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P-nitro aryl methoxycamptothecine anoxic activated prodrug used for antitumor drug

A technology of nitroarylmethoxycamptree and hypoxia-activated prodrugs, which is applied in the field of antitumor drugs, can solve the problems of toxic and side effects, insoluble, unstable plasma metabolism, etc., and achieve low toxic and side effects, high selectivity, Effect of improving water solubility and stability

Active Publication Date: 2014-12-17
济南良福精合医药科技有限公司
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  • 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 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
Later studies showed that the drug was only 10% as effective as natural camptothecin [Giovanella, et al. Cancer Res. 1991; 51: 3052-5]

Method used

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  • P-nitro aryl methoxycamptothecine anoxic activated prodrug used for antitumor drug
  • P-nitro aryl methoxycamptothecine anoxic activated prodrug used for antitumor drug
  • P-nitro aryl methoxycamptothecine anoxic activated prodrug used for antitumor drug

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Experimental program
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Effect test

Embodiment 1

[0063] Embodiment 1. p-nitrobenzyl SN-38 and preparation method thereof

[0064] 1) Chemical name of p-nitrobenzyl SN-38:

[0065] (4S)-4,11-diethyl-4-hydroxy-9-(4-nitrobenzyloxy)-1H-pyrano[3',4':6,7]indoleazino[1 ,2-b] Quinoline-3,14(4H,12H)-dione.

[0066] The chemical structural formula of p-nitrobenzyl SN-38:

[0067]

[0068] 2) The preferred preparation method of p-nitrobenzyl SN-38:

[0069] Dissolve 4.32 g of p-nitrobenzyl bromide and 3.92 g of SN-38 in 10 ml of 1,4-dioxane, add 3.28 g of cesium carbonate at room temperature, raise the temperature to 85°C after the addition, and stir for 5 hours. The system was cooled to room temperature. 200 ml of dichloromethane and 200 ml of water were added, the organic phase was separated, and the aqueous layer was extracted with dichloromethane (200 ml x 3). The organic phases were combined and dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product which was separ...

Embodiment 2

[0074] Example 2. The application effect of nitrobenzyl SN-38 and the comparison with camptothecin derivatives standard drug irinotecan

[0075] 1) Identification of anticancer activity of nitrobenzyl SN-38 and comparative analysis with irinotecan:

[0076] image 3 Shown are the growth curves of subcutaneous colon cancer tumors HCT116 and HT29 in nude mice treated with p-nitrobenzyl SN-38 and irinotecan, and the comparative analysis of tumor growth with the control group.

[0077] 5 × 106 human colon cancer HCT116 and HT29 cells in logarithmic growth phase were subcutaneously injected into the left flank 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, the irinotecan group and the p-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 p-nit...

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Abstract

The invention relates to an p-nitro aryl methoxycamptothecine anoxic activated prodrug used for an antitumor drug, its chemical name is (4S)-4,11-diethyl-4-hydroxy-9-(4-nitro aryl methoxy)-1H-pyrano [3',4': 6, 7]-indolizino[1,2-b) quinoline-3,14(4H,12H)-dione; by using an p-nitro aryl methylated modifier, under the alkaline condition, a reaction is carried out with SN-38 for p-nitro aryl methylation to prepare the p-nitro aryl methoxycamptothecine anoxic activated prodrug used for the antitumor drug-p-nitro aryl methoxy SN-38. The predrug can be used as a main effective component to prepare the antitumor drug, especially for the preparation of antitumor agents for treating colon cancer.

Description

technical field [0001] The invention belongs to the field of antineoplastic drugs, and relates to a novel antineoplastic drug camptothecin hypoxia-activated prodrug—p-nitroarylmethyl SN-38 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. But it has severe side effects such as obvious 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 ring of CPT makes it uns...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61K31/4738A61K31/496A61K31/5377A61P35/00
Inventor 孙学英路国梁李杰齐放高砚芳
Owner 济南良福精合医药科技有限公司
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