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Heterocyclic acetophenone potentiators of metabotropic glutamate receptors

An azetidinyl and phenyl technology, applied in the field of mGluR2 receptor synergists, can solve problems such as phosphoinositide hydrolysis and increased intracellular calcium transfer

Inactive Publication Date: 2007-07-04
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, class I mGluR receptors, including mGlulR and mGlu5R, are known to activate phospholipase C (PLC) through the Gaq-protein, resulting in phosphoinositide hydrolysis and increased intracellular calcium mobilization

Method used

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  • Heterocyclic acetophenone potentiators of metabotropic glutamate receptors
  • Heterocyclic acetophenone potentiators of metabotropic glutamate receptors
  • Heterocyclic acetophenone potentiators of metabotropic glutamate receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220]

[0221] 7-{4-[3-Hydroxy-2-methyl-4-(3-methyl-butyryl)-phenoxy]-butoxy}-chromen-2-one

[0222] Under stirring at 45°C, potassium carbonate (2.39g, 17.3mmol) was added to 1-(2,4-dihydroxy-3-methyl-phenyl)-3-methyl-butan-1-one (150mg , 0.68mmol) and 1,4-dibromobutane (6.22g, 28.8mmol) in acetone (100mL). The reaction mixture was stirred for 16 h, then the acetone was removed in vacuo. The residue was then mixed with dichloromethane (100 mL) and water (100 mL). The organic layer was separated and washed with MgSO 4 Drying and concentration in vacuo gave a residue which was purified by column chromatography on silica gel (eluting with 0-60% ethyl acetate / hexanes) to afford 3.26 g (98%) of 1-[4-(4-bromo-butan oxy)-2-hydroxy-3-methyl-phenyl]-3-methyl-butan-1-one as a white solid. Potassium carbonate (161 mg, 1.16 mmol) was then added to 1-[4-(4-bromo-butoxy)-2-hydroxy-3-methyl-phenyl]-3-methanol with stirring at 45°C Butan-1-one (200 mg, 0.58 mmol) and 7-hydroxycoumar...

Embodiment 2

[0225]

[0226] 1-[2-Hydroxy-3-methyl-4-(4-phenoxy-butoxy)-phenyl]-3-methyl-butan-1-one

[0227] Under stirring at 45°C, potassium carbonate (398 mg, 12.88 mmol) was added to 1-(2,4-dihydroxy-3-methyl-phenyl)-3-methyl-butan-1-one (300 mg, 1.44mmol) and (4-bromo-butoxy)-benzene (396mg, 1.73mmol) in acetone (20mL). The reaction mixture was stirred for 16 h, then the acetone was removed in vacuo. The residue was then mixed with dichloromethane (50 mL) and water (50 mL). The organic layer was separated and washed with MgSO 4 Drying and concentration in vacuo gave a residue which was purified by column chromatography on silica gel (eluting with 0-60% ethyl acetate / hexanes) to give 381 mg (74%) of 1-[2-hydroxy-3-methyl- 4-(4-Phenoxy-butoxy)-phenyl]-3-methyl-butan-1-one as a colorless oil.

[0228] 1 H NMR (CDCl 3 , 500MHz), δ13.04(s, 1H), 7.62(d, 1H), 7.32-7.28(m, 2H), 6.98-6.91(m, 3H), 6.45(d, 1H), 4.16-4.07(m , 4H), 2.79(d, 2H), 2.30-2.28(m, 1H), 2.10(s, 3H), 2.07-2.03(m...

Embodiment 3

[0230]

[0231] 1-[3-Bromo-2-hydroxy-4-(4-phenoxy-butoxy)-phenyl]-3-methyl-butan-1-one

[0232] A procedure similar to that outlined in Example 2 was followed, starting with 1-(3-bromo-2,4-dihydroxy-phenyl)-3-methyl-butan-1-one.

[0233] 1 H NMR (CDCl 3 , 500MHz), δ13.57(s, 1H), 7.23(d, 1H), 7.31-7.28(m, 2H), 6.97-6.91(m, 3H), 6.50(d, 1H), 4.22(t, 2H ), 4.09(t, 2H), 2.80(d, 2H), 2.31-2.28(m, 1H), 2.11-2.05(m, 4H), 1.02(d, 6H). MS(ESI): 421(M+ h)+ .

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PUM

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Abstract

The present invention is directed to compounds which are potentiators of metabotropic glutamate receptors, including the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

Description

Background of the invention [0001] In the mammalian central nervous system (CNS), the excitatory amino acid L-glutamate (sometimes referred to herein simply as glutamate) mediates most excitatory neurotransmission through its various receptors. Excitatory amino acids, including glutamate, are of great physiological importance and they are involved in a variety of physiological processes such as long-term potentiation (learning and memory), development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception Play a role. [0002] Glutamate acts through at least two different types of receptors. One class consists of ionotropic glutamate (iGlu) receptors that function as ligand-gated ion channels. Glutamate is believed to regulate fast neuronal transmission by activating iGlu receptors at synapses connecting two neurons in the CNS. A second general type of receptor is the G-protein or "metabotropic" glutamate (mGluR) receptor linke...

Claims

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Application Information

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IPC IPC(8): C07D213/02C07D215/00C07D217/00A61K31/44A61K31/47
CPCC07D205/04C07D277/74C07D471/04C07D417/04C07C49/84C07D307/80C07D235/08C07C45/71C07D215/20C07C323/12C07D213/89C07D233/60C07D271/10C07C217/92C07D311/58C07D257/04C07D311/24C07D213/68C07D235/16C07D233/20C07D235/06C07D213/71C07D213/65C07D263/58C07D401/04C07D213/30C07D217/02C07D213/74C07D473/38C07D209/08C07C235/42C07D235/10C07D213/70C07D213/53C07D213/84C07D231/56C07C69/734C07C255/54C07D235/18C07C217/76C07D213/64C07D239/34C07D311/22C07D311/16C07C69/92A61P25/00A61P25/06A61P25/08A61P25/18A61P25/22A61P25/24A61P43/00
Inventor A·B·平克顿J·-M·韦尼耶R·V·库贝J·H·哈钦森D·黄C·博纳福S·P·戈瓦克T·卡梅尼卡
Owner MERCK & CO INC
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