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Application of 5- aryl (heterocycle) methylenethiazolidine-2,4-dione in preparation of PPAR (Peroxisome Proliferator Activated Receptor) agonist

A technology of heterocyclic methylene thiazolidine and aryl methylene thiazolidine, which is applied in the field of chemical pharmaceuticals and can solve problems such as compound termination research

Inactive Publication Date: 2012-10-17
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, many pharmaceutical companies and research institutions at home and abroad have invested a large amount of manpower and material resources in the research and development of PPARα / γ dual agonists. Although many compounds have entered the clinic, none of them have been successfully marketed yet, and some compounds Termination of the study due to adverse reactions at the later stage of the clinical study

Method used

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  • Application of 5- aryl (heterocycle) methylenethiazolidine-2,4-dione in preparation of PPAR (Peroxisome Proliferator Activated Receptor) agonist
  • Application of 5- aryl (heterocycle) methylenethiazolidine-2,4-dione in preparation of PPAR (Peroxisome Proliferator Activated Receptor) agonist
  • Application of 5- aryl (heterocycle) methylenethiazolidine-2,4-dione in preparation of PPAR (Peroxisome Proliferator Activated Receptor) agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1, thiazolidine-2, the synthesis of 4-dione

[0019]

[0020] Add chloroacetic acid, thiourea and concentrated hydrochloric acid (the amount ratio of the three is 1mol: 1.1mol: 250ml) into the reaction flask, heat and reflux for 3 hours, cool and stir to crystallize, filter, and wash the crystals with water to obtain 2-imino-4 -thiazolone hydrochloride; then add an appropriate amount of water and a certain amount of activated carbon to the crystal, heat and reflux for 2 m hours, filter while it is hot, cool and stir the filtrate to crystallize, filter, wash the crystal with water, and dry to obtain thiazolidine-2, 4-diketone. The results of the synthesis experiments are shown in Table 1.

[0021] Table 1 Thiazolidine-2,4-dione synthetic experimental results

[0022]

[0023] Thiazolidine-2,4-dione: white crystals; IR (KBr, cm -1 ): 3134(s, v NH ), 3047(s, v ＝CH ), 2949, 2825 (s, v CH2 ), 1739 (s, v C＝O ), 1655 (s, v C＝O ), 618.0 (m, v C-S ); 1...

Embodiment 2

[0025] Embodiment 2, the synthetic (solid phase condensation method) of target compound TM-7

[0026]

[0027] Add aldehyde, thiazolidine-2,4-dione and anhydrous sodium acetate (the molar ratio of the three is 1.1:1.0:1.0) into the mortar, mix and grind to powder, then transfer to the reaction bottle, oil bath 125 ℃ reaction, it can be seen that the solid raw material melts rapidly, and then thickens. Stop the reaction when the solidification is complete. 6. After stirring at room temperature for 30 minutes, let stand at 4°C, filter with suction, wash the filter cake with water, dry at 100°C, disperse with ether-ethyl acetate (volume ratio 2:1) mixed solvent overnight, filter with suction, and dry to obtain Target compound TM-7. The results of the synthesis experiments are shown in Table 2.

[0028] Table 2 The synthesis experiment result of target compound TM-7

[0029]

[0030]

[0031] After retrieval, the TM-7 series of target compounds are all known compounds ...

Embodiment 3

[0070] Embodiment 3, the synthesis of target compound TM-8

[0071] 1. Solid phase condensation method

[0072]

[0073] Add aldehyde, thiazolidine-2,4-dione and anhydrous sodium acetate (the molar ratio of the three is 1.1:1.0:1.0) into the mortar, mix and grind to powder, then transfer to the reaction bottle, oil bath 125 ℃ reaction, it can be seen that the solid raw material melts rapidly and then thickens, stop the reaction when the solidification is complete, add an appropriate amount of DMF while it is hot to completely dissolve the solid, add water to precipitate a large amount of solid, adjust the pH to 5-6 with 2N HCl, and stir at room temperature for 30 minutes Stand at 4°C, filter with suction, wash the filter cake with water, dry at 100°C, disperse with ether-ethyl acetate (volume ratio 2:1) mixed solvent overnight, filter with suction, and dry to obtain the target compound TM-8. The synthesis experiment results are shown in Table 3.

[0074] 2. Liquid phase c...

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Abstract

The invention provides application of 5-arylmethylenethiazolidine-2,4-dione shown as the general formula I and 5-heterocyclemethylenethiazolidine-2,4-dione shown as the general formula II in preparation of a PPAR (Peroxisome Proliferator Activated Receptor) agonist, wherein 5-arylmethylenethiazolidine-2,4-dione and 5-heterocyclemethylene-thiazolidine-2,4-dione both has PPAR agonistic activity, the relative agonist ratio of a part of compounds to pioglitazone which is an existing PPARgamma agonist is higher than 100% and can be 239.77% at most, and therefore the part of compounds can be developed into high-efficiency low-toxicity antidiabetic drug possibly or can be used as antidiabetic leading molecules to be applied to the further structural optimization.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy and relates to the application of a class of 5-aryl (heterocyclic) methylenethiazolidine-2,4-dione in the field of pharmacy. Background technique [0002] Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which are divided into three subtypes: α, β / δ and γ. They are activated after binding to ligands and can bind to retinoid X receptors ( RXR) combines to form a heterodimer, and then binds to the peroxisome proliferator response element (PPRE) in the promoter region of the target gene to regulate the transcription of the target gene. Among them, PPARα is mainly related to lipid metabolism and is the target of lipid-lowering drugs of fibrates; PPARδ is widely distributed and its role is still unclear; It plays an important role in atherosclerosis, inflammatory response and immunity, and has become an important target for screening drugs for diseases such as obesity, diabet...

Claims

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Application Information

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IPC IPC(8): A61K31/426C07D277/34A61P31/10
Inventor 杨大成晏菊芳张坤陈欣范莉蒋渝许荩刘红萍周礼江于子涵
Owner SOUTHWEST UNIVERSITY
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