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Cetp Inhibitors

a technology of hdl-c and inhibitors, applied in the field of chemical compounds, can solve the problems of chd risk, high risk of statins, and true burden on health care systems, and achieve the effect of only reducing the risk of approximately one-third

Inactive Publication Date: 2008-05-22
ALI AMJAD +12
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively inhibit CETP, potentially leading to significant improvements in circulating lipid profiles by increasing HDL and decreasing LDL levels, providing a complementary therapeutic option to existing treatments for atherosclerosis and coronary heart disease.

Problems solved by technology

Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world.
More recently, epidemiologic studies have demonstrated an inverse relationship between High Density Lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.
Despite the significant therapeutic advance that statins such as simvastatin (ZOCOR®) represent, statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events.
Niacin, which provides the most effective therapy for raising HDL-C that has been clinically documented, suffers from patient compliance issues, due in part to side effects such as flushing.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0227]

2-Amino-5-(trifluoromethyl)benzonitrile

[0228]A 2-liter flask was charged with 100 g (0.348 mol) of 4-amino-3-iodobenzotrifluoride, 40 g of CuCN and 750 mL of DMF. The mixture was heated to and then maintained at reflux for 1 hour. The reaction was cooled and poured into 3 L of water containing 300 mL of concentrated ammonium hydroxide. To the mixture was added 1 L CH2Cl2. The mixture was then filtered through celite. The layers were separated and the aqueous layer was back extracted with CH2Cl2. The organic extracts were combined and the solvent removed 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 aqueous HCl and brine. The solution was dried over anhydrous MgSO4 and filtered through a silica gel plug containing a layer of MgSO4 on top. The plug was washed with 0.5 L ether. The ether solutions were combined and concentrated to 750 mL and let stand at room tempe...

example 2

[0229]

2-Iodo-5-(trifluoromethyl)benzonitrile

[0230]To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) at 35° C. was added t-butyl nitrite (21 mL) dropwise. The reaction was maintained at 30-35° C. during the addition. The reaction was aged for 30 min and then was heated to 60° C. for 30 minutes. The reaction mixture was cooled, diluted with ether and washed 2× with water, 2× with aqueous sodium bisulfite, water and then brine. The solution was dried over anhydrous MgSO4, filtered through a silica gel plug and then concentrated giving 100 g of a red oil. The product was purified by silica gel chromatography eluting sequentially with hexanes, 3:1 hexanes / CH2Cl2 and 1:1 hexanes / CH2Cl2 to afford 2-iodo-5-(trifluoromethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.5, 1.8 Hz, 1H).

example 3

[0231]

5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile

[0232]To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (2.0 g, 6.7 mmol) and (5-isopropyl-2-methoxyphenyl)boronic acid (1.6 g, 8.4 mmol) in dimethyl ethylene glycol (30.4 mL) was added 2M Na2CO3 (6.8 mL), ethanol (9.6 mL), and water (10 mL). The solution was degassed with nitrogen for 2 minutes. Pd(PPh3)4 (774 mg, 0.67 mmol) was added and the solution was degassed with nitrogen again for 2 minutes. The solution was divided equally into two 40 mL microwave tubes. Each tube was degassed with nitrogen for 1 minute, sealed, and placed in a microwave reactor. The wattage was set for 200 W until the temperature reached 150° C. and then the temperature was held at 150° C. for ten minutes. The tubes were then cooled to room temperature, combined, poured into H2O (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification ...

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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 benzocycloalkyl substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalkyl substituent connected directly to the ring or attached to the ring through a —CH2—.

Description

FIELD OF THE INVENTION[0001]This invention relates to a class of chemical compounds that inhibit cholesterol ester transfer protein (CETP) and therefore may have utility in the treatment and prevention of atherosclerosis.BACKGROUND OF THE INVENTION[0002]Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and greater than one half million deaths are attributed to CHD each year. Further, this toll is expected to grow over the next quarter century as an epidemic in obesity and diabetes continues to grow.[0003]It has long been recognized that in mammals, variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA Reductase inhibitors, especially the statins, in reducing coro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/422A61K31/40A61K31/4166A61K31/427A61K31/4439A61K31/501A61P9/10C07D233/32C07D263/20C07D417/10C07D417/04C07D413/10C07D413/04C07D401/04C07D285/10C07D233/44C07D207/24A61K31/506A61K31/497A61K31/433A61K31/4168A61K31/421
CPCC07D207/26C07D207/27C07D233/32C07D233/52C07D263/20C07D263/22C07D263/24C07D285/10C07D413/04C07D413/06C07D413/10C07D417/10C07F7/10C07F7/1804C07D401/04C07D417/04A61K31/421C07D263/04A61K31/4015A61K31/4166A61K31/4168A61K31/422A61K31/427A61K31/433A61K31/4439A61K31/497A61K31/501A61K31/506C07D233/38C07D233/50C07D263/26C07D285/06A61P3/00A61P3/04A61P3/06A61P39/02A61P43/00A61P7/00A61P9/00A61P9/08A61P9/10A61P9/12A61P9/14A61P3/10A61K45/06
Inventor ALI, AMJADNAPOLITANO, JOANN M.DENG, QIAOLINLU, ZHIJIANSINCLAIR, PETER J.TAYLOR, GAYLE E.THOMPSON, CHRISTOPHER F.QURAISHI, NAZIASMITH, CAMERON J.HUNT, JULIANNE A.DOWST, ADRIAN A.CHEN, YI-HENGLI, HONG
Owner ALI AMJAD
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