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Indole compound as well as preparation method and application thereof

A technology of compound and indole, which is applied in the field of indole compound and its preparation, and can solve problems such as no drugs on the market

Active Publication Date: 2021-09-17
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] BRD4 inhibitors have good application prospects as drugs in the pharmaceutical industry, but there are no drugs on the market at present. In order to achieve better therapeutic effects and meet market demand, continue to develop a highly efficient BRD4 inhibitor

Method used

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  • Indole compound as well as preparation method and application thereof
  • Indole compound as well as preparation method and application thereof
  • Indole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1, intermediate 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-toluenesulfonyl- Preparation of 1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one

[0054]

[0055] 4-Bromo-6-methyl-1-p-toluenesulfonyl-1H-pyrrolo[2,3-C]pyridin-7(6H)-one (381mg, 1mmol), biboronic acid pinacol ester (300mg , 1.2mmol), potassium acetate (200mg, 2mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (40mg, 0.05mmol), added to the circle In a bottom flask, dioxane (5 mL) was then added, replaced with nitrogen three times, and heated at 100° C. for 4 hours. The completion of the reaction was monitored by TLC. The organic solvent was spun off under reduced pressure, diluted with water and extracted with ethyl acetate. The ethyl acetate phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, the solid mixture was dried with silica gel, and purified on ...

Embodiment 2

[0056] Example 2, 6-methyl-4-(1-(pentane-2-yl)-1H-indol-6-yl)-1,6-dihydro-7H-pyrrole[2,3-c] Preparation of pyridin-7-one

[0057]

[0058] Preparation of step 1 intermediate 6-bromo-1-(pentane-2-yl)-1H-indole

[0059]

[0060] Sodium hydride (5.66g, 141.7mmol) was placed in DMF (100ml) of 6-bromoindole (2.31g, 118.1mmol), stirred in an ice bath for 20 minutes, and under ice bath, 2-bromopentane (2.14 g, 141.7 mmol), the ice bath was removed, and the temperature was naturally raised to room temperature overnight, and TLC detected that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the product with a yield of 98%.

[0061] Step 2 6-Methyl-4-(1-(pentane-2-yl)-1H-indol-6-yl)-1,6-dihydro-7H-pyrrole[2,3-c]pyridine- Preparation of 7-keto

[0062]

[0063] 6-me...

Embodiment 3

[0065] Example 3, 6-methyl-4-(1-(butane-2-yl)-1H-indol-6-yl)-1,6-dihydro-7H-pyrrole[2,3-c] Pyridin-7-one

[0066]

[0067] Using 2-bromobutane as a raw material, the target compound was obtained through a reaction similar to Example 2 with a yield of 78%.

[0068] 1 H NMR(400MHz,DMSO)δ12.10(s,1H),7.65(s,1H),7.60(d,J=8.2Hz,1H),7.49(d,J=3.1Hz,1H),7.35(s ,2H),7.25(d,J=8.2Hz,1H),6.71–6.18(m,2H),4.57(d,J=6.9Hz,1H),3.59(d,J=8.5Hz,3H),1.87 (dd,J=13.6,6.6Hz,2H),1.47(d,J=6.7Hz,3H),1.33–1.11(m,2H),0.75(t,J=7.2Hz,3H).

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Abstract

The invention provides an indole compound which has a structure as shown in a formula I. The invention also provides a preparation method and application of the compound shown in the formula I. The compound as shown in the formula I has excellent inhibitory activity on BRD4 protein and has potential application value in preparation of drugs for treating tumors.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to an indole compound and its preparation method and application. Background technique [0002] BRD4 protein is the most important functional protein in the bromodomain and extra-terminal family protein (BET) family, which contains two bromodomains and an ultra-terminal domain. BRD4 not only plays a role in transcriptional regulation, but also controls the activation of DNA damage checkpoints, repairs and maintains telomeres, and plays roles other than transcription. As a histone reader, BRD4 accumulates in highly acetylated and transcriptionally prone chromatin regions, including promoters and ENH, and acts as a nucleation center for the assembly of large protein complexes, promoting RNA PolII activity and stimulating transcription initiation and elongation , this function is largely dependent on the BDs of BRD4 and their ability to recognize acetylated proteins. [...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D413/04C07D413/14A61P35/00A61P35/04A61P29/00A61P9/00A61P37/00A61P3/00
CPCC07D471/04C07D413/04C07D413/14A61P35/00A61P35/04A61P29/00A61P9/00A61P37/00A61P3/00
Inventor 张力丹余洛汀赵立峰
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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