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Five-membered nitrogen azole heterocyclic derivative as well as preparation method and application thereof

A technology of drugs and compounds, applied in the field of medicine, can solve problems such as high blood-brain barrier penetration and toxicity, and achieve good bioavailability, good cell activity, and high oral absorption

Pending Publication Date: 2021-08-13
王能能
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first-generation XPO1 inhibitor selinexor showed high blood-brain barrier penetration and toxicity problems in preclinical and clinical studies

Method used

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  • Five-membered nitrogen azole heterocyclic derivative as well as preparation method and application thereof
  • Five-membered nitrogen azole heterocyclic derivative as well as preparation method and application thereof
  • Five-membered nitrogen azole heterocyclic derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Step 1.1: Preparation of compound 1

[0020]

[0021] 3-Bromo-1,2,4-triazole (4.44g, 30.0mmol) was dissolved in 30ml of DMF, triethylenediamine (6.73g, 60.0mmol) was added, and stirred at room temperature for 30 minutes. Then (2Z)-isopropyl-3-iodoprop-2-enoate (7.92 g, 33.0 mmol) was added and stirred at room temperature for 1 h. The mixture was poured into 100ml ice water and the aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic phases were washed twice with 50 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography gave the target product (6.25 g, 24.0 mmol, 80% yield) as an off-white solid.

[0022] t R =1.222min, MS(ESI)m / z=259.8,261.7[M+H] + .

[0023] Step 1.2: Preparation of compound 2

[0024]

[0025] Dissolve (Z)-3-(3-bromo-1H-1,2,4-triazol-1-yl)isopropylacrylate (3.6g, 13.8mmol) in dichloromethane (50ml) at 0°C Bromine (4.41 g, ...

Embodiment 2

[0056] Embodiment 2: the preparation of compound P-B1

[0057] Preparation of intermediate Int-2

[0058] Step 1.1: Preparation of compound 1

[0059]

[0060] 3-Bromo-1,2,4-triazole (4.44g, 30.0mmol) was dissolved in 30ml of DMF, triethylenediamine (6.73g, 60.0mmol) was added, and stirred at room temperature for 30 minutes. Then (2Z)-isopropyl-3-iodoprop-2-enoate (7.92 g, 33.0 mmol) was added and stirred at room temperature for 1 h. The mixture was poured into 100ml ice water and the aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic phases were washed twice with 50 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography gave the target product (6.25 g, 24.0 mmol, 80% yield) as an off-white solid.

[0061] t R =1.222min, MS(ESI)m / z=259.8,261.7[M+H] + .

[0062] Step 1.2: Preparation of compound 2

[0063]

[0064] Dissolve (Z)-3-(3-bromo-1H-1,2,...

Embodiment 3

[0093] Embodiment 3: cell anti-proliferation activity (IC 50 )test

[0094] To prepare cells, add 100uL cells to a 96-well plate and incubate overnight at 37°C. The next day, the cells were diluted with DMSO to prepare the desired final concentration. Dilute the sample 3 times to the required concentration, add 50uL sample to the cell culture medium, 37°C, 5% CO 2 Incubate for 72h. After equilibrating to room temperature, pipette 40uL Add Reagent to the well plate, mix well, and incubate at room temperature for 60 minutes before detection.

[0095] [Table 3] Determination results of compounds

[0096]

[0097]

[0098] In Table 3: A≤30nM, 30nM1μM, NT: not tested

[0099] It can be seen from the data in the above table that the compounds of the present invention have stronger antiproliferative activity on tumor cells (human multiple myeloma cells (MM.1S)), such as compounds P-A1 and P-B1 on human multiple myeloma cells MM. Compared with the positive drug KPT-8602,...

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PUM

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Abstract

The invention discloses a five-membered nitrogen azole heterocyclic derivative, and discloses a preparation method and an application thereof. The invention belongs to the technical field of medicines, and provides a five-membered nitrogen azole heterocyclic derivative which reduces the cytotoxicity of a compound and improves the cell viability, oral absorption rate and bioavailability of a medicine. The compound provided by the invention has the advantages of low cytotoxicity, good cell viability, high oral absorbability and good bioavailability. In addition, a second object of the invention is to provide the compounds and pharmaceutically acceptable salts and compositions thereof that are also useful for the treatment of a variety of diseases, disorders or conditions associated with abnormal cell responses triggered by improper nuclear transport. The compounds provided by the invention are also useful for the study of nuclear transport modulation in biological and pathological phenomena, such as the study of kinase-mediated intracellular signal transduction pathways and the comparative evaluation of new nuclear transport modulators.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a five-membered azole heterocyclic derivative and a preparation method and application thereof. Background technique [0002] Eukaryotic nuclei have a double-membrane structure, and small molecules of protein, nucleic acid, and salt in the cytoplasm diffuse through nuclear pores, and nucleoplasmic transport receptors mediate the transport of macromolecular substances across the nuclear membrane. Specific proteins and RNA are transported into and out of the nucleus by specific transport molecules, where proteins that transport molecules out of the nucleus are classified as nuclear export proteins. Nuclear exportin 1 (exportin 1, XPO1), also known as chromosomal region stabilizing protein 1 (CRM1), is a component of the Golgi apparatus, one of the most important nuclear export receptors of the karyopherin-β family, and is the main export protein nuclear receptors. Nuc...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D401/06C07B59/00A61K31/506A61K31/4709A61K9/00A61P35/00
CPCC07D403/06C07D401/06C07B59/002A61K9/0053A61P35/00C07B2200/05
Inventor 王能能李妍
Owner 王能能
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