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Diphenyl substituted cycloalkanes, compositions containing such compounds and methods of use

A compound, phenyl technology, applied in the field of compounds that inhibit 5-lipoxygenase-activated protein, can solve problems such as danger

Inactive Publication Date: 2008-03-05
MERCK & CO INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, based on studies described in Helgadottir, A., et al. Nature Genetics, vol 36, no. 3 (March 2004) 233-239, it is believed that the gene encoding 5-lipoxygenase activating protein confers Risk of heart attack and stroke
[0005] Despite significant therapeutic advances in the treatment and prevention of atherosclerosis and the resulting atherosclerotic diseases, such as the improvements that have been achieved with HMG-CoA reductase inhibitors, further treatment options are clearly needed

Method used

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  • Diphenyl substituted cycloalkanes, compositions containing such compounds and methods of use
  • Diphenyl substituted cycloalkanes, compositions containing such compounds and methods of use
  • Diphenyl substituted cycloalkanes, compositions containing such compounds and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0297] Reaction scheme 1

[0298]

[0299] Step A: 2,2'-[[2-(1-phenylcyclopentyl)-1,4-phenylene]bis(oxymethylene)]bis -1,3-Benzothiazole (1a) and 4-(1,3-Benzothiazol-2-ylmethoxy) - Preparation of 2-(1-phenylcyclopentyl)phenol (1b)

[0300] At room temperature, 2-(chloromethyl)-1,3-benzothiazole (57.0 mg, 0.31 mmol; according to Mylari, B.L.; Scott, P.J.; Zembrowski, W.J. Synth. prepared), potassium iodide (51.0 mg, 0.31 mmol) and potassium carbonate (71.0 mg, 0.52 mmol) were added to a stirred solution of i-1e (65.0 mg, 0.26 mmol) in DMF (0.75 mL). After 18 hours, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, and dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (gradient elution; 0-30% EtOAc / hexanes as eluent; 4% triethylamine modifier) ​​to afford the title compounds 1a and 1b. ...

Embodiment 2

[0308] Reaction Scheme 2

[0309]

[0310] Step A: 4-[(6-Fluoroquinolin-2-yl)methoxy]-2-(1-phenylcyclobutyl)phenol Preparation of (2a)

[0311] Compound 2a can be prepared from intermediate i-2d and 2-(bromomethyl)-6-fluoroquinoline according to the method outlined in Step A of Scheme 1 .

[0312] Step B: 4-[(6-Fluoroquinolin-2-yl)methoxy]-2-(1-phenylcyclobutyl)phenyl Preparation of triflate (2b)

[0313] Trifluoromethanesulfonic anhydride (1.3 equiv) was added dropwise to a stirred solution of 2a (1.0 equiv) in pyridine / toluene (1:1) at 0°C. The resulting mixture was warmed to room temperature and aged until the reaction was considered complete. The reaction mixture was poured into water and extracted three times with EtOAc. The combined organic extracts were washed with water and dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel to afford the title compound 2b.

[0314] Step C: 4-[(6-Fluoroqui...

Embodiment 3

[0326] Reaction scheme 3

[0327]

[0328] Step A: 4-[(6-Fluoroquinolin-2-yl)methoxy]-2-(1-phenylcyclopentyl)phenol Preparation of (3a)

[0329] Compound 3a can be prepared from intermediate i-1e and 2-(bromomethyl)-6-fluoroquinoline according to the method outlined in Step A of Scheme 1 .

[0330] Step B: 4-[(6-Fluoroquinolin-2-yl)methoxy]-2-(1-phenylcyclopentyl)phenyl Preparation of triflate (3b)

[0331] Compound 3b can be prepared from intermediate 3a according to the method outlined in Step B of Scheme 2.

[0332] Step C: 2-{[4-allyl-3-(1-phenylcyclopentyl)phenoxy]methyl}-6- Preparation of fluoroquinoline (3c)

[0333] Lithium chloride (5.0 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.016 equiv) and allyl(tributyl)stannane ( 2.0 equiv) was added to a solution of 3a in 1-methyl-2-pyrrolidone and the resulting mixture was irradiated in a microwave apparatus (300W) at 120°C until the reaction was considered complete. The reactio...

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Abstract

The instant invention provides compounds of Formula (I) which are 5-lipoxygenase activating protein inhibitors. Compounds of Formula (I) are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.

Description

field of invention [0001] The present invention relates to compounds that inhibit 5-lipoxygenase activating protein (FLAP), compositions containing such compounds, and methods of treatment using such compounds to treat and prevent atherosclerosis and related diseases and conditions. Background of the invention [0002] Inhibition of leukotriene biosynthesis has been an active area of ​​pharmaceutical research for many years. Leukotrienes are potent inotropic and inflammatory mediators derived from the oxidation of arachidonic acid by 5-lipoxygenase. [0003] One class of leukotriene biosynthesis inhibitors are those known to act by inhibiting 5-lipoxygenase (5-LO). Typically, 5-LO inhibitors are sought for treatment of allergic rhinitis, asthma and inflammatory disorders, including arthritis. An example of a 5-LO inhibitor is the marketed drug Zileuton, which is indicated for the treatment of asthma. Recently, it was reported that 5-LO may be an important factor in the at...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61K31/66A61K31/501C07D215/12C07D471/00C07D471/02
CPCC07D215/14C07D401/12C07D403/12C07D487/04C07D513/04C07D413/12A61P1/00A61P1/16A61P11/00A61P11/06A61P13/12A61P17/00A61P19/02A61P25/04A61P25/06A61P27/02A61P29/00A61P35/02A61P37/06A61P37/08A61P43/00A61P9/00A61P9/10A61P9/12
Inventor H·M·阿姆斯特隆L·L·常R·弗雷内特D·麦唐纳H·O·区M·特里恩F·乌贾因瓦拉
Owner MERCK & CO INC
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