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Modulators of dopamine neurotransmission

a dopamine neurotransmission and modulator technology, applied in the field of new substituted 4(phenyl nalkyl)piperazines and 4(phenyl nalkyl)piperidines, can solve problems such as inability to obtain, and achieve the effects of improving rehabilitation, improving mental and motor function, and reducing tremors

Inactive Publication Date: 2010-05-04
SANIONA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides new compounds that can modulate dopaminergic systems in the brain, specifically by acting as dopamine receptor antagonists or agonists. These compounds have been found to have high oral bioavailability and good pharmacokinetic properties. They can be used to treat disorders in the central nervous system, particularly those related to dysfunctions of dopamine systems. Compounds of this invention have been found to have a unique action profile, with clear antagonist effects on brain neurochemistry but no or mild inhibitory effects on behavior. They can activate or inhibit brain functions depending on the situation and can be used as oral pharmaceuticals."

Problems solved by technology

These properties have not been described earlier, and they are not possible to obtain with the earlier known compounds.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

1-(4-Chloro-3-trifluoromethyl-phenyl)-4-propyl-piperazine

[0090]A mixture of 5-bromo-2-chlorobenzotrifluoride (0.2 g, 0.85 mmol), n-propyl piperazine (0.15 g, 1.17 mmol), sodium tert-butoxide (0.134 g) dppf (14 mg) and [Pd2(dba)3 (10 mg) in dioxane (5 ml) was heated under argon at 100° C. for 24 h. After cooling to room temperature, the reaction mixture was taken up in Et2O (40-50 ml) and washed with brine (15-20 ml). The organic fraction was dried (MgSO4), filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using CH2Cl2:MeOH (9:1 (v / v)). The amine was converted into the HCl-salt and recrystallized from ethanol / diethylether; m.p. 268° C. (HCl); MS m / z (rel. intensity, 70 eV)) 307 (M+, 6), 279 (33), 277 (98), 70 (bp), 56 (40). Rf=0.35 (EtOAc)

example 2

1-(3-Chloro-5-trifluoromethyl-phenyl)-4-propyl-piperazine

[0091]A suspension of 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine (100 mg) and ground K2CO3 (200 mg) was stirred in CH3CN (30 mL) at room temperature. A solution of 1-bromo-propyl (52 mg) in CH3CN (5 mL) was added dropwise. The mixture was stirred at 50° C. overnight. The reaction mixture was filtered and the volatiles were evaporated in vacuum. The oily residue was chromatographed on a silica column with MeOH: CH2Cl2 (1:9 (v / v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (85 mg). MS m / z (relative intensity, 70 eV) 306 (M+, 25), 277 (bp), 234 (23), 206 (23), 179 (23).

example 3

1-(3-Chloro-5-trifluoromethyl-phenyl)-4-ethyl-piperazine

[0092]Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and iodoethane, the title compound was recovered by the procedure described in Example 2. MS m / z (rel. intensity, 70 eV)) 292 (M+, bp), 277 (88), 234 (33), 206 (55), 179 (49).

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Abstract

New 3-substituted 4-(phenyl-N-alkyl)-piperazine and 4-(phenyl-N-alkyl)-piperidine compounds of Formula (1) wherein X is N, CH, or C, however X may only be C when the compound comprises a double bind at the dotted line; R1 is CF3, OSO2CF3, OSO2CH3, SOR7, SO2R7, COR7, CN, OR3, NO2, CONHR3, 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, or I; R2 is F, Cl, Br, I, CN, CF3, CH3, OCH3, OH, and NH2; R3 and R4 are independently H or a C1-C4 alkyl; R5 is a C1-C4 alkyl, an allyl, CH2SCH3, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or —(CH2)R6; R6 is a C3-C6 cycloalkyl, 2-tetrahydrofurane, or 3-tetra-hydrofurane; R7 is a C1-C3 alkyl, CF3, or N(R4)2, and pharmaceutically acceptable salts thereof are disclosed. Also pharmaceutical compositions comprising the above compounds and methods wherein the above compounds are used for treatment of disorders in the central nervous system are disclosed.

Description

FIELD OF THE INVENTION[0001]The present invention relates to new modulators of dopamine neurotransmission, and more specifically to new substituted 4-(phenyl N-alkyl)-piperazines and 4-(phenyl N-alkyl)-piperidines, and use thereof.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 intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.[0003]Drugs that act, directly or indirectly, at central dopami...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D211/04A61K31/445A61K31/4409C07D295/06A61K31/451A61K31/495A61P3/04A61P15/10A61P21/02A61P25/00A61P25/04A61P25/06A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P43/00C07D211/18C07D211/24C07D211/34C07D211/70C07D241/04C07D295/073C07D295/08C07D295/096C07D295/12C07D295/14
CPCC07D211/18C07D241/04C07D295/073C07D295/096A61P15/10A61P21/02A61P25/00A61P25/04A61P25/06A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P3/04A61P43/00C07D211/70
Inventor SONESSON, CLASANDERSSON, BENGTSVAN, INGELA MARIANNEWATERS, SUSANNAWATERS, NICHOLASTEDROFF, JOAKIM
Owner SANIONA AB
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