Resveratrol derivative and application thereof to medicament

A drug and pharmaceutical technology, applied in the field of resveratrol derivatives and their medical applications, can solve the problems of biological activity to be improved, low oral bioavailability, and poor water solubility of resveratrol

Active Publication Date: 2015-01-07
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, resveratrol has poor water solubility and low oral bioavailability, and its biological activity needs to be improved

Method used

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  • Resveratrol derivative and application thereof to medicament
  • Resveratrol derivative and application thereof to medicament
  • Resveratrol derivative and application thereof to medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] Example 1 3,5-dihydroxy-4'-(4-methyl-4-isobutoxycarbonylpentyloxy)-(E)-stilbene (Ia 1 )Synthesis

[0157] Add 10g (43.8mmol) resveratrol, 36.26g (262.8mmol) K 2 CO 3 , 100mL of dry DMF, stirred and heated to 55°C under the protection of nitrogen, added dropwise 38.67g (175.2mmol) of 5-chloro-2,2-dimethylpentanoic acid isobutyl ester, after the addition was completed, continue to heat and react at 55°C for 24h , stop heating, after cooling, add 100mL ethyl acetate to the reaction solution; Wash the resulting solution 3 times with 1N hydrochloric acid, 50mL / time; wash the organic layer with anhydrous Na 2 SO 4 Dry, filter, concentrate and separate by column chromatography with 200-300 mesh silica gel, elute with a mixed solvent of petroleum ether: ethyl acetate: acetic acid (9.5: 0.5: 0.1) to obtain 7.9 g of Ia1 light yellow solid, 1 H-NMR (d 6 -DMSO): δppm 0.88-0.90 (6H, m), 1.15 (6H, s), 1.63 (4H, s), 1.82-1.91 (1H, m), 3.78-3.80 (2H, d, J=6.4Hz) , 3.95(2H, m), ...

Embodiment 2

[0158] Example 2 3,5-dihydroxy-4'-(4-methyl-4-carboxypentyloxy)-(E)-stilbene (Ia 2 )Synthesis

[0159] 1.13g Ia 1 Dissolved in 20mL of methanol, 4g of LiOH·H 2 O was made into 15 mL of aqueous solution. With stirring, the aqueous solution of LiOH was slowly added dropwise to Ia 1 In methanol solution, the reaction was stirred at room temperature for 4 days, and the reaction was tracked by TLC until the raw material point completely disappeared. Then add 80mL of water to the reaction solution, adjust the pH to 3-4 with 3M hydrochloric acid, extract 3 times with ethyl acetate (20mL / time); combine the extracts, wash with water until neutral, and wash the organic layer with anhydrous Na 2 SO 4 Dry, filter, and evaporate to dryness under reduced pressure to obtain Ia 2 0.78g of white solid, 1 H-NMR (d 6 -DMSO): δppm1.12 (6H, s), 1.61-1.63 (4H, m), 3.94-3.97 (2H, m), 6.12 (1H, m), 6.40 (2H, m), 6.89-7.00 (4H , m), 7.48-7.50 (2H, d, J=8.8Hz), 9.22 (2H, s), 12.15 (1H, s). ...

Embodiment 3

[0161] Example 3 3,5-dimethoxy-4'-(4-methyl-4-isobutoxycarbonylpentyloxy)-(E)-stilbene (Ia 3 )Synthesis

[0162] Will Ia 1 1.12g (2.72mmol) was dissolved in 20mL acetone, and 1.13g (8.19mmol) K was added successively 2 CO 3 and 0.35 mL (6.83 mmol) CH 3 1, Heating and reflux reaction under the protection of nitrogen for 24h, stop heating, after cooling, filter, wash the filter cake with acetone, combine the filtrate and lotion, after concentration, use 200-300 purpose silica gel to separate through column chromatography, use petroleum ether: ethyl acetate Esters (9:1) mixed solvent elution to give Ia 3 0.95g of colorless oil, 1 H-NMR (d 6 -DMSO): δppm0.85-0.90 (6H, m), 1.16 (6H, s), 1.63 (4H, m), 1.84-1.88 (1H, m), 3.79 (6H, m), 3.94 (2H, m ), 6.39-6.40 (1H, m), 6.74 (2H, br.s), 6.91 (2H, d, J = 8.8Hz), 7.02 (2H, d, J = 16Hz), 7.21 (1H, d, J = 16.4 Hz), 7.52 (2H, d, J = 8.4 Hz).

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Abstract

The invention relates to a resveratrol derivative and application thereof to a medicament, and particularly discloses a compound shown as a formula I or pharmaceutically acceptable salt, ester, solvate and stereoisomers thereof. In the formula I, R1, R2 and R3 are independently selected from a hydrogen atom, C1 to C3 alkyl or a substituted group shown as a formula i; at least one of R1, R2 and R3 is the substituted group shown as the formula i; R is selected from the hydrogen atom, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C3 to C6 naphthenic base, benzyl or phenyl; R4 and R5 are independently selected from the hydrogen atom, the substituted or unsubstituted C1 to C5 alkyl, or substituted or the unsubstituted C3 to C6 naphthenic base; and n is an integer of between 1 and 5. The invention also discloses a medicinal composition containing the compound shown as the formula I, and the application of the compound shown as the formula I to the preparation of a medicament for treating and / or preventing cardiovascular and cerebrovascular diseases. The compound shown as the formula I can be effectively used for treating and / or preventing the cardiovascular and cerebrovascular diseases such as hyperlipemia.

Description

technical field [0001] The present invention relates to novel resveratrol derivatives or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds as active ingredients, and the use of said derivatives or pharmaceutically acceptable salts for the preparation of lipid-lowering drugs the use of. Background technique [0002] Cardiovascular and cerebrovascular diseases are the number one disease that threatens human life and health, and hypercholesterolemia characterized by elevated levels of plasma low-density lipoprotein and very low-density lipoprotein is one of the main pathogenic factors of cardiovascular and cerebrovascular diseases; blood lipids Elevation can also lead to fatty liver and cirrhosis. Blood lipid lowering therapy has become an important means to prevent and treat coronary heart disease and other cardiovascular and cerebrovascular diseases, and it is also an effective measure to treat fatty liver, liver fibrosis and l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/712C07C59/68C07C59/70A61K31/216A61K31/192A61P9/00A61P3/06A61P39/06A61P7/00A61P7/02A61P9/08
Inventor 仲伯华李伟何新华贾红心
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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