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2-indolinone errα inverse agonist and its pharmaceutical composition and application

A technology of indolinone and compound, applied in the field of medicinal chemistry, can solve the problems of restricting the development of ERRα inverse agonists, rare types, low druggability, etc.

Active Publication Date: 2022-05-20
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reported structures of ERRα inverse agonists are rare, and no candidate molecules have entered clinical research, which limits the further development of ERRα inverse agonists
[0007] Therefore, there is an urgent need for new types of compounds, especially compounds with novel skeletons, to solve the problem of low druggability of current ERRα inverse agonists and to fill the gap in the clinical application of ERRα inverse agonists

Method used

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  • 2-indolinone errα inverse agonist and its pharmaceutical composition and application
  • 2-indolinone errα inverse agonist and its pharmaceutical composition and application
  • 2-indolinone errα inverse agonist and its pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Example 1 4-(4-((5-fluoro-1-(2-ethylmorpholine)-2-indolinone-3-ylide)methyl)-2-methoxyphenoxy)-3 -Trifluoromethylbenzonitrile (LS 1-86)

[0149] 4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrole

[0150]

[0151] Step 1 4-(4-Formyl-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (3)

[0152] 4-fluoro-3-(trifluoromethyl)benzonitrile (1,5g, 26.5mmol), vanillin (2,4g, 26mmol), potassium carbonate (6.1g, 44mmol) dissolved in anhydrous N,N- Dimethylformamide (50 mL), stirred overnight at room temperature. After the reaction was complete, ice water (200 mL) was added with stirring, and a large amount of solids precipitated out. It was filtered under reduced pressure and dried under vacuum to obtain a white solid (7.6 g, yield 92%).

[0153] 1 H NMR (400MHz, DMSO-d 6 ):δ10.02(s,1H),8.36(d,J=2.0Hz,1H),8.04(dd,J=8.4,2.0Hz,1H),7.72(d,J=2.0Hz,1H),7.66 (dd,J=8.0,2.0Hz,1H),7.45(d,J=8.4Hz,1H),6.95(d,J=8....

Embodiment 2

[0169] Example 2 4-(2-methoxy-4-((2-indolone-3-ylide)methyl)phenoxy)-3-trifluoromethylbenzonitrile (LS 1-61)

[0170] 4-(2-methoxy-4-((2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile

[0171]

[0172] The synthesis method is as in Example 1, step 2.

[0173] 1 H NMR (400MHz, DMSO-d 6 ):δ10.67(s,1H),10.63(s,0.9H),8.75(d,J=2.0Hz,1H),8.33(d,J=1.6Hz,1.8H),8.03(td,J= 8.8,2.0Hz,2H),7.95(dd,J=8.4,1.6Hz,1H),7.87(s,1H),7.73(d,J=7.6Hz,1H),7.69-7.62(m,1.8H) ,7.59(d,J=1.6Hz,0.9H),7.43(dd,J=8.8,1.6Hz,0.9H),7.36(d,J=8.4Hz,0.9H),7.31(d,J=8.4Hz ,1H),7.27-7.20(m,1.8H),7.05-6.96(m,2H),6.96-6.81(m,3.9H),3.80(s,3H),3.77(s,2.7H).

[0174] Further separation gave isomer A 1 H NMR (400MHz, DMSO-d 6 ):δ10.68(s,1H),8.76(d,J=2.0Hz,1H),8.34(d,J=1.6Hz,1H),8.03(dd,J=8.4,2.0Hz,1H),7.96 (dd,J=8.8,2.0Hz,1H),7.88(s,1H),7.74(d,J=7.2Hz,1H),7.32(d,J=8.4Hz,1H),7.24(td,J= 7.6Hz, 1.2Hz, 1H), 7.02(td, J=7.6Hz, 0.8Hz, 1H), 6.94(d, J=8.8Hz, 1H), 6.86(d, J=7.6Hz, 1H), 3.81( s,3H).

...

Embodiment 3

[0176] Example 3 4-(4-((5-bromo-1-H-2-indolone-3-ylide)methyl)-2-methoxyphenoxy)-3-trifluoromethylbenzyl Nitrile (LS 1-59)

[0177] 4-(4-((5-bromo-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrole

[0178]

[0179] The synthesis method is as in Example 1, Step 2.

[0180] 1 H NMR (400MHz, DMSO-d 6 ):δ10.81(s,1H),10.80(s,0.4H),8.75(d,J=2.0Hz,1H),8.39-8.30(m,1.4H),8.11-7.93(m,3.8H) ,7.79-7.69(m,1H),7.63(s,0.6H),7.49-7.37(m,2.4H),7.33(d,J=8.4Hz,1H),6.96(dd,J=17.2,8.8Hz ,1.4H),6.90-6.77(m,1.4H),3.80(s,3H),3.79(s,1.2H).

[0181] MS(ESI):m / z 515[M+H] + .

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Abstract

The invention provides an indolinone compound having a structure represented by formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a prodrug molecule thereof and applications thereof. This type of compound can effectively inhibit the combination of estrogen-related receptor α (ERRα) and co-activator PGC‑1α, and is a new type of ERRα inverse agonist, which has certain anti-proliferation activity on tumor cells and has a small effect on db / db The glucose tolerance in rats was also significantly improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an indolinone compound and its application. Background technique [0002] Estrogen-Related Receptors (ERRs) belong to the nuclear receptor superfamily of transcription factors, including three subtypes of ERRα, ERRβ and ERRγ, because they have higher sequence and structural homology with estrogen receptors ERs sex, hence the name. Different from ERs, ERRs do not bind to hormonal ligands such as estrogen, and no other endogenous ligands have been found so far. They are a type of "orphan nuclear receptors". Among them, ERRα (NR3B1) was first discovered by Giguère V et al. in 1988. It is widely distributed in metabolically active tissues and organs such as skeletal muscle, heart, kidney, liver and adipose tissue, and is a transcriptional regulator that maintains the balance of cellular energy metabolism. [0003] Studies have shown that ERRα can be expressed to varying degrees i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34A61K31/404A61K31/5377A61K31/496A61P35/00A61P3/10A61P3/00A61P3/06A61P3/04A61P25/28A61P25/16A61P5/50A61P9/12A61P9/10A61P1/16
CPCC07D209/34A61P35/00A61P3/10A61P3/00A61P3/06A61P3/04A61P25/28A61P25/16A61P5/50A61P9/12A61P9/10A61P1/16
Inventor 丁克李姗彭丽洁司鸿飞张章任小梅雷冲
Owner JINAN UNIVERSITY