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

A compound, alkyl technology, used in the field of treatment and prevention of atherosclerosis and related diseases and disorders

Inactive Publication Date: 2006-09-06
MERCK & CO INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, based on studies described by 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 causes myocardial infarction and risk of stroke

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
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preparation example Construction

[0261] Preparation of intermediates:

[0262] Route I-1

[0263]

[0264] Bis[2.2.1]heptan-7-one (I-1a) was prepared according to Gassman, P.G.J.Org.Chem. 1964, 29, 160-163 and references cited therein.

[0265]Route I-2

[0266]

[0267] Preparation of (±)-2-(2-phenylbicyclo[2.2.1]hept-2-yl)benzene-1,4-diol (I-2b)

[0268] Step A: Preparation of (±)-2-phenylbicyclo[2.2.1]heptane-2-ol (I-2a)

[0269] To a solution of norcamphor (60.0 g, 0.54 mole) in THF (1 L) was added phenylmagnesium bromide (200 mL of a 3M solution in diethyl ether, 0.60 mole) at -65°C. The temperature was maintained between -65°C and -20°C during the addition. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0°C and saturated aqueous ammonium chloride (200 mL) was carefully added. 1N Hydrochloric acid was added until the residual salt was dissolved. The mixture was then extracted twice with...

Embodiment 1a

[0286] Examples 1a, 1b and 1c

[0287] Step A v1: (±)-2-{[2-(2-Phenylbicyclo[2.2.1]hept-2-yl)-4-(quinolin-2-ylmethoxy)phenoxy]methanol Base} quinoline (1a) and (±)-2-{[2-(2-phenylbicyclo[2.2.1]hept-2-yl)-4-(quinolin-2-ylmethoxy)phenol Preparation of (1b)

[0288] Potassium tert-butoxide (23.1 mL of a 1M solution in THF, 23.1 mmol) was added dropwise to a solution of I-2b (6.48 g, 23.1 mmol) in DMF (130 mL) at room temperature. During the addition, the reaction mixture turned from heterogeneous to homogeneous. The resulting solution was left at room temperature for 20 minutes. After this time a solution of 2-(chloromethyl)quinoline (2.90 g, 22.0 mmol) in DMF (5 mL) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water / 1N hydrochloric acid (300 mL:25 mL) at 0 °C and extracted 3 times with EtOAc. The combined organic extracts were washed 3 times with water and dried (MgSO 4 ) and concen...

Embodiment 2a2bb

[0302] Example 2a.2bb 2c and 2d

[0303] Step A: (±)-2-(2-Phenylbicyclo[2.2.1]hept-2-yl)-4-(quinolin-2-ylmethoxy)phenyl triflate (2a ) preparation

[0304] A solution of 1b (500 mg, 1.19 mmol) in pyridine (5 mL) was diluted with toluene (5 mL) and cooled to 0 °C. To this mixture was added trifluoromethanesulfonic anhydride (0.20 mL, 1.19 mmol) dropwise. The resulting mixture was stirred at room temperature for 18 h. A second portion of trifluoromethanesulfonic anhydride (0.06 mL, 0.36 mmol) was added and after about 4 h, the reaction mixture was diluted with water and extracted 3 times with EtOAc. The combined organic extracts were washed with water and dried (MgSO 4 ) and concentrate. Flash chromatography (silica gel; hexane / EtOAc 9:1) of the residue gave a solid (533 mg) which was triturated with hexane to give 2a , as a solid (402 mg), m.p. 131-132°C.

[0305] Step B: Preparation of (±)-methyl 2-(2-phenylbicyclo[2.2.1]hept-2-yl)-4-(quinolin-2-ylmethoxy)benzoate (2b) ...

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Abstract

The instant invention provides compounds of formula: (I) which are 5-lipoxygenase activating protein inhibitors: formula (I). Compounds of formula (I) are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cyto-protective 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 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 contractile and inflammatory mediators produced by 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). In general, 5-LO inhibitors have been sought for the treatment of allergic rhinitis, elimination and inflammatory conditions, including rhinitis. An example of a 5-LO inhibitor is the marketed drug Zileton, which is used in the treatment of asthma. Recently, it has been reported that 5-LO may be an important pathogenic ...

Claims

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Application Information

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IPC IPC(8): A61K31/535C07D221/02C07D231/02C07D263/02C07D
CPCC07D401/12C07D215/12C07D237/28C07D417/12C07D215/14C07D413/12C07D277/64C07D471/02A61P1/04A61P1/12A61P1/16A61P11/00A61P11/02A61P11/06A61P13/12A61P15/00A61P15/06A61P17/00A61P17/02A61P19/02A61P25/00A61P25/04A61P25/06A61P25/08A61P27/02A61P29/00A61P29/02A61P35/02A61P35/04A61P37/06A61P37/08A61P43/00A61P7/00A61P7/02A61P9/10A61P9/12
Inventor L·楚M·T·古莱特F·乌贾因沃拉R·弗伦内特Y·吉拉尔M·特里恩D·麦唐纳J·H·哈钦森L·常
Owner MERCK & CO INC
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