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New disubstituted phenylpiperidines as modulators of dopamine neurotransmission

A technology of propylpiperidine and piperidine, which is applied to new 4--1-alkylpiperidines and piperazines and their application fields, and can solve problems such as unillustrated ortho-substitution

Inactive Publication Date: 2007-07-11
NSAB FILIAL AF NEUROSEARCH SVERIGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] However, only mono-substitution of aryl rings is disclosed in WO01 / 46145 (general formula II), while ortho-substitution is not exemplified

Method used

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  • New disubstituted phenylpiperidines as modulators of dopamine neurotransmission
  • New disubstituted phenylpiperidines as modulators of dopamine neurotransmission
  • New disubstituted phenylpiperidines as modulators of dopamine neurotransmission

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0703] 4-[2-Fluoro-3-(methylsulfonyl)phenyl]-1-propylpiperidine

[0704] To a solution of 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.4g, 1.55mmol) in acetonitrile (40ml) was added potassium carbonate (0.3g, 2.17mmol) and 1- Iodopropane (0.151 mL, 1.55 mmol) and the mixture was heated at reflux for 15 hours. The mixture was cooled to ambient temperature and water (50ml) was added. The aqueous residue was extracted with ethyl acetate (3 x 50ml) and the combined organic phases were dried and purified by flash chromatography (ethyl acetate / methanol, 1:1) to give the title compound (0.37g, 79%). Conversion of amine to hydrochloride and recrystallization from ethanol / ether: M.p. 255-257°C. MS m / z (relative intensity, 70eV) 299(M+, 2), 271(16), 270(bp), 147 (9) 133 (10).

Embodiment 2

[0706] 1-Ethyl-4-[2-fluoro-3-(methylsulfonyl)phenyl]-piperidine

[0707] Prepared according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]-piperidine (0.185g, 0.72mmol), acetonitrile (10ml), potassium carbonate (0.2g, 1.44mmol), 1-Iodoethane (0.06ml, 0.75mmol). Yield: 0.15g (73%). The amine was converted into several different salts and recrystallized from ethanol / ether. Hydrochloride m.p.273-275℃, hydrobromide m.p.267-268℃, fumarate m.p.204-206℃, oxalate m.p.163-165℃, sulfate m.p.263-265℃, maleate p.112-113° C. MS m / z (relative intensity, 70 eV) 285 (M+, 12), 271 (15), 270 (bp), 147 (7) 133 (8).

[0708] Embodiment 2: (synthesized by another approach)

[0709] 1-Ethyl-4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine

[0710] 1-Ethyl-4-[2-fluoro-3-(methylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine (5g, 17,7mmol), formic acid (3.4ml, 90MMol ) and palladium on carbon (1.1 g) in isopropanol (50 ml) was shaken in a Parr apparatus for 20 hours. The reaction mixture was fi...

Embodiment 3

[0712] 4-[2-Chloro-3-(methylsulfonyl)phenyl]-1-propylpiperidine

[0713] 4-[2-Chloro-3-(methylsulfonyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (0.46g, 1.47mmol), platinum oxide (0.11g) Hydrogenate with a mixture of hydrochloric acid (0.1 mL, conc.) in methanol (30 mL) under an atmosphere of hydrogen at 50 psi for 1 hour. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 0.48 g of crude product as the hydrochloride salt. Purification by flash chromatography (ethyl acetate / methanol, 1:1) afforded the title compound (0.35 g, 75%). Conversion of amine to hydrochloride and recrystallization from ethanol / ether: M.p. 250-252°C. MS m / z (relative intensity, 70eV) 315(M+, 3), 288(37), 287(15), 286 (bp) 129(7).

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Abstract

The present invention relates to compounds which have therapeutic effects against disorders in the central nervous system, and in particular new 4-(ortho, meta-disubstituted phenyl)-1-alkypiperidines and piperazines, wherein R1, R2, R3 and Y are as defined.

Description

field of invention [0001] The present invention relates to novel modulators of dopamine neurotransmission, and more particularly, the present invention relates to novel 4-(ortho, meta-disubstituted phenyl)-1-alkylpiperidines and piperazines and their application. 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...

Claims

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Application Information

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IPC IPC(8): C07D211/18C07D211/22C07D211/52A61K31/495A61P25/00C07D295/06C07D295/14C07D
Inventor C·索内松L·斯万松N·瓦特斯
Owner NSAB FILIAL AF NEUROSEARCH SVERIGE
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