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4' substituted compounds having 5-ht6 receptor affinity

A compound and solvate technology, applied in the field of compounds with selective 5-HT6 affinity, can solve the problem of selective agonists and antagonists hindering receptor function research in vivo

Inactive Publication Date: 2010-06-09
MEMORY PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although 5HT 6 Receptors have unique pharmacological profiles, but a lack of selective agonists and antagonists hampers in vivo studies of receptor function

Method used

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  • 4' substituted compounds having 5-ht6 receptor affinity
  • 4' substituted compounds having 5-ht6 receptor affinity
  • 4' substituted compounds having 5-ht6 receptor affinity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] 4-methyl-7-[(4-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazine, (1) Preparation

[0264]

[0265] step 1. The starting compound 4-(1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester [(A) 2.00×10 2mg, 0.000664 mol] was mixed together with tetrahydrofuran (1.0 mL, 0.01 mol) and N,N-dimethylformamide (1 mL, 0.015 mol) in a vial. The mixture was stirred at 0°C for 10 minutes. Under nitrogen atmosphere, sodium bis(trimethylsilyl)amide (1.0 mL of a 1M solution) in tetrahydrofuran was added via syringe and the resulting mixture was stirred for 10 minutes, to which was added 4-methyl-3 in one portion, 4-Dihydro-2H-1,4-benzoxazine-7-sulfonyl chloride (246 mg, 0.000995 mol). The reaction mixture was stirred for 3 hours, after which time LC-MS (8080_8 min) indicated that the reaction was complete. Solvent was removed in vacuo. The crude residue was purified by flash chromatography on a 40 g silica gel cartridge using 1:1 ethyl acetate:h...

Embodiment 2

[0302] Preparation of tert-butyl 4-(1H-indol-4-yl)-piperazine-1-carboxylate (A)

[0303]

[0304] Synthesis of 4-piperazin-1-yl-1H-indole

[0305] To a 1000 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 1H-indol-4-ylamine (2.8 g, 21.05 mmol, 1.00 equiv) in i-PrOH (800 mL). To this was added bis(2-chloroethyl)amine hydrochloride (4.5 g, 25.21 mmol, 1.20 equiv). To this mixture was added Na 2 CO 3 (8.9 g, 83.96 mmol, 4.00 equiv). The resulting reaction solution was allowed to react overnight with stirring while maintaining its temperature at reflux on an oil bath. filter. The filtrate was concentrated by evaporation on a rotary evaporator under vacuum. 4.3 g of 4-piperazin-1-yl-1H-indole (crude) are thus obtained in the form of a red oil.

[0306] Synthesis of tert-butyl 4-(1H-indol-4-yl)-piperazine-1-carboxylate

[0307] To a 1000 mL round bottom flask was added a solution of 4-piperazin-1-yl-1H-indole ...

Embodiment 3

[0310] 4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indazole (B) and 4-(1-methyl-piperidin-4-yl)- 1H- Synthesis of Indazole (C)

[0311]

[0312] Synthesis of 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl trifluoro-acetate (D)

[0313]

[0314]To a 250 mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of BuLi (8.5 mL, 2.5M / L, 21.25 mmol, 1.20 equiv) in THF (20 mL). Its temperature was cooled to -78°C. Then a solution of diisopropylamine (2.14 g, 21.15 mmol, 1.20 equiv) in THF (20 mL) was added dropwise thereto under stirring while cooling it to a temperature of -78°C. The resulting solution was allowed to react at -78°C for 30 minutes with stirring. Then a solution of 1-methylpiperidin-4-one (2 g, 17.67 mmol, 1.00 equiv) in THF (32 mL) was added dropwise thereto with stirring while cooling it to a temperature of -78°C. The resulting solution was allowed to react at -78°C for 120 minutes with stirring. C ...

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Abstract

The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I), wherein R1, R2, R5, R6, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

Description

[0001] This application claims priority to US Provisional Application US 60 / 940,025, filed May 24, 2007, and US Provisional Application US 61 / 022,734, filed January 22, 2008, each of which is incorporated herein by reference in its entirety. field of invention [0002] The present invention relates to serotonin 5-HT 6 field of affinity. More specifically, the present invention relates to 5-HT 6 New compounds with affinity for receptors, especially selective for 5-HT 6 Compounds of affinity, methods of making these compounds, compositions comprising these compounds, and methods of use thereof. Background of the invention [0003] Human 5-hydroxytryptamine-6 ​​(5-HT 6 ) receptor, one of the most recently cloned serotonergic receptors, is a 440 amino acid polypeptide with seven transmembrane domains typical of G protein-coupled receptors. It is one of 14 receptors that mediate the action of the neurotransmitter serotonin (5-HT, serotonin) (Hoyer et al., Neuropharmacology, 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/04C07D401/12C07D403/12C07D405/12C07D409/12C07D413/12
CPCC07D401/12C07D403/12C07D405/12C07D409/12C07D209/04C07D413/12A61P1/00A61P25/00A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P3/04A61P43/00A61K31/4439
Inventor R·邓恩T·M·源W·谢A·郑一姆
Owner MEMORY PHARMA CORP
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