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

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

Active Publication Date: 2011-10-19
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] Add 1-chloroethyl chloromethyl ester (1.42ml, 13.08mmol) to (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (1.04 g, 3.25 mmol) in a solution of 1,2-dichloroethane (10 ml), the mixture was heated to reflux for 2 hours, after which the solvent was evaporated. The mixture was dissolved in methanol (20ml), heated to reflux for 1 hour, the solvent was evaporated, and the mixture was subjected to HPLC in waters OBD C18, 5μm (MeOH / 33mM NH 3 , 20:80 to 50:50) to obtain 0.47 g (63%) of the title compound. [a] D = +6.5° (methanol). Amine is converted to oxalate and recrystallized 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] Add iodoethane (0.13ml, 1.63mmol) 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 phase was dried (Na 2 SO 4 ), to evaporate the solvent. By HPLC in waters OBD C18, 5μm(MeOH / 33mM NH 3 , 20:80 to 65:35) to obtain 0.106g (38%) of the title compound. [a] D = +16.5° (methanol). Amine is converted to fumarate and recrystallized from 2-propan / 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. Combine (-)-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 and refluxed for 1 hour. Purified by HPLC on waters OBD C18, 5 μm (MeOH / 33mM NH3, 20:80 to 50:50) to obtain the title compound (0.38g, 65%). [a] D = -7.1° (methanol). Amine is converted to oxalate and recrystallized 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 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 a new 3-phenyl-3-methoxy-pyrrolidine derivative, which is suitable for regulating the extracellular levels of catecholamine, dopamine and norepinephrine in the cerebral cortex region of the mammalian brain, more specifically It is suitable 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-order functions, such as thought, sensation, 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 CNS actually project and distribute in all areas ...

Claims

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Application Information

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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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