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Indole compound for preparing coronavirus therapeutic drug

A coronavirus and compound technology, applied in the field of chemical medicine, can solve the problems of low infectivity, damage to cell export, etc., and achieve the effects of treating viral infection, expanding the time interval of administration, and strong inhibitory effect.

Pending Publication Date: 2022-07-29
南京雷正医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, disruption of microtubule trafficking impairs cell egress. These poorly assembled virions have less cell surface S protein and are therefore less infectious.

Method used

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  • Indole compound for preparing coronavirus therapeutic drug
  • Indole compound for preparing coronavirus therapeutic drug
  • Indole compound for preparing coronavirus therapeutic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: (2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4-dimethoxy-5-(methoxy-d3)phenyl)methanone (Compound 1)

[0032]

[0033] Preparation of 1-(phenylsulfonyl)-1H-indole-5-carbaldehyde (1-2):

[0034]Indole-3-carbaldehyde (1-1) (5 g, 34.5 mmol) was dissolved in ethanol (100 mL) at room temperature, potassium hydroxide (2.1 g, 37.9 mmol) was added and stirred until clear. Concentrate under reduced pressure to remove ethanol, dissolve the residue in acetone (100 mL), and add benzenesulfonyl chloride (6.7 g, 37.9 mmol). Stir at room temperature for 0.5 hour. After filtration, the filtrate was concentrated to obtain crude product, which was recrystallized from methanol to obtain 1-(phenylsulfonyl)-IH-indole-5-carbaldehyde (1-2) (4 g, white solid, yield: 41%). MS-ESI(m / z): 286[M+l] + .

[0035] Preparation of 3-(1 H-imidazol-2-yl)-1-(phenylsulfonyl)-1 H-indole (1-3):

[0036] At 0 °C, 1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (1-2) (4 g, 14.0 mmol) was dissolved in ...

Embodiment 6

[0048] Example 6: (3,4-Dimethoxy-5-(methoxy-d3)phenyl)(2-(1-methyl-1H-indol-3-yl)-1H-imidazole-5 Preparation of -yl)methanone (Compound 6)

[0049]

[0050] The synthetic method refers to Example 1 to obtain (3,4-dimethoxy-5-(methoxy-d3)phenyl)(2-(1-methyl-1H-indol-3-yl)-1H -imidazol-5-yl)methanone (6) (15 mg, yellow solid). MS-ESI(m / z): 395[M+l] + .

[0051] 1 H NMR (400MHz, CD 3 OD)δ: 8.20(s, 1H), 7.86(s, 1H), 7.81(s, 1H), 7.50-7.42(m, 3H), 7.26-7.21(m, 2H), 4.01(s, 3H), 3.96(s, 3H), 3.92(s, 3H).

[0052] Examples 7-11 (see Table 2) were synthesized following a basic procedure similar to that of Example 6 to give the desired products.

[0053] Table 2 Structure and data of Examples 7-11

[0054]

[0055]

Embodiment 12

[0056] Example 12: In vitro tubulin polymerization assay

[0057] Bovine brain tubulin (0.4 mg, >97% purity) was mixed with 10 μM of test compound and incubated in 100 μL of the solution in normal tubulin buffer pH 6.9 (80 mM PIPES, 2.0 mM MgCl 2 , 0.5 mM EGTA and 1 mM GTP). Then cool to 0°C, then add GTP, transfer the above mixture to a cuvette, measure the OD value with a spectrophotometer, raise the temperature to 30°C, measure the change in the OD value, thereby reacting the test sample to the microscopic Effects of tubulin assembly. IC 50 For 20 minutes incubation, the concentration of the test sample at which the polymer solubility is inhibited by 50%.

[0058] Table 3 In vitro tubulin inhibitory activity data

[0059] compound Inhibition of tubulin polymerization IC 50 +SD (μM)

[0060] Tubulin assembly experiments were performed on this series of compounds. A total of 3 parallel experiments were carried out, and the experimental results were averaged....

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Abstract

The invention discloses an indole compound for preparing a coronavirus therapeutic drug, and belongs to the field of chemical medicines. The indole compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof has excellent tubulin polymerization inhibition activity, and can inhibit tubulin and destroy cytoskeleton, so that coronavirus cannot be transported, and the purpose of effectively treating virus infection is achieved. Meanwhile, the compound disclosed by the invention is relatively good in metabolic stability and relatively long in metabolic half-life period, so that the medical dosage can be reduced, and the administration time interval can be expanded.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to an indole compound for preparing a coronavirus therapeutic drug. Background technique [0002] Novel coronavirus pneumonia (COVID-19), referred to as "new coronary pneumonia", refers to the pneumonia caused by the 2019 new coronavirus (SARS-CoV-2) infection, which has been confirmed to be an acute respiratory infectious disease caused by a new coronavirus infection . [0003] The coronavirus superfamily (Coronaviridae) includes several large pathogenic RNA genomes of human pathogens, such as influenza and viral encephalitis, which are divided into alpha, beta, delta, and gamma coronavirus families, which are then further divided into Lineages A, B, C and D. SARS-CoV-2 is an enveloped, non-segmented, positive single-stranded RNA virus with an unusually large RNA genome consisting of a nucleocapsid and rod-like protrusions extending from its surface called Spike prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07B59/00A61K31/4178A61P31/14
CPCC07D403/04C07B59/002A61P31/14C07B2200/05
Inventor 唐春雷范为正
Owner 南京雷正医药科技有限公司
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