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Pegylated lapatinib and its injection and preparation method

A technology of PEGylation and lapatinib, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of undiscovered products and achieve high yield, The effect of mild reaction conditions and simple operation

Active Publication Date: 2018-05-01
CHONGQING UPGRA BIOLOGICAL SCI & TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the polymer coupling technology reports and products for lapatinib, which is both an anticancer drug and an anticancer stem cell drug, have not yet been found

Method used

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  • Pegylated lapatinib and its injection and preparation method
  • Pegylated lapatinib and its injection and preparation method
  • Pegylated lapatinib and its injection and preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] synthesis Methods:

[0059] 1. Preparation

[0060] Glycine (19.1274g, 254.7943mmol) was dissolved in 1,4-dioxane (200mL), 2N NaOH solution (80uL, 160mmol) was added, and after the temperature of the solution dropped to room temperature, Boc 2 O (77.8524g, 356.7120mmol), reacted at room temperature for 12 hours, concentrated by evaporation, and finally washed with ethyl acetate (150mL×2), adjusted the pH value to 4 with hydrochloric acid, and then washed with ethyl acetate (150mL×5) After extraction, the organic phases were combined and dried with anhydrous sodium sulfate. The filtrate was concentrated and dried to obtain 44.6 g of the product with a yield of 100%.

[0061] 2. Preparation

[0062] Add P1 (90.4mg, 0.5163mmol), lapatinib (300g, 0.5163mmol), HBTU (290.6mg, 0.7745mmol) and HOBT (104.6mg, 107745mmol) in a 50mL flask, dissolve with DMF (15mL), The solution was cooled in a cryostat reaction bath at 0 °C for 20 minutes, then DIEA (0.41 mL, 2.3234 mmol)...

Embodiment 2

[0068] synthesis Methods:

[0069] Add P3 (9.6mg, 0.015mmol) and single-arm polyethylene glycol M-SC-20K (200mg, 0.01mmol) with a molecular weight of 20,000 in a cylindrical bottle, dissolve with dichloromethane (5mL), and stir at room temperature for one week , to stop the reaction, the mixture was spin-dried, and the product was dissolved in water and placed in a dialysis bag for dialysis. The aqueous solution of the product was then concentrated under reduced pressure, dried in vacuo, dissolved in dichloromethane, precipitated by adding anhydrous ether while stirring, filtered, and dried in vacuo to obtain 182.6 mg of the product, with a yield of 89.0%.

Embodiment 3

[0071] synthesis Methods:

[0072] Add P3 (9.6mg, 0.015mmol) and single-armed polyethylene glycol M-SC-40K (200mg, 0.01mmol) with a molecular weight of 40,000 in a cylindrical bottle, dissolve with dichloromethane (8mL), and stir at room temperature After one week, the reaction was stopped, the mixture was spin-dried, and the product was dissolved in water and placed in a dialysis bag for dialysis. Then the aqueous solution of the product was concentrated under reduced pressure, dried in vacuo, dissolved in dichloromethane, precipitated by adding anhydrous ether while stirring, filtered, and dried in vacuo to obtain 168.4 mg of the product, with a yield of 83.1%.

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Abstract

The present invention provides a pegylated lapatinib, an injection and a preparation method thereof, wherein the general formula of the pegylated lapatinib is defined in the specification, A is selected from a single-arm or multi-arm polyethylene glycol or poly ethylene glycol derivative, X is selected from the formula defined in the specification, Y and M are independently and respectively selected from double carboxylic acids having amino or corresponding acyl substituents, N is selected from an amino acid or peptide, LPT is lapatinib, a is 0 or 1, b is 0 or 1, c is 1 or 2, d is 1 or 2, and e is equal to the arm number of X. According to the present invention, the pegylated drug of lapatinib is synthesized, such that the lapatinib toxicity is reduced, the water solubility and the biological stability are improved, the drug resistance of cancer cells and cancer stem cells are avoided, the targeting property is enhanced, and the anticancer treatment effect is significantly improved.

Description

technical field [0001] The invention relates to the field of lapatinib conjugates, in particular to pegylated lapatinib and its injection and preparation method. Background technique [0002] Lapatinib is an oral small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, mainly used in combination with capecitabine to treat ErbB-2 overexpression, and those who have previously received anthracyclines, Advanced or metastatic breast cancer treated with paclitaxel or trastuzumab was approved to enter the market by the US FDA in 2007. Lapatinib can inhibit cancer stem cells, such as U87-MG brain cancer stem cells and SUM225 breast cancer stem cells. [0003] The molecular weight of lapatinib is 581.06, which is a small molecule anticancer drug. It has the disadvantages of poor water solubility, poor biological stability, and large toxic and side effects, and the small molecule lapatinib diffuses into cancer cells or cancer stem cells and will be destroyed by p -...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/333A61K47/60A61K31/517A61K9/08A61P35/00
Inventor 李高全张翠芳谢爱云陈毛芬
Owner CHONGQING UPGRA BIOLOGICAL SCI & TECH LTD
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