Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases

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

Active Publication Date: 2009-01-07
JANSSEN PHARMA NV
View PDF11 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it has been found that MCH also induces the release of corticotropin-releasing factor (CRF) from hypothalamic explants, this effect can be sensitively blocked by MCH-1 receptor antagonists (J. Neuroendrocrinol. (2003) 15, 268- 2729), but there is no direct evidence that the compounds of WO 98 / 11075 also have this effect, so this should not be taken as a starting point for the development of MCH-1 antagonists

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases
  • Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases
  • Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0178] a) Preparation of intermediate compound 1

[0179]

[0180] React in the microwave. 2-phenoxyethylamine (0.010mol), 2,3 dichloropyrazine (0.012mol) and 1,8-diazabicyclo(5.4.0.)undec-7-ene (DBU)(0.012 mol) in CH 3 The mixture in CN (20ml) was heated at 180°C for 20 minutes. The solvent was evaporated. The residue was purified by an open silica gel short column (eluent: CH 2 Cl 2 ). The product fractions were collected and the solvent was evaporated. Obtained: 2.5 g of intermediate compound 1 (quantitative yield; used in the next reaction step without further purification).

[0181] b) Preparation of intermediate compound 2

[0182]

[0183] React in the microwave. A mixture of intermediate compound 1 (0.0092 mol) in NaOH (10 ml; 50%) and DMSO (10 ml) was heated at 150° C. for 30 minutes. The reaction mixture was cooled to 0 °C. EtOAc and water were added at 0 °C. The organic layer was separated and dried (Na 2 SO 4 ), filter Dicalite and evaporate...

Embodiment A2

[0185] Preparation of intermediate compound 3

[0186]

[0187] Stir 4-bromo-2-methoxyphenol (0.0246mol), 2-hydroxyethylpyrrolidine (0.0492mol) and triphenylphosphine (0.0492mol) in THF (50ml; anhydrous) at 0°C in the mixture. In a microwave oven, diethyl azodicarboxylate (0.0492 mol) was added at 0°C. The reaction mixture was stirred at 100°C for 5 minutes. Join Na 2 CO 3 aqueous solution. The mixture was extracted with EtOAc. The separated organic layer was dried (Na 2 SO 4 ), filtered and evaporated the solvent. The residue was captured by adding Amberlyst 15 (0.123 mol) followed by NH 3 / CH 3 OH to release it, followed by purification through an open silica gel short column (eluent: CH 2 CI 2 (CH 3 OH / NH 3 )95 / 5). The product fractions were collected and the solvent was evaporated. Obtained: 6.7 g of intermediate compound 3 (91%).

Embodiment A3

[0189] a) Preparation of intermediate compound 4

[0190]

[0191] A mixture of NaH (0.0049 mol; 60%) in DCE (1.7 ml) was stirred at 0°C. At 0°C, a solution of 2-phenylethanethiol (0.0031 mol) in DCE (5.6 ml) was added in portions. The reaction mixture was stirred at room temperature for 30 min. A solution of 2,3-dichloropyrazine (0.0033 mol) in DCE (1.7 ml) was added and the resulting reaction mixture was heated in a microwave oven at 80° C. for 10 minutes. The mixture was filtered through Celite and the residue on the filter was washed with CH 2 Cl 2 . The solvent of the filtrate was evaporated. The residue was purified by an open silica gel short column (eluent: CH 2 Cl 2 / Hexane 1 / 1, then CH 2 Cl 2 ). The product fractions were collected and the solvent was evaporated. Obtained: 0.5 g of intermediate compound 4 (72%).

[0192] b) Preparation of intermediate compound 5

[0193]

[0194] React in the microwave. A mixture of intermediate compound 4 (0....

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The present invention concerns aryl and heteroaryl substituted pyrazinone derivatives having antagonistic melanin-concentrating hormone (MCH) activity, in particular MCH-I activity 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, whereinthe variables are defined in Claim 1. It further relates to their preparation, compositions comprising them and their use as a medicine. The compounds according to the invention are useful for the prevention and / or treatment of psychiatric disorders, including but not limited to anxiety, eating disorders, mood disorders, such as bipolar disorders and depression, psychoses, such as schizophrenia, and sleeping disorders; obesity; diabetes; sexual disorders and neurological disorders.

Description

technical field [0001] The field of the invention relates to aryl and heteroaryl substituted pyrazinone derivatives having melanin concentrating hormone (MCH) antagonizing activity, particularly MCH-1 antagonizing activity. The invention also relates to formulations, compositions comprising these compounds and their use as medicaments. Background of the invention [0002] Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid polypeptide that is primarily produced by radiation of hypothalamic neurons throughout the central nervous system (CNS) (J. Comp. Neurol. (1992) 319, 218-245 ). MCH mediates its action through two G protein-coupled receptors (GPCRs) called MCH-1 and MCH-2 (reviewed in Doggrell, 2003). While only the MCH-1 receptor is expressed in rodents, both humans and primates express both MCH-1 and MCH-2 receptors (Genomics (2002), 79, 785-792). Initially, the MCH-1 receptor was considered a valuable target for the treatment of obesity because MCH promotes...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/20C07D403/10A61K31/497A61P31/18
CPCC07D401/14C07D401/12C07D241/20C07D403/10C07D403/12C07D491/10C07D401/10C07D401/04A61P11/00A61P15/00A61P15/10A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P3/10A61P3/14A61P31/18A61P3/04A61P3/06A61P43/00A61P5/24
Inventor J·I·安德雷斯-吉尔M·J·艾卡扎尔-瓦卡R·M·艾瓦雷茨-埃施科巴J·奥亚扎巴尔桑塔马里纳F·M·多特詹伯格J·马克里特基D·辛普森S·马蒂尼茨冈扎尔茨
Owner JANSSEN PHARMA NV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap