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

A cardiovascular and cerebrovascular disease, GX-B technology, applied in the direction of cardiovascular system diseases, drug combination, organic chemistry, etc., can solve the problem of poor fat solubility and water solubility of crocetin, clinical application limitations, high drug concentration and dosage To prevent or treat cardiovascular and cerebrovascular diseases, overcome low bioavailability, and improve bioavailability

Active Publication Date: 2018-05-22
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-b, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases
  • A crocetin derivative gx-b, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases
  • A crocetin derivative gx-b, its preparation method, and its application in preventing or treating cardiovascular and cerebrovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1 prepares crocetin derivative GX-B

[0041]

[0042] Separately take crocetin GX-1 (purchased from Sigma) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg), HOBt (1.25mmol, 169mg) in 25ml reaction vials. In an ice bath, add Et 3 N (1.25mmol, 172μl) and CH 2 Cl 2 10ml, finally added morpholine (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 Each 10ml of O was washed 3 times, and finally the solvent EA was removed in vacuo to obtain the crude product. The obtained crude product was separated by a silica gel column, and three column volumes of CHCl 3 Perform elution. The product GX-B was finally obtained, and its structure was characterized by NMR. Yellow powder, yield...

Embodiment 2

[0043] Embodiment 2: Preparation of crocetin derivative GX-M:

[0044]

[0045] 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

[0046] Embodiment 3: Preparation of crocetin derivative GX-N:

[0047]

[0048]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 a crocetin acidamide GX-B and a preparation method thereof. The preparation method of crocetin GX-B comprises the following steps of (1) taking crocetin GX-1.EDC1(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), and HOBt ( 1-Hydroxy Benzotriazole) in a reaction bottle, under the condition of an ice bath, adding Et3N, then adding an organic amines compound, performing a reaction at 0 DEG C for 2-8 hours, and enabling standing overnight; (2) after the reaction is thorough, stopping the reaction, filtering reaction liquid for removing a solvent, adding EA for dissolving, and performing washing, wherein after the solvent is removed, coarse products are obtained; and (3) separating the coarse products with a silicagel column, and performing eluting so as to products. The crocetin acidamide derivatives GX-B disclosed by the invention solves the problem that the bleeding diathesis of the crocetin is low, so that the bioavailability is low, can be prepared into oral preparations of tablets, slow-release tablets, granules, a suspension and the like, and is clinically and widely applied for preventing and treating the cardiovascular and cerebrovascular diseases.

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): C07D295/185A61K31/5377A61P9/00A61P9/10
CPCC07D295/185
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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