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ARYLSULFONYLTHIOPHENECARBOXAMIDES AND ARYLSULFONYLFURANCARBOXAMIDES AS Kv3 POTASSIUM CHANNEL ACTIVATORS

A formamide and sulfonyl technology, applied in the field of novel compounds that activate Kv3 potassium channels, can solve problems such as unmet needs

Inactive Publication Date: 2021-11-26
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is an unmet need for novel therapies for the treatment of the disorder

Method used

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  • ARYLSULFONYLTHIOPHENECARBOXAMIDES AND ARYLSULFONYLFURANCARBOXAMIDES AS Kv3 POTASSIUM CHANNEL ACTIVATORS
  • ARYLSULFONYLTHIOPHENECARBOXAMIDES AND ARYLSULFONYLFURANCARBOXAMIDES AS Kv3 POTASSIUM CHANNEL ACTIVATORS
  • ARYLSULFONYLTHIOPHENECARBOXAMIDES AND ARYLSULFONYLFURANCARBOXAMIDES AS Kv3 POTASSIUM CHANNEL ACTIVATORS

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0095] 1. A compound (I) having formula I

[0096]

[0097] in

[0098] X is selected from the group consisting of: S and O;

[0099] R1 is selected from the group consisting of: H, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, C 3 -C 8 Cycloalkyl, C 1 -C 4 Thioalkyl, C 1 -C 4 Thiofluoroalkyl, fluorine and chlorine;

[0100] R2 and R6 are independently selected from the group consisting of: H, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, and halogens such as fluorine and chlorine;

[0101] R3 is selected from the group consisting of H, fluorine and C 1 -C 4 alkyl;

[0102] R7 is selected from the group consisting of: H, C 1 -C 4 Alkyl, halogens such as fluorine and chlorine, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkyl and C 1 -C 4 Fluoroalkoxy;

[0103] HetAr is selected from the group consisting of 5-membered heteroaryl and 6-membered heteroaryl; with the proviso that HetAr is not imidazole, furan or thiophene;

[0104] When R1...

example 1

[0213] Preparation of 5-chloro-N-((5-methylpyrazin-2-yl)methyl)thiophene-2-carboxamide:

[0214]

[0215] To a solution of 5-chlorothiophene-2-carboxylic acid (1.0 g, 6.2 mmol) and 1-(5-methylpyrazin-2-yl)methanamine (982 mg, 6.15 mmol) in DMF (10 mL) was added HATU (3.51 g, 9.23 mmol) and DIPEA (2.4 g, 18 mmol), and the resulting mixture was stirred at 25°C for 1 hour. The mixture was concentrated in vacuo, and the crude product was purified by flash chromatography (gradient using petroleum ether and ethyl acetate) to yield 1.5 g of 5-chloro-N-((5-methylpyrazine-2- base) methyl) thiophene-2-carboxamide.

[0216] Preparation of 5-((4-methoxyphenyl)thio)-N-((5-methylpyrazin-2-yl)methyl)thiophene-2-carboxamide:

[0217]

[0218] To 5-chloro-N-[(5-methylpyrazin-2-yl)methyl]thiophene-2-carboxamide (200mg, 0.75mmol) and 4-methoxybenzene-1-thiol (104mg, 0.747mmol) in a solution in DMF (5mL) was added Cs 2 CO 3 (206mg, 1.49mmol) and Cul (25mg, 0.15mmol), the resulting mixt...

example 2

[0225] Preparation of N-((5-methylpyrazin-2-yl)methyl)-5-(phenylthio)thiophene-2-carboxamide:

[0226]

[0227] To a solution of 5-chloro-N-[(5-methylpyrazin-2-yl)methyl]thiophene-2-carboxamide (350 mg, 1.31 mmol) in DMF (5 mL) was added sodium benzenethiol ( 173mg, 1.31mmol), K 2 CO 3 (361 mg, 2.62 mmol) and KI (43 mg, 0.26 mmol). The resulting mixture was stirred at 110°C for 16 hours. After cooling, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 50 mL), the organic phases were combined, washed with brine, dried and concentrated. The crude product was purified by flash chromatography to give N-((5-methylpyrazin-2-yl)methyl)-5-(phenylthio)thiophene-2-carboxamide (150 mg).

[0228] Preparation of N-((5-methylpyrazin-2-yl)methyl)-5-(phenylsulfonyl)thiophene-2-carboxamide (Compound 18):

[0229]

[0230] To N-[(5-methylpyrazin-2-yl)methyl]-5-(phenylsulfonyl)thiophene-2-carboxamide (150 mg, 0.439 mmol) in MeOH (2 mL) and H 2 ...

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Abstract

The present invention provides novel compounds which activate the Kv3 potassium channels. The compounds have the structure (I). Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and use of the compounds to treat disorders responsive to the activation of Kv3 potassium channels.

Description

technical field [0001] The present invention relates to novel compounds that activate Kv3 potassium channels. Separate aspects of the invention relate to pharmaceutical compositions comprising said compounds and the use of these compounds in the treatment of disorders responsive to Kv3 potassium channel activation. Background technique [0002] Voltage-dependent potassium (Kv) channels channel potassium ions (Kv) in response to changes in membrane potential + ) across the cell membrane and can thus regulate the excitability of the cell by modulating (increasing or decreasing) the electrical activity of the cell. Functional Kv channels exist as multimeric structures formed by the association of four α subunits and four β subunits. The α subunit contains six transmembrane domains, a pore-forming loop, and a voltage sensor, and is arranged symmetrically around a central pore. The β subunit or accessory subunit interacts with the α subunit and can modify the properties of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/00C07D405/12C07D409/12A61K31/497A61K31/381A61K31/34
CPCC07D409/12C07D405/12A61P25/00
Inventor A.G.森斯L·K·拉斯穆森俞玩玩
Owner H LUNDBECK AS