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Quick release type medicine phosphatide compound and medicine composition thereof

A phospholipid compound and compound technology, applied in the field of medicine, can solve the problems of decreased liposome stability, decreased drug efficacy, difficulty in obtaining a sufficiently high prototype drug concentration, etc.

Inactive Publication Date: 2016-04-06
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The downside is that phospholipid prodrug molecules usually release the drug with substituents by breaking the chemical bond between the drug and the phospholipid, which then slowly releases the prototype drug
Due to the slow release rate of the prototype drug from the prodrug molecule, it is difficult to obtain a high enough concentration of the prototype drug at the target site, resulting in a decrease in drug efficacy
On the other hand, the prodrug formed by covalently bonding the drug molecule into the phospholipid molecular structure is assembled into a liposome. Due to the destruction of the symmetry and regularity of the hydrophobic chain in the phospholipid molecule or the change of the hydrophilic head structure, the lipid Decreased stability of plastids affects the effective release of prototype drugs

Method used

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  • Quick release type medicine phosphatide compound and medicine composition thereof
  • Quick release type medicine phosphatide compound and medicine composition thereof
  • Quick release type medicine phosphatide compound and medicine composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Synthesis of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine (see the synthetic route figure 1 )

[0142] Dissolve 1 g of camptothecin in 100 mL of chloroform, add 1.0 g of triethylamine, 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, and add dithio 0.6 g of diethylene glycol succinic acid monoester was reacted at room temperature for 24 hours, and the resulting reaction liquid was purified by column chromatography to obtain 0.65 g of camptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester. Dissolve 0.6g of the intermediate camptothecin carbonate-dithiodiethylene glycol-succinic acid monoester in 20mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.3g of GPC and 0.6g of DBU, react at room temperature for 24h, and the obtained reaction The solution was purified by column chromatography to obtain 0.35...

Embodiment 2

[0146] Synthesis of bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine (route see figure 2 )

[0147] Dissolve 1.0 g of paclitaxel in 30 mL of chloroform, add 0.5 mL of triethylamine, add 0.6 g of tert-butyldimethylsilyl chloride (TBDMSCl), react at 0°C for 3 h, add glacial ether, precipitate a white precipitate, and centrifuge. Further separation by column chromatography (eluent, chloroform / methanol: 7 / 1, v / v) obtained 0.82 g of paclitaxel 2'-blocked product 2'-tert-butyldimethylsilyloxy-paclitaxel, as White powdery solid.

[0148] Dissolve 0.5 g of 2'-tert-butyldimethylsilyloxy-paclitaxel in 50 mL of chloroform, add 0.5 g of triethylamine and 0.2 g of triphosgene, react at room temperature for 6 h, and remove the solvent by rotary evaporation; dissolve the solid in 10 mL of DMSO , add 0.3g of triethylamine, add 0.3g of dithiodiethylene glycol adipate monoester, react at room temperature for 24h, and the resulting reaction solution is purified ...

Embodiment 3

[0152] Synthesis of bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine (see the synthetic route image 3 )

[0153] The gemcitabine derivative 3'-O-BOC-5'-O-BOC-gemcitabine protected by tert-butoxycarbonyl (BOC) was synthesized according to the method in the literature (J.Org.Chem.1999, 64, 8319-8322).

[0154] Dissolve 1 g of 3′-O-BOC-5′-O-BOC-gemcitabine in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, and remove the solvent by rotary evaporation; dissolve the solid in 10 mL of DMSO , add 0.3 g of triethylamine, add 0.6 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and purify the resulting reaction solution by column chromatography to obtain 3'-O-BOC-5'-O-BOC - Gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinic acid monoester 0.72g; intermediate 3'-O-BOC-5'-O-BOC-gemcitabine-4-N-amino Dissolve 0.6g of formate-dithiodiethy...

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Abstract

The invention discloses a quick release type medicine phosphatide compound and a medicine composition thereof. In the compound, a medicine Y1 and a medicine Y2 are connected with a quick release type hydrophobic spacer arm and an enhancement type hydrophobic spacer arm through chemical bonds, the two spacer arms are cooperated to enhance the hydrophobic effect to form hydrophobic lipotropy chains, the two hydrophobic chains are connected with a phospholipid hydrophilic head to form an amphipathic molecule. The medicine composition is the quick release type medicine phosphatide compound or a combined medicine composition of the compound and a carrier acceptable in pharmacodynamics. The quick release type medicine phosphatide compound and lipidosome nano particles thereof can be used as a liquid preparation, a solid preparation, a semi-solid preparation, a sterilization preparation and a sterile preparation, are low in toxicity and can be used for efficiently treating various tumor diseases.

Description

technical field [0001] The invention relates to a quick-release drug phospholipid compound with anti-tumor and other disease-treating effects, its pharmaceutical composition and application, and relates to the technical field of medicine. Background technique [0002] Many small-molecule chemical drugs are difficult to penetrate cell membranes because of their strong hydrophobicity, strong hydrophilicity, and poor lipophilicity, resulting in poor efficacy in treating diseases. [0003] Some plant-derived drugs with strong physiological activities are strongly hydrophobic, making administration difficult and their applications limited. Camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) are alkaloids extracted from the seeds or root bark of Camptothecin, a deciduous plant of the Davidiaceae family, and have strong cytotoxic activity. Camptothecin compounds form a stable triplet complex of camptothecin-topoisomerase I-DNA, so that the DNA double helix structure cannot be rep...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/4745A61K31/704A61K31/7068A61K31/337A61K31/69A61K38/05A61K33/24A61K31/192A61K31/4406A61K31/7048A61K31/55A61K31/365A61P35/00
CPCA61K31/4745A61K31/192A61K31/337A61K31/365A61K31/4406A61K31/55A61K31/69A61K31/704A61K31/7048A61K31/7068A61K33/24A61K38/05
Inventor 李新松杜亚伟凌龙兵何瑞玉
Owner SOUTHEAST UNIV
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