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Carfilzomib prodrug and preparation method thereof

A technology of carfilzomib and prodrug, which is applied in the field of carfilzomib prodrug and its preparation, can solve the problems of increased toxic and side effects, poor water solubility, and difficulty in preparation, and achieve reduced toxic and side effects, enhanced stability, and improved water solubility. sexual effect

Active Publication Date: 2016-09-07
LIANGJIANG MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, due to its poor water solubility, it is difficult to prepare a composition with a high enough concentration to produce the required pharmacological effects. Currently, the substituted cyclodextrin inclusion technology is used, which requires the addition of a large amount of cyclodextrin. The preparation process needs to be in weak acidity. environment, it is easy to produce new impurities in the preparation process, which will inevitably increase the toxicity and side effects and affect its clinical application

Method used

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  • Carfilzomib prodrug and preparation method thereof
  • Carfilzomib prodrug and preparation method thereof
  • Carfilzomib prodrug and preparation method thereof

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preparation example Construction

[0033] The present invention also provides the preparation method of the above-mentioned carfilzomib prodrug, comprising:

[0034] A) carrying out amino protection of L-leucine;

[0035] B) reacting amino-protected L-leucine with polyethylene glycol, and then deprotecting to obtain L-leucine polyethylene glycol compound;

[0036] C) reacting the L-leucine polyethylene glycol compound obtained in step B) with carfilzomib in the presence of titanium tetrachloride to obtain the carfilzomib prodrug shown in formula (I) .

[0037] Described reaction scheme is as follows:

[0038]

[0039] Firstly, the amino group of L-leucine was protected with di-tert-butyl dicarbonate (BOC).

[0040] Specifically, L-leucine is dissolved in 1,4-dioxane, a saturated aqueous solution of sodium hydroxide is added into an ice bath, and stirred, and the stirring time is preferably 20-40 minutes; then, BOC is added dropwise for reaction. The 1,4-dioxane can be dissolved in the amount of L-leucine...

Embodiment 1

[0059] Add 100g of L-leucine to 500g of 1,4-dioxane, add a saturated aqueous solution of sodium hydroxide (2eq) in an ice bath, stir for 30min, and add BOC dropwise 2 O (1.5eq), monitor the reaction of raw materials, concentrate, add water to dilute after concentration, adjust PH=3 with 1M HCl, precipitate solid, add water to acetone for recrystallization, and obtain 770.0 g of amino-protected L-leucine (monohydrate) , yield 81%, purity 99.2%.

[0060] Add 200g of amino-protected L-leucine to the reaction flask, add 500g of DCM to dissolve, react in ice bath, add DCC (1.2eq), DMAP (1.2eq), stir for 1h, add 500g of PEG400, naturally rise to room temperature for 10h After the reaction, 500 g of DCM was added, washed with water, dried and concentrated, and 350 g of oil was obtained by column chromatography.

[0061] Then add 350g of the oily substance to the reaction flask, add 500g of DCM and stir to dissolve, add 1500g of TFA dropwise in an ice bath, concentrate after the reac...

Embodiment 2

[0069] Solubility assay

[0070] Carfilzomib and the carfilzomib prodrug prepared in Example 1 were dissolved in water respectively to prepare a supersaturated solution, and the solubility of the HPLC detector was used. The results are shown in Table 2, and Table 2 is prepared in Example 1 of the present application. Comparison of water solubility of carfilzomib prodrug and carfilzomib.

[0071] Table 2 Carfilzomib prodrug prepared in Example 1 of the present application and carfilzomib water solubility comparison

[0072] Different pH water solubility mg / ml

[0073] As can be seen from Table 2, the solubility of the carfilzomib prodrug prepared in the present invention is significantly increased in water.

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Abstract

The invention provides a carfilzomib prodrug with a structural formula (I). The invention uses a short-chain PEG molecule as a hydrophilic end, and carfilzomib as a hydrophobic end; and the two parts are connected by L-leucine in the form of imine, so as to prepare a novel carfilzomib prodrug. The carfilzomib prodrug improves the water solubility, is easy for preparation into high-concentration solution, and can be produced into a finished product with enhanced stability by freeze-drying. At the same time, the carfilzomib prodrug is a compound sensitive to acid, maintains stability in blood (alkaline) circulation, and can quickly release carfilzomib drug once arriving in the tumor tissue (acidic), in order to achieve targeted drug delivery, enhance curative effect of chemotherapy and reduce side effects.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a carfilzomib prodrug and a preparation method thereof. Background technique [0002] Carfilzomib is an intravenously administered tetrapeptide epoxyketone skeleton proteasome inhibitor for the treatment of recurrent multiple It was approved for marketing by the US Food and Drug Administration (FDA) on July 20, 2012. [0003] However, due to its poor water solubility, it is difficult to prepare a composition with a high enough concentration to produce the required pharmacological effects. Currently, the substituted cyclodextrin inclusion technology is used, which requires the addition of a large amount of cyclodextrin, and the preparation process needs to be in weak acidity. It is easy to produce new impurities during the preparation process of the preparation, which will inevitably increase the toxic and side effects and affect its clinical application. Co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06
Inventor 黄祥黄诗贵余灏贺耘
Owner LIANGJIANG MEDICINE CO LTD
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