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Novel KCNQ potassium channel agonist and preparation method and application thereof

A technology of general formula, C1-C4, applied to a new type of KCNQ potassium channel agonist, its preparation and use, can solve the problems of unclear mechanism of action, high neurotoxicity, etc.

Active Publication Date: 2015-11-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On April 26, 2013, the FDA Drug Safety Committee disclosed that retigabine may also cause some pigment reactions during clinical application, including blue skin and retinal pigment changes, etc., but its specific mechanism of action is still unclear, and It is recommended that all patients taking this drug participate in regular eye examinations (S. Jankovic et al., Expert Opinion on Drug Discovery, 2013, 8(11), 1-9; F. Rode et al., European Journal of Pharmacology, 2010, 638, 121-127)
However, further safety evaluation studies have found that the neurotoxicity of the compound disclosed in WO2013060097 is relatively high. For example, when SD rats are administered compound K21 orally once, when the dose is ≥ 30 mg / kg, the rats can be observed to die, and the lethal dose of toxicity is significantly higher than The reported lethal dose of retigabine in rats (100mg / kg, data from FDA Phamacology Review(s), Potiga tablets)

Method used

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  • Novel KCNQ potassium channel agonist and preparation method and application thereof
  • Novel KCNQ potassium channel agonist and preparation method and application thereof
  • Novel KCNQ potassium channel agonist and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0086] One, the preparation embodiment of compound

[0087] In the following preparation examples, nuclear magnetic resonance (NMR) is measured with a Mercury-Vx300M instrument produced by Varian (Varian), NMR calibration: δH7.26ppm (CDCl 3 ), 2.50ppm (DMSO-d 6 ), 3.15ppm (CD 3 OD); the reagents were mainly provided by Shanghai Chemical Reagent Company; the thin-layer chromatography (TLC) silica gel plate was produced by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model HSGF254; the normal phase column chromatography silica gel used for compound purification was Shandong Qingdao Ocean Chemical Factory Branch factory production, model zcx-11, 200-300 mesh.

preparation Embodiment 11

[0089] Preparation Example 1.1, Synthesis of 4-(N-p-fluorobenzyl-N-propargyl-amino)-2,6-dimethylphenylcarbamate methyl ester (K43)

[0090]

[0091] Compound 2,6-dimethylaniline K43-a (1.2g, 10mmol) was dissolved in dichloromethane (4mL) and pyridine (25mL), added p-toluenesulfonyl chloride (p-TsCl) (2.29g, 12mmol), reflux 6h. After cooling to room temperature, the reaction system was poured into 3M hydrochloric acid solution (20 mL), then dichloromethane (20 mL) was added, and the layers were separated. The obtained organic phase was washed twice with water (20 mL), concentrated, and the residue was recrystallized in ethanol. The product K43-b was obtained as a white solid (2.1 g, yield 76%). 1 H NMR (300MHz, CDCl 3 ): δ7.58(d, J=8.4Hz, 2H), 7.25(d, J=8.4Hz, 2H), 7.00-7.11(m, 3H), 5.96(s, 1H), 2.42(s, 3H) ,2.04(s,6H).

[0092] The obtained compound K43-b (2.10g, 7.6mmol) was dissolved in glacial acetic acid (AcOH) (40mL), water (40mL) and sodium nitrate (1.3g, 15.2mmol...

preparation Embodiment 12

[0099] Preparation Example 1.2, using operations similar to Preparation Example 1, the following compounds were prepared:

[0100]

[0101]

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PUM

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Abstract

The present invention provides a compound with a structure represented by general formula I or a pharmaceutically acceptable salt thereof, a preparation method for the compound or the salt, and a use of the compound or the pharmaceutically acceptable salt thereof in the preparation of medicaments for treating nervous system diseases, such as epilepsy, convulsion, neuropathic pain, acute ischemic stroke or neurodegenerative diseases. Compared with Retigabine, the compound of the present invention has better brain tissue absorption. Moreover, the compound provided by the present invention not only has greatly improved efficacy, but also has far fewer neurological side effects than Retigabine, and therefore has a wider safe window.

Description

technical field [0001] The present invention belongs to the field of pharmacy, and in particular, relates to a novel KCNQ potassium ion channel agonist, a preparation method thereof and the potassium channel agonist or its pharmaceutically acceptable salt or a drug combination containing any of them Use of the drug in the preparation of drugs for treating neurological diseases such as epilepsy, convulsions, neuropathic pain, acute ischemic stroke and neurodegenerative diseases. Background technique [0002] Ion channels are an important family of membrane proteins on the cell membrane, which play an important role in nerve and muscle excitation, hormone secretion, cell differentiation, sensory conduction, learning and memory, blood pressure control, salt and water balance, etc. Studies have found that mutations in more than 60 ion channels are closely related to diseases. At present, ion channels have become the third largest drug target after GPCR (G protein-coupled recept...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/28C07C269/04C07C269/06C07C333/08C07C275/64C07C273/18C07C231/02C07C235/16C07C237/04C07C237/22C07C233/62C07C235/74C07D307/24A61K31/27A61K31/277A61K31/17A61K31/167A61K31/341A61P25/00A61P25/08A61P25/28A61P9/10
CPCA61K31/167A61K31/17A61K31/27A61K31/277A61K31/341A61P9/10A61P25/00A61P25/04A61P25/08A61P25/28A61P43/00C07D307/24C07C231/02C07C233/62C07C235/16C07C235/74C07C237/04C07C237/22C07C269/04C07C269/06C07C271/28C07C273/18C07C275/64C07C333/08C07C2601/02C07C2601/14C07C237/48
Inventor 南发俊利民高召兵张仰明胡海宁许海燕刘桦楠皮晓平
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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