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Aryl piperazine derivatives useful for the treatment of neuropsychiatry disorders

A technology of arylpiperazine and derivatives, which is applied in the field of arylpiperazine derivatives, and can solve problems such as no reports of arylpiperazine derivatives

Inactive Publication Date: 2009-10-28
UNIV DEGLI STUDI DI ROMA LA SAPIENZA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the arylpiperazine derivatives of the present invention have not been reported

Method used

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  • Aryl piperazine derivatives useful for the treatment of neuropsychiatry disorders
  • Aryl piperazine derivatives useful for the treatment of neuropsychiatry disorders
  • Aryl piperazine derivatives useful for the treatment of neuropsychiatry disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Preparation Example

[0084] In order to get 5 1 and 5 2 The synthetic strategy followed is reported in Scheme 1 below.

[0085] Commercially available 6-methylquinoline was oxidized to the corresponding quinoline-6-carboxylic acid (2) in acidic medium by using chromium trioxide. The acid 2 was converted to the hydroxyamide 3 by means of a coupling reaction with 4-aminobutanol in the presence of 1-hydroxybenzotriazole (HOBt) and 1,3-dicyclohexylcarbodiimide (DCC). . The latter, following bromination of the hydroxyl group, leads to the bromo-derivative 4, which is treated with the appropriate arylpiperazine in the presence of a base to give the desired product (5 1，2 ).

[0086] plan 1

[0087]

[0088] a) CrO 3 、H 2 O / H 2 SO 4 Reflux; b) 4-amino-1-butanol, EDC, HOBt, TEA, CH 2 Cl 2 dry, rt; c) CBr 4 、PPh 3 、CH 3 CN, rt; d) for 5 1 1-phenylpiperazine or for 5 2 8, TEA, CH 3 CN, reflow.

[0089] Synthesis of 5 was obtained from Boc-piperazine and 1-b...

Embodiment 2

[0122] biological activity

[0123] In vitro binding studies

[0124] The affinity of Compound 5 of the present invention for dopamine and serotonin receptor subtypes was determined by a standard receptor binding assay performed by MDS Pharma Services using the specific assay conditions described below.

[0125] From these assays, compound 5 of the present invention was found to be selective for dopamine D3 with a Ki in the subnanomolar range.

[0126] Dopamine D3 (MDS Catalog No.219800)

[0127] Human Recombinant CHO Cells

[0128] Ligand = 0.7nM [ 3 H]-Spiperone

[0129] Nonspecific = 25 μM S(-)-sulpiride

[0130] 5-hydroxytryptamine 5-HT 1A (MDS Catalog No.271110)

[0131] Human recombinant (CHO cells)

[0132] Ligand = 1.5nM [ 3 H]8-OH-DPAT

[0133] Nonspecific = 10 μM ergobenzyl ester

[0134] 5-hydroxytryptamine 5-HA 2A (MDS Catalog No.271650)

[0135] Human recombinant (CHO cells)

[0136] Ligand = 0.5nM [ 3 H]ketanserin

[0137] Nonspecifi...

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PUM

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Abstract

This invention provides novel aryl piperazine derivatives represented by Formula (I) having medical utility, in particular as modulators of dopamine and serotonin receptors, preferably the D3, 5HT1A and 5-HT2A receptor subtypes, and in particular useful for the treatment of neuropsychiatric disorders, incl. schizophrenia.

Description

technical field [0001] The present invention provides novel arylpiperazine derivatives which are useful in medicine, especially as receptors for dopamine and serotonin, preferably D 3 , 5HT 1A and 5-HT 2A Modulators of receptor subtypes, and particularly useful in the treatment of neuropsychiatric disorders including schizophrenia. Background technique [0002] Dopamine is associated with several important excitatory and inhibitory functions in the central and peripheral nervous system via dopaminergic receptors. Dopamine receptors were originally divided into two main classes: D 1 and D 2 . The five dopamine receptors cloned so far belong to the above categories. Therefore, D 1 -like receptors including D 1 and D 5 , while D 2 -like receptors including D 2 、D 3 and D 4 . [0003] dopamine receptors, and in particular D 2 -like receptors are considered as potential therapeutic targets for different neurological and psychiatric disorders, especially psychiatric...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48A61K31/4709A61P25/18
Inventor G·卡姆皮亚尼S·布逖尼C·法特鲁索S·弗朗斯施尼Z·I·萨勒K·S·尼尔森J·施尔-克鲁戈L·S·马德森J·施尔－克鲁戈
Owner UNIV DEGLI STUDI DI ROMA LA SAPIENZA
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