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An m-nitroarylmethoxy camptothecin anoxic activation prodrug for antitumor drugs

A hypoxia-activated prodrug, nitrobenzyloxycamptotheca technology, used in antitumor drugs, drug combinations, organic chemistry, etc., can solve the problems of toxic side effects, unstable plasma metabolism, low bioavailability, etc. High selectivity, improved water solubility and stability, low toxicity and side effects

Active Publication Date: 2015-04-15
济南良福精合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Carboxylesterase transferase is mainly distributed in the small intestine and liver, but its activity is low in tumor tissues and cells, resulting in a low concentration of SN-38 in these tissues, resulting in delayed diarrhea and toxic side effects of bone marrow transplantation. And because the concentration in tumor cells is low, it can't play its anti-tumor effect more effectively
Moreover, SN-38 is poorly soluble in aqueous solution [Allen J, et al. Int. J. Pharm. 2004; 270: 93–107.], has low bioavailability, and is rapidly or unstablely metabolized in plasma [Burke TG & Mi Z., J. Med. Chem. 1993; 36: 2580-2.], limiting the wide application of the drug
For this reason, some inventions have been improved on this problem to increase its bioavailability, such as the synthetic sodium salt of camptothecin water-soluble carboxylic acid, but this form of camptothecin has serious toxicity and not high anticancer activity [Gottlieb, et al. Cancer Chemother Rep 1970;54:461-70; Schaeppi, et al. Cancer Chemother. Rep. 1974: 5: 25-36], resulting in clinical phase II trials having to be interrupted

Method used

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  • An m-nitroarylmethoxy camptothecin anoxic activation prodrug for antitumor drugs
  • An m-nitroarylmethoxy camptothecin anoxic activation prodrug for antitumor drugs
  • An m-nitroarylmethoxy camptothecin anoxic activation prodrug for antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: Example of m-nitrobenzyl SN-38 and its preparation method

[0062] 1) The chemical name of m-nitrobenzyl SN-38 is:

[0063] (4S)-4,11-Diethyl-4-hydroxy-9-(3-nitrobenzyloxy)-1H-pyrano[3',4':6,7]indoleazino[1 ,2-b] quinoline-3,14(4H,12H)-dione;

[0064] The structural formula is:

[0065]

[0066] 2) The preferred preparation method of m-nitrobenzyl SN-38 is as follows:

[0067] Dissolve 2.30 g of m-nitrobenzyl alcohol (3-nitrobenzyl alcohol) and 3.92 g of SN-38 in 40 ml of tetrahydrofuran, add 3.67 g of triphenylphosphine at room temperature, cool to 0°C, and dropwise add 2.78 g of azo After adding diethyl diformate, it was raised to room temperature, and after stirring for 3 hours, 200 ml of dichloromethane and 200 ml of water were added, and the organic phase was separated, and the aqueous layer was extracted 3 times with 200 ml of dichloromethane. The organic phases were combined and dried with anhydrous sodium sulfate, and the solvent was remove...

Embodiment 2

[0072] Example 2. The application effect of m-nitrobenzyl SN-38 and its comparison with the camptothecin derivative standard drug irinotecan

[0073] 1) Identification of anticancer activity of m-nitrobenzyl SN-38 and comparative analysis with irinotecan:

[0074] image 3It shows the growth of subcutaneous lung cancer A549 tumor in nude mice after treatment with m-nitrobenzyl SN-38 and irinotecan, and the comparison analysis with the growth of tumor in the control group.

[0075] 1 × 106 human lung cancer A549 cells in logarithmic growth phase were subcutaneously injected into the back of 6-week-old female Balb / c nude mice. When the tumor grew to 100 mm3 (day 0), the animals were randomly divided into three groups, namely the control group, irinotecan group and m-nitrobenzyl SN-38 group, and were given intraperitoneal injection of normal saline, irinotecan (50mg / kg, sorbitol / lactic acid buffer [45 mg / ml sorbitol / 0.9 mg / ml lactic acid] and m-nitrobenzyl SN-38 (50 mg / kg) eve...

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Abstract

The invention relates to an m-nitroarylmethoxy camptothecin anoxic activation prodrug for tumor resistance, which has a chemical name of (4S)-4,11-diethyl-4-hydroxy-9-(3-nitroarylmethoxy)-1H-pyrano[3',4':6,7]indolezino[1,2-b]quinoline-3,14(4H,12H)-dione. The invention adopts m-nitroarylmethanol as a modifier; an aethrization reaction is carried out with SN-38 under a Mitsunobu reaction condition; the hydroxy is protected; and the m-nitroarylmethoxy camptothecin anoxic activation prodrug with less toxicity is prepared, which is called m-nitroarylmethyl SN-38 for short. The prodrug is used as a main effective component for preparing antitumor drugs, and especially used for preparing antitumor drugs for treating lung cancer.

Description

technical field [0001] The invention belongs to a novel antitumor drug, and relates to an anoxic-activated prodrug of m-nitroarylmethoxycamptothecin (abbreviated as m-nitroarylmethyl SN-38) for lung cancer treatment and a preparation method thereof. Background technique [0002] Campotothecin (CPT) is an alkaloid extracted from the unique Chinese plant camptothecin, which can inhibit DNA topoisomerase I, prevent cancer cell replication and play an anti-cancer role. Topoisomerase I plays an important role in the replication, transcription and recombination of tumor cell DNA. CPT has a good curative effect on malignant tumors such as colorectal cancer, gastric cancer, liver cancer, bladder cancer and leukemia. However, it has severe side effects such as bone marrow suppression, hemorrhagic cystitis, and gastrointestinal reactions including nausea, vomiting, and diarrhea [Fujita K, Sparreboom A. Current Clinical Pharmacology. 2010; 5:2 09-17]. In addition, because the lactone...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61P35/00
Inventor 孙学英冯宗侠高砚芳齐放何银杰
Owner 济南良福精合医药科技有限公司
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