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Crocetin derivative GX-D, preparation method thereof and application thereof in prevention or treatment of cardiovascular and cerebrovascular diseases

A saffron, GX-D technology, applied in cardiovascular system diseases, drug combinations, organic chemistry, etc., can solve the problem of poor lipid solubility and water solubility of crocus acid, clinical application limitations, high drug concentration and dosage, etc. To prevent or treat cardiovascular and cerebrovascular diseases, overcome low bioavailability, and improve bioavailability

Active Publication Date: 2016-12-21
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, crocetin has poor fat solubility and water solubility, is extremely difficult to dissolve in water and common organic solvents except pyridine and organic bases similar to pyridine, and is difficult to achieve higher drug concentration and dosage. In addition, Due to the high fat solubility of the drug, it can be easily absorbed by the epithelial cell mucosa of the gastrointestinal tract, and crocetin has low bioavailability due to its extremely poor fat solubility, and its clinical application is greatly limited.
[0006] At the same time, there are still many technical difficulties in solving the solubility problem through crocetin derivatives, such as the unstable structure of the derivatives and the decrease in activity.

Method used

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  • Crocetin derivative GX-D, preparation method thereof and application thereof in prevention or treatment of cardiovascular and cerebrovascular diseases
  • Crocetin derivative GX-D, preparation method thereof and application thereof in prevention or treatment of cardiovascular and cerebrovascular diseases
  • Crocetin derivative GX-D, preparation method thereof and application thereof in prevention or treatment of cardiovascular and cerebrovascular diseases

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 prepares crocetin derivative GX-D

[0037]

[0038] Take GX-1 (purchased from Sigma Company) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg), HOBt (1.25mmol, 169mg) in a 100ml reaction bottle. In an ice bath, add Et 3 N (1.25mmol, 172μl) and CH 2 Cl 2 20ml, finally added piperidine (1.0mmol), reacted at 0°C for 4h, then reacted overnight at room temperature. Use TLC and LC-MS to detect whether the product is generated, and stop the reaction after confirming that the reaction is complete. The reaction solution was filtered, the solvent was removed in vacuo, 10ml of EA was added to dissolve, and 2% HCl, 5% NaHCO 3 , H 2 O each 10ml was washed 3 times, and finally the solvent was removed in vacuo to obtain the crude product. The obtained crude product GX-D is separated with a silica gel column, first two column volumes of CHCl 3 Carry out elution, then increase the eluent polarity CHCl 3 :CH 3 OH=10:1 for elution. Finally, the product GX-D was obtained, ...

Embodiment 2

[0039] Embodiment 2: Preparation of crocetin derivative GX-M:

[0040]

[0041] Separately take crocetin GX-1 (purchased from Sigma) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg), HOBt (1.25mmol, 169mg) in 25ml reaction vials. Under ice bath condition, add Et3N (2.5mmol, 350μl) and CH 2 Cl 2 20ml, finally added 4-fluorobenzylamine (1.1mmol, 125μl), reacted at 0°C for 4h, then reacted overnight at room temperature. Use TCL and LC-MS to detect whether the product is generated, and stop the reaction after confirming that the reaction is complete. The reaction solution was filtered, the solvent was removed in vacuo, 10ml of EA was added to dissolve, and then washed three times with 2% HCl, 5% NaHCO3, 10ml of H2O respectively, and finally the solvent EA was removed in vacuo to obtain the crude product. The resulting crude product was separated on a silica gel column, eluting with three column volumes of CHCl3. Obtain the product GX-M crude product, then again silica gel column se...

Embodiment 3

[0042] Embodiment 3: Preparation of crocetin derivative GX-N:

[0043]

[0044]Separately take crocetin GX-1 (purchased from Sigma) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg), HOBt (1.25mmol, 169mg) in 25ml reaction vials. Under ice bath condition, add Et3N (2.5mmol, 350μl) and CH 2 Cl 2 20ml, finally added 3,5-difluorobenzylamine (1.1mmol, 130μl), reacted at 0°C for 4h, then reacted overnight at room temperature. Use TCL and LC-MS to detect whether the product is generated, and stop the reaction after confirming that the reaction is complete. The reaction solution was filtered, the solvent was removed in vacuo, 10ml of EA was added to dissolve, and then washed three times with 2% HCl, 5% NaHCO3, 10ml of H2O respectively, and finally the solvent EA was removed in vacuo to obtain the crude product. The resulting crude product was separated on a silica gel column, eluting with three column volumes of CHCl3. The crude product GX-N was obtained, and then separated on a silica...

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Abstract

The invention relates to crocetin amide GX-D and a preparation method thereof, and preparation method includes the following steps: 1) taking crocetin, EDCl (1-ethyl-(3-dimethyl amino propyl) carbonyl diimine hydrochloride), HOBt (1-Hydroxy benzotriazole) into a reaction bottle; under ice bath conditions, adding Et3N and CH2Cl2, then adding an organic amine compound for reacting for 2-8 hours at 0 DEG C, and staying overnight at room temperature; 2) after the reaction is completed, stopping the reaction, filtering reaction liquid, removing the solvent, adding EA for dissolving, washing, and removing the solvent to obtain a coarse product; and 3) separating the coarse product by a silica gel column, and eluting to obtain the product. The crocetin amide derivative GX-D overcomes the problem of low bioavailability caused by very low lipid solubility of crocetin, can be prepared into tablets, sustained-release tablets, granules, suspension agents and other oral preparations for prevention or treatment of cardiovascular and cerebrovascular diseases, and has widespread clinical application.

Description

technical field [0001] The invention relates to a new crocetin derivative, in particular to a pharmaceutically acceptable amide of crocetin, a preparation method thereof, and an application of the derivative in preventing and treating cardiovascular and cerebrovascular diseases. Background technique [0002] Saffron (Crocus sativus L.), also known as saffron, is the dry stigma of Crocus sativus L., a plant of the Iridaceae genus Crocus. Saffron is a kind of precious Chinese herbal medicine. It is widely used clinically in the treatment or prevention of cardiovascular and cerebrovascular diseases, as well as tumor, inflammation, pain suppression and protection of liver, kidney and nervous system, and has significant curative effect. [0003] The main medicinal substances of saffron include crocetin, crocin, dimethyl crocetin, crocin, etc., and also contain eucalyptol, pinene, and multivitamins. Modern studies at home and abroad have shown that crocetin is the main active com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/182C07C233/13A61P9/00A61P9/10
CPCC07C233/13C07D295/182
Inventor 陆文岐姜志宏尚强高进孔祥生张润容
Owner LIVZON PHARM GRP INC
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