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Preparation and use of thiocarbonyl compound

A thiocarbonyl, compound technology, applied in the field of tumor-related drugs

Inactive Publication Date: 2012-04-04
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the clinical research of isoxazoline compounds for anti-tumor use has not been reported. For the existing anti-tumor drugs, this type of compound has a novel structure. Preliminary studies have shown that some targeted drugs have better efficacy and activity and have potential for development.

Method used

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  • Preparation and use of thiocarbonyl compound
  • Preparation and use of thiocarbonyl compound
  • Preparation and use of thiocarbonyl compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0043] Reference example 1 (preparation of intermediate 1)

[0044]

[0045] 3,4 difluorobenzaldehyde as the starting material reacts with hydroxylamine hydrochloride under alkaline and room temperature conditions to generate 3,4 difluorobenzoxime (intermediate 2), and then reacts with N-chlorosuccinimide to generate 3 , 4 difluorobenzoxime chloride (intermediate 3), 3 and allyl acetamide carry out cyclization reaction under low temperature conditions to obtain intermediate 5: (±)-N-5-(acetamidomethyl)-3- (3,4 difluorophenyl) isoxazoline, 5 reacts with anhydrous piperazine heating to generate intermediate 1: (±)-N-[[3-[3-fluoro-4-(1-piperazinyl) )phenyl]-4,5 dihydro-5-isoxazolyl]methyl]acetamide. m.p.160.5-161.3°C, 1 H-NMR (DMSO-d 6 , 400MHz) δ: 1.81 (s, 3H, CH 3 ), 3.04-3.62 (m, 8H, Piperazinyl-H), 4.68-4.72 (m, 1H, CH), 7.06-7.42 (m, 3H, Ar-H), 8.09 (t, 1H, NH).

Embodiment 1

[0047] Ij: (±)-N-[[3-[3-fluoro-4-[4-[(p-fluorobenzaldehyde hydrazone)thiocarbonyl]-1-piperazinyl]phenyl]-4,5- Dihydro-5-isoxazolyl]methyl]acetamide.

[0048]

[0049] Dissolve 1g of intermediate 1 and 0.71g of methyl p-fluorobenzaldehyde hydrazone dithiocarbamate in 40ml of absolute ethanol, pass through nitrogen protection, connect the airway tube at the end of the condenser, and connect an inverted suspension at the end of the airway tube Put a glass funnel in a beaker filled with ethanol, react at 30-50°C for 5-6 hours, then heat up, reflux for 5-24 hours, TLC detects that the reaction is complete, filter while hot, and rinse the filter cake with a small amount of ethyl acetate , and dried to obtain 1.08 g of yellow solid with a yield of 69.9%. m.p.208.8-209.8℃, HPLC99.1%, 1 H-NMR (DMSO-d6, 400MHz) δ: 1.80(s, 3H, CH 3 ), 3.19-3.25 (m, 2H, Isoxazole-CH 2 ), 3.31-4.07 (m, 8H, Piperazinyl-H), 4.67-4.74 (m, 1H, CH), 7.10-7.72 (m, 7H, Ar-H), 8.10 (t, 1H, NHC=O), 8.16 (s,...

Embodiment 2-4

[0051] With reference to the operation of Example 1, the difference is that the methyl dithioformate compound containing different substituents is selected to replace the methyl p-fluorobenzaldehyde hydrazone dithioformate in Example 1, and react with intermediate 1 to prepare the following formula I compound.

[0052]

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Abstract

The invention belongs to the field of anti-tumor relative medicine, and provides a thiocarbonyl isoxazoline derivative comprising a structure represented by general formula I and pharmaceutically acceptable salt thereof; in the formula, R stands for FORMULA. The invention further provides use of the compound or pharmaceutically acceptable salt thereof as medicine, specifically as anti-tumor medicine.

Description

technical field [0001] The invention belongs to the field of tumor-related drugs, and more specifically relates to a class of isoxazoline derivatives containing thiocarbonyl substituents and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and antitumor drugs. use. technical background [0002] For a long time, tumors have been one of the major diseases that threaten human health, and its morbidity and mortality are increasing year by year and showing a younger trend. Traditional cytotoxic therapy drugs non-specifically block cell division and lead to cell death, so they have large toxic side effects and great damage to normal cells. With the continuous deepening of the research on the signal transduction pathway of tumor cells, new anti-tumor targeted drugs have been found that have the characteristics of multi-target, high efficiency, small side effects, and less drug resistance, and have attracted more and more attention. For exam...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12C07D261/04A61K31/496A61P35/00A61P35/02
Inventor 刘冰妮刘默刘登科刘颖刘巍张智强徐为人
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH