyltransferase existing on the endoplasmic reticulum membrane and plays an important role in the secretion of WNT. Porcupine inhibitors can inhibit the secretion of WNT and thus inhibit the WNT signal pathway. The WNT / β-catenin signal pathway plays a very important role in regulating the development and tissue homeostasis of the human body. More and more studies have shown that in the process of liver fibrosis, the WNT pathway of liver stellate cells is continuously activated, and down-regulation of the WNT / β-catenin signal pathway can inhibit the activation of liver stellate cells and liver fibrosis. Therefore, development of a series of compounds with Wnt signal pathway inhibiting activity has important application value for screening of medicines for preventing and / or treating liver fibrosis.

[0003] The present inventors disclosed in the previous patent CN202410961646.X that a compound is applied to preparation of a medicine with preventing and / or treating liver fibrosis; the patent discloses that the compounds of the general structure have Wnt signal pathway inhibiting activity, but most of the compounds have high IC50 values, and some compounds do not show related activity. Development of a compound with a new general structure, especially development of a compound with a new general structure and better overall activity has important application value. SUMMARY

[0004] In order to solve at least one of the technical problems in the prior art, the present application provides a compound and application of the compound in preparation of a medicine with Wnt signal pathway inhibiting activity.

[0005] The technical scheme of the present application is as follows:

[0006] The present application first provides a compound with the structure shown in formula I:

[0007] Formula I.

[0008] Preferably, in formula I,

[0009] A is selected from C0-C3;

[0010] X is selected from C1-C3;

[0011] Y is selected from a C atom, an N atom or an S atom;

[0012] R1 is selected from a nitrogen-containing group or a halogen atom;

[0013] R2 is selected from a nitrogen-containing group or a halogen atom.

[0014] Preferably, in formula I, A is selected from a C0 or C1 structure; X is selected from a C1 or C2 structure; Y is selected from a C atom or a N atom.

[0015] Preferably, in formula I, R1 is selected from a nitro group; R2 is selected from a halogen atom.

[0016] Preferably, the halogen atom is a bromine atom.

[0017] Preferably, the compound is selected from any one of the following structures:

[0018] ;

[0019] ;

[0020] .

[0021] Preferably, the compound is a compound having an inhibitory activity on Wnt signaling pathway.

[0022] The present application also provides a use of the above compound in the preparation of a medicament having an inhibitory activity on Wnt signaling pathway.

[0023] Preferably, the dosage form of the medicament is a tablet, a capsule, a pill or an injection.

[0024] Beneficial effects: the present application provides a compound with a novel structure, research shows that the compound has an inhibitory activity on Wnt signaling pathway; especially the compound Wnt-131, the IC50 value is much smaller than the compound Wnt-120 and the compound Wnt-133; at the same time, it is also much smaller than all the compounds in the invention patent CN202410961646.X, and has very excellent inhibitory activity on Wnt signaling pathway; therefore, it has important application value to use it as an active ingredient for preparing a medicament having an inhibitory activity on Wnt signaling pathway. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 is a hydrogen spectrum of the compound WNT120.

[0026] Figure 2 is a hydrogen spectrum of the compound WNT131.

[0027] Figure 3 is a hydrogen spectrum of the compound WNT133. DETAILED DESCRIPTION

[0028] The application will be further described in conjunction with specific examples, but the examples do not limit the application in any form. Unless otherwise specified, the reagents, methods and devices used in the application are conventional reagents, methods and devices in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0029] Example 1 Preparation of compound (abbreviated as WNT120)

[0030]

[0031] Into a reaction bottle, 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 sequentially added, after addition, the reaction was carried out at 25±5℃ for 4h. TLC monitoring showed that the reaction was completed (PE / EtOAc = 2 / 1), 10 mL ethyl acetate and 5 mL water were added to the reaction solution, and the organic phase was collected after separation. The organic phase was washed with 10 mL 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 the product (WNT120) 180 mg (yield 40.0%). 1 H NMR (500 MHz, DMSO) δ 11.24 (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).

[0032] Example 2 Preparation of compound (abbreviated as WNT131)

[0033]

[0034] To the reaction flask was added 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-nitroindoline (164 mg, 1 mmol, 1 eq) successively, after addition, 25±5 °C for reaction 4 hours. TLC monitoring reaction complete (petroleum ether / ethyl acetate = 2 / 1), to the reaction liquid was added 10 mL of ethyl acetate and 5 mL of water, extraction and separation, 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 give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the product (WNT131) 127 mg, yield 34%. 1 H NMR (500 MHz, DMSO) δ 10.23 (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).

[0035] Example 3 Preparation of compound (WNT133)

[0036]

[0037] To the reaction flask was added 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-nitroindoline (164 mg, 1 mmol, 1 eq) successively, after addition, 25±5 °C for reaction 4 hours. TLC monitoring reaction complete (petroleum ether / ethyl acetate = 2 / 1), to the reaction liquid was added 10 mL of ethyl acetate and 5 mL of water, extraction and separation, 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 give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the product (WNT131) 127 mg, yield 34%. 1H 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).

[0038] Inhibition experiment of Wnt signaling pathway

[0039] To detect whether the synthesized compounds have the activity of inhibiting Wnt signaling pathway, we usually select luciferase reporter gene detection experiment. The experiment uses 293T-Wnt-Luciferase-Reporter and L Wnt-3A cells, and the LWnt-3A cells are Wnt protein producing cells, and the 293T-Wnt-Luciferase-Reporter cells are Wnt protein response cells.

[0040] Experimental procedure: 293T-Wnt-Luciferase-Reporter and L Wnt-3A cells are co-cultured at a density of 1:1, and after adding the test compound for 24 hours, the 50% inhibition concentration of the test compound on the activation of the Wnt reporter gene in the model is detected by using Bright-Glo Luciferase Assay System.

[0041] Table 1. Inhibition of Wnt signaling pathway by compounds of the present application

[0042]

[0043] The results are shown in Table 1. The IC50 value of the compound having the general structure of the present application is smaller than that of the compound of formula I in the application patent CN202410961646.X as a whole. This shows that the compound having the general structure of the present application has better inhibitory activity of Wnt signaling pathway. In particular, the IC50 value of compound Wnt-131 is much smaller than that of compound Wnt-120 and compound Wnt-133; at the same time, it is also much smaller than all the compounds in the application patent CN202410961646.X. This shows that the compound Wnt-131 of the present application has very excellent inhibitory activity of Wnt signaling pathway, and its inhibitory activity of Wnt signaling pathway is much higher than that of the known compound.

Claims

1. A compound, characterized in that, The compound is selected from the following structures: 。 2. Use of the compound of claim 1 in the preparation of a medicament for inhibiting Wnt signaling pathway activity.

3. Use according to claim 2, characterized in that, The dosage form of the medicament is tablet, capsule, pill or injection.

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