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Water-soluble polymer derivative of Venotog

A technology of water-soluble polymers and drugs, which is applied in the field of drugs for the treatment or alleviation of cancer, can solve the problems of unapproved, increased toxicity, and inability to improve the therapeutic effect of irinotecan, and achieve excellent balance and reduce the burden.

Active Publication Date: 2021-07-23
DELTA FLY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, the toxicity increased, the therapeutic effect of the existing drug irinotecan could not be improved, and it was not approved as a new drug

Method used

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  • Water-soluble polymer derivative of Venotog
  • Water-soluble polymer derivative of Venotog
  • Water-soluble polymer derivative of Venotog

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] [Example 1] Synthesis and analysis of compounds of formula (II)

[0089] Under a nitrogen atmosphere, CTPEG (4.530 g, 1 equivalent) was added to 55 mL of a DMF solvent, and heated at 50° C. to dissolve uniformly. Add N,N-diisopropylethylamine (hereinafter referred to as "DIC") (0.296 g, 20 equivalents), 1-hydroxybenzotriazole (hereinafter referred to as "HOBT") (0.258 g , 6 equivalents) and venetoclax (0.474 g, 4.8 equivalents). After continuing to stir at 60°C for 6 hours, cool to 40°C, then dropwise add methyl tetrabutyl ether (hereinafter referred to as "MTBE") heated to 30°C over 20 minutes while stirring, and then cool over 60 minutes , after stirring for 30 minutes, the resulting crystals were filtered and collected, washed with 20 mL of MTBE, and the obtained crystals were dissolved in 20 mL of absolute ethanol heated to 40° C., and 70 mL of MTBE was added dropwise over 20 minutes, and after 60 Minutes cooled to 0 ° C, stirred for 30 minutes, the resulting prec...

Embodiment 2

[0090] [Example 2] Cell killing effect of the compound of formula (I) and the compound of formula (II)

[0091] The concentration dependence of the cell killing effect of the compound of formula (I) and the compound of formula (II) was investigated in the following manner.

[0092] Using MV4-11 of the human acute myeloid leukemia cell line, study the respective IC of the compound of formula (I) and the compound of formula (II) 50 (50% inhibition rate) (see image 3 (1)). As a result, the IC of the compound of formula (I) 50 (50% inhibition rate) is 0.16pM, the IC of the compound of formula (II) 50 It was 0.85 pM, and both compounds were confirmed to have high inhibitory rates. Among them, the protein binding rate of the compound of formula (I) is high (≥99.9%), so a medium with low serum content (Opti-MEM) is used.

[0093] Using PANC-1 of a human pancreatic cancer cell line, the ICs of the compound of formula (I) and the compound of formula (II) were studied 50 (50% inh...

Embodiment 3

[0095] [Example 3] Cell killing effect of compound of formula (II) and protease activity of cancer cells

[0096] The protease activity measurement results of U937 (human histiocytic lymphoma cell line), MV4-11 (human acute myeloid leukemia cell line), PANC-1 (human pancreatic cancer cell line) and A549 (human lung cancer cell line) are shown At Figure 4 . Protease activity using AAT Bioquest's "Amplite TM Universal Fluorimetric Protease Activity Assay Kit*Green Fluorescence*” was measured, and the fluorescent intensity obtained was corrected by the amount of protein measured by Bio-Rad’s “DC ProteinAssay”. As a result, the formula measured in the above-mentioned embodiment 2 ( II) The compound confirms the correlation between the 50% inhibitory concentration of MV4-11, PANC-1 and A549, and the protease activity of cancer cell lines. That is, it is confirmed that the protease activity of cancer cells is higher, based on the formula (II ) the higher the inhibition rate of ...

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Abstract

The purpose of the present invention is to provide a novel means for administering Vinotog which is capable of reducing the burden on a patient due to administration and has an excellent balance between effect and safety, and to provide a water-soluble polymer derivative comprising a plurality of Vinotog, and to provide a novel means for administering Vinotog to a patient due to administration of Vinotog, and to provide a water-soluble polymer derivative comprising a plurality of Vinotog, and to provide a novel means for administering Vinotog to a patient due to administration of Vinotog. And the plurality of Venotocorks are respectively bonded to terminal carboxyl groups of the multi-arm water-soluble polymer through amido bonds.

Description

technical field [0001] The present invention relates to a drug or method for treating or relieving cancer, which uses a water-soluble polymer derivative formed by bonding venetoclax to the end of a multi-armed water-soluble polymer as an active ingredient. Background technique [0002] Venetoclax has the effect of selectively binding and inhibiting Bcl-2. In many cancers, overexpression of Bcl-2 is observed, thereby preventing the natural death, self-destruction (apoptosis) process of cancer cells. Venetoclax has the effect of inhibiting the Bcl-2 and restoring the apoptosis process of cancer cells. Venetoclax has been clinically used as a therapeutic drug for relapsed and refractory chronic lymphocytic leukemia and first-time acute myelogenous leukemia not suitable for intensive chemotherapy. On the other hand, venetoclax has a high binding rate to human proteins (99.9% or more), and also has a low oral absorption rate, so a single oral administration is too large, and it...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61K47/60A61P35/00A61P35/02C08G65/334
CPCA61K31/496A61K47/60A61K9/0019A61P35/02A61P35/00C08G65/3348A61K31/635A61K9/10A61K9/08A61K47/38A61K47/02
Inventor 江岛清石田龙弘
Owner DELTA FLY PHARMA
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