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Furoxan NO donor-type statin derivative and preparation method thereof

A technology of derivatives and statins, which is applied in the field of medicinal chemical synthesis, can solve the problems of few research reports, achieve the effect of enhancing curative effect, good therapeutic effect, and avoiding the effect of mismatching mechanism of action

Active Publication Date: 2019-08-16
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, NO-donating drugs mainly involve cardiovascular system drugs, non-steroidal anti-inflammatory drugs, anti-tumor drugs, and anti-allergic drugs, and Bidil, an NO-donating anti-heart failure drug, was launched in the United States in 2005. More than 10 Each is in different stages of clinical research, but there are few reports on the research on blood lipid-regulating and anti-atherosclerotic drugs.

Method used

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  • Furoxan NO donor-type statin derivative and preparation method thereof
  • Furoxan NO donor-type statin derivative and preparation method thereof
  • Furoxan NO donor-type statin derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Preparation of benzenesulfonyl substituted furazan nitrogen oxides

[0059] 1.1 Preparation of 2-phenylthioacetic acid (9):

[0060] Take 99.8g (100ml, 0.98mol) of thiophenol, dissolve 39.2g (0.98mol) of NaOH in 500ml of 95% EtOH, and after the NaOH dissolves completely drop to room temperature, add dropwise 101g (1.07mol) of chloroacetic acid and NaOH 2 CO 3 500ml of the aqueous solution prepared by 56.7g (0.535mol) was added, stirred at room temperature for 3h after the dropwise addition, and then refluxed for 1h. Reduce to room temperature and use 6N HCl to adjust pH = 2, evaporate EtOH under reduced pressure, stir overnight at room temperature, add 1 L of water to the system, stir for 1 h, a large amount of white solid appears, filter, and dry the sample to obtain 9164 g of white solid (mp=63.3- 64.5°C, literature value mp=60-62°C).

[0061] 1.2 Preparation of 3,4-diphenylsulfonyl-1,2,5-oxadiazole-2-oxide (11):

[0062]Dissolve 164g (0.98mol) of compound 9 in gl...

Embodiment 2

[0089] Preparation of Phenyl Substituted Furazan Oxides

[0090] 2.1 Preparation of 3-hydroxymethyl-4-phenyl-1,2,5-oxadiazole-2-oxide (25):

[0091]Take 10g (0.075mol) of cinnamyl alcohol and dissolve it in 120ml of glacial acetic acid, stir mechanically, after the cinnamyl alcohol is dissolved, add 15.5g (0.22mol) of sodium nitrite, react for 2h, add 200ml of water to the reaction solution to terminate the reaction, EA 500ml *2 Extraction, washing the EA layer with 100ml saturated brine, concentrating the EA layer, column chromatography [PE / EA=2:1 (v:v) elution], after post-treatment, 259.8g of yellow oily substance was obtained. .

[0092] 2.2 3-[(4-Methoxyformyloxy)phenyl]-2-propenoic acid (4-phenyl-1,2,5-oxadiazole-2-oxide-3)-methyl ester (26) Preparation of:

[0093] Take 6.0g (27mmol) of compound 15, dissolve it in 60ml of pyridine, add 4.9ml (37.8mmol, 7.8mmol / ml) of benzenesulfonyl chloride dropwise in an ice-salt bath, react at room temperature for 30min, and add 2...

Embodiment 3

[0099] Preparation of intermediate 4-coumaric acid derivatives

[0100] 3.1 Preparation of E-4-hydroxy-phenylacrylic acid-4'-bromobutyl ester (4):

[0101] Take 4.9g of 4-coumaric acid (FW164, 30mmol) and dissolve it in 200ml of acetone. After dissolving, add 24ml of triethylamine and 12ml of 1,4-dibromobutane (100mmol), and reflux for 6h (60°C). After filtration, the filtrate was concentrated to an oily substance, and column chromatography [PE / EA=3:1 (v:v) elution] was performed to obtain 4.8 g of white solid 4.

[0102] 3.2 Preparation of E-4-hydroxy-phenylacrylate-4'-(nitrooxy)butyl ester (5):

[0103] Dissolve 4.8g (16mmol) of compound 5 in 100ml acetonitrile, add AgNO 3 6.9g (41mmol), reflux reaction for 5h (85°C), lowered to room temperature, filtered, the filtrate was concentrated to oily matter, column chromatography [PE / EA=3:1 (v:v) elution], after post-treatment to obtain Crude 5 11.2 g.

[0104] 3.3 Preparation of E-4-(2-chloromethyl)benzyloxyphenylacrylate-4'-...

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Abstract

The invention discloses a furoxan NO donor-type statin derivative and a preparation method thereof, and belongs to the technical field of medicinal chemical synthesis. The derivative has the structural formula represented by the following formula: wherein R is an alkyl, R1 is a statin residual group, and R2 is an aryl or an aryl sulfonyl. A statin drug is selected to "hybridize" with a NO donor, both NO and the statin drug have good therapeutic effects on atherosclerosis, and the problem of the mismatch of action mechanisms of NO and the statin drug is effectively avoided. In addition, 4-coumaric acid is selected as a linking group, and thus the therapeutic effect of the drug can be effectively enhanced. The compound can effectively release NO in vitro, and the useful attempt for the development of NO donor anti-atherosclerosis drugs is made.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to furazan nitrogen oxide NO donor statin derivatives and a preparation method thereof. Background technique [0002] Atherosclerosis (AS) is the main pathological basis of cardiovascular and cerebrovascular diseases. Current studies have found that nitric oxide (NO) and statins have a positive effect on improving atherosclerosis. [0003] As a messenger substance and effector molecule, NO plays important physiological functions in cardiovascular, immune, nervous and other systems. In addition to its vasodilation activity, NO also has biological activities such as inhibiting platelet aggregation, hindering smooth muscle cell proliferation and immune regulation. Therefore, it is of great significance to the treatment of cardiovascular diseases such as hypertension and atherosclerosis. [0004] Statins are a class of drugs that can lower LDL cholesterol by ...

Claims

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Application Information

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IPC IPC(8): C07D271/08C07D413/12A61P9/10
CPCA61P9/10C07D271/08C07D413/12
Inventor 陈宇瑛邹云艾林
Owner CHENGDU UNIV
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