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

A nitroarylmethoxy camptotheca, hypoxia-activated prodrug technology, applied in the field of anti-tumor drugs, can solve the problems of unstable plasma metabolism, toxic side effects, insoluble, etc., and achieves improved water solubility and stability, low Toxic side effects, highly selective effects

Active Publication Date: 2014-12-03
济南良福精合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1. o-nitrobenzyl SN-38 and its preparation method

[0064] 1) The chemical name of o-nitrobenzyl SN-38 is:

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

[0066] The chemical structural formula is:

[0067]

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

[0069] Prepared by reaction of o-nitrobenzyl bromide and SN-38

[0070] Dissolve 4.75 g of o-nitrobenzyl bromide and 3.92 g of SN-38 in 40 ml of N,N-dimethylformamide, add 1.38 g of potassium 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. Add 200 ml of dichloromethane and 200 ml of water, separate the organic phase, and extract the aqueous layer with dichloromethane (50 ml × 3); combine the organic phases and dry them with anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtai...

Embodiment 2

[0076] Example 2. The application effect of o-nitrobenzyl SN-38 and its comparison with the standard drug irinotecan of camptothecin derivatives

[0077] 1) Identification of anticancer activity of o-nitrobenzyl SN-38 and comparative analysis with irinotecan:

[0078] image 3 It shows the growth of subcutaneous liver cancer HepG2 tumor in nude mice after treatment with o-nitrobenzyl SN-38 and irinotecan, and the comparative analysis with the growth of tumor in the control group.

[0079] 1 × 106 human liver cancer HepG2 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 o-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 o-nitro...

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Abstract

The invention relates to an o-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 o-nitro aryl methylated modifier, under the alkaline condition, a reaction is carried out with SN-38 for o-nitro aryl methylation to prepare the o-nitro aryl methoxycamptothecine anoxic activated prodrug used for the antitumor drug-o-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 antitumor drugs, and relates to a novel camptothecin hypoxia-activated prodrug o-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. 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 ring of CPT makes it unstable in aqueous solution, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61P35/00
Inventor 何银杰李杰孙学英齐放高砚芳
Owner 济南良福精合医药科技有限公司
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