Triazole compound and its preparation method and application

A compound, the technology of triazole, applied in the field of medicine, can solve the problems of high neurotoxicity, poor water solubility, and restrictions on off-the-shelf drugs

Inactive Publication Date: 2020-10-16
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inventors found that because the chemical structure of JQ1 is similar to that of benzodiazepine sedative-hypnotics, it has side effects such as greater neurotoxicity, poor water solubility, and high cytotoxicity, which limits its possibility of becoming a drug

Method used

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  • Triazole compound and its preparation method and application
  • Triazole compound and its preparation method and application
  • Triazole compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1 Compound preparation

[0101] The synthetic route of compound of the present invention is as follows:

[0102]

[0103] The reagents used in the above preparation process are: (a) triethyl orthoacetate, 130 ° C; (b) sodium carbonate; tetrakis (triphenylphosphine) palladium; 2-fluoro-5-nitrophenylboronic acid, 1, 4-dioxane and water; 95°C; (c) cesium carbonate with R 2 , R 3 Substituent phenol, DMSO, 100°C; (d) 10% palladium carbon / H 2 ; methanol, room temperature; (e) pyridine, containing R 1 Sulfonyl chloride or acid chloride of the substituent, dichloromethane, 0°C to room temperature.

[0104] (1) Intermediate 2: Preparation of 6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine

[0105] Dissolve 1.87g (10mmol) of 2-hydrazino-5-bromopyridine in 50mL of triethyl orthoacetate, raise the temperature to 130°C for 1 hour, pour the mixture into 100mL of ice water, and extract with ethyl acetate (60mL×3) Extract, combine the organic phases, dry the organic...

Embodiment 2

[0172] Example 2 : Detection of inhibitory activity of compounds on BRD4 protein

[0173] The inhibitory activity of compounds on BRD4 was detected by Homogeneous Time-Resolved Fluorescence (HTRF). The specific principles and experimental methods are as follows:

[0174] Experimental principle: HTRF combines the advantages of fluorescence resonance energy transfer FRET and time-resolved fluorescence TRF, and combines the homogeneous experimental method of FRET with the low background characteristics of TRF. It has the advantages of simple operation, high sensitivity, large throughput, The experimental data is stable and reliable.

[0175]Experimental procedure: Compounds were diluted with DMSO. Use the Diluent Buffer in the kit to dilute BRD4 (BD2, BD2) and Biotin-labeled histone H4 peptide, and prepare the reaction solution. Use DtectionBuffer in the kit to dilute Anti-GST-TB 2+ Cryptate and SA-XL-665, and configure the detection solution. Take a 384-well plate and arr...

Embodiment 3

[0183] Example 3 : EC of compound in J-Lat HIV-1 latent virus infected cell line 50

[0184] Experiment principle: EC 50 is the half-maximal effect concentration, which refers to the compound concentration corresponding to when the compound reaches 50% effect of activating HIV latent virus activity, and the unit is μM.

[0185] Experimental procedure: Take well-grown pseudovirus-infected J-Lat cells and spread them in 96-well transparent plates, and the amount of cells used is 2×10 per well. 5 Each, add different concentrations of the test compound (prepared according to the method of Example 1) respectively, the final concentrations are respectively 320, 160, 80, 40, 20, 10, 5, 0 μ M, JQ1 is the positive control group, and the untreated group is negative For the control, at least 3 replicate wells for each concentration, and each experiment was repeated 3 times. at 5% CO 2 After culturing in the incubator for 24 hours, collect the cells by centrifugation, discard the su...

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Abstract

The invention provides triazole compounds and a preparation method and application thereof. The provided triazole compounds or pharmaceutically acceptable salts thereof have the structure shown as a formula (I), wherein R1, R2 and R3 are respectively and independently selected from -SO2R4, -SO2R5, COR6, H, and halogen; R4, R5 and R6 are respectively and independently selected from an aryl group, a heteroaryl group, a linear or branched alkyl group, an alkenyl group and a cycloalkyl group, wherein the aryl group, the heteroaryl group, the linear or branched alkyl group, the alkenyl group and the cycloalkyl group are unsubstituted or substituted by R7; R7 is selected from halogen, a C1-5 straight or branched alkyl group, a haloalkyl group, a C1-5 straight or branched alkoxy group and a nitro group. The compounds have good inhibitory activity against BRD4, HIV latent virus infection activation activity, low toxicity, high druggability and a more potential clinical application value.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to triazole compounds and their preparation methods and applications. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily regarded as an acknowledgment or in any form to imply that the information constitutes the prior art already known to those skilled in the art. [0003] Human Immunodeficiency Virus (Human Immunodeficiency Virus, HIV), also known as AIDS virus, is a retrovirus that can cause dysfunction of the human immune system. After entering the human body, it mainly attacks T lymphocytes, blocks cellular immunity and humoral immunity, causes the immune system to collapse, causes the spread of various diseases, and eventually leads to AIDS (AIDS), which poses a great threat to human health and social stability. Due to the l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P31/18
CPCA61P31/18C07D471/04
Inventor 李荀于海鹏郑永唐黄旭升
Owner SHANDONG UNIV
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