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Synthesis and uses of CETP inhibitor

A compound and composition technology, applied in the fields of pentacyclic triterpenoid derivatives as CETP inhibitors, novel pentacyclic triterpenoid derivatives and their preparation, prevention and treatment of atherosclerosis and hyperlipidemia, capable of Solve the problems of not being able to effectively reduce cardiovascular and cerebrovascular adverse events, unknown cardiovascular diseases, etc., and achieve the effect of high application development value, cheap raw materials, and easy availability of raw materials

Active Publication Date: 2017-08-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Eli Lilly's Evacetrapib terminated its Phase III clinical trial in October 2015 due to its inability to effectively reduce the occurrence of cardiovascular and cerebrovascular adverse events
The only CETP inhibitor currently in phase III clinical trials is Merck's Anacetrapib, and its results are expected to be completed within 2017, but whether it can really improve cholesterol levels and reduce the risk of cardiovascular disease remains unknown

Method used

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  • Synthesis and uses of CETP inhibitor
  • Synthesis and uses of CETP inhibitor
  • Synthesis and uses of CETP inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 3β-(3-(((2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4 -yl)amino)-3-oxopropionyl)oxy-oleanane-12-en-28-acid (I-1)

[0044]

[0045] step one

[0046] At room temperature, benzyl oleanolic acid II-1 (200 mg) was dissolved in anhydrous toluene (3 mL), cyclo()isopropyl malonate V-1 (78 mg) was added, the temperature was raised to 120°C, and refluxed. 8 hours; the reaction solution was lowered to room temperature, poured into water (20 mL), the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain a crude product , by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain 106 mg of benzyl oleanolic acid benzyl malonate monoester (III-1) as a light yellow viscous liquid with a yield of 46%.

[0047] Step 2

[0048] Compound III-1 (100 mg) was dissolved in dry...

Embodiment 2

[0052] 3β-(4-(((2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4 -yl)amino)-4-oxobutyryl)oxy-oleanane-12-en-28-acid (I-2)

[0053]

[0054] step one

[0055] At room temperature, benzyl oleanolic acid II-1 (200 mg) was dissolved in anhydrous pyridine (3 mL), succinic anhydride V-2 (180 mg) and 4-dimethylaminopyridine (45 mg) were added successively, and the temperature was raised to 130 ° C, refluxed for 7 hours; the reaction solution was lowered to room temperature, water (20 mL) and dichloromethane (10 mL) were added respectively, first washed with 1.0 M hydrochloric acid (10 mL x 2), and then the organic phase was washed with water and saturated brine successively, It was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain a crude product, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to obtain 230 mg of benzyl succinic acid benzyl oleanate mon...

Embodiment 3

[0061] 3β-(5-(((2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4 -yl)amino)-5-oxopentanoyl)oxy-oleanane-12-en-28-acid (I-3)

[0062]

[0063] step one

[0064] At room temperature, benzyl oleanolic acid II-1 (200 mg) was dissolved in anhydrous pyridine (3 mL), glutaric anhydride V-3 (208 mg) and 4-dimethylaminopyridine (45 mg) were added successively, and the temperature was raised to 130 ° C, refluxed for 15 hours; the reaction solution was lowered to room temperature, water (20 mL) and dichloromethane (10 mL) were added respectively, first washed with 1.0 M hydrochloric acid (10 mL x 2), and then the organic phase was washed with water and saturated brine successively, It was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain a crude product, which was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain 222 mg of benzyl glutaric acid benzyl oleanolic ac...

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PUM

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Abstract

The present invention discloses synthesis and uses of a CETP inhibitor, wherein the derivative is a compound represented by a formula I. According to the present invention, the pharmacodynamics experiment results show that the compound represented by the formula I provides good inhibitory effect on CETP, and achieves the nano-molar level; and the basic mother nucleus of the compound represented by the formula I is derived from pentacyclic triterpene in natural products, the raw material has the low cost and is easy to obtain, the risk of the raw material of the present invention is lower than the risk of the common small molecular compound in the field of the safety of the patent medicine, and the high application development value is provided; and the compound represented by the formula I can be used for preparing anti-hyperlipidemia drugs, anti-atherosclerosis drugs, and other drugs for treatment of other cardiovascular and cerebrovascular diseases. The invention further provides a preparation method of the compound represented by the formula I.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to novel pentacyclic triterpenoid derivatives and their preparation method and use in pharmacy, in particular to the use of pentacyclic triterpenoid derivatives as CETP inhibitors in preventing and treating atherosclerosis and Use in hyperlipidemia. Background technique [0002] Atherosclerosis (AS) is prone to occur in large and medium arteries, such as heart vessels, causing ischemia and hypoxia in blood supply tissues, and clinical symptoms and signs such as coronary heart disease, myocardial infarction and peripheral vascular disease appear. The main pathological basis of vascular disease. Hyperlipidemia is one of the main risk factors of coronary atherosclerotic heart disease (CHD) that promotes atherosclerosis and endangers human health, and reducing blood lipids can reduce the incidence of coronary atherosclerotic heart disease. [0003] A large number of epidemiological ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/56A61P3/06A61P9/10A61P9/00A61P3/00
CPCC07J63/008Y02P20/55
Inventor 孙宏斌常永志赵文峰温小安柳军
Owner CHINA PHARM UNIV
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