Polyethylene glycol-modified phospholipid derivative taking anilino-quinazoline as targeting ligand and preparation method thereof

A technology of anilinoquinazoline and anilinoquinazoline group, applied in polyethylene glycol modified phospholipid derivatives, the application field of new materials in anti-tumor drug preparations, to improve the effect of tumor treatment and drug efficacy , reduce the effect of toxic and side effects

Inactive Publication Date: 2012-08-29
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Although there are many studies on the tumor targeting effect of liposomes, and a variety of tumor-targeting drug liposomes have been designed, so far, no researchers have tried to use small molecule drugs with high specificity for tumors or their Tumor targeting of liposomes using fragments as targeting ligands for liposomes

Method used

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  • Polyethylene glycol-modified phospholipid derivative taking anilino-quinazoline as targeting ligand and preparation method thereof
  • Polyethylene glycol-modified phospholipid derivative taking anilino-quinazoline as targeting ligand and preparation method thereof
  • Polyethylene glycol-modified phospholipid derivative taking anilino-quinazoline as targeting ligand and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of polyethylene glycol 2000 bis-p-toluenesulfonate (TsO-PEG-TsO)

[0050] 1g HO-PEG 2000 -OH was dissolved in 20 mL of dichloromethane, then 0.35 g of triethylamine and 0.76 g of p-toluenesulfonyl chloride were added and stirred at room temperature for 10 hours. Using dichloromethane / ether (1:5) to recrystallize, the final TsO-PEG 2000 -TsO 0.89g, the yield is 90%.

[0051] 1 H-NMR (500MHZ, CDCl 3 )δ(ppm):2.47(s,6H,Ar-CH 3 ), 3.59 (m, multi H, back bone–OCH 2 CH 2 O-),4.19(t,4H,-CH 2 OTs),7.28(d,4H,J=7.9Hz,Ar-H),7.76(d,4H,J=7.9Hz,Ar-H).IR(KBr,cm -1 ):2885,1592,1463,1358,1266,1245

Embodiment 2

[0053] Preparation of polyethylene glycol 2000 bisphthalimide (phthalimide-PEG2000-phthalimide)

[0054] The TsO-PEG obtained in the previous step reaction 2000 - Dissolve TsO (0.7g) in 8mL DMF, add 0.65g phthaloyl potassium salt, reflux for 6h to stop the reaction, concentrate under reduced pressure to obtain light yellow oil, add 10mL dichloromethane, filter out insoluble matter, and the filtrate The crude product obtained by concentrating under reduced pressure was recrystallized with dichloromethane / diethyl ether (1:6) to obtain 0.55 g of the final product with a yield of 85%.

[0055] 1 H-NMR (500MHZ, CDCl 3 )δ (ppm): 3.61 (m, multi H, back bone–OCH 2 CH 2 O-),7.65-7.88(m,8H,Ar-H).IR(KBr,cm -1 ):2882,1715,1463,1356,1261.

Embodiment 3

[0057] Polyethylene glycol 2000 diethylamine (H 2 N-PEG 2000 -NH 2 ) preparation

[0058] The phthalimide-PEG obtained in the previous step reaction 2000 - phthalimide (0.6g) was dissolved in 10mL of absolute ethanol, 1.5mL of hydrazine hydrate was added, and the reaction was refluxed for 3h. Concentration under reduced pressure gave a yellow oil, which was recrystallized from dichloromethane / diethyl ether (1:10) to give 0.52 g of the final product, with a yield of 94%.

[0059] 1 H-NMR (500MHZ, CDCl 3 )δ(ppm):2.92(m,4H,-CH 2 NH 2 ),3.65(m,multi H,back bone–OCH 2 CH 2 O-).IR(KBr,cm -1 ): 3356, 2879, 1465, 1357, 1266.

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Abstract

The invention provides a polyethylene glycol-modified phospholipid derivative taking a 4-substituted anilino-quinazoline group as a targeting ligand and a preparation method thereof. The method comprises the following steps of: performing condensation with para-methylbenzene sulfonyl chloride, substitution with phthalimide potassium salt and hydrolysis with a hydrazine hydrate by taking polyethylene glycol (PEG) as a starting raw material to obtain diamine PEG; and reacting with targeting ligands, i.e., N-(3-chlorin-4-fluorin)-6-(3-chloropropyl)-7-methoxylquinazoline-4-amine and distearoylphosphatidylethanolamine (DSPE) to respectively obtain 4-anilino-quinazoline group-PEG-DSPE. A liposome preparation of the 4-anilino-quinazoline group-PEG-DSPE can be used for realizing target administration of tumor cells and reducing the toxic and side effects of a tumor medicament; and the pharmacodynamic structure of gefitinib can give play to dual medicament effects together with other liposome-coated antitumor medicaments, so that the tumor treatment effect is enhanced greatly.

Description

technical field [0001] The invention relates to the field of pharmaceutical polymer excipients and medicaments, in particular to a class of polyethylene glycol-modified phospholipid derivatives with 4-substituted anilinoquinazoline groups as targeting ligands, and also relates to the use of such novel materials in Application in antineoplastic drug preparations. Background technique [0002] Liposome is a molecular orderly assembly spontaneously formed by phospholipids in water by means of hydrophobic association. The water phase and the oil phase between the bimolecular membranes. Its properties are similar to cell membranes, so it has good biocompatibility. However, when liposomes enter the blood circulation system, they are easily recognized by the reticulo-endothelial system (RES) and quickly leave the blood stream. Therefore, "long circulation" is the basic property that liposome must possess as a drug delivery system. A large number of studies have shown that chemi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/34A61K9/127A61P35/00
Inventor 蔡进吉民
Owner SOUTHEAST UNIV
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