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2-azetidinones as anti-hypercholesterolemic agents

An alkyl, pharmaceutical technology, applied in the field of LDL-cholesterol, 2-azetidinone and its pharmaceutically acceptable salts and esters, can solve problems such as reduction of coronary morbidity and mortality

Inactive Publication Date: 2006-11-29
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although simvastatin resulted in a significant reduction in coronary morbidity and mortality, the risk actually remains in the treatment of patients

Method used

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  • 2-azetidinones as anti-hypercholesterolemic agents
  • 2-azetidinones as anti-hypercholesterolemic agents
  • 2-azetidinones as anti-hypercholesterolemic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] plan 1

[0152]

[0153] Acetic acid (1S)-1-(4-fluorophenyl)-3-[(2S,3R)-1-(4-fluorophenyl)-2-(4-hydroxyphenyl)-4-oxoazepine Preparation of cyclobutan-3-yl]propyl ester (15) (also referred to herein as E(OAc)OH)

[0154] The intermediates have been described previously and can be prepared according to the methods outlined in Vaccaro.W.D.; Davis, H.R.Jr.Bioorg.Med.Chem.Lezt.1998,8,313. 15 .

Embodiment 2

[0156] Scenario 2

[0157]

[0158] (4S)-3-[(5S)-5-(Benzyloxy)-5-(4-fluorophenyl)pentanoyl (pentanoyl)]-4-phenyl-1,3-oxazolidine-2- Preparation of ketone (16)

[0159] (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-  A solution of oxazolidin-2-one (prepared according to WO 02 / 079174A2, 2002) (1.0 equivalent) in an appropriate volume of dimethylformamide was added with sodium hydride (1.5 equivalent, 60% dispersed in mineral oil) and heated at room temperature The resulting mixture was stirred for 40 minutes. The reaction was then cooled to 0°C and benzyl bromide (1.2 equiv) was added and the reaction was allowed to warm to room temperature with stirring until complete reaction was deemed complete. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water, and dried (Na 2 SO 4 ), filtered, and the filtrate was concentr...

Embodiment 3

[0161] Option 3

[0162]

[0163] Step A: Preparation of 4-(acetylthio)benzoic acid (17)

[0164] To 4-mercaptobenzoic acid (1.0 eq) was added an appropriate volume of acetic anhydride and pyridine (1:1) with stirring at 0°C and the solution was allowed to warm to room temperature and age until the reaction was deemed complete. The mixture was poured into water and extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered, and the filtrate was concentrated in vacuo. Can be obtained by purification of the crude residue using various chromatographic techniques 17 .

[0165] Step B: Preparation of S-[4-(hydroxymethyl)phenyl]ethanethioate (18)

[0166] To a solution of 17 (1.0 equiv) in an appropriate volume of THF was added slowly the borane-THF complex (2.5 equiv) at -10°C. The reaction was allowed to warm to room temperature and stirred until complete. The reaction mixture was quenched by slow addi...

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PUM

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Abstract

The instant invention provides novel cholesterol absorption inhibitors of Formula I and the pharmaceutically acceptable salts and esters thereof. The compounds are useful for lowering plasma cholesterol levels, particularly LDL cholesterol, and for treating and preventing atherosclerosis and atherosclerotic disease events.

Description

Background of the invention [0001] The present invention relates to substituted 2-azetidinones (azetidinones) and pharmaceutically acceptable salts and esters thereof, and to their use alone or in combination with other active agents for the treatment of hypercholesterolemia and for preventing, stopping or Slows the progression of atherosclerosis and related conditions and diseases. [0002] It has been clear for decades that elevated blood cholesterol is a major risk factor for coronary heart disease, and many studies have shown that lipid-lowering therapy can reduce the risk of CHD. Before 1987, lipid-lowering substances were largely limited to diets low in saturated fat and cholesterol, bile acid sequestrants (cholestyramine and colestipol), niacin, fibrates and Probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. The combination of a lipid-lowering diet with or without niacin and a bile acid sequestrant achieves a significant ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/351C07D205/08C07D405/10C07D405/12C07D409/10C07D409/12C07H15/26A61P3/06C07D263/24
CPCC07D409/12C07D405/12C07D205/08C07D263/24A61P3/06A61P9/10
Inventor H·I·辛斯F·乌贾因瓦拉M·麦科斯R·W·迈尔斯
Owner MERCK & CO INC
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