Thiazole derivatives as PPARª€ delta ligands and their manufacturing process

A derivative, thiazole technology, applied in the field of thiazole derivatives as PPARδ ligands and its manufacture, can solve the problem of PPARδ selectivity decline and other issues

Inactive Publication Date: 2008-03-19
SEOUL NAT UNIV R&DB FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this ligand is a dual-activating ligand that is also active against hPPARα, thus reducing the selectivity for PPARδ

Method used

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  • Thiazole derivatives as PPARª€ delta ligands and their manufacturing process
  • Thiazole derivatives as PPARª€ delta ligands and their manufacturing process
  • Thiazole derivatives as PPARª€ delta ligands and their manufacturing process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1: Preparation of 4-iodo-2-methyl-phenoxy-tert-butyldimethylsilane (III) [Step A]

[0146] 3.0 g (12.8 mmol) of 4-iodo-2-methylphenol and 1.74 g (25.6 mmol, 2.0 equivalents) of imidazole were completely dissolved in 45 ml of dimethylformamide. 2.12 g (14.1 mmol, 1.1 equivalents) of tert-butyldimethylchlorosilane were slowly added to the solution, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction product was extracted with aqueous ammonium chloride and ethyl acetate, and the organic layer was dried with magnesium sulfate. The residue was purified by a silica gel column, and the solvent was distilled off under reduced pressure, thereby obtaining 4.4 g (yield 98%) of the target compound.

[0147] 1 H NMR (300MHz, CDCl 3 )δ7.47(d, 1H, J=0.6Hz), 7.35(dd, 1H, J=8.4, 2.3Hz), 6.54(d, 1H, J=8.4Hz), 2.18(s, 3H), 1.03( s, 9H), 0.22 (s, 6H).

[0148] 13 C NMR (75.5MHz, CDCl 3 )δ 154.3, 139.9, 135.9, 132.3, 121...

Embodiment 2

[0149] Example 2: Preparation of 4-bromo-phenoxy-tert-butyldimethylsilane (III) [Step A]

[0150] 500mg (2.90mmol) of 4-bromophenol and 409mg (6.0mmol, 2.00eq) of imidazole were completely dissolved in dimethylformamide. 436 mg (2.90 mmol, 1.0 equivalent) of tert-butyldimethylchlorosilane was slowly added to the solution, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction product was extracted with aqueous ammonium chloride and ethyl acetate, and the organic layer was dried with magnesium sulfate. The residue was purified by a silica gel column, and the solvent was distilled off under reduced pressure, thereby obtaining 811 mg (yield 97%) of the target compound.

[0151] 1 H NMR (300MHz, CDCl 3 )δ7.32(d, 2H, J=8.8Hz), 6.72(d, 2H, J=10.0Hz), 0.98(s, 9H), 0.18(s, 6H)

[0152] 13 C NMR (75.5MHz, CDCl 3 )δ155.3, 132.7, 122.3, 114.0, 26.0, 18.6, -4.1

Embodiment 3

[0153] Example 3: 5-[4-(tert-butyldimethylsilyloxy)-3-methyl-phenylthiomethyl]-4-methyl-2-[(4-trifluoromethyl ) phenyl]-thiazole (V) preparation [step B]

[0154] 1.5g (4.32mmol) of 4-iodo-2-methyl-phenoxy-tert-butyldimethylsilane prepared in Example 1 was dissolved in 120ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, and cooled to - 78°C. 2.54 ml (1.0 equiv) of tert-butyllithium (1.7 M in hexane) was slowly added to the solution. The mixture was stirred for 10 minutes, and then 138 mg (4.32 mmol, 1.0 equivalent) of sulfur in solid phase was added thereto at the same temperature in one portion. Allow the mixture to react for 40 minutes until its temperature reaches 15° C., then slowly add 1.26 g (4.32 mmol, 1.0 equivalents) of 5-chloromethyl-4-methyl represented by formula III dissolved in 10 ml of anhydrous THF -2-[(4-Trifluoromethyl)phenyl]-thiazole. After the reaction was continued for about 1 hour, the reaction was quenched with aqueous ammonium chloride,...

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PUM

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Abstract

The present invention relates to novel thiazole derivative compounds having activity for peroxisome prolif erator-activated receptor d (PPARd), as well as their intermediates and synthesis methods thereof .

Description

technical field [0001] The present invention relates to novel thiazole derivatives represented by formula I, intermediates and preparation methods thereof, which can be used as peroxisome proliferator activation for treating obesity, hyperlipidemia, arteriosclerosis and diabetes Activating ligands for receptor delta (PPARδ): [0002] [Formula 1] [0003] [0004] Among them, A is hydrogen, R 2 or [0005] Background technique [0006] Among various nuclear receptors, peroxisome proliferator-activated receptors (PPAR) include three subtypes: PPARα, PPARγ and PPARδ (Nature, 1990, 347, pages 645-650; Proc.Natl.Acad . Sci. USA, 1994, 91, pp. 7335-7359). PPARα, PPARγ, and PPARδ have different functions depending on different tissues in the body, and are expressed at different sites. PPARα is mainly expressed in human heart, kidney, skeletal muscle and colon (Mol. Pharmacol. 1998, 53, pp. 14-22; Toxicol. Lett. 1999, 110, pp. 119-127; J. Biol. Chem. 1998, 273, pp. 16710...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/26
CPCA23K1/1625C07D277/26C07D417/12A23L1/30A23K1/1618A23K20/121A23K20/132A23L33/10A61P3/00A61P3/04A61P3/06A61P43/00A61P9/10A61P3/10Y02P20/55A44B11/2584
Inventor 姜宪中咸政烨黄厚商
Owner SEOUL NAT UNIV R&DB FOUND
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