Thiazolidinedione derivatives and pharmaceutical compositions containing same

A technology of thiazolidinedione and compounds, applied in the field of thiazolidinedione derivatives and pharmaceutical compositions containing them, capable of solving problems such as limited therapeutic application and weight gain

Active Publication Date: 2021-01-12
SUZHOU ZELGEN BIOPHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing thiazolidinediones have limited their therapeutic applicatio

Method used

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  • Thiazolidinedione derivatives and pharmaceutical compositions containing same
  • Thiazolidinedione derivatives and pharmaceutical compositions containing same
  • Thiazolidinedione derivatives and pharmaceutical compositions containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0177] (E)-2-(4-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)phenyl)-3-(3-methoxy-5- (methoxy-d 3 ) Preparation of phenyl) methyl acrylate

[0178]

[0179] The first step: 3-hydroxy-5-(methoxy-d 3 ) preparation of benzaldehyde

[0180] 3,5-Dihydroxybenzaldehyde (5.6 g, 40.54 mmol), potassium carbonate (7.5 g, 54.27 mmol) and N,N-dimethylformamide (100 mL) were sequentially added to a 500 mL round bottom flask. Under ice bath (0-5°C), add p-toluenesulfonic acid-d dropwise over 30 minutes 3 - A solution of the methyl ester (6.85 g, 36.20 mmol) in N,N-dimethylformamide (50 mL). The reaction solution was then reacted at 0-5°C for 1 hour, and then raised to room temperature for 18 hours. The resulting mixture was quenched with water (200 mL), then adjusted to pH 2 with hydrochloric acid and extracted with ethyl acetate (100 mL×4). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentr...

Embodiment 2

[0200] (E)-3-(3,5-bis(methoxy-d 3 )Phenyl)-2-(4-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)phenyl)methyl acrylate

[0201]

[0202] The first step: 3,5-bis(methoxy-d 3 ) preparation of benzaldehyde

[0203] In a 100mL round bottom flask, add 3,5-dihydroxybenzaldehyde (4g, 28.96mmol), p-toluenesulfonic acid-d 3- Methyl ester (12g, 63.70mmol), potassium carbonate (12g, 86.88mmol) and N,N-dimethylformamide (50mL). The reaction solution was heated to 65°C for 32 hours, cooled to room temperature, quenched with water (300 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were washed with saturated brine (100 mL×2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (crude product 4.67 g), which was directly used in the next reaction without purification.

[0204] 1 H NMR (400MHz, DMSO-d 6 ) δ9.93 (s, 1H), 7.07 (d, J = 2.4Hz, 2H), 6.83 (t, J = 2.4Hz, 1H).

...

Embodiment 3

[0221] (E)-3-(3,5-bis(methoxy-d 3 ) phenyl) -2-(4-(4-((2,4-dioxothiazolidine-5-yl) methyl) phenoxy) phenyl) acrylic acid

[0222]

[0223] The first step: (E)-3-(3,5-bis(methoxy-d 3 ) phenyl) -2-(4-(4-((2,4-dioxothiazolidine-5-yl) methyl) phenoxy) phenyl) acrylic acid

[0224] Add (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)phenyl)methyl acrylate (0.88g, 1.67mmol), Lithium hydroxide monohydrate (200 mg, 4.76 mmol), tetrahydrofuran (4 mL) and water (3 mL). The reaction solution was reacted at room temperature for 24 hours, then quenched with water (10 mL), and then extracted with ethyl acetate (10 mL×3). The aqueous phase was adjusted to pH 1 with hydrochloric acid and then filtered. The filter cake was washed with water and dried to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain the target compound (0.66 g, yield 77.1%).

[0225] LC-MS: m / z 512(M+H) + . 1 H NMR ...

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PUM

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Abstract

The present invention relates to thiazolidinedione derivatives and pharmaceutical compositions comprising the same. Specifically, the compounds disclosed by the invention have a structure shown as a formula (I), and the definitions of all groups and substituents are as described in the specification; the invention also discloses application of the compounds as a peroxisome proliferator-activated receptor (PPAR) agonist, and particularly relates to application of the compounds in prevention and/or treatment of non-alcoholic steatohepatitis and related diseases.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a thiazolidinedione derivative and a pharmaceutical composition containing it. Background technique [0002] Non-alcoholic fatty liver disease (NAFLD) affects approximately 10-30% of the general adult population and 60-80% of type 2 diabetic patients. In the United States, the incidence of NAFLD accounts for about 10-46% of the total population, and about 10-30% of patients will develop nonalcoholic steatohepatitis (NASH, nonalcoholic steatohepatitis). Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fatty degeneration of liver cell damage, which can lead to major diseases such as advanced liver fibrosis, liver cirrhosis, liver failure, and liver tumors. By 2025, its drug use is expected to exceed $35-40 billion. Early targets include PPAR, FXR, GLP, ACC and THR β Wait, but so far, there is no clinically approved treatment for NASH (Sumida Y, Yoneda M., J Gastr...

Claims

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Application Information

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IPC IPC(8): C07D277/34C07F9/6539A61K31/426A61K31/675A61P1/16A61P3/04A61P3/10A61P9/10A61P29/00A61P35/00
CPCC07D277/34C07F9/6539A61P1/16A61P3/04A61P3/10A61P9/10A61P29/00A61P35/00A61K31/426A61K31/675A61K31/425A61P37/00C07D277/20
Inventor 吕彬华盛泽林庞旭东崔大为刘瑞峰
Owner SUZHOU ZELGEN BIOPHARML
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