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Amine or (THIO)amide containing lxr modulators

A technology of substituents and oxo groups, applied in the field of new compounds, can solve problems such as inactivity

Pending Publication Date: 2020-03-24
PHENEX FXR GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, when the ester in SR9238 is cleaved, the formed acid SR10389 is inactive towards LXR

Method used

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  • Amine or (THIO)amide containing lxr modulators
  • Amine or (THIO)amide containing lxr modulators
  • Amine or (THIO)amide containing lxr modulators

Examples

Experimental program
Comparison scheme
Effect test

preparation example P1

[0424]

[0425] Step 1: (4-Bromo-2-mercaptophenyl)methanol (P1a)

[0426]

[0427] To a solution of 4-bromo-2-mercaptobenzoic acid (1.50 g, 6.50 mmol) in THF (30 mL) was added BH 3 (13 mL, 1 M in THF). The mixture was stirred overnight and quenched with water (30 mL). EA (20 mL) was added and the organic layer was separated and the aqueous layer was washed with EA (3 x 20 mL). The combined organic layers were washed with brine (30 mL), washed with Na 2 SO 4 Drying and concentration afforded Compound P1a as a yellow solid.

[0428] Step 2: Ethyl 2-((5-bromo-2-(hydroxymethyl)phenyl)thio)acetate (P1b)

[0429]

[0430] To a mixture of compound P1a (436 mg, 2.00 mmol) and ethyl 2-bromoacetate (306 mg, 2.00 mmol) in DMF (10 mL) was added Cs 2 CO 3 (2.0 g, 6.0 mmol), and the mixture was stirred overnight, diluted with water (100 mL), and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL), washed with Na 2 SO 4 Drying, con...

preparation example P2

[0434]

[0435] Step 1: N-(4-Bromobenzyl)-2-mesitylethan-1-amine (P2a)

[0436]

[0437] A solution of 2-mesitylethan-l-amine (300 mg, 1.84 mmol) and 4-bromobenzaldehyde (339 mg, 1.84 mmol) in MeOH (30 mL) was stirred at room temperature overnight. After adding NaBH 4 (105 mg, 2.76 mmol), the mixture was stirred overnight at room temperature, diluted with water, adjusted to pH~11 by addition of 1N NaOH, concentrated and extracted with EA (3x). The combined organic layers were washed with water and brine, washed with Na 2 SO 4 Drying, filtration and concentration afforded compound P2a as a yellow oil.

[0438] Step 2: N-(4-bromobenzyl)-2-mesityl-N-((5-(trifluoromethyl)furan-2-yl)methyl)ethane-1- Amine (P2)

[0439] Compound P2a (724mg, 2.19mmol), 2-(bromomethyl)-5-(trifluoromethyl)furan (499mg, 2.19mmol) and K 2 CO 3 (604 mg, 4.37 mmol) in ACN (40 mL) was added KI (363 mg, 2.19 mmol). The mixture was stirred at 80 °C overnight, cooled, filtered, concentrated ...

preparation example P3

[0444]

[0445] Step 1: tert-butyl 4-bromo-2,6-difluorobenzoate (P3a)

[0446]

[0447] 4-bromo-2,6-difluorobenzoic acid (25.0g, 110mmol), Boc2 A mixture of O (50.0 g, 242 mmol) and DMAP (1.3 g, 11 mmol) in tert-BuOH (200 mL) was stirred overnight at 40 °C, concentrated and purified by FCC (PE:EA=50:1) to give Compound P3a as a yellow oil. MS: 292(M+1) + .

[0448] Step 2: tert-butyl 4-bromo-2-fluoro-6-((2-methoxy-2-oxoethyl)thio)benzoate (P3b)

[0449]

[0450] To a solution of methyl 2-mercaptoacetate (11.2 g, 106 mmol) in anhydrous DMF (50 mL) was added NaH (60%, 5.1 g, 130 mmol) at 0°C. The mixture was stirred for 30 min. The mixture was then added to a solution of compound P3a (31 g, 106 mmol) in anhydrous DMF (100 mL). 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 Washed with O and brine, concentrated and purified by FCC (PE:EA...

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PUM

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Abstract

The present invention relates to derivatives of formula (I) which bind to the liver X receptor (LXR[alpha] and / or LXR[beta]) and act preferably as inverse agonists of LXR.

Description

technical field [0001] The present invention relates to novel compounds which are modulators of the liver X receptor (LXR) and to 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 a...

Claims

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Application Information

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IPC IPC(8): C07D307/52A61P19/02A61P29/00A61P31/12A61P35/00C07C233/66C07C255/60C07D207/335C07D307/82C07D405/14C07D407/12C07D409/12C07D413/12C07D417/12C07D471/04C07D307/68C07D405/12A61K31/341A61K31/443A61K31/4709A61P1/16A61P3/04A61P3/06A61P11/06
CPCA61K31/443A61P1/16C07C233/66C07C233/87C07C255/60C07C2602/08C07D207/335C07D307/52C07D307/68C07D307/82C07D405/12C07D405/14C07D407/12C07D409/12C07D413/12C07D417/12C07D471/04C07D487/04A61K31/341A61K31/4709A61K31/4375A61P3/10
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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