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Farnesoid x receptor agonists

A technology for subjects and mammals, applied in the field of farnesoid X receptors in the case of a fatty diet, can solve the problem that the function of ileal bile acid binding protein needs to be studied and so on

Inactive Publication Date: 2011-02-16
GLAXOSMITHKLINE LC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The function of this ileal bile acid-binding protein remains to be investigated

Method used

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  • Farnesoid x receptor agonists
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  • Farnesoid x receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0544] Example 1: 5-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)benzene base]-1H-indole-2-carboxylic acid

[0545]

[0546] 1a) 1-(1,1-dimethylethyl) 5-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-1,2-dicarboxylate · 2-ethyl ester

[0547]

[0548] Di-tert-butyl dicarbonate (1.78 g, 8.13 mmol) and N,N-dimethylaminopyridine (83 mg, 0.68 mmol) were added to 5-[(phenylmethyl) in tetrahydrofuran (20 mL) at room temperature Oxy]-1H-indole-2-carboxylic acid ethyl ester (2.0 g, 6.77 mmol). After stirring for 1.5 hours, ethyl acetate was added, and the mixture was washed with water and brine, then dried over sodium sulfate. The solution was concentrated, and the residue was taken up in methanol (40 mL) and chloroform (40 mL). Palladium on carbon (10%, 100 mg) was added and the mixture was shaken under hydrogen (40 psi) in a Parr apparatus for 1 h at room temperature. Pass the solution through Pad filter, then concentrate. Dichloromethane (20 mL) w...

Embodiment 2

[0558] Example 2: 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)benzene base]-2,3-dihydro-1H-indene-1-carboxylic acid

[0559]

[0560] 2a) Methyl 6-hydroxy-2,3-dihydro-1H-indene-1-carboxylate

[0561]

[0562] A solution of 1,3-dithiane (2.37 g, 19.7 mmol) in tetrahydrofuran (30 mL) was cooled to -15°C and n-butyllithium (2.5M in hexane, 7.40 mL, 18.5 mmol) was added. After stirring at -15°C for 1 hour, 6-(methyloxy)-2,3-dihydro-1H-inden-1-one (2.0 g, 12.3 mmol) in tetrahydrofuran (75 mL) was added dropwise, and then The mixture was warmed to room temperature over 3 hours. Ethyl acetate was added, the mixture was washed with water and brine, then dried over sodium sulfate and concentrated. The residue was taken up in toluene (75 mL) and p-toluenesulfonic acid (350 mg, 1.85 mmol) was added. The mixture was heated to reflux in a Dean Stark apparatus for 1.5 hours, then passed Plug filtered and concentrated. The residue was purified by sil...

Embodiment 3

[0573] Example 3: 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)benzene base]-1H-indole-3-carboxylic acid

[0574]

[0575] 3a) 1-(1,1-dimethylethyl) 6-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-1,3-dicarboxylate · 3-ethyl ester

[0576]

[0577] Ethyl 6-[(phenylmethyl)oxy]-1H-indole-3-carboxylate in chloroform (10 mL) and methanol (5 mL) [according to Bioorg.Med.Chem, 9 (8) 2119 (2001 ) preparation] (350 mg, 1.19 mmol) and palladium / carbon (10%, 100 mg) mixture was vigorously stirred under hydrogen (1 atm) for 1.5 h. Pass the mixture through Pad filter, then concentrate. The residue was taken up in dichloromethane (8 mL), cooled to 0 °C, triethylamine (250 μL, 1.78 mmol) was added followed by trifluoromethanesulfonic anhydride (240 μL, 1.42 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated and the residue was taken up in ethyl acetate. The organics were washed with water and brine, then concentrated. T...

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Abstract

The present invention relates to famesoid X receptors (FXR, NR1 H4) FXR is a member of the nuclear receptor class of ligand-activated transcription factors. More particularly, the present invention relates to compounds useful as agonists for FXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same Novel isoxazole compounds are disclosed as part of pharmaceutical compositions for the treatment of a condition mediated by decreased FXR activity, such as obesity, diabetes, cholestatic liver disease and metabolic syndrome.

Description

Background of the invention [0001] The present invention relates to the farnesoid X receptor (FXR, NR1H4). More specifically, the present invention relates to compounds useful as agonists of FXR, pharmaceutical formulations comprising such compounds and their use in therapy. [0002] FXR is a member of the class of ligand-activated transcription factor nuclear receptors. Physiological concentrations of bile acids bind and activate FXR [Parks, D.J., et al. 1999 Science 284: 1365-1368; Makishima, M., et al. 1999 Science 284: 1362-1365]. Bile acids are amphiphilic molecules that form micelles and emulsify dietary lipids. This property also makes bile acids cytotoxic if sufficient concentrations are achieved, and thus mechanisms developed to ensure tight regulation of bile acid concentrations. FXR plays a key role in regulating bile acid homeostasis [Makishima, M. 2005 J. Pharmacol. Sci. 97: 177-183; Kuipers, F., et al. 2004 Rev. Endocrine Metab. Disorders 5: 319-326]. [0003...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/80
CPCC07D495/04C07D413/14C07D261/08C07D413/12A61P1/00A61P1/16A61P3/00A61P3/04A61P3/10A61P43/00
Inventor D·N·迪顿F·纳瓦斯三世P·K·斯皮林
Owner GLAXOSMITHKLINE LC
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