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Compounds with Kv4 ion channel activity

A compound and metabolite technology, applied in the field of preparing the pharmaceutical composition and preparing the compound, can solve the problem of not being able to use the drug

Inactive Publication Date: 2007-12-05
DEVGEN PTE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] A major disadvantage of some known compounds concerns that the drugs do not work in a selective manner, i.e. they do not choose between different ion channels

Method used

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  • Compounds with Kv4 ion channel activity
  • Compounds with Kv4 ion channel activity
  • Compounds with Kv4 ion channel activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0247] Example 1: Preparation of compounds according to the invention

[0248] The practice of the present invention will employ, unless otherwise indicated, conventional techniques in the fields of synthetic organic chemistry, biological testing and the like, which are within the skill of the art. Such techniques are explained fully in the literature. Purity of compounds was confirmed by liquid chromatography / mass spectrometry (LC / MS) according to Method A, unless otherwise indicated:

[0249] Method A:

[0250] HPLC: Waters Alliance 2690 with Photodiode Array Detector Waters 996. Mass spectrometer: Micromass Platform ZMD LC. Ionization: Electrospray (polarity: negative and positive).

[0251] method:

[0252] Phase: Tosohaas TSK-gel super ODS ( , 2μm), column: 4.6 × 50mm; Solvent A: water and formic acid (26.5mM); Solvent B: acetonitrile and formic acid (17mM); Flow rate: 2.75ml / min; Gradient 5min: from 100%A and 0 in 3 minutes %B to 20%A and 80%B. Constant 80% B fo...

Embodiment 2

[0306] Example 2: Non-limiting examples of compounds according to the invention

[0307] The present invention includes compounds of formulas I to LVII and stereoisomers, tautomers, racemates, prodrugs, metabolites, or pharmaceutically acceptable salts and / or solvates thereof.

[0308] Compound 1: 5-Chloro-benzofuran-2-carboxylic acid (R)-[(4-nitrophen-1-yl)ethyl]-amide

[0309] This compound was obtained according to Protocol A from 5-chloro-benzofuran-2-carboxylic acid and (R)-(4-nitrophen-1-yl)ethanamine.

[0310] Compound 2: 5-chloro-benzofuran-2-carboxylic acid 3,5-dimethoxybenzyl-amide

[0311] The present compound was obtained according to Protocol A from 5-chloro-benzofuran-2-carboxylic acid and 3,5-dimethoxybenzylamine.

[0312] Compound 3: 5-Chloro-benzofuran-2-carboxylic acid 2-(5-methylindol-3-yl)-ethyl-amide

[0313] This compound was obtained according to Protocol A from 5-chloro-benzofuran-2-carboxylic acid and 2-(5-methylindol-3-yl)-ethylamine.

[0314] Com...

Embodiment 3

[0331] Example 3: Biological Assay Using Caenorhabditis elegans (C.e / egans) Screening

[0332] A C. elegans-based high-throughput screen for Kv4.3 modulators has been used to establish the in vivo SAR (structure-activity relationship: effect of chemical structure on biological activity) of compounds according to the invention for Kv4.3.

[0333] The test employed a stable transgenic C. elegans strain that functionally expresses human Kv4.3 in the pharynx and a visual selection GFP marker in the body wall muscle.

[0334] Methods describing the construction of transgenic C. elegans strains expressing human Kv4.3 are described in WO03 / 097682. Briefly, 5 ng / μl pGV8 plasmid (human Kv4.3), 20 ng / μl pDW2821 (GFP-tagged), and 40 ng / μl genomic C. elegans DNA were microinjected into the gonads of wild-type strain N2 to generate practical The strain UG1755. Transgenic animals were isolated and extrachromosomal arrays were integrated into the C. elegans genome. 50% of the cell lines t...

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Abstract

The present invention relates to compounds that interact with ion channels. In particular, the invention relates to compounds having the structural Formula (I), (II), (III) or (IV), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or a pharmaceutically acceptable salt and / or solvate thereof, Formula (I), (II), (III), (IV), wherein X<1>, X<2>, Y, Z, W, R<1>, R<8> , R<9>, R<10>, L, A, z, and n have the meaning defined in claim 1. The invention also relates to methods for preparing said compounds, to pharmaceutical compositions comprising said compounds, and to the use of said compounds in methods for treatment of the human and animal body.

Description

field of invention [0001] The present invention relates to compounds that interact with ion channels. [0002] In particular, the present invention relates to compounds that interact with ion channels of the Kv family, especially the Kv4 subfamily. [0003] The invention also relates to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds in methods of treatment of the human and animal body and / or the use of said compounds in the preparation of such pharmaceutical compositions. use. [0004] For example, the compounds of the present invention are useful for the prevention and / or treatment of conditions or diseases associated with ion channels, especially for the prevention and / or treatment of conditions or diseases associated with Kv family ion channels, and more particularly for the prevention and / or treatment of Conditions or diseases associated with Kv4 family ion channels. [0005] Other as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/85C07D403/12C07D401/06A61K31/343A61P9/00C07D209/42A61K31/404C07D401/04C07D307/82C07D333/70C07D409/12C07D401/12C07D215/48
CPCC07D401/12C07D307/85C07D307/82C07D403/12C07D401/06C07D333/70C07D409/12C07D215/48C07D209/42C07D401/04A61P9/00A61P25/00A61K31/343
Inventor 彼得拉·布洛姆扬·奥克塔夫·德·克佩尔埃里克·皮埃尔·保罗·勒内·富曼特罗蒂图斯·扬·卡莱塔迪尔克·莱森
Owner DEVGEN PTE LTD
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