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Compounds for modulating FXR activity and uses thereof

A compound and active technology, applied in the field of compounds that regulate FXR activity and their preparation

Pending Publication Date: 2022-04-12
GANNEX PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although progress has been made in the development of novel FXR agonists, there is still much room for improvement

Method used

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  • Compounds for modulating FXR activity and uses thereof
  • Compounds for modulating FXR activity and uses thereof
  • Compounds for modulating FXR activity and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Preparation of 6-((3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)quinolin-7-yl)oxy)fume acid (compound 1)

[0068]

[0069] (a) Compound 1A-2 (1.0g, 4.46mmol, 1.0eq), compound 1A-1 (1.55g, 4.46mmol, 1.0eq) and cesium carbonate (2.90g, 8.92mmol, 2.0eq) were dissolved in DMF ( 10ml), stirred at 65°C for 2 hours. After cooling to room temperature, 10 ml of water and 10 ml of EA (ethyl acetate) were added, and the organic phase was concentrated to dryness to obtain compound 1A-3 (1.61 g, yield: 73.5%, which was used in the next step without further purification) , namely: 4-(((6-bromoquinolin-2-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole, LCMS (ESI ): Calculated as C 22 h 15 BrCl 2 N 2 o 2 ;[M+H] + : 489.0, measured value: 489.0.

[0070]

[0071] (b) Compound 1A-3 (200mg, 0.408mmol, 1.0eq) was dissolved in anhydrous THF (2ml), and then 2 Add KOAc (80mg, 0.816mmol, 2.0eq), Pd(dppf) 2 Cl 2 (30 mg, 0.408 mmol, 0.1 equiv) and ...

Embodiment 2

[0080] Preparation of 6-(((7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)quinolin-3-yl)oxy) Niacin (Compound 2)

[0081]

[0082] (a) Compound 2B-1 (1.0g, 4.46mmol, 1.0eq), compound 1A-6 (0.96g, 4.46mmol, 1.0eq) and cesium carbonate (2.90g, 8.92mmol, 2.0eq) were dissolved in DMF ( 10ml), stirred at 65°C for 2 hours. After being cooled to room temperature, add 10ml water and 10ml EA (ethyl acetate), the organic phase is concentrated to dryness, obtains compound 2B-2 (1.1g, productive rate: 68.7%), namely: 6-((7-bromoquinone Methyl nicotinate, LCMS (ESI): calculated as C16H11BrN2O3; [M+H] + : 359.0, measured value: 359.0.

[0083]

[0084] (b) Compound 2B-2 (200mg, 0.56mmol, 1.0eq) was dissolved in anhydrous THF (2ml), and then heated under N 2 Add KOAc (110 mg, 1.12 mmol, 2.0 equiv), Pd(dppf) 2 Cl 2 (41mg, 0.056mmol, 0.1eq) and bis(pinacolate)diboron (142mg, 0.56mmol, 1.0eq), the reaction mixture was heated to reflux for 2h. After cooling to room te...

Embodiment A

[0094] Example A: FXR Agonist Binding Capability

[0095] In this example, the analysis of the binding activity of compounds 1 and 2 prepared in Examples 1 and 2 to FXR was carried out using a time-resolved fluorescence resonance energy transfer coactivator peptide recruitment experiment. The assay uses LanthaScreen-labeled anti-GST antibody, fluorescein-labeled SRC2-2 coactivator peptide, and GST-tagged FXR-LBD. LanthaScreen-labeled anti-GST antibody indirectly labels FXR-LBD by binding to the GST tag. FXR-LBD can form heterodimer FXR-LBD / RXRα with RXRα, and the compound can bind to FXR-LBD / RXRα and cause a conformational change of FXR-LBD, thereby increasing the effect of heterodimer on SRC2-2 coactivation Peptide recruitment capacity. At the same time, this results in a tighter binding of FXR-LBD (labeled with GST) and SRC2-2 coactivator peptide, and then adding anti-GST antibody (labeled with LanthaScreen), LanthaScreen reacts with fluorescein to produce fluorescence. ...

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Abstract

The present invention provides compounds useful for modulating FXR activity having the structure of formula (I) wherein M, Q, T, W, Y and Z are independently selected from carbon and nitrogen, and at least one of M, Q, T, W, Y and Z is nitrogen, pharmaceutically acceptable salts, esters or stereoisomers thereof.

Description

technical field [0001] The present invention relates to the field of medicines related to diseases mediated by FXR. Specifically, the present invention relates to compounds for modulating FXR activity, their preparation methods and pharmaceutical uses. Background technique [0002] Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and is mainly expressed in the liver, kidney and intestine. It acts as a heterodimer with the retinoic acid X receptor (RXR) and binds to response elements in target gene promoters to regulate gene transcription. The FXR-RXR heterodimer binds with the highest affinity to the inverted repeat-1 (IR-1) response element, where the hexamers that bind the consensus receptor are separated by one nucleotide. FXR is part of an interrelated process in which FXR is activated by bile acids, the end products of cholesterol metabolism, which serve to inhibit the catabolism of cholesterol. [0003] FXR is a key regulator of cho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/4709A61P1/16A61P3/06A61P29/00A61P31/14A61P13/02A61P13/08A61P13/04A61P3/04A61P3/10A61P9/10
Inventor 杨百灵古德蒙森·克里斯蒂安董留玉陈进华
Owner GANNEX PHARM CO LTD