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3-phenyl-3-methoxypyrrolidine derivatives as modulators of cortical catecholaminergic neurotransmission

A technology of methoxypyrrolidine and methylpyrrolidine, which is applied in the field of therapeutic application and treatment of central nervous system disorders, and can solve the problems of undisclosed medical uses of compounds

Active Publication Date: 2014-01-22
INTEGRATIVE RES LAB SWEDEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Document EP586,229 discloses the compound 3-(2,4-difluorophenyl)-3-methoxypyrrolidine; but does not disclose the medical use of the compound

Method used

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  • 3-phenyl-3-methoxypyrrolidine derivatives as modulators of cortical catecholaminergic neurotransmission
  • 3-phenyl-3-methoxypyrrolidine derivatives as modulators of cortical catecholaminergic neurotransmission
  • 3-phenyl-3-methoxypyrrolidine derivatives as modulators of cortical catecholaminergic neurotransmission

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] (+)-3-(3-Chloro-2-fluorophenyl)-3-methoxypyrrolidine

[0157] 1-Chloroethylchloromethyl ester (1.42ml, 13.08mmol) was added to (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (1.04g, 3.25mmol) in a solution in 1,2-dichloroethane (10ml) and the mixture was heated to reflux for 2 hours after which time the solvent was evaporated. The mixture was dissolved in methanol (20ml), heated to reflux for 1 hour, the solvent was evaporated, and the solvent was evaporated by HPLC on waters OBD C18, 5 μm (MeOH / 33mM NH 3 , 20:80 to 50:50) to afford the title compound 0.47 g (63%). [a] D = +6.5° (methanol). Amine conversion to oxalate, recrystallization from methanol / diethyl ether: M.p. 183-185°C. MS m / z (relative intensity, 70 eV) 229 (M+, 1), 199 (86), 187 (bp), 157 (49), 133 (42).

Embodiment 2

[0159] (+)-3-(3-Chloro-2-fluorophenyl)-1-ethyl-3-methoxypyrrolidine

[0160] Iodoethane (0.13ml, 1.63mmol) was added to (+)-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.25g, 1.08mmol) and triethylamine (0.305ml, 2.17mmol) in tetrahydrofuran (20ml) and the solution was stirred at ambient temperature for 26 hours. Water (20ml) was added, the aqueous phase was extracted with EtOAc (2x50ml), and the combined organic phases were dried (Na 2 SO 4 ), evaporate the solvent. By HPLC in waters OBD C18, 5μm (MeOH / 33mM NH 3 , 20:80 to 65:35) to afford the title compound 0.106 g (38%). [a] D =+16.5° (methanol). Conversion of amine to fumarate, recrystallization from 2-propanol / diisopropanol ether: M.P. 131-133°C. MS m / z (relative intensity, 70 eV) 257 (M+, 9), 242 (bp), 227 (44), 157 (44), 71 (89).

Embodiment 3

[0162] (-)-3-(3-Chloro-2-fluorophenyl)-3-methoxypyrrolidine

[0163] Prepared according to Example 1. (-)-1-benzyl-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.82g, 2.56mmol), 1,2-dichloroethane (10ml ), 1-chloroethyl chloroformate (1.12ml, 10.25mmol) was refluxed for 2 hours, and methanol (20ml) was added to reflux for 1 hour. Purification by HPLC on waters OBD C18, 5 [mu]m (MeOH / 33 mM NH3, 20:80 to 50:50) afforded the title compound (0.38 g, 65%). [a] D = -7.1° (methanol). Amine conversion to oxalate, recrystallization from methanol / diethyl ether: M.p. 183-185°C. MS m / z (relative intensity, 70 eV) 229 (M+, 1), 199 (87), 187 (bp), 157 (55), 133 (51).

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Abstract

The present invention relates to novel 3-phenyl-3-methoxy-pyrrolidine derivatives, useful for modulating dopamine neurotransmission and 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-3-methoxy-pyrrolidine 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-3-methoxy-pyrrolidine derivatives suitable for modulating extracellular levels of catecholamines, dopamine and norepinephrine in the cerebral cortex regions of the mammalian brain, more particularly For the treatment of central nervous system disorders. [0002] In other aspects, the invention relates to pharmaceutical compositions comprising the 3-phenyl-3-methoxy-pyrrolidine 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/12A61K31/40A61P25/18
CPCC07D207/12A61P15/00A61P15/04A61P15/08A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P3/00A61P3/04A61P43/00A61K31/38A61K31/445A61K45/06
Inventor C·索内松L·斯万松F·彼得松
Owner INTEGRATIVE RES LAB SWEDEN
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