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

A technology of crocus acid and crocus, applied in the field of new crocus acid derivatives, can solve the problems of poor fat solubility and water solubility of crocus acid, limited clinical application, low bioavailability, etc. Or treat cardiovascular and cerebrovascular diseases, improve bioavailability, and overcome the effects of extremely low fat solubility

Active Publication Date: 2018-06-29
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-ring, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases
  • A crocetin derivative gx-ring, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases
  • A crocetin derivative gx-ring, 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 prepares crocetin derivative GX-Ring

[0037]

[0038] Take GX-1 (purchased from Sigma) (0.25mmol, 80mg) in a 100ml reaction bottle. Add 220ml of CH2Cl, add oxalyl chloride (0.1mmol, 100μl) and 1-2 drops of DMF under ice-bath conditions, and stir at room temperature for 4h. When the color of the solution is dark red and basically clear, add ethylenediamine (0.25mmol) and triethylamine (2.0mmol,) to react, react at room temperature overnight, add 100μl H2O and stir the reaction for 5 hours to stop the reaction, use TLC and LC- MS detects whether the product is formed. The reaction solution was filtered, the solvent was removed in vacuo, and 20ml of EA was added to dissolve it, followed by washing with 2% HCl, 5% NaHCO3, and 20ml of H2O three times respectively, and the solvent was removed in vacuo to obtain a crude product. The GX-Ring is separated with a silica gel column, first eluted with 2-3 column volumes of CHCl3, and then the polarity of the elue...

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 present invention relates to a crocetin derivative GX-Ring and a preparation method thereof. The preparation method comprises the following steps of A, adding crocetin and CH2Cl2 in a reaction bottle, adding oxalyl chloride and DMF under the condition of an ice bath, stirring at the room temperature, subjecting an obtained mixture to reaction for 4 to 6 hours, continuously adding amide for further reaction, placing an obtained product overnight at the room temperature, adding H2O and stirring for reaction; B, filtering an obtained reaction liquid to remove a solvent, adding EA to dissolve a solute, washing and removing the solvent to obtain a crude product; C, separating the crude product through a silicagel column, and eluting to obtain a product. The above crocetin derivative GX-Ring can be prepared into tablets, sustained release tablets, granules, suspensions and other oral preparations for preventing or treating cardiovascular and cerebrovascular diseases. The clinical application of the crocetin derivative GX-Ring is wider in range.

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): C07C231/02C07C235/76A61P9/00A61P9/10
CPCC07C231/02C07C235/76
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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