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Novel 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission

A technology of azetidine and azetidine, applied in the field of new 3-phenyl-azetidine derivatives, can solve the problem of unreported 3-phenyl-azetidine derivatives, etc. question

Inactive Publication Date: 2011-10-19
NSAB FILIAL AF NEUROSEARCH SVERIGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the 3-phenyl-azetidine derivatives of the present invention have not been reported

Method used

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  • Novel 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission
  • Novel 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission
  • Novel 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] 3-(2,3-Difluorophenyl)-1-ethylazetidin-3-ol

[0128] 1,3-Dichloro-2-(2,3-difluorophenyl)propan-2-ol (6.0 g, 24.89 mmol) was dissolved in acetonitrile (90 ml), transferred to 6 different microwave vials, Each vial contained an equal amount (1.0 g, 2.49 mmol). Sodium bicarbonate (1.04 g, 12.44 mmol (total 6.27 g, 74.67 mmol)) was added to each tube and the tube was sealed. Ethylamine in tetrahydrofuran (2.0M, 2.07ml, 4.15mmol) was added through the septum (total 12.44ml, 24.89mmol), and the mixture was heated under microwave irradiation at 120°C for 30min. Ethylamine in tetrahydrofuran (2.0M, 1.03ml, 2.07mmol (a total of 6.22ml, 12.44mmol), the mixture was heated under microwave irradiation at 120°C for 30min. A solution of water (100ml) and tert-butyl methyl ether (100ml) was added thereto, and the organic phase was collected. Using tert-butyl methyl ether (100ml) to extract the aqueous phase and dry the combined organic phase (Na 2 SO 4 ) and evaporate. The crude p...

Embodiment 2

[0130] 3-(3,4-Difluorophenyl)-1-ethylazetidin-3-ol

[0131] 3-(3,4-difluorophenyl)azetidin-3-ol (0.3g, 1.62mmol) triethylamine (0.68ml, 4.87mmol) and iodoethane (0.19ml, 2.44mmol ) in tetrahydrofuran (15ml) was stirred at ambient temperature for 15 hours. The solvent was evaporated, aqueous hydrochloric acid (50 mL. 10%) was added and the mixture was washed with tert-butyl methyl ether (2 x 50 mL). The aqueous phase was made basic by addition of aqueous sodium hydroxide (5M) and extracted with tert-butyl methyl ether (2 x 50ml). The combined organic phases were dried (Na 2 SO 4 ), evaporated under reduced pressure to give the crude product (0.26 g). Purification by flash column chromatography (ethyl acetate / methanol 1:1) on silica gel afforded 0.2 g (58%) of the title compound. Amine conversion to fumarate, recrystallization from methanol / ether: M.p. 177-179°C. MS m / z (relative intensity, 70 eV) 213 (M+, 1), 141 (86), 127 (45), 114 (58), 58 (bp).

Embodiment 3

[0133] 3-(3,5-Difluorophenyl)-1-ethylazetidin-3-ol

[0134] Dissolve 1,3-dichloro-2-(3,5-difluorophenyl)propan-2-ol (1.0g, 4.15mmol) in acetonitrile (10ml), add sodium bicarbonate (1.39g, 16.59mmol and ethylamine in water (70%, 0.33ml, 4.15mmol), the mixture was refluxed for 10 hours. Water (50ml) and tert-butyl methyl ether (50ml) were added, and the organic phase was collected. The aqueous phase was extracted with tert-butyl methyl ether (50ml, The combined organic phases were extracted with aqueous hydrochloric acid (10%, 50 ml). The aqueous phase was basified, extracted with tert-butyl methyl ether (2×50 ml), dried (Na 2 SO 4 ) and evaporated to give 0.35 g of crude product. Purification by flash column chromatography (ethyl acetate / MeOH 1:0→1:1) on silica gel afforded the title compound (0.2 g, 23%). Amine conversion to fumarate, recrystallization from ethanol / diethyl ether / diisopropyl ether: M.p. 140-141°C. MS m / z (relative intensity, 70 eV) 213 (M+, 1), 156 (36), 14...

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PUM

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Abstract

The present invention relates to novel 3-phenyl-azetidine derivatives, useful for modulating extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous system disorders. In other aspects the invention relates to pharmaceutical compositions comprising the 3-phenyl-azetidine derivatives of the invention and to the use of these compounds for therapeutic applications.

Description

technical field [0001] The present invention relates to novel 3-phenyl-azetidine derivatives suitable for modulating the extracellular levels of catecholamines, dopamine and norepinephrine in the cerebral cortex regions of the mammalian brain, more particularly for the therapeutic Disorders of the central nervous system. [0002] In other aspects, the invention relates to pharmaceutical compositions comprising the 3-phenyl-azetidine derivatives of the invention and the use of these compounds in therapeutic applications. Background technique [0003] The cerebral cortex contains several major areas involved in higher functions such as thinking, feeling, memory and planning. Biogenic amines, namely dopamine, norepinephrine and serotonin, are important for cortical function in mammals. The ascending dopamine and norepinephrine pathways innervate the cortex. The serotonergic neurons of the CNS project to virtually all regions of the brain including the cerebral cortex. Prima...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04A61K31/397A61P25/00
CPCA61P1/00A61P3/00A61P3/04A61P15/00A61P15/10A61P21/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P43/00C07D205/04
Inventor C·索内松L·斯万松F·彼德森
Owner NSAB FILIAL AF NEUROSEARCH SVERIGE
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