Substituted pyrazinone derivatives as alpha2c-adrenoreceptor antagonists

A technology of pyrazinone and derivatives, applied in the field of substituted pyrazinone derivatives

Inactive Publication Date: 2009-01-14
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

None of these compounds are selective for any three α-adrenergic receptors

Method used

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  • Substituted pyrazinone derivatives as alpha2c-adrenoreceptor antagonists
  • Substituted pyrazinone derivatives as alpha2c-adrenoreceptor antagonists
  • Substituted pyrazinone derivatives as alpha2c-adrenoreceptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0112] Preparation of intermediate compound (1-4)

[0113]

[0114] Option 1B

[0115] Alkylation reactions of raw material 2,3-dichloropyrazine (I-1) and amino derivatives (I-2) (Scheme 1A) or (I-5) (Scheme 1B) alkylation reaction can be in the proton In an inert solvent such as DMF or DMSO, in an inorganic base such as K 2 CO 3 、Na 2 CO 3 , NaOH or KOH, at normal temperature, or by conventional heating or microwave radiation for a period of time to ensure that the reaction is complete. Under conventional heating, the reaction can usually be carried out for about 16 hours.

[0116]The hydrolysis reaction can be carried out in an acidic inorganic solvent such as 10% HCI in water, using a co-solvent such as THF, by conventional heating or microwave heating for a period of time to ensure the reaction is complete, and the reaction can usually be carried out for about 16 hours under conventional heating, or Under basic conditions such as NaOH aqueous solution or in DMSO ...

Embodiment C1

[0370] Example C.1: α 2C - Adrenergic receptor binding assay

[0371] Cell culture and plasma membrane preparation

[0372] will be stably transfected with human epinephrine-α 2A , -α 2B or alpha 2C CHO cells with recipient cDNA were cultured in Dulbecco's Modified Eagle's Medium (DMEM) / Ham's F12 nutrient mixture (ratio 1:1) (Gibco, Gent-Belgium) supplemented with 10% heat-inactivated Fetal bovine serum (Life Technologies, Merelbeke-Belgium) and antibiotics (100 IU / ml penicillin G, 100 μg / ml streptomycin sulfate, 110 μg / ml pyruvate and 100 μg / ml L-glutamine). The day before harvest, cells were induced with 5 mM sodium butyrate. After reaching 80-90% confluence, the cells were taken out and added to Ca-free 2+ and Mg 2+ Cells were harvested by centrifugation at 1500xg for 10 minutes in phosphate-buffered saline. Cells were homogenized in Tris-HCl 50 mM using an Ultraturrax homogenizer and centrifuged at 23,500 xg for 10 minutes. The pellet was washed once by re...

Embodiment D1

[0393] Example D.1: Oral drops

[0394] Dissolve 500 g a.i. in 0.5 L 2-hydroxypropionic acid and 1.5 L polyethylene glycol at 60-80°C. After cooling to 30-40°C, 35 L of polyethylene glycol was added and the mixture was stirred well. Then add 1750 g of sodium saccharin to 2.5 L of pure water and add 2.5 L of cola essence and appropriate amount of polyethylene glycol to 50 L under stirring to obtain an oral drop solution containing 10 mg / ml a.i. Fill the resulting solution into suitable containers.

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Abstract

The present invention concerns substituted pyrazinone derivatives according to the general Formula (I) a pharmaceutically acceptable acid or base addition salt thereof, a stereo- chemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein the variables are defined in Claim 1, having se- lective a2C-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine. The compounds according to the invention are usefull for the prevention and/or treatment of central nervous system disorders, mood disorders, anxiety disorders, stress-related disorders associated with depression and/or anxiety, cognitive disorders, personality disorders, schizoaffective disorders, Parkinson's disease, dementia of the Alzheimer's type, chronic pain conditions, neurodegenerative diseases, addiction disorders, mood disorders and sexual dysfunction.

Description

technical field [0001] The present invention relates to selective α 2C - Adrenergic receptor antagonist activity as well as substituted pyrazinone derivatives having 5-HT reuptake inhibitory activity. The invention also relates to their preparation, pharmaceutical compositions comprising said derivatives and their use as medicaments, in particular for the treatment of diseases of the central nervous system. Background of the invention [0002] Adrenoceptors form the binding site between the endogenous catecholamines epinephrine and norepinephrine and numerous target cells in the body that mediate the biological effects of the sympathetic nervous system. They are divided into three main subtypes, α 1 、α 2 and beta 3 . So far, nine different subtypes of adrenaline have been cloned from several species: α 1A 、α 1B 、α 1D 、α 2A 、α 2B 、α 2C , β 1 , β 2 and beta 3 . (Hieble, J.P. et al. J. Med. Chem. 1995, 38, 3415-3444). Available α 2 Ligands are only marginally s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/497A61P25/00
CPCC07D401/14C07D401/12C07D413/14C07D405/14C07D409/14A61P25/00A61P25/04A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P43/00
Inventor J·I·安德雷斯-吉尔M·J·艾卡扎尔-瓦卡M·L·利纳雷斯德拉莫雷纳S·马蒂尼茨冈扎尔茨J·奥亚扎巴尔桑塔马里纳J·帕斯托尔-弗南德茨J·A·维加拉米罗W·H·I·M·德林肯伯格
Owner JANSSEN PHARMA NV
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