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Selective sodium channel regulator, preparation and application thereof

A technology selected from, solvates, applied in the field of selective sodium channel modulators and their preparation and application, capable of solving problems such as poor therapeutic window and lack of isotype selectivity

Pending Publication Date: 2021-06-29
MINGHUI PHARMA SHANGHAI LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A major disadvantage of some known Nav's inhibitors is their poor therapeutic window, which may be a result of their lack of isoform selectivity

Method used

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  • Selective sodium channel regulator, preparation and application thereof
  • Selective sodium channel regulator, preparation and application thereof
  • Selective sodium channel regulator, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084]

[0085]

[0086] first step

[0087] Under nitrogen protection, compound 1a (10.00g, 38.90mmol) and potassium carbonate (16.10g, 116.72mmol) were dissolved in N,N-dimethylformamide (100mL), then iodomethane (8.30g, 58.35mmol) was added ), reacted at room temperature for 2 hours. After the reaction, add water (50mL) to quench the reaction, and add ethyl acetate (50mL), separate the layers, extract the aqueous phase with ethyl acetate (30mLx 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, Concentration under reduced pressure gave 1b (12.00 g), yield: 99%.

[0088] 1 H NMR (400MHz, DMSO-d 6 )δ7.66(dd, J=8.7,0.4Hz,1H),7.10(d,J=2.6Hz,1H),6.91–6.84(m,1H),3.85(s,3H).

[0089] second step

[0090] To a solution of compound 1b (12.00 g, 44.28 mmol) in tetrahydrofuran (100 mL) was slowly added dropwise a solution of n-butyllithium tetrahydrofuran (2.5M, 20 mL, 0.50 mmol) under nitrogen protection at -78°C. Stirring was continued for 30 minu...

Embodiment 2

[0109]

[0110] first step

[0111] Compound 2a (200mg, 1.56mmol) was dissolved in toluene (5mL), potassium hydroxide (263mg, 4.68mmol) and benzyl alcohol (336mg, 3.12mmol) were added to the reaction system, and then nitrogen was replaced three times, and the temperature was raised to 120 °C overnight. After the system was cooled to room temperature, water (50 mL) was added to the reaction system and extracted with ethyl acetate (50 mL x 3). After the organic phases were combined, they were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave a residue, and the residue was purified by column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 2b (212 mg), yield: 58%.

[0112] MS-ESI calculated value [M+1] + 201, measured value: 201.

[0113] second step

[0114] Dissolve 1h (600mg, 1.45mmol) in N,N-dimethylformamide (10mL), then add 2b (300mg, 1.45mmol), 2-(7-benzotriaz...

Embodiment 3

[0121]

[0122] first step

[0123] Dissolve 1f (300mg, 1.17mmol), 3a (148mg, 1.17mmol) in N,N-dimethylformamide (10mL), slowly add cesium carbonate (767mg, 2.35mmol) at 0°C, and replace nitrogen with 0 Stir at room temperature for 2 hours at ℃, dilute the reaction system with water (30mL), and extract with ethyl acetate (50mL x 3), combine the organic phases, wash with saturated brine (20mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure A residue was obtained, and the residue was purified by column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 3b (380 mg), yield: 90%.

[0124] 1 H NMR (400MHz, CDCl 3 )δ7.85(s,1H),7.04–6.90(m,3H),4.48–4.41(m,2H),2.20(s,3H),1.42–1.36(m,3H).

[0125] second step

[0126] 3b (380 mg, 1.05 mmol) was dissolved in tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, nitrogen was replaced and stirred at room temperature for 2 hours. Add 6N dilute hyd...

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PUM

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Abstract

The invention provides a compound as a selective sodium channel regulator, a synthesis method and a use method thereof, and particularly provides a compound as shown in a formula (I), a preparation method of the compound and application of the compound as the selective sodium channel regulator. The compounds exhibit excellent activity as sodium channel modulators.

Description

technical field [0001] The present invention relates to a class of compounds as selective sodium channel modulators, isomers, solvates and salts of the compounds and medicines with the compounds or their salts as active ingredients, and their therapeutic and / or Use in medicines for preventing sodium channel regulation-related target diseases, such as pain. Background technique [0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Still, there are many situations where pain persists beyond its usefulness, or patients would benefit from pain suppression. [0003] Neuropathic pain is a form of chronic pain caused by sensory nerve damage, which can be divided into two categories, pain caused by neurometabolic damage and pain caused by damage to nerve continuity. Metabolic impairment pain indications include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Pain indicati...

Claims

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Application Information

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IPC IPC(8): C07D213/81A61K31/444A61P29/00A61P21/00A61P13/00A61P11/14A61P9/06
CPCC07D213/81A61P29/00A61P21/00A61P13/00A61P11/14A61P9/06
Inventor 李傲姚元山P·K·贾达夫曹国庆
Owner MINGHUI PHARMA SHANGHAI LTD
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