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Low-oxygen activated joint chloroethane nitrourea compound and preparation method and application

A compound and composition technology, applied in the field of pharmacy, can solve the problems of non-targeting, increased toxicity and side effects of chemotherapy drugs, and enhanced damage to normal cells, etc.

Active Publication Date: 2016-04-20
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the study found that due to O 6 - The inhibition of AGT by benzylguanine is not targeted, and in combination with alkylating agents, O 6 - Benzylguanine inhibits the AGT activity in tumor cells, but also acts on normal cells, resulting in the inhibition of AGT activity in normal cells, thereby destroying the normal cell's DNA damage repair mechanism and increasing the DNA damage of normal cells , leading to increased toxic and side effects of chemotherapy drugs
[0006] In summary, the drug resistance of CENUs in clinical application is an important factor limiting its further development and application.
Although the sensitivity of tumor cells to CENUs can be improved by inhibiting the activity of AGT, due to the non-targeting of existing AGT inhibitors, the damage effect of CENUs on normal cells is enhanced, thereby reducing the chemotherapy effect of CENUs

Method used

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  • Low-oxygen activated joint chloroethane nitrourea compound and preparation method and application
  • Low-oxygen activated joint chloroethane nitrourea compound and preparation method and application
  • Low-oxygen activated joint chloroethane nitrourea compound and preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: N-(2-chloroethyl)-N'-3-(O 6 -Benzyl-N 2 -Synthesis of (((4-nitrobenzyl)oxy)carbonyl)9-guanyl)ethyl-N-nitrosourea (compound 1)

[0062] 1) N9-Bromoethyl-O 6 -Synthesis of benzylguanine

[0063] Weigh O 6 -Benzylguanine (0.96g, 4mmol), anhydrous potassium carbonate (1.66g, 12mmol) were added to a three-necked flask, 100mL of acetone was added, the temperature was slowly raised to 50°C, and 1,2-dibromoethane (1.4 mL, 16mmol), continue to react for 60h after dripping, filter the reaction solution, collect the filtrate, distill the solvent under reduced pressure at 40°C and spin dry the solvent, then use silica gel column chromatography to separate and purify, the eluent is petroleum ether and ethyl acetate, using Gradient elution, the volume ratio of petroleum ether / ethyl acetate gradually increased from 1:2 to 1:4, and vacuum drying at 40°C gave white solid N9-bromoethyl-O 6 - Benzylguanine (1.11 g, 3.2 mmol), 80% yield.

[0064] UV lambda: 250, 283nm. ...

Embodiment 2

[0080] Embodiment 2: N-(2-chloroethyl)-N'-3-(O 6 -Benzyl-N 2 -Synthesis of (((4-nitrobenzyl)oxy)carbonyl)9-guaninyl)propyl-N-nitrosourea (Compound 2)

[0081] 1) N9-bromopropyl-O 6 -Synthesis of benzylguanine

[0082] Weigh O 6- Benzylguanine (1.44g, 6mmol), anhydrous potassium carbonate (3.32g, 24mmol) were added to a three-necked flask, 150mL of acetone was added, the temperature was slowly raised to 55°C, and 1,3 dibromopropane (3.03mL, 30mmol), continue to react for 65h after dropping, filter the reaction solution, collect the filtrate, and distill off the solvent under reduced pressure at 40°C, then separate and purify with silica gel column chromatography, the eluent is petroleum ether and ethyl acetate, and adopt gradient elution , the volume ratio of petroleum ether / ethyl acetate gradually increased from 1:2 to 1:4, and dried under vacuum at 40°C to obtain white solid N9-bromopropyl-O 6 - Benzylguanine (1.59 g, 4.4 mmol), yield 73%.

[0083] UV lambda: 250, 284nm...

Embodiment 3

[0099] Embodiment 3: N-(2-chloroethyl)-N'-3-(O 6 -Benzyl-N 2 -Synthesis of (((4-nitrobenzyl)oxy)carbonyl)9-guaninyl)butyl-N-nitrosourea (compound 3)

[0100] 1) N9-bromobutyl-O 6 -Synthesis of benzylguanine

[0101] Weigh O 6 -Benzylguanine (0.72g, 3mmol), anhydrous potassium carbonate (1.66g, 12mmol) were added to a three-necked flask, 80mL of acetone was added, the temperature was slowly raised to 55°C, and 1,4 dibromobutane (1.8mL , 15mmol), continue to react for 70h after dropping, filter the reaction solution, collect the filtrate, and distill off the solvent under reduced pressure at 40°C, then separate and purify with silica gel column chromatography, the eluent is petroleum ether and ethyl acetate, and adopt gradient washing After removal, the volume ratio of petroleum ether / ethyl acetate was gradually increased from 1:2 to 1:4, and vacuum-dried at 40°C to obtain a white solid N9-bromobutyl-O 6 - Benzylguanine (0.79 g, 2.1 mmol), 70% yield.

[0102] UV lambda: 25...

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Abstract

The invention relates to a compound with a formula (II) structure or a pharmaceutically accepted salt. The formula (II) structure is shown in the attached figure. The compound with the formula II structure has good targeting property and tumor cell killing capability, and can be used for preparing targeting tumor chemotherapy drugs. The compound has the advantages that on one hand, chloroethene-based carbon positive ions can be decomposed in vitro, the crosslinking with DNA (deoxyribonucleic acid) is caused, and the function of inhibiting the growth of tumor cells is realized; on the other hand, an O6-benzylguanine similar drug effect group is selectively released in cancer cells under the low-oxygen condition, the function of inhibiting the AGT (angiotensinogen) activity of the tumor cells is realized in a targeting way, and the drug resistance of the tumor cells to nitrosourea drugs is decreased.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to hypoxic activation combined with chloroethylnitrosourea compounds, a preparation method and application. Background technique [0002] Chloroethylnitrosoureas (CENUs) are an important class of bifunctional antitumor alkylating agents, which are widely used in clinical practice. As shown in the structure of compound Ⅰ, clinically representative CENUs drugs mainly include carmustine (BCNU), semustine (Me-CCNU), nimustine (ACNU), and lomustine (CCNU). . CENUs are broad-spectrum antitumor drugs, which are clinically used in the treatment of brain tumors, myeloma, malignant melanoma, malignant lymphoma, lung cancer, breast cancer, gastric cancer and leukemia. Because CENUs easily cross the blood-brain barrier, its concentration in the cerebrospinal fluid can reach 30-35% of the plasma concentration, so it has a good curative effect especially on brain tumors. CENUs play an antican...

Claims

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Application Information

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IPC IPC(8): C07D473/18A61K31/522A61P35/00A61P35/02
CPCA61K9/0019A61K9/0053A61K9/08A61K9/2059A61K9/4866A61K47/02A61K47/26C07D473/18
Inventor 赵丽娇彭瑞增任婷张淑芬钟儒刚
Owner BEIJING UNIV OF TECH
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