Substituted piperidines as modulators of dopamine neurotransmission

A kind of technology of propylpiperidine and ethylpiperidine, applied in the field of new regulators of dopamine neurotransmission

Inactive Publication Date: 2007-11-21
NSAB FILIAL AF NEUROSEARCH SVERIGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0053] Furthermore, neither of the two patent applications discloses 2,3-substitution of aryl rings, and alternative substitution patterns (such as 3,4-disubstitution with hal

Method used

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  • Substituted piperidines as modulators of dopamine neurotransmission
  • Substituted piperidines as modulators of dopamine neurotransmission
  • Substituted piperidines as modulators of dopamine neurotransmission

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] 4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1-propylpiperidin-4-ol

[0238] To a solution of 3-bromo-2-fluorobenzotrifluoride (5.0 g, 20.5 mmol) in dry tetrahydrofuran (70 ml) under nitrogen at -78°C was added n-butyllithium (in hexane 2.5M, 9.0ml, 22.5mmol). The mixture was stirred for 1 hour, after which time a solution of freshly distilled 4-propyl-1-piperidone (2.6 g, 20.5 mmol) in dry tetrahydrofuran (30 mL) was added dropwise. The compound was stirred at -78°C for 30 minutes and then allowed to reach ambient temperature. Water (100ml) was added and the mixture was extracted with ethyl acetate (3x100ml). The combined organic phases were dried (MgSO 4 ), filtered and evaporated to dryness. The oily residue was purified by flash chromatography (ethyl acetate / methanol, 1:1) to give the title compound (2.8 g, 45%). The amine was converted to the hydrochloride and recrystallized from ethanol / ether: M.p. 175-177°C. MS m / z (relative intensity, 70 eV) 305 (M+, 5), 276 (bp...

Embodiment 2

[0240] 4-[4-Chloro-3-(trifluoromethyl)phenyl]-1-(2-methoxyethyl)piperidin-4-ol

[0241] To a mixture of 4-[chloro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.5g, 1.79mmol) and potassium carbonate (0.62g, 4.47mmol) in acetonitrile (40ml) was added 1-bromo-2-methoxyethane (0.17ml, 1.79mmol) and a small amount of sodium iodide crystals, and the mixture was heated under reflux for 15 hours. The mixture was cooled to ambient temperature, water (50ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases were dried (MgSO 4 ) and evaporated under reduced pressure to give an oil. Purification by flash chromatography (ethyl acetate / methanol, 1:1) afforded the title compound (0.41 g, 70%). The amine was converted to the hydrochloride and recrystallized from ethanol / ether: M.p. 181-183°C. MS m / z (relative intensity, 70 eV) 337 (M+, 1), 294 (29), 292 (bp), 274 (72) 201 (29).

Embodiment 3

[0243] 4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1-ethylpiperidin-4-ol

[0244] Prepared as in Example 1: 3-bromo-2-fluorobenzotrifluoride (5.0 g, 20.6 mmol), tetrahydrofuran (50 ml), n-butyllithium (2.5M in hexane, 9.0 ml, 22.5 mmol), 4 - Ethyl-1-piperidone (2.6 g, 20.6 mmol). Yield: 4.0 g. Conversion of amine to hydrochloride and recrystallization from ethanol / ether: M.p. 177-180°C. MS m / z (relative intensity, 70 eV) 291 (M+, 18), 277 (15), 276 (bp), 258 (37), 191 (27).

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Abstract

The present invention relates to compounds having therapeutic effects against disorders in the central nervous system, and in particular substituted hydroxypiperidines of the formula 1: wherein R1, R2, and R3 are as defined herein.

Description

field of invention [0001] The present invention relates to novel modulators of dopamine neurotransmission, and more particularly, the present invention relates to novel substituted piperidines and their use. Background of the invention [0002] Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopamine in the brain has been intensively studied. To date, it is well established that dopamine is essential in several aspects of brain function, including motor, cognitive, sensory, affective, and autonomic functions (eg, appetite regulation, body temperature, sleep). Therefore, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain function. Indeed, drugs that act directly or indirectly on central dopamine receptors are commonly used to treat neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. However, currently available dopaminergi...

Claims

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Application Information

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IPC IPC(8): C07D211/52A61K31/445A61P25/00C07D
CPCC07D211/52A61P3/04A61P15/00A61P25/00A61P25/06A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30
Inventor C·索内松L·斯万松N·瓦特斯
Owner NSAB FILIAL AF NEUROSEARCH SVERIGE
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