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Substituted morpholine and thiomorpholine derivatives

A technology of thiomorpholine and derivatives, which is applied in the field of openers of KCNQ family potassium ion channels, and can solve problems such as reducing neuronal excitability

Inactive Publication Date: 2007-03-14
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Modulation of M-currents has a surprising effect on neuronal excitability, for example, activation of currents will reduce neuronal excitability

Method used

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  • Substituted morpholine and thiomorpholine derivatives
  • Substituted morpholine and thiomorpholine derivatives
  • Substituted morpholine and thiomorpholine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0540] 1a N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide.

[0541] In a sealed microwaved vial, 2-bromo-4-morpholin-4-yl-6-trifluoromethyl-aniline (0.236 g) and 4-fluorophenylacetyl chloride (0.105 mL) were dissolved in acetonitrile (5 ml) and heated to 150°C for 10 minutes. Water (25 mL) was added and the product was extracted with ethyl acetate (3 x 25 mL). The organic phase was washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography to provide 0.027 g (9%) of the title compound as an off-white solid. LC-MS (m / z) 462 (MH + ); R =2.84, (UV, ELSD) 96%, 100%. 1 H NMR (500MHz, DMSO-d 6 ): 3.23(m, 4H), 3.62(s, 2H), 3.72(m, 4H), 7.14(dd, 2H), 7.19(d, 1H), 7.35(dd, 2H), 7.46(d, 1H) , 9.78 (s, 1H).

[0542] The following compounds were prepared analogously:

[0543] 1b 2-Cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide.

[0544]...

Embodiment 2

[0562] 2a 2-Cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide.

[0563] Bis(dibenzylideneacetone)palladium (37 mg) and (2'-dicyclohexylphophanyl-biphenyl-2-yl)-dimethyl-amine (38 mg) were desiccated in a dry atmosphere under argon atmosphere. Mix in degassed toluene (2 mL) for 5 minutes. To this mixture was added N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (200 mg), potassium tert-butoxide (90 mg) and thiomorpholine (80 mg) and the reaction mixture was heated to 90 °C in a sealed 4 mL vial under argon atmosphere for 16 hours, cooled and filtered through silica (2 g). Water / brine (1:1, 4 mL, total) was added, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by preparative LC-MS to provide 5.6 mg (3% yield) of the title compound. LC-MS-TOF (m / z) 333 (MH + ); R =2.03, (UV, ELSD) 98%, 100%.

[0564] The following co...

Embodiment 3

[0582] 3a 2-Bicyclo[2.2.1]hept-2-yl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide.

[0583] Bicyclo[2.2.1]hept-2-yl-acetic acid (0.41 g) was dissolved in a 1:1 mixture of thionyl chloride and 1,2-dichloroethane (10 mL, total) under argon atmosphere Heat to 50°C for 2 hours. The solvent was removed in vacuo, the resulting acid chloride was redissolved in acetonitrile (5 mL), and 2,6-dimethyl-4-morpholin-4-yl-aniline (0.50 g) was added. In a sealed microwaved vial, the reaction mixture was heated to 150°C for 10 minutes. Water (25 mL) was added and the product was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to provide 0.074 g (9%) of the title compound as an off-white solid. LC-MS-TOF (m / z) 343 (MH + ); R =2.21, (UV, ELSD) 98%, 100%. 1 H NMR (500MHz, DMSO-d 6 ): 1.14(m, 4H), 1.41(m, 4H), 1.90(m, 1H),...

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Abstract

The present invention relates to morpholine and thiomorpholine derivatives of the general formula I or pharmaceutically acceptable salts thereof, and their use.

Description

field of invention [0001] The present invention relates to novel substituted morpholine and thiomorpholine derivatives which are openers of potassium ion channels of the KCNQ family. The compounds are useful in the treatment of conditions and diseases that are sensitive to the opening of potassium ion channels of the KCNQ family, one such disease being epilepsy. Background of the invention [0002] Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chloride, and sodium, into and out of cells. Such channels are present in all animal and human cells and affect a variety of processes including neuronal conduction, muscle contraction and cell secretion. [0003] Humans have more than 70 gene-encoded potassium channel subtypes with great diversity in structure and function (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30). Neuronal potassium channels found in the brain are primarily responsible for maintaining a negative resting ...

Claims

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Application Information

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IPC IPC(8): C07D295/12C07D265/06C07D279/12C07D417/04A61K31/4406A61K31/541A61K31/5355A61P25/22A61K31/5375A61K31/5377A61K31/54C07D265/30C07D295/135C07D307/85C07D413/04C07D413/10C07D417/10
CPCC07D307/85C07D279/12C07D417/04C07D295/135C07D265/06A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28C07D265/30C07D295/12C07D413/04
Inventor C·温策尔托尔内M·罗特兰德N·汉津A·里岑W·P·沃特森
Owner H LUNDBECK AS
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