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NO donor type statin derivative, and preparation method and application thereof

A statin and reaction technology, applied in the field of N-aryl-N'-hydroxyguanidine NO-donor statin derivatives and their preparation, to reduce cholesterol and triglyceride levels, treat peripheral ischemia, improve high density Effects of lipoprotein levels

Active Publication Date: 2017-07-11
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

[0006] However, whether it is possible to combine N-aryl-N'-hydroxyguanidine NO donor drugs with statins to obtain new compounds with better technical effects has not yet been reported.

Method used

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  • NO donor type statin derivative, and preparation method and application thereof
  • NO donor type statin derivative, and preparation method and application thereof
  • NO donor type statin derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]Example 1: (3R,5R)-7-[5-isopropyl-3-phenyl-2-(4-fluorophenyl)-4-(anicarboyl)pyrrole-1-]-3, 5-Dihydroxyheptanoic acid-{4-{N'-[(tert-butoxycarbonyl)oxy]-N-(4-chlorophenyl)formamidoyl}carbamoyl}benzyl ester

[0040]

[0041] Step 1: N-(4-chlorophenyl)-N'-benzoylthiourea is compound 2a

[0042]

[0043] At room temperature, dissolve 18.42g of NH4SCN in 250ml of acetone, add 29.5g of PhCOCl at one time under stirring, heat up to reflux for 15min, stop heating, cool to room temperature, slowly add 20.58g of 4-chloroaniline in batches, and continue stirring until the reaction Completely, cool to room temperature. The reaction solution was poured into 700 g of crushed ice, filtered after the ice melted, the filtrate was discarded, the filter cake was recrystallized with acetone, and dried to obtain 41.5 g of white to off-white needle crystals with a yield of 88.5%. mp:144.5-145.4

[0044] Step 2: 1-(4-Chlorophenyl)-thiourea is compound 3a

[0045]

[0046] Add 41.0 ...

Embodiment 2

[0064] Example 2: (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-]-3,5-dihydroxy-6(E)-heptenoic acid -{4-{N'-[(tert-butoxycarbonyl)oxy]-N-(4-chlorophenyl)formamidoyl}carbamoyl}benzyl ester is the compound NO-6a-Pita

[0065]

[0066] Dissolve 0.4g of 6a and 0.8g of pitavastatin calcium in 10ml of DMF, add 0.8g of KI, and stir at room temperature for 48h. The reaction solution was poured into 50 ml of deionized water, extracted with ethyl acetate, and then the EA layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the filter cake, and the filtrate was concentrated to obtain a crude product. Column chromatography separation to obtain the target product NO-6a-Pita

[0067] M+1: 823.1, 1H-NMR (DMSO-d6, 400MHz): δ8.02 (d, 2H, J = 8.4), 7.85 (d, 1H, J = 8.4), 7.64 (d, 1H), 7.60 ( d,2H,J=8.4),7.50(d,2H,J=8.8),7.41(d,2H,J=8.8),7.37-7.23(m,6H),6.51(d,1H),5.61(dd ,1H),5.22(s,2H),4.88(d,1H),4.81(d,1H),4.13(m,1H),3.82(m,1H),2.49(...

Embodiment 3

[0068] Example 3: (3R,5S)-7-[6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-4-(4-chlorophenyl)pyrimidine-5- ]-3,5-Dihydroxy-6(E)-heptenoic acid-{4-{N'-[(tert-butoxycarbonyl)oxy]-N-(4-chlorophenyl)formamidoyl}amino Formyl}benzyl ester is the compound NO-6a-Rosu

[0069]

[0070] Dissolve 0.4g of 6a and 0.8g of rosuvastatin calcium in 10ml of DMF, add 0.8g of KI, and stir at room temperature for 48h. The reaction solution was poured into 50 ml of deionized water, extracted with ethyl acetate, and then the EA layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the filter cake, and the filtrate was concentrated to obtain a crude product. Column chromatography separation to obtain the target product NO-6a-Ato

[0071] M+1: 883.3, 1H-NMR (DMSO-d6, 400MHz): δ8.03(d, 2H), 7.70(dd, 2H), 7.59(d, 2H), 7.50(d, 2H), 7.41(d, 2H),7.26(dd,2H),6.52(d,1H),5.51(dd,1H),5.21(s,2H),4.97(d,1H),4.85(d,1H),4.20(m,1H ),3.90(m,1H),3.55(s,3H),3.44(s,3H...

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Abstract

The invention provides a compound having a structural formula represented by the general formula (I); the compound has good NO releasing activity, has good application prospects, and can be used for resisting inflammation, resisting thrombosis, having antiplatelet activity, lowering cholesterol and triglyceride levels and / or improving high density lipoprotein levels, treating peripheral ischemia, diabetes patient blood vessel complications or atherosclerosis and the like. The invention also provides a method for preparing the compound.

Description

technical field [0001] The present invention relates to the field of pharmacy and medicinal chemistry, and relates to a NO-donating statin derivative, a preparation method and application thereof, in particular to an N-aryl-N'-hydroxyguanidine NO-donating statin derivative and a preparation method thereof and application. Background technique [0002] Nitric oxide (Nitric oxide, NO) is an important gaseous small molecule that was discovered in mammals in the 1980s to perform the messenger function. In 1992, it was selected as the star molecule of the year by the American Science magazine. Since the late 1980s, people have mainly studied the physiological function of NO. It is found that it can relax blood vessels and participate in blood pressure regulation; it can reduce the aggregation of platelets and has antithrombotic function; it can also inhibit the proliferation of vascular smooth muscle and have anti-atherosclerotic effects; it can affect the release of neurotransm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34C07D215/14C07D239/42C07C277/08C07C279/22A61K31/40A61K31/47A61K31/22A61K31/505A61P3/06A61P9/10A61P9/14A61P29/00A61P7/02
CPCC07C279/22C07D207/34C07D215/14C07D239/42
Inventor 陈宇瑛罗刚艾林王式跃
Owner SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP
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