Thiazolidinedione analogues

A technology of drugs and compositions, applied in the field of thiazolidinedione analogues, capable of solving problems such as unsatisfactory side effects and sodium reabsorption

Inactive Publication Date: 2013-02-27
METABOLIC SOLUTIONS DEVMENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compounds involved in the activation of PPARγ also cause sodium reabsorption and other unsatisfactory side effects

Method used

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  • Thiazolidinedione analogues
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] Example 1: 5-[4-(2-oxo-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione.

[0175]

[0176] step 1: Preparation of 4-(2-hydroxy-2-phenylethoxy)benzaldehyde.

[0177] Add toluene (85ml), 4-hydroxybenzaldehyde (9.89g, 81.0mmol), PEG4000 (polyethylene glycol, 1.15g ) and 1M NaOH (85ml) and the stirred mixture was heated at 78°C overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on a medium silica gel column eluting with 0-10% EtOAc / DCM. will mainly contain higher R f Fractions from the spot were combined and evaporated in vacuo to give 1.85 g of the title compound as a yellow oil. will mainly contain lower R f Fractions from the spot were combined and evaporated in vacuo to give 0.64 g of the regioisomer as a colorless viscous oil. The combined fractions were combined and rechr...

Embodiment 2

[0184] Example 2: Preparation of 5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione.

[0185] step 1: Preparation of 4-[2-(fluorophenyl)-2-hydroxyethoxy]benzaldehyde

[0186] To a stirred solution of 2-(4-fluorophenyl)oxirane (5.60 g, 40.0 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), 1M NaOH (65 ml ) and PEG4000 (polyethylene glycol, 0.85 g) and the reaction mixture was heated at 78° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (2x150ml) and the combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed on silica gel (eluting with 30-40% EtOAc / hexanes). will contain higher R f The spot fractions were combined and evaporated in vacuo to give 2.38 g of the regioisomer of the product as a white solid. will contain lower R f The spot fractions were combined and evaporated in vacuo to ...

Embodiment 3

[0193] Example 3: Preparation of 5-{4-[2-(2-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione.

[0194]

[0195] step 1: Preparation of 2-(2-fluorophenyl)oxirane.

[0196] Add o-fluorostyrene (5.0g, 41.0mmol) and acetic acid (2.33mL, 40.9mmol) in dioxane (33ml) and H at 0°C 2 To the solution in O (78ml) was added N-bromosuccinimide (8.02g, 45.0mol) in three portions. The reaction mixture was warmed to room temperature and stirred overnight. Sodium carbonate (8.68 g, 81.9 mmol) was added portionwise, followed by 1M NaOH (ca. 10 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give 5.31 g of the title compound as a slightly colored oil which was used without further purification. C 8 h 7 MS(ESI+)m / z138.1(M+H) of FO + ...

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Abstract

The present invention relates to thiazolidinedione analogues that are useful for treating liver afflictions such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

Description

[0001] Cross References to Related Applications [0002] This PCT application claims priority to US Application 61 / 326,400, filed April 21, 2010, the contents of which are incorporated herein by reference. technical field [0003] The present invention provides pharmaceutical compositions comprising selective thiazolidinedione analogs for use in the treatment and prevention of diabetes, hypertension, liver disease and inflammatory diseases. Background technique [0004] Over the past few decades, scientists have postulated that PPARγ is the generally accepted site of action for insulin-sensitizing thiazolidinedione compounds. [0005] Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, are ligand-activated transcription factors that regulate gene expression. PPARs are involved in autoimmune and other diseases, namely diabetes, cardiovascular and gastrointestinal diseases, and Alzheimer's disease. [0006] PPARγ is a ke...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/06A61K9/08A61K9/48A61K31/425A61K9/00
CPCC07D277/34A61K31/425A61K45/06A61K31/426A61P1/16A61P29/00A61P43/00A61K2300/00A61K9/48A61K9/08
Inventor G.R.科尔卡R.C.加德伍德T.帕克
Owner METABOLIC SOLUTIONS DEVMENT
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