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Five-membered heterocycle substituted benzamide compound as well as preparation method and application thereof

A compound and single substitution technology, applied in the field of benzamide compounds and their preparation, can solve the problems of low specificity and low potency of SphK2 inhibitors, and achieve the effect of strong inhibitory effect and multiple selection possibilities

Active Publication Date: 2022-05-13
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] One of the purposes of the present invention is to provide a five-membered heterocyclic substituted benzamide compound, which can be used as an efficient and highly selective SphK2 inhibitor to solve the problems of low efficacy and low specificity of existing SphK2 inhibitors

Method used

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  • Five-membered heterocycle substituted benzamide compound as well as preparation method and application thereof
  • Five-membered heterocycle substituted benzamide compound as well as preparation method and application thereof
  • Five-membered heterocycle substituted benzamide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the preparation of series compound shown in formula (I)

[0040] S1), 3g (20mmol) methyl p-hydroxybenzoate, 5.4g (40mmol) potassium carbonate, 0.4g (2mmol) potassium iodide were added to dissolve in a 15mL eggplant-shaped bottle filled with DMF, and then 1.6g (24mmol) was added Chloroacetonitrile was heated to reflux at 85°C for 4 hours, and the end point of the reaction was detected by TLC. The solvent was removed under reduced pressure to obtain a crude product, which was recrystallized from ethyl acetate to obtain 3.2 g of product C with a yield of 85%. 1 H NMR (600MHz, CDCl 3 )δ8.07–8.04(m,2H), 7.02–7.00(m,2H), 4.83(s,2H), 3.91(s,3H).

[0041] S2), dissolve 2.86g (15mmol) of compound C with 20mL of absolute ethanol solution, add 5.2g (75mmol) of hydroxylamine hydrochloride and 8.8g (105mmol) of sodium bicarbonate, heat and reflux at 85°C for 1 hour, and then detect the reaction by TLC At the end point, filter while hot, wash the filter cake 3-4 times...

Embodiment 2

[0065] Embodiment 2: The activity research of series compound of the present invention to SphK2

[0066] (1) Experimental materials: target compound and positive control PF543 (Target mol, T8840), sphingosine kinase 2 kit (Cayman, 701870), microplate reader (Bio-Stack) and black 96-well plate.

[0067] (2) Experimental method:

[0068] Compound 3, which has strong inhibitory effects on the three cancer cells, was selected, and the inhibition rates at different concentrations of 5 μM, 10 μM, 25 μM, 50 μM, 80 μM, and 100 μM were respectively determined. The experimental results are shown in Table 2.

[0069] Table 2

[0070] concentration 5μM 10μM 25μM 50μM 80μM 100μM Inhibition rate(%) 66.7 66.7 88.9 >100 >100 ＞100

[0071] All samples were tested for single well inhibition rate at a concentration of 10 μM, and the experimental results are shown in Table 3.

[0072] table 3

[0073] Numbering Inhibition rate(%) 6 60 8...

Embodiment 3

[0079] Example 3: Research on the effect of the series of compounds of the present invention on the proliferation of cancer cells

[0080] (1) Experimental materials: target compound and positive control PF543, trypsin, cleaning solution PBS, fetal bovine serum (Gemini), human histiocytic lymphoma cell U937, human breast cancer cell MCF-7 and human gastric cancer cell MGC-308 ( Shanghai Chinese Academy of Sciences Cell Bank), microplate reader (thermo scientific) and 96-well plate, DMEM medium and 1640 medium (Solarbio, where the final concentrations of penicillin and streptomycin are 100U / mL and 100μ / mL, respectively).

[0081] (2) Experimental method:

[0082] The cells grown to the logarithmic phase were made into uniformly dispersed single-cell suspension, and 90 μL of single-cell suspension per well was about (2-5)×10 4 cells / ml were seeded into 96-well plates in 5% CO 2 , Incubate in a 37°C incubator for 48h. After the cells adhered to the wall, add 10 μL of samples o...

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Abstract

The invention provides a five-membered heterocycle substituted benzamide compound as well as a preparation method and application thereof. The structural formula of the compound is shown as a formula (I). The five-membered heterocycle substituted benzamide compound provided by the invention can remarkably inhibit sphingosine kinase 2 (SphK2), can be used for preparing a medicine for preventing and / or treating related diseases mediated by the SphK2, has a very strong inhibition effect on the SphK2 and cancer cells, can form a new generation of anticancer lead compound, and has a very good application prospect. Not only is a new source provided for preparation of medicines for preventing and / or treating cancers, but also more selection possibilities are provided for development and application of SphK2 small-molecule inhibitors.

Description

technical field [0001] The invention relates to benzamide compounds and their preparation methods and applications, in particular to five-membered heterocyclic substituted benzamide compounds and their preparation methods and applications. Background technique [0002] With the development of lipidomics, the important functions of the sphingolipid signaling pathway in mammals have been gradually discovered, and targeting the sphingolipid signaling pathway has become a new strategy for the treatment of tumors. Ceramide (Cer), sphingosine (Sphingosine, Sph), sphingosine-1-phosphate (Sphingosine-1-phosphosine, S1P) belong to sphingolipid substances in the body, they not only participate in the composition of cell membrane, but also can As a lipid signaling molecule, it participates in the processes of cell proliferation, differentiation and apoptosis. Studies have shown that Cer / Sph promotes cell apoptosis, while S1P promotes cell survival, and its imbalance will promote the o...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D271/06A61K31/4245A61P35/00
CPCC07D413/12C07D271/06A61P35/00Y02P20/55
Inventor 杨侃张金淼曹飞李龙飞宋亚丽
Owner HEBEI UNIVERSITY
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