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Compounds for the treatment of neuromuscular disorders

A neuromuscular, compound technology, applied in the field of improving and/or preventing neuromuscular disorders, treating, preventing and/or improving neuromuscular disorders

Pending Publication Date: 2020-09-25
NMD PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This treatment leads to improvement in most patients but is associated with side effects, some of which are severe (Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev. 2014, Oct 13; 10)

Method used

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  • Compounds for the treatment of neuromuscular disorders
  • Compounds for the treatment of neuromuscular disorders
  • Compounds for the treatment of neuromuscular disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1680] Example 1: (S)-2-(4-Bromo-2-(isoxazol-5-yl)phenoxy)propanoic acid; following General Procedure A

[1681]

[1682] At 0°C, DIAD (3.87mL, 19.88mmol) was added dropwise to (R)-tert-butyl 2-hydroxypropionate (1.2) (2.076g, 14.20mmol), 4-bromo-2 In a solution of -(isoxazol-5-yl)phenol (1.1) (3.75 g, 15.62 mmol) and triphenylphosphine (5.21 g, 19.88 mmol) in THF (150 mL). The solution was stirred for an additional 15 minutes at 0°C. The bright yellow solution was warmed to room temperature and stirred overnight. MeOH (10 mL) was added and the volatiles were removed in vacuo to give a dark orange oil. Formic acid (55 mL, 1434 mmol) was added and the mixture was heated at 70 °C for 1 h. Volatiles were removed in vacuo and excess formic acid was removed by co-evaporation with toluene (30 mL). Aqueous NaOH (0.5M) was added and the aqueous layer was washed with EtOAc (2 x 25 mL). The aqueous layer was acidified with aqueous HCl (1M) and extracted with EtOAc (3 x 25 mL). ...

Embodiment 2

[1685] Example 2: (2S)-2-[4-Bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propionic acid according to General Procedure A

[1686]

[1687]Hydroxylamine hydrochloride (1.59g, 22.88mmol) was added to 5-bromo-2-hydroxybenzaldehyde (2.1) (2.3g, 11.44mmol) and pyridine (2.78ml, 34.3mmol) in ethanol (20ml) at room temperature in the stirred solution. After 4 hours, the mixture was diluted with water (200ml), the pH of the solution was adjusted to 4-5 by adding 1M hydrochloric acid, and stirred for 3 hours. The resulting precipitated solid was collected by filtration, washed with water (3 x 10 mL), and dried in vacuo at 45 °C for 3 days to give (E)-5-bromo-2-hydroxybenzaldehyde oxime (2.2) (1.986 g, 9.14 mmol, 80% yield) off-white solid. Product analyzed by LCMS (Waters Acquity UPLC, X-Select, Waters X-Select UPLC C18, 1.7 μm, 2.1 x 30 mm, acidic (0.1% formic acid) 3 min method, 5-95% MeCN / water): m / z 216 / 218 (M+H) + (ES + ); 99.4% purity at 1.268 min (diode array). 1H NMR...

Embodiment 3

[1690] Example 3: (S)-2-(4-Bromo-2-(isoxazol-3-yl)phenoxy)propanoic acid according to General Procedure A

[1691]

[1692] To a stirred solution of (E)-5-bromo-2-hydroxybenzaldehyde oxime (2.2) (485 mg, 2.245 mmol) in DMF (10 mL, 129 mmol) was added N-chlorosuccinimide (360 mg, 2.69 mmol), and then add 1 drop of 1M hydrochloric acid. After 1 hour, ethynyltrimethylsilane (0.311 mL, 2.245 mmol) was added, followed by triethylamine (0.407 mL, 2.92 mmol). After 16 hours, the mixture was diluted with water (50 mL), adjusted to pH 5-6 by 1M hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic extract was washed with brine (25ml), dried (MgSO 4 ) and evaporated in vacuo. The residue was dissolved in dichloromethane (5 mL), the solution was filtered, and then added to a 24 g silica gel column equilibrated in isohexane. The column was eluted with a gradient of 0-50% ethyl acetate in isohexane to give 4-bromo-2-(5-(trimethylsilyl)isoxazol-3-yl)phenol (3.1) (4...

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Abstract

The present invention relates to compounds suitable for treating, ameliorating and / or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade. The compounds as defined herein preferably inhibit the ClC-1 ion channel.

Description

technical field [0001] The present invention relates to compounds for the treatment, improvement and / or prevention of neuromuscular disorders, including reversal of drug-induced neuromuscular blockade, and their use in the treatment, improvement and / or prevention of neuromuscular disorders, including reversal of drug-induced neuromuscular blockade use in . Compounds as defined herein preferably inhibit the ClC-1 ion channel. The present invention further relates to methods of treating, preventing and / or ameliorating neuromuscular disorders by administering said composition to a human in need thereof. [0002] Background of the invention [0003] Walking, breathing and eye movements are examples of basic daily physiological activities driven by the contractile activity of skeletal muscles. Skeletal muscle itself is quiescent, and contractile activity occurs only in response to commands from the central nervous system (CNS). This neuronal command takes the form of an action ...

Claims

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Application Information

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IPC IPC(8): C07D317/18C07D233/56C07D261/08C07D261/20C07D271/06C07D277/22C07D277/66C07D213/04A61K31/357A61K31/381A61K31/415A61K31/4164A61K31/423A61K31/4245A61K31/426A61K31/428A61K31/4402C07D231/12C07D333/06C07D271/10A61P21/00A61P21/04
CPCA61K31/357A61K31/381A61K31/415A61K31/4164A61K31/423A61K31/4245A61K31/426A61K31/428A61K31/4402C07D333/16C07D213/30C07D277/24C07D233/60C07D307/12C07D261/04C07D307/42C07D263/32C07D285/06C07D285/12C07D231/12C07D261/08C07D261/20C07D271/06C07D271/10C07D277/66A61K31/42A61P25/00A61P21/00
Inventor L·J.S.克努森N·凯利T·霍尔姆彼得森M·伊库珀A·乌布朗
Owner NMD PHARMA AS
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