Modulators of dopamine neurotransmission

a technology of dopamine neurotransmission and modulators, applied in the field of new modulators of dopamine neurotransmission, can solve problems such as inability to obtain, and achieve the effects of high oral bioavailability and good pharmacokinetic properties

Inactive Publication Date: 2016-08-23
PRILENIA NEUROTHERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0032]Given the involvement of dopamine in a large variety of CNS functions and the clinical shortcomings of presently available pharmaceuticals acting on dopamine systems, the novel class of dopaminergic modulators presented in this invention may prove superior to presently known dopaminergic compounds in the treatment of several disorders related to dysfunctions of the CNS, in terms of efficacy as well as side effects.
[0033]Some compounds according to the invention have been found to have surprisingly good pharmacokinetic properties including high oral bioavailability. They are thus suitable for the preparation of orally administered pharmaceuticals. There is no guidance in the prior art how to obtain compounds with this effect on dopamine systems in the brain.

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-(3-Methanesulfonyl-phenyl)-4-propyl-pierazine

[0123]A suspension of 1-(3-methanesulfonyl-phenyl)-piperazine (350 mg) and ground K2CO3 (403 mg) was stirred in CH3CN (25 mL) at room temperature. 1-Iodopropane (712 μL) was added. The mixture was refluxed 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 (1:30 (v / v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-(3-methanesulfonyl-phenyl)-4-propyl-piperazine (220 mg). The amine was converted into the HCl salt and recrystallized from ethanol / diethylether: m.p. 233° C. MS m / z (relative intensity, 70 eV) 282 (M+, 30), 254 (15), 253 (bp), 210 (17), 70 (21).

[0124]The following compounds according to Examples 2-11 were prepared in a manner similar to the one described in Example 1.

example 2

1-Propyl-4-(3-Trifluoromethanesulfonyl-phenyl)-piperazine

[0125]MS m / z (relative intensity, 70 eV) 336 (M+, 16), 307 (bp), 77 (18), 70 (38), 56 (23).

example 3

1-[3-(4-Propyl-piperazin-1-yl)-phenyl]-ethanone

[0126]Beginning with 1-(3-Piperazin-1-yl-phenyl)-ethanone and n-Pr-I: m.p. 119° C. (oxalate), MS m / z (rel. intensity, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf 0.23 (EtOAc).

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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 N, CH, or C, however X may only be C when the compound comprises a double bond at the dotted line; R1 is OSO2CF3, OSO2CH3, SOR3, SO2R3, COR3, NO2, or CONHR3 and when X is CH or C R1 may also be CF3, CN, F, Cl, Br, or I; R2 is a C1-C4 alkyl, an allyl, CH2SCH3, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-trifluoropropyl, 4,4,4,-trifluorobutyl, or —(CH2)—R4; R3 is a C1-C3 alkyl CF3, or N(R2)2; R4 is a C3-C6 cycloalkyl, 2-tetrahydrofurane or 3-tetra-hydrofurane, as well as 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

[0001]This application is a reissue application of U.S. Pat. No. 6,903,120, issued Jun. 7, 2005 from U.S. Ser. No. 10 / 168,173, filed Nov. 21, 2002, which was a §371 national stage of PCT International Application No. PCT / SE00 / 02674, filed Dec. 22, 2000, which claims priority of Swedish Patent Application No. 9904724-3, filed Dec. 22, 1999.FIELD OF THE INVENTION[0002]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[0003]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, modulatio...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D211/22C07D405/00C07D211/20C07D211/32C07D405/06C07D211/34C07D211/18C07D295/155C07D211/24C07D211/70C07D211/00C07D295/073C07D295/096C07D295/112
CPCC07D295/073C07D211/18C07D211/20C07D211/22C07D211/24C07D211/32C07D211/34C07D211/70C07D295/096C07D295/112C07D295/155C07D405/06
Inventor SONESSON, CLASANDERSSON, BENGTWATERS, SUSANNAWATERS, NICHOLASTEDROFF, JOAKIM
Owner PRILENIA NEUROTHERAPEUTICS LTD
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