Use of chromone derivatives as dopamine d3 receptor antagonists for the treatment of autism spectrum disorders

A use, chromene technology, applied in the field of use of chromone derivatives as dopamine D3 receptor antagonists for the treatment of autism spectrum disorders, can solve the problem of not teaching the treatment of ASD and the like

Active Publication Date: 2018-08-03
PIERRE FABRE MEDICAMENT SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no approved treatments that target the core symptoms of ASD, namely deficits in social interaction and communication, and restricted interests
[0027] Additionally, genetic research is inconclusive and does not teach a cure for ASD, especially deficits in social interaction

Method used

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  • Use of chromone derivatives as dopamine d3 receptor antagonists for the treatment of autism spectrum disorders
  • Use of chromone derivatives as dopamine d3 receptor antagonists for the treatment of autism spectrum disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] According to the present invention, N-(3-{4-[4-(8-oxo-8H-[1,3] Dioxole[4,5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide hydrochloride as dopamine D3 receptor ligands and modulators of this receptor activity. Through [ 3 H] Inhibition of Spiperone Binding Inhibition constants (Ki) were determined. The inventors have demonstrated that the compounds according to the invention behave as potent dopamine D3 receptor ligands with 0.17 nmol l -1 The Ki value. This same compound showed a significant 71-fold attenuation of affinity for the dopamine D2 receptor.

[0048]The agonist, partial agonist or antagonist activity of the compounds according to the invention on the dopamine D3 receptor is evaluated by using the MAP-kinase activity assay on the human recombinant dopamine D3 receptor (Cussac et al., Mol.Pharmacol.1999, vol. 56, p1025-1030). The intrinsic activity of this compound is zero, indicating that it is a full antagonist.

Embodiment 2

[0050] N-(3-{4-[4-(8-oxo-8H-[1,3]dioxole[4,5-g] Chrom-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide hydrochloride, the female rats had been administered the sodium salt of valproic acid. The experimental setup of the valproic acid autism rat model was adapted from published data (Dendrinos et al., Front. Integr. Neurosci. 2011, vol 5, art 68; Markram et al., Neuropsychopharm. -912; Schneider et al., Neuropsychopharm. 2005, vol30, p 80-89).

[0051] method:

[0052] Pregnant (maximum gestational age 8 days) female Sprague-Dürer rats [OFA (SD) Charles River Lyon, France] were isolated for 4 days. In an environmentally controlled room (temperature 21±1°C; relative humidity 55±5%), under a 12h light / dark cycle (lights turned on at 07:00 am), in full-bottomed cages (ML-H cages, 370x235x180mm ,LxWxH; floor area 870cm 2 ) in group housing (2 animals per cage) with free access to food (A04, Safe, Augy, France) and filtered water (0.2 μm pore size). Until the offspring...

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Abstract

The present invention claims the use of chromone derivatives which are dopamine D3 receptor antagonists and pharmaceutical compositions and combinations comprising at least said derivatives for the treatment of autism spectrum disorders.

Description

technical field [0001] The present invention relates to N-(3-{4-[4-(8-oxo-8H-[1,3]dioxole[4,5-g]chromen-7-yl)- Butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of autism spectrum disorders. Background technique [0002] Patent application WO 2011 / 027289 discloses chromone derivatives, processes for their preparation and their therapeutic use for the treatment of neurological or psychiatric disorders. The chromone derivatives according to WO 2011 / 027289 are partial agonists or antagonists of the dopamine D3 receptor. [0003] In particular, WO 2011 / 027289 discloses N-(3-{4-[4-(8-oxo-8H-[1,3]dioxole[4,5 -g] chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide (Example 21 of WO 2011 / 027289). [0004] [0005] Among diseases treated by chromone derivatives, WO 2011 / 027289 claims Parkinson's disease, psychosis, schizophrenia, movement disorders associated with Parkinson's di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/36A61K38/11A61K31/136A61K31/16A61K31/196A61K31/197A61K31/4168A61K31/55A61P25/00A61P25/18A61P25/28A61K38/095
CPCA61K31/13A61K31/185A61K31/196A61K31/197A61K31/4168A61K31/55A61K38/095A61K31/496A61P25/00A61P25/18A61P25/28A61P43/00A61K2300/00A61K45/06
Inventor A·奥克莱尔P·莫泽P·索科洛夫
Owner PIERRE FABRE MEDICAMENT SAS
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