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FK409 NO donor type statins antilipemic medicine derivative and preparation method thereof

A technology of drugs and compounds, which is applied in the field of FK409 NO-donating statin blood lipid-lowering drug derivatives and its preparation, to achieve the effect of improving endothelial function, prolonging the action time, and increasing the half-life

Active Publication Date: 2017-08-29
SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Foreign studies on FK409-type NO donors only report the connection with niacin analogues, but it is still blank in China

Method used

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  • FK409 NO donor type statins antilipemic medicine derivative and preparation method thereof
  • FK409 NO donor type statins antilipemic medicine derivative and preparation method thereof
  • FK409 NO donor type statins antilipemic medicine derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Synthesis of (E,E)-4-ethyl-2,4-diene-hexanoic acid ethyl ester

[0069]

[0070] Ice bath, under nitrogen protection, in the anhydrous THF solution of 150ml, add the NaH (4.8g, 120mmol) of weight concentration of 60%, stir well, then add dropwise triethyl phosphoroacetate (20.16g, 90mmol) and ( E) A mixed solution of 2-ethyl-2-ene-butyraldehyde (5g, 51mmol) in anhydrous THF (20ml) was stirred for 15 minutes, then removed from the ice bath, warmed to room temperature and stirred for 4.5h. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated to obtain a crude product, and subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane=1 / 30) 5.0 g of a colorless oil were isolated.

Embodiment 2

[0072] Synthesis of (E,E)-4-ethyl-2,4-diene-1-hexanol

[0073]

[0074] At room temperature and protected from light, to the suspension of lithium aluminum hydride (0.742g, 19.52mmol) in anhydrous ether (100ml), the product obtained in Example 1 [(E,E)-4-ethyl- 2,4-diene-hexanoic acid ethyl ester (5.0g, 29.76mmol)] in ether solution, after stirring for 2 hours, TLC showed that the raw material still exists, add about 0.4g lithium aluminum hydride, stir for 3 hours and then process. The reaction was quenched with ethyl acetate, filtered, the organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was subjected to silica gel column chromatography (eluent: ethyl acetate / cyclohexane=1 / 4) to obtain 2.71 g of colorless Transparent oil.

Embodiment 3

[0076] Synthesis of [(E,E)-4-ethyl-2,4-dien-1-yl]-4-chloro-butyric acid hexyl ester

[0077]

[0078] In an ice bath, add the product (E,E)-4-ethyl-2,4-diene-1-hexanol (2.87g, 22.78mol) obtained in Example 2 to triethylamine / dichloromethane (100ml / 150ml) into the mixed solution, add 4-chloro-butyryl chloride (6.8g, 0.0482mol) dropwise, stir and react under ice bath for 4h, extract the reaction solution with dichloromethane, wash the organic layer with saturated brine, and then wash with anhydrous magnesium sulfate Dry and concentrate to obtain a crude product, which is separated by silica gel column chromatography (eluent: ethyl acetate / cyclohexane=1 / 30) to obtain 4.3 g of a colorless transparent oil.

[0079] ESI-MS: 231.7(M+1) +

[0080] 1 H-NMR (400MHz, CDCl 3 , 25℃): 6.18(1H, d); 5.64(1H, m); 5.55(1H, q); 4.62(2H, d); 3.60(2H, t); 2.51(2H, t); , q); 2.10 (2H, m); 1.72 (3H, d); 0.99 (3H, t).

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PUM

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Abstract

The invention mainly provides an FK409 NO donor type statins antilipemic medicine derivative and a preparation method thereof. Through in-vitro activity determination, the derivative provided by the invention has the good NO release activity; through the NO released by the donor part, the in-vivo and in-vitro half-life period of a target compound can be increased, so that the action time can be prolonged. On the basis of the statins antilipemic pharmacological action, the non-blood-fat-regulating activity of the medicine such as the blood vessel relaxing and the platelet aggregation resistance of the medicine is enhanced; in addition, untoward effects caused by statins is reduced. The general formula of the derivative is shown as the formula , and the formula is shown in the specification.

Description

technical field [0001] The invention relates to an FK409 NO donor type statin blood lipid-lowering drug derivative and a preparation method thereof. Background technique [0002] Since the 1990s, NO has gradually become one of the hotspots and frontiers of life science and medical research due to its great potential in medicine, which has opened up a new way for the discovery of new drugs. [0003] NO donors are those compounds that release NO under physiological conditions. As a messenger substance and effector molecule, NO plays an extremely important role in cardiovascular, nervous and immune systems. Such as relaxation of vascular smooth muscle, inhibition of platelet adhesion and aggregation, inhibition of proliferation and migration of vascular smooth muscle, anti-inflammation, anti-oxidation and other effects. [0004] To date, hundreds of NO donors have been developed and widely used in various biological studies. According to its structure, it is mainly divided i...

Claims

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Application Information

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IPC IPC(8): C07D207/34C07D215/14C07D239/42A61K31/40A61K31/47A61K31/505A61P29/00A61P7/02A61P3/06
CPCC07D207/34C07D215/14C07D239/42
Inventor 陈宇瑛薛雨艾林王式跃
Owner SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP
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