A reduction-responsive 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug and its preparation method

A technology of amphiphilic polymers and hydroxycamptothecin, which can be used in drug combinations, pharmaceutical formulations, medical preparations of non-active ingredients, etc., and can solve problems such as inability to release the original drug

Active Publication Date: 2021-09-21
烟台药物研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The present invention aims at the deficiency that the polymer drug formed by linking the hydrophilic polymer with the disulfide bond and the hydrophobic drug disclosed in the prior art cannot release the original drug when the disulfide bond is broken, and provides a reduction-responsive 7-ethyl- Amphiphilic polymer drug prodrug of 10-hydroxycamptothecin and preparation method thereof

Method used

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  • A reduction-responsive 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug and its preparation method
  • A reduction-responsive 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug and its preparation method
  • A reduction-responsive 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug and its preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0040] A reduction-responsive amphiphilic polymer prodrug of 7-ethyl-10-hydroxycamptothecin has a molecular structure as shown below:

[0041]

[0042] Where n is 40-50.

[0043] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0044](1) Preparation of TBDPS-7-ethyl-10-hydroxycamptothecin:

[0045] Add 7-ethyl-10-hydroxycamptothecin (2.0 g, 5.1 mmol) into 100 mL of dichloromethane, add triethylamine (3.2 mL, 23 mmol) and TBDPSCl (5.3 mL, 20.4 mmol), and reflux overnight. After cooling to room temperature, the organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, separated, dried, and concentrated under reduced pressure. The concentrated solution was dropped into a large amount of n-hexane for precipitation, filtered, and vacuum-dried to obtain 3.0 g of a yellow solid with a yield of 93%. product 1 H NMR and MS tests showed that TBDPS-7-ethyl-10-hydroxycamptothecin wit...

Embodiment 2

[0056] A reduction-responsive amphiphilic polymer prodrug of 7-ethyl-10-hydroxycamptothecin has a molecular structure as shown below:

[0057]

[0058] where 400

[0059] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0060] (1) (preparation of TMS-7-ethyl-10-hydroxycamptothecin:

[0061] 7-Ethyl-10-hydroxycamptothecin (2.0 g, 5.1 mmol) was added to 100 mL of dichloromethane, triethylamine (3.2 mL, 23 mmol) and (CH 3 ) 3 SiCl (1.9 mL, 15.3 mmol), reflux overnight. After cooling to room temperature, the organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, separated, dried, and concentrated under reduced pressure. The concentrated solution was dropped into a large amount of n-hexane for precipitation, filtered, and vacuum-dried to obtain 2.19 g of a yellow solid with a yield of 89%.

[0062] (2) (Preparation of TMS-PySS-7-ethyl-10-hydroxycamptothecin:

[006...

Embodiment 3

[0069] A reduction-responsive amphiphilic polymer prodrug of 7-ethyl-10-hydroxycamptothecin has a molecular structure as shown below:

[0070]

[0071] where 500

[0072] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0073] (1) Preparation of TBDPS-7-ethyl-10-hydroxycamptothecin:

[0074] Add 7-ethyl-10-hydroxycamptothecin (2.0 g, 5.1 mmol) into 100 mL of dichloromethane, add triethylamine (3.2 mL, 23 mmol) and TBDPSCl (1.3 mL, 5.1 mmol), and reflux overnight. After cooling to room temperature, the organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, separated, dried, and concentrated under reduced pressure. The concentrated solution was dropped into a large amount of n-hexane for precipitation, filtered, and vacuum-dried to obtain 2.6 g of a yellow solid with a yield of 81%. product 1 H NMR and MS tests showed that TBDPS-7-ethyl-10-hydroxycamptothecin was...

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Abstract

The invention relates to a reduction-responsive polymer prodrug of 7-ethyl-10-hydroxycamptothecin and a preparation method thereof, which has the following molecular structure: wherein, the degree of polymerization n is 5-1000, m is 1 or 2. The drug prodrug provided by the invention can realize targeted drug delivery, not only retains the advantages of the nano-drug loading system, but also takes advantage of the characteristic of specific degradation of disulfide bonds at tumor sites. Compared with conventional linking arms such as 2,2'-dithiodiacetic acid and 3,3'-dithiodipropionic acid, the anticancer drug in the molecular form of the original drug can be obtained without further hydrolysis.

Description

technical field [0001] The invention relates to an amphiphilic polymer drug prodrug and a preparation method thereof, in particular to an amphiphilic polymer drug prodrug of 7-ethyl-10-hydroxycamptothecin and a preparation method thereof. Background technique [0002] Chemotherapy is a basic tumor treatment method, which mainly uses anticancer drugs to kill tumor cells to achieve the purpose of treating tumors. Clinically commonly used anticancer drugs mainly include camptothecins, taxanes, vinblastine, and anthraquinones, etc., but these anticancer drugs have poor physical and chemical properties (such as insoluble in water, poor selectivity, etc.), and are not effective for normal The cells and tissues have serious toxic and side effects, resulting in poor tumor chemotherapy effect, so the clinical application is limited. [0003] 7-Ethyl-10-hydroxycamptothecin (abbreviated as SN-38) is one of the important derivatives of camptothecin drugs. SN-38 is the metabolite of ir...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4745A61K9/107A61K47/14A61P35/00C08G65/334
CPCA61K9/1075A61K31/4745A61K47/14C08G65/3348
Inventor 任春光李亚平孔德旭李泽民栾委静李暖暖李艺张丽谢洪磊李双民
Owner 烟台药物研究所
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