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A crocetin derivative gx-e, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases

A technology of GX-E and crocetin, applied in the prevention and treatment of cardiovascular and cerebrovascular diseases, the pharmaceutically acceptable amide of crocetin and its preparation field, which can solve the problem of fat-soluble and water-soluble crocetin To prevent or treat cardiovascular and cerebrovascular diseases, improve bioavailability, and overcome extremely low fat solubility

Active Publication Date: 2018-06-26
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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  • A crocetin derivative gx-e, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases
  • A crocetin derivative gx-e, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases
  • A crocetin derivative gx-e, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Preparation of crocetin derivative GX-E

[0037]

[0038] Take crocetin GX-1 (purchased from Sigma) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg), HOBt (1.25mmol, 169mg) in a 100ml reaction bottle. Under ice bath conditions, Et3N (2.5mmol, 350μl) and CH2Cl220ml were added, and finally diethylamine (1.0mmol, 112μl) was added, and reacted at 0°C for 4h, and then reacted at room temperature overnight. TLC and LC-MS were used to detect whether the product was generated. Stop the reaction, filter the reaction solution, remove the solvent in vacuo, add 10ml of EA to dissolve, wash with 2% HCl, 5% NaHCO3, and 10ml of H2O three times respectively, and remove the solvent in vacuo to obtain a crude product. The crude product GX-E was separated with a silica gel column, firstly eluted with 4-5 column volumes of CHCl3, and then increased the polarity of the eluent CHCl3:CH3OH=10:1 for elution. GX-E was obtained, and its structure was characterized by NMR. Yellow powd...

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 conditions, Et3N (2.5mmol, 350μl) and CH2Cl220ml were added, and finally 4-fluorobenzylamine (1.1mmol, 125μl) was added, reacted at 0°C for 4h, and 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...

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 conditions, Et3N (2.5mmol, 350μl) and CH2Cl220ml were added, and finally 3,5-difluorobenzylamine (1.1mmol, 130μl) was added, reacted at 0°C for 4h, and 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 separat...

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Abstract

The invention relates to a crocetin amide GX-E, a preparing method thereof. The method includes 1) weighing crocetin, EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and HOBt (1-hydroxybenzotriazole) into a reaction flask, adding Et<3>N and CH2Cl<2> under an ice bath condition, adding an organic amine compound, reacting at 0 DEG C for 2-8 h, and staying overnight at room temperature, 2) after the reaction is finished, stopping the reaction, filtering the reaction liquid to remove a solvent, adding EA, dissolving, washing, and removing the solvent to obtain a crude product, and 3) subjecting the crude product to separation and elution with a silica gel column to obtain a product. The crocetin amide derivative GX-B overcomes a problem that bioavailability is low due to extremely low lipid solution of the crocetin, can be prepared into tablets, sustained-release tablets, granules, suspension, and other oral preparations for preventing or treating cardiovascular and cerebrovascular diseases, and is wide in 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 Patents(China)
IPC IPC(8): C07C233/09C07C233/13C07C231/02A61P9/00A61P9/10
CPCC07C231/02C07C233/09C07C233/13
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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