Liver x receptors (LXR) modulators

A solvate, enantiomer technology, applied in the field of regulation related diseases, can solve problems such as inactivity

Inactive Publication Date: 2019-12-06
PHENEX FXR GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, when the ester in SR9238 is cleaved

Method used

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  • Liver x receptors (LXR) modulators
  • Liver x receptors (LXR) modulators
  • Liver x receptors (LXR) modulators

Examples

Experimental program
Comparison scheme
Effect test

preparation example P1

[0384]

[0385] Methyl 2-((3-bromophenyl)sulfonyl)propionate (P1)

[0386] Methyl 2-((3-bromophenyl)sulfonyl)acetate (500mg, 1.71mmol) and K 2 CO 3 (354 mg, 2.57 mmol) in acetone (20 mL) was added MeI (0.11 mL, 1.71 mmol). The reaction mixture was stirred overnight at 30 °C and filtered. The filtrate was concentrated to afford crude compound P1 as a yellow oil. MS: 307(M+1) + .

preparation example P2

[0388]

[0389] Methyl 2-((3-bromophenyl)sulfonyl)-2-methylpropanoate (P2)

[0390] A suspension of 2-((3-bromophenyl)sulfonyl)acetate (500 mg, 1.71 mmol) and NaH (152 mg, 60% on oil, 3.8 mmol) in anhydrous DMF (10 mL) was dissolved at 0 After stirring at °C for 0.5 h, MeI (0.7 mL, 3.77 mmol) was added to the solution at 0 °C. The mixture was stirred at room temperature for 2 h, washed with H 2 O diluted and extracted with EA (3x). The combined organic layers were washed with brine, washed with Na 2 SO 4 Drying and concentration afforded crude compound P2 as a yellow oil. MS: 321(M+1) + .

preparation example P3

[0392]

[0393] Step 1: tert-butyl 4-bromo-2,6-difluorobenzoate (P3a)

[0394]

[0395] 4-bromo-2,6-difluorobenzoic acid (25.0g, 110mmol), Boc 2 A mixture of O (50.0 g, 242 mmol) and 4-dimethylaminopyridine (1.3 g, 11 mmol) in tert-BuOH (200 mL) was stirred overnight at 40 °C, concentrated and passed through FCC (PE:EA=50:1 ) to obtain compound P3a as a yellow oil. MS: 292(M+1) + .

[0396] Step 2: tert-butyl 4-bromo-2-fluoro-6-((2-methoxy-2-oxyethyl)thio)benzoate (P3b)

[0397]

[0398] To a solution of methyl 2-thioglycolate (11.2 g, 106 mmol) in anhydrous DMF (50 mL) was added NaH (5.1 g, 60%, 127 mmol) at 0 °C. The mixture was stirred for 30 min. Then a solution of compound P3a (31 g, 106 mmol) in anhydrous DMF (100 mL) was added to the mixture. The mixture was stirred at room temperature for 2 h, washed with H 2 Diluted with O (1000 mL) and extracted with EA (3x). The combined organic layers were washed with H 2 O and brine washed, concentrated and p...

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Abstract

The present invention relates to sulfonamide-, sulfinamide- or sulfonimidamide containing compounds which bind to the liver X receptor (LXRalpha and/or LXRbeta) and act preferably as inverse agonistsof LXR.

Description

technical field [0001] The present invention relates to novel compounds which are modulators of liver X receptors and pharmaceutical compositions comprising them. The invention further relates to the use of said compounds in the prevention and / or treatment of diseases associated with the modulation of liver X receptors. Background technique [0002] Liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor protein superfamily. Both receptors form heterodimeric complexes with retinoid X receptors (RXRα, β or γ) and bind to LXR response elements (eg DR4-type elements) located in the promoter regions of LXR response genes. Both receptors are transcription factors that are physiologically regulated by binding ligands such as oxysterol or intermediates such as desmosterol in the cholesterol biosynthetic pathway. In the absence of ligand, LXR-RXR heterodimers are thought to still bind to DR4-type elements in complex with co-repressors such as NCOR1, lea...

Claims

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Application Information

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IPC IPC(8): C07D333/20C07D405/12C07D407/12C07D409/12C07D307/52C07C311/21
CPCA61P1/16A61P3/00A61P3/04A61P3/06A61P3/08A61P3/10A61P31/14A61P35/00C07C311/16C07C311/19C07C311/21C07D307/52C07D333/20C07D405/12C07D407/12C07D409/12A61K31/34A61K31/381A61K31/426A61K31/4436A61K31/195
Inventor C·盖格M·伯克尔E·汉布鲁克U·多伊施勒C·克里莫瑟
Owner PHENEX FXR GMBH
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