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Nitric oxide donating type tamibarotene derivative, its preparation method and use

A technology of tamibarotene and nitric oxide, which is applied in the fields of organic chemistry, drug combination, pharmaceutical formula, etc., can solve the problems of few research reports and so on.

Inactive Publication Date: 2011-12-28
济南铂卅医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, people have developed a variety of NO donors and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, Alzheimer's disease (AD) drugs, cardiovascular drugs, central nervous system drugs, and anti-tumor drugs. Hybrid NO donor drugs, but there are few research reports on the hybrid NO donor drugs of anti-leukemia drugs and NO donors

Method used

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  • Nitric oxide donating type tamibarotene derivative, its preparation method and use
  • Nitric oxide donating type tamibarotene derivative, its preparation method and use
  • Nitric oxide donating type tamibarotene derivative, its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: 3-Hydroxymethyl-4-phenyl-1,2,5-oxadiazole-2-oxide ( 2 ) preparation

[0050] Add cinnamyl alcohol (53.7g, 0.40mol) and sodium nitrite (55.2g, 0.80mol) into 500mL of chloroform, stir at room temperature until the cinnamyl alcohol is completely dissolved, then slowly add glacial acetic acid (48.0g, 0.80mol), after the dropwise addition, continue to stir and react at room temperature for 1.0h, filter with suction, wash the filtrate twice with distilled water, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure to remove the solvent, and obtain a brownish-yellow oily substance, which is subjected to silica gel column chromatography Separation (ethyl acetate:petroleum ether=1:5), the eluate was concentrated under reduced pressure to give a light yellow solid ( 2 ) (48.0g, 62.4%), mp 64~66℃.

[0051]

Embodiment 2

[0052] Example 2: 3-Chloromethyl-4-phenyl-1,2,5-oxadiazole-2-oxide ( 3 ) preparation

[0053] 3-Hydroxymethyl-4-phenyl-1,2,5-oxadiazole-2-oxide ( 2 ) (38.4g, 0.2mol) and anhydrous pyridine (32.2mL, 0.4mol) were added to 600mL of anhydrous dichloromethane, stirred at room temperature to dissolve completely, cooled to 0~5°C in an ice-water bath, and then slowly dropped in 1.0h Add thionyl chloride (28.4mL, 0.4mol), remove the ice water bath after the dropwise addition, stir the reaction at room temperature for 12.0h, slowly pour the reaction solution into 500mL ice water under vigorous stirring, separate the organic layer, and successively use saturated chloride Sodium solution, saturated sodium bicarbonate solution, saturated sodium chloride solution and distilled water washed, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated to remove solvent, separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:20), washed Dehy...

Embodiment 3

[0055] Example 3: 3-((4-carboxyphenoxy)methyl)-4-phenyl-1,2,5-oxadiazole-2-oxide ( 5 ) preparation

[0056] 3-Chloromethyl-4-phenyl-1,2,5-oxadiazole-2-oxide ( 3 ) (10.5g, 0.05mol) and methyl p-hydroxybenzoate (7.6g, 0.05mol) were dissolved in 250mL DMF, then anhydrous potassium carbonate (27.6g, 0.2mol) and potassium iodide (8.3g, 0.05mol) were added , stirred at room temperature for 12 hours, then poured the reaction solution into 1000mL water to precipitate solids under vigorous stirring, filtered the filter cake in 500mL ether, washed it with saturated sodium bicarbonate solution, saturated sodium chloride solution and distilled water successively, and no dried over sodium sulfate, suction filtered, the filtrate was concentrated to remove the solvent, the residue was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:5), and the eluent was concentrated under reduced pressure to obtain a white crystalline solid ( 4 ) (13.6g, 83.4%), mp 97.0~98...

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Abstract

The invention relates to the field of pharmaceutical chemistry, and discloses nitric oxide donor tamibarotene derivatives and their preparation method and use. Specially, the invention provides nitric oxide donor tamibarotene derivatives shown in the structural general formula (I), wherein a definition of R is shown in the patent specification. The nitric oxide donor tamibarotene derivatives are a type of multi-target compounds prepared from Furoxan type nitric oxide donors and a retinoic acid receptor (RAR) agonist through heterozygosis of ester bonds or amide bonds of various connecting groups. The nitric oxide donor tamibarotene derivatives are suitable for being utilized as anti-tumor drugs for treating all types of leukemia.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to nitric oxide donating type tamibarotene derivatives and a preparation method thereof, as well as the medical application of these compounds, especially the application as anti-leukemia drugs. Background technique [0002] Nitric oxide (NO) is an important cell messenger molecule that widely exists in various organisms. As a messenger molecule, it can freely pass through the biomembrane and transmit information between cells. The endogenous NO in the body is produced by Molecular oxygen is generated by oxidizing the guanidine N atom at the end of L-Arg under the catalysis of nitric oxide synthase (NOS). NO is widely involved in the regulation of many physiological processes in the body, and plays an important biological role in the immune system, nervous system, and cardiovascular system. Especially in the immune system, NO plays an extremely important role as a key eff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61K31/4245A61P35/02
Inventor 徐文方边海勇张磊王学健冯金红
Owner 济南铂卅医药科技有限公司
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