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Probucol derivative, preparation method and application thereof

A technology of probucol, derivatives, applied in the field of medicine, able to solve problems such as lack of effectiveness

Active Publication Date: 2018-07-20
DEMOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Theory and clinical practice have proved that the current single-target drug intervention in diabetes complicated with cardiovascular disease lacks ideal effectiveness, which indicates that the corresponding therapeutic drugs need multifunctional compounds with good effects on glucose metabolism, lipid metabolism and inflammatory response

Method used

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  • Probucol derivative, preparation method and application thereof
  • Probucol derivative, preparation method and application thereof
  • Probucol derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0258] Example 1: Methyl 2-((2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)propyl-2-yl)thio)acetate

[0259]

[0260] Step 1: 2,6-Di-tert-butyl-4-thiocyanophenol

[0261]

[0262] 2,6-di-tert-butylphenol (2.06g, 10mmol), NaBr (1.02g, 10mmol), NaSCN (1.62g, 20mmol) were added to a three-necked flask containing MeOH (30mL), and the above mixture was washed with ice Cool in a water bath and keep the temperature at 0-5°C. then Br 2 (0.56 mL, 11 mmol) in MeOH (5 mL) was slowly added dropwise, controlling the temperature not to exceed 5°C. After the dropwise addition was completed, the resulting mixture was naturally raised from room temperature with stirring, and monitored by TLC. Concentrate under reduced pressure to remove methanol, and add the residue to H 2 O (100mL), extracted with EtOAc (100mL×3), Na 2 SO 4dry. EtOAc was removed by concentration under reduced pressure, and the crude product 2,6-di-tert-butyl-4-thiocyanophenol was directly used in the next step.

[...

Embodiment 2

[0270] Example 2: 2-((2-((3,5-di-tert-butyl 4-hydroxyphenyl)thio)propan-2-yl)thio)acetic acid

[0271]

[0272] At 0°C, methyl 2-((2-((3,5-di-tert-butyl-4-hydroxyphenyl)thia)propyl-2-yl)thio)ethyl ester (200mg, 0.52mmol ) in THF (5 mL) was added water and lithium hydroxide (218 mg, 5.2 mmol). The reaction was stirred at room temperature overnight, EtOAc (50 mL) was added, followed by 1N HCl (5 mL) and the organic phase was separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was passed through a chromatographic column (silica gel, EtOAc:PE=1:1 to 3:1) to obtain the product 2-((2-((3,5-di-tert-butyl 4-hydroxyphenyl)thio)propane -2-yl)thio)acetic acid (120 mg, yield 62%), yellow solid. 1 H NMR (300MHz, CDCl 3 ):δ7.31(s,2H),5.38(s,1H),3.63(s,2H),1.55(s,6H),1.43(s,18H).LC-MS:371[M+H] + .HPLC:98.1%at 242nm,t R =2.11min.

Embodiment 3

[0273] Example 3: Ethyl 3-((2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)propan-2-yl)thio)propionate

[0274]

[0275] Ethyl mercaptopropionate (1.7 g, 12.8 mmol) and 2,6-di-tert-butyl-4-mercaptophenol (1.5 g, 6.3 mmol) were added to dry acetone (20 mL) at 0 °C, Then MeOH (20 mL) was slowly added dropwise at 0° C., followed by HCl gas was slowly bubbled in until the pH reached 2-3. The resulting reaction was stirred overnight at room temperature. The organic solvent was removed under reduced pressure, the residue was added EtOAc (100 mL), and saturated NaHCO 3 Wash with brine and dry over anhydrous sodium sulfate. The crude product was passed through a chromatography column (silica gel, EtOAc:PE=1:50 to 1:20) to obtain the product 3-((2-((3,5-di-tert-butyl-4-hydroxyphenyl)sulfur) Ethyl propan-2-yl)thio)propionate (649 mg, yield 25%). Colorless oil. 1 H NMR (300MHz, CDCl 3 ): δ7.32(s, 2H), 5.36(s, 1H), 4.15(q, 2H, J=3Hz), 3.03(t, 2H, J=6Hz), 2.76(d, 2H, J=6Hz) ,1.52(s,6...

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Abstract

The invention relates to the fields of compounds, and specifically relates to a probucol derivative, a preparation method and the application thereof. The probucol derivative has a structure shown asa general formula I. The probucol derivative provided by the invention can be used for prevention and curing of vascular diseases such as diabetes and cardiovascular and cerebrovascular diseases or complications thereof, can be used for reducing blood glucose, reducing blood fat, reducing cholesterol, reducing the weight, reducing triglyceride, resisting inflammation and oxidation and the like effectively, and has a wide application prospect.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a probucol derivative, a preparation method thereof and applications in different disease fields. Background technique [0002] Obesity easily leads to disorders of sugar and lipid metabolism, which are the main causes of diabetes, atherosclerosis and aging. Glucose and lipid metabolism can occur independently and often simultaneously in the above diseases. As a result of glycosylation of biological macromolecules, diabetic patients are more likely to cause lipid metabolism disorders and various complications, such as nephropathy, retinopathy, neuropathy, atherosclerotic cardiovascular and cerebrovascular diseases, tumors and neurodegeneration. Diabetic complications, especially vascular complications, are the main cause of death in patients. [0003] Probucol is a lipid-lowering drug marketed in the United States in the 1970s. The drug has strong antioxidant activity, can re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/52C07C323/20C07D311/58C07D495/04C07C323/32C07D295/088C07D339/04C07D249/08C07D339/06C07C323/49C07C319/20C07C319/24A61K31/216A61K31/192A61K31/10A61K31/353A61K31/225A61K31/381A61K31/235A61K31/222A61K31/4365A61K31/137A61K31/135A61K31/5375A61K31/223A61K31/4196A61K31/18A61P3/10A61P3/06A61P3/04A61P1/16A61P9/00A61P13/12A61P27/02
CPCC07C323/20C07C323/32C07C323/49C07C323/52C07D249/08C07D295/088C07D311/58C07D339/04C07D339/06C07D495/04C07C2601/02C07C323/31A61P1/16A61P13/12A61P27/02A61P3/04A61P3/06A61P3/10A61P9/00C07C323/22C07D265/30
Inventor 律嵩谢文委何双江
Owner DEMOTECH INC
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