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CETP inhibitors

A -C1-C5, -OC2-C6 technology, applied in the field of inhibiting cholesteryl ester transfer protein, can solve the problem of no CETP inhibitor

Inactive Publication Date: 2007-06-13
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No CETP inhibitors are currently marketed

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0276]

[0277] 2-Amino-5-(trifluoromethyl)benzonitrile

[0278] To a 2 liter flask was added 100 g (0.348 mol) 4-amino-3-iodobenzotrifluoride, 40 g CuCN and 750 mL DMF. The mixture was heated to reflux and held at reflux for 1 hour. The reaction was cooled and poured into 3 L of water containing 300 mL of concentrated ammonium hydroxide. To this mixture was added 1 L CH 2 Cl 2 . The mixture was then filtered through celite. Separate the layers with CH 2 Cl 2 The aqueous layer was back extracted. The organic extracts were combined, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1.5 L of ether, and the resulting solution was washed with 1N ammonium hydroxide, aqueous sodium bisulfite, 1N hydrochloric acid and brine. The solution was dried over anhydrous magnesium sulfate and filtered through a plug of silica gel with a layer of magnesium sulfate on top. The silica gel plug was washed with 0.5 L of ether. The ether solutions wer...

Embodiment 2

[0281]

[0282] 2-iodo-5-(trifluoromethyl)benzonitrile

[0283] To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) was added tert-butyl nitrite (21 mL) dropwise at 35°C. During the addition, the reaction was maintained at 330-35°C. The reaction was aged for 30 minutes, then heated at 60°C for 30 minutes. The reaction mixture was cooled, washed with ether, followed by 2x water, 2x aqueous sodium bisulfite, water and brine. The solution was dried over anhydrous magnesium sulfate, filtered through a plug of silica gel, and concentrated to obtain 100 g of a red oil. The product was purified by silica gel chromatography with hexane, 3:1 hexane / CH 2 Cl 2 and 1:1 hexane / CH 2 Cl 2 Elution afforded 2-iodo-5-(trifluoromethyl)benzonitrile.

[0284] 1 HNMR (CDCl 3 , 500MHz) δ8.10(d, J=8.5Hz, 1H), 7.85(d, J=1.8Hz, 1H), 7.52(dd, J=8.5, 1.8Hz, 1H).

Embodiment 3

[0286]

[0287] 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile

[0288] To 2-iodo-5-(trifluoromethyl)benzonitrile (2.0g, 6.7mmol) and (5-isopropyl-2-methoxyphenyl)boronic acid (1.6g, 8.4mmol) in dimethyl Add 2M Na to the solution in ethylene glycol (30.4mL) 2 CO 3 (6.8mL), ethanol (9.6mL) and water (10mL). The solution was degassed with nitrogen for 2 minutes. Add Pd(PPh 3 ) 4 (774 mg, 0.67 mmol), and the solution was again degassed with nitrogen for 2 minutes. This solution was equally divided into two 40 mL microwave tubes. Each tube was degassed with nitrogen for 1 min, sealed, and placed in a microwave reactor. Set the wattage to 200W until the temperature reaches 150°C, then hold the temperature at 150°C for 10 minutes. The microwave tubes were then cooled to room temperature, combined, and poured into H 2 O (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and...

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Abstract

Compounds having the structures of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis: In the compounds of Formula I, B or R2 is a phenyl group which has an ortho aryl, heterocyclic, benzoheterocyclic or benzocycloalky substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalky substituent connected directly to the ring or attached to the ring through a -CH2-.

Description

field of invention [0001] The present invention relates to a class of compounds that inhibit cholesteryl ester transfer protein (CETP) and are therefore useful in the treatment and prevention of atherosclerosis. Background of the invention [0002] Atherosclerosis and its clinical outcomes, coronary heart disease (CHD), stroke, and peripheral vascular disease impose a considerable burden on health management systems in developed countries. In the United States alone, approximately 13 million patients are diagnosed with CHD, and more than 500,000 patients die from CHD each year. Additionally, this cost is projected to increase over the next quarter century as the obesity and diabetes epidemics continue to grow. [0003] It has long been recognized that, in mammals, changes in the distribution of circulating lipoproteins are associated with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA reductase inhibitors, particularly statins, in reducing coronary ev...

Claims

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Application Information

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IPC IPC(8): C07D263/20C07D263/22C07D263/24C07D233/32C07D207/26C07D285/10C07D401/04C07D413/04C07D413/10C07D417/04C07D417/10A61K31/4015A61K31/4166A61K31/421
Inventor A·阿利J·M·纳波利塔诺邓巧临吕志俭P·J·辛克莱尔G·E·泰勒C·F·汤普森N·库赖施C·J·史密斯J·A·亨特A·A·道斯特陈奕亨李虹
Owner MERCK & CO INC
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